Hypercholesterolemia is associated with hyperactive cardiac mTORC1 and mTORC2 signaling

Nutritional excess and hyperlipidemia increase the heart’s susceptibility to ischemic injury. Mammalian target of rapamycin (mTOR) controls the cellular response to nutritional status and may play a role in ischemic injury. To explore the effect of hypercholesterolemia on cardiac mTOR signaling, we assessed mTOR signaling in hypercholesterolemic swine (HC) that are also susceptible to increased cardiac ischemia-reperfusion injury. Yucatan pigs were fed a high-fat/high-cholesterol diet for 4 weeks to induce hypercholesterolemia, and mTOR signaling was measured by immunoblotting and immunofluorescence in the non-ischemic left ventricular area. Total myocardial mTOR and raptor levels were markedly increased in the HC group compared to the normocholesterolemic group, and directly correlated with serum cholesterol levels. mTOR exhibited intense perinuclear staining in myocytes only in the HC group. Hypercholesterolemia was associated with hyperactive signaling upstream and downstream of both mTOR complexes, including myocardial Akt, S6K1, 4EBP1, S6 and PKC-alpha, increased levels of cardiac hypertrophy markers, and a trend toward lower levels of myocardial autophagy. Hypercholesterolemia can now be added to the growing list of conditions associated with aberrant mTOR signaling. Hypercholesterolemia produces a unique profile of alterations in cardiac mTOR signaling, which is a potential target in cardiac diseases associated with hypercholesterolemia and nutritional excess

Effects of gender and ethnicity on outcomes after aortic valve replacement

ObjectiveTo evaluate the clinical outcomes after aortic valve replacement or aortic valve replacement and coronary artery bypass grafting in a large contemporary population, and to determine if outcomes are associated with patient ethnicity and gender status.MethodsUsing the Massachusetts Cardiac Surgery Database, we identified 6809 adults aged 18 years or older who had undergone isolated aortic valve replacement or aortic valve replacement and coronary artery bypass grafting in all non-federal acute-care Massachusetts hospitals from 2002 to 2008. Univariate and multivariate logistic regression analyses were used to identify differences in patient characteristics, major morbidity, and 30-day and 1-year mortality between men (n = 4043) and women (n = 2766) and between whites (n = 6481) and nonwhites (n = 328).ResultsThe unadjusted 30-day mortality rate was 2.6% for the men and 3.1% for the women (P = .296) and 2.8% for whites and 3.7% for nonwhites (P = .342). In adjusted logistic regression models, the 30-day mortality was not different between the female and male patients (odds ratio, 0.88; 95% confidence interval, 0.26–3.02, P = .84) nor between the nonwhites and whites (odds ratio, 1.57; 95% confidence interval, 0.45–5.44; P = .48). The incidence of postoperative stroke was greater in women (3.0% women and 2.2% men, P = .031), and the incidence of postoperative myocardial infarction (10.9% women and 13.6% men; P = .001) and septicemia (1.2% women and 2.0% men; P = .009) was greater in men.ConclusionsEthnicity and gender were not associated with greater 30-day and 1-year mortality after aortic valve replacement or aortic valve replacement and coronary artery bypass grafting. Differences in postoperative outcomes were not observed between ethnic groups

Phosphorylation and translocation of heat shock protein 27 and αB-crystallin in human myocardium after cardioplegia and cardiopulmonary bypass

ObjectivesCardiac surgery using cardioplegia and cardiopulmonary bypass subjects myocardium to hypothermic reversible ischemic injury that can impair cardiac function. Research in animal and cell models demonstrates that acute myocardial ischemia/reperfusion injury causes phosphorylation of heat shock protein 27 and αB-crystallin. Phosphorylation of heat shock protein 27 and αB-crystallin is implicated in the regulation of both beneficial and detrimental responses to ischemic injury. The phosphorylation status of these proteins in human myocardium after ischemic insults associated with cardioplegia and cardiopulmonary bypass is unknown.MethodsRight atrial appendage and chest wall skeletal muscle samples were collected from patients before and after cardioplegia and cardiopulmonary bypass. Cardioplegia and cardiopulmonary bypass-induced changes in phosphorylation and localization of heat shock protein 27 and αB-crystallin were determined using immunoblot and confocal microscopy with total and phospho-specific antibodies.ResultsCardioplegia and cardiopulmonary bypass increased the phosphorylation of heat shock protein 27 on serine 15, 78, and 82, and αB-crystallin on serine 59 and 45, but not serine 19. The majority of heat shock protein 27 and αB-crystallin localized to I-bands of cardiac myofilaments and shifted to a detergent insoluble fraction after cardioplegia and cardiopulmonary bypass. Cardioplegia and cardiopulmonary bypass–induced phosphorylation of specific heat shock protein 27 and αB-crystallin residues were associated with additional subcellular locations. Increases in phosphorylation of heat shock protein 27 and αB-crystallin were negatively correlated with cardiac function after surgery.ConclusionCardiac surgery using cardioplegia and cardiopulmonary bypass is associated with phosphorylation and myofilament translocation of heat shock protein 27 and αB-crystallin in human myocardium. Phosphorylation of specific heat shock protein 27 and αB-crystallin serine residues is associated with distinct localization. Understanding the human myocardial small heat shock protein response may have significant implications for surgical myocardial protection

