Brain G protein gamma subunits contain an all-trans-geranylgeranylcysteine methyl ester at their carboxyl termini.

We have shown previously that guanine nucleotide-binding protein (G protein) beta gamma complexes purified from bovine brain membranes are methyl esterified on a C-terminal cysteine residue of the gamma polypeptide. In the present study, 3H-methylated G beta gamma complexes cleaved to their constituent amino acids by exhaustive proteolysis were shown to contain radiolabeled material that coeluted with geranylgeranylcysteine methyl ester on reversed-phase HPLC and two TLC systems. Further treatment by performic acid oxidation yielded radiolabeled material that coeluted with L-cysteic acid methyl ester, verifying that the prenyl modification occurs on a C-terminal cysteine residue. Analysis by gas chromatography-coupled mass spectrometry of material released from purified G beta gamma by treatment with Raney nickel positively identified the covalently bound lipid as an all-trans-geranylgeranyl (C20) isoprenoid moiety. To delineate the distribution of this modification among gamma subunits, purified G beta gamma complexes were separated into 5-kDa (gamma 5) and 6-kDa (gamma 6) forms of the gamma polypeptide by reversed-phase HPLC. Gas chromatography-coupled mass spectrometry analyses of Raney nickel-treated purified gamma 5 and gamma 6 subunits showed that both polypeptides were modified by geranylgeranylation. These results demonstrate that at least two forms of brain gamma subunit are posttranslationally modified by geranylgeranylation and carboxyl methylation. These modifications may be important for targeting G beta gamma complexes to membranes.     

Improvement of atrial function and atrial reverse remodeling after cardiac resynchronization therapy for heart failure.

OBJECTIVES: We sought to examine whether cardiac resynchronization therapy (CRT) improves atrial function and induces atrial reverse remodeling. BACKGROUND: Cardiac resynchronization therapy is an established therapy for advanced heart failure with prolonged QRS duration, which improves left ventricle (LV) function and is associated with LV reverse remodeling. METHODS: A total of 107 heart failure patients (66 +/- 11 years) who received CRT and were followed up for 3 months were studied. Atrial function was assessed by M-mode, 2-dimensional echocardiography, transmitral Doppler, tissue Doppler velocity, and strain (epsilon) imaging. Left atrial (LA) emptying fraction based on the change in areas (LAA-EF) and volumes (LAV-EF) were calculated. The LV reverse remodeling was defined by a reduction of LV end-systolic volume >10%. RESULTS: In the responders of LV reverse remodeling (n = 62), LAA-EF and LAV-EF were significantly increased (p < 0.001). Responders also had significant decrease in LA size area and volumetric measurements, both before (p < 0.05) and after atrial systole (p < 0.001). However, these parameters were unchanged in the nonresponders (n = 45, p = NS). In the responders, tissue Doppler velocity analysis showed improvement of contraction velocity in both left (p = 0.005) and right atria (p = 0.018), whereas epsilon in both atria were increased in all the phases of cardiac cycle, namely ventricular end-systole (p < 0.001), early diastole (p < 0.001), and late diastole (p = 0.007). CONCLUSIONS: Cardiac resynchronization therapy improves both left and right atrial pump function. The increase in atrial epsilon throughout the cardiac cycle is likely reflecting the improvement of atrial compliance. These changes lead to LA reverse remodeling with reduction of LA size before and after atrial systole.     

Characteristics of bacteremia between community-acquired and nosocomial Klebsiella pneumoniae infection: risk factor for mortality and the impact of capsular serotypes as a herald for community-acquired infection

