Highly conserved histone proteins offer a platform to evaluate these driving forces. While the conservation of histone H3 and H4 “”tail”" domains and surface residues are driven by functional importance, the driving force behind the conservation of buried histone residues has not been examined. Using a computational approach, we determined the thermodynamically preferred amino acids at each buried position in H3 and H4. In agreement with what is normally observed in proteins, we find a significant correlation between thermodynamic stability
and evolutionary conservation in the buried residues in H4. In striking contrast, we find that thermodynamic stability of buried H3 residues does not correlate with evolutionary conservation. Given that these H3 residues are not post-translationally modified and only regulate H3-H3 and H3-H4 stabilizing interactions, our data imply an unknown function responsible for driving conservation Staurosporine of these buried H3 residues.”
“Background: Dofetilide, a class III antiarrhythmic, is one of the few alternatives to amiodarone in patients with atrial fibrillation (AF) and heart failure or coronary artery disease (CAD). While amiodarone has been IC-83 extensively studied, little is known about predictors of response to dofetilide. We sought to identify clinical
parameters associated with dofetilide success in a large cohort of patients with AF.
Methods/Results: A total of 287 patients with AF started on dofetilide between 2001 and 2008 were included. Dofetilide was deemed “”completely effective”" if the patient remained on dofetilide at followup and had no recurrences of AF clinically or by electrocardiogram. Dofetilide efficacy was analyzed in relation to clinical variables relevant to AF and AF recurrence. After a follow-up of 10.2 +/- 7.7 months, 54.7% of the patients remained on dofetilide and it was completely effective in 26.8%. The discontinuation
rate during initial hospitalization was 13.3% from excessive QT prolongation and one patient with torsades de pointes (successfully treated). A history of CAD was the Trk receptor inhibitor only univariate predictor of efficacy (odds ratio [OR] 2.27, 95% confidence interval [CI] 1.29-4.01, P < 0.05). CAD remained the only significant factor associated with efficacy of dofetilide in a multivariate regression model (OR 2.01, 95% CI 1.11-3.70, P < 0.05, n = 270). The overall efficacy of dofetilide in patients with CAD was 41.1%, compared to 23.5% in those without CAD (P < 0.05).
Conclusions: In this large cohort of patients with AF, underlying coronary disease was significantly associated with dofetilide success. This finding may have utility for clinical decisions regarding initiation of dofetilide. (PACE 2012; 35:170-173)”
“Background: The ACT recommended by WHO is very effective and well-tolerated. However, these combinations need to be administered for three days, which may limit adherence to treatment.