Termansenhyllested8742

To mimic in vitro AMD conditions, hydroquinone, a component of cigarette smoke, was used as the oxidative insult. Cytosolic and mitochondrial protection against oxidative stress were tested using cytosolic and mitochondrial specific assays. The results provide evidence that these lipophilic cysteine prodrugs provide increased protection against oxidative stress in human RPE cells compared with NAC. BACKGROUND Hyperglycemia plays a role in promoting insulin resistance in adipocytes, hepatocytes and myocytes. Its effects on insulin signaling in endothelial cells remain, however, incompletely understood. AIM To investigate the proteomic and metabolomic profiles of human aortic endothelial cells (HAECs) exposed to insulin, normal glucose (NG), high glucose (HG) or its hyperosmolar control high mannitol (HM), and to examine whether and how HG or HM may promote insulin resistance. METHODS AND RESULTS We exposed HAECs to HG and HM in shorter (3 h) and longer-term experiments (24 h), followed by insulin treatment for 45 min. Label-free proteomics and network analysis showed a downregulation of proteins linked to the PI3K-Akt/mTOR/eNOS signaling pathway in HAECs. Metabolomic profiling showed decreased levels of "odd-chain acylcarnitines" such as C3. At immunoblotting, HG or HM blunted insulin ability to activate the PI3K/AKT/eNOS pathway, which was reverted through a silencing of aquaporin 1 (AQP1) and Tonicity enhancer binding protein (TonEBP), while inducing p-P38 and pERK1/2. CONCLUSIONS HG impairs the PI3K/AKT/eNOS pathway and shifts insulin signaling towards the activation of mitogenic and pro-inflammatory effectors, such as p38 and ERK1/2. These effects may explain the progression of insulin resistance as a result of endothelial glucotoxicity. OBJECTIVE To assess the effect of a modified definition of dystocia and of a different timing of interventions during spontaneous labor on the rate of oxytocin use and on its consequences on labor outcome. METHODS We compared oxytocin use and labor outcome before and after the introduction of a new protocol for the management of spontaneous labor. By protocol, oxytocin use and/or artificial rupture of the membranes was restricted to cases without progress in cervical dilatation for ≥ 1h and/or no progress of fetal descent for ≥ 1h at full dilatation. The main outcome measure was the rate of oxytocin use. Secondary outcome criteria were the consequences on labor (duration of labor, tachysystole and uterine hyperstimulation, abnormal fetal heart rate, cesarean delivery rate) and neonatal outcome. RESULTS Oxytocin use was strongly reduced from 2015 (69.2%) to 2016 (39.8%; p less then 0.01) and 2017 (31.9% ; p less then 0.01). Abnormal FHR rates decreased simultaneously (respectively 52%, 37% et 29%, p less thet the cost of a limited prolongation of labor, mainly in nulliparous women. The general population, including children and adolescents, is exposed to 4-methylimidazole (4-MI) in the diet. 4-MI is a by-product of caramel color manufacturing. It has been previously classified as a possible human carcinogen and displays potential reproductive toxicity. A follow up assessment of reproductive toxicity was conducted in rats utilizing the reproductive assessment by continuous breeding paradigm, in which multiple generations were exposed to 4-MI in diet at 750, 2500, and 5000 ppm. 4-MI exposure was associated with delays in preputial separation and vaginal opening, impairment in reproductive performance, and concomitant histopathological findings in the prostate, testis, and epididymis at 2500 and 5000 ppm. The Lowest Observed Adverse Effect Level for reproductive (based on prostate atrophy) and developmental toxicity (based on delays in preputial separation and vaginal opening) was 750 ppm, equivalent to approximately 50-60 mg/kg bw/day. OBJECTIVE To compare the effectiveness and efficiency of methods used to identify and export conference abstracts into a bibliographic management tool. STUDY DESIGN AND SETTING Case study. The effectiveness and efficiency of methods to identify and export conference abstracts presented at the American Society of Hematology (ASH) conference 2016-2018 for a systematic review were evaluated. A reference standard handsearch of conference proceedings was compared to 1) contacting Blood (the journal who report ASH proceedings); 2) keyword searching; 3) searching Embase; 4) searching MEDLINE via EndNote; and 5) searching CPCI-S. Effectiveness was determined by the number of abstracts identified compared with the reference standard, while efficiency was a comparison between the resources required to identify and export conference abstracts compared to the reference standard. RESULTS 604 potentially eligible and 15 confirmed eligible conference abstracts (abstracts included in the review) were identified by the handsearch. Comparator 2 was the only method to identify all abstracts and it was more efficient than the reference standard. Comparators 1, and 3-5 missed a number of eligible abstracts. CONCLUSION This study raises potentially concerning questions about searching for conferences' abstracts by methods other than directly searching the original conference proceedings. Efficiency of exporting would be improved if journals permitted bulk downloads. OBJECTIVE The question-behaviour effect refers to whether asking people questions can result in changes in behaviour. Staurosporine in vivo Such changes in behaviour can lead to bias in trials. This study aims to update a systematic review of randomised controlled trials investigating the question-behaviour effect, in light