Anti-adrenergic effects of endothelin on human atrial action potentials are potentially anti-arrhythmic

Endothelin-1 (ET-1) is elevated in patients with atrial fibrillation (AF) and heart failure. We investigated effects of ET-1 on human atrial cellular electrophysiological measurements expected to influence the genesis and maintenance of AF. Action potential characteristics and L-type Ca<sup>2+</sup> current (I<sub>CaL</sub>) were recorded by whole cell patch clamp, in atrial isolated myocytes obtained from patients in sinus rhythm. Isoproterenol (ISO) at 0.05 μM prolonged the action potential duration at 50% repolarisation (APD<sub>50</sub>: 54 ± 10 vs. 28 ± 5 ms; <i>P</i> < 0.05, <i>N</i> = 15 cells, 10 patients), but neither late repolarisation nor cellular effective refractory period (ERP) were affected. ET-1 (10 nM) reversed the effect of ISO on APD<sub>50</sub>, and had no basal effect (in the absence of ISO) on repolarisation or ERP. During repetitive stimulation, ISO (0.05 μM) produced arrhythmic depolarisations (<i>P</i> < 0.05). Each was abolished by ET-1 at 10 nM (<i>P</i> < 0.05). ISO (0.05 μM) increased peak I<sub>CaL</sub> from –5.5 ± 0.4 to –14.6 ± 0.9 pA/pF (P < 0.05; N = 79 cells, 34 patients). ET-1 (10 nM) reversed this effect by 98 ± 10% (P < 0.05), with no effect on basal I<sub>CaL</sub>. Chronic treatment of patients with a β-blocker did not significantly alter basal APD50 or I<sub>CaL</sub>, the increase in APD50 or I<sub>CaL</sub> by 0.05 μM ISO, nor the subsequent reversal of this effect on APD50 by 10 nM ET-1. The marked anti-adrenergic effects of ET-1 on human atrial cellular action potential plateau, arrhythmic depolarisations and I<sub>CaL</sub>, without affecting ERP and independently of β-blocker treatment, may be expected to contribute a potentially anti-arrhythmic influence in the atria of patients with AF and heart failure

Modelling Hen Harrier Dynamics to Inform Human-Wildlife Conflict Resolution : A Spatially-Realistic, Individual-Based Approach

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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

The dual role of the X-linked FoxP3 gene in human cancers

The FoxP3 (forkhead box P3) gene is an X-linked gene that is submitted to inactivation. It is an essential transcription factor in CD4(+)CD25(+)FoxP3 regulatory T cells, which are therapeutic targets in disseminated cutaneous melanoma. Moreover, FoxP3 is an important tumor suppressor gene in carcinomas and has putative cancer suppressor gene function in cutaneous melanoma as well. Therefore understanding the structure and function of the FoxP3 gene is crucial to gaining insight into the biology of melanoma to better develop immunotherapeutics and future therapeutic strategies

Post-operative atrial fibrillation is influenced by beta-blocker therapy but not by pre-operative atrial cellular electrophysiology

We investigated whether post-cardiac surgery (CS) new-onset atrial fibrillation (AF) is predicted by pre-CS atrial cellular electrophysiology, and whether the antiarrhythmic effect of beta-blocker therapy may involve pre-CS pharmacological remodeling. Atrial myocytes were obtained from consenting patients in sinus rhythm, just prior to CS. Action potentials and ion currents were recorded using whole-cell patch-clamp technique. Post-CS AF occurred in 53 of 212 patients (25%). Those with post-CS AF were older than those without (67 ± 2 vs 62 ± 1 years, P = 0.005). In cells from patients with post-CS AF, the action potential duration at 50% and 90% repolarization, maximum upstroke velocity, and effective refractory period (ERP) were 13 ± 4 ms, 217 ± 16 ms, 185 ± 10 V/s, and 216 ± 14 ms, respectively (n = 30 cells, 11 patients). Peak L-type Ca2+ current, transient outward and inward rectifier K+ currents, and the sustained outward current were −5.0 ± 0.5, 12.9 ± 2.4, −4.1 ± 0.4, and 9.7 ± 1.0 pA/pF, respectively (13-62 cells, 7-19 patients). None of these values were significantly different in cells from patients without post-CS AF (P > 0.05 for each, 60-279 cells, 29-86 patients), confirmed by multiple and logistic regression. In patients treated >7 days with a beta-blocker pre-CS, the incidence of post-CS AF was lower than in non-beta-blocked patients (13% vs 27%, P = 0.038). Pre-CS beta-blockade was associated with a prolonged pre-CS atrial cellular ERP (P = 0.001), by a similar degree (∼20%) in those with and without post-CS AF. Conclusion: Pre-CS human atrial cellular electrophysiology does not predict post-CS AF. Chronic beta-blocker therapy is associated with a reduced incidence of post-CS AF, unrelated to a pre-CS ERP-prolonging effect of this treatment

The role of parasite-driven selection in shaping landscape genomic structure in red grouse (Lagopus lagopus scotica)

Acknowledgements This study was funded by a BBSRC studentship (MAW) and NERC grants NE/H00775X/1 and NE/D000602/1 (SBP). The authors are grateful to Mario Röder and Keliya Bai for fieldwork assistance, and all estate owners, factors and keepers for access to field sites, most particularly MJ Taylor and Mike Nisbet (Airlie), Neil Brown (Allargue), RR Gledson and David Scrimgeour (Delnadamph), Andrew Salvesen and John Hay (Dinnet), Stuart Young and Derek Calder (Edinglassie), Kirsty Donald and David Busfield (Glen Dye), Neil Hogbin and Ab Taylor (Glen Muick), Alistair Mitchell (Glenlivet), Simon Blackett, Jim Davidson and Liam Donald (Invercauld), Richard Cooke and Fred Taylor† (Invermark), Shaila Rao and Christopher Murphy (Mar Lodge), and Ralph Peters and Philip Astor (Tillypronie). S.B.P. and S.M.R. conceived and designed the study. M.A.W. performed field and laboratory work. A.D. and M.C.J. developed SNP markers. M.A.W. analysed the data. M.A.W. and S.B.P. wrote the manuscript.Peer reviewedPostprin

Breeding ground correlates of the distribution and decline of the Common Cuckoo Cuculus canorus at two spatial scales

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordMany migratory bird species are undergoing population declines as a result of potentially multiple, interacting mechanisms. Understanding the environmental associations of spatial variation in population change can help tease out the likely mechanisms involved. Common Cuckoo Cuculus canorus populations have declined by 69% in England but increased by 33% in Scotland. The declines have mainly occurred in lowland agricultural landscapes, but their mechanisms are unknown. At both the local scale within the county of Devon (SE England) and at the national (UK) scale, we analysed the breeding season distribution of Cuckoos in relation to habitat variation, the abundance of host species and the abundance of moth species whose caterpillars are a key food of adult Cuckoos. At the local scale, we found that Cuckoos were more likely to be detected in areas with more semi-natural habitat, more Meadow Pipits Anthus pratensis (but fewer Dunnocks Prunella modularis) and where, later in the summer, higher numbers of moths were captured whose larvae are Cuckoo prey. Nationally, Cuckoos have become more associated with upland heath characterized by the presence of Meadow Pipit hosts, and with wetland habitats occupied by Eurasian Reed Warbler Acrocephalus scirpaceus hosts. The core distribution of Cuckoos has shifted from south to north within the UK. By the end of 2009, the abundance of macro-moth species identified as prey had also declined four times faster than that of species not known to be taken by Cuckoos. The abundance of these moths has shown the sharpest declines in grassland, arable and woodland habitats and has increased in semi-natural habitats (heaths and rough grassland). Our study suggests that Cuckoos are likely to remain a very scarce bird in lowland agricultural landscapes without large-scale changes in agricultural practices.Biotechnology and Biological Sciences Research Council (BBSRC)Royal Society for the Protection of Birds and Natural Englan