The epigenetic impacts of social stress: how does social adversity become biologically embedded?

Epigenetic mechanisms are implicated in the processes through which social stressors erode health in humans and other animals. Here I review progress in elucidating the biological pathways underlying the social gradient in health, with particular emphasis on how behavioral stresses influence epigenomic variation linked to health. The evidence that epigenetic changes are involved in embedding of social status-linked chronic stress is reviewed in the context of current knowledge about behavior within animal dominance hierarchies and the impacts of social position on behaviors that affect health. The roles of epigenetic mechanisms in responses to trauma and the evidence for their involvement in intergenerational transmission of the biological impacts of traumatic stress are also considered. Taken together, the emerging insights have important implications for development of strategies to improve societal health and well-being

Incorporating clinical guidelines through clinician decision-making

<p>Abstract</p> <p>Background</p> <p>It is generally acknowledged that a disparity between knowledge and its implementation is adversely affecting quality of care. An example commonly cited is the failure of clinicians to follow clinical guidelines. A guiding assumption of this view is that adherence should be gauged by a standard of conformance. At least some guideline developers dispute this assumption and claim that their efforts are intended to inform and assist clinical practice, not to function as standards of performance. However, their ability to assist and inform will remain limited until an alternative to the conformance criterion is proposed that gauges how evidence-based guidelines are incorporated into clinical decisions.</p> <p>Methods</p> <p>The proposed investigation has two specific aims to identify the processes that affect decisions about incorporating clinical guidelines, and then to develop ad test a strategy that promotes the utilization of evidence-based practices. This paper focuses on the first aim. It presents the rationale, introduces the clinical paradigm of treatment-resistant schizophrenia, and discusses an exemplar of clinician non-conformance to a clinical guideline. A modification of the original study is proposed that targets psychiatric trainees and draws on a cognitively rich theory of decision-making to formulate hypotheses about how the guideline is incorporated into treatment decisions. Twenty volunteer subjects recruited from an accredited psychiatry training program will respond to sixty-four vignettes that represent a fully crossed 2 × 2 × 2 × 4 within-subjects design. The variables consist of criteria contained in the clinical guideline and other relevant factors. Subjects will also respond to a subset of eight vignettes that assesses their overall impression of the guideline. Generalization estimating equation models will be used to test the study's principal hypothesis and perform secondary analyses.</p> <p>Implications</p> <p>The original design of phase two of the proposed investigation will be changed in recognition of newly published literature on the relative effectiveness of treatments for schizophrenia. It is suggested that this literature supports the notion that guidelines serve a valuable function as decision tools, and substantiates the importance of decision-making as the means by which general principles are incorporated into clinical practice.</p

Diffuse Gamma Rays: Galactic and Extragalactic Diffuse Emission

"Diffuse" gamma rays consist of several components: truly diffuse emission from the interstellar medium, the extragalactic background, whose origin is not firmly established yet, and the contribution from unresolved and faint Galactic point sources. One approach to unravel these components is to study the diffuse emission from the interstellar medium, which traces the interactions of high energy particles with interstellar gas and radiation fields. Because of its origin such emission is potentially able to reveal much about the sources and propagation of cosmic rays. The extragalactic background, if reliably determined, can be used in cosmological and blazar studies. Studying the derived "average" spectrum of faint Galactic sources may be able to give a clue to the nature of the emitting objects.Comment: 32 pages, 28 figures, kapproc.cls. Chapter to the book "Cosmic Gamma-Ray Sources," to be published by Kluwer ASSL Series, Edited by K. S. Cheng and G. E. Romero. More details can be found at http://www.gamma.mpe-garching.mpg.de/~aws/aws.htm

Discontinuous properties of current-induced magnetic domain wall depinning

The current-induced motion of magnetic domain walls (DWs) confined to nanostructures is of great interest for fundamental studies as well as for technological applications in spintronic devices. Here, we present magnetic images showing the depinning properties of pulse-current-driven domain walls in well-shaped Permalloy nanowires obtained using photoemission electron microscopy combined with X-ray magnetic circular dichroism. In the vicinity of the threshold current density (J th = 4.2 × 10 11 â.A.m-2) for the DW motion, discontinuous DW depinning and motion have been observed as a sequence of "Barkhausen jumps". A one-dimensional analytical model with a piecewise parabolic pinning potential has been introduced to reproduce the DW hopping between two nearest neighbour sites, which reveals the dynamical nature of the current-driven DW motion in the depinning regime

Suppression of Stochastic Domain Wall Pinning Through Control of Gilbert Damping

Finite temperature micromagnetic simulations were used to investigate the magnetisation structure, propagation dynamics and stochastic pinning of domain walls in rare earth-doped Ni80Fe20 nanowires. We first show how the increase of the Gilbert damping, caused by the inclusion rare-earth dopants such as holmium, acts to suppress Walker breakdown phenomena. This allows domain walls to maintain consistent magnetisation structures during propagation. We then employ finite temperature simulations to probe how this affects the stochastic pinning of domain walls at notch-shaped artificial defect sites. Our results indicate that the addition of even a few percent of holmium allows domain walls to pin with consistent and well-defined magnetisation configurations, thus suppressing dynamically-induced stochastic pinning/depinning phenomena. Together, these results demonstrate a powerful, materials science-based solution to the problems of stochastic domain wall pinning in soft ferromagnetic nanowires

