Sildenafil Citrate-Restored eNOS and PDE5 Regulation in Sickle Cell Mouse Penis Prevents Priapism Via Control of Oxidative/Nitrosative Stress

Sildenafil citrate revolutionized the practice of sexual medicine upon its federal regulatory agency approval approximately 15 years ago as the prototypical phosphodiesterase type 5 inhibitor indicated for the treatment of male erectile dysfunction. We now provide scientific support for its alternative use in the management of priapism, a clinical disorder of prolonged and uncontrolled penile erection. Sildenafil administered continuously to sickle cell mice, which show a priapism phenotype, reverses oxidative/nitrosative stress effects in the penis, mainly via reversion of uncoupled endothelial nitric oxide synthase to the functional coupled state of the enzyme, which in turn corrects aberrant signaling and function of the nitric oxide/cyclic GMP/protein kinase G/phosphodiesterase type 5 cascade. Priapism tendencies in these mice are reverted partially toward normal neurostimulated erection frequencies and durations after sildenafil treatment in association with normalized cyclic GMP concentration, protein kinase G activity and phosphodiesterase type 5 activity in the penis. Thus, sildenafil exerts pleiotropic effects in the penis that extend to diverse erection disorders. © 2013 Bivalacqua et al

GC Insights: Open-access R code for translating the co-occurrence of natural hazards into impact on joint financial risk

Hydro-meteorological hazard is often estimated by academic and public sector researchers using publicly funded climate models, whilst the ensuing risk quantification uses proprietary insurance sector models, which can inhibit the effective translation of risk-related environmental science into modified practice or policy. For co-occurring hazards, this work proposes as an interim solution an open-access R code that deploys a metric (i.e. inter-hazard correlation coefficient, r) obtainable from scientific research that is usable in practice without restricted data (climate or risk) being exposed. This tool is evaluated for a worked example that estimates the impact on joint financial risk at an annual 1-in-200-year level of wet and windy weather in the UK co-occurring rather than being independent, but the approach can be applied to other multi-hazards in various sectors (e.g. road, rail and telecommunications) now or in future climates

Synoptic conditions conducive for compound wind-flood events in Great Britain in present and future climates

Extreme wind is the main driver of loss in North-West Europe, with flooding being the second-highest driver. These hazards are currently modelled independently, and it is unclear what the contribution of their co-occurrence is to loss. They are often associated with extra-tropical cyclones, with studies focusing on co-occurrence of extreme meteorological variables. However, there has not been a systematic assessment of the meteorological drivers of the co-occurring \textit{impacts} of compound wind-flood events. This study quantifies this using an established storm severity index (SSI) and recently developed flood severity index (FSI), applied to the UKCP18 12km regional climate simulations, and a Great Britain (GB) focused hydrological model. The meteorological drivers are assessed using 30 weather types, which are designed to capture a broad spectrum of GB weather. Daily extreme compound events (exceeding 99th percentile of both SSI and FSI) are generally associated with cyclonic weather patterns, often from the positive phase of the North Atlantic Oscillation (NAO+) and Northwesterly classifications. Extreme compound events happen in a larger variety of weather patterns in a future climate. The location of extreme precipitation events shifts southward towards regions of increased exposure. The risk of extreme compound events increases almost four-fold in the UKCP18 simulations (from 14 events in the historical period, to 55 events in the future period). It is also more likely for there to be multi-day compound events. At seasonal timescales years tend to be either flood-prone or wind-damage-prone. In a future climate there is a larger proportion of years experiencing extreme seasonal SSI and FSI totals. This could lead to increases in reinsurance losses if not factored into current modelling

Meta-Analyst: software for meta-analysis of binary, continuous and diagnostic data

<p>Abstract</p> <p>Background</p> <p>Meta-analysis is increasingly used as a key source of evidence synthesis to inform clinical practice. The theory and statistical foundations of meta-analysis continually evolve, providing solutions to many new and challenging problems. In practice, most meta-analyses are performed in general statistical packages or dedicated meta-analysis programs.</p> <p>Results</p> <p>Herein, we introduce Meta-Analyst, a novel, powerful, intuitive, and free meta-analysis program for the meta-analysis of a variety of problems. Meta-Analyst is implemented in C# atop of the Microsoft .NET framework, and features a graphical user interface. The software performs several meta-analysis and meta-regression models for binary and continuous outcomes, as well as analyses for diagnostic and prognostic test studies in the frequentist and Bayesian frameworks. Moreover, Meta-Analyst includes a flexible tool to edit and customize generated meta-analysis graphs (e.g., forest plots) and provides output in many formats (images, Adobe PDF, Microsoft Word-ready RTF). The software architecture employed allows for rapid changes to be made to either the Graphical User Interface (GUI) or to the analytic modules.</p> <p>We verified the numerical precision of Meta-Analyst by comparing its output with that from standard meta-analysis routines in Stata over a large database of 11,803 meta-analyses of binary outcome data, and 6,881 meta-analyses of continuous outcome data from the Cochrane Library of Systematic Reviews. Results from analyses of diagnostic and prognostic test studies have been verified in a limited number of meta-analyses versus MetaDisc and MetaTest. Bayesian statistical analyses use the OpenBUGS calculation engine (and are thus as accurate as the standalone OpenBUGS software).</p> <p>Conclusion</p> <p>We have developed and validated a new program for conducting meta-analyses that combines the advantages of existing software for this task.</p

Trauma management incorporating focused assessment with computed tomography in trauma (FACTT) - potential effect on survival

