Activation of apoptotic pathways in experimental acute afterload-induced right ventricular failure

Objective: The pathobiology of persistent right ventricular failure observed after an acute increase in right ventricular afterload remains incompletely understood. We hypothesized that persistent right ventricular dysfunction might be related to activation of apoptotic pathways. Design: Prospective, randomized, controlled animal study. Setting: University research laboratory. Subjects: Mongrel dogs. Interventions: Fourteen anesthetized dogs were randomized to a transient 90-min pulmonary artery constriction operation to induce persistent right ventricular failure or to a sham operation followed 30 mins later by hemodynamic measurements and sampling of cardiac tissue. Measurements and main results: We evaluated effective arterial elastance to estimate right ventricular afterload and end-systolic elastance to estimate right ventricular contractility. Transient increase in pulmonary artery pressure persistently increased effective arterial elastance from 0.75 ± 0.08 to 1.37 ± 0.18 mm Hg/mL and decreased end-systolic elastance from 1.06 ± 0.09 to 0.49 ± 0.09 mm Hg/mL, end-systolic elastance/effective arterial elastance from 1.44 ± 0.06 to 0.34 ± 0.03, and cardiac output from 3.78 ± 0.16 to 1.46 ± 0.10 L/min, indicating right ventricular failure. At the pathobiologic level, we assessed apoptosis by real-time quantitative polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay, and immunohistochemistry. As compared with the sham-operated group, and with the left ventricle in animals with persistent right ventricular failure, there were decreased right ventricular and septal expressions of Bcl-2 with no changes in expressions of Bax, resulting in an increased Bax/Bcl-2 ratio. Right ventricular and septal Bcl-XL, and right ventricular Bcl-w gene expressions were decreased as compared with the sham-operated group, whereas Bak gene expression did not change. There were activations of right ventricular caspases-8 and-9 and of right ventricular and septal caspase-3. Diffuse right ventricular and septal apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. There were also increased right ventricular and septal protein expressions of tumor necrosis factor-alpha. Conclusions: Acute afterload-induced persistent right ventricular failure appears to be related to an early activation of apoptotic pathways and to a local overexpression of tumor necrosis factor-alpha, a proinflammatory cytokine. Copyright © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Primary Proton Spectrum of Cosmic Rays measured with Single Hadrons

The flux of cosmic-ray induced single hadrons near sea level has been measured with the large hadron calorimeter of the KASCADE experiment. The measurement corroborates former results obtained with detectors of smaller size if the enlarged veto of the 304 m^2 calorimeter surface is encounted for. The program CORSIKA/QGSJET is used to compute the cosmic-ray flux above the atmosphere. Between E_0=300 GeV and 1 PeV the primary proton spectrum can be described with a power law parametrized as dJ/dE_0=(0.15+-0.03)*E_0^{-2.78+-0.03} m^-2 s^-1 sr^-1 TeV^-1. In the TeV region the proton flux compares well with the results from recent measurements of direct experiments.Comment: 13 pages, accepted by Astrophysical Journa

Prospective open-label study of add-on and monotherapy topiramate in civilians with chronic nonhallucinatory posttraumatic stress disorder

BACKGROUND: In order to confirm therapeutic effects of topiramate on posttraumatic stress disorder (PTSD) observed in a prior study, a new prospective, open-label study was conducted to examine acute responses in chronic, nonhallucinatory PTSD. METHODS: Thirty-three consecutive newly recruited civilian adult outpatients (mean age 46 years, 85% female) with DSM-IV-diagnosed chronic PTSD, excluding those with concurrent auditory or visual hallucinations, received topiramate either as monotherapy (n = 5) or augmentation (n = 28). The primary measure was a change in the PTSD Checklist-Civilian Version (PCL-C) score from baseline to 4 weeks, with response defined as a ≥ 30% reduction of PTSD symptoms. RESULTS: For those taking the PCL-C at both baseline and week 4 (n = 30), total symptoms declined by 49% at week 4 (paired t-test, P < 0.001) with similar subscale reductions for reexperiencing, avoidance/numbing, and hyperarousal symptoms. The response rate at week 4 was 77%. Age, sex, bipolar comorbidity, age at onset of PTSD, duration of symptoms, severity of baseline PCL-C score, and monotherapy versus add-on medication administration did not predict reduction in PTSD symptoms. Median time to full response was 9 days and median dosage was 50 mg/day. CONCLUSIONS: Promising open-label findings in a new sample converge with findings of a previous study. The use of topiramate for treatment of chronic PTSD, at least in civilians, warrants controlled clinical trials

