Mesenteric Resistance Arteries in Type 2 Diabetic db/db Mice Undergo Outward Remodeling

Resistance vessel remodeling is controlled by myriad of hemodynamic and neurohormonal factors. This study characterized structural and molecular remodeling in mesenteric resistance arteries (MRAs) in diabetic (db/db) and control (Db/db) mice.Structural properties were assessed in isolated MRAs from 12 and 16 wk-old db/db and Db/db mice by pressure myography. Matrix regulatory proteins were measured by Western blot analysis. Mean arterial pressure and superior mesenteric blood flow were measured in 12 wk-old mice by telemetry and a Doppler flow nanoprobe, respectively.Blood pressure was similar between groups. Lumen diameter and medial cross-sectional area were significantly increased in 16 wk-old db/db MRA compared to control, indicating outward hypertrophic remodeling. Moreover, wall stress and cross-sectional compliance were significantly larger in diabetic arteries. These remodeling indices were associated with increased expression of matrix regulatory proteins matrix metalloproteinase (MMP)-9, MMP-12, tissue inhibitors of matrix metalloproteinase (TIMP)-1, TIMP-2, and plasminogen activator inhibitor-1 (PAI-1) in db/db arteries. Finally, superior mesenteric artery blood flow was increased by 46% in 12 wk-old db/db mice, a finding that preceded mesenteric resistance artery remodeling.These data suggest that flow-induced hemodynamic changes may supersede the local neurohormonal and metabolic milieu to culminate in hypertrophic outward remodeling of type 2 DM mesenteric resistance arteries

The Genetic Association Between ADHD Symptoms and Reading Difficulties: The Role of Inattentiveness and IQ

Previous studies have documented the primarily genetic aetiology for the stronger phenotypic covariance between reading disability and ADHD inattention symptoms, compared to hyperactivity-impulsivity symptoms. In this study, we examined to what extent this covariation could be attributed to “generalist genes” shared with general cognitive ability or to “specialist” genes which may specifically underlie processes linking inattention symptoms and reading difficulties. We used multivariate structural equation modeling on IQ, parent and teacher ADHD ratings and parent ratings on reading difficulties from a general population sample of 1312 twins aged 7.9–10.9 years. The covariance between reading difficulties and ADHD inattention symptoms was largely driven by genetic (45%) and child-specific environment (21%) factors not shared with IQ and hyperactivity-impulsivity; only 11% of the covariance was due to genetic effects common with IQ. Aetiological influences shared among all phenotypes explained 47% of the variance in reading difficulties. The current study, using a general population sample, extends previous findings by showing, first, that the shared genetic variability between reading difficulties and ADHD inattention symptoms is largely independent from genes contributing to general cognitive ability and, second, that child-specific environment factors, independent from IQ, also contribute to the covariation between reading difficulties and inattention symptoms

NGM282 for Treatment of Patients With Primary Biliary Cholangitis: A Multicenter, Randomized, Double Blind Placebo Controlled Trial

Patients with primary biliary cholangitis (PBC) who had an inadequate response to ursodiol have few treatment options. Alkaline phosphatase (ALP) and bilirubin levels correlate with the risk of liver transplant or death in PBC patients. Fibroblast growth factor (FGF) 19 is a hormone that acts directly in the liver to regulate bile acid synthesis. We evaluated NGM282, an engineered analogue of FGF19, for the treatment of PBC. In this 28-day, double-blind, placebo-controlled phase 2 trial, 45 PBC patients who had an inadequate response to ursodiol were randomly assigned 1:1:1 to receive subcutaneous daily doses of either NGM282 at 0.3 mg (n = 14), 3 mg (n = 16), or placebo (n = 15). The primary endpoint was a change in ALP from baseline after 28 days of treatment. At day 28, ALP was significantly reduced with NGM282 treatment at both 0.3 mg (least-squares mean -51.0 IU/L [standard error (SE) 15.4]) and 3 mg (-66.0 IU/L [SE 16.0]) versus placebo (3.3 IU/L [SE 14.8]), with least-squares mean differences of -54.3 IU/L (95% confidence interval -104.2 to -4.5; P = 0.0149) and -69.3 IU/L (95% confidence interval -120.5 to -18.3; P = 0.0030), respectively. Fifty percent (7 of 14) of patients receiving NGM282 0.3 mg and 46% (6 of 13) of those receiving NGM282 3mg achieved 15% or greater reduction in ALP levels from baseline, compared with 7% (1 of 15) of patients receiving placebo. NGM282 also significantly reduced serum concentrations of transaminases and immunoglobulins. Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, with gastrointestinal disorders more frequent in the NGM282 treatment groups. No worsening of pruritus was observed with NGM282 treatment. Conclusion: NGM282 administered for 28 days resulted in significant improvements in ALP and transaminase levels compared with placebo, with an acceptable safety profile in patients with PBC. (Hepatology Communications 2018; 00:000-000)