Long-term reproducibility of electrophysiologically guided therapy with sotalol in patients with ventricular tachyarrhythmias

AbstractOBJECTIVESGoal of this study was to assess the long-term reproducibility of electrophysiologic drug testing in patients with ventricular tachyarrhythmias (VT/VF).BACKGROUNDProgrammed ventricular stimulation (PVS) is still widely used to guide antiarrhythmic therapy in patients with sustained ventricular tachycardia/fibrillation (VT/VF). Sotalol is considered as one of the most effective drugs for VT/VF. Because there is no proof of long-term reproducibility of a successful drug test with sotalol, we investigated the long-term reproducibility of drug testing with sotalol.METHODSThirty patients with VT/VF (age: 57 ± 11 years, 20 patients with coronary heart disease, 7 patients with no structural heart disease, 3 with others) and reproducible induction of VT/VF (28 patients VT, two patients VF) in a baseline PVS, were suppressible with sotalol (mean dosage 395 ± 137 mg) in a subsequent PVS. After a mean follow-up of 13 ± 10 months a PVS was again performed in patients, who had no evidence of progressive cardiac disease, who did not experience any arrhythmia recurrences or who were drug compliant. Irrespective of the inducibility after long-term therapy with sotalol, all patients were kept on the initial sotalol regimen. All 30 patients had a stable cardiac condition, were free of VT/VF recurrences and were drug compliant.RESULTSDespite the clinical efficacy of sotalol, in 12 patients (40%) VT/VF could again be induced after 13 ± 10.2 months. Inducibility was independent of age, heart disease, ejection fraction and follow-up time. During a further follow-up of 22.1 ± 10.9 months, five patients experienced nonfatal VT recurrences independently of the prior inducibility.CONCLUSIONSThis study shows a lacking long-term reproducibility of an initial effective PVS with sotalol. Despite an uneventful clinical follow-up, late electrophysiologic testing showed a VT/VF inducibility in a high portion of patients. Hence, electrophysiologic testing performed late after the initial drug test may no longer be predictive of outcome

Electrophysiologic Effects of Chronic Amiodarone Therapy and Hypothyroidism

ABSTRACT Amiodarone is a widely used antiarrhythmic drug, the mechanisms of action of which remain incompletely understood. Indirect evidence suggests that the class III properties of amiodarone may be mediated by cardiac antithyroid effects. We sought to determine whether the effects of chronic amiodarone on repolarization in guinea pig hearts can be attributed to an antithyroid action by studying the changes in dofetilide-sensitive rapid (I Kr ) and dofetilide-resistant slow (I Ks ) delayed rectifier currents, inward rectifier K ϩ current (I K1 ), and action potentials of ventricular myocytes from five groups of guinea pigs: control, hypothyroid, amiodarone-treated for 7 days, hypothyroid plus amiodarone, and vehicle (dimethyl sulfoxide) treated. I Ks was reduced by amiodarone (to 61% of control, P Ͻ .05, at 50 mV) but was more strongly reduced by hypothyroidism (to 35% of control, P Ͻ .01, 50 mV). Amiodarone significantly reduced I Kr and I K1 (by 55 and 64% at 10 mV and Ϫ50 mV, respectively), which were unaffected by hypothyroidism. Amiodarone alone and hypothyroidism alone had similar action potential-prolonging actions. Hypothyroid animals treated with amiodarone showed a combination of ionic effects (strong I Ks reduction, similar to hypothyroidism alone; reduced I Kr and I K1 , similar to amiodarone alone), along with action potential prolongation significantly greater than that caused by either intervention alone. We conclude that chronic amiodarone and hypothyroidism have different effects on ionic currents and that their combination prolongs action potential duration to a greater extent than either alone in guinea pig hearts, suggesting that the class III actions of amiodarone are not mediated by a cardiac hypothyroid state