Interspecific Germline Transmission of Cultured Primordial Germ Cells

In birds, the primordial germ cell (PGC) lineage separates from the soma within 24 h following fertilization. Here we show that the endogenous population of about 200 PGCs from a single chicken embryo can be expanded one million fold in culture. When cultured PGCs are injected into a xenogeneic embryo at an equivalent stage of development, they colonize the testis. At sexual maturity, these donor PGCs undergo spermatogenesis in the xenogeneic host and become functional sperm. Insemination of semen from the xenogeneic host into females from the donor species produces normal offspring from the donor species. In our model system, the donor species is chicken (Gallus domesticus) and the recipient species is guinea fowl (Numida meleagris), a member of a different avian family, suggesting that the mechanisms controlling proliferation of the germline are highly conserved within birds. From a pragmatic perspective, these data are the basis of a novel strategy to produce endangered species of birds using domesticated hosts that are both tractable and fecund

A randomized, double-blind, placebo-controlled trial to assess the efficacy of topiramate in the treatment of post-traumatic stress disorder

<p>Abstract</p> <p>Background</p> <p>Topiramate might be effective in the treatment of posttraumatic stress disorder (PTSD) because of its antikindling effect and its action in both inhibitory and excitatory neurotransmitters. Open-label studies and few controlled trials have suggested that this anticonvulsant may have therapeutic potential in PTSD. This 12-week randomized, double-blind, placebo-controlled clinical trial will compare the efficacy of topiramate with placebo and study the tolerability of topiramate in the treatment of PTSD.</p> <p>Methods and design</p> <p>Seventy-two adult outpatients with DSM-IV-diagnosed PTSD will be recruited from the violence program of Federal University of São Paulo Hospital (UNIFESP). After informed consent, screening, and a one week period of wash out, subjects will be randomized to either placebo or topiramate for 12 weeks. The primary efficacy endpoint will be the change in the Clinician-administered PTSD scale (CAPS) total score from baseline to the final visit at 12 weeks.</p> <p>Discussion</p> <p>The development of treatments for PTSD is challenging due to the complexity of the symptoms and psychiatric comorbidities. The selective serotonin reuptake inhibitors (SSRIs) are the mainstream treatment for PTSD, but many patients do not have a satisfactory response to antidepressants. Although there are limited clinical studies available to assess the efficacy of topiramate for PTSD, the findings of prior trials suggest this anticonvulsant may be promising in the management of these patients.</p> <p>Trial Registration</p> <p>NCT 00725920</p

Is American Public Administration Detached From Historical Context?: On the Nature of Time and the Need to Understand It in Government and Its Study

The study of public administration pays little attention to history. Most publications are focused on current problems (the present) and desired solutions (the future) and are concerned mainly with organizational structure (a substantive issue) and output targets (an aggregative issue that involves measures of both individual performance and organizational productivity/services). There is much less consideration of how public administration (i.e., organization, policy, the study, etc.) unfolds over time. History, and so administrative history, is regarded as a “past” that can be recorded for its own sake but has little relevance to contemporary challenges. This view of history is the product of a diminished and anemic sense of time, resulting from organizing the past as a series of events that inexorably lead up to the present in a linear fashion. To improve the understanding of government’s role and position in society, public administration scholarship needs to reacquaint itself with the nature of time.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline