NRSF-dependent epigenetic mechanisms contribute to programming of stress-sensitive neurons by neonatal experience, promoting resilience.

Resilience to stress-related emotional disorders is governed in part by early-life experiences. Here we demonstrate experience-dependent re-programming of stress-sensitive hypothalamic neurons, which takes place through modification of neuronal gene expression via epigenetic mechanisms. Specifically, we found that augmented maternal care reduced glutamatergic synapses onto stress-sensitive hypothalamic neurons and repressed expression of the stress-responsive gene, Crh. In hypothalamus in vitro, reduced glutamatergic neurotransmission recapitulated the repressive effects of augmented maternal care on Crh, and this required recruitment of the transcriptional repressor repressor element-1 silencing transcription factor/neuron restrictive silencing factor (NRSF). Increased NRSF binding to chromatin was accompanied by sequential repressive epigenetic changes which outlasted NRSF binding. chromatin immunoprecipitation-seq analyses of NRSF targets identified gene networks that, in addition to Crh, likely contributed to the augmented care-induced phenotype, including diminished depression-like and anxiety-like behaviors. Together, we believe these findings provide the first causal link between enriched neonatal experience, synaptic refinement and induction of epigenetic processes within specific neurons. They uncover a novel mechanistic pathway from neonatal environment to emotional resilience.

Single-center experience of percutaneous abdominal aortic aneurysm repair with local anesthesia and conscious sedation: technique and results.

AIM: Totally percutaneous endovascular abdominal aortic aneurysm repair (PEVAR) by using the "Preclose" technique has been previously described. We retrospectively analyzed data, collected prospectively at our institution, regarding PEVAR via femoral artery access with local anesthesia and conscious sedation. METHODS: Between January 2001 and May 2009, 1150 patients underwent PEVAR in the endovascular suite of the cardiac catheterization laboratory at our institution. Of those procedures, 915 (79%) were performed with local anesthesia and conscious sedation. RESULTS: The majority of patients were male (87%). Their mean age was 72±10 years, and 98% had a risk status of American Society of Anesthesiologists class III or IV. The PEVAR involved bilateral percutaneous femoral access with 12F to 24F sheaths (depending on the stent-graft system). The mean total procedure time was 149 minutes. Percutaneous closure of the arterial access sites with the Prostar XL was successful in 1727 (94.3%) of the 1830 femoral arteries in which PEVAR was attempted, whereas 103 femoral arteries (5.6%) required surgical repair because adequate hemostasis was not attained at the access site. There were no procedural deaths, but 6 patients (0.6%) died within 30 days of the procedure: 3 died of intestinal ischemia, 1 of stroke, 1 of refractory ventricular arrhythmia, and 1 of worsening renal failure. Mean length of hospital stay was 1.3±2 days. CONCLUSION: PEVAR with local anesthesia and intravenous sedation is safe and feasible and should be considered for patients for whom general anesthesia poses a high risk.