The Effects of Carboxyl-group Specific Modification and Triiodo-L-thyronine on Cardiac Sodium Channels

The patch clamp method was used to evaluate the effects of 3,5,3\u27-triiodo-L-thyronine (T3) and carboxyl modification on adult rabbit ventricular Na+ channels. In contrast to TTX-sensitive Na+ channels, Ca2+ block of cardiac Na+ channels was not prevented by selective carboxyl modification by trimethyloxonium (TMO) or water soluble carbodiimide (WSC). In 2 mM Ca2+, TMO-treated patches exhibited 3 discrete conductance (γNa) levels. An abbreviation of mean open time (MOT) accompanied each decrease in γNa. The effects on channel gating of elevating external Ca2+ differed from those of TMO pretreatment. Ensemble averages after TMO showed a shortening of the time to peak current and an acceleration of the rate of current decay. WSC caused a decrease in γNa and an abbreviation of MOT at all potentials tested. We conclude that alteration of the surface potential by a single carboxyl modification is inadequate to explain the effects of TMO and WSC. Physiological concentrations of T3 increased bursting as measured by the ratio of long events (LE) to the total number of events. In the cell-attached patch configuration, addition of 5 nM T3 to the pipette increased the %LE at all potentials examined. The increase had a biphasic voltage-dependence and peaked at -50 mV. A similar increase in the %LE occurred with 50 nM T3 suggesting saturation at ≤5 nM. LEs sometimes were grouped into runs, but the more usual pattern suggested that modal shifts occurred in ~1 s. Addition of T3 to the bath but not the pipette in cell-attached patches failed to alter the MOT, unitary current, or %LE. Na+ channel gating also was unaffected by patch excision or by addition of T3 to the cytoplasmic face of inside-out patches. Nevertheless, with T3 in the pipette, patch excision to the inside-out configuration caused a dramatic increase in the %LE, especially near the threshold potential, and an increase in the MOT. These results suggested that T3 was not membrane permeable during the time scale of the experiments and that T3\u27s action required close proximity to the extracellular face of the Na+ channel

Statins Decrease Oxidative Stress and ICD Therapies

Recent studies demonstrate that statins decrease ventricular arrhythmias in internal cardioverter defibrillator (ICD) patients. The mechanism is unknown, but evidence links increased inflammatory and oxidative states with increased arrhythmias. We hypothesized that statin use decreases oxidation. Methods. 304 subjects with ICDs were surveyed for ventricular arrhythmia. Blood was analyzed for derivatives of reactive oxygen species (DROMs) and interleukin-6 (IL-6). Results. Subjects included 252 (83%) men, 58% on statins, 20% had ventricular arrhythmias. Average age was 63 years and ejection fraction (EF) 20%. ICD implant duration was 29 ± 27 months. Use of statins correlated with lower ICD events (r = 0.12, P = .02). Subjects on statins had lower hsCRP (5.2 versus 6.3; P = .05) and DROM levels (373 versus 397; P = .03). Other factors, including IL-6 and EF did not differ between statin and nonstatin use, nor did beta-blocker or antiarrhythmic use. Multivariate cross-correlation analysis demonstrated that DROMs, statins, IL-6 and EF were strongly associated with ICD events. Multivariate regression shows DROMs to be the dominant predictor. Conclusion. ICD event rate correlates with DROMs, a measure of lipid peroxides. Use of statins is associated with reduced DROMs and fewer ICD events, suggesting that statins exert their effect through reducing oxidation

Automated external cardioversion defibrillation monitoring in cardiac arrest: a randomized trial

