21 research outputs found

    Interaction between FKBP5 Variability and Recent Life Events in the Anxiety Spectrum: Evidence for the Differential Susceptibility Model',

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    Background Gene-environment interaction (GxE) research has highlighted the importance of investigating the FK506 binding protein 51 (FKBP5) gene as a sensitivity gene. However, previous GxE studies with FKBP5 have not measured the full environmental spectrum or applied statistical tests to discern whether the GxE interaction fits better with the differential-susceptibility or diathesis-stress hypotheses. This study examined whether single nucleotide polymorphisms (SNPs) on FKBP5 gene moderate the association of positive and negative recent life events (LEs) with depressive symptoms, state-anxiety, neuroticism, and social anxiety traits. Methods A total of 86 nonclinical young adults were administered psychological measures and were genotyped for five FKBP5 SNPs (rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916). Results Regression analyses indicated significant GxE interactions for social anxiety and neuroticism. The interactions predicting neuroticism fit different models for different SNPs, although the overall effect indicated by the haplotype was consistent with the differential-susceptibility hypothesis: the risk-haplotype group presented higher neuroticism in the presence of more negative LEs and lower neuroticism in the presence of more positive LEs. The GxE interactions for social anxiety were consistent with the diathesis-stress model. The lack of significance in the for-better side for social anxiety might be related to the fact that it mapped onto low extraversion, which is associated with a lower permeability to positive experiences. Discussion Findings underscore the importance of testing the differential-susceptibility model in relation to FKBP5 to adequately characterize its role in healthy and pathological developmental processes

    Inhibition of circulating immune cell activation: a molecular antiinflamatory effect of the mediterranean diet.

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    Background: Adherence to the Mediterranean diet (Med-Diet) is associated with a reduced risk of cardiovascular disease (CVD). However, the molecular mechanisms involved are not fully understood. Objective: The objective was to compare the effects of 2 Med-Diets with those of a low-fat diet on immune cell activation and soluble inflammatory biomarkers related to atherogenesis in subjects at high risk of CVD. Design: In a controlled study, we randomly assigned 112 older subjects with diabetes or 3 CVD risk factors to 3 dietary intervention groups: Med-Diet with supplemental virgin olive oil (VOO), Med-Diet with supplemental nuts, and low-fat diet. Changes from baseline in cellular and serum inflammatory biomarkers were assessed at 3 mo. Results: One hundred six participants (43% women; average age: 68 y) completed the study. At 3 mo, monocyte expression of CD49d, an adhesion molecule crucial for leukocyte homing, and of CD40, a proinflammatory ligand, decreased (P , 0.05) after both Med-Diets but not after the low-fat diet. Serum interleukin-6 and soluble intercellular adhesion molecule-1, inflammatory mediators crucial in firm adhesion of leukocytes to endothelial surfaces, decreased (P ,0.05) in both Med-Diet groups. Soluble vascular cellular adhesion molecule-1 and C-reactive protein decreased only after the Med-Diet with VOO (P , 0.05), whereas interleukin-6, soluble vascular cellular adhesion molecule-1, and soluble intercellular adhesion molecule- 1 increased (P ,0.05) after the low-fat diet. Conclusions: Med-Diets supplemented with VOO or nuts downregulate cellular and circulating inflammatory biomarkers related to atherogenesis in subjects at high risk of CVD. The results support the recommendation of the Med-Diet as a useful tool against CVD

    Antiviral efficacy of NS3-serine protease inhibitor BILN-2061 in patients with chronic genotype 2 and 3 hepatitis C

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    BILN-2061, a specific and potent peptidomimetic inhibitor of the HCV NS3 protease, has recently been shown to markedly lower serum hepatitis C virus (HCV)-RNA levels in patients chronically infected with HCV genotype 1 in three 2-day proof of principle studies. The aim of the current study was to assess the antiviral efficacy of BILN-2061 in patients with genotypes 2 and 3 HCV infection. The antiviral efficacy, pharmacokinetics, and tolerability of 500 mg twice-daily BILN-2061 given as monotherapy for 2 days in 10 patients chronically infected with non-genotype 1 HCV (genotype 2: n = 3; genotype 3: n =7) and minimal liver fibrosis (Ishak score 0-2) were assessed in a placebo-controlled (placebo n = 2), double-blind pilot study. HCV-RNA levels decreased by > or =1 log(10) copies/mL in 4 of 8 patients treated with BILN-2061. One patient showed a weak response of <1 log(10) copies/mL. Three of 8 treated patients showed no response. There was no correlation between baseline viral concentration or genotype and response. BILN-2061 exhibited good systemic exposure after oral administration and was well tolerated. In conclusion, the antiviral efficacy of the HCV serine protease inhibitor BILN-2061 is less pronounced and more variable in patients with HCV genotype 2 or 3 infection compared with previous results in patients with HCV genotype 1. A lower affinity of BILN-2061 for the NS3 protease of genotypes 2 and 3 HCV is most likely a major contributor to these finding

    Interaction between FKBP5 Variability and Recent Life Events in the Anxiety Spectrum: Evidence for the Differential Susceptibility Model',

