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

Enhancing the Messages Displayed on Dynamic Message Signs

A human factors study was carried out to help enhance ways tocommunicate with highway motorists through dynamic message signs (DMS).Overhead mounted DMSs have been increasingly used by highway authorities inthe United States to present real-time traffic information and travel advice tomotorists. It is critical to post sign messages that can be quickly and clearlyunderstood by motorists, especially in high-volume traffic and construction/repairzones. Properly worded and formatted sign messages could spell the differencebetween comprehension and confusion. Message display factors investigated inthe study include display effects, color schemes, wording, and formats. Twoapproaches were employed in this study. First, a questionnaire survey wasdeveloped to collect motorists’ preferences regarding various message displayfactors. Second, a series of lab driving simulation experiments were set up toassess the effects of these factors and their interactions on motorists’comprehension of DMS messages. Study results suggested that static, one-framedmessages with more specific wording and no abbreviations were preferred.Amber or green or a green-amber combination were the most favored colors.Younger subjects took less response time to the DMS stimuli with higheraccuracy than older subjects. There were no significant gender differences

Using data envelopment analysis to support best-value contractor selection

Selecting an appropriate contractor or supplier is essential to the successful implementation of a public procurement project. The Taiwan government frequently applies the best-value (BV) tendering method, a multi-criteria evaluation method, to procure projects. However, the selection process of the winner for a BV-based procurement project is generally subjective and thus is easily accused of corruptions. To develop a systematic method to support contractor selection, this study proposes using the Data Envelopment Analysis (DEA) to facilitate the criteria evaluations for each bidder during the short-listing stage. The evaluation results of using the DEA are a list of potential BV winners who are then suggested to enter into the final selection stage. Based on three case studies related to service procurement projects, this research finds that the DEA is suitable of assessing the relative efficiencies among bidders when the BV approach is applied. Lessons learned here should be helpful in applying the DEA to aid bid evaluations in other supplier selection problems. First published online: 24 Aug 201

Type I IL-1 Receptor (IL-1RI) as Potential New Therapeutic Target for Bronchial Asthma

The IL-1R/TLR family has been receiving considerable attention as potential regulators of inflammation through their ability to act as either activators or suppressors of inflammation. Asthma is a chronic inflammatory disease characterized by airway hyperresponsiveness, allergic inflammation, elevated serum total, allergen-specific IgE levels, and increased Th2 cytokine production. The discovery that the IL-1RI–IL-1 and ST2–IL-33 pathways are crucial for allergic inflammation has raised interest in these receptors as potential targets for developing new therapeutic strategies for bronchial asthma. This paper discusses the current use of neutralizing mAb or soluble receptor constructs to deplete cytokines, the use of neutralizing mAb or recombinant receptor antagonists to block cytokine receptors, and gene therapy from experimental studies in asthma. Targeting IL-1RI–IL-1 as well as ST2–IL-33 pathways may promise a disease-modifying approach in the future

Juvenile Dermatomyositis: A 20-year Retrospective Analysis of Treatment and Clinical Outcomes

BackgroundJuvenile dermatomyositis is a rare childhood multisystem autoimmune disease involving primarily the skin and muscles, and it may lead to long-term disability. This study aimed to describe the clinical course of juvenile dermatomyositis and determine if any early clinical or laboratory features could predict outcome.MethodsMedical charts of patients aged ≤18 years and diagnosed with juvenile dermatomyositis (according to the criteria of Bohan and Peter) at the Pediatric Department, National Taiwan University Hospital, between 1989 and 2009 were reviewed. The endpoints for disease assessment were complete clinical response and complete clinical remission. Cox's proportional hazards model was fitted to identify important predictors of complete clinical remission.ResultsA total of 39 patients with juvenile dermatomyositis were reviewed. Two