Insulin treatment enhances the myocardial angiogenic response in diabetes

ObjectiveGrowth factor and cell-based angiogenesis are attractive therapeutic options for diabetic patients with end-stage coronary disease. Reduced collateral vessel formation observed in diabetes is associated with increased expression of anti-angiogenic proteins, angiostatin and endostatin. The aim of this study was to determine the effects of insulin treatment on the diabetic angiogenic response to chronic myocardial ischemia.MethodsYucatan miniswine were treated with alloxan (pancreatic β-cell specific toxin, 150 mg/kg) and divided into two groups. In the diabetic group (DM, n = 8), blood glucose levels were kept greater than 250 mg/dL, and in the insulin-treated group (IDM, n = 6), intramuscular insulin was administered daily to keep blood glucose less than 150 mg/dL. A third group of age-matched swine served as nondiabetic controls (ND; n = 8). Eight weeks later, all animals underwent circumflex artery ameroid constrictor placement to induce chronic ischemia. Myocardial perfusion was assessed at 3 and 7 weeks after ameroid placement using microspheres. Microvascular function, capillary density, and myocardial expression of anti-angiogenic mediators were evaluated.ResultsDiabetic animals exhibited significant impairments in endothelium-dependent microvessel relaxation to adenosine diphosphate and substance P, which were reversed in insulin-treated animals. Collateral-dependent perfusion in the ischemic circumflex territory, which was profoundly reduced in diabetic animals (−0.18 ± 0.02 vs +0.23 ± 0.07 mL · min−1 · g−1; P < .001), improved significantly with insulin treatment (0.12 ± 0.05 mL · min−1 · g−1; P < .01). Myocardial expression of anti-angiogenic proteins, angiostatin and endostatin, showing a 4.3- and 3.6-fold increase in diabetic animals respectively (both P < .01 vs ND), was markedly reduced in insulin-treated animals (2.3- and 1.8-fold vs ND; both P < .01).ConclusionsInsulin treatment successfully reversed diabetic coronary endothelial dysfunction and significantly improved the endogenous angiogenic response. These pro-angiogenic effects may be mediated through downregulation of anti-angiogenic mediators. Insulin therapy appears to be a promising modality to enhance the angiogenic response in diabetic patients

Life satisfaction and residential satisfaction among college students at two Stuttgart universities : first descriptive results of a social science study on patterns of general and specific satisfaction among college students at the Vaihingen and the Hohenheim campus

