Showing papers by "Medical Research Council published in 2011"
TL;DR: Mitophagy, the specific autophagic elimination of mitochondria, has been identified in yeast, and in mammals during red blood cell differentiation, mediated by NIP3-like protein X (NIX; also known as BNIP3L).
Abstract: Mitophagy is the selective elimination of mitochondria through autophagy Recent studies have uncovered the molecular mechanisms mediating mitophagy in yeast and mammalian cells and have revealed that the dysregulation of one of these mechanisms — the PINK1–parkin-mediated signalling pathway — may contribute to Parkinson's disease
2,608 citations
TL;DR: A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function, and these findings suggest potential novel therapeutic pathways for cardiovascular disease prevention.
Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
1,829 citations
St James's University Hospital1, University College London2, Paris Descartes University3, Oslo University Hospital4, University of British Columbia5, University of Valencia6, Charité7, University of Duisburg-Essen8, Edinburgh Cancer Research Centre9, University of Copenhagen10, University of Helsinki11, Laval University12, University of Leeds13, Cambridge University Hospitals NHS Foundation Trust14, Medical Research Council15, Princess Margaret Cancer Centre16
TL;DR: In patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months, higher than the average for women with ovarian cancer.
Abstract: A B S T R AC T Background Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease. Methods We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 addi tional cycles or until progression of disease. Outcome measures included progressionfree survival, first analyzed per protocol and then updated, and interim overall survival. Results
1,752 citations
Wellcome Trust1, University of London2, Dana Corporation3, University of Toronto4, Federal University of São Paulo5, Duke University6, University of Wisconsin-Madison7, University of Oxford8, John E. Fogarty International Center9, University of Queensland10, Chinese Center for Disease Control and Prevention11, Harvard University12, Johns Hopkins University13, Muhimbili University of Health and Allied Sciences14, King's College London15, University of Ibadan16, Cayetano Heredia University17, University of California, Berkeley18, Indian Institute of Science19, University of Cambridge20, World Health Organization21, Health Canada22, University of Cape Town23, National Health and Medical Research Council24, Medical Research Council25, Canadian Institutes of Health Research26, National Institutes of Health27
TL;DR: A consortium of researchers, advocates and clinicians announces here research priorities for improving the lives of people with mental illness around the world, and calls for urgent action and investment.
Abstract: A consortium of researchers, advocates and clinicians announces here research priorities for improving the lives of people with mental illness around the world, and calls for urgent action and investment.
1,726 citations
McMaster University1, Norwegian Institute of Public Health2, University of Basel3, University of London4, Oregon Health & Science University5, Autonomous University of Barcelona6, Bond University7, University at Buffalo8, University of Florida9, Health Canada10, Medical Research Council11, Case Western Reserve University12
TL;DR: Credibility is increased if subgroup effects are based on a small number of a priori hypotheses with a specified direction; subgroup comparisons come from within rather than between studies; tests of interaction generate low P-values; and have a biological rationale.
1,535 citations
TL;DR: These sequences provide a starting point for a new era in the functional analysis of a key model organism and show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus.
Abstract: We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.
1,453 citations
TL;DR: BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids.
914 citations
TL;DR: This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours.
875 citations
Public Health Foundation of India1, University of Edinburgh2, International Centre for Diarrhoeal Disease Research, Bangladesh3, Centers for Disease Control and Prevention4, University of Barcelona5, University of Oxford6, University of the Witwatersrand7, National Institutes of Health8, University of California, Berkeley9, Fukushima Medical University10, Medical Research Council11, All India Institute of Medical Sciences12, University of Colorado Denver13, Research Institute for Tropical Medicine14, Kenya Medical Research Institute15, Johns Hopkins University16, Pasteur Institute17, Delta State University18, University of Pretoria19, Columbia University20, World Health Organization21, Emory University22, Dartmouth College23, University of Split24
TL;DR: The role of influenza in childhood mortality from ALRI is estimated by combining incidence estimates with case fatality ratios from hospital-based reports and identifying studies with population-based data for influenza seasonality and monthly ALRI mortality.