Higher pre-infection vitamin E levels are associated with higher mortality in HIV-1-infected Kenyan women: a prospective study

Background: Low vitamin E levels are often found in HIV-1 infection, and studies have suggested that higher levels may decrease the risk of disease progression. However, vitamin E supplementation has also been reported to increase CCR5 expression, which could increase HIV- 1 replication. We hypothesized that vitamin E levels at HIV-1 acquisition may influence disease progression. Methods: Vitamin E status was measured in stored samples from the last pre-infection visit for 67 Kenyan women with reliably estimated dates of HIV-1 acquisition. Regression analyses were used to estimate associations between pre-infection vitamin E and plasma viral load, time to CD4 count less than 200 cells/[micro]L, and mortality. Results: After controlling for potential confounding factors, each 1 mg/L increase in pre-infection vitamin E was associated with 0.08 log[sub]10 copies/mL (95% CI -0.01 to +0.17) higher set point viral load and 1.58-fold higher risk of mortality (95% CI 1.15�2.16). The association between higher preinfection vitamin E and mortality persisted after adjustment for set point viral load (HR 1.55, 95% CI 1.13�2.13). Conclusion: Higher pre-infection vitamin E levels were associated with increased mortality. Further research is needed to elucidate the role vitamin E plays in HIV-1 pathogenesis.This research was supported by National Institutes of Health grants AI-43844 and AI-38518 (all authors), and Fogarty International Center grant D43 TW000007 (SMG)

Low serum albumin and the acute phase response predict low serum selenium in HIV-1 infected women

BACKGROUND: Low serum selenium has been associated with lower CD4 counts and greater mortality among HIV-1-seropositive individuals, but most studies have not controlled for serum albumin and the presence of an acute phase response. METHODS: A cross-sectional study was conducted to evaluate relationships between serum selenium concentrations and CD4 count, plasma viral load, serum albumin, and acute phase response markers among 400 HIV-1-seropositive women. RESULTS: In univariate analyses, lower CD4 count, higher plasma viral load, lower albumin, and the presence of an acute phase response were each significantly associated with lower serum selenium concentrations. In multivariate analyses including all four of these covariates, only albumin remained significantly associated with serum selenium. For each 0.1 g/dl increase in serum albumin, serum selenium increased by 0.8 μg/l (p < 0.001). Women with an acute phase response also had lower serum selenium (by 5.6 μg/l, p = 0.06). CONCLUSION: Serum selenium was independently associated with serum albumin, but not with CD4 count or plasma viral load, in HIV-1-seropositive women. Our findings suggest that associations between lower serum selenium, lower CD4 count, and higher plasma viral load may be related to the frequent occurrence of low serum albumin and the acute phase response among individuals with more advanced HIV-1 infection

Micronutrient malnutrition and wasting in adults with pulmonary tuberculosis with and without HIV co-infection in Malawi

BACKGROUND: Wasting and micronutrient malnutrition have not been well characterized in adults with pulmonary tuberculosis. We hypothesized that micronutrient malnutrition is associated with wasting and higher plasma human immunodeficiency virus (HIV) load in adults with pulmonary tuberculosis. METHODS: In a cross-sectional study involving 579 HIV-positive and 222 HIV-negative adults with pulmonary tuberculosis in Zomba, Malawi, anthropometry, plasma HIV load and plasma micronutrient concentrations (retinol, α-tocopherol, carotenoids, zinc, and selenium) were measured. The risk of micronutrient deficiencies was examined at different severity levels of wasting. RESULTS: Body mass index (BMI), plasma retinol, carotenoid and selenium concentrations significantly decreased by increasing tertile of plasma HIV load. There were no significant differences in plasma micronutrient concentrations between HIV-negative individuals and HIV-positive individuals who were in the lowest tertile of plasma HIV load. Plasma vitamin A concentrations <0.70 μmol/L occurred in 61%, and zinc and selenium deficiency occurred in 85% and 87% respectively. Wasting, defined as BMI<18.5 was present in 59% of study participants and was independently associated with a higher risk of low carotenoids, and vitamin A and selenium deficiency. Severe wasting, defined as BMI<16.0 showed the strongest associations with deficiencies in vitamin A, selenium and plasma carotenoids. CONCLUSIONS: These data demonstrate that wasting and higher HIV load in pulmonary tuberculosis are associated with micronutrient malnutrition

Linkage between fitness of yeast cells and adenylate kinase catalysis

Enzymes have evolved with highly specific values of their catalytic parameters kcat and KM. This poses fundamental biological questions about the selection pressures responsible for evolutionary tuning of these parameters. Here we are address these questions for the enzyme adenylate kinase (Adk) in eukaryotic yeast cells. A plasmid shuffling system was developed to allow quantification of relative fitness (calculated from growth rates) of yeast in response to perturbations of Adk activity introduced through mutations. Biophysical characterization verified that all variants studied were properly folded and that the mutations did not cause any substantial differences to thermal stability. We found that cytosolic Adk is essential for yeast viability in our strain background and that viability could not be restored with a catalytically dead, although properly folded Adk variant. There exist a massive overcapacity of Adk catalytic activity and only 12% of the wild type kcat is required for optimal growth at the stress condition 20°C. In summary, the approach developed here has provided new insights into the evolutionary tuning of kcat for Adk in a eukaryotic organism. The developed methodology may also become useful for uncovering new aspects of active site dynamics and also in enzyme design since a large library of enzyme variants can be screened rapidly by identifying viable colonies