156 research outputs found

    A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

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    This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

    Societal-level versus individual-level predictions of ethical behavior: a 48-society study of collectivism and individualism

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    Is the societal-level of analysis sufficient today to understand the values of those in the global workforce? Or are individual-level analyses more appropriate for assessing the influence of values on ethical behaviors across country workforces? Using multi-level analyses for a 48-society sample, we test the utility of both the societal-level and individual-level dimensions of collectivism and individualism values for predicting ethical behaviors of business professionals. Our values-based behavioral analysis indicates that values at the individual-level make a more significant contribution to explaining variance in ethical behaviors than do values at the societal-level. Implicitly, our findings question the soundness of using societal-level values measures. Implications for international business research are discussed

    Short-Lived Trace Gases in the Surface Ocean and the Atmosphere

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    The two-way exchange of trace gases between the ocean and the atmosphere is important for both the chemistry and physics of the atmosphere and the biogeochemistry of the oceans, including the global cycling of elements. Here we review these exchanges and their importance for a range of gases whose lifetimes are generally short compared to the main greenhouse gases and which are, in most cases, more reactive than them. Gases considered include sulphur and related compounds, organohalogens, non-methane hydrocarbons, ozone, ammonia and related compounds, hydrogen and carbon monoxide. Finally, we stress the interactivity of the system, the importance of process understanding for modeling, the need for more extensive field measurements and their better seasonal coverage, the importance of inter-calibration exercises and finally the need to show the importance of air-sea exchanges for global cycling and how the field fits into the broader context of Earth System Science

    Effectiveness of Terbutaline Pump for the Prevention of Preterm Birth. A Systematic Review and Meta-Analysis

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    Subcutaneous terbutaline (SQ terbutaline) infusion by pump is used in pregnant women as a prolonged (beyond 48-72 h) maintenance tocolytic following acute treatment of preterm contractions. The effectiveness and safety of this maintenance tocolysis have not been clearly established. We aimed to systematically evaluate the effectiveness and safety of subcutaneous (SQ) terbutaline infusion by pump for maintenance tocolysis.MEDLINE, EMBASE, CINAHL, the Cochrane Library, the Centre for Reviews and Dissemination databases, post-marketing surveillance data and grey literature were searched up to April 2011 for relevant experimental and observational studies. Two randomized trials, one nonrandomized trial, and 11 observational studies met inclusion criteria. Non-comparative studies were considered only for pump-related harms. We excluded case-reports but sought FDA summaries of post-marketing surveillance data. Non-English records without an English abstract were excluded. Evidence of low strength from observational studies with risk of bias favored SQ terbutaline pump for the outcomes of delivery at <32 and <37 weeks, mean days of pregnancy prolongation, and neonatal death. Observational studies of medium to high risk of bias also demonstrated benefit for other surrogate outcomes, such as birthweight and neonatal intensive care unit (NICU) admission. Several cases of maternal deaths and maternal cardiovascular events have been reported in patients receiving terbutaline tocolysis.Although evidence suggests that pump therapy may be beneficial as maintenance tocolysis, our confidence in its validity and reproducibility is low, suggesting that its use should be limited to the research setting. Concerns regarding safety of therapy persist

    Biologic Treatments for Sports Injuries II Think Tank-Current Concepts, Future Research, and Barriers to Advancement, Part 2:Rotator Cuff

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    Rotator cuff tears are common and result in considerable morbidity. Tears within the tendon substance or at its insertion into the humeral head represent a considerable clinical challenge because of the hostile local environment that precludes healing. Tears often progress without intervention, and current surgical treatments are inadequate. Although surgical implants, instrumentation, and techniques have improved, healing rates have not improved, and a high failure rate remains for large and massive rotator cuff tears. The use of biologic adjuvants that contribute to a regenerative microenvironment have great potential for improving healing rates and function after surgery. This article presents a review of current and emerging biologic approaches to augment rotator cuff tendon and muscle regeneration focusing on the scientific rationale, preclinical, and clinical evidence for efficacy, areas for future research, and current barriers to advancement and implementation

    In Vitro Downregulation of Matrix Metalloproteinase-9 in Rat Glial Cells by CCR5 Antagonist Maraviroc: Therapeutic Implication for HIV Brain Infection

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    BACKGROUND: Matrix metalloproteinases (MMPs) released by glial cells are important mediators of neuroinflammation and neurologic damage in HIV infection. The use of antiretroviral drugs able to combat the detrimental effect of chronic inflammation and target the exaggerated MMP activity might represent an attractive therapeutic challenge. Recent studies suggest that CCR5 antagonist maraviroc (MVC) exerts immunomodulant and anti-inflammatory activity beyond its anti-HIV properties. We investigated the in vitro effect of MVC on the activity of MMPs in astrocyte and microglia cultures. METHODOLOGY/PRINCIPAL FINDINGS: Primary cultures of rat astrocytes and microglia were activated by exposure to phorbol myristate acetate (PMA) or lypopolysaccharide (LPS) and treated in vitro with MVC. Culture supernatants were subjected to gelatin zymography and quantitative determination of MMP-9 and MMP-2 was done by computerized scanning densitometry. MMP-9 levels were significantly elevated in culture supernatants from both LPS- and PMA-activated astrocytes and microglia in comparison to controls. The treatment with MVC significantly inhibited in a dose-dependent manner the levels and expression of MMP-9 in PMA-activated astrocytes (p&lt;0,05) and, to a lesser extent, in PMA-activated microglia. By contrast, levels of MMP-2 did not significantly change, although a tendency to decrease was seen in PMA-activated astrocytes after treatment with MVC. The inhibition of levels and expression of MMP-9 in PMA-activated glial cells did not depend on cytotoxic effects of MVC. No inhibition of MMP-9 and MMP-2 were found in both LPS-activated astrocytes and microglia. CONCLUSIONS: The present in vitro study suggests that CCR5 antagonist compounds, through their ability to inhibit MMP-9 expression and levels, might have a great potential for the treatment of HIV-associated neurologic damage

    Factors Affecting Population Dynamics of Maternally Transmitted Endosymbionts in Bemisia tabaci

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    While every individual of Bemisia tabaci (Hemiptera: Aleyrodidae) harbors the primary symbiont (P-symbiont) Portiera, the infection frequencies of the six secondary symbionts (S-symbionts) including Hamiltonella, Arsenophonus, Cardinium, Wolbachia, Rickettsia and Fritschea vary greatly among different populations. To characterize the factors influencing the infection dynamics of the six S-symbionts in B. tabaci, gene-specific PCR were conducted to screen for the presence of the P-symbiont Portiera and the six S-symbionts in 61 (17 B and 44 Q biotypes) field populations collected from different plant species and locations in China. All individuals of the 61 populations hosted the P-symbiont Portiera, but none of them harbored Arsenophonus and Fritschea. The presence and infection rates of Hamiltonella, Cardinium, Rickettsia, Wolbachia and their co-infections Rickettsia + Hamiltonella (RH), Rickettsia + Cardinium (RC), Hamiltonella + Cardinium (HC) and Rickettsia + Hamiltonella + Cardinium (RHC) varied significantly among the 61 field populations; and the observed variations can be explained by biotypes, sexes, host plants and geographical locations of these field populations. Taken together, at least three factors including biotype, host plant and geographical location affect the infection dynamics of S-symbionts in B. tabaci
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