804 citations
Medical Research Council1, University of Oxford2, National Institute for Health Research3, Structural Genomics Consortium4, University of Bristol5, University of Bath6, University of Queensland7, National Institutes of Health8, Cedars-Sinai Medical Center9, University of Toronto10, University of Alberta11, Memorial University of Newfoundland12, University of Leeds13, Norfolk and Norwich University Hospital14, Repatriation General Hospital15, University of Porto16, Sapienza University of Rome17, QIMR Berghofer Medical Research Institute18, Second Military Medical University19, Telethon Institute for Child Health Research20, Wellcome Trust Sanger Institute21, University of London22, Trinity College, Dublin23, Cardiff University24, Wellcome Trust25, Wellcome Trust Centre for Human Genetics26, St George's, University of London27, King's College London28, Churchill Hospital29, University of Leicester30, University of Cambridge31, Moorfields Eye Hospital32, University College London33, University of Texas Health Science Center at Houston34, Princess Alexandra Hospital35
TL;DR: In this paper, the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all their datasets (p < 5x 10(-6) overall, with support in each of the three datasets studied).
Abstract: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 x 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.
798 citations
TL;DR: A simple, programme-relevant stillbirth classification that can be used with verbal autopsy would provide a basis for comparable national estimates, and a new focus on all deaths around the time of birth is crucial to inform programmatic investment.
Queen Mary University of London1, King's College London2, University of Cambridge3, Medical Research Council4, South London and Maudsley NHS Foundation Trust5, University of Cumbria6, John Radcliffe Hospital7, Royal Free Hospital8, Frenchay Hospital9, Western General Hospital10, University of Edinburgh11
TL;DR: CBT and GET can safely be added to SMC to moderately improve outcomes for chronic fatigue syndrome, but APT is not an effective addition.
TL;DR: It is shown in a mouse model that influenza infection acutely induced airway hyper-reactivity (AHR), a cardinal feature of asthma, independently of T helper type 2 (TH2) cells and adaptive immunity.
Abstract: Patients with asthma, a major public health problem, are at high risk for serious disease from influenza virus infection, but the pathogenic mechanisms by which influenza A causes airway disease and asthma are not fully known. We show here in a mouse model that influenza infection acutely induced airway hyper-reactivity (AHR), a cardinal feature of asthma, independently of T helper type 2 (T(H)2) cells and adaptive immunity. Instead, influenza infection induced AHR through a previously unknown pathway that required the interleukin 13 (IL-13)-IL-33 axis and cells of the non-T cell, non-B cell innate lymphoid type called 'natural helper cells'. Infection with influenza A virus, which activates the NLRP3 inflammasome, resulted in much more production of IL-33 by alveolar macrophages, which in turn activated natural helper cells producing substantial IL-13.
TL;DR: It is concluded that CMV chemotherapy improves outcome as first-line adjunctive treatment for invasive bladder cancer and neoadjuvant chemotherapy followed by definitive local therapy should be viewed as state of the art, as compared with cystectomy or radiotherapy alone.
Abstract: Purpose This article presents the long-term results of the international multicenter randomized trial that investigated the use of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) chemotherapy in patients with muscle-invasive urothelial cancer of the bladder treated by cystectomy and/or radiotherapy. Nine hundred seventy-six patients were recruited between 1989 and 1995, and median follow-up is now 8.0 years. Patients and Methods This was a randomized phase III trial of either no neoadjuvant chemotherapy or three cycles of CMV. Results The previously reported possible survival advantage of CMV is now statistically significant at the 5% level. Results show a statistically significant 16% reduction in the risk of death (hazard ratio, 0.84; 95% CI, 0.72 to 0.99; P = .037, corresponding to an increase in 10-year survival from 30% to 36%) after CMV. Conclusion We conclude that CMV chemotherapy improves outcome as first-line adjunctive treatment for invasive bladder cancer. Two large randomized trials...
TL;DR: It is reported that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPin causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIn-deficient mice.
