HLA-C cell surface expression and control of HIV/AIDS correlate with a variant upstream of HLA-C.

A variant 35 kb upstream of the HLA-C gene (-35C/T) was previously shown to associate with HLA-C mRNA expression level and steady-state plasma HIV RNA levels. We genotyped this variant in 1,698 patients of European ancestry with HIV. Individuals with known seroconversion dates were used for disease progression analysis and those with longitudinal viral load data were used for viral load analysis. We further tested cell surface expression of HLA-C in normal donors using an HLA-C-specific antibody. We show that the -35C allele is a proxy for high HLA-C cell surface expression, and that individuals with high-expressing HLA-C alleles progress more slowly to AIDS and control viremia significantly better than individuals with low HLA-C expressing alleles. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells.

Serum androgen levels in elite female athletes.

OBJECTIVE: Prior to the implementation of the blood steroidal module of the Athlete Biological Passport, we measured the serum androgen levels among a large population of high-level female athletes as well as the prevalence of biochemical hyperandrogenism and some disorders of sex development (DSD). METHODS AND RESULTS: In 849 elite female athletes, serum T, dehydroepiandrosterone sulphate, androstenedione, SHBG, and gonadotrophins were measured by liquid chromatography-mass spectrometry high resolution or immunoassay. Free T was calculated. The sampling hour, age, and type of athletic event only had a small influence on T concentration, whereas ethnicity had not. Among the 85.5% that did not use oral contraceptives, 168 of 717 athletes were oligo- or amenorrhoic. The oral contraceptive users showed the lowest serum androgen and gonadotrophin and the highest SHBG concentrations. After having removed five doped athletes and five DSD women from our population, median T and free T values were close to those reported in sedentary young women. The 99th percentile for T concentration was calculated at 3.08 nmol/L, which is below the 10 nmol/L threshold used for competition eligibility of hyperandrogenic women with normal androgen sensitivity. Prevalence of hyperandrogenic 46 XY DSD in our athletic population is approximately 7 per 1000, which is 140 times higher than expected in the general population. CONCLUSION: This is the first study to establish normative serum androgens values in elite female athletes, while taking into account the possible influence of menstrual status, oral contraceptive use, type of athletic event, and ethnicity. These findings should help to develop the blood steroidal module of the Athlete Biological Passport and to refine more evidence-based fair policies and recommendations concerning hyperandrogenism in female athletes.

Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

SITC 26th annual meeting - summary.

ABSTRACT: The 26th annual meeting of the Society for Immunotherapy of Cancer took place in Bethesda on November 4 to 6, 2011 and was organized by Charles G. Drake (Johns Hopkins University) Dolores J. Schendel (Helmholtz Zentrum Muenchen - German Research Center for Environmental Health Institute of Molecular Immunology), Jeffrey Schlom (National Cancer Institute, National Institutes of Health), and Jedd D. Wolchok (Memorial Sloan-Kettering Cancer Center). It was an event marked by a number of extraordinary circumstances: it attracted a record attendance of 805 participants from 24 different countries. The gathering came in the wake of great as well as very sad news for the tumor immunology community. Good news included the approval of anti-CTLA-4 as a therapy for metastatic melanoma in April and the announcement in early October of the Nobel Prize in Physiology and Medicine awarded to pioneering studies in the field of immunology. Indeed, one part of the prize went to Dr. Bruce Beutler, Scripps Research Institute, La Jolla, USA and Dr. Jules Hoffman, Institute for Molecular Cell Biology, Strasbourg, France, for their discoveries in innate immunity and the other part to Dr. Ralph Steinman, The Rockfeller University, New York, for his discovery of dendritic cells. Sad news was the losses of two giants in the field. Jürg Tschopp of the University of Lausanne in March and Ralph Steinman, who passed away just three days before his Nobel Prize announcement. The loss of these two charismatic scientific leaders was particularly sad for the Annual Meeting as both J. Tschopp and R. Steinman were confirmed speakers at this meeting: the former to deliver the keynote lecture and the latter as recipient of the Richard V. Smalley prize.

Les divers sens de la notion d'autonomie en médecine et leur pertinence en clinique [The various senses of autonomy and their relevance to clinical practice]

Since the introduction of the principle of respect of autonomy in medical ethics, the respect of the will of the patient occupied a central place in the decision-making process. To face up to the difficulties that appeared during the application of this principle in clinical medicine, Bruce Miller proposed in the early eighties one way to clarify the significance of this notion in the field of medical practice. He showed that the concept of autonomy can be understood under four senses which deserve to be explored in case of ethical conflict. This article shows, through the analysis of a clinical situation, the relevance of the approach suggested by this author and proposes to refer to this approach in case of ethical dilemmas in clinical practice.

Adiponectin and heme oxygenase-1 suppress TLR4/MyD88-independent signaling in rat Kupffer cells and in mice after chronic ethanol exposure.

Alcoholic liver disease is mediated via activation of TLR4 signaling; MyD88-dependent and -independent signals are important contributors to injury in mouse models. Adiponectin, an anti-inflammatory adipokine, suppresses TLR4/MyD88-dependent responses via induction of heme oxygenase-1 (HO-1). Here we investigated the interactions between chronic ethanol, adiponectin, and HO-1 in regulation of TLR4/MyD88-independent signaling in macrophages and an in vivo mouse model. After chronic ethanol feeding, LPS-stimulated expression of IFN-β and CXCL10 mRNA was increased in primary cultures of Kupffer cells compared with pair-fed control mice. Treatment of Kupffer cells with globular adiponectin (gAcrp) normalized this response. LPS-stimulated IFN-β/CXCL10 mRNA and CXCL10 protein was also reduced in RAW 264.7 macrophages treated with gAcrp or full-length adiponectin. gAcrp and full-length adiponectin acted via adiponectin receptors 1 and 2, respectively. gAcrp decreased TLR4 expression in both Kupffer cells and RAW 264.7 macrophages. Small interfering RNA knockdown of HO-1 or inhibition of HO-1 activity with zinc protoporphyrin blocked these effects of gAcrp. C57BL/6 mice were exposed to chronic ethanol feeding, with or without treatment with cobalt protoporphyrin, to induce HO-1. After chronic ethanol feeding, mice were sensitized to in vivo challenge with LPS, expressing increased IFN-β/CXCL10 mRNA and CXCL10 protein in liver compared with control mice. Pretreatment with cobalt protoporphyrin 24 h before LPS challenge normalized this effect of ethanol. Adiponectin and induction of HO-1 potently suppressed TLR4-dependent/MyD88-independent cytokine expression in primary Kupffer cells from rats and in mouse liver after chronic ethanol exposure. These data suggest that induction of HO-1 may be a useful therapeutic strategy in alcoholic liver disease.

Promoting good practices for handling nanomaterials : an international wiki project

As production and use of nanomaterials in commercial products grow it is imperative to ensure these materials are used safely with minimal unwanted impacts on human health or the environment. Foremost among the populations of potential concern are workers who handle nanomaterials in a variety of occupational settings, including university laboratories, industrial manufacturing plants and other institutions. Knowledge about prudent practices for handling nanomaterials is being developed by many groups around the world but may be communicated in a way that is difficult for practitioners to access or use. The GoodNanoGuide is a collaborative, open-access project aimed at creating an international forum for the development and discussion of prudent practices that can be used by researchers, workers and their representatives, occupational safety professionals, governmental officials and even the public. The GoodNanoGuide is easily accessed by anyone with access to a web browser and aims to become a living repository of good practices for the nanotechnology enterprise. Interested individuals are invited to learn more about the GoodNanoGuide at http://goodnanoguide.org.