Chronic beta-adrenoceptor blockade and human atrial cell electrophysiology: evidence of pharmacological remodelling

<b>Objective:</b> Chronic beta-adrenoceptor antagonist (β-blocker) treatment reduces the incidence of reversion to AF in patients, possibly via an adaptive myocardial response. However, the underlying electrophysiological mechanisms are presently unclear. We aimed to investigate electrophysiological changes in human atrial cells associated with chronic treatment with β-blockers and other cardiovascular-acting drugs. <b>Methods:</b> Myocytes were isolated enzymatically from the right atrial appendage of 40 consenting patients who were in sinus rhythm. The cellular action potential duration (APD), effective refractory period (ERP), L-type Ca<sup>2+</sup> current (<i>I</i><sub>CaL</sub>), transient (<i>I</i><sub>TO</sub>) and sustained (<i>I</i><sub>KSUS</sub>) outward K<sup>+</sup> currents, and input resistance (<i>R</i><sub>i</sub>) were recorded using the whole cell patch clamp. Drug treatments and clinical characteristics were compared with electrophysiological measurements using simple and multiple regression analyses. P<0.05 was taken as statistically significant. <b>Results:</b> In atrial cells from patients treated chronically with β-blockers, the APD<sub>90</sub> and ERP (75 beats/min stimulation) were significantly longer, at 213±11 and 233±11 ms, respectively (<i>n</i> = 15 patients), than in cells from non-β-blocked patients, at 176±12 and 184±12 ms (n = 11). These cells also displayed a significantly reduced action potential phase 1 velocity (22±3 vs. 34±3 V/s). Chronic β-blockade was also associated with a significant reduction in the heart rate (58±3 vs. 69±5 beats/min) and in the density of ITO (8.7±1.3 vs. 13.7±2.1 pA/pF), an increase in the Ri (214±24 vs. 132±14 MΩ), but no significant change in <i>I</i><sub>CaL</sub> or <i>I</i><sub>KSUS</sub>. The <i>I</i><sub>TO</sub> blocker 4-aminopyridine largely mimicked the changes in phase 1 and ERP associated with chronic β-blockade, in cells from non-β-blocked patients. Chronic treatment of patients with calcium channel blockers or angiotensin converting enzyme inhibitors (<i>n</i> = 11–13 patients) was not associated with any significant changes in atrial cell electrophysiology. <b>Conclusion:</b> The observed atrial cellular electrophysiological changes associated with chronic β-blockade are consistent with a long-term adaptive response, a type of ‘pharmacological remodelling’, and provide mechanistic evidence supportive of the anti-arrhythmic actions of β-blockade

Atrial cellular electrophysiological changes in patients with ventricular dysfunction may predispose to AF

<b>Background:</b> Left ventricular systolic dysfunction (LVSD) is a risk factor for atrial fibrillation (AF), but the atrial cellular electrophysiological mechanisms in humans are unclear. Objective This study sought to investigate whether LVSD in patients who are in sinus rhythm (SR) is associated with atrial cellular electrophysiological changes that could predispose to AF. <b>Methods:</b> Right atrial myocytes were obtained from 214 consenting patients in SR who were undergoing cardiac surgery. Action potentials or ion currents were measured using the whole-cell-patch clamp technique. <b>Results:</b> The presence of moderate or severe LVSD was associated with a shortened atrial cellular effective refractory period (ERP) (209 ± 8 ms; 52 cells, 18 patients vs 233 ± 7 ms; 134 cells, 49 patients; P <0.05); confirmed by multiple linear regression analysis. The left ventricular ejection fraction (LVEF) was markedly lower in patients with moderate or severe LVSD (36% ± 4%, n = 15) than in those without LVSD (62% ± 2%, n = 31; P <0.05). In cells from patients with LVEF ≤ 45%, the ERP and action potential duration at 90% repolarization were shorter than in those from patients with LVEF > 45%, by 24% and 18%, respectively. The LVEF and ERP were positively correlated (r = 0.65, P <0.05). The L-type calcium ion current, inward rectifier potassium ion current, and sustained outward ion current were unaffected by LVSD. The transient outward potassium ion current was decreased by 34%, with a positive shift in its activation voltage, and no change in its decay kinetics. <b>Conclusion:</b> LVSD in patients in SR is independently associated with a shortening of the atrial cellular ERP, which may be expected to contribute to a predisposition to AF

Adjustment of the electric current in pulsar magnetospheres and origin of subpulse modulation

The subpulse modulation of pulsar radio emission goes to prove that the plasma flow in the open field line tube breaks into isolated narrow streams. I propose a model which attributes formation of streams to the process of the electric current adjustment in the magnetosphere. A mismatch between the magnetospheric current distribution and the current injected by the polar cap accelerator gives rise to reverse plasma flows in the magnetosphere. The reverse flow shields the electric field in the polar gap and thus shuts up the plasma production process. I assume that a circulating system of streams is formed such that the upward streams are produced in narrow gaps separated by downward streams. The electric drift is small in this model because the potential drop in narrow gaps is small. The gaps have to drift because by the time a downward stream reaches the star surface and shields the electric field, the corresponding gap has to shift. The transverse size of the streams is determined by the condition that the potential drop in the gaps is sufficient for the pair production. This yields the radius of the stream roughly 10% of the polar cap radius, which makes it possible to fit in the observed morphological features such as the "carousel" with 10-20 subbeams and the system of the core - two nested cone beams.Comment: 8 pages, 1 figur

Valuing health-related quality of life in heart failure: a systematic review of methods to derive quality-adjusted life years (QALYs) in trial-based cost-utility analyses

The accurate measurement of health-related quality of life (HRQoL) and the value of improving it for patients are essential for deriving quality-adjusted life years (QALYs) to inform treatment choice and resource allocation. The objective of this review was to identify and describe the approaches used to measure and value change in HRQoL in trial-based economic evaluations of heart failure interventions which derive QALYs as an outcome. Three databases (PubMed, CINAHL, Cochrane) were systematically searched. Twenty studies reporting economic evaluations based on 18 individual trials were identified. Most studies (n = 17) utilised generic preference-based measures to describe HRQoL and derive QALYs, commonly the EQ-5D-3L. Of these, three studies (from the same trial) also used mapping from a condition-specific to a generic measure. The remaining three studies used patients’ direct valuation of their own health or physician-reported outcomes to derive QALYs. Only 7 of the 20 studies reported significant incremental QALY gains. Most interventions were reported as being likely to be cost-effective at specified willingness to pay thresholds. The substantial variation in the approach applied to derive QALYs in the measurement of and value attributed to HRQoL in heart failure requires further investigation

Molecular dynamics modelling of radiation damage in normal, partly inverse and inverse spinels

The radiation response of perfect crystals of MgAl2O4, partially inverted MgGa2O4 and fully inverse MgIn2O4 were investigated using molecular dynamics. Dynamical cascades were initiated in these spinels over a range of trajectories with energies of 400 eV and 2 keV for the primary knock-on event. Collision cascades were set up on each of the cation and anion sublattices and were monitored up to 10 ps. Simulations in the normal MgAl2O4 spinel for the 2 keV energy regime resulted in similar defect structures as obtained at the post-threshold 400 eV energies, with little clustering occurring. The predominant defect configurations were split interstitials and cation antisites. For the inverse spinels, a much wider variety of lattice imperfections was observed. More defects were also produced due to the formation of interstitialvacancy cation chains and oxygen crowdions

Analysis of Residual Stresses in Laser-Shock-Peened and Shot-Peened Marine Steel Welds

Laser peening is now the preferred method of surface treatment in many applications. The magnitude and depth of the compressive residual stress induced by laser peening can be influenced strongly by the number of peen layers (the number of laser hits at each point) and by processing conditions including the use of a protective ablative layer. In this study, residual stresses have been characterized in laser and shot-peened marine butt welds with a particular focus at the fatigue crack initiation location at the weld toe. X-ray diffraction, synchrotron X-ray diffraction, incremental center-hole drilling, and the contour method were used for determination of residual stress. Results showed that the use of ablative tape increased the surface compressive stress, and the depth of compressive stress increased with an increase in number of peening layers. A key result is that variation of residual stress profile across laser peen spots was seen, and the residual stress magnitude varies between the center and edges of the spots

Excitation of standing kink oscillations in coronal loops

In this work we review the efforts that have been done to study the excitation of the standing fast kink body mode in coronal loops. We mainly focus on the time-dependent problem, which is appropriate to describe flare or CME induced kink oscillations. The analytical and numerical studies in slab and cylindrical loop geometries are reviewed. We discuss the results from very simple one-dimensional models to more realistic (but still simple) loop configurations. We emphasise how the results of the initial value problem complement the eigenmode calculations. The possible damping mechanisms of the kink oscillations are also discussed

Pulsars as Fantastic Objects and Probes

Pulsars are fantastic objects, which show the extreme states of matters and plasma physics not understood yet. Pulsars can be used as probes for the detection of interstellar medium and even the gravitational waves. Here I review the basic facts of pulsars which should attract students to choose pulsar studies as their future projects.Comment: Invited Lecture on the "First Kodai-Trieste Workshop on Plasma Astrophysics", Kodaikanal Obs, India. Aug.27-Sept.7th, 2007. In: "Turbulence, Dynamos, Accretion Disks, Pulsars and Collective Plasma Processes". Get a copy from: http://www.springerlink.com/content/978-1-4020-8867-

Measurement of the B0-anti-B0-Oscillation Frequency with Inclusive Dilepton Events

The $B^0$-$\bar B^0$ oscillation frequency has been measured with a sample of 23 million \B\bar B pairs collected with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we select events in which both B mesons decay semileptonically and use the charge of the leptons to identify the flavor of each B meson. A simultaneous fit to the decay time difference distributions for opposite- and same-sign dilepton events gives $\Delta m_d = 0.493 \pm 0.012{(stat)}\pm 0.009{(syst)}$ ps$^{-1}$.Comment: 7 pages, 1 figure, submitted to Physical Review Letter

Structural characterisation of neutrophil glycans by ultra sensitive mass spectrometric glycomics methodology

Neutrophils are the most abundant white blood cells in humans and play a vital role in several aspects of the immune response. Numerous reports have implicated neutrophil glycosylation as an important factor in mediating these interactions. We report here the application of high sensitivity glycomics methodologies, including matrix assisted laser desorption ionisation (MALDI-TOF) and MALDI-TOF/TOF analyses, to the structural analysis of N- and O-linked carbohydrates released from two samples of neutrophils, prepared by two separate and geographically remote laboratories. The data produced demonstrates that the cells display a diverse range of sialylated and fucosylated complex glycans, with a high level of similarity between the two preparations