Abstract: SHARPIN is a ubiquitin-binding and ubiquitin-like-domain-containing protein which, when mutated in mice, results in immune system disorders and multi-organ inflammation. Here we report that SHARPIN functions as a novel component of the linear ubiquitin chain assembly complex (LUBAC) and that the absence of SHARPIN causes dysregulation of NF-κB and apoptotic signalling pathways, explaining the severe phenotypes displayed by chronic proliferative dermatitis (cpdm) in SHARPIN-deficient mice. Upon binding to the LUBAC subunit HOIP (also known as RNF31), SHARPIN stimulates the formation of linear ubiquitin chains in vitro and in vivo. Coexpression of SHARPIN and HOIP promotes linear ubiquitination of NEMO (also known as IKBKG), an adaptor of the IκB kinases (IKKs) and subsequent activation of NF-κB signalling, whereas SHARPIN deficiency in mice causes an impaired activation of the IKK complex and NF-κB in B cells, macrophages and mouse embryonic fibroblasts (MEFs). This effect is further enhanced upon concurrent downregulation of HOIL-1L (also known as RBCK1), another HOIP-binding component of LUBAC. In addition, SHARPIN deficiency leads to rapid cell death upon tumour-necrosis factor α (TNF-α) stimulation via FADD- and caspase-8-dependent pathways. SHARPIN thus activates NF-κB and inhibits apoptosis via distinct pathways in vivo.
TL;DR: It is found that the mental health effect of poverty alleviation interventions was inconclusive, although some conditional cash transfer and asset promotion programmes had mental health benefits and mental health interventions were associated with improved economic outcomes in all studies.
TL;DR: Evidence is presented that suggests M can adopt two conformations and that membrane curvature is regulated by one M conformer, providing insight into how M protein functions to promote virus assembly.
Technion – Israel Institute of Technology1, Centre national de la recherche scientifique2, University of Cambridge3, University of Oviedo4, French Institute of Health and Medical Research5, University of Paris-Sud6, Université de Montréal7, University of Southampton8, Paris Descartes University9, University of Auckland10, Washington State University11, McGill University12, Baylor College of Medicine13, Boston University14, QIMR Berghofer Medical Research Institute15, Medical Research Council16, University of Gothenburg17
TL;DR: Translational epigenetic research in child health is a reiterative process that ranges from research in the basic sciences, preclinical research, and pediatric clinical research and creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and theDevelopment of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs.
Abstract: Plasticity in developmental programming has evolved in order to provide the best chances of survival and reproductive success to the organism under changing environments. Environmental conditions that are experienced in early life can profoundly influence human biology and long-term health. Developmental origins of health and disease and life-history transitions are purported to use placental, nutritional, and endocrine cues for setting long-term biological, mental, and behavioral strategies in response to local ecological and/or social conditions. The window of developmental plasticity extends from preconception to early childhood and involves epigenetic responses to environmental changes, which exert their effects during life-history phase transitions. These epigenetic responses influence development, cell- and tissue-specific gene expression, and sexual dimorphism, and, in exceptional cases, could be transmitted transgenerationally. Translational epigenetic research in child health is a reiterative process that ranges from research in the basic sciences, preclinical research, and pediatric clinical research. Identifying the epigenetic consequences of fetal programming creates potential applications in clinical practice: the development of epigenetic biomarkers for early diagnosis of disease, the ability to identify susceptible individuals at risk for adult diseases, and the development of novel preventive and curative measures that are based on diet and/or novel epigenetic drugs.
TL;DR: increasing matrix stiffness promotes proliferation and chemotherapeutic resistance, whereas a soft environment induces reversible cellular dormancy and stem cell characteristics in HCC, which has implications for both the treatment of primary HCC and the prevention of tumor outgrowth from disseminated tumor cells.
TL;DR: Whether the use of medications with possible and definite anticholinergic activity increases the risk of cognitive impairment and mortality in older people and whether risk is cumulative is investigated.
