Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state

MeCP2 is a nuclear protein with an affinity for methylated DNA that can recruit histone deacetylases. Deficiency or excess of MeCP2 causes severe neurological problems, suggesting that the number of molecules per cell must be precisely regulated. We quantified MeCP2 in neuronal nuclei and found that it is nearly as abundant as the histone octamer. Despite this high abundance, MeCP2 associates preferentially with methylated regions and high-throughput sequencing showed that its genome-wide binding tracks methyl-CpG density. MeCP2 deficiency results in global changes in neuronal chromatin structure, including elevated histone acetylation and a doubling of histone H1. Neither change is detectable in glia, where MeCP2 occurs at lower levels. The mutant brain also shows elevated transcription of repetitive elements. Our data argue that MeCP2 may not act as a gene-specific transcriptional repressor in neurons, but might instead dampen transcriptional noise genome-wide in a DNA methylation-dependent manner

MitraClip Therapy in Surgical High-Risk Patients Identification of Echocardiographic Variables Affecting Acute Procedural Outcome

Objectives The aim of the study was to assess predictors of acute procedural failure in surgical high-risk patients undergoing MitraClip (Abbott Vascular, Abbott Park, Illinois) therapy. Background MitraClip implantation is a novel percutaneous option to treat significant mitral regurgitation (MR). Methods In 300 patients (75 +/- 9 years of age, 190 [63%] men), of whom 32 (10.7%) had been unsuccessfully treated (discharge MR grade of >2+), baseline clinical and echocardiographic variables were evaluated by exact logistic regression and classification tree analyses to assess their impact on acute procedural failure. Acute procedural failure was differentiated into aborted procedure (no MitraClip implanted; n = 11) and clip failure (inadequate MR reduction despite MitraClip implantation; n = 21). Results Multivariate logistic regression identified effective regurgitant orifice area (EROA), mitral valve orifice area (MVOA), and mean transmitral pressure gradient (TMPG) as independent predictors of overall acute procedural failure. Classification tree analysis revealed that an EROA > 70.8 mm(2) (n = 28) was associated with a high rate (25%) of clip failures, whereas the combination of an MVOA = 4mmHg (n = 16) was associated with a high rate (37.5%) of aborted procedures. Failure rates of 3.0 cm(2) (n 217) or an MVOA 70.8 mm(2) and a TMPG >= 4 mm Hg as independently predictive of clip failure, but an MVOA = 4 mm Hg as independently predictive of procedure abortion. Conclusions In surgical high-risk patients undergoing MitraClip therapy, a TMPG >= 4 mm Hg, an EROA >= 70.8 mm(2), and an MVOA <= 3.0 cm(2) carry an increased risk of procedural failure. (C) 2014 by the American College of Cardiology Foundatio