of several large pre-registered studies being published. STUDY DESIGN AND SETTING A systematic search for newly published trials covered 2012 to July 2018. Eligible trials randomly allocated participants to measurement versus non-measurement control conditions or to different forms of measurement. Studies that reported health-related behaviour as outcomes were included. RESULTS Forty-three studies (33 studies from the original systematic review and 10 new studies) compared measurement versus no-measurement. An overall small effect was found using a random effect model SMD = 0.06 (95% CI 0.02-0.09), n= 104,388. Statistical heterogeneity was substantial (I2 =54%). In an analysis restricted to studies with a low risk of bias, the QBE remained small but significant. There was positive evidence of publication bias. CONCLUSION This update shows a small but significant question-behaviour effect in trials with health-related outcomes, but with considerable unexplained heterogeneity. Future trials are needed with lower risk of bias are needed, with pre-registered protocols and greater attention to blinding. OBJECTIVE This study investigated trial consultations to identify whether and to what extent discussions of retention are present. STUDY DESIGN AND SETTING This embedded mixed-methods study design included a purposive sample of audio-recorded trial consultations obtained from four sites of a large multicentre UK based surgical RCT. Study participants included potential trial participants, trial Surgeons and Research Nurses. RESULTS Forty-four participants were included in this study Potential trial participants (n=37); trial Surgeons (n=4); and Research Nurses (n=3). Analysis revealed no discussion of retention across 79% of consultations. Of the remaining 21% where discussions of retention were present, only 3% (maximum) of the conversation related to retention. There was some evidence of good practice but on the whole the discussions contained inaccuracies about timing and delivery of questionnaires and the right to withdraw often highlighted without providing trial consequences. CONCLUSION This study is the first to explore trial consultations for discussions of retention. It suggests that there may be room for improvement within current practice. Further research is required to determine the generalizability of the findings reported to other clinical trials. OBJECTIVE Identify current practice for recruitment prediction and monitoring within clinical trials. STUDY DESIGN AND SETTING Chief investigators (CIs) were surveyed to identify data sources and adjustments made to support recruitment prediction. Statisticians were surveyed to determine methods and adjustments used when predicting and monitoring recruitment. Participants were identified from the National Institute for Health Research recently funded studies, the UK Clinical Research Collaboration registered Clinical Trial Units network or by the European Clinical Research Infrastructure Network. RESULTS Fifty-one CIs (UK=32, ECRIN=19) and 104 statisticians (UK=51, ECRIN=53) were contacted. Response rates varied (CIs UK=53% ECRIN=32%; statisticians UK=98% ECRIN=36%). Multiple data sources are used to support recruitment rates, most commonly audit data from multiple sites. Variation in individual site recruitment rates are frequently incorporated but staggered site openings were featured more commonly amongst UK respondents. Simple prediction methods are preferred to rarely used statistical models. Lack of familiarity with statistical methods are barriers to their use with evidence needed to justify the time required to support their implementation. CONCLUSION Simplistic methods will continue as the mainstay of prediction, however generation of evidence supporting the benefits of complex statistical models should promote their implementations. Multiple data sources to support recruitment prediction are being used and further work on the quality of these data is needed. Pressure to be optimistic about recruitment rates for the trial to be attractive to funders was felt by a sizeable minority. OBJECTIVE Expansion of visceral adipose tissue (VAT) and metabolic inflammation are consequences of obesity and associated with type 2 diabetes (DM). Metabolically activated adipose tissue macrophages (ATMs) undergo qualitative and quantitative changes that influence their inflammatory responses. How these cells contribute to insulin resistance (IR) in humans is not well understood. Cholesterol 25-Hydroxylase (CH25H) converts cholesterol into 25-Hydroxycholesterol (25-HC), an oxysterol that modulates immune responses. Using human and murine models, we investigated the role of CH25H in metabolic inflammation. METHODS We performed transcriptomic (RNASeq) analysis on the human whole AT biopsies and sorted ATMs from obese non-diabetic (NDM) and obese diabetic (DM) subjects to inquire if CH25H was increased in DM. We challenged mice lacking Ch25h with a high-fat diet (HFD) to characterize their metabolic and immunologic profiling. Ch25h KO mice and human adipose tissue biopsies from NDM and DM subjects were analyzAT. Finally, by testing AT explants, bone marrow-derived macrophages (BMDMs) and SVF cells from Ch25h deficient mice, we observed that 25-HC is required for the expression of pro-inflammatory genes. 25-HC was also able to induce inflammatory genes in preadipocytes. CONCLUSIONS Our data suggest a critical role for CH25H/25-HC in the progression of meta-inflammation and insulin resistance in obese humans and mouse models of obesity. In response to obesogenic stimuli, CH25H/25-HC could exert a pro-inflammatory role.