Background Immediate recognition of life-threatening conditions and injuries is the key to trauma management. To date, the impact of focused assessment with computed tomography in trauma (FACTT) has not been formally assessed. We aimed to find out whether the concept of using FACTT during primary trauma survey has a negative or positive effect on survival. Methods In a retrospective, multicentre study, we compared our time management and probability of survival (Ps) in major trauma patients who received FACTT during trauma resuscitation with the trauma registry of the German Trauma Society (DGU). FACTT is defined as whole-body computed tomography (WBCT) during primary trauma survey. We determined the probability of survival according to the Trauma and Injury Severity Score (TRISS), the Revised Injury Severity Classification score (RISC) and the standardized mortality ratio (SMR). Results We analysed 4.817 patients from the DGU database from 2002 until 2004, 160 (3.3%) were from our trauma centre at the Ludwig-Maximilians-University (LMU) and 4.657 (96.7%) from the DGU group. 73.2% were male with a mean age of 42.5 years, a mean ISS of 29.8. 96.2% had suffered from blunt trauma. Time from admission to FAST (focused assessment with sonography for trauma)(4.3 vs. 8.7 min), chest x-ray (8.1 vs. 16.0 min) and whole-body CT (20.7 vs. 36.6 min) was shorter at the LMU compared to the other trauma centres (p < 0.001). SMR calculated by TRISS was 0.74 (CI95% 0.40-1.08) for the LMU (p = 0.24) and 0.92 (CI95% 0.84-1.01) for the DGU group (p = 0.10). RISC methodology revealed a SMR of 0.69 (95%CI 0.47-0.92) for the LMU (p = 0.043) and 1.00 (95%CI 0.94-1.06) for the DGU group (p = 0.88). Conclusion Trauma management incorporating FACTT enhances a rapid response to life-threatening problems and enables a comprehensive assessment of the severity of each relevant injury. Due to its speed and accuracy, FACTT during primary trauma survey supports rapid decision-making and may increase survival

Early Treatment with Fumagillin, an Inhibitor of Methionine Aminopeptidase-2, Prevents Pulmonary Hypertension in Monocrotaline-Injured Rats

Pulmonary Hypertension (PH) is a pathophysiologic condition characterized by hypoxemia and right ventricular strain. Proliferation of fibroblasts, smooth muscle cells, and endothelial cells is central to the pathology of PH in animal models and in humans. Methionine aminopeptidase-2 (MetAP2) regulates proliferation in a variety of cell types including endothelial cells, smooth muscle cells, and fibroblasts. MetAP2 is inhibited irreversibly by the angiogenesis inhibitor fumagillin. We have previously found that inhibition of MetAP2 with fumagillin in bleomycin-injured mice decreased pulmonary fibrosis by selectively decreasing the proliferation of lung myofibroblasts. In this study, we investigated the role of fumagillin as a potential therapy in experimental PH. In vivo, treatment of rats with fumagillin early after monocrotaline injury prevented PH and right ventricular remodeling by decreasing the thickness of the medial layer of the pulmonary arteries. Treatment with fumagillin beginning two weeks after monocrotaline injury did not prevent PH but was associated with decreased right ventricular mass and decreased cardiomyocyte hypertrophy, suggesting a direct effect of fumagillin on right ventricular remodeling. Incubation of rat pulmonary artery smooth muscle cells (RPASMC) with fumagillin and MetAP2-targeting siRNA inhibited proliferation of RPASMC in vitro. Platelet-derived growth factor, a growth factor that is important in the pathogenesis of PH and stimulates proliferation of fibroblasts and smooth muscle cells, strongly increased expression of MetP2. By immunohistochemistry, we found that MetAP2 was expressed in the lesions of human pulmonary arterial hypertension. We propose that fumagillin may be an effective adjunctive therapy for treating PH in patients

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Gnotobiotic IL-10−/−; NF-κBEGFP Mice Develop Rapid and Severe Colitis Following Campylobacter jejuni Infection

Limited information is available on the molecular mechanisms associated with Campylobacter jejuni (C. jejuni) induced food-borne diarrheal illnesses. In this study, we investigated the function of TLR/NF-κB signaling in C. jejuni induced pathogenesis using gnotobiotic IL-10−/−; NF-κBEGFP mice. In vitro analysis showed that C. jejuni induced IκB phosphorylation, followed by enhanced NF-κB transcriptional activity and increased IL-6, MIP-2α and NOD2 mRNA accumulation in infected-mouse colonic epithelial cells CMT93. Importantly, these events were blocked by molecular delivery of an IκB inhibitor (Ad5IκBAA). NF-κB signalling was also important for C.jejuni-induced cytokine gene expression in bone marrow-derived dendritic cells. Importantly, C. jejuni associated IL-10−/−; NF-κBEGFP mice developed mild (day 5) and severe (day 14) ulcerating colonic inflammation and bloody diarrhea as assessed by colonoscopy and histological analysis. Macroscopic analysis showed elevated EGFP expression indicating NF-κB activation throughout the colon of C. jejuni associated IL-10−/−; NF-κBEGFP mice, while fluorescence microscopy revealed EGFP positive cells to be exclusively located in lamina propria mononuclear cells. Pharmacological NF-κB inhibition using Bay 11-7085 did not ameliorate C. jejuni induced colonic inflammation. Our findings indicate that C. jejuni induces rapid and severe intestinal inflammation in a susceptible host that correlates with enhanced NF-κB activity from lamina propria immune cells