Tectonic evolution of Lavinia Planitia, Venus

High resolution radar images from the Magellan spacecraft have revealed the first details of the morphology of the Lavinia Planitia region of Venus. Lavinia is a broad lowland over 2000 km across, centered at about 45 deg S latitude, 345 deg E longitude. Herein, the tectonic evolution of Lavinia is discussed, and its possible relationship to processes operating in the planet's interior. The discussion is restricted to the region from 37.3 to 52.6 deg S latitude and from about 340 to 0 deg E longitude. One of the most interesting characteristics of Lavinia is that the entire region possesses a regional tectonic framework of striking regularity. Lavinia is also transected by a complex pattern of belts of intense tectonic deformation known as ridge belts. Despite the gross topographic similarity of all of the ridge belts in Lavinia, they exhibit two rather distinct styles of near surface deformation. One is composed of sets of broad, arch-like ridges rising above the surrounding plains. In the other type, obvious fold-like ridges are rare to absent in the radar images. Both type show evidence for small amounts of shear distributed across the belts

Valsartan for attenuating disease evolution in early sarcomeric hypertrophic cardiomyopathy: the design of the Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) trial

Background: Hypertrophic cardiomyopathy (HCM) is often caused by sarcomere gene mutations, resulting in left ventricular hypertrophy (LVH), myocardial fibrosis, and increased risk of sudden cardiac death and heart failure. Studies in mouse models of sarcomeric HCM demonstrated that early treatment with an angiotensin receptor blocker (ARB) reduced development of LVH and fibrosis. In contrast, prior human studies using ARBs for HCM have targeted heterogeneous adult cohorts with well-established disease. The VANISH trial is testing the safety and feasibility of disease-modifying therapy with an ARB in genotyped HCM patients with early disease. Methods: A randomized, placebo-controlled, double-blind clinical trial is being conducted in sarcomere mutation carriers, 8 to 45 years old, with HCM and no/minimal symptoms, or those with early phenotypic manifestations but no LVH. Participants are randomly assigned to receive valsartan 80 to 320 mg daily (depending on age and weight) or placebo. The primary endpoint is a composite of 9 z-scores in domains representing myocardial injury/hemodynamic stress, cardiac morphology, and function. Total z-scores reflecting change from baseline to final visits will be compared between treatment groups. Secondary endpoints will assess the impact of treatment on mutation carriers without LVH, and analyze the influence of age, sex, and genotype. Conclusions: The VANISH trial is testing a new strategy of disease modification for treating sarcomere mutation carriers with early HCM, and those at risk for its development. In addition, further insight into disease mechanisms, response to therapy, and phenotypic evolution will be gained

Human Immunodeficiency Virus (HIV)-Infected CCR6+ Rectal CD4+ T Cells and HIV Persistence On Antiretroviral Therapy.

BackgroundIdentifying where human immunodeficiency virus (HIV) persists in people living with HIV and receiving antiretroviral therapy is critical to develop cure strategies. We assessed the relationship of HIV persistence to expression of chemokine receptors and their chemokines in blood (n = 48) and in rectal (n = 20) and lymph node (LN; n = 8) tissue collected from people living with HIV who were receiving suppressive antiretroviral therapy.MethodsCell-associated integrated HIV DNA, unspliced HIV RNA, and chemokine messenger RNA were quantified by quantitative polymerase chain reaction. Chemokine receptor expression on CD4+ T cells was determined using flow cytometry.ResultsIntegrated HIV DNA levels in CD4+ T cells, CCR6+CXCR3+ memory CD4+ T-cell frequency, and CCL20 expression (ligand for CCR6) were highest in rectal tissue, where HIV-infected CCR6+ T cells accounted for nearly all infected cells (median, 89.7%). Conversely in LN tissue, CCR6+ T cells were infrequent, and there was a statistically significant association of cell-associated HIV DNA and RNA with CCL19, CCL21, and CXCL13 chemokines.ConclusionsHIV-infected CCR6+ CD4+ T cells accounted for the majority of infected cells in rectal tissue. The different relationships between HIV persistence and T-cell subsets and chemokines in rectal and LN tissue suggest that different tissue-specific strategies may be required to eliminate HIV persistence and that assessment of biomarkers for HIV persistence may not be generalizable between blood and other tissues

Using Automated Health Plan Data to Assess Infection Risk from Coronary Artery Bypass Surgery

We determined if infection indicators were sufficiently consistent across health plans to allow comparison of hospitals’ risks of infection after coronary artery bypass surgery. Three managed care organizations accounted for 90% of managed care in eastern Massachusetts, from October 1996 through March 1999. We searched automated inpatient and outpatient claims and outpatient pharmacy dispensing files for indicator codes suggestive of postoperative surgical site infection. We reviewed full text medical records of patients with indicator codes to confirm infection status. We compared the hospital-specific proportions of cases with an indicator code, adjusting for health plan, age, sex, and chronic disease score. A total of 536 (27%) of 1,953 patients had infection indicators. Infection was confirmed in 79 (53%) of 149 reviewed records with adequate documentation. The proportion of patients with an indicator of infection varied significantly (p<0.001) between hospitals (19% to 36%) and health plans (22% to 33%). The difference between hospitals persisted after adjustment for health plan and patients’ age and sex. Similar relationships were observed when postoperative antibiotic information was ignored. Automated claims and pharmacy data from different health plans can be used together to allow inexpensive, routine monitoring of indicators of postoperative infection, with the goal of identifying institutions that can be further evaluated to determine if risks for infection can be reduced

Favorable outcome of early treatment of new onset child and adolescent migraine-implications for disease modification.

There is evidence that the prevalence of migraine in children and adolescents may be increasing. Current theories of migraine pathophysiology in adults suggest activation of central cortical and brainstem pathways in conjunction with the peripheral trigeminovascular system, which ultimately results in release of neuropeptides, facilitation of central pain pathways, neurogenic inflammation surrounding peripheral vessels, and vasodilatation. Although several risk factors for frequent episodic, chronic, and refractory migraine have been identified, the causes of migraine progression are not known. Migraine pathophysiology has not been fully evaluated in children. In this review, we will first discuss the evidence that early therapeutic interventions in the child or adolescent new onset migraineur, may halt or limit progression and disability. We will then review the evidence suggesting that many adults with chronic or refractory migraine developed their migraine as children or adolescents and may not have been treated adequately with migraine-specific therapy. Finally, we will show that early, appropriate and optimal treatment of migraine during childhood and adolescence may result in disease modification and prevent progression of this disease

Impact of animal strain on gene expression in a rat model of acute cardiac rejection

<p>Abstract</p> <p>Background</p> <p>The expression levels of many genes show wide natural variation among strains or populations. This study investigated the potential for animal strain-related genotypic differences to confound gene expression profiles in acute cellular rejection (ACR). Using a rat heart transplant model and 2 different rat strains (Dark Agouti, and Brown Norway), microarrays were performed on native hearts, transplanted hearts, and peripheral blood mononuclear cells (PBMC).</p> <p>Results</p> <p>In heart tissue, strain alone affected the expression of only 33 probesets while rejection affected the expression of 1368 probesets (FDR 10% and FC ≥ 3). Only 13 genes were affected by both strain and rejection, which was < 1% (13/1368) of all probesets differentially expressed in ACR. However, for PBMC, strain alone affected 265 probesets (FDR 10% and FC ≥ 3) and the addition of ACR had little further effect. Pathway analysis of these differentially expressed strain effect genes connected them with immune response, cell motility and cell death, functional themes that overlap with those related to ACR. After accounting for animal strain, additional analysis identified 30 PBMC candidate genes potentially associated with ACR.</p> <p>Conclusion</p> <p>In ACR, genetic background has a large impact on the transcriptome of immune cells, but not heart tissue. Gene expression studies of ACR should avoid study designs that require cross strain comparisons between leukocytes.</p

Distinct cortical and striatal actions of a β-arrestin-biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties.

The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed β-arrestin2 (βarr2)-biased D2R partial agonists to simultaneously target hyper- and hypodopaminergia. Using neuron-specific βarr2-KO mice, we show that the antipsychotic-like effects of a βarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-βarr2 signaling. Furthermore, βarr2-biased D2R agonism enhances firing of cortical fast-spiking interneurons. This enhanced cortical agonism of the biased ligand can be attributed to a lack of G-protein signaling and elevated expression of βarr2 and G protein-coupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that βarr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies

N-terminal pro-B-type natriuretic peptide by itself predicts death and cardiovascular events in high-risk patients with type 2 diabetes

Background: NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) improves the discriminatory ability of risk‐prediction models in type 2 diabetes mellitus (T2DM) but is not yet used in clinical practice. We assessed the discriminatory strength of NT‐proBNP by itself for death and cardiovascular events in high‐risk patients with T2DM. Methods and Results: Cox proportional hazards were used to create a base model formed by 20 variables. The discriminatory ability of the base model was compared with that of NT‐proBNP alone and with NT‐proBNP added, using C‐statistics. We studied 5509 patients (with complete data) of 8561 patients with T2DM and cardiovascular and/or chronic kidney disease who were enrolled in the ALTITUDE (Aliskiren in Type 2 Diabetes Using Cardiorenal Endpoints) trial. During a median 2.6‐year follow‐up period, 469 patients died and 768 had a cardiovascular composite outcome (cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction, stroke, or heart failure hospitalization). NT‐proBNP alone was as discriminatory as the base model for predicting death (C‐statistic, 0.745 versus 0.744, P=0.95) and the cardiovascular composite outcome (C‐statistic, 0.723 versus 0.731, P=0.37). When NT‐proBNP was added, it increased the predictive ability of the base model for death (C‐statistic, 0.779 versus 0.744, P&lt;0.001) and for cardiovascular composite outcome (C‐statistic, 0.763 versus 0.731, P&lt;0.001). Conclusions: In high‐risk patients with T2DM, NT‐proBNP by itself demonstrated discriminatory ability similar to a multivariable model in predicting both death and cardiovascular events and should be considered for risk stratification