No abstract

Nav channels are essential for metazoan membrane depolarization, and Nav channel dysfunction is directly linked with epilepsy, ataxia, pain, arrhythmia, myotonia, and irritable bowel syndrome. Human Nav channelopathies are primarily caused by variants that directly affect Nav channel permeability or gating. However, a new class of human Nav channelopathies has emerged based on channel variants that alter regulation by intracellular signaling or cytoskeletal proteins. Fibroblast growth factor homologous factors (FHFs) are a family of intracellular signaling proteins linked with Nav channel regulation in neurons and myocytes. However, to date, there is surprisingly little evidence linking Nav channel gene variants with FHFs and human disease. Here, we provide, to our knowledge, the first evidence that mutations in SCN5A (encodes primary cardiac Nav channel Nav1.5) that alter FHF binding result in human cardiovascular disease. We describe a five*generation kindred with a history of atrial and ventricular arrhythmias, cardiac arrest, and sudden cardiac death. Affected family members harbor a novel SCN5A variant resulting in p.H1849R. p.H1849R is localized in the central binding core on Nav1.5 for FHFs. Consistent with these data, Nav1.5 p.H1849R affected interaction with FHFs. Further, electrophysiological analysis identified Nav1.5 p.H1849R as a gain-of-function for INa by altering steady-state inactivation and slowing the rate of Nav1.5 inactivation. In line with these data and consistent with human cardiac phenotypes, myocytes expressing Nav1.5 p.H1849R displayed prolonged action potential duration and arrhythmogenic afterdepolarizations. Together, these findings identify a previously unexplored mechanism for human Nav channelopathy based on altered Nav1.5 association with FHF proteins.

Purpose To evaluate the effect of flip angle (FA) on accuracy and within-examination repeatability of hepatic proton-density fat fraction (PDFF) estimation with complex data-based magnetic resonance imaging (MRI). Materials and Methods PDFF was estimated at 3T in thirty subjects, using two sets of five MRI sequences with FA from 1° to 5° in each set. One set used 7ms repetition time and acquired 6 echoes (TR7/E6); the other used 14ms and acquired 12 echoes (TR14/E12). For each FA in both sets, the accuracy of MRI-PDFF was assessed relative to MR spectroscopy (MRS)-PDFF using four regression parameters (slope, intercept, average bias, R2). Each subject had four random sequences repeated; within-examination repeatability of MRI-PDFF for each FA was assessed with intraclass correlation coefficient (ICC). Pairwise comparisons were made using bootstrap-based tests. Results Most FAs provided high MRI-PDFF estimation accuracy (intercept range -1.25–0.84, slope 0.89–1.06, average bias 0.24–1.65, R2 0.85–0.97). Most comparisons of regression parameters between FAs were not significant. Informally, in the TR7/E6 set, FAs of 2° and 3° provided the highest accuracy, while FAs of 1° and 5° provided the lowest. In the TR14/E12 set, accuracy parameters did not differ consistently between FAs. FAs in both sets provided high within-examination repeatability (ICC range 0.981–0.998). Conclusion MRI-PDFF was repeatable and, for most FAs, accurate in both sequence sets. In the TR7/E6 sequence set, FAs of 2° and 3° informally provided the highest accuracy. In the TR14/E12 sequence set, all FAs provided similar accuracy.

No abstract

Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

IV, therapeutic study.

Significance This study defines a functional role for β IV -spectrin in pancreas, expands the pathways for calcium/calmodulin-dependent protein kinase II (CaMKII) local control in excitable cells, and identifies a mechanism for CaMKII-dependent regulation of K ATP channels.

Cefepime is a hew broad-spectrum cephalosporin with excellent gram-positive and gram-negative activity including activity against Staphylococcus aureus, Pseudomonas aeruginosa, and Enterobacter cloacae. The pharmacokinetic disposition of cefepine is similar to that of ceftazidime. We compared the pharmacokinetic characteristics and the extent and duration of bactericidal activity in serum and suction-induced blister fluid after single 2-g intravenous doses of cefepime, ceftazidime, and cefoperazone given to healthy subjects. One clinical isolate each of E. cloacae, P. aeruginosa, and S. aureus was used to assess bactericidal activity. Results of the pharmacokinetic analysis were similar to previously reported data for these drugs. The high serum protein binding of cefoperazone (-90%) contributed to poor blister fluid penetration. The other drugs penetrated well into this fluid compartment. Cefepime showed significantly greater bactericidal activity in serum and blister fluid against E. cloacae than the other study drugs, ceftazidime was significantly better in serum and blister fluid against P. aeruginosa, and cefoperazone was significantly better against S. aureus only in serum. None of the study drugs had significant bactericidal activity in blister fluid against S. aureus. Cefepime is a promising antimicrobial agent for the treatment of infections due to E. cloacae.Cefepime is an experimental cephalosporin antibiotic with bactericidal activity against many gram-positive and gramnegative microorganisms. Advantages over currently available cephalosporins include the decreased potential for selection of resistant bacterial mutants and retention of activity against ceftazidime-or cefoperazone-resistant enteric gram-negative bacilli such as Enterobacter cloacae (4). Single cefepime doses ranging from 62.5 to 2,000 mg have been administered intravenously over 30 min to healthy male volunteers without significant adverse effects. In addition, 2,000-mg doses of cefepime were well tolerated when administered over infusion times of 15, 10, 5, and 3 min (2).Several models have been developed to study tissue penetration of antibiotics. One of these models, the dermal suction blister, is generally considered to provide valuable information on the kinetics of antibiotics in small abscesses and edema of soft-tissue infections (15). The penetration characteristics of cefepime in a suction blister tissue penetration model have not been described. In addition, data on bactericidal activity in blister fluid of any antimicrobial agent have not yet been published. Clinical Research Center and randomly received single intravenous doses (2 g each) of cefepime, ceftazidime, or cefoperazone on three separate occasions (a minimum of 4 days and a maximum of 14 days between doses). One additional subject received only ceftazidime. The drugs were diluted to a final volume of 20 ml in suitable vehicles and administered over 30 min with a constant-rate syringe pump.Informed consent was obtained from each subject prior to participation, and...