In diesem Bericht werden erste Ergebnisse einer im Sommersemester 1999 durchgeführten Befragung unter rund 1000 Studierenden am Campus Vaihingen und Hohenheim vorgestellt. Im Zentrum des Interesses der Umfrage standen neben der allgemeinen Lebenszufriedenheit und den Zufriedenheiten der Studierenden in verschiedenen Lebensbereichen die Bewertung und Wahrnehmung der Wohnsituation und des jeweiligen Campus durch die Studierenden. Das Design der Studie wurde so gewählt, dass zum einem ein Vergleich der Situation der Studierenden am Campus Hohenheim und am Campus Vaihingen möglich ist. Zusätzlich ermöglicht das Studiendesign auch Vergleiche zwischen Studierenden, die am Campus wohnen und studieren, mit solchen, die 'nur' am Campus studieren. Die Ergebnisse belegen recht hohe Grade von Zufriedenheiten, die jedoch z.T. sehr deutlich nach verschiedenen sozialen Kontexten variieren. Als auffälligste Ergebnisse sind zu nennen, dass die Studierenden in Vaihingen mit ihrer Campussituation geringer zufrieden sind als die Studierenden in Hohenheim. Zudem zeigen die Analysen zu verschiedenen Bereichszufriedenheiten (u.a. Lebensstandard, Wohnsituation und Studium) und zur allgemeinen Lebenszufriedenheit, dass die Studierenden, die am Campus Vaihingen wohnen und studieren, im Vergleich zu allen anderen Studierenden stets geringere Zufriedenheiten äußern.This report presents first results of a survey among 1000 college students at the Vaihingen and the Hohenheim campus. The study concentrates on patterns of students general and specific life satisfaction. It explores students perception and evaluation of different areas of living at each campus. Due to its research design comparisons can be made between the situation at the Vaihingen and the Hohenheim campus and between students residing at the campus and students residing at other places outside the college area. The results show rather high degrees of satisfaction with variations according to different social contexts of living. The most striking results document higher degrees of satisfaction at the Hohenheim campus than at the Vaihingen campus. Students doing both residing and studying at the Vaihingen campus show the lowest degrees of satisfaction in comparison to all other groups of students concerning general life satisfaction and satisfaction with different area-specific topics (i.e. general standard of living, specific situations of housing and specific situations of studying and acade-mic activities)

Die Zufriedenheit von Stuttgarter Studierenden mit ihrer Lebens- und Wohnsituation: erste deskriptive Ergebnisse einer sozialwissenschaftlichen Studie zu allgemeinen und bereichsspezifischen Zufriedenheiten der Studienrenden des Campus Vaihingen und des Campus Hohenheim

"In diesem Bericht werden erste Ergebnisse einer im Sommersemester 1999 durchgeführten Befragung unter rund 1000 Studierenden am Campus Vaihingen und Hohenheim vorgestellt. Im Zentrum des Interesses der Umfrage standen neben der allgemeinen Lebenszufriedenheit und den Zufriedenheiten der Studierenden in verschiedenen Lebensbereichen die Bewertung und Wahrnehmung der Wohnsituation und des jeweiligen Campus durch die Studierenden. Das Design der Studie wurde so gewählt, dass zum einem ein Vergleich der Situation der Studierenden am Campus Hohenheim und am Campus Vaihingen möglich ist. Zusätzlich ermöglicht das Studiendesign auch Vergleiche zwischen Studierenden, die am Campus wohnen und studieren, mit solchen, die 'nur' am Campus studieren. Die Ergebnisse belegen recht hohe Grade von Zufriedenheiten, die jedoch z.T. sehr deutlich nach verschiedenen sozialen Kontexten variieren. Als auffälligste Ergebnisse sind zu nennen, dass die Studierenden in Vaihingen mit ihrer Campussituation geringer zufrieden sind als die Studierenden in Hohenheim. Zudem zeigen die Analysen zu verschiedenen Bereichszufriedenheiten (u.a. Lebensstandard, Wohnsituation und Studium) und zur allgemeinen Lebenszufriedenheit, dass die Studierenden, die am Campus Vaihingen wohnen und studieren, im Vergleich zu allen anderen Studierenden stets geringere Zufriedenheiten äußern." (Autorenreferat)"This report presents first results of a survey among 1000 college students at the Vaihingen and the Hohenheim campus. The study concentrates an patterns of students' general and specific life satisfaction. It explores students' perception and evaluation of different areas of living at each campus. Due to its research design comparisons can be made between the situation at the Vaihingen and the Hohenheim campus and between students residing at the campus and students residing at other places outside the college area. The results show rather high degrees of satisfaction with variations according to different social contexts of living. The most striking results document higher degrees of satisfaction at the Hohenheim campus than at the Vaihingen campus. Students doing both residing and studying at the Vaihingen campus show the lowest degrees of satisfaction in comparison to all other groups of students concerning general life satisfaction and satisfaction with different area-specific topics (i.e. general standard of living, specific situations of housing and specific situations of studying and academic activities)." (author's abstract

Susceptibility sets and the final outcome of collective Reed–Frost epidemics

This paper is concerned with exact results for the final outcome of stochastic SIR (susceptible → infective → recovered) epidemics among a closed, finite and homogeneously mixing population. The factorial moments of the number of initial susceptibles who ultimately avoid infection by such an epidemic are shown to be intimately related to the concept of a susceptibility set. This connection leads to simple, probabilistically illuminating proofs of exact results concerning the total size and severity of collective Reed–Frost epidemic processes, in terms of Gontcharoff polynomials, first obtained in a series of papers by Claude Lef`evre and Philippe Picard. The proofs extend easily to include general final state random variables defined on SIR epidemics, and also to multitype epidemics

Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection.