Abstract: PARTICIPANTS: Thirteen thousand four participants aged 65 and older. MEASUREMENTS: Baseline use of possible or definite anticholinergics determined according to the Anticholinergic Cognitive Burden Scale and cognition determined using the Mini-Mental State Examination (MMSE). The main outcome measure was decline in the MMSE score at 2 years. RESULTS: At baseline, 47% of the population used a medication with possible anticholinergic properties, and 4% used a drug with definite anticholinergic properties. After adjusting for age, sex, educational level, social class, number of nonanticholinergic medications, number of comorbid health conditions, and cognitive performance at baseline, use of medication with definite anticholinergic effects was associated with a 0.33-point greater decline in MMSE score (95% confidence interval (CI) 50.03‐0.64, P 5.03) than not taking anticholinergics, whereas the use of possible anticholinergics at baseline was not associated with further decline (0.02, 95% CI 5 0.14‐0.11, P 5.79). Twoyear mortality was greater for those taking definite (OR 51.68; 95% CI 51.30‐2.16; Po.001) and possible (OR 51.56; 95% CI 51.36‐1.79;Po.001) anticholinergics. CONCLUSION: The use of medications with anticholinergic activity increases the cumulative risk of cognitive impairment and mortality. J Am Geriatr Soc 2011.
TL;DR: The criteria for defining progression are now acceptable in clinical trials of recurrent disease as they have since been validated and the GCIG requests that data from all clinical trials using these definitions are made available to GCIG trial centers so that continual validation and improvement can be accomplished.
Abstract: The Gynecological Cancer Intergroup (GCIG) has previously reached consensus regarding the criteria that should be used in clinical trial protocols to define progression-free survival after first-line therapy as well as the criteria to define response to treatment in recurrent disease using the serum marker CA 125 and has specified the situations where these criteria should be used. However, the publications did not include detailed definitions, nor were they written to accommodate the new version of Response Evaluation Criteria In Solid Tumors (RECIST) criteria (version 1.1) now available. Thus, we recommend that the definitions described later in detail are incorporated into clinical trial protocols to maintain consistency. The criteria for defining progression are now acceptable in clinical trials of recurrent disease as they have since been validated (Pujade-Lauraine, personal communication, 2010). The GCIG requests that data from all clinical trials using these definitions are made available to GCIG trial centers so that continual validation and improvement can be accomplished. These definitions were developed from analyzing patients receiving cytotoxic chemotherapy and have not yet been validated in patients receiving molecular targeting agents.
Medical Research Council1, Harvard University2, Lund University3, University of Minnesota4, Duke University5, University of Oulu6, Novo Nordisk7, Technische Universität München8, University College London9, University of Lausanne10, University of Eastern Finland11, National University of Singapore12, King's College London13, University of Bristol14, George Washington University15, National Institutes of Health16, University of Bergen17, University of Michigan18, University of North Carolina at Chapel Hill19, University of Groningen20, Utrecht University21, University of Copenhagen22, Erasmus University Rotterdam23, University of Tübingen24, Harokopio University25, Washington University in St. Louis26, University of Maryland, Baltimore27, University of Granada28, Complutense University of Madrid29, University of Turku30, University of Southern Denmark31, Umeå University32, University of Gothenburg33, Laval University34, University of London35, Pennington Biomedical Research Center36, Lille University of Science and Technology37, Newcastle University38, University of Iceland39, Danube University Krems40, Broad Institute41, University of California, Los Angeles42, Hammersmith Hospital43, University of Cambridge44, National Institute for Health and Welfare45
TL;DR: In this paper, a meta-analysis of data from 45 studies of adults and nine studies of children and adolescents was conducted to confirm or refute unambiguously whether physical activity attenuates the association of FTO with obesity risk.
Abstract: Background: The FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n=218,166) and nine studies of children and adolescents (n=19,268). Methods and Findings: All studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTOxPA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents. Conclusions: The association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.
TL;DR: Felsenstein's pruning algorithm is extended to allow efficient likelihood computations for models in which variation over branches (and not just sites) is described in the random effects likelihood framework, and this model treats the selective class of every branch at a particular site as an unobserved state that is chosen independently of that at any other branch.
