Calcium channel diversity in the cardiovascular system

The flux of calcium ions (Ca2+) into the cytosol, where they serve as intracellular messengers, is regulated by two distinct families of Ca2+ channel proteins. These are the intracellular Ca2+ release channels, which allow Ca2+ to enter the cytosol from intracellular stores, and the plasma membrane Ca2+ channels, which control Ca2+ entry from the extracellular space. Each of these two families of channel proteins contains several subgroups. The intracellular channels include the large Ca2+ channels (“ryanodine receptors”) that participate in cardiac and skeletal muscle excitation-contraction coupling, and smaller inositol trisphosphate (InsP3)—activated Ca2+ channels. The latter serve several functions, including the pharmacomechanical coupling that activates smooth muscle contraction, and possibly regulation of diastolic tone in the heart. The InsP3-activated Ca2+ channels may also participate in signal transduction systems that regulate cell growth. The family of plasma membrane Ca2+ channels includes L-type channels, which respond to membrane depolarization by generating a signal that opens the intracellular Ca2+ release channels. Calcium ion entry through L-type Ca2+ channels in the sinoatrial (SA) node contributes to pacemaker activity, whereas L-type Ca2+ channels in the atrioventricular (AV) node are essential for AV conduction. The T-type Ca2+ channels, another member of the family of plasma membrane Ca2+ channels, participate in pharmacomechanical coupling in smooth muscle. Opening of these channels in response to membrane depolarization participates in SA node pacemaker currents, but their role in the working cells of the atria and ventricle is less clear. Like the InsP3-activated intracellular Ca2+ release channels, T-type plasma membrane channels may regulate cell growth. Because most of the familiar Ca2+ channel blocking agents currently used in cardiology, such as nifedipine, verapamil and diltiazem, are selective for L-type Ca2+ channels, the recent development of drugs that selectively block T-type Ca2+ channels offers promise of new approaches to cardiovascular therapy

Changing strategies in the management of heart failure

AbstractForty years ago therapy for congestive heart failure was limited largely to the mercurial diuretics and a variety of cardiac glycoside preparations; these were often ineffective, and the common practice of “pushing” digitalis caused serious, sometimes lethal side effects. Today, a more complete understanding of the regulation of cardiac work and pathophysiology of heart failure is having a profound impact on therapeutic strategy for this common condition. Despite more powerful means to augment myocardial contractility and much more effective diuretics, therapy that relies only on inotropic stimulation and diuresis is no longer optimal for the majority of patients with heart failure. Thus, strategies for the therapy of heart failure must take into account new understanding of mechanisms that initiate, perpetuate and exacerbate the hemodynamic and myocardial abnormalities in these patients.Recognition of the detrimental effects of excessive afterload and the importance of relaxation (lusitropic) as well as contraction (inotropic) abnormalities has led to widespread acceptance of vasodilator therapy, which has dramatically improved our ability to alleviate the symptoms of heart failure. Changes that result from altered gene expression in the hypertrophied myocardium of patients with congestive heart failure can give rise to a cardiomyopathy of overload that, although initially compensatory, may hasten death. These and other advances in our understanding of the pathophysiology, biochemistry and molecular biology of heart failure provide a basis for new therapeutic strategies that can slow the progressive myocardial damage that causes many of these patients to die, while at the same time improving well-being in patients with congestive heart failure

Denominators of Eisenstein cohomology classes for GL_2 over imaginary quadratic fields

We study the arithmetic of Eisenstein cohomology classes (in the sense of G. Harder) for symmetric spaces associated to GL_2 over imaginary quadratic fields. We prove in many cases a lower bound on their denominator in terms of a special L-value of a Hecke character providing evidence for a conjecture of Harder that the denominator is given by this L-value. We also prove under some additional assumptions that the restriction of the classes to the boundary of the Borel-Serre compactification of the spaces is integral. Such classes are interesting for their use in congruences with cuspidal classes to prove connections between the special L-value and the size of the Selmer group of the Hecke character.Comment: 37 pages; strengthened integrality result (Proposition 16), corrected statement of Theorem 3, and revised introductio

Dynamical overlap fermions, results with hybrid Monte-Carlo algorithm

We present first, exploratory results of a hybrid Monte-Carlo algorithm for dynamical, n_f=2, four-dimensional QCD with overlap fermions. As expected, the computational requirements are typically two orders of magnitude larger for the dynamical overlap formalism than for the more conventional (Wilson or staggered) formulations.Comment: 13 pages, 2 figure

Numerical convergence of the block-maxima approach to the Generalized Extreme Value distribution

In this paper we perform an analytical and numerical study of Extreme Value distributions in discrete dynamical systems. In this setting, recent works have shown how to get a statistics of extremes in agreement with the classical Extreme Value Theory. We pursue these investigations by giving analytical expressions of Extreme Value distribution parameters for maps that have an absolutely continuous invariant measure. We compare these analytical results with numerical experiments in which we study the convergence to limiting distributions using the so called block-maxima approach, pointing out in which cases we obtain robust estimation of parameters. In regular maps for which mixing properties do not hold, we show that the fitting procedure to the classical Extreme Value Distribution fails, as expected. However, we obtain an empirical distribution that can be explained starting from a different observable function for which Nicolis et al. [2006] have found analytical results.Comment: 34 pages, 7 figures; Journal of Statistical Physics 201

The rigid limit in Special Kahler geometry; From K3-fibrations to Special Riemann surfaces: a detailed case study

The limiting procedure of special Kahler manifolds to their rigid limit is studied for moduli spaces of Calabi-Yau manifolds in the neighbourhood of certain singularities. In two examples we consider all the periods in and around the rigid limit, identifying the nontrivial ones in the limit as periods of a meromorphic form on the relevant Riemann surfaces. We show how the Kahler potential of the special Kahler manifold reduces to that of a rigid special Kahler manifold. We extensively make use of the structure of these Calabi-Yau manifolds as K3 fibrations, which is useful to obtain the periods even before the K3 degenerates to an ALE manifold in the limit. We study various methods to calculate the periods and their properties. The development of these methods is an important step to obtain exact results from supergravity on Calabi-Yau manifolds.Comment: 79 pages, 8 figures. LaTeX; typos corrected, version to appear in Classical and Quantum Gravit

Mathematics of Gravitational Lensing: Multiple Imaging and Magnification

The mathematical theory of gravitational lensing has revealed many generic and global properties. Beginning with multiple imaging, we review Morse-theoretic image counting formulas and lower bound results, and complex-algebraic upper bounds in the case of single and multiple lens planes. We discuss recent advances in the mathematics of stochastic lensing, discussing a general formula for the global expected number of minimum lensed images as well as asymptotic formulas for the probability densities of the microlensing random time delay functions, random lensing maps, and random shear, and an asymptotic expression for the global expected number of micro-minima. Multiple imaging in optical geometry and a spacetime setting are treated. We review global magnification relation results for model-dependent scenarios and cover recent developments on universal local magnification relations for higher order caustics.Comment: 25 pages, 4 figures. Invited review submitted for special issue of General Relativity and Gravitatio