Chronic beta-adrenoceptor blockade and human atrial cell electrophysiology: evidence of pharmacological remodelling

OBJECTIVE: Chronic beta-adrenoceptor antagonist (beta-blocker) treatment reduces the incidence of reversion to AF in patients, possibly via an adaptive myocardial response. However, the underlying electrophysiological mechanisms are presently unclear. We aimed to investigate electrophysiological changes in human atrial cells associated with chronic treatment with beta-blockers and other cardiovascular-acting drugs. METHODS: Myocytes were isolated enzymatically from the right atrial appendage of 40 consenting patients who were in sinus rhythm. The cellular action potential duration (APD), effective refractory period (ERP), L-type Ca(2+) current (I(CaL)), transient (I(TO)) and sustained (I(KSUS)) outward K(+) currents, and input resistance (R(i)) were recorded using the whole cell patch clamp. Drug treatments and clinical characteristics were compared with electrophysiological measurements using simple and multiple regression analyses. P<0.05 was taken as statistically significant. RESULTS: In atrial cells from patients treated chronically with beta-blockers, the APD(90) and ERP (75 beats/min stimulation) were significantly longer, at 213+/-11 and 233+/-11 ms, respectively (n=15 patients), than in cells from non-beta-blocked patients, at 176+/-12 and 184+/-12 ms (n=11). These cells also displayed a significantly reduced action potential phase 1 velocity (22+/-3 vs. 34+/-3 V/s). Chronic beta-blockade was also associated with a significant reduction in the heart rate (58+/-3 vs. 69+/-5 beats/min) and in the density of I(TO) (8.7+/-1.3 vs. 13.7+/-2.1 pA/pF), an increase in the R(i) (214+/-24 vs. 132+/-14 MOmega), but no significant change in I(CaL) or I(KSUS). The I(TO) blocker 4-aminopyridine largely mimicked the changes in phase 1 and ERP associated with chronic beta-blockade, in cells from non-beta-blocked patients. Chronic treatment of patients with calcium channel blockers or angiotensin converting enzyme inhibitors (n=11-13 patients) was not associated with any significant changes in atrial cell electrophysiology. CONCLUSION: The observed atrial cellular electrophysiological changes associated with chronic beta-blockade are consistent with a long-term adaptive response, a type of 'pharmacological remodelling', and provide mechanistic evidence supportive of the anti-arrhythmic actions of beta-blockade.     

Phospholipase A2 levels in acute chest syndrome of sickle cell disease

Acute chest syndrome (ACS) is associated with significant morbidity and is the leading cause of death in patients with sickle cell disease (SCD). Recent reports suggest that bone marrow fat embolism can be detected in many cases of severe ACS. Secretory phospholipase A2 (sPLA2) is an important inflammatory mediator and liberates free fatty acids, which are felt to be responsible for the acute lung injury of the fat embolism syndrome. We measured SPLA2 levels in 35 SCD patients during 20 admissions for ACS, 10 admissions for vaso-occlusive crisis, and during 12 clinic visits when patients were at the steady state. Eleven non-SCD patients with pneumonia were also evaluated. To determine if there was a relationship between sPLA2 and the severity of ACS we correlated SPLA2 levels with the clinical course of the patient. In comparison with normal controls (mean = 3.1 +/- 1.1 ng/mL), the non- SCD patients with pneumonia (mean = 68.6 +/- 82.9 ng/mL) and all three SCD patient groups had an elevation of SPLA2 (steady state mean = 10.0 +/- 8.4 ng/mL; vaso-occlusive crisis mean = 23.7 +/- 40.5 ng/mL; ACS mean = 336 +/- 209 ng/mL). In patients with ACS sPLA2 levels were 100- fold greater than normal control values, 35 times greater than values in SCD patients at baseline, and five times greater than non-SCD patients with pneumonia. The degree of SPLA2 elevation in ACS correlated with three different measures of clinical severity and, in patients followed sequentially, the rise in SPLA2 coincided with the onset of ACS. The dramatic elevation of SPLA2 in patients with ACS but not in patients with vaso-occlusive crisis or non-SCD patients with pneumonia and the correlation between levels of SPLA2 and clinical severity suggest a role for SPLA2 in the diagnosis and, perhaps, in the pathophysiology of patients with ACS.     

Age-dependent neurological phenotypes in a mouse model of PRRT2-related diseases

Paroxysmal kinesigenic dyskinesia is an episodic movement disorder caused by dominant mutations in the proline-rich transmembrane protein PRRT2, with onset in childhood and typically with improvement or resolution by middle age. Mutations in the same gene may also cause benign infantile seizures, which begin in the first year of life and typically remit by the age of 2 years. Many details of PRRT2 function at the synapse, and the effects of mutations on neuronal excitability in the pathophysiology of epilepsy and dyskinesia, have emerged through the work of several groups over the last decade. However, the age dependence of the phenotypes has not been explored in detail in transgenic models. Here, we report our findings in heterozygous and homozygous Prrt2 knockout mice that recapitulate the age dependence of dyskinesia seen in the human disease. We show that Prrt2 deletion reduces the levels of synaptic proteins in a dose-dependent manner that is most pronounced at postnatal day 5 (P5), attenuates at P60, and disappears by P180. In a test for foot slippage while crossing a balance beam, transient loss of coordination was most pronounced at P60 and less prominent at age extremes. Slower traverse time was noted in homozygous knockout mice only, consistent with the ataxia seen in rare individuals with biallelic loss of function mutations in Prrt2. We thus identify three age-dependent phenotypic windows in the mouse model, which recapitulate the pattern seen in humans with PRRT2-related diseases.

     

Utility of snout wipe samples for influenza A virus surveillance in exhibition swine populations

Background

Sporadic influenza A virus (IAV) outbreaks in humans and swine have resulted from commingling of large numbers of people and pigs at agricultural fairs in the United States. Current antemortem IAV surveillance strategies in swine require collecting nasal swabs, which entails restraining pigs with snares. Restraint is labor-intensive for samplers, stressful for pigs, and displeasing to onlookers because pigs often resist and vocalize.

Objective

To evaluate the utility of snout wipes in exhibition swine as a method to make IAV surveillance efforts less intrusive, less labor-intensive, and more widely accepted among pig owners and exhibition officials.

Methods

Three materials (rayon/polyester gauze, cotton gauze, and Swiffer® Sweeper dry cloths) were inoculated with IAV, and viral recoveries from these materials were quantified using qRT-PCR and TCID₅₀ assays. In a field trial, paired cotton gauze snout wipes and gold standard polyester-tipped nasal swabs were collected from 553 pigs representing 29 agricultural fairs and the qualitative results of rRT-PCR and viral isolation were compared.

Results and Conclusions

Viral recoveries from potential snout wipe materials ranged from 0·26 to 1·59 log₁₀ TCID₅₀/ml less than that of the positive control in which no substrate was included; rayon/polyester gauze performed significantly worse than the other materials. In the field, snout wipes and nasal swabs had high levels of agreement for both rRT-PCR detection and virus isolation. Although further investigation and refinement of the sampling method is needed, results indicate that snout wipes will facilitate convenient and undisruptive IAV surveillance in pigs at agricultural fairs.     

Single incision laparoscopic adjustable gastric band: technique,feasibility, safety and learning curve

Introduction

Single incision laparoscopic surgery (SILS) is established in many procedures but not in bariatric surgery. One explanation may be that SILS is technically demanding in morbidly obese patients. This report describes our technique and experience with single incision laparoscopic adjustable gastric banding (SILAGB).

Methods

Prospective data collection was performed on consecutive obese patients who underwent SILAGB between November 2009 and February 2011. A single 3cm transverse incision in the right upper quadrant was used for a Covidien SILS^™ multichannel access port. The technique is described with a standard pars flaccida approach and the ‘tips and tricks’ needed for a wide range of candidates using standard laparoscopic equipment.

Results

A total of 29 patients (27 female) with a median body mass index of 41kg/m² (range: 35–52kg/m²) and median age of 44 years (range: 22–57 years) underwent SILAGB. There were no ‘conversions’ to a standard laparoscopic technique. Two cases required the addition of one single 5mm port. The only complications were two postoperative wound infections (one with a port site infection requiring replacement of the port) and one faulty band requiring replacement. There were therefore two returns to theatre and no 30-day deaths. All patients were discharged on the first postoperative day. In this series, operative times reduced significantly to be comparable with the conventional laparoscopic approach.

Conclusions

SILAGB is safe and feasible in the morbidly obese. Proficiency in this technique using conventional laparoscopic equipment can be achieved with a short learning curve.     

Thoracic surgical management of colorectal lung metastases: a questionnaire survey of members of the Society for Cardiothoracic Surgery in great Britain and Ireland

Introduction

Distant metastases to liver and lung are not uncommon in colorectal cancer. Resection of metastases is accepted widely as the standard of care. However, there is no firm evidence base for this. This questionnaire survey was carried out to assess the current practice preferences of cardiothoracic surgeons in Great Britain and Ireland.

Methods

An online questionnaire survey was emailed to cardiothoracic surgeons in Great Britain and Ireland. The survey was live for 12 weeks. Responses were collated with SurveyMonkey^®.

Results

Overall, there were 75 respondents. The majority (83%) indicated thoracic surgery as a specialist interest. Almost all (99%) used thoracic computed tomography (CT) for staging; 70% added liver CT and 51% added pelvic CT. Fluorodeoxyglucose positron emission tomography was used by 86%. The most frequent indication for pulmonary resection (97%) was solitary lung metastasis without extrathoracic disease. Video assisted thoracoscopic surgery (VATS) was used by 85%. In addition, thoracotomy was used by 96%. A third (33%) used radiofrequency ablation. Synchronous liver and lung resection was contraindicated for 83% of respondents. Over three-quarters (77%) thought that scientific equipoise exists presently for lung resection for colorectal lung metastases but only 21% supported a moratorium on this type of surgery until further evidence becomes available.

Conclusions

The results confirm that the majority of respondents use conventional cross-sectional imaging and either VATS or formal thoracotomy for resection. The results emphasise the continuing need for formal randomised trials to provide evidence of any survival benefit from pulmonary metastasectomy for colorectal lung metastases.