Abstract: Adaptive evolution frequently occurs in episodic bursts, localized to a few sites in a gene, and to a small number of lineages in a phylogenetic tree. A popular class of “branch-site” evolutionary models provides a statistical framework to search for evidence of such episodic selection. For computational tractability, current branch-site models unrealistically assume that all branches in the tree can be partitioned a priori into two rigid classes—“foreground” branches that are allowed to undergo diversifying selective bursts and “background” branches that are negatively selected or neutral. We demonstrate that this assumption leads to unacceptably high rates of false positives or false negatives when the evolutionary process along background branches strongly deviates from modeling assumptions. To address this problem, we extend Felsenstein's pruning algorithm to allow efficient likelihood computations for models in which variation over branches (and not just sites) is described in the random effects likelihood framework. This enables us to model the process at every branch-site combination as a mixture of three Markov substitution models—our model treats the selective class of every branch at a particular site as an unobserved state that is chosen independently of that at any other branch. When benchmarked on a previously published set of simulated sequences, our method consistently matched or outperformed existing branch-site tests in terms of power and error rates. Using three empirical data sets, previously analyzed for episodic selection, we discuss how modeling assumptions can influence inference in practical situations.
TL;DR: To assess which antiretroviral therapies may be effective in decreasing the risk of mother-to-child transmission of HIV infection as well as their effect on neonatal and maternal mortality and morbidity, the Cochrane Controlled Trials Register and conference abstracts were searched.
Abstract: BACKGROUND: At the end of 2000 it was estimated that over 36 million people were living with the human immunodeficiency virus (HIV). This includes 1.4 million children less than 15 years of age. This is one of several reviews assessing the available evidence for preventing mother-to-child transmission of HIV infection. The other reviews will address other interventions, including Caesarean section, breast feeding, vaginal lavage and vitamin A supplementation. OBJECTIVES: To assess which antiretroviral therapies may be effective in decreasing the risk of mother-to-child transmission of HIV infection as well as their effect on neonatal and maternal mortality and morbidity. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register and the Cochrane Controlled Trials Register. We also searched conference abstracts from the International AIDS Conferences and Conference on Retroviruses and Opportunistic Infections. SELECTION CRITERIA: Randomised trials comparing any antiretroviral therapy aimed at decreasing the risk of mother-to-child transmission of HIV infection with placebo or no treatment, or any two or more antiretroviral therapies or regimens aimed at decreasing the risk of mother-to-child transmission of HIV infection. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. MAIN RESULTS: Zidovudine monotherapy Any zidovudine regimen versus placebo significantly reduces the risk of mother-to-child transmission (Peto odds ratio (OR) 0.46, 95% confidence interval (CI) 0.35 to 0.60). Zidovudine also appears to decrease the risk of infant death within the first year of birth (OR 0.57, 95% CI 0.38 to 0.85) and the risk of maternal death (OR 0.32, 95% CI 0.16 to 0.66). There is no evidence that zidovudine influences the incidence of premature delivery (OR 0.86, 95% CI 0.57 to 1.29) or low birth weight (OR 0.74, 95% CI 0.53 to 1.04). The risk of transmission using a 'short-short' course of zidovudine (from 35 weeks in pregnancy for the mother and for the baby until 3 days old) was higher than the risk using a 'long-long' course (from 28 weeks in pregnancy for the mother and for the baby until 6 weeks old), (OR 2.55, 95% CI 1.26 to 5.18). However, the effectiveness of the 'long-short' course (from 28 weeks in pregnancy for the mother and for the baby until 3 days old) and the 'short-long' course (from 35 weeks in pregnancy for the mother and for the baby until 6 weeks old) did not differ from that of the 'long-long' course. Nevirapine One large randomised controlled trial demonstrates that nevirapine given to mothers as a single dose at the onset of labour and to babies as a single dose within 72 hours of birth is more effective than an intrapartum and post-partum regimen of zidovudine (OR 0.51, 95% CI 0.33 to 0.79). When nevirapine is given to mothers already receiving standard antiretroviral therapy, however, there appears to be no additional advantage (OR 1.10, 95% CI 0.42 to 2.86). Combination Therapy Preliminary findings of the effect of combination therapy using zidovudine and lamivudine (3TC) suggest a decrease in the risk of transmission when the combination is given during the antenatal and intrapartum period or during the intrapartum and postpartum period compared with placebo. There is no evidence that intrapartum zidovudine and lamivudine alone are sufficient to decrease the risk of transmission compared with placebo. REVIEWER'S CONCLUSIONS: Implications for practice The randomised trials included in this review provide evidence that short course zidovudine and single-dose nevirapine are effective therapies for reducing mother-to-child transmission of HIV. The challenge for low and middle income countries will be to institute this therapy in practice. In industrialised countries practice has already moved on from the current evidence and combination antiretroviral therapy aimed primarily at preventing disease progression in the mother is the standard of care. Implications for research The potential value of nevirapine used for longer durations in breastfeeding populations should be considered as it may further reduce the risk of mother-to-child transmission, particularly if combined with early weaning. On-going evaluation of combination antiretroviral therapy is essential and will have an immediate benefit for countries with the resources to adopt such treatment. The search for effective, affordable, safe and acceptable alternatives to antiretroviral therapy for reducing mother-to-child transmission in resource poor countries should remain on the research agenda.
