4 research outputs found
Effect of ruboxistaurin in patients with diabetic macular edema: Thirty-month results of the randomized PKC-DMES clinical trial
Objective: To evaluate the safety and efficacy of orally administered ruboxistaurin (RBX) as a mesylate salt in patients with diabetic macular edema (DME). 1 Design: Multicenter, double-masked, randomized, placebo-controlled study of 686 patients receiving placebo or RBX orally ( 4, 16, or 32 mg/d) for 30 months. At baseline, patients had DME farther than 300 mu m from the center of the macula, an Early Treatment Diabetic Retinopathy Study retinopathy severity level from 20 to 47A without prior photocoagulation, and an Early Treatment Diabetic Retinopathy Study visual acuity of 75 or more letters in the study eye. The primary study outcome was progression to sight-threatening DME or application of focal/grid photocoagulation for DME. Main Outcome Measure: Masked grading of stereoscopic fundus photographs. Results: The delay in progression to the primary outcome was not statistically significant ( 32 mg of RBX vs placebo, P=.14 [unadjusted]; Cox proportional hazards model adjusted for covariates, hazards ratio=0.73; 95% confidence interval, 0.53-1.0; P=.06). However, application of focal/ grid photocoagulation prior to progression to sight-threatening DME varied by site, and a secondary analysis of progression to sight-threatening DME alone showed that 32 mg of RBX per day reduced progression, compared with placebo (P=.054 [ unadjusted]; Cox proportional hazards model, hazards ratio= 0.66; 95% confidence interval, 0.47-0.93; P=.02). Conclusions: Although progression to the primary outcome was not delayed, daily oral administration of RBX may delay progression of DME to a sight-threatening stage. Ruboxistaurin was well tolerated in this study
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Novel genetic loci associated with hippocampal volume
The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans