Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients

Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we evaluated antiarrhythmic efficacy of carvedilol and flecainide in CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying different mutations in RYR2. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion and IA115 or V4653F mutation in RYR2 and of a healthy individual. Ca2+ kinetics and drug effects were studied with Fluo-4 AM indicator. Carvedilol abolished Ca2+ abnormalities in 31% of L4115F, 36% of V4653F, and 46% of exon 3 deletion carrying CPVT cardiomyocytes and flecainide 33%, 30%, and 52%, respectively. Both drugs lowered the intracellular Ca2+ level and beating rate of the cardiomyocytes significantly. Moreover, flecainide caused abnormal Ca2+ transients in 61% of controls compared to 26% of those with carvedilol. Carvedilol and flecainide were equally effective in CPVT iPSC-CMs. However, flecainide induced arrhythmias in 61% of control cells. CPVT cardiomyocytes carrying the exon 3 deletion had the most severe Ca2+ abnormalities, but they had the best response to drug therapies. According to this study, the arrhythmia-abolishing effect of neither of the drugs is optimal. iPSC-CMs provide a unique platform for testing drugs for CPVT.Peer reviewe

Fine Particulate Air Pollution and Mortality in Nine California Counties: Results from CALFINE

Many epidemiologic studies provide evidence of an association between daily counts of mortality and ambient particulate matter < 10 μm in diameter (PM(10)). Relatively few studies, however, have investigated the relationship of mortality with fine particles [PM < 2.5 μm in diameter (PM(2.5))], especially in a multicity setting. We examined associations between PM(2.5) and daily mortality in nine heavily populated California counties using data from 1999 through 2002. We considered daily counts of all-cause mortality and several cause-specific subcategories (respiratory, cardiovascular, ischemic heart disease, and diabetes). We also examined these associations among several subpopulations, including the elderly (> 65 years of age), males, females, non-high school graduates, whites, and Hispanics. We used Poisson multiple regression models incorporating natural or penalized splines to control for covariates that could affect daily counts of mortality, including time, seasonality, temperature, humidity, and day of the week. We used meta-analyses using random-effects models to pool the observations in all nine counties. The analysis revealed associations of PM(2.5) levels with several mortality categories. Specifically, a 10-μg/m(3) change in 2-day average PM(2.5) concentration corresponded to a 0.6% (95% confidence interval, 0.2–1.0%) increase in all-cause mortality, with similar or greater effect estimates for several other subpopulations and mortality subcategories, including respiratory disease, cardiovascular disease, diabetes, age > 65 years, females, deaths out of the hospital, and non-high school graduates. Results were generally insensitive to model specification and the type of spline model used. This analysis adds to the growing body of evidence linking PM(2.5) with daily mortality

Kinematical twist-3 effects in DVCS as a quark spin rotation

We point out that the kinematical twist-3 contributions to the DVCS amplitude, required to restore electromagnetic gauge invariance of the twist-2 amplitude up to O(t/q^2), can be understood as a spin rotation applied to the twist-2 quark density matrix in the target. This allows for a compact representation of the twist-3 effects, as well as for a simple physical interpretation.Comment: 4 pages, revtex, 3 eps figures included using eps

Assessment of human influenza pandemic scenarios in Europe

The response to the emergence of the 2009 influenza A(H1N1) pandemic was the result of a decade of pandemic planning, largely centred on the threat of an avian influenza A(H5N1) pandemic. Based on a literature review, this study aims to define a set of new pandemic scenarios that could be used in case of a future influenza pandemic. A total of 338 documents were identified using a searching strategy based on seven combinations of keywords. Eighty-three of these documents provided useful information on the 13 virus-related and health-system-related parameters initially considered for describing scenarios. Among these, four parameters were finally selected (clinical attack rate, case fatality rate, hospital admission rate, and intensive care admission rate) and four different levels of severity for each of them were set. The definition of six most likely scenarios results from the combination of four different levels of severity of the four final parameters (256 possible scenarios). Although it has some limitations, this approach allows for more flexible scenarios and hence it is far from the classic scenarios structure used for pandemic plans until 2009

Comparing introduction to Europe of highly pathogenic avian influenza viruses A(H5N8) in 2014 and A(H5N1) in 2005

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Beta-Lactam Sensitive Bacteria Can Acquire ESBL-Resistance via Conjugation after Long-Term Exposure to Lethal Antibiotic Concentration

Beta-lactams are commonly used antibiotics that prevent cell-wall biosynthesis. Beta-lactam sensitive bacteria can acquire conjugative resistance elements and hence become resistant even after being exposed to lethal (above minimum inhibitory) antibiotic concentrations. Here we show that neither the length of antibiotic exposure (1 to 16 h) nor the beta-lactam type (penam or cephem) have a major impact on the rescue of sensitive bacteria. We demonstrate that an evolutionary rescue can occur between different clinically relevant bacterial species (Klebsiella pneumoniae and Escherichia coli) by plasmids that are commonly associated with extended-spectrum beta-lactamase (ESBL) positive hospital isolates. As such, it is possible that this resistance dynamic may play a role in failing antibiotic therapies in those cases where resistant bacteria may readily migrate into the proximity of sensitive pathogens. Furthermore, we engineered a Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) -plasmid to encode a guiding CRISPR-RNA against the migrating ESBL-plasmid. By introducing this plasmid into the sensitive bacterium, the frequency of the evolutionarily rescued bacteria decreased by several orders of magnitude. As such, engineering pathogens during antibiotic treatment may provide ways to prevent ESBL-plasmid dispersal and hence resistance evolution

~1400-nm continuous-wave diamond Raman laser intracavity-pumped by an InGaAs semiconductor disk laser

We present a ~1400nm-emitting diamond Raman laser intracavity-pumped by an ~1180nm semiconductor disk laser. We measured a maximum output power of 2.3 W at ~1400nm with an output coupling of 3.5%. The Raman laser was tunable from 1373 to 1415nm using a 4-mm-thick birefringent filter

DVCS on the nucleon : study of the twist-3 effects

We estimate the size of the twist-3 effects on deeply virtual Compton scattering (DVCS) observables, in the Wandzura-Wilczek approximation. We present results in the valence region for the DVCS cross sections, charge asymmetries and single spin asymmetries, to twist-3 accuracy.Comment: 20 pages, 6 figure