<p>Abstract</p> <p>Background</p> <p>In-hospital cardiac arrest has a poor prognosis despite active electrocardiography monitoring. The initial rhythm of approximately 25% of in-hospital cardiopulmonary resuscitation (CPR) events is pulseless ventricular tachycardia/ventricular fibrillation (VT/VF). Early defibrillation is an independent predictor of survival in CPR events caused by VT/VF. The automated external cardioverter defibrillator (AECD) is a device attached by pads to the chest wall that monitors, detects, and within seconds, automatically delivers electric countershock to an appropriate tachyarrhythmia.</p> <p>Study Objectives</p> <p>• To evaluate safety of AECD monitoring in hospitalized patients.</p> <p>• To evaluate whether AECDs provide earlier defibrillation than hospital code teams.</p> <p>Methods</p> <p>The study is a prospective trial randomizing patients admitted to the telemetry ward to standard CPR (code team) or standard CPR plus AECD monitoring (PowerHeart CRM). The AECD is programmed to deliver one 150 J biphasic shock to patients in sustained VT/VF. Data is collected using the Utstein criteria for cardiac arrest. The primary endpoint is time-to-defibrillation; secondary outcomes include neurological status and survival to discharge, with 3-year follow-up.</p> <p>Results</p> <p>To date, 192 patients have been recruited in the time period between 10/10/2006 to 7/20/2007. A total of 3,655 hours of telemetry data have been analyzed in the AECD arm. The AECD has monitored ambulatory telemetry patients in sinus rhythm, sinus tachycardia, supraventricular tachycardia, atrial flutter or fibrillation, with premature ventricular complexes and non-sustained VT without delivery of inappropriate shocks. One patient experienced sustained VT during AECD monitoring, who was successfully defibrillated (17 seconds after meeting programmed criteria). There are no events to report in the control arm. The patient survived the event without neurological complications. During the same time period, mean time to shock for VT/VF cardiac arrest occurring outside the telemetry ward was 230 ± 50 seconds.</p> <p>Conclusion</p> <p>AECD monitoring is safe and likely results in earlier defibrillation than standard telemetry monitoring.</p> <p>Trial Registration</p> <p>National Institutes of Health registration ID: NCT00382928</p

On the seasonality of eddies in the Western Mediterranean Sea: answers with altimetry and modeling.

Trabajo presentado en la EGU General Assemby 2013, celebrada del 7 al 12 de abril de 2013 en Viena (Austria)Eighteen years of weekly SLA merged maps in the Western Mediterranean are analyzed using the new method proposed by Chelton et al. (2011) to identify and track mesoscale eddies. The method has been adapted to take into account the specificity of the Mediterranean basin. Results are similar to the global ocean results with a radius smaller due to a smaller Rossby radius. The areas of intense rotational speed and amplitude of eddies are similar to the areas of intense eddy kinetic energy calculated from altimetry sea level anomalies. Eddies propagation speed shows a wide range of values without a clear preferred direction. Nevertheless, eddies seems to propagate following the main currents. Temporal analysis of the number of eddies per day is made focusing on the annual and semiannual variability. This annual and semi-annual cycle is analyzed using a regional model of the Mediterranean Sea and studying the interaction with atmospheric forcingsPeer reviewe

Effect of α7 nicotinic acetylcholine receptor activation on cardiac fibroblasts: A mechanism underlying RV fibrosis associated with cigarette smoke exposure