TL;DR: It is suggested that aflatoxin exposure and its association with growth impairment in children could contribute a significant public health burden in less developed countries.
Abstract: Aflatoxins, fungal toxins produced by Aspergillus flavus and Aspergillus parasiticus in a variety of food crops, are well known as potent human hepatocarcinogens. Relatively less highlighted in the literature is the association between aflatoxin and growth impairment in children. Foodborne aflatoxin exposure, especially through maize and groundnuts, is common in much of Africa and Asia—areas where childhood stunting and underweight are also common, due to a variety of possibly interacting factors such as enteric diseases, socioeconomic status, and suboptimal nutrition. The effects of aflatoxin on growth impairment in animals and human children are reviewed, including studies that assess aflatoxin exposure in utero and through breastfeeding. Childhood weaning diets in various regions of the world are briefly discussed. This review suggests that aflatoxin exposure and its association with growth impairment in children could contribute a significant public health burden in less developed countries.
TL;DR: There is evidence for dissociated underlying pathophysiologies for these two disorders that may have implications for future anatomy-based differential diagnosis and prevention and intervention.
TL;DR: Meta-analysis of prevalence data and reported odds ratios of risk factors demonstrated strong evidence that a history of violence is significantly associated with IPV in pregnancy and alcohol abuse by a partner also increases a woman's chances of being abused during pregnancy.
Abstract: Background
Intimate partner violence (IPV) is very high in Africa. However, information obtained from the increasing number of African studies on IPV among pregnant women has not been scientifically analyzed. This paper presents a systematic review summing up the evidence from African studies on IPV prevalence and risk factors among pregnant women.
TL;DR: This article identified new regions showing association with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2.
Abstract: Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
TL;DR: Findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP, as well as two new MAP loci associated with both of these traits.
Abstract: Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans(1-3). We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 x 10(-8) to P = 2.3 x 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.
TL;DR: The role of AMPK as an energy sensor is reviewed and the recent finding that ADP, as well as AMP, causes activation of mammalian AMPK is considered, which provides a mechanism for the regulation of AM PK in which AMP and ADP protect it against dephosphorylation.
Abstract: Maintaining sufficient levels of ATP (the immediate source of cellular energy) is essential for the proper functioning of all living cells As a consequence, cells require mechanisms to balance energy demand with supply In eukaryotic cells the AMP-activated protein kinase (AMPK) cascade has an important role in this homeostasis AMPK is activated by a fall in ATP (concomitant with a rise in ADP and AMP), which leads to the activation of catabolic pathways and the inhibition of anabolic pathways Here we review the role of AMPK as an energy sensor and consider the recent finding that ADP, as well as AMP, causes activation of mammalian AMPK We also review recent progress in structural studies on phosphorylated AMPK that provides a mechanism for the regulation of AMPK in which AMP and ADP protect it against dephosphorylation Finally, we briefly survey some of the outstanding questions concerning the regulation of AMPK