Role of efflux pumps and mutations in genes for topoisomerases II and IV in fluoroquinolone-resistant Pseudomonas aeruginosa strains

We have investigated the occurrence of mutations in topoisomerase II (DNA gyrase) subunit B(gyrB) and topoisomerase IV subunit E(parE) and the hyperexpression of genes for four efflux pump proteins in 20 previously described, fluoroquinolone-resistant clinical strains of Pseudomonas aeruginosa. Amino acid alterations were found in GyrB in five strains and in ParE in three strains with MIC of norfloxacin > or = 8 mg/L, and it is likely that some of the alterations contribute to the quinolone resistance exhibited by these strains. Seventeen of the 20 strains overproduced mRNA for one or more pump proteins (MexB, MexD, MexF, or MexY), which caused multidrug resistance phenotype in more than half of strains. Two strains were hypermutable and one of them was highly resistant, but the other strain was only moderately resistant.     

Effects of ACE Inhibitors or ↓-Blockers in Patients Treated with the Fixed-Dose Combination of Isosorbide Dinitrate/Hydralazine in the African-American Heart Failure Trial

BACKGROUND: In the A-HeFT (African-American Heart Failure Trial), treatment of African-American patients with New York Heart Association (NYHA) class III/IV heart failure (HF) with fixed-dose combination (FDC) of isosorbide dinitrate/hydralazine (I/H) reduced mortality and morbidity and improved patient reported functional status compared with standard therapy alone. OBJECTIVE: To examine the benefit of FDC I/H in subgroups based on baseline drug therapy and to investigate whether ACE inhibitors and/or angiotensin receptor antagonists (angiotensin receptor blockers) [ARBs] or beta-adrenoceptor antagonists (beta-blockers) provided additional benefit in FDC I/H-treated African-American patients with HF. STUDY DESIGN: The A-HeFT was a double-blind, placebo-controlled study enrolling 1050 patients stabilized on optimal HF therapies and with NYHA class III/IV HF with systolic dysfunction conducted during the years 2001-4 with up to 18 months follow-up. The primary endpoint was a composite of mortality, first HF hospitalization, and improvement of quality of life at 6 months. Secondary endpoints included mortality, hospitalizations, and change in quality of life. Prospective Kaplan-Meier survival analyses were used for differences between FDC I/H and placebo groups and retrospective analyses were conducted within FDC I/H-treated and placebo groups. RESULTS: Subgroup analysis for mortality, event-free survival (death or first HF hospitalization), and HF hospitalization showed that FDC I/H, compared with placebo, was effective with or without ACE inhibitors or beta-blockers or other standard medications with all-point estimates favoring the FDC I/H group. Within the placebo-treated group, beta-blockers or ACE inhibitors and/or ARBs were efficacious in improving survival (hazard ratio [HR] 0.33; p<0.0001 for [beta]-blocker use and HR 0.39; p=0.01 for ACE inhibitor and/or ARB use). However, within the FDC I/H-treated group, use of beta-blockers, but not ACE inhibitors and/or ARBs, provided additional significant benefit for survival (HR 0.44; p=0.029 and HR 0.60; p=0.34, respectively), event-free survival (HR 0.62; p=0.034 and HR 0.72; p=0.29, respectively) and the composite score of death, HF hospitalization and change in quality of life (p=0.016 and p=0.13, respectively). CONCLUSION: Based on the analysis of baseline medication use in the A-HeFT, FDC I/H was superior to placebo with or without beta-blockers or ACE inhibitor. However, beta-blockers but not ACE inhibitors and/or ARBs provided additional significant benefit in African-Americans with HF treated with FDC I/H. These analyses are hypotheses generating and their confirmation in clinical trials needs to be considered.     

