Doxycycline reduces the migration of tuberous sclerosis complex-2 null cells - effects on RhoA-GTPase and focal adhesion kinase

& Sons Ltd and Foundation for Cellular and Molecular Medicine. Lymphangioleiomyomatosis (LAM) is associated with dysfunction of the tuberous sclerosis complex (TSC) leading to enhanced cell proliferation and migration. This study aims to examine whether doxycycline, a tetracycline antibiotic, can inhibit the enhanced migration of TSC2-deficient cells, identify signalling pathways through which doxycycline works and to assess the effectiveness of combining doxycycline with rapamycin (mammalian target of rapamycin complex 1 inhibitor) in controlling cell migration, proliferation and wound closure. TSC2-positive and TSC2-negative mouse embryonic fibroblasts (MEF), 323-TSC2-positive and 323-TSC2-null MEF and Eker rat uterine leiomyoma (ELT3) cells were treated with doxycycline or rapamycin alone, or in combination. Migration, wound closure and proliferation were assessed using a transwell migration assay, time-lapse microscopy and manual cell counts respectively. RhoA-GTPase activity, phosphorylation of p70S6 kinase (p70S6K) and focal adhesion kinase (FAK) in TSC2-negative MEF treated with doxycycline were examined using ELISA and immunoblotting techniques. The enhanced migration of TSC2-null cells was reduced by doxycycline at concentrations as low as 20 pM, while the rate of wound closure was reduced at 2-59 μM. Doxycycline decreased RhoA-GTPase activity and phosphorylation of FAK in these cells but had no effect on the phosphorylation of p70S6K, ERK1/2 or AKT. Combining doxycycline with rapamycin significantly reduced the rate of wound closure at lower concentrations than achieved with either drug alone. This study shows that doxycycline inhibits TSC2-null cell migration. Thus doxycycline has potential as an anti-migratory agent in the treatment of diseases with TSC2 dysfunction. © 2015 John Wile

LF-15 & T7, synthetic peptides derived from tumstatin, attenuate aspects of airway remodelling in a murine model of chronic OVA-induced allergic airway disease

Background: Tumstatin is a segment of the collagen-IV protein that is markedly reduced in the airways of asthmatics. Tumstatin can play an important role in the development of airway remodelling associated with asthma due to its antiangiogenic properties. This study assessed the anti-angiogenic properties of smaller peptides derived from tumstatin, which contain the interface tumstatin uses to interact with the aVb3 integrin. Methods: Primary human lung endothelial cells were exposed to the LF-15, T3 and T7 tumstatin-derived peptides and assessed for cell viability and tube formation in vitro. The impact of the anti-angiogenic properties on airways hyperresponsiveness (AHR) was then examined using a murine model of chronic OVA-induced allergic airways disease. Results: The LF-15 and T7 peptides significantly reduced endothelial cell viability and attenuated tube formation in vitro. Mice exposed to OVA+ LF-15 or OVA+T7 also had reduced total lung vascularity and AHR was attenuated compared to mice exposed to OVA alone. T3 peptides reduced cell viability but had no effect on any other parameters. Conclusion: The LF-15 and T7 peptides may be appropriate candidates for use as novel pharmacotherapies due to their small size and anti-angiogenic properties observed in vitro and in vivo. © 2014 Grafton et al

The Genome of the "Great Speciator" Provides Insights into Bird Diversification

Among birds, white-eyes (genus Zosterops) have diversified so extensively that Jared Diamond and Ernst Mayr referred to them as the “great speciator.” The Zosterops lineage exhibits some of the fastest rates of species diversification among vertebrates, and its members are the most prolific passerine island colonizers. We present a high-quality genome assembly for the silvereye (Zosterops lateralis), a white-eye species consisting of several subspecies distributed across multiple islands. We investigate the genetic basis of rapid diversification in white-eyes by conducting genomic analyses at varying taxonomic levels. First, we compare the silvereye genome with those of birds from different families and searched for genomic features that may be unique to Zosterops. Second, we compare the genomes of different species of white-eyes from Lifou island (South Pacific), using whole genome resequencing and restriction site associated DNA. Third, we contrast the genomes of two subspecies of silvereye that differ in plumage color. In accordance with theory, we show that white-eyes have high rates of substitutions, gene duplication, and positive selection relative to other birds. Below genus level, we find that genomic differentiation accumulates rapidly and reveals contrasting demographic histories between sympatric species on Lifou, indicative of past interspecific interactions. Finally, we highlight genes possibly involved in color polymorphism between the subspecies of silvereye. By providing the first whole-genome sequence resources for white-eyes and by conducting analyses at different taxonomic levels, we provide genomic evidence underpinning this extraordinary bird radiation

