Differential Rate and Potassium-Dependent Effects of the Class III Agents d-Sotalol and Dofetilide on Guinea Pig Papillary Muscle

The class III agents d-sotalol and dofetilide have been shown to exhibit differential effects in large controlled clinical trials. The aim of this study was to investigate the basic electrophysiological properties of these two antiarrhythmia agents in an in vitro experimental model with regard to potential antiarrhythmic and proarrhythmic action. Using standard microelectrode techniques, we evaluated the electrophysiological effects of d-sotalol and dofetilide on action potential parameters recorded from guinea pig papillary muscle at 2.5 mM, 3.5 mM, and 5.6 mM extracellular potassium concentrations. The following parameters were recorded: resting membrane potential (RMP), action potential amplitude (APA), action potential duration at 90% repolarization (APD 90), and maximum upstroke velocity (Vmax). Under all conditions studied, both d-sotalol and dofetilide exhibited highly selective reverse rate-dependent class III action. In contrast to dofetilide, the class III activity of d-sotalol was markedly influenced by changes in extracellular potassium concentrations, predominantly at low pacing rates. Hypokalemia enhanced the action potential–prolonging effects of d-sotalol, whereas hyperkalemia diminished this effect. In addition, reverse rate dependence associated with dofetilide was significantly more pronounced than reverse rate dependence associated with d-sotalol. Our observations provide a potential electrophysiological basis for differential antiarrhythmic and proarrhythmic mechanisms associated with these two drugs.     

Visually detected NREM Stage 2 sleep spindles in kindergarten children are associated with current and future emotional and behavioural characteristics

Sleep electroencephalogram spindles are associated with efficient cortical–subcortical connectivity, and intellectual and learning abilities. In the present study, we assessed healthy preschoolers with a twofold aim: (i) to explore associations of non‐rapid eye movement S2 spindles with emotional/behavioural characteristics cross‐sectionally; and (ii) longitudinally. A total of 43 children who were 5 years old underwent objective sleep electroencephalogram monitoring in their homes. Emotional and behavioural dimensions were assessed by parents and teachers with the Strengths & Difficulties Questionnaire at baseline and at follow‐up 1 year later. Non‐rapid eye movement S2 spindles were visually scored and compared with Strengths & Difficulties Questionnaire dimensions. High non‐rapid eye movement S2 spindle density was associated with less internalizing behaviour, more prosocial behaviour and a low total problem score. In girls, high non‐rapid eye movement S2 spindle density was related to low hyperactivity, while in boys it was associated with less internalizing behaviour, more externalizing behaviour and more hyperactivity. Longitudinally, a higher number of non‐rapid eye movement S2 spindles at 5 years old predicted fewer peer problems 12 months later. In kindergarten children, high non‐rapid eye movement S2 spindle density is associated with observable current and future favourable emotional/behavioural patterns. However, gender differences were also found, as should be taken into account in future studies.     

High resolution copy number analysis of IRF4 translocation‐positive diffuse large B‐cell and follicular lymphomas

Translocations affecting chromosome subband 6p25.3 containing the IRF4 gene have been recently described as characteristic alterations in a molecularly distinct subset of germinal center B‐cell‐derived lymphomas. Secondary changes have yet only been described in few of these lymphomas. Here, we performed array‐comparative genomic hybridization and molecular inversion probe microarray analyses on DNA from 12 formalin‐fixed paraffin‐embedded and two fresh‐frozen IRF4 translocation‐positive lymphomas, which together with the previously published data on nine cases allowed the extension of copy number analyses to a total of 23 of these lymphomas. All except one case carried chromosomal imbalances, most frequently gains in Xq28, 11q22.3‐qter, and 7q32.1‐qter and losses in 6q13‐16.1, 15q14‐22.31, and 17p. No recurrent copy‐neutral losses of heterozygosity were observed. TP53 point mutations were detected in three of six cases with loss of 17p. Overall this study unravels a recurrent pattern of secondary genetic alterations in IRF4 translocation‐positive lymphomas. © 2012 Wiley Periodicals, Inc.     

Incidence of venous obstruction following insertion of an implantable cardioverter defibrillator. A study of systematic contrast venography on patients presenting for their first elective ICD generator replacement.

AIMS: The number of implantable cardioverter defibrillator (ICD) implantations, as well as follow-up procedures such as generator exchanges, lead revisions and lead system upgrades, is ever-increasing. Lead revisions and implantation of additional leads require venous access at the site of the previous ICD implantation. The aim of our study was therefore to evaluate the incidence of venous obstruction after chronic transvenous ICD system implantation. METHODS AND RESULTS: One hundred and five consecutive patients admitted for their first elective ICD generator replacement were included. All patients underwent bilateral contrast venography and the images were analyzed by two attending radiologists. Venous obstruction was classified as moderate stenosis (50-75% diameter reduction), severe stenosis (>75%) or total occlusion. Venous obstruction of various degrees was found in 25% of the patients. Complete occlusion was found in 9%, severe stenosis in 6% and moderate stenosis in 10% of the patients. The incidence of venous obstruction was increased in patients with a pacemaker prior to the initial ICD system implantation (67%). No difference was found in patients with a single defibrillator lead compared with patients who had an additional superior vena cava (SVC) shocking coil. However, the presence of a second shocking coil in the SVC incorporated in a single ICD lead was associated with an increased incidence of venous obstruction. No difference was found between silicone and polyurethane insulated leads. CONCLUSION: This study shows that venous obstruction occurs relatively frequently after ICD implantation. Therefore, contrast venography should always be obtained if malfunction of a preexistent lead is suspected or a system upgrade is considered.