BACKGROUND: Although several epidemiological surveys of Klebsiella clinical isolates have been performed, few studies have correlated the clinical isolate with disease. OBJECTIVE: To compare the clinical and bacteriological characteristics of Klebsiella pneumoniae bacteremia acquired as community or nosocomial infections. METHODS: We prospectively enrolled 158 consecutively hospitalized patients with K pneumoniae bacteremia. Clinical data were reviewed. Antimicrobial susceptibility testing and capsular serotyping were performed. We used the chi(2) test, the Fisher exact test, or the t test for statistic analysis. RESULTS: Underlying diabetes mellitus was more common in community-acquired than in nosocomial infection (46/94 [49%] vs. 8/64 [12%]; P<.001). On the other hand, neoplastic disease (34/64 [53%] vs. 13/94 [14%]; P<.001) and antibiotic resistance (P<.01) were more frequent in patients with nosocomial compared with community-acquired infections. Klebsiella pneumoniae liver abscesses, which were all community acquired, accounted for the source of 22 (23%) of 94 community-acquired K pneumoniae infections. No attributable source of infection was found for 37 (58%) of the 64 nosocomial infections vs. 15 (16%) of the 94 community-acquired infections. Only 58 isolates (36.7%) could be serotyped; of these, capsular serotypes K1, K2, and K28 accounted for 37 (23.4%), 8 (5.1%), and 6 (3.8%), respectively, of all strains. However, typeable isolates were significantly more common among community-acquired than nosocomial isolates (42/94 [45%] vs. 16/64 [25%]; P =.01), especially for serotype K1 (28/94 [30%] vs. 9/64 [14%]; P =.02). Significant risk factors for mortality included nosocomial infection, lung infection, thrombocytopenia, leukopenia, ceftazidime resistance, inappropriate antimicrobial therapy, and septic shock. CONCLUSIONS: Significant differences were identified between community-acquired and nosocomial K pneumoniae bacteremia. Ceftazidime resistance in nosocomial K pneumoniae bacteremia carried a high risk for mortality, and serotype K1 in K pneumoniae was more prevalent in community-acquired infection, suggesting more virulence.     

Antianginal effects of intravenous nitroglycerin over 24 hours

To determine the constancy of hemodynamic and antianginal effects of the constant infusion of intravenous nitroglycerin (NTG) and their relationship to infusion rate and plasma NTG concentration, we administered maximal tolerated doses of intravenous NTG (range 10 to 120 micrograms/min, mean = 52 +/- 33 micrograms/min) and placebo to 10 patients with chronic stable angina for 25 hr each in a randomized, double-blind fashion. Sublingual NTG (0.4 mg) was given at 24.5 hr of infusion as a positive control. Bicycle exercise time (NIH protocol), blood pressure, heart rate, exercise ST response, and venous plasma NTG were determined before and at 1, 4, 8, 24, and 24.5 hr. Plasma NTG was linearly related to infusion rate, reached a steady state within 15 min and was unchanged over 24 hr (mean = 5.5 +/- 1.2 ng/ml). Mean plasma NTG clearance was 9.3 liters/min. However, during dose titration, patients demonstrated different relationships between plasma NTG and hemodynamic effects, with widely varying slopes and intercepts. Intravenous NTG produced a sustained reduction in blood pressure and a rise in heart rate at rest, and a reduction in blood pressure during submaximal exercise at as late as 24 hr, associated with reduced submaximal ST segment abnormality. In contrast, exercise tolerance to onset of angina showed a marked initial increase on intravenous NTG but fell progressively and did not differ from that with placebo at 24 hr. Increased exercise tolerance was associated with an increase in maximal heart rate and double product (heart rate X blood pressure), suggesting that direct coronary vasodilation and/or reduced left ventricular volume were the principal determinants of increased exercise tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)     

TIPS for acute and chronic Budd-Chiari syndrome: a single-centre experience

BACKGROUND/AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) is a technically challenging but feasible treatment for Budd-Chiari syndrome (BCS). However, information about the outcome, particularly in patients with liver failure, is scarce. We report our experience of TIPS for BCS. METHODS: Fifteen patients with BCS underwent TIPS. Eight had hepatic failure and seven underwent TIPS for BCS uncontrolled by medical treatment. RESULTS: Fourteen out of 15 had successful TIPS placement. Out of the eight hepatic failure patients, four died soon after TIPS: one liver rupture, one portal vein rupture, one liver failure and one pulmonary oedema. Another patient had a significant intrahepatic haematoma, which resolved with conservative management. TIPS was successfully placed in all of the seven patients with chronic BCS, in whom there was an average follow-up of 20 months. Ascites resolved and liver function improved in all. One patient died after 18 months from the original hepatic metastatic disease. Four patients have had evidence of TIPS dysfunction requiring three balloon dilatations and one restenting. No patient has required liver transplantation. CONCLUSIONS: TIPS should be the first line treatment for BCS uncontrolled by medical therapy. However, mortality in BCS with hepatic failure is high and liver transplantation could be a better option.