State based model of long-term potentiation and synaptic tagging and capture

Recent data indicate that plasticity protocols have not only synapse-specific but also more widespread effects. In particular, in synaptic tagging and capture (STC), tagged synapses can capture plasticity-related proteins, synthesized in response to strong stimulation of other synapses. This leads to long-lasting modification of only weakly stimulated synapses. Here we present a biophysical model of synaptic plasticity in the hippocampus that incorporates several key results from experiments on STC. The model specifies a set of physical states in which a synapse can exist, together with transition rates that are affected by high- and low-frequency stimulation protocols. In contrast to most standard plasticity models, the model exhibits both early- and late-phase LTP/D, de-potentiation, and STC. As such, it provides a useful starting point for further theoretical work on the role of STC in learning and memory

The Genetic Signature of Sex-Biased Migration in Patrilocal Chimpanzees and Humans

A large body of theoretical work suggests that analyses of variation at the maternally inherited mitochondrial (mt)DNA and the paternally inherited non-recombining portion of the Y chromosome (NRY) are a potentially powerful way to reveal the differing migratory histories of men and women across human societies. However, the few empirical studies comparing mtDNA and NRY variation and known patterns of sex-biased migration have produced conflicting results. Here we review some methodological reasons for these inconsistencies, and take them into account to provide an unbiased characterization of mtDNA and NRY variation in chimpanzees, one of the few mammalian taxa where males routinely remain in and females typically disperse from their natal groups. We show that patterns of mtDNA and NRY variation are more strongly contrasting in patrilocal chimpanzees compared with patrilocal human societies. The chimpanzee data we present here thus provide a valuable comparative benchmark of the patterns of mtDNA and NRY variation to be expected in a society with extremely female-biased dispersal

Five-Year Outcomes after Off-Pump or On-Pump Coronary-Artery Bypass Grafting.

BACKGROUND: We previously reported that there was no significant difference at 30 days or at 1 year in the rate of the composite outcome of death, stroke, myocardial infarction, or renal failure between patients who underwent coronary-artery bypass grafting (CABG) performed with a beating-heart technique (off-pump) and those who underwent CABG performed with cardiopulmonary bypass (on-pump). We now report the results at 5 years (the end of the trial). METHODS: A total of 4752 patients (from 19 countries) who had coronary artery disease were randomly assigned to undergo off-pump or on-pump CABG. For this report, we analyzed a composite outcome of death, stroke, myocardial infarction, renal failure, or repeat coronary revascularization (either CABG or percutaneous coronary intervention). The mean follow-up period was 4.8 years. RESULTS: There were no significant differences between the off-pump group and the on-pump group in the rate of the composite outcome (23.1% and 23.6%, respectively; hazard ratio with off-pump CABG, 0.98; 95% confidence interval [CI], 0.87 to 1.10; P=0.72) or in the rates of the components of the outcome, including repeat coronary revascularization, which was performed in 2.8% of the patients in the off-pump group and in 2.3% of the patients in the on-pump group (hazard ratio, 1.21; 95% CI, 0.85 to 1.73; P=0.29). The secondary outcome for the overall period of the trial - the mean cost in U.S. dollars per patient - also did not differ significantly between the off-pump group and the on-pump group ($15,107 and$14,992, respectively; between-group difference, $115; 95$697 to $927). There were no significant between-group differences in quality-of-life measures. CONCLUSIONS: In our trial, the rate of the composite outcome of death, stroke, myocardial infarction, renal failure, or repeat revascularization at 5 years of follow-up was similar among patients who underwent off-pump CABG and those who underwent on-pump CABG. (Funded by the Canadian Institutes of Health Research; CORONARY ClinicalTrials.gov number, NCT00463294 .)

Life Expectancy at Birth for People with Serious Mental Illness and Other Major Disorders from a Secondary Mental Health Care Case Register in London

Despite improving healthcare, the gap in mortality between people with serious mental illness (SMI) and general population persists, especially for younger age groups. The electronic database from a large and comprehensive secondary mental healthcare provider in London was utilized to assess the impact of SMI diagnoses on life expectancy at birth.People who were diagnosed with SMI (schizophrenia, schizoaffective disorder, bipolar disorder), substance use disorder, and depressive episode/disorder before the end of 2009 and under active review by the South London and Maudsley NHS Foundation Trust (SLAM) in southeast London during 2007-09 comprised the sample, retrieved by the SLAM Case Register Interactive Search (CRIS) system. We estimated life expectancy at birth for people with SMI and each diagnosis, from national mortality returns between 2007-09, using a life table method.A total of 31,719 eligible people, aged 15 years or older, with SMI were analyzed. Among them, 1,370 died during 2007-09. Compared to national figures, all disorders were associated with substantially lower life expectancy: 8.0 to 14.6 life years lost for men and 9.8 to 17.5 life years lost for women. Highest reductions were found for men with schizophrenia (14.6 years lost) and women with schizoaffective disorders (17.5 years lost).The impact of serious mental illness on life expectancy is marked and generally higher than similarly calculated impacts of well-recognised adverse exposures such as smoking, diabetes and obesity. Strategies to identify and prevent causes of premature death are urgently required

Genetic diversity and demographic instability in Riftia pachyptila tubeworms from eastern Pacific hydrothermal vents