UCL Qualitative health research symposium 2017: collaboration in qualitative health research

In recent years, there have been increasing calls for collaboration between academia and the wider healthcare community in health research. This is largely driven by efforts to engage the public in the “co-production” of evidence-based healthcare and healthcare decision-making, as well as penetrate borders between disciplines. As a result, traditional "lone researcher" models of qualitative health research have shifted to include research teams which are increasingly made up of qualitative researchers alongside quantitative researchers, members of the public, health professionals, policy-makers and other stakeholders. In these ways, health research is assumed to be more relevant, ethically justifiable, and broadly applicable. However, such collaborations may be complex and may create challenges. To date, there has been limited critical consideration of these challenges and little is known about the assumptions and effectiveness of these collaborations. We organised a one-day symposium to explore themes related to engagement, co-production and collaborative meaning making in qualitative health research. The oral presentations and posters used examples of collaborative studies to critically explore the processes used to carry out research as a diverse team. The discussions throughout the day alluded to the need to understand the multiple forms and levels of patient and public involvement in research, and distinguish between patient representatives and members of the public. Collaborative research requires flexibility, and might lead the researcher to occupy “mediating” roles such as that of the “cultural broker” or “boundary spanner”. The symposium created a forum to critically reflect on current approaches to inform improved ways of collaborating and engaging with diverse stakeholders to meaningfully impact on health and healthcare delivery. We should continue to search for ways to unpack the concept of “collaboration” to identify the purpose of collaborative relationships, the required activities and the actors involved

A Review of Pharmacologic Treatment for Compulsive Buying Disorder

At present, no treatment recommendations can be made for compulsive buying disorder. Recent studies have found evidence for the efficacy of psychotherapeutic options, but less is known regarding the best pharmacologic treatment. The purpose of this review is to present and analyze the available published evidence on the pharmacological treatment of compulsive buying disorder. To achieve this, we conducted a review of studies focusing on the pharmacological treatment of compulsive buying by searching the PubMed/MEDLINE database. Selection criteria were applied, and 21 studies were identified. Pharmacological classes reported included antidepressants, mood stabilizers, opioid antagonists, second-generation antipsychotics, and N-methyl-D-aspartate receptor antagonists. We found only placebo-controlled trials for fluvoxamine; none showed effectiveness against placebo. Three open-label trials reported clinical improvement with citalopram; one was followed by a double-blind discontinuation. Escitalopram was effective in an open-label trial but did not show efficacy in the double-blind phase. Memantine was identified as effective in a pilot open-label study. Fluoxetine, bupropion, nortriptyline, clomipramine, topiramate and naltrexone were only reported to be effective in clinical cases. According to the available literature, there is no evidence to propose a specific pharmacologic agent for compulsive buying disorder. Future research is required for a better understanding of both pathogenesis and treatment of this disorder.info:eu-repo/semantics/publishedVersio

Health system costs of potentially inappropriate prescribing in Ontario, Canada: A protocol for a population-based cohort study

All rights reserved. No commercial use is permitted unless otherwise expressly granted. Introduction Adverse drug events (ADEs) are common in older persons and contribute significantly to emergency department visits, hospitalisations and mortality. ADEs are often due to potentially inappropriate prescriptions (PIP) or potentially inappropriate omissions (PIO), and are avoidable if inappropriate prescriptions or omissions are identified and prevented. Identifying PIP/PIO at the population level through the application of PIP/PIO assessment tools to health administrative data can provide a unique opportunity to assess the economic burden of PIP/PIO on the healthcare system beyond medication costs which is yet to be done. The objective of this study is to assess the economic burden associated with PIP/PIO and to estimate the incremental costs associated with distinct PIP/PIO in the province of Ontario. Methods and analysis We will conduct a retrospective cohort study using Ontario's health administrative databases. Eligible patients aged 66 years and older who were prescribed at least one medication between 1 April 2003 and 31 March 2014 (approximately 2.4 million patients) will be included. Population attributable fraction methodology will be used to assess the overall burden of PIP in Ontario, while regression analyses will be used to estimate the incremental costs of having specific PIP criteria and aid in prioritising targets for intervention. Ethics and dissemination This study was approved by the Institutional Review Board at Sunnybrook Health Sciences Centre, Toronto, Canada. Dissemination will occur via publication, presentation at national and international conferences, and knowledge exchange with various stakeholders

A modern multicentennial record of radiocarbon variability from an exactly dated bivalve chronology at the Tree Nob site (Alaska coastal current)

