ABSTRACT
PH domains, by binding to phosphoinositides, often serve as membrane-targeting modules. Using crystallographic, biochemical, and cell biological approaches, we have uncovered a mechanism that the integrin-signaling adaptor Skap-hom uses to mediate cytoskeletal interactions. Skap-hom is a homodimer containing an N-terminal four-helix bundle dimerization domain, against which its two PH domains pack in a conformation incompatible with phosphoinositide binding. The isolated PH domains bind PI[3,4,5]P(3), and mutations targeting the dimerization domain or the PH domain's PI[3,4,5]P(3)-binding pocket prevent Skap-hom localization to ruffles. Targeting is retained when the PH domain is deleted or by combined mutation of the PI[3,4,5]P(3)-binding pocket and the PH/dimerization domain interface. Thus, the dimerization and PH domain form a PI[3,4,5]P(3)-responsive molecular switch that controls Skap-hom function.
Subject(s)
Adaptor Proteins, Signal Transducing/chemistry , Adaptor Proteins, Signal Transducing/metabolism , Phosphatidylinositols/chemistry , Phosphatidylinositols/metabolism , Adaptor Proteins, Signal Transducing/genetics , Amino Acid Sequence , Animals , Dimerization , Green Fluorescent Proteins/metabolism , Mice , Mice, Knockout , Models, Chemical , Models, Molecular , Molecular Sequence Data , Phosphatidylinositols/genetics , Point Mutation , Protein Binding , Protein Conformation , Protein Structure, Secondary , Protein Structure, Tertiary , Retroviridae/genetics , Sequence Homology, Amino Acid , Transduction, GeneticABSTRACT
BACKGROUND: Central venous cannulation is technically challenging in obese patients. We hypothesized that positive end-expiratory pressure (PEEP) increases the size of the internal jugular vein (IJV) in obese adults. METHODS: The circumference and cross-sectional area of the IJV were measured in obese patients under general anesthesia at PEEP 0, 5, and 10 cm H2O. Results are reported as means ± SE. RESULTS: PEEP at 10 cm H2O was tolerated by 18 of 24 obese patients. Each 5 cm H2O of PEEP increased the cross-sectional area by 0.16 ± 0.02 cm (P < 0.0001) and the circumference by 0.23 ± 0.03 cm (P < 0.0001). CONCLUSIONS: PEEP modestly increases the size of the IJV in obese adults but was poorly tolerated because of hypotension.
Subject(s)
Anesthesia , Jugular Veins/anatomy & histology , Obesity/complications , Positive-Pressure Respiration/adverse effects , Adult , Aged , Anatomy, Cross-Sectional , Catheterization, Central Venous , Female , Humans , Male , Middle Aged , Surgical Procedures, OperativeABSTRACT
STUDY OBJECTIVE: The aim of this study was to compare the effectiveness of epsilon-aminocaproic acid (εACA) and tranexamic acid (TXA) in contemporary clinical practice during a national medication shortage. DESIGN: A retrospective cohort study. SETTING: The study was performed in all consecutive cardiac surgery patients (n=128) admitted to the cardiac-surgical intensive care unit after surgery at a single academic center immediately before and during a national medication shortage. MEASUREMENTS: Demographic, clinical, and outcomes data were compared by descriptive statistics using χ2 and t test. Surgical drainage and transfusions were compared by multivariate linear regression for patients receiving εACA before the shortage and TXA during the shortage. MAIN RESULTS: In multivariate analysis, no statistical difference was found for surgical drain output (OR 1.10, CI 0.97-1.26, P=.460) or red blood cell transfusion requirement (OR 1.79, CI 0.79-2.73, P=.176). Patients receiving εACA were more likely to receive rescue hemostatic medications (OR 1.62, CI 1.02-2.55, P=.041). CONCLUSIONS: Substitution of εACA with TXA during a national medication shortage produced equivalent postoperative bleeding and red cell transfusions, although patients receiving εACA were more likely to require supplemental hemostatic agents.