Association between exposure to environmental tobacco smoke and biomarkers of oxidative stress among patients hospitalised with acute myocardial infarction

Objective To determine whether exposure to environmental tobacco smoke was associated with oxidative stress among patients hospitalised for acute myocardial infarction.<p></p> Design An existing cohort study of 1,261 patients hospitalised for acute myocardial infarction.<p></p> Setting Nine acute hospitals in Scotland.<p></p> Participants Sixty never smokers who had been exposed to environmental tobacco smoke (admission serum cotinine ≥3.0 ng/mL) were compared with 60 never smokers who had not (admission serum cotinine ≤0.1 ng/mL).<p></p> Intervention None.<p></p> Main outcome measures Three biomarkers of oxidative stress (protein carbonyl, malondialdehyde (MDA) and oxidised low-density lipoprotein (ox-LDL)) were measured on admission blood samples and adjusted for potential confounders.<p></p> Results After adjusting for baseline differences in age, sex and socioeconomic status, exposure to environmental tobacco smoke was associated with serum concentrations of both protein carbonyl (beta coefficient 7.96, 95% CI 0.76, 15.17, p = 0.031) and MDA (beta coefficient 10.57, 95% CI 4.32, 16.81, p = 0.001) but not ox-LDL (beta coefficient 2.14, 95% CI −8.94, 13.21, p = 0.703).<p></p> Conclusions Exposure to environmental tobacco smoke was associated with increased oxidative stress. Further studies are requires to explore the role of oxidative stress in the association between environmental tobacco smoke and myocardial infarction.<p></p&gt

Rilpivirine analogs potently inhibit drug-resistant HIV-1 mutants

Background: Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are a class of antiretroviral compounds that bind in an allosteric binding pocket in HIV-1 RT, located about 10 from the polymerase active site. Binding of an NNRTI causes structural changes that perturb the alignment of the primer terminus and polymerase active site, preventing viral DNA synthesis. Rilpivirine (RPV) is the most recent NNRTI approved by the FDA, but like all other HIV-1 drugs, suboptimal treatment can lead to the development of resistance. To generate better compounds that could be added to the current HIV-1 drug armamentarium, we have developed several RPV analogs to combat viral variants that are resistant to the available NNRTIs. Results: Using a single-round infection assay, we identified several RPV analogs that potently inhibited a broad panel of NNRTI resistant mutants. Additionally, we determined that several resistant mutants selected by either RPV or Doravirine (DOR) caused only a small increase in susceptibility to the most promising RPV analogs. Conclusions: The antiviral data suggested that there are RPV analogs that could be candidates for further development as NNRTIs, and one of the most promising compounds was modeled in the NNRTI binding pocket. This model can be used to explain why this compound is broadly effective against the panel of NNRTI resistance mutants

Stable isotope analysis provides new information on winter habitat use of declining avian migrants that is relevant to their conservation

Winter habitat use and the magnitude of migratory connectivity are important parameters when assessing drivers of the marked declines in avian migrants. Such information is unavailable for most species. We use a stable isotope approach to assess these factors for three declining African-Eurasian migrants whose winter ecology is poorly known: wood warbler Phylloscopus sibilatrix, house martin Delichon urbicum and common swift Apus apus. Spatially segregated breeding wood warbler populations (sampled across a 800 km transect), house martins and common swifts (sampled across a 3,500 km transect) exhibited statistically identical intra-specific carbon and nitrogen isotope ratios in winter grown feathers. Such patterns are compatible with a high degree of migratory connectivity, but could arise if species use isotopically similar resources at different locations. Wood warbler carbon isotope ratios are more depleted than typical for African-Eurasian migrants and are compatible with use of moist lowland forest. The very limited variance in these ratios indicates specialisation on isotopically restricted resources, which may drive the similarity in wood warbler populations' stable isotope ratios and increase susceptibility to environmental change within its wintering grounds. House martins were previously considered to primarily use moist montane forest during the winter, but this seems unlikely given the enriched nature of their carbon isotope ratios. House martins use a narrower isotopic range of resources than the common swift, indicative of increased specialisation or a relatively limited wintering range; both factors could increase house martins' vulnerability to environmental change. The marked variance in isotope ratios within each common swift population contributes to the lack of population specific signatures and indicates that the species is less vulnerable to environmental change in sub-Saharan Africa than our other focal species. Our findings demonstrate how stable isotope research can contribute to understanding avian migrants' winter ecology and conservation status

Design and feasibility testing of a novel group intervention for young women who binge drink in groups

BackgroundYoung women frequently drink alcohol in groups and binge drinking within these natural drinking groups is common. This study describes the design of a theoretically and empirically based group intervention to reduce binge drinking among young women. It also evaluates their engagement with the intervention and the acceptability of the study methods.MethodsFriendship groups of women aged 18–35 years, who had two or more episodes of binge drinking (>6 UK units on one occasion; 48g of alcohol) in the previous 30 days, were recruited from the community. A face-to-face group intervention, based on the Health Action Process Approach, was delivered over three sessions. Components of the intervention were woven around fun activities, such as making alcohol free cocktails. Women were followed up four months after the intervention was delivered. Results The target of 24 groups (comprising 97 women) was recruited. The common pattern of drinking was infrequent, heavy drinking (mean consumption on the heaviest drinking day was UK 18.1 units). Process evaluation revealed that the intervention was delivered with high fidelity and acceptability of the study methods was high. The women engaged positively with intervention components and made group decisions about cutting down. Twenty two groups set goals to reduce their drinking, and these were translated into action plans. Retention of individuals at follow up was 87%.ConclusionsThis study successfully recruited groups of young women whose patterns of drinking place them at high risk of acute harm. This novel approach to delivering an alcohol intervention has potential to reduce binge drinking among young women. The high levels of engagement with key steps in the behavior change process suggests that the group intervention should be tested in a full randomised controlled trial

