A novel potassium channel gene has been cloned, characterized, and associated with cardiac arrhythmia. The gene encodes MinK-related peptide 1 (MiRP1), a small integral membrane subunit that assembles with HERG, a pore-forming protein, to alter its function. Unlike channels formed only with HERG, mixed complexes resemble native cardiac IKr channels in their gating, unitary conductance, regulation by potassium, and distinctive biphasic inhibition by the class III antiarrhythmic E-4031. Three missense mutations associated with long QT syndrome and ventricular fibrillation are identified in the gene for MiRP1. Mutants form channels that open slowly and close rapidly, thereby diminishing potassium currents. One variant, associated with clarithromycin-induced arrhythmia, increases channel blockade by the antibiotic. A mechanism for acquired arrhythmia is revealed: genetically based reduction in potassium currents that remains clinically silent until combined with additional stressors.

Potassium leak conductances were recently revealed to exist as independent molecular entities. Here, the genomic structure, cardiac localization, and biophysical properties of a murine example are considered. Kcnk3 subunits have two pore-forming P domains and unique functional attributes. At steady state, Kcnk3 channels behave like open, potassium-selective, transmembrane holes that are inhibited by physiological levels of proton. With voltage steps, Kcnk3 channels open and close in two phases, one appears to be immediate and one is time-dependent ( ‫؍‬ ϳ5 ms). Both proton block and gating are potassium-sensitive; this produces an anomalous increase in outward flux as external potassium levels rise because of decreased proton block. Single Kcnk3 channels open across the physiological voltage range; hence they are "leak" conductances; however, they open only briefly and rarely even after exposure to agents that activate other potassium channels.

Background Cognitive behavioral therapy (CBT) is an evidence-based treatment for alcohol use disorders, yet is rarely implemented with high fidelity in clinical practice. Computer-based delivery of CBT offers the potential to address dissemination challenges, but to date there have been no evaluations of a web-based CBT program for alcohol use within a clinical sample. Methods This study randomized treatment-seeking individuals with a current alcohol use disorder to one of three treatments at a community outpatient facility: (1) standard treatment-as-usual (TAU); (2) TAU plus on-site access to a computerized CBT targeting alcohol use (TAU+CBT4CBT); or (3) CBT4CBT plus brief weekly clinical monitoring (CBT4CBT+monitoring). Participant alcohol use was assessed weekly during an 8-week treatment period, as well as 1, 3, and 6 months after treatment. Results Sixty-eight individuals (65% male; 54% African American) were randomized (TAU = 22; TAU+CBT4CBT = 22; CBT4CBT+monitoring = 24). There were significantly higher rates of treatment completion among participants assigned to one of the CBT4CBT conditions compared to TAU (Wald = 6.86, p < .01). Significant reductions in alcohol use were found across all conditions within treatment, with participants assigned to TAU+CBT4CBT demonstrating greater increases in percentage of days abstinent (PDA) compared to TAU, t(536.4) = 2.68, p < .01, d = 0.71, 95% CI [0.60, 3.91], for the full sample. Preliminary findings suggest the estimated costs of all self-reported AUD-related services utilized by participants were considerably lower for those assigned to CBT4CBT conditions compared to TAU, both within treatment and during follow-up. Conclusions This trial demonstrated the safety, feasibility, and preliminary efficacy of web-based CBT4CBT targeting alcohol use. CBT4CBT was superior to TAU at increasing PDA when delivered as an add-on, and it was not significantly different from TAU or TAU+CBT4CBT when delivered with clinical monitoring only.

Recent evidence suggests that the P2X 7 receptor may play a role in the pathophysiology of preclinical models of pain and inflammation. Therefore, pharmacological agents that target this receptor may potentially have clinical utility as antiinflammatory and analgesic therapy. We investigated and characterized the previously reported P2X 7 antagonist N-(adamantan-1-ylmethyl)-5-[(3R-amino-pyrrolidin-1-yl)methyl]-2-chloro-benzamide, hydrochloride salt (AACBA; GSK314181A). In vitro, AACBA was a relatively potent inhibitor of both human P2X 7 -mediated calcium flux and quinolinium,4-[(3-methyl-2(3H)-benzoxazolylidene)methyl]-1-[3-(triemethylammonio)propyl]-diiodide (YO-PRO-1) uptake assays, with IC 50 values of approximately 18 and 85 nM, respectively. Compared with the human receptor, AACBA was less potent at the rat P2X 7 receptor, with IC 50 values of 29 and 980 nM in the calcium flux and YO-PRO-1 assays, respectively. In acute in vivo models of pain and inflammation, AACBA dose-dependently reduced lipopolysaccharideinduced plasma interleukin-6 release and prevented or reversed carrageenan-induced paw edema and mechanical hypersensitivity. In chronic in vivo models of pain and inflammation, AACBA produced a prophylactic, but not therapeutic-like, prevention of the clinical signs and histopathological damage of collageninduced arthritis. Finally, AACBA could not reverse L 5 spinal nerve ligation-induced tactile allodynia when given therapeutically. Consistent with previous literature, these results suggest that P2X 7 receptors do play a role in animal models of pain and inflammation. Further study of P2X 7 antagonists both in preclinical and clinical studies will help elucidate the role of the P2X 7 receptor in pain and inflammatory mechanisms and may help identify potential clinical benefits of such molecules.

This first trial of computerized CBT as a virtual stand-alone intervention delivered in a clinical setting to a diverse sample of patients with current substance use disorders indicated that it was safe, effective, and durable relative to standard treatment approaches and was well-liked by participants. Clinician-delivered individual CBT, while efficacious within the treatment period, was unexpectedly associated with a higher dropout rate and lower effects at follow-up.