163 research outputs found
Increased vulnerability of human ventricle to re-entrant excitation in hERG-linked variant 1 short QT syndrome
No full textThe short QT syndrome (SQTS) is a genetically heterogeneous condition characterized by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies arrhythmogenic mechanisms in the rapid-delayed rectifier K+ current (IKr)-linked SQT1 variant of the SQTS. Markov chain (MC) models were found to be superior to Hodgkin-Huxley (HH) models in reproducing experimental data regarding effects of the N588K mutation on KCNH2-encoded hERG. These ionic channel models were then incorporated into human ventricular action potential (AP) models and into 1D and 2D idealised and realistic transmural ventricular tissue simulations and into a 3D anatomical model. In single cell models, the N588K mutation abbreviated ventricular cell AP duration at 90% repolarization (APD90) and decreased the maximal transmural voltage heterogeneity (δV) during APs. This resulted in decreased transmural heterogeneity of APD90 and of the effective refractory period (ERP): effects that are anticipated to be anti-arrhythmic rather than pro-arrhythmic. However, with consideration of transmural heterogeneity of IKr density in the intact tissue model based on the ten Tusscher-Noble-Noble-Panfilov ventricular model, not only did the N588K mutation lead to QT-shortening and increases in T-wave amplitude, but δV was found to be augmented in some local regions of ventricle tissue, resulting in increased tissue vulnerability for uni-directional conduction block and predisposing to formation of re-entrant excitation waves. In 2D and 3D tissue models, the N588K mutation facilitated and maintained re-entrant excitation waves due to the reduced substrate size necessary for sustaining re-entry. Thus, in SQT1 the N588K-hERG mutation facilitates initiation and maintenance of ventricular re-entry, increasing the lifespan of re-entrant spiral waves and the stability of scroll waves in 3D tissue.</p
Perception of validity of clinical and preclinical methods for assessment of torsades de pointes liability
No full textIn 2007 a meeting on drug-induced torsades de pointes (TdP) was held in London, UK, under the auspices of the British Society for Cardiovascular Research (BSCR). One of the objectives was to explore the validity of available biomarkers, risk factors and preclinical investigational methods for the detection of drug-induced TdP liability preclinical methods and clinical 'thorough QT' testing. The first symposium was entitled "How validated are current models and biomarkers for testing drug-induced torsades de pointes liability?" Validation, as far as the symposium was concerned, meant that the endpoints measured in the method predict TdP liability specifically, selectively and quantitatively. Topics (and the publications derived from the presentations) were: human volunteer phase 1 studies [Vik, T., Pollard, C., & Sager, P. (2008-this issue), the anaesthetized rabbit TDP model [Carlsson, L. (2008-this issue), the AV blocked canine preparation [Oros, A., Beekman, J.D.M., & Vos, M. A. (2008- this issue), QT interval and its corrections in the in vivo conscious canine [Fossa, A. A. (2008-this issue), the rabbit heart failure model [Hamlin, R. L., & Kijtawornrat, A. (2008-this issue), the rabbit Langendorff preparation and the Screenit approach [Dumotier, B. M., Deurinck, M., Yang, Y., Traebert, M., & Suter, W. (2008-this issue), the wedge preparation [Yan G.-X. (2008-this issue)] and hERG screens [Hancox, J.C., McPate, M.J., El Harchi, A., & Zhang, Y. h. (2008-this issue). Unbeknownst to the speakers before the start of the sessions, the audience were invited, during the session, to rate each approach on a 0 to 10 scale in terms of the extent to which each approach appeared to be validated. The outcome of this exercise forms the basis of this article. We invite you to evaluate for yourselves the accompanying reviews in this edition of Pharmacology and Therapeutics. (C) 2008 Elsevier Inc. All rights reserved
Refining insights into high-affinity drug binding to the human ether-à-go-go-related gene potassium channel
No full textRegulation of cardiac Na+-Ca2+ exchanger activity by protein kinase phosphorylation--still a paradox?
No full textA novel, voltage-dependent nonselective cation current activated by insulin in guinea pig isolated ventricular myocytes
No full textSuperconductors in alternating fields
No full textAfter a general introduction to the fundamentals of superconductivity, the concept of the critical state is introduced and its application to alternating field conditions discussed. A comprehensive review of the a.c. measurements in the literature and the relevance to the predictions of the theories is then given. Details of the comprehensive experimental facilities constructed are described, including the development of a sophisticated technique for the measurement of a.c. losses. The equipment is essentially a sensitive wattmeter, with a small analogue computer used to operate on the voltages, from pickup-coils wound directly on the samples.
The experiments reported start with work undertaken to
investigate the dissipation in applied fields, below the critical field. The part played by surface irregularities is explored and the general field dependence of the losses explained on a simple model. A large section is then devoted to the response of type II superconductors to large fields. Results are given on high-K materials and on both reversible and hysteretic niobium samples. The predictions of the critical state model are found to hold, if suitable modifications are made to account for the field region below Rcl and the surface currents. In particular, the applied field Hm can be replaced by (Hm - .6.H/2),where AH is the overall shielding effect of the surface currents. The value of these currents has been determined from the pickup-coil voltage waveforms and the interpretation of these waveshapes has also been advanced to determine the critical current density. A decrease in the surface currents, with roughening of the sample surface, is described, and their variation with bulk properties discussed. A correlation between the critical current density and the surface currents has been discovered, and examined on the basis of "surface barrier" pinning
Role of voltage-gated sodium, potassium and calcium channels in the development of cocaine-associated cardiac arrhythmias
No full textImages of Sacrifice: Religion, Power, and Colonial Ambition in the Americas
No full textThe article addresses images of sacrifice from Mesoamerica and the adoption of this imagery during Protestant colonization as a way to limit the Spanish power. The author posits that while initially serving the purpose of demonizing the Spanish Catholic presence in the Americas, the use of this imagery led Protestant powers to assert claims of religious and political superiority over both the Spanish and the indigenous peoples
- …