<p>Abstract</p> <p>Background</p> <p>Deep-sea hydrothermal vent animals occupy patchy and ephemeral habitats supported by chemosynthetic primary production. Volcanic and tectonic activities controlling the turnover of these habitats contribute to demographic instability that erodes genetic variation within and among colonies of these animals. We examined DNA sequences from one mitochondrial and three nuclear gene loci to assess genetic diversity in the siboglinid tubeworm, <it>Riftia pachyptila</it>, a widely distributed constituent of vents along the East Pacific Rise and Galápagos Rift.</p> <p>Results</p> <p>Genetic differentiation (<it>F</it>_<it>ST</it>) among populations increased with geographical distances, as expected under a linear stepping-stone model of dispersal. Low levels of DNA sequence diversity occurred at all four loci, allowing us to exclude the hypothesis that an idiosyncratic selective sweep eliminated mitochondrial diversity alone. Total gene diversity declined with tectonic spreading rates. The southernmost populations, which are subjected to superfast spreading rates and high probabilities of extinction, are relatively homogenous genetically.</p> <p>Conclusions</p> <p>Compared to other vent species, DNA sequence diversity is extremely low in <it>R. pachyptila</it>. Though its dispersal abilities appear to be effective, the low diversity, particularly in southern hemisphere populations, is consistent with frequent local extinction and (re)colonization events.</p

Internal medicine residency training for unhealthy alcohol and other drug use: recommendations for curriculum design

<p>Abstract</p> <p>Background</p> <p>Unhealthy substance use is the spectrum from use that risks harm, to use associated with problems, to the diagnosable conditions of substance abuse and dependence, often referred to as substance abuse disorders. Despite the prevalence and impact of unhealthy substance use, medical education in this area remains lacking, not providing physicians with the necessary expertise to effectively address one of the most common and costly health conditions. Medical educators have begun to address the need for physician training in unhealthy substance use, and formal curricula have been developed and evaluated, though broad integration into busy residency curricula remains a challenge.</p> <p>Discussion</p> <p>We review the development of unhealthy substance use related competencies, and describe a curriculum in unhealthy substance use that integrates these competencies into internal medicine resident physician training. We outline strategies to facilitate adoption of such curricula by the residency programs. This paper provides an outline for the actual implementation of the curriculum within the structure of a training program, with examples using common teaching venues. We describe and link the content to the core competencies mandated by the Accreditation Council for Graduate Medical Education, the formal accrediting body for residency training programs in the United States. Specific topics are recommended, with suggestions on how to integrate such teaching into existing internal medicine residency training program curricula.</p> <p>Summary</p> <p>Given the burden of disease and effective interventions available that can be delivered by internal medicine physicians, teaching about unhealthy substance use must be incorporated into internal medicine residency training, and can be done within existing teaching venues.</p

Preventive evidence into practice (PEP) study: implementation of guidelines to prevent primary vascular disease in general practice protocol for a cluster randomised controlled trial

There are significant gaps in the implementation and uptake of evidence-based guideline recommendations for cardiovascular disease (CVD) and diabetes in Australian general practice. This study protocol describes the methodology for a cluster randomised trial to evaluate the effectiveness of a model that aims to improve the implementation of these guidelines in Australian general practice developed by a collaboration between researchers, non-government organisations, and the profession.This study is funded by an Australian National Health and Medical Research Council (NHMRC) Partnership grant (ID 568978) together with the Australian National Heart Foundation, Royal Australian College of General Practitioners, and the BUPA Foundation. MH is supported by a NHMRC Senior Principle Research Fellowship

Prescribing indicators at primary health care centers within the WHO African region: a systematic analysis (1995-2015)

Abstract Background Rational medicine use is essential to optimize quality of healthcare delivery and resource utilization. We aim to conduct a systematic review of changes in prescribing patterns in the WHO African region and comparison with WHO indicators in two time periods 1995–2005 and 2006–2015. Methods Systematic searches were conducted in PubMed, Scopus, Web of science, Africa-Wide Nipad, Africa Journals Online (AJOL), Google scholar and International Network for Rational Use of Drugs (INRUD) Bibliography databases to identify primary studies reporting prescribing indicators at primary healthcare centres (PHCs) in Africa. This was supplemented by a manual search of retrieved references. We assessed the quality of studies using a 14-point scoring system modified from the Downs and Black checklist with inclusions of recommendations in the WHO guidelines. Results Forty-three studies conducted in 11 African countries were included in the overall analysis. These studies presented prescribing indicators based on a total 141,323 patient encounters across 572 primary care facilities. The results of prescribing indicators were determined as follows; average number of medicines prescribed per patient encounter = 3.1 (IQR 2.3–4.8), percentage of medicines prescribed by generic name =68.0 % (IQR 55.4–80.3), Percentage of encounters with antibiotic prescribed =46.8 % (IQR 33.7–62.8), percentage of encounters with injection prescribed =25.0 % (IQR 18.7–39.5) and the percentage of medicines prescribed from essential medicines list =88.0 % (IQR 76.3–94.1). Prescribing indicators were generally worse in private compared with public facilities. Analysis of prescribing across two time points 1995–2005 and 2006–2015 showed no consistent trends. Conclusions Prescribing indicators for the African region deviate significantly from the WHO reference targets. Increased collaborative efforts are urgently needed to improve medicine prescribing practices in Africa with the aim of enhancing the optimal utilization of scarce resources and averting negative health consequences