Synergistic effect of imp/ostA and msbA in hydrophobic drug resistance of Helicobacter pylori

<p>Abstract</p> <p>Background</p> <p>Contamination of endoscopy equipment by <it>Helicobacter pylori </it>(<it>H. pylori</it>) frequently occurs after endoscopic examination of <it>H. pylori</it>-infected patients. In the hospital, manual pre-cleaning and soaking in glutaraldehyde is an important process to disinfect endoscopes. However, this might not be sufficient to remove <it>H. pylori </it>completely, and some glutaraldehyde-resistant bacteria might survive and be passed to the next patient undergoing endoscopic examination through unidentified mechanisms. We identified an Imp/OstA protein associated with glutaraldehyde resistance in a clinical strain, NTUH-C1, from our previous study. To better understand and manage the problem of glutaraldehyde resistance, we further investigated its mechanism.</p> <p>Results</p> <p>The minimal inhibitory concentrations (MICs) of glutaraldehyde andexpression of <it>imp/ostA </it>RNA in 11 clinical isolates from the National Taiwan University Hospital were determined. After glutaraldehyde treatment, RNA expression in the strains with the MICs of 4–10 μg/ml was higher than that in strains with the MICs of 1–3 μg/ml. We examined the full-genome expression of strain NTUH-S1 after glutaraldehyde treatment using a microarray and found that 40 genes were upregulated and 31 genes were downregulated. Among the upregulated genes, <it>imp/ostA </it>and <it>msbA</it>, two putative lipopolysaccharide biogenesis genes, were selected for further characterization. The sensitivity to glutaraldehyde or hydrophobic drugs increased in both of <it>imp/ostA </it>and <it>msbA </it>single mutants. The <it>imp/ostA </it>and <it>msbA </it>double mutant was also hypersensitive to these chemicals. The lipopolysaccharide contents decreased in individual <it>imp/ostA </it>and <it>msbA </it>mutants and dramatically reduced in the <it>imp/ostA </it>and <it>msbA </it>double mutant. Outer membrane permeability assay demonstrated that the <it>imp/ostA </it>and <it>msbA </it>double mutation resulted in the increase of outer membrane permeability. Ethidium bromide accumulation assay demonstrated that MsbA was involved in efflux of hydrophobic drugs.</p> <p>Conclusion</p> <p>The expression levels of <it>imp/ostA </it>and <it>msbA </it>were correlated with glutaraldehyde resistance in clinical isolates after glutaraldehyde treatment. Imp/OstA and MsbA play a synergistic role in hydrophobic drugs resistance and lipopolysaccharide biogenesis in <it>H. pylori</it>.</p

Interaction between Red Yeast Rice and CYP450 Enzymes/P-Glycoprotein and Its Implication for the Clinical Pharmacokinetics of Lovastatin

Red yeast rice (RYR) can reduce cholesterol through its active component, lovastatin. This study was to investigate the pharmacokinetic properties of lovastatin in RYR products and potential RYR-drug interactions. Extracts of three registered RYR products (LipoCol Forte, Cholestin, and Xuezhikang) were more effective than pure lovastatin in inhibiting the activities of cytochrome P450 enzymes and P-glycoprotein. Among CYP450 enzymes, RYR showed the highest inhibition on CYP1A2 and CYP2C19, with comparable inhibitory potencies to the corresponding typical inhibitors. In healthy volunteers taking the RYR product LipoCol Forte, the pharmacokinetic properties of lovastatin and lovastatin acid were linear in the dose range of 1 to 4 capsules taken as a single dose and no significant accumulation was observed after multiple dosing. Concomitant use of one LipoCol Forte capsule with nifedipine did not change the pharmacokinetics of nifedipine. Yet, concomitant use of gemfibrozil with LipoCol Forte resulted in a significant increase in the plasma concentration of lovastatin acid. These findings suggest that the use of RYR products may not have effects on the pharmacokinetics of concomitant comedications despite their effects to inhibit the activities of CYP450 enzymes and P-gp, whereas gemfibrozil affects the pharmacokinetics of lovastatin acid when used concomitantly with RYR products

