Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington\u27s Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington\u27s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington\u27s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Strain-related regional alterations of calcium-handling proteins in myocardial remodeling

BackgroundCardiac remodeling has been shown to have deleterious effects at both the global and local levels. The objective of this study is to investigate the role of strain in the initiation of structural and functional changes of myocardial tissue and its relation to alteration of calcium-handling proteins during cardiac remodeling after myocardial infarction.MethodsSixteen sonomicrometry transducers were placed in the left ventricular free wall of 9 sheep to measure the regional strain in the infarct, adjacent, and remote myocardial regions. Hemodynamic, echocardiographic, and sonomicrometry data were collected before myocardial infarction, after infarction, and 2, 6, and 8 weeks after infarction. Regional myocardial tissues were collected for calcium-handling proteins at the end study.ResultsAt time of termination, end-systolic strains in 3 regionally distinct zones (remote, adjacent, and infarct) of myocardium were measured to be −14.65 ± 1.13, −5.11 ± 0.60 (P ≤ .05), and 0.92 ± 0.56 (P ≤ .05), respectively. The regional end-systolic strain correlated strongly with the abundance of 2 major calcium-handling proteins: sarcoplasmic reticulum Ca2+ adenosine triphosphatase subtype 2a (r2 = 0.68, P ≤ .05) and phospholamban (r2 = 0.50, P ≤ .05). A lesser degree of correlation was observed between the systolic strain and the abundance of sodium/calcium exchanger type 1 protein (r2 = 0.17, P ≤ .05).ConclusionsRegional strain differences can be defined in the different myocardial regions during postinfarction cardiac remodeling. These differences in regional strain drive regionally distinct alterations in calcium-handling protein expression