Inhibition of Ion Channels and Heart Beat in Drosophila by Selective COX-2 Inhibitor SC-791

Recent findings suggest that modulation of ion channels might be implicated in some of the clinical effects of coxibs, selective inhibitors of cyclooxygenase-2 (COX-2). Celecoxib and its inactive analog 2,5-dimethyl-celecoxib, but not rofecoxib, can suppress or augment ionic currents and alter functioning of neurons and myocytes. To better understand these unexpected effects, we have recently investigated the mechanism of inhibition of human Kv2.1 channels by a highly selective COX-2 inhibitor SC-791. In this study we have further explored the SC-791 action on ion channels and heartbeat in Drosophila, which lacks cyclooxygenases and thus can serve as a convenient model to study COX-2-independent mechanisms of coxibs. Using intracellular recordings in combination with a pharmacological approach and utilizing available Drosophila mutants, we found that SC-791 inhibited voltage-activated K+ and L-type Ca2+ channels in larval body-wall muscles and reduced heart rate in a concentration-dependent manner. Unlike celecoxib and several other K+ channel blockers, SC-791 did not induce arrhythmia. Instead, application of SC-791 resulted in a dramatic slowing of contractions and, at higher concentrations, in progressively weaker contractions with gradual cessation of heartbeat. Isradipine, a selective blocker of L-type Ca2+ channels, showed a similar pattern of heart arrest, though no prolongation of contractions was observed. Ryanodine was the only channel modulating compound of those tested additionally that was capable of slowing contractions. Like SC-791, ryanodine reduced heart rate without arrhythmia. However, it could not stop heartbeat completely even at 500 µM, the highest concentration used. The magnitude of heart rate reduction, when SC-791 and ryanodine were applied together, was smaller than expected for independent mechanisms, raising the possibility that SC-791 might be interfering with excitation-contraction coupling in Drosophila heart

Rotating traversable wormholes

The general form of a stationary, axially symmetric traversable wormhole is discussed. This provides an explicit class of rotating wormholes that generalize the static, spherically symmetric ones first considered by Morris and Thorne. In agreement with general analyses, it is verified that such a wormhole generically violates the null energy condition at the throat. However, for suitable model wormholes, there can be classes of geodesics falling through it which do not encounter any energy-condition-violating matter. The possible presence of an ergoregion surrounding the throat is also noted.Comment: 15 pages, harvmac; 1 figure in PicTeX; minor changes; to appear in Phys. Rev.

Inflating Lorentzian Wormholes

It has been speculated that Lorentzian wormholes of the Morris- Thorne type might be allowed by the laws of physics at submicroscopic, e.g. Planck, scales and that a sufficiently advanced civilization might be able to enlarge them to classical size. The purpose of this paper is to explore the possibility that inflation might provide a natural mechanism for the enlargement of such wormholes to macroscopic size. A new classical metric is presented for a Lorentzian wormhole which is imbedded in a flat deSitter space. It is shown that the throat and proper length of the wormhole inflate. The resulting properties and stress-energy tensor associated with this metric are discussed.Comment: 24 pg

Natural Wormholes as Gravitational Lenses

Visser has suggested traversable 3-dimensional wormholes that could plausibly form naturally during Big Bang inflation. A wormhole mouth embedded in high mass density might accrete mass, giving the other mouth a net *negative* mass of unusual gravitational properties. The lensing of such a gravitationally negative anomalous compact halo object (GNACHO) will enhance background stars with a time profile that is observable and qualitatively different from that recently observed for massive compact halo objects (MACHOs) of positive mass. We recommend that MACHO search data be analyzed for GNACHOs.Comment: 4 pages; plus 4 figures; ReV_TeX 3.0; DOE/ER/40537-001/NPL94-07-01

Quantum Dynamics of Lorentzian Spacetime Foam

A simple spacetime wormhole, which evolves classically from zero throat radius to a maximum value and recontracts, can be regarded as one possible mode of fluctuation in the microscopic ``spacetime foam'' first suggested by Wheeler. The dynamics of a particularly simple version of such a wormhole can be reduced to that of a single quantity, its throat radius; this wormhole thus provides a ``minisuperspace model'' for a structure in Lorentzian-signature foam. The classical equation of motion for the wormhole throat is obtained from the Einstein field equations and a suitable equation of state for the matter at the throat. Analysis of the quantum behavior of the hole then proceeds from an action corresponding to that equation of motion. The action obtained simply by calculating the scalar curvature of the hole spacetime yields a model with features like those of the relativistic free particle. In particular the Hamiltonian is nonlocal, and for the wormhole cannot even be given as a differential operator in closed form. Nonetheless the general solution of the Schr\"odinger equation for wormhole wave functions, i.e., the wave-function propagator, can be expressed as a path integral. Too complicated to perform exactly, this can yet be evaluated via a WKB approximation. The result indicates that the wormhole, classically stable, is quantum-mechanically unstable: A Feynman-Kac decomposition of the WKB propagator yields no spectrum of bound states. Though an initially localized wormhole wave function may oscillate for many classical expansion/recontraction periods, it must eventually leak to large radius values. The possibility of such a mode unstable against growth, combined withComment: 37 pages, 93-

Is Quantum Spacetime Foam Unstable?