Initial Presentations Predict Mortality in Pulmonary Tuberculosis Patients - A Prospective Observational Study

Despite effective anti-TB treatments, tuberculosis remains a serious threat to public health and is associated with high mortality. Old age and multiple co-morbidities are known risk factors for death. The association of clinical presentations with mortality in pulmonary tuberculosis patients remains an issue of controversy.This prospective observational study enrolled newly diagnosed, culture-proven pulmonary tuberculosis patients from five medical centers and one regional hospital, which were referral hospitals of TB patients. Radiographic findings and clinical symptoms were determined at the time of diagnosis. Patients who died for any reason during the course of anti-TB treatment were defined as mortality cases and death that occurred within 30 days of initiating treatment was defined as early mortality. Clinical factors associated with overall mortality and early mortality were investigated.A total of 992 patients were enrolled and 195 (19.7%) died. Nearly one-third (62/195, 31.8%) of the deaths occurred before or within 30 days of treatment initiation. Older age (RR = 1.04, 95%CI: 1.03–1.05), malignancy (RR = 2.42, 95%CI: 1.77–3.31), renal insufficiency (RR = 1.77, 95%CI: 1.12–2.80), presence of chronic cough (RR = 0.63, 95%CI: 0.47–0.84), fever (RR = 1.45, 95%CI: 1.09–1.94), and anorexia (RR = 1.49, 95%CI: 1.07–2.06) were independently associated with overall mortality. Kaplan-Meier survival analysis demonstrated significantly higher mortality in patients present with fever (p<0.001), anorexia (p = 0.005), and without chronic cough (p<0.001). Among patients of mortality, those with respiratory symptoms of chronic cough (RR = 0.56, 95%CI: 0.33–0.98) and dyspnea (HR = 0.51, 95%CI: 0.27–0.98) were less likely to experience early mortality. The radiological features were comparable between survivors and non-survivors.In addition to demographic characteristics, clinical presentations including the presence of fever, anorexia, and the absence of chronic cough, were also independent predictors for on-treatment mortality in pulmonary tuberculosis patients

Natural Product Chemistry of Gorgonian Corals of Genus Junceella—Part II

The structures, names, bioactivities, and references of 81 new secondary metabolites obtained from gorgonian corals belonging to the genus Junceella are described in this review. All compounds mentioned in this review were obtained from sea whip gorgonian corals Junceella fragilis and Junceella juncea, collected from the tropical and subtropical Indo-Pacific Ocean

Improved Image Quality for Static BLADE Magnetic Resonance Imaging Using the Total-Variation Regularized Least Absolute Deviation Solver.

In order to improve the image quality of BLADE magnetic resonance imaging (MRI) using the index tensor solvers and to evaluate MRI image quality in a clinical setting, we implemented BLADE MRI reconstructions using two tensor solvers (the least-squares solver and the L1 total-variation regularized least absolute deviation (L1TV-LAD) solver) on a graphics processing unit (GPU). The BLADE raw data were prospectively acquired and presented in random order before being assessed by two independent radiologists. Evaluation scores were examined for consistency and then by repeated measures analysis of variance (ANOVA) to identify the superior algorithm. The simulation showed the structural similarity index (SSIM) of various tensor solvers ranged between 0.995 and 0.999. Inter-reader reliability was high (Intraclass correlation coefficient (ICC) = 0.845, 95% confidence interval: 0.817, 0.87). The image score of L1TV-LAD was significantly higher than that of vendor-provided image and the least-squares method. The image score of the least-squares method was significantly lower than that of the vendor-provided image. No significance was identified in L1TV-LAD with a regularization strength of λ= 0.4-1.0. The L1TV-LAD with a regularization strength of λ= 0.4-0.7 was found consistently better than least-squares and vendor-provided reconstruction in BLADE MRI with a SENSitivity Encoding (SENSE) factor of 2. This warrants further development of the integrated computing system with the scanner