Evaluation of two years of mass chemotherapy against ascariasis in Hamadan,Islamic Republic of Iran

OBJECTIVE: To evaluate the mass treatment of ascariasis in rural areas of Hamadan Province, Islamic Republic of Iran. METHODS: A control programme in rural areas of Hamadan Province, which began in November 1997, involved giving all persons a single dose of 400 mg albendazole at intervals of three months. The efficacy of the treatment was evaluated by the formalin-ether concentration technique for stool examination and by the Stoll quantitative method. FINDINGS: The average rate of infection with Ascaris before treatment was 53.3%, ranging from 40% in Hamadan district to 75% in Toysercan. Two areas, Malayer and Nahavand, were excluded from the programme because the infection rates were only 13% and 4%, respectively. After two years of mass treatment the infection rate had decreased to 6%. The proportion of positive cases excreting only unfertilized eggs increased to 32%. No side-effects of mass treatment were observed. CONCLUSION: Systematic mass treatment giving high coverage proved to be very effective in the control of ascariasis, notwithstanding a lack of other preventive measures.     

Anomalous course of the right coronary artery in the right atrial wall: a word of caution

We report a case of anomalous course of the right coronary artery in the wall of right atrium which was encountered during coronary artery bypass surgery. As the stenotic lesion in the vessel was proximal, the large posterior descending branch of the right coronary was grafted. Such an anomalous course of the right coronary artery has not been previously described in the literature and lack of knowledge of such an abnormal course may result in inadvertant damage during cannulation of the inferior vena cava or coronary sinus.     

Asymptomatic Paget’s disease of bone presenting with complete atrioventricular block

Paget＇s disease of bone is a deforming bone disease （osteitis deformans） characterized by increased bone remodeling, bone hypertrophy, and abnormal bone structure, leading to bone expansion, deformities, easy fractures, and occasionally, neoplastic transformation. It is the second most common bone disorder after osteoporosis. The disease is relatively rare in Asia but is common in Europe and North America, affecting approximately 2% of the population over 50 years,     

Parathyroid hormone regulation of NA+,K+-ATPase requires the PDZ 1 domain of sodium hydrogen exchanger regulatory factor-1 in opossum kidney cells

It was demonstrated that expression of murine sodium hydrogen exchanger regulatory factor (NHERF-1) lacking the ezrin-binding domain blocks parathyroid hormone (PTH) regulation of Na+,K+-ATPase in opossum kidney (OK) cells. The hypothesis that the NHERF-1 PDZ domains contribute to PTH regulation of Na+,K+-ATPase was tested by comparison of PTH regulation of Na+,K+-ATPase in wild-type OK (OK-WT) cells, NHERF-deficient OKH cells, OK-WT transfected with siRNA for NHERF (NHERF siRNA OK-WT), and OKH cells that were stably transfected with full-length NHERF-1 or constructs with mutated PDZ domains. OKH cells and NHERF siRNA OK-WT showed decreased expression of NHERF-1 but equivalent expression of ezrin and Na+,K+-ATPase alpha1 subunit when compared with OK-WT cells. PTH decreased Na+,K+-ATPase activity and stimulated phosphorylation of the Na+,K+-ATPase alpha1 in OK-WT cells but not in NHERF-deficient cells. Rubidium (86Rb) uptake was equivalent in OK-WT, OKH, and OKH cells that were transfected with all but the double PDZ domain mutants. PTH decreased 86Rb uptake significantly in OK-WT but not in OKH cells. PTH also significantly inhibited 86Rb uptake in OKH cells that were transfected with full-length NHERF-1 or NHERF-1 with mutated PDZ 2 but not in OKH cells that were transfected with mutated PDZ 1. Transfection with NHERF expressing both mutated PDZ domains resulted in diminished basal 86Rb uptake that was not inhibited further by PTH. PTH stimulated protein kinase Calpha activity and alpha1 subunit phosphorylation in OK-WT but not in NHERF-deficient cells. Transfection of OKH cells with NHERF constructs that contained an intact PDZ1 domain restored PTH-stimulated protein kinase Calpha activity and alpha1 subunit phosphorylation. These results demonstrate that NHERF-1 is necessary for PTH-mediated inhibition of Na+,K+-ATPase activity and that the inhibition is mediated through the PDZ1, not PDZ2, domain.