Discordant Gene Expression Signatures and Related Phenotypic Differences in Lamin A- and A/C-Related Hutchinson-Gilford Progeria Syndrome (HGPS)

Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder displaying features reminiscent of premature senescence caused by germline mutations in the LMNA gene encoding lamin A and C, essential components of the nuclear lamina. By studying a family with homozygous LMNA mutation (K542N), we showed that HGPS can also be caused by mutations affecting both isoforms, lamin A and C. Here, we aimed to elucidate the molecular mechanisms underlying the pathogenesis in both, lamin A- (sporadic) and lamin A and C-related (hereditary) HGPS. For this, we performed detailed molecular studies on primary fibroblasts of hetero- and homozygous LMNA K542N mutation carriers, accompanied with clinical examinations related to the molecular findings. By assessing global gene expression we found substantial overlap in altered transcription profiles (13.7%; 90/657) in sporadic and hereditary HGPS, with 83.3% (75/90) concordant and 16.7% (15/90) discordant transcriptional changes. Among the concordant ones we observed down-regulation of TWIST2, whose inactivation in mice and humans leads to loss of subcutaneous fat and dermal appendages, and loss of expression in dermal fibroblasts and periadnexial cells from a LMNAK542N/K542N patient further confirming its pivotal role in skin development. Among the discordant transcriptional profiles we identified two key mediators of vascular calcification and bone metabolism, ENPP1 and OPG, which offer a molecular explanation for the major phenotypic differences in vascular and bone disease in sporadic and hereditary HGPS. Finally, this study correlates reduced TWIST2 and OPG expression with increased osteocalcin levels, thereby linking altered bone remodeling to energy homeostasis in hereditary HGPS

Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009

Insulin resistance is a hallmark of type 2 diabetes mellitus and is associated with a metabolic and cardiovascular cluster of disorders (dyslipidaemia, hypertension, obesity [especially visceral], glucose intolerance, endothelial dysfunction), each of which is an independent risk factor for cardiovascular disease (CVD). Multiple prospective studies have documented an association between insulin resistance and accelerated CVD in patients with type 2 diabetes, as well as in non-diabetic individuals. The molecular causes of insulin resistance, i.e. impaired insulin signalling through the phosphoinositol-3 kinase pathway with intact signalling through the mitogen-activated protein kinase pathway, are responsible for the impairment in insulin-stimulated glucose metabolism and contribute to the accelerated rate of CVD in type 2 diabetes patients. The current epidemic of diabetes is being driven by the obesity epidemic, which represents a state of tissue fat overload. Accumulation of toxic lipid metabolites (fatty acyl CoA, diacylglycerol, ceramide) in muscle, liver, adipocytes, beta cells and arterial tissues contributes to insulin resistance, beta cell dysfunction and accelerated atherosclerosis, respectively, in type 2 diabetes. Treatment with thiazolidinediones mobilises fat out of tissues, leading to enhanced insulin sensitivity, improved beta cell function and decreased atherogenesis. Insulin resistance and lipotoxicity represent the missing links (beyond the classical cardiovascular risk factors) that help explain the accelerated rate of CVD in type 2 diabetic patients

Predicting Psychological Distress Among Former Soviet Immigrants

This study investigated whether age, gender, marital status, education, employ ment, length of time in the U.S. and immigration demands (novelty, occupation, language, discrimination, loss, and not feeling at home) were predictors of psychological distress in a sample of 1,647 former Soviet immigrants. Multiple regression analysis indicated that the combined model of demographic and demand of immigration variables was significant. Results indicated that women, older immigrants, those with less than a college education, and those with greater immigration demands related to novelty, language, discrimination, loss, and not feeling at home were most distressed

Full of sound and fury, signifying something : the impact of autonomic arousal on EGM gambling

An experiment was conducted to observe the influence of autonomic arousal on subsequent gambling behavior. Thirty-seven male and 32 female regular Electronic Gaming Machine (EGM) players were recruited through newspaper advertisements. Participants were randomly assigned to either: (1) a control condition, or (2) an experimental condition that introduced a loud white-noise event (80 db) at fixed 120 s intervals throughout the 5-min EGM gambling session. Galvanic Skin Response (GSR) measurements showed that the manipulation was successful in elevating autonomic arousal. The results showed differences in behavioral response to the manipulation based on prior experience with gambling problems. Persons with many gambling problems had lower average bet-sizes in the white-noise condition compared to the control, while those with few or no problems had higher average bet-sizes. The results suggest that arousal may provide different signals to gamblers with few versus many problems. Gamblers with many problems may interpret their arousal as a sign that they will soon lose money, while gamblers with few or no problems may associate feelings of arousal exclusively with winning