Converse Smith-Martin cell cycle kinetics by transformed B lymphocytes

Recent studies using direct live cell imaging have reported that individual B lymphocytes have correlated transit times between their G1 and S/G2/M phases. This finding is in contradiction with the influential model of Smith and Martin that assumed the bulk of the total cell cycle time variation arises in the G1 phase of the cell cycle with little contributed by the S/G2/M phase. Here we extend these studies to examine the relation between cell cycle phase lengths in two B lymphoma cell lines. We report that transformed B lymphoma cells undergo a short G1 period that displays little correlation with the time taken for the subsequent S/G2/M phase. Consequently, the bulk of the variation noted for total division times within a population is found in the S/G2/M phases and not the G1 phase. Models that reverse the expected source of variation and assume a single deterministic time in G1 followed by a lag + exponential distribution for S/G2/M fit the data well. These models can be improved further by adopting two sequential distributions or by using the stretched lognormal model developed for primary lymphocytes. We propose that shortening of G1 transit times and uncoupling from other cell cycle phases may be a hallmark of lymphocyte transformation that could serve as an observable phenotypic marker of cancer evolution.K. Pham, A. Kan, L. Whitehead, R. J. Hennessy, K. Rogers, P. D. Hodgki

Theories of American Imperialism: A Critical Evaluation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68828/2/10.1177_048661347400600303.pd

Prolonged conservative treatment or 'early' surgery in sciatica caused by a lumbar disc herniation: rationale and design of a randomized trial [ISRCT 26872154]

BACKGROUND: The design of a randomized multicenter trial is presented on the effectiveness of a prolonged conservative treatment strategy compared with surgery in patients with persisting intense sciatica (lumbosacral radicular syndrome). METHODS/DESIGN: Patients presenting themselves to their general practitioner with disabling sciatica lasting less than twelve weeks are referred to the neurology outpatient department of one of the participating hospitals. After confirmation of the diagnosis and surgical indication MRI scanning is performed. If a distinct disc herniation is discerned which in addition covers the clinically expected site the patient is eligible for randomization. Depending on the outcome of the randomization scheme the patient will either be submitted to prolonged conservative care or surgery. Surgery will be carried out according to the guidelines and between six and twelve weeks after onset of complaints. The experimental therapy consists of a prolonged conservative treatment under supervision of the general practitioner, which may be followed by surgical intervention in case of persisting or progressive disability. The main primary outcome measure is the disease specific disability of daily functioning. Other primary outcome measures are perceived recovery and intensity of legpain. Secondary outcome measures encompass severity of complaints, quality of life, medical consumption, absenteeism, costs and preference. The main research question will be answered at 12 months after randomization. The total follow-up period covers two years. DISCUSSION: Evidence is lacking concerning the optimal treatment of lumbar disc induced sciatica. This pragmatic randomized trial, focusses on the 'timing' of intervention, and will contribute to the decision of the general practictioner and neurologist, regarding referral of patients for surgery

Low-temperature SCR of NO with NH 3 over noble metal promoted Fe-ZSM-5 catalysts

We have reported previously the excellent performance of Fe-exchanged ZSM-5 for selective catalytic reduction (SCR) of NO with ammonia at high temperatures (300–400 °C). In this work, we found that the reaction temperature could be decreased to 200–300 °C when a small amount of noble metal (Pt, Rh, or Pd) was added to the Fe-ZSM-5. The SCR activity follows the order Pt/Fe-ZSM-5 > Rh/Fe-ZSM-5 > Pd/Fe-ZSM-5 at 250 °C. On the Pt promoted Fe-ZSM-5, 90% NO conversion was obtained at 250 °C at GHSV  = 1.1 ×  10 5  h −1 . Moreover, the noble metal improved the resistance to H 2 O and SO 2 . The presence of H 2 O and SO 2 decreased the SCR performance only very slightly.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44250/1/10562_2004_Article_3462.pd

Mouse Hepatitis Coronavirus RNA Replication Depends on GBF1-Mediated ARF1 Activation

