Cardiac arrhythmias cause more than 300,000 sudden deaths each year in the USA alone. Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from ventricular tachyarrhythmias, specifically torsade de pointes. Four LQT genes have been identified: KVLQT1 (LQT1) on chromosome 11p15.5, HERG (LQT2) on chromosome 7q35-36, SCN5A (LQT3) on chromosome 3p21-24, and MinK (LQT5) on chromosome 21q22. SCN5A encodes the cardiac sodium channel, and LQT-causing mutations in SCN5A lead to the generation of a late phase of inactivation-resistant whole-cell inward currents. Mexiletine, a sodium channel blocker, is effective in shortening the QT interval corrected for heart rate (QTc) of patients with SCN5A mutations. HERG encodes the cardiac I(Kr) potassium channel. Mutations in HERG act by a dominant-negative mechanism or by a loss-of-function mechanism. Raising the serum potassium concentration can increase outward HERG potassium current and is effective in shortening the QTc of patients with HERG mutations. KVLQT1 is a cardiac potassium channel protein that interacts with another small potassium channel MinK to form the cardiac I(Ks) potassium channel. Like HERG mutations, mutations in KVLQT1 and MinK can act by a dominant-negative mechanism or a loss-of-function mechanism. An effective treatment for LQT patients with KVLQT1 or MinK mutations is expected to be developed based on the functional characterization of the I(Ks) potassium channel. Genetic testing is now available for some patients with LQT.
Brugada syndrome (BrS) is a fatal arrhythmia that causes an estimated 4% of all sudden death in high-incidence areas. SCN5A encodes cardiac sodium channel Na V 1.5 and causes 25 to 30% of BrS cases. Here, we report generation of a knock-in (KI) mouse model of BrS ( Scn5a G1746R/+ ). Heterozygous KI mice recapitulated some of the clinical features of BrS, including an ST segment abnormality (a prominent J wave) on electrocardiograms and development of spontaneous ventricular tachyarrhythmias (VTs), seizures, and sudden death. VTs were caused by shortened cardiac action potential duration and late phase 3 early afterdepolarizations associated with reduced sodium current density ( I Na ) and increased Kcnd3 and Cacna1c expression. We developed a gene therapy using adeno-associated virus serotype 9 (AAV9) vector-mediated MOG1 delivery for up-regulation of MOG1, a chaperone that binds to Na V 1.5 and traffics it to the cell surface. MOG1 was chosen for gene therapy because the large size of the SCN5A coding sequence (6048 base pairs) exceeds the packaging capacity of AAV vectors. AAV9- MOG1 gene therapy increased cell surface expression of Na V 1.5 and ventricular I Na , reversed up-regulation of Kcnd3 and Cacna1c expression, normalized cardiac action potential abnormalities, abolished J waves, and blocked VT in Scn5a G1746R/+ mice. Gene therapy also rescued the phenotypes of cardiac arrhythmias and contractile dysfunction in heterozygous humanized KI mice with SCN5A mutation p.D1275N. Using a small chaperone protein may have broad implications for targeting disease-causing genes exceeding the size capacity of AAV vectors.
Abstract Epilepsy is one of the most common neurological diseases. Here we report the first de novo mutation in the BK channel (p.N995S) that causes epilepsy in two independent families. The p.N995S mutant channel showed a markedly increased macroscopic potassium current mediated by increases in both channel open probability and channel open dwell time. Mutation p.N995S affects the voltage-activation pathway of BK channel, but does not affect the calcium sensitivity. Paxilline blocks potassium currents from both WT and mutant BK channels. We also identified two variants of unknown significance, p.E656A and p.N1159S in epilepsy patients. However, they do not affect BK channel functions, therefore, are unlikely to be a cause of disease. These results expand the BK channelopathy to a more common disease of epilepsy, suggest that the BK channel is a drug target for treatment of epilepsy, and highlight the importance of functional studies in the era of precision medicine.
Acetic acid is bacteriostatic or bactericidal to many gram-negative and gram-positive microorganisms, especially Pseudomonas. Nevertheless, it has also been found to possess cytotoxic effects in concentrations as low as 0.25% inhibiting the epithelialization process during wound healing.In this multiple case series, we present 2 cases of chronic traumatic leg wounds treated with gauze moistened with acetic acid (0.25%), which were covered with a securing dressing and compression stockinet. Both patients were told to apply gauze moistened with acetic acid (0.25%) twice daily. In both cases, the wound progressed to blue-green drainage and wet yellow slough tissue to near-complete beefy granulation tissue. At this point, acetic acid was replaced with collagen or petrolatum dressing until complete wound closure was achieved. The treatment of these wounds illustrated successful use of acetic acid for chronic wound care.Our experience with these cases suggests that appearance of blue-green wound drainage and wet yellow slough tissue is a reasonable indication for the use of gauze moistened with acetic acid (0.25%). Further research is needed to test the efficacy of these principles in guiding acetic acid use in wound care.
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