The present review summarizes the beneficial and detrimental roles of reactive oxygen species in myocardial ischemia/reperfusion injury and cardioprotection. In the first part, the continued need for cardioprotection beyond that by rapid reperfusion of acute myocardial infarction is emphasized. Then, pathomechanisms of myocardial ischemia/reperfusion to the myocardium and the coronary circulation and the different modes of cell death in myocardial infarction are characterized. Different mechanical and pharmacological interventions to protect the ischemic/reperfused myocardium in elective percutaneous coronary interventions and coronary artery bypass grafting, in acute myocardial infarction and in cardiotoxicity from cancer therapy are detailed. The second part keeps the focus on ROS providing a comprehensive overview of molecular and cellular mechanisms involved in ischemia/reperfusion injury. Starting from mitochondria as the main sources and targets of ROS in ischemic/reperfused myocardium, a complex network of cellular and extracellular processes is discussed, including relationships with Ca2+ homeostasis, thiol group redox balance, hydrogen sulfide modulation, cross-talk with NAPDH oxidases, exosomes, cytokines and growth factors. While mechanistic insights are needed to improve our current therapeutic approaches, advancements in knowledge of ROS-mediated processes indicate that detrimental facets of oxidative stress are opposed by ROS requirement for physiological and protective reactions. This inevitable contrast is likely to underlie unsuccessful clinical trials and limits the development of novel cardioprotective interventions simply based upon ROS removal

The quest for the solar g modes

Solar gravity modes (or g modes) -- oscillations of the solar interior for which buoyancy acts as the restoring force -- have the potential to provide unprecedented inference on the structure and dynamics of the solar core, inference that is not possible with the well observed acoustic modes (or p modes). The high amplitude of the g-mode eigenfunctions in the core and the evanesence of the modes in the convection zone make the modes particularly sensitive to the physical and dynamical conditions in the core. Owing to the existence of the convection zone, the g modes have very low amplitudes at photospheric levels, which makes the modes extremely hard to detect. In this paper, we review the current state of play regarding attempts to detect g modes. We review the theory of g modes, including theoretical estimation of the g-mode frequencies, amplitudes and damping rates. Then we go on to discuss the techniques that have been used to try to detect g modes. We review results in the literature, and finish by looking to the future, and the potential advances that can be made -- from both data and data-analysis perspectives -- to give unambiguous detections of individual g modes. The review ends by concluding that, at the time of writing, there is indeed a consensus amongst the authors that there is currently no undisputed detection of solar g modes.Comment: 71 pages, 18 figures, accepted by Astronomy and Astrophysics Revie

Practical Issues in Imputation-Based Association Mapping

Imputation-based association methods provide a powerful framework for testing untyped variants for association with phenotypes and for combining results from multiple studies that use different genotyping platforms. Here, we consider several issues that arise when applying these methods in practice, including: (i) factors affecting imputation accuracy, including choice of reference panel; (ii) the effects of imputation accuracy on power to detect associations; (iii) the relative merits of Bayesian and frequentist approaches to testing imputed genotypes for association with phenotype; and (iv) how to quickly and accurately compute Bayes factors for testing imputed SNPs. We find that imputation-based methods can be robust to imputation accuracy and can improve power to detect associations, even when average imputation accuracy is poor. We explain how ranking SNPs for association by a standard likelihood ratio test gives the same results as a Bayesian procedure that uses an unnatural prior assumption—specifically, that difficult-to-impute SNPs tend to have larger effects—and assess the power gained from using a Bayesian approach that does not make this assumption. Within the Bayesian framework, we find that good approximations to a full analysis can be achieved by simply replacing unknown genotypes with a point estimate—their posterior mean. This approximation considerably reduces computational expense compared with published sampling-based approaches, and the methods we present are practical on a genome-wide scale with very modest computational resources (e.g., a single desktop computer). The approximation also facilitates combining information across studies, using only summary data for each SNP. Methods discussed here are implemented in the software package BIMBAM, which is available from http://stephenslab.uchicago.edu/software.html