Beneficial and adverse effects of testosterone on the cardiovascular system in men

Context: The widespread use of T therapy, particularly in aging males, necessitates knowledge of the relationship between T and the cardiovascular system. Evidence Acquisition: The review is based on a 1970 to 2013 PubMed search with terms related to androgens in combination with cardiovascular disease, including T, dihydrotestosterone, trial, mortality, cardiovascular disease, myocardial infarction, blood pressure, endothelial function, dyslipidemia, thrombosis, ventricular function, and arrhythmia. Original articles, systematic reviews and meta-analyses, and relevant citations were screened. Evidence Synthesis: Low T has been linked to increased blood pressure, dyslipidemia, atherosclerosis, arrhythmia, thrombosis, endothelial dysfunction, as well as to impaired left ventricular function. On the one hand, a modest association is suggested between low endogenous T and incident cardiovascular disease or cardiovascular mortality, implying unrecognized beneficial T effects, residual confounding, or a relationship with health status. On the other hand, treatments with T to restore "normal concentrations" have so far not been proven to be beneficial with respect to cardiovascular disease; neither have they definitely shown specific adverse cardiovascular effects. The cardiovascular risk-benefit profile of T therapy remains largely evasive in view of a lack of well-designed and adequately powered randomized clinical trials. Conclusions: The important knowledge gap as to the exact relationship between T and cardiovascular disease would support a cautious, restrained approach to T therapy in aging men, pending clarification of benefits and risks by adequately powered clinical trials of sufficient duration

Signaling by insulin receptors and related protein tyrosine kinases

The insulin receptor is a member of the largely expanding family of plasma membrane receptors. In general, ligand binding induces receptor dimerization leading to activation and tyrosine phosphorylation of the cytoplasmic catalytic domain of the receptor. Activation of receptor tyrosine kinases leads to several cellular responses like proliferation, differentiation and survival. The insulin receptor family distinguishes from the other receptor tyrosine kinases in that it also mediates a metabolic response like stimulation of glucose uptake and glycogen synthesis. In this review the general principles of signaling by receptor tyrosine kinases are discussed. Besides, we point out the signaling pathways used by the insulin receptor itself.Biomedical Reviews 1996; 5: 5-30

Insulin resistance associates with hepatic lobular inflammation in subjects with obesity

Purpose: Obese subjects with nonalcoholic fatty liver disease (NAFLD) are more prone to develop additional metabolic disturbances such as systemic insulin resistance (IR) and type 2 diabetes. NAFLD is defined by hepatic steatosis, lobular inflammation, ballooning and stage of fibrosis, but it is unclear if and which components could contribute to IR. Objective: To assess which histological components of NAFLD associate with IR in subjects with obesity, and if so, to what extent. Methods: This cross-sectional study included 78 obese subjects (mean age 46 +/- 11 years; BMI 42.2 +/- 4.7 kg/m(2)). Glucose levels were analysed by hexokinase method and insulin levels with electrochemiluminescence. Homeostasis model assessment-estimated insulin resistance (HOMA-IR) was calculated. Liver biopsies were evaluated for histological components of NAFLD. Results: A positive association between overall NAFLD Activity Score and HOMA-IR was found (r(s) = 0.259, P = 0.022). As per individual components, lobular inflammation and fibrosis stage were positively associated with HOMA-IR, glucose and insulin levels (P < 0.05), and HOMA-IR was higher in patients with more inflammatory foci or higher stage of fibrosis. These findings were independent of age, BMI, triglyceride levels, diabetes status and sex (all P < 0.043). In a combined model, lobular inflammation, but not fibrosis, remained associated with HOMA-IR. Conclusion: In this group of obese subjects, a major contributing histological component of NAFLD to the relation between NAFLD severity and IR seems to be the grade of hepatic lobular inflammation. Although no causal relationship was assessed, preventing or mitigating this inflammatory response in obesity might be of importance in controlling obesity-related metabolic disturbances

Extrapolating Survival Data Using Historical Trial-Based a Priori Distributions

Objectives: To show how clinical trial data can be extrapolated using historical trial data-based a priori distributions. Methods: Extrapolations based on 30-month pivotal multiplemyeloma trial data were compared with 75-month data from the same trial. The 30-month data represent a typical decision-making scenario where early results from a clinical trial are extrapolated. Mature historical trial data with the same comparator as in the pivotal trial were incorporated in 2 stages. First, the parametric distribution selection was based on the historical trial data. Second, the shape parameter estimate of the historical trial was used to define an informative a priori distribution for the shape of the 30-month pivotal trial data. The method was compared with standard approaches, fitting parametric distributions to the 30-month data with noninformative prior. The predicted survival of each method was compared with the observed survival (DAUC) in the 75-month trial data. Results: The Weibull had the best fit to the historical trial and the log-normal to the 30-month pivotal trial data. The DAUC of the Weibull with informative priors was considerably smaller compared with the standard Weibull. Also, the predicted median survival based on the Weibull with informative priors was more accurate (melphalan and prednisone [MP] 40 months, and bortezomib [V] combined with MP [VMP] 62 months) than based on the standard Weibull (MP 45 months and VMP 72 months) when compared with the observed median (MP 41.3 months and VMP 56.4 months). Conclusions: Extrapolation of clinical trial data is improved by using historical trial data-based informative a priori distributions

Eating style, television viewing and snacking in pre-adolescent children

Introduction: Television viewing is considered to be a risk factor for overweight in children because of its association with reduced physical activity and increased calorie intake. Objective: The aim of the present study is to examine whether eating styles affect the relationship between television viewing (TV-viewing) and snacking. Method: In a sample of 962 pre-adolescents, selfreported television viewing and snacking were assessed in relation to dietary restraint, external eating and emotional eating, as measured with the child version of the Dutch Eating Behavior Questionnaire. With regression analyses we assessed the possible moderating role of emotional, external and restrained eating on the relation between TV-viewing and snacking. In all analyses we controlled for age, sex, BMI and the possible confounding effects of the other eating styles. Results: Emotional eating, and not dietary restraint or external eating, moderated the relationship between TVviewing and snacking. Conclusion: TV-viewing seems to be more strongly related to snacking in children with higher levels of emotional eating. TV-viewing may also be a risk factor for the development of emotional eating