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    Background Gene-environment interaction (GxE) research has highlighted the importance of investigating the FK506 binding protein 51 (FKBP5) gene as a sensitivity gene. However, previous GxE studies with FKBP5 have not measured the full environmental spectrum or applied statistical tests to discern whether the GxE interaction fits better with the differential-susceptibility or diathesis-stress hypotheses. This study examined whether single nucleotide polymorphisms (SNPs) on FKBP5 gene moderate the association of positive and negative recent life events (LEs) with depressive symptoms, state-anxiety, neuroticism, and social anxiety traits. Methods A total of 86 nonclinical young adults were administered psychological measures and were genotyped for five FKBP5 SNPs (rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916). Results Regression analyses indicated significant GxE interactions for social anxiety and neuroticism. The interactions predicting neuroticism fit different models for different SNPs, although the overall effect indicated by the haplotype was consistent with the differential-susceptibility hypothesis: the risk-haplotype group presented higher neuroticism in the presence of more negative LEs and lower neuroticism in the presence of more positive LEs. The GxE interactions for social anxiety were consistent with the diathesis-stress model. The lack of significance in the for-better side for social anxiety might be related to the fact that it mapped onto low extraversion, which is associated with a lower permeability to positive experiences. Discussion Findings underscore the importance of testing the differential-susceptibility model in relation to FKBP5 to adequately characterize its role in healthy and pathological developmental processes

    Interaction between <i>FKBP5</i> variability and recent life events in the anxiety spectrum: Evidence for the differential susceptibility model

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    <div><p>Background</p><p>Gene-environment interaction (GxE) research has highlighted the importance of investigating the FK506 binding protein 51 (<i>FKBP5</i>) gene as a sensitivity gene. However, previous GxE studies with <i>FKBP5</i> have not measured the <i>full</i> environmental spectrum or applied statistical tests to discern whether the GxE interaction fits better with the differential-susceptibility or diathesis-stress hypotheses. This study examined whether single nucleotide polymorphisms (SNPs) on <i>FKBP5</i> gene moderate the association of positive and negative recent life events (LEs) with depressive symptoms, state-anxiety, neuroticism, and social anxiety traits.</p><p>Methods</p><p>A total of 86 nonclinical young adults were administered psychological measures and were genotyped for five <i>FKBP5</i> SNPs (rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916).</p><p>Results</p><p>Regression analyses indicated significant GxE interactions for social anxiety and neuroticism. The interactions predicting neuroticism fit different models for different SNPs, although the overall effect indicated by the haplotype was consistent with the differential-susceptibility hypothesis: the risk-haplotype group presented higher neuroticism in the presence of more negative LEs and lower neuroticism in the presence of more positive LEs. The GxE interactions for social anxiety were consistent with the diathesis-stress model. The lack of significance in the for-better side for social anxiety might be related to the fact that it mapped onto low extraversion, which is associated with a lower permeability to positive experiences.</p><p>Discussion</p><p>Findings underscore the importance of testing the differential-susceptibility model in relation to <i>FKBP5</i> to adequately characterize its role in healthy and pathological developmental processes.</p></div

    Metabolic, mitochondrial, renal and hepatic safety of enfuvirtide and raltegravir antiretroviral administration: Randomized crossover clinical trial in healthy volunteers

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    Context: Classical antiretroviral agents may acutely impact on metabolic, mitochondrial, renal and hepatic function in HIV-infected and uninfected persons. Fusion and integrase inhibitors are supposed to be safer, but have been scarcely investigated. To avoid any interference with HIV or other antiretrovirals, we assessed markers of these toxicities in healthy adult volunteers treated with Enfuvirtide (T20) or Raltegravir (RAL). Methods: Twenty-six healthy participants were randomized to T20/90mg vs. placebo (n = 12) or RAL/400mg vs. placebo (n = 14) every 12h in two 7-day periods separated by a 4-week washout period. Major end-points were changes in lipid profile (total cholesterol, high-density-lipoprotein (HDL)-cholesterol, low-density-lipoprotein (LDL)-cholesterol, triglycerides), insulin resistance (glucose) and mitochondrial toxicity (mitochondrial DNA content-mtDNA-in peripheral blood mononuclear cells). Renal and hepatic toxicity (creatinine, alanine transaminase (AST), alanine aminotransferase (ALT), bilirubin and total plasma proteins) and overall safety were also analysed. Effect of period, treatment, and basal measures were evaluated for each end-point. Results: Neither T20-administration nor RAL-administration yielded to any statistic significant change in the markers of metabolic, mitochondrial, renal or hepatic toxicity assessed. No symptoms indicative of drug toxicity were neither found in any subject. Conclusions: In absence of HIV infection, or concomitant treatment, short-term exposure to T20 or RAL in healthy adult volunteers did not lead to any indicative changes in toxicity markers thus presuming the safe profile of both drugs

    The three significant interactions of FKBP5 variants with recent live events (LESms) for social anxiety, with Regions of significance on X (shaded areas).

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    <p><b>Description:</b> Blue lines represent nonrisk-groups and black lines risk-groups. All 3 graphs demonstrate a diathesis-stress effect: the risk-groups only differed from the nonrisk-groups by showing significantly <i>higher</i> social anxiety if they experienced more negative life events. All graphs were plotted at 2 <i>SD</i> from the mean of LESms (range; -1.401, 2.532).</p
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