Coronary artery endothelial dysfunction is positively correlated with low density lipoprotein and inversely correlated with high density lipoprotein subclass particles measured by nuclear magnetic resonance spectroscopy.

OBJECTIVE: The association between cholesterol and endothelial dysfunction remains controversial. We tested the hypothesis that lipoprotein subclasses are associated with coronary endothelial dysfunction. METHODS AND RESULTS: Coronary endothelial function was assessed in 490 patients between November 1993 and February 2007. Fasting lipids and nuclear magnetic resonance (NMR) lipoprotein particle subclasses were measured. There were 325 females and 165 males with a mean age of 49.8+/-11.6 years. Coronary endothelial dysfunction (epicardial constriction>20% or increase in coronary blood flow<50% in response to intracoronary acetylcholine) was diagnosed in 273 patients, the majority of whom (64.5%) had microvascular dysfunction. Total cholesterol and LDL-C (low density lipoprotein cholesterol) were not associated with endothelial dysfunction. One-way analysis and multivariate methods adjusting for age, gender, diabetes, hypertension and lipid-lowering agent use were used to determine the correlation between lipoprotein subclasses and coronary endothelial dysfunction. Epicardial endothelial dysfunction was significantly correlated with total (p=0.03) and small LDLp (LDL particles) (p<0.01) and inversely correlated with total and large HDLp (high density lipoprotein particles) (p<0.01). CONCLUSIONS: Epicardial, but not microvascular, coronary endothelial dysfunction was associated directly with LDL particles and inversely with HDL particles, suggesting location-dependent impact of lipoprotein particles on the coronary circulation

INTEGRAL and Swift/XRT observations of the source PKS 0208-512

The active galaxy PKS 0208-512, detected at lower energies by COMPTEL, has been claimed to be a MeV blazar from EGRET. We report on the most recent INTEGRAL observations of the blazar PKS 0208-512, which are supplemented by Swift ToO observations. The high energy X-ray and gamma-ray emission of PKS 0208-512 during August - December 2008 has been studied using 682 ks of INTEGRAL guest observer time and ~ 56 ks of Swift/XRT observations. These data were collected during the decay of a gamma-ray flare observed by Fermi/LAT. At X-ray energies (0.2 - 10 keV) PKS 0208-512 is significantly detected by Swift/XRT, showing a power-law spectrum with a photon index of ~ 1.64. Its X-ray luminosity varied by roughly 30% during one month. At hard X-/soft gamma-ray energies PKS 0208-512 shows a marginally significant (~ 3.2 sigma) emission in the 0.5-1 MeV band when combining all INTEGRAL/SPI data. Non-detections at energies below and above this band by INTEGRAL/SPI may indicate intrinsic excess emission. If this possible excess is produced by the blazar, one possible explanation could be that its jet consists of an abundant electron-positron plasma, which may lead to the emission of an annihilation radiation feature. Assuming this scenario, we estimate physical parameters of the jet of PKS 0208-512.Comment: accepted for publication in A&

EGRET Observations of the Extragalactic Gamma Ray Emission

The all-sky survey in high-energy gamma rays (E$>$30 MeV) carried out by the Energetic Gamma Ray Experiment Telescope (EGRET) aboard the Compton Gamma-Ray Observatory provides a unique opportunity to examine in detail the diffuse gamma-ray emission. The observed diffuse emission has a Galactic component arising from cosmic-ray interactions with the local interstellar gas and radiation as well an almost uniformly distributed component that is generally believed to originate outside the Galaxy. Through a careful study and removal of the Galactic diffuse emission, the flux, spectrum and uniformity of the extragalactic emission is deduced. The analysis indicates that the extragalactic emission is well described by a power law photon spectrum with an index of -(2.10+-0.03) in the 30 MeV to 100 GeV energy range. No large scale spatial anisotropy or changes in the energy spectrum are observed in the deduced extragalactic emission. The most likely explanation for the origin of this extragalactic high-energy gamma-ray emission is that it arises primarily from unresolved gamma-ray-emitting blazars.Comment: 19 pages latex, 10 figures, accepted for publication in Ap

Sustained proliferation in cancer: mechanisms and novel therapeutic targets

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression

Thrive: Success Strategies for the Modern-Day Faculty Member

The THRIVE collection is intended to help faculty thrive in their roles as educators, scholars, researchers, and clinicians. Each section contains a variety of thought-provoking topics that are designed to be easily digested, guide personal reflection, and put into action. Please use the THRIVE collection to help: Individuals study topics on their own, whenever and wherever they want Peer-mentoring or other learning communities study topics in small groups Leaders and planners strategically insert faculty development into existing meetings Faculty identify campus experts for additional learning, grand rounds, etc. If you have questions or want additional information on a topic, simply contact the article author or email [email protected]://digitalcommons.unmc.edu/facdev_books/1000/thumbnail.jp

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

First Cycle 4 multiwavelength observations of the gamma-ray quasar PKS 0208-512

We present first results of CGRO Cycle 4 multiwavelength observations of the gamma-ray quasar PKS 0208-512. A bright, variable gamma-ray source, PKS 0208-512 has been detected numerous times by the EGRET experiment aboard the CGRO, possessing one of the hardest spectra observed to date. The recent COMPTEL observations of Blom et al. (1995) indicate that PKS 0208-512 may belong to a new class of AGN that flare at MeV energies. During the current CGRO Cycle 4 observing cycle we have obtained observations of PKS 0208-512 at high- and mediumenergy gamma-rays with the EGRET and COMPTEL instruments aboard the Compton Observatory, at X-ray energies with ASCA, and at ultraviolet wavelengths with IUE. Preliminary analysis of our first CGRO Cycle 4 multiwavelength observations of PKS 0208-512 indicates a significant softening in the high-energy gamma-ray spectrum of this source, compared to earlier epochs. A possible correlation is also noted in flux variations between simultaneous ultraviolet (IUE) and X-ray (ASCA) measurements of this source. Our multiwavelength observations of PKS 0208-512 will be greatly expanded during the CGRO Cycle 5 in 1996, and our results on 0208-512 will ultimately be included in a larger survey of the gamma-ray properties of flat-spectrum radio quasars toward the region of the South Galactic Pole (see Vestrand et al., these proceedings)