The perplexing complexity of cardiac arrhythmias: Beyond electrical remodeling

Cardiac arrhythmias continue to pose a major medical challenge and significant public health burden. Atrial fibrillation, the most prevalent arrhythmia, affects more than two million Americans annually and is associated with a twofold increase in mortality. In addition, more than 250,000 Americans each year suffer ventricular arrhythmias, often resulting in sudden cardiac death. Despite the high incidence and societal impact of cardiac arrhythmias, presently there are insufficient insights into the molecular mechanisms involved in arrhythmia generation, propagation, and/or maintenance or into the molecular determinants of disease risk, prognosis, and progression. In addition, present therapeutic strategies for arrhythmia abatement often are ineffective or require palliative device therapy after persistent changes in the electrical and conduction characteristics of the heart have occurred, changes that appear to increase the risk for arrhythmia progression. This article reviews our present understanding of the complexity of mechanisms that regulate cardiac membrane excitability and cardiac function and explores the role of derangements in these mechanisms that interact to induce arrhythmogenic substrates. Approaches are recommended for future investigations focused on providing new mechanistic insights and therapeutic interventions.     

Der(16)t(1;16)(q21;q13) in Wilms' tumor: Friend or foe

The der(16)t(1;16)(q21;q13) chromosomal abnormality has been reported rarely in Wilms' tumor. This abnormality has also been found in several other pediatric and adult neoplasms, and may imply a poor prognosis in at least some of these solid tumors. To investigate its clinical significance in Wilms' tumor, we examined the records of 65 consecutive children with Wilms' tumor whose tumor cells were successfully karyotyped. The t(1;16) was present in seven patients (10%) whose ages ranged from 2.5 to 4.7 years (median 3.5 years) at diagnosis. Six of the seven patients were female. All four stages of Wilms' tumor were represented (two patients had stage IV disease). No patient had bilateral disease. All tumors were of “favorable histology.” All seven patients are alive and off therapy with a median follow-up of 3.2 years (range, 2 to 8.5 years). One patient with this abnormality developed brain metastases within 4 months of completion of therapy. Comparison of these patients with the remaining 58 Wilms' tumor patients revealed no significant differences with regard to disease stage, histology, survival, or relapse-free survival. Cytogenetic evidence of der(16)t(1;16)(q21;q13) in Wilms' tumor does not appear to portend an adverse clinical outcome, although only a larger study that includes molecular detection methods can provide more conclusive evidence. © 1996 Wiley-Liss, Inc.     

Development of rapid and selective epoxidation of α-pinene using single-step addition of H2O2 in an organic solvent-free process

This study reports substantial improvement in the process for oxidising α-pinene, using environmentally friendly H₂O₂ at high atom economy (∼93%) and selectivity to α-pinene oxide (100%). The epoxidation of α-pinene with H₂O₂ was catalysed by tungsten-based polyoxometalates without any solvent. The variables in the screening parameters were temperatures (30–70 °C), oxidant amount (100–200 mol%), acid concentrations (0.02–0.09 M) and solvent types (i.e., 1,2-dichloroethane, toluene, p-cymene and acetonitrile). Screening the process parameters revealed that almost 100% selective epoxidation of α-pinene to α-pinene oxide was possible with negligible side product formation within a short reaction time (∼20 min), using process conditions of a 50 °C temperature in the absence of solvent and α-pinene/H₂O₂/catalyst molar ratio of 5 : 1 : 0.01. A kinetic investigation showed that the reaction was first-order for α-pinene and catalyst concentration, and a fractional order (∼0.5) for H₂O₂ concentration. The activation energy (E_a) for the epoxidation of α-pinene was ∼35 kJ mol⁻¹. The advantages of the epoxidation reported here are that the reaction could be performed isothermally in an organic solvent-free environment to enhance the reaction rate, achieving nearly 100% selectivity to α-pinene oxide.

Products obtained from the oxidation of α-pinene with hydrogen peroxide (H₂O₂) in the presence of tungsten-based polyoxometalates (α-pinene 1, α-pinene oxide 2, pinanediol 3, campholenic aldehyde 4, sobrerol 5, verbenol 6 and verbenone 7).     

Weight gain during the dolutegravir transition in the African Cohort Study

IntroductionDolutegravir (DTG) has become a preferred component of first‐line antiretroviral therapy (ART) in many settings but may be associated with excess weight gain. We evaluated changes in weight and body mass index (BMI) after switch to single‐tablet tenofovir/lamivudine/dolutegravir (TLD) by people living with HIV (PLWH) in four African countries.MethodsThe African Cohort Study (AFRICOS) prospectively follows adults with and without HIV in Kenya, Uganda, Tanzania and Nigeria. Demographics, ART regimen, weight, BMI and waist‐to‐hip ratio were collected every 6 months. Multivariable Cox proportional hazards modelling was used to estimate hazard ratios and 95% confidence intervals (CIs) for factors associated with developing a BMI ≥25 kg/m². Linear mixed effects models with random effects were used to examine the average change in BMI, weight and waist‐to‐hip ratio.ResultsFrom 23 January 2013 to 1 December 2020, 2950 PLWH were enrolled in AFRICOS and 1474 transitioned to TLD. In adjusted models, PLWH on TLD had 1.77 times the hazard of developing a high BMI (95% CI: 1.22–2.55) compared to PLWH on non‐TLD ART. Examining change in weight among all PLWH on ART, participants on TLD gained an average of 0.68 kg (95% CI: 0.32–1.04) more than PLWH on other regimens after adjusting for duration on ART, sex, age, study site and CD4 nadir. Among participants who switched to TLD, the average change in weight prior to TLD switch was 0.35 kg/year (95% CI: 0.25–0.46) and average change in weight was 1.46 kg/year (95% CI: 1.18–1.75) in the year following transition to TLD after adjustment for confounders.ConclusionsElevated BMI and weight gain among PLWH on TLD are concerning safety signals. Implications for the development of metabolic comorbidities should be monitored, particularly if annual weight gain persists during continued follow‐up after transitioning to TLD.