Sodium channel haploinsufficiency and structural change in ventricular arrhythmogenesis

Normal cardiac excitation involves orderly conduction of electrical activation and recovery dependent upon surface membrane, voltage‐gated, sodium (Na⁺) channel α‐subunits (Na_v1.5). We summarize experimental studies of physiological and clinical consequences of loss‐of‐function Na⁺ channel mutations. Of these conditions, Brugada syndrome (BrS) and progressive cardiac conduction defect (PCCD) are associated with sudden, often fatal, ventricular tachycardia (VT) or fibrillation. Mouse Scn5a^+/? hearts replicate important clinical phenotypes modelling these human conditions. The arrhythmic phenotype is associated not only with the primary biophysical change but also with additional, anatomical abnormalities, in turn dependent upon age and sex, each themselves exerting arrhythmic effects. Available evidence suggests a unified binary scheme for the development of arrhythmia in both BrS and PCCD. Previous biophysical studies suggested that Na_v1.5 deficiency produces a background electrophysiological defect compromising conduction, thereby producing an arrhythmic substrate unmasked by flecainide or ajmaline challenge. More recent reports further suggest a progressive decline in conduction velocity and increase in its dispersion particularly in ageing male Na_v1.5 haploinsufficient compared to WT hearts. This appears to involve a selective appearance of slow conduction at the expense of rapidly conducting pathways with changes in their frequency distributions. These changes were related to increased cardiac fibrosis. It is thus the combination of the structural and biophysical changes both accentuating arrhythmic substrate that may produce arrhythmic tendency. This binary scheme explains the combined requirement for separate, biophysical and structural changes, particularly occurring in ageing Na_v1.5 haploinsufficient males in producing clinical arrhythmia.     

Biomechanical strength of deep-frozen versus lyophilized large cortical allografts

OBJECTIVE: To compare biomechanical strength of deep-frozen versus lyophilized large cortical allografts. DESIGN: In vivo transplantation studies performed in tibia of adult cats using 4 cm deep-frozen and lyophilized, gamma-irradiated allografts to bridge large cortical defect model. BACKGROUND: Bridging large cortical bone defect is a challenging problem. Options include autografts, allografts, bioceramics and prostheses. Allografts provide a suitable option. METHODS: Forty mature cats were used. A large defect (4 cm) was created in mid-diaphysis of right tibia. In 16 cats, cortical defect was reconstructed using deep-frozen allografts (-80 degrees C) with intra-medullary rodding. In another 16 cats, lyophilized, gamma-irradiated allografts were used. Observation periods include 8, 12, 16 and 24 weeks. The specimens were procured together with unoperated legs as controls. Mechanical testing was performed using a materials testing machine with torsion test device of up to 500 Nm at speed of 0.18 rpm. Parameters studied included maximum torque, torsional stiffness and energy of absorption. RESULTS: Deep-frozen allografts did not reach 100% strength, achieving only 64% at 6 months. In marked contrast, lyophilized allografts were significantly weaker with only 12% maximum torque strength at 6 months. Lyophilized allografts were significantly weaker than deep-frozen allografts in all observation periods (p < 0.05). CONCLUSION: Deep-frozen allografts did not reach 100% normal strength and were significantly weaker than non-vascularised autografts. Lyophilized allografts were significantly weaker than deep-frozen allografts. RELEVANCE: For the reconstruction of massive cortical bone defects, only deep-frozen cortical allografts should be used. Lyophilized allografts are not suitable.     

A Necessary Step Toward Kidney Donor Safety: The Transition From Locking Polymer Clips to Transfixion Techniques in Laparoscopic Donor Nephrectomy

Donor safety is of paramount importance in addressing end-stage renal failure through living kidney transplantation. The United States Food and Drug Administration (FDA) issued a Class II recall on the use of Hem-o-lok (Teleflex, Limerick, Pennsylvania, United States) polymer clips on the renal artery in laparoscopic donor nephrectomy (LDN) in June 2006 following 3 reported cases of donor deaths secondary to slipped ligature. The National University Hospital of Singapore made the transition regarding hilar control in minimally invasive donor nephrectomy, from using polymer and titanium clips to transfixion techniques (pure or hand-assisted laparoscopic) via laparoscopic staples or intracorporeal suturing, respectively. This study assessed safety during the transition in arterial transfixion techniques in minimally invasive donor nephrectomy for both donors and recipients. Forty-five consecutive kidney donors underwent donor nephrectomy over a 2-year period starting from June 2010. A total of 37 donors who underwent LDN (pure laparoscopic or hand-assisted laparoscopic) were included in the analysis. Of the 37 patients, 23 kidney donors had renal arterial control using Hem-o-lok while 14 patients from November 2011 onward underwent transfixion of the renal artery. The 2 groups of donor who underwent renal arterial control by either clips ligature or transfixion technique were comparable. The outcomes for the recipients in each group were similar with no statistical difference between postoperative creatinine level, incidence of delayed graft function, or graft survival at 1 year. We conclude that the transition in renal arterial control technique to transfixion techniques in LDN in line with FDA recommendation is feasible and affords equivalent donor and recipient outcomes.     

Successful Treatment of Idiopathic Hypereosinophilic Syndrome with Imatinib Mesylate: A Case Report

Patients with idiopathic hypereosinophilic syndrome (HES) show persistent hypereosinophilia of unknown etiology that is associated with end-organ damage. Different treatments, including the use of corticosteroids and cytotoxics, have been investigated for HES with modest success. We describe a patient with HES who had significant end-organ damage from hypereosinophilia and remained refractory to conventional therapy. Therapy with imatinib mesylate, a selective tyrosine kinase inhibitor that is highly effective in treating patients with BCR-ABL-positive chronic myeloid leukemia, was tried with the patient. The result was impressive, with hematologic remission achieved after 12 days of administration. Our finding concurs with recent reports that imatinib mesylate may be a promising agent in the treatment of some cases of HES.