A very simple wormhole geometry is considered as a model of a mode of topological fluctutation in Planck-scale spacetime foam. Quantum dynamics of the hole reduces to quantum mechanics of one variable, throat radius, and admits a WKB analysis. The hole is quantum-mechanically unstable: It has no bound states. Wormhole wave functions must eventually leak to large radii. This suggests that stability considerations along these lines may place strong constraints on the nature and even the existence of spacetime foam.Comment: 15 page

Evolving wormhole geometries

We present here analytical solutions of General Relativity that describe evolving wormholes with a non-constant redshift function. We show that the matter that threads these wormholes is not necessarily exotic. Finally, we investigate some issues concerning WEC violation and human traversability in these time-dependent geometries.Comment: 12 pages latex, 3 figures, to appear in Phys. Rev. D., Title correcte

Classical Scalar Fields and the Generalized Second Law

It has been shown that classical non-minimally coupled scalar fields can violate all of the standard energy conditions in general relativity. Violations of the null and averaged null energy conditions obtainable with such fields have been suggested as possible exotic matter candidates required for the maintenance of traversable wormholes. In this paper, we explore the possibility that if such fields exist, they might be used to produce large negative energy fluxes and macroscopic violations of the generalized second law (GSL) of thermodynamics. We find that it appears to be very easy to produce large magnitude negative energy fluxes in flat spacetime. However we also find, somewhat surprisingly, that these same types of fluxes injected into a black hole do {\it not} produce violations of the GSL. This is true even in cases where the flux results in a decrease in the area of the horizon. We demonstrate that two effects are responsible for the rescue of the GSL: the acausal behavior of the horizon and the modification of the usual black hole entropy formula by an additional term which depends on the scalar field.Comment: 25 pages, 2 figures; paper substantially rewritten, major changes in the conclusion

ГОСПИТАЛЬНЫЕ РЕЗУЛЬТАТЫ БИМАММАРНОГО КОРОНАРНОГО ШУНТИРОВАНИЯ

HighlightsThe present study was conducted to evaluate in-hospital outcomes of one of the most effective and simultaneously controversial surgical techniques for myocardial revascularization using two internal thoracic arteries (ITA).To this date, this is the most complete analysis that has been carried out at the Research Institute on the topic of studying bilateral internal thoracic artery grafting (BITA). The results obtained are of great importance for the subsequent evaluation of long-term results. AbstractAim. To analyze in-hospital outcomes of BITA.Methods. The study included 232 patients who were admitted to the Cardiac Surgery Department for coronary artery bypass grafting (CABG). All patients were divided into 2 groups depending on the use of either single or bilateral ITA conduits. Both groups included equal number of patients – 116. In-hospital outcomes were analyzed.Results. BITA and CABG with single ITA were proven to be comparable regarding myocardial infarction, stroke, the need for percutaneous coronary intervention, death, and composite endpoint. At the same time BITA patients significantly more often had longer hospital stay and required inotropic drugs.Conclusion. BITA is a safe procedure comparable to classic CABG in terms of in-hospital complications, but at the same time, this intervention is associated with longer hospital stay, and extended inotropic drugs use.Основные положенияНастоящее исследование проведено для оценки госпитальных результатов одной из самых эффективных и одновременно противоречивых хирургических технологий реваскуляризации миокарда с применением двух внутренних грудных артерий.Представленный анализ является наиболее крупным из когда-либо выполненных специалистами НИИ КПССЗ по изучению бимаммарного коронарного шунтирования. Также полученные данные имеют важное значение для последующей оценки отдаленных результатов. РезюмеЦель. Оценить госпитальные результаты бимаммарного коронарного шунтирования.Материалы и методы. Изучены данные 232 историй болезни пациентов, поступивших в кардиохирургическое отделение для проведения коронарного шунтирования. Все больные были разделены на две группы в зависимости от использования одной или двух внутренних грудных артерий. В первую и вторую группы вошло равное количество пациентов – по 116 (50%) в каждой. Оценены результаты госпитального послеоперационного периода.Результаты. Бимаммарное и аортокоронарное шунтирование с использованием одной внутренней грудной артерии сопоставимы по таким госпитальным осложнениям, как инфаркт миокарда, инсульт, необходимость в чрескожном коронарном вмешательстве, а также по комбинированной конечной точке. Вместе с тем пациенты, перенесшие бимаммарное шунтирование, достоверно чаще нуждались в приеме инотропных препаратов, а также дольше находились в стационаре.Заключение. Бимаммарное шунтирование – безопасная процедура, сравнимая по госпитальным осложнениям с классическим аортокоронарным шунтированием, вместе с тем такое вмешательство требует более продолжительного пребывания пациентов в стационаре, а также дополнительного использования инотропных препаратов.