This is the final version. Available from Cambridge University Press via the DOI in this record. Quantifying the marine radiocarbon reservoir effect, offsets (ΔR), and ΔR variability over time is critical to improving dating estimates of marine samples while also providing a proxy of water mass dynamics. In the northeastern Pacific, where no high-resolution time series of ΔR has yet been established, we sampled radiocarbon (14C) from exactly dated growth increments in a multicentennial chronology of the long-lived bivalve, Pacific geoduck (Paneopea generosa) at the Tree Nob site, coastal British Columbia, Canada. Samples were taken at approximately decadal time intervals from 1725 CE to 1920 CE and indicate average ΔR values of 256 ± 22 years (1σ) consistent with existing discrete estimates. Temporal variability in ΔR is small relative to analogous Atlantic records except for an unusually old-water event, 1802–1812. The correlation between ΔR and sea surface temperature (SST) reconstructed from geoduck increment width is weakly significant (r2 = .29, p = .03), indicating warm water is generally old, when the 1802–1812 interval is excluded. This interval contains the oldest (–2.1σ) anomaly, and that is coincident with the coldest (–2.7σ) anomalies of the temperature reconstruction. An additional 32 14C values spanning 1952–1980 were detrended using a northeastern Pacific bomb pulse curve. Significant positive correlations were identified between the detrended 14C data and annual El Niño Southern Oscillation (ENSO) and summer SST such that cooler conditions are associated with older water. Thus, 14C is generally relatively stable with weak, potentially inconsistent associations to climate variables, but capable of infrequent excursions as illustrated by the unusually cold, old-water 1802–1812 interval.National Science FoundationNational Science Foundatio

Pulmonary Predictors of Incident Diabetes in Smokers.

BACKGROUND: Diabetes mellitus and its complications are a large and increasing burden for health care worldwide. Reduced pulmonary function has been observed in diabetes (both type 1 and type 2), and this reduction is thought to occur prior to diagnosis. Other measures of pulmonary health are associated with diabetes, including lower exercise tolerance, greater dyspnea, lower quality of life (as measured by the St. George's Respiratory Questionaire [SGRQ]) and susceptibility to lung infection and these measures may also predate diabetes diagnosis. METHODS: We examined 7080 participants in the COPD Genetic Epidemiology (COPDGene) study who did not report diabetes at their baseline visit and who provided health status updates during 4.2 years of longitudinal follow-up (LFU). We used Cox proportional hazards modeling, censoring participants at final LFU contact, reported mortality or report of incident diabetes to model predictors of diabetes. These models were constructed using known risk factors as well as proposed markers related to pulmonary health, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, respiratory exacerbations (RE), 6-minute walk distance (6MWD), pulmonary associated quality of life (as measured by the SGRQ), corticosteroid use, chronic bronchitis and dyspnea. RESULTS: Over 21,519 person years of follow-up, 392 of 7080 participants reported incident diabetes which was associated with expected predictors; increased body mass index (BMI), high blood pressure, high cholesterol and current smoking status. Age, gender and accumulated smoking exposure were not associated with incident diabetes. Additionally, preserved ratio with impaired spirometry (PRISm) pattern pulmonary function, reduced 6MWD and any report of serious pulmonary events were associated with incident diabetes. CONCLUSIONS: This cluster of pulmonary indicators may aid clinicians in identifying and treating patients with pre- or undiagnosed diabetes

Trapped in the prison of the mind: notions of climate-induced (im)mobility decision-making and wellbeing from an urban informal settlement in Bangladesh

The concept of Trapped Populations has until date mainly referred to people ‘trapped’ in environmentally high-risk rural areas due to economic constraints. This article attempts to widen our understanding of the concept by investigating climate-induced socio-psychological immobility and its link to Internally Displaced People’s (IDPs) wellbeing in a slum of Dhaka. People migrated here due to environmental changes back on Bhola Island and named the settlement Bhola Slum after their home. In this way, many found themselves ‘immobile’ after having been mobile—unable to move back home, and unable to move to other parts of Dhaka, Bangladesh, or beyond. The analysis incorporates the emotional and psychosocial aspects of the diverse immobility states. Mind and emotion are vital to better understand people’s (im)mobility decision-making and wellbeing status. The study applies an innovative and interdisciplinary methodological approach combining Q-methodology and discourse analysis (DA). This mixed-method illustrates a replicable approach to capture the complex state of climate-induced (im)mobility and its interlinkages to people’s wellbeing. People reported facing non-economic losses due to the move, such as identity, honour, sense of belonging and mental health. These psychosocial processes helped explain why some people ended up ‘trapped’ or immobile. The psychosocial constraints paralysed them mentally, as well as geographically. More empirical evidence on how climate change influences people’s wellbeing and mental health will be important to provide us with insights in how to best support vulnerable people having faced climatic impacts, and build more sustainable climate policy frameworks