Histone Deacetylase Complexes Promote Trinucleotide Repeat Expansions

Genetic analysis in budding yeast and in cultured human astrocytes reveals that specific histone deacetylase complexes accelerate expansion mutations in DNA triplet repeats

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Phosphorylation Fails to Activate Chloride Channels from Cystic Fibrosis Airway Cells

Chloride impermeability of epithelial cells can account for many of the experimental and clinical manifestations of cystic fibrosis (CF)1,2. Activation of apical-membrane Cl− channels by cyclic AMP-mediated stimuli is defective in CF airway epithelial cells3,4, despite normal agonist-induced increases in cellular cAMP levels4,5. This defect in Cl− channel regulation has been localized to the apical membrane by exposing the cytoplasmic surface of excised membrane patches to the catalytic subunit (C subunit) of cAMP-dependent protein kinase and ATP. In membranes from normal cells, C-subunit activated Cl− channels with properties identical to those stimulated by cAMP-dependent agonists during cell-attached recording. Activation by the C subunit was not observed in CF membranes, but the presence of Cl− channels was verified by voltage-induced activation. The failure of the C subunit to activate the Cl− channels of CF membranes indicates that the block in their cAMP-mediated activation lies distal to induction of cAMP-dependent protein kinase activity and focuses our attention on the Cl− channel and its membrane-associated regulatory proteins as the probable site of the CF defect

Phosphorylation Fails to Activate Chloride Channels from Cystic Fibrosis Airway Cells

Chloride impermeability of epithelial cells can account for many of the experimental and clinical manifestations of cystic fibrosis (CF)1,2. Activation of apical-membrane Cl− channels by cyclic AMP-mediated stimuli is defective in CF airway epithelial cells3,4, despite normal agonist-induced increases in cellular cAMP levels4,5. This defect in Cl− channel regulation has been localized to the apical membrane by exposing the cytoplasmic surface of excised membrane patches to the catalytic subunit (C subunit) of cAMP-dependent protein kinase and ATP. In membranes from normal cells, C-subunit activated Cl− channels with properties identical to those stimulated by cAMP-dependent agonists during cell-attached recording. Activation by the C subunit was not observed in CF membranes, but the presence of Cl− channels was verified by voltage-induced activation. The failure of the C subunit to activate the Cl− channels of CF membranes indicates that the block in their cAMP-mediated activation lies distal to induction of cAMP-dependent protein kinase activity and focuses our attention on the Cl− channel and its membrane-associated regulatory proteins as the probable site of the CF defect

AS160 Modulates Aldosterone-stimulated Epithelial Sodium Channel Forward Trafficking

AS160 assists in defining an intracellular compartment in which ENaC accumulates under basal conditions, and this compartment is accessed by aldosterone, via SGK-mediated phosphorylation of AS160, to permit the forward trafficking of ENaC to the apical membrane