Background-We and others have reported mutations in the cardiac predominant sodium channel gene SCN5A in patients with atrial fibrillation (AF). We also have reported that SCN1B is associated with Brugada syndrome and isolated cardiac conduction disease. We tested the hypothesis that mutations in the 4 sodium channel ␤-subunit genes SCN1B-SCN4B contribute to AF susceptibility. Methods and Results-Screening for mutations in the 4 ␤-subunit genes was performed in 480 patients with AF (118 patients with lone AF and 362 patients with AF and cardiovascular disease) and 548 control subjects (188 ethnically defined anonymized subjects and 360 subjects without AF). The effects of mutant ␤-subunits on SCN5A mediated currents were studied using electrophysiological studies. We identified 2 nonsynonymous variants in SCN1B (resulting in R85H, D153N) and 2 in SCN2B (R28Q, R28W) in patients with AF. These occur at residues highly conserved across mammals and were absent in control subjects. In 3 of 4 mutation carriers, the ECGs showed saddleback-type ST-segment elevation in the right precordial leads. Transcripts encoding both SCN1B and SCN2B were detected in human atrium and ventricle. In heterologous expression studies using Chinese hamster ovary cells, the mutant ␤1-or ␤2-subunits reduced SCN5A-mediated current and altered channel gating compared with coexpression of wild-type subunits. Conclusions-Loss of function mutations in sodium channel ␤-subunits were identified in patients with AF and were associated with a distinctive ECG phenotype. These findings further support the hypothesis that decreased sodium current enhances AF susceptibility. (Circ Arrhythmia Electrophysiol. 2009;2:268-275.)

Analysis of a large data set from multiple institutions shows that surgical removal of symptomatic large prostatic adenomas can be carried out with good outcomes by using robot-assisted laparoscopy.

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Rationale: Voltage-gated sodium channels initiate action potentials in excitable tissues. Mice in which Scn5A (the predominant sodium channel gene in heart) has been knocked out die early in development with cardiac malformations by mechanisms which have yet to be determined. Objective: Here we addressed this question by investigating the role of cardiac sodium channels in zebrafish heart development. Methods and Results: Transcripts of the functionally-conserved Scn5a homologs scn5Laa and scn5Lab were detected in the gastrulating zebrafish embryo and subsequently in the embryonic myocardium. Antisense knockdown of either channel resulted in marked cardiac chamber dysmorphogenesis and perturbed looping. These abnormalities were associated with decreased expression of the myocardial precursor genes nkx2.5, gata4, and hand2 in anterior lateral mesoderm and significant deficits in the production of cardiomyocyte progenitors. These early defects did not appear to result from altered membrane electrophysiology, as prolonged pharmacological blockade of sodium current failed to phenocopy channel knockdown. Moreover, embryos grown in calcium channel blocker-containing medium had hearts that did not beat but developed normally. Conclusions: These findings identify a novel and possibly nonelectrogenic role for cardiac sodium channels in heart development. (Circ Res. 2010;106:1342-1350.)Key Words: ion channels Ⅲ heart development Ⅲ zebrafish Ⅲ scn5La T he Na v 1 family of voltage-gated sodium channels are multi-protein complexes that account for the initial upstroke (phase 0) of the action potential in neurons, myocytes, and other excitable cells by permitting a rapid influx of Na ϩ ions. 1 Ten distinct pore-forming (␣) subunit genes (SCNxA) have been cloned, 1-3 and SCN5A encodes Na v 1.5, the predominant sodium channel isoform in myocardium. 4 Perturbed expression or function of Na v 1.5 in patients can cause a range of phenotypes including the long QT syndrome, Brugada syndrome, progressive cardiac conduction system disease, and atrial arrhythmias. 5,6 Mice heterozygous for Scn5a deletion display slow conduction and susceptibility to ventricular tachycardia. 7 By contrast, Scn5a Ϫ/Ϫ homozygotes die between embryonic day (E)10 and E11 with abnormalities of ventricular morphogenesis, indicating that Scn5a is also required for normal development. 7 The mechanisms underlying these defects have not been determined.Here, we used zebrafish to examine the role of sodium channels in the developing heart. Zebrafish embryos are optically transparent and externally fertilized, facilitating the study of early organ formation. Genetic manipulation is readily achieved using antisense morpholinos, and embryos are also permeable to small molecule drugs placed in their medium. The stages of zebrafish cardiac development have been welldelineated: cardiac precursors are located at the blastula margin at 5 hours postfertilization (hpf). 8 These bilateral precursors undergo a complex series of movements that result in the formation of a ...

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Positive surgical margins after partial nephrectomy increase the risk of disease recurrence, primarily in patients with adverse pathological features.

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Summary Malignant migrating partial seizures in infancy (MMPEI) is an early onset epileptic encephalopathy with few known etiologies. We sought to identify a novel cause of MMPEI in a child with MMPEI whose healthy parents were consanguineous. We used array comparative genomic hybridization (CGH) to identify copy number variants (CNVs) genome-wide and long-range PCR to further delineate the breakpoints of a deletion found by CGH. The proband had an inherited homozygous deletion of chromosome 20p13, disrupting the promoter region and first three coding exons of the gene PLCB1. Additional MMPEI cases were screened for similar deletions or mutations in PLCB1 but did not harbor mutations. Our results suggest that loss of PLCβ1 function is one cause of MMPEI, consistent with prior studies in a Plcb1 knockout mouse model that develops early onset epilepsy. We provide novel insight into the molecular mechanisms underlying MMPEI and further implicate PLCB1 as a candidate gene for severe childhood epilepsies. This work highlights the importance of pursuing genetic etiologies for severe early onset epilepsy syndromes.