Coronaviruses induce in infected cells the formation of double membrane vesicles, which are the sites of RNA replication. Not much is known about the formation of these vesicles, although recent observations indicate an important role for the endoplasmic reticulum in the formation of the mouse hepatitis coronavirus (MHV) replication complexes (RCs). We now show that MHV replication is sensitive to brefeldin A (BFA). Consistently, expression of a dominant-negative mutant of ARF1, known to mimic the action of the drug, inhibited MHV infection profoundly. Immunofluorescence analysis and quantitative electron microscopy demonstrated that BFA did not block the formation of RCs per se, but rather reduced their number. MHV RNA replication was not sensitive to BFA in MDCK cells, which are known to express the BFA-resistant guanine nucleotide exchange factor GBF1. Accordingly, individual knockdown of the Golgi-resident targets of BFA by transfection of small interfering RNAs (siRNAs) showed that GBF1, but not BIG1 or BIG2, was critically involved in MHV RNA replication. ARF1, the cellular effector of GBF1, also appeared to be involved in MHV replication, as siRNAs targeting this small GTPase inhibited MHV infection significantly. Collectively, our results demonstrate that GBF1-mediated ARF1 activation is required for efficient MHV RNA replication and reveal that the early secretory pathway and MHV replication complex formation are closely connected

The 13th Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-IV Survey Mapping Nearby Galaxies at Apache Point Observatory

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) began observations in July 2014. It pursues three core programs: APOGEE-2,MaNGA, and eBOSS. In addition, eBOSS contains two major subprograms: TDSS and SPIDERS. This paper describes the first data release from SDSS-IV, Data Release 13 (DR13), which contains new data, reanalysis of existing data sets and, like all SDSS data releases, is inclusive of previously released data. DR13 makes publicly available 1390 spatially resolved integral field unit observations of nearby galaxies from MaNGA,the first data released from this survey. It includes new observations from eBOSS, completing SEQUELS. In addition to targeting galaxies and quasars, SEQUELS also targeted variability-selected objects from TDSS and X-ray selected objects from SPIDERS. DR13 includes new reductions ofthe SDSS-III BOSS data, improving the spectrophotometric calibration and redshift classification. DR13 releases new reductions of the APOGEE-1data from SDSS-III, with abundances of elements not previously included and improved stellar parameters for dwarf stars and cooler stars. For the SDSS imaging data, DR13 provides new, more robust and precise photometric calibrations. Several value-added catalogs are being released in tandem with DR13, in particular target catalogs relevant for eBOSS, TDSS, and SPIDERS, and an updated red-clump catalog for APOGEE.This paper describes the location and format of the data now publicly available, as well as providing references to the important technical papers that describe the targeting, observing, and data reduction. The SDSS website, http://www.sdss.org, provides links to the data, tutorials and examples of data access, and extensive documentation of the reduction and analysis procedures. DR13 is the first of a scheduled set that will contain new data and analyses from the planned ~6-year operations of SDSS-IV.PostprintPeer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

A global experiment on motivating social distancing during the COVID-19 pandemic

Finding communication strategies that effectively motivate social distancing continues to be a global public health priority during the COVID-19 pandemic. This cross-country, preregistered experiment (n = 25,718 from 89 countries) tested hypotheses concerning generalizable positive and negative outcomes of social distancing messages that promoted personal agency and reflective choices (i.e., an autonomy-supportive message) or were restrictive and shaming (i.e., a controlling message) compared with no message at all. Results partially supported experimental hypotheses in that the controlling message increased controlled motivation (a poorly internalized form of motivation relying on shame, guilt, and fear of social consequences) relative to no message. On the other hand, the autonomy-supportive message lowered feelings of defiance compared with the controlling message, but the controlling message did not differ from receiving no message at all. Unexpectedly, messages did not influence autonomous motivation (a highly internalized form of motivation relying on one’s core values) or behavioral intentions. Results supported hypothesized associations between people’s existing autonomous and controlled motivations and self-reported behavioral intentions to engage in social distancing. Controlled motivation was associated with more defiance and less long-term behavioral intention to engage in social distancing, whereas autonomous motivation was associated with less defiance and more short- and long-term intentions to social distance. Overall, this work highlights the potential harm of using shaming and pressuring language in public health communication, with implications for the current and future global health challenges