INTRODUCTION: Right ventricular dysfunction is associated with numerous smoking-related illnesses including chronic obstructive pulmonary disease (COPD) where it is present even in absence of pulmonary hypertension. It is unknown if exposure to cigarette smoke has direct effects on RV function and cardiac fibroblast proliferation or collagen synthesis. In this study, we evaluated cardiac function and fibrosis in mice exposed to cigarette smoke (CS) and determined mechanisms of smoke-induced changes in cardiac fibroblast signaling and fibrosis. METHODS: AKR mice were exposed to cigarette smoke for six weeks followed by echocardiography and evaluation of cardiac hypertrophy, collagen content, and pulmonary muscularization. Proliferation and collagen content were evaluated in primary isolated rat cardiac fibroblasts (CF) exposed to cigarette smoke extract (CSE) or nicotine. Markers of cell proliferation, fibrosis, and proliferative signaling were determined by immunoblot or Sircol collagen assay. RESULTS: Mice exposed to CS had significantly decreased RV function as determined by TAPSE. There were no changes in LV parameters. RV collagen content was significantly elevated but there was no change in RV hypertrophy or pulmonary vascular muscularization. CSE directly increased cardiac fibroblast proliferation and collagen content in CF. Nicotine alone reproduced these effects. CSE and nicotine-induced fibroblast proliferation and collagen content were mediated through α7 nicotinic acetylcholine receptors and were dependent on PKC-α, PKC-δ, and reduced p38-MAPK phosphorylation. CONCLUSION: CS and nicotine have direct effects on cardiac fibroblasts to induce proliferation and fibrosis which may negatively affect right heart function

CD8+ T cell concentration determines their efficiency in killing cognate antigen–expressing syngeneic mammalian cells in vitro and in mouse tissues

We describe a quantitative model for assessing the cytolytic activity of antigen-specific CD8+ T cells in vitro and in vivo in which the concentration of antigen-specific CD8+ T cells determines the efficiency with which these cells kill cognate antigen–expressing melanoma cells in packed cell pellets, in three-dimensional collagen-fibrin gels in vitro, and in established melanomas in vivo. In combination with a clonogenic assay for melanoma cells, collagen-fibrin gels are 4,500–5,500-fold more sensitive than the packed cell pellet–type assays generally used to measure CD8+ T cell cytolytic activity. An equation previously used to describe neutrophil bactericidal activity in vitro and in vivo also describes antigen-specific CD8+ T cell–mediated cytolysis of cognate antigen-expressing melanoma cells in collagen-fibrin gels in vitro and in transplanted tumors in vivo. We have used this equation to calculate the critical concentration of antigen-specific CD8+ T cells, which is the concentration of these cells required to hold constant the concentration of a growing population of cognate antigen-expressing melanoma cells. It is ∼3.5 × 105/ml collagen-fibrin gel in vitro and ∼3 × 106/ml or /g melanoma for previously published studies of ex vivo–activated adoptively transferred tumor antigen–specific CD8+ T cell killing of cognate antigen–expressing melanoma cells in established tumors in vivo. The antigen-specific CD8+ T cell concentration required to kill 100% of 2 × 107/ml cognate antigen-expressing melanoma cells in collagen fibrin gels is ≥107/ml of gel

The development and trial of an unmanned aerial system for the measurement of methane flux from landfill and greenhouse gas emission hotspots

This paper describes the development of a new sampling and measurement method to infer methane flux using proxy measurements of CO2 concentration and wind data recorded by Unmanned Aerial Systems (UAS). The flux method described and trialed here is appropriate to the spatial scale of landfill sites and analogous greenhouse gas emission hotspots, making it an important new method for low-cost and rapid case study quantification of fluxes from currently uncertain (but highly important) greenhouse gas sources.We present a case study using these UAS-based measurements to derive instantaneous methane fluxes from a test landfill site in the north of England using a mass balance model tailored for UAS sampling and co-emitted CO2 concentration as a methane-emission proxy. Methane flux (and flux uncertainty) during two trials on 27 November 2014 and 5 March 2015, were found to be 0.140 kg s−1 (±61% at 1σ), and 0.050 kg s−1 (±54% at 1σ), respectively. Uncertainty contributing to the flux was dominated by ambient variability in the background (inflow) concentration (>40%) and wind speed (>10%); with instrumental error contributing only ∼1–2%. The approach described represents an important advance concerning the challenging problem of greenhouse gas hotspot flux calculation, and offers transferability to a wide range of analogous environments. This new measurement solution could add to a toolkit of approaches to better validate source-specific greenhouse emissions inventories – an important new requirement of the UNFCCC COP21 (Paris) climate change agreement