Gene sequence variations of the platelet P2Y12 receptor are associated with coronary artery disease

<p>Abstract</p> <p>Background</p> <p>The platelet P2Y₁₂receptor plays a key role in platelet activation. The H2 haplotype of the P2Y₁₂receptor gene (<it>P2RY12</it>) has been found to be associated with maximal aggregation response to adenosine diphosphate (ADP) and with increased risk for peripheral arterial disease. No data are available on its association with coronary artery disease (CAD).</p> <p>Methods </p> <p>The H2 haplotype of the <it>P2RY12 </it>was determined in 1378 unrelated patients of both sexes selected according to the presence of significant coronary artery disease (CAD group) or having normal coronary angiogram at cardiac catheterization (CAD-free group). Significant coronary artery disease was angiographically determined, and was defined as a greater than 50% visually estimated luminal diameter stenosis in at least one major epicardial coronary artery.</p> <p>Results</p> <p>In the studied population 71.9% had CAD (n = 991) and 28.1% had normal coronary angiogram (n = 387). H2 haplotype carriers were more frequent in the CAD group (p = 0.03, OR = 1.36, 95%CI = 1.02–1.82). The H2 haplotype was significantly associated with CAD in non-smokers (p = 0.007, OR = 1.83 95%CI = 1.17–2.87), but not in smokers. The association remained significant after adjustment for other covariates (age, triglycerides, HDL, hypertension, diabetes) by multivariate logistic regression (p = 0.004, OR = 2.32 95%CI = 1.30–4.15).</p> <p>Conclusion</p> <p>Gene sequence variations of the P2Y₁₂receptor gene are associated with the presence of significant CAD, particularly in non-smoking individuals.</p

Spatio-temporal Models of Lymphangiogenesis in Wound Healing

Several studies suggest that one possible cause of impaired wound healing is failed or insufficient lymphangiogenesis, that is the formation of new lymphatic capillaries. Although many mathematical models have been developed to describe the formation of blood capillaries (angiogenesis), very few have been proposed for the regeneration of the lymphatic network. Lymphangiogenesis is a markedly different process from angiogenesis, occurring at different times and in response to different chemical stimuli. Two main hypotheses have been proposed: 1) lymphatic capillaries sprout from existing interrupted ones at the edge of the wound in analogy to the blood angiogenesis case; 2) lymphatic endothelial cells first pool in the wound region following the lymph flow and then, once sufficiently populated, start to form a network. Here we present two PDE models describing lymphangiogenesis according to these two different hypotheses. Further, we include the effect of advection due to interstitial flow and lymph flow coming from open capillaries. The variables represent different cell densities and growth factor concentrations, and where possible the parameters are estimated from biological data. The models are then solved numerically and the results are compared with the available biological literature.Comment: 29 pages, 9 Figures, 6 Tables (39 figure files in total

Persistence of viral reservoirs in multiple tissues after antiretroviral therapy suppression in a macaque RT-SHIV model

Although antiretroviral therapy (ART) can suppress HIV-1 replication sufficiently to eliminate measurable plasma viremia, infected cells remain and ensure viral recrudescence after discontinuation of ART. We used a macaque model of HIV-1/AIDS to evaluate the location of infected cells during ART. Twelve macaques were infected with RT-SHIVmne, a SIV containing HIV-1 reverse transcriptase, conferring sensitivity to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Ten to fourteen weeks post-infection, 6 animals were treated with 3 or 4 antiretroviral drugs for 17-20 weeks; 6 control animals remained untreated. Viral DNA (vDNA) and RNA (vRNA) were measured in peripheral blood mononuclear cells (PBMC) and at necropsy in multiple tissues by quantitative PCR and RT-PCR. The majority of virally infected cells were located in lymphoid tissues with variable levels in the gastrointestinal tract of both treated and untreated animals. Tissue viral DNA levels correlated with week 1 plasma viremia, suggesting that tissues that harbor proviral DNA are established within the first week of infection. PBMC vDNA levels did not correlate with plasma viremia or tissue levels of vDNA. vRNA levels were high in lymphoid and gastrointestinal tissues of the untreated animals; animals on ART had little vRNA expressed in tissues and virus could not be cultured from lymph node resting CD4+ cells after 17-20 weeks on ART, indicating little or no ongoing viral replication. Strategies for eradication of HIV-1 will need to target residual virus in ART suppressed individuals, which may not be accurately reflected by frequencies of infected cells in blood. © 2013 Kline et al

A CLASP-modulated cell edge barrier mechanism drives cell-wide cortical microtubule organization in Arabidopsis

It is well known that the parallel order of microtubules in the plant cell cortex defines the direction of cell expansion, yet it remains unclear how microtubule orientation is controlled, especially on a cell-wide basis. Here we show through 4D imaging and computational modelling that plant cell polyhedral geometry provides spatial input that determines array orientation and heterogeneity. Microtubules depolymerize when encountering sharp cell edges head-on, whereas those oriented parallel to those sharp edges remain. Edge-induced microtubule depolymerization, however, is overcome by the microtubule-associated protein CLASP, which accumulates at specific cell edges, enables microtubule growth around sharp edges and promotes formation of microtubule bundles that span adjacent cell faces. By computationally modelling dynamic 'microtubules on a cube' with edges differentially permissive to microtubule passage, we show that the CLASP-edge complex is a 'tuneable' microtubule organizer, with the inherent flexibility to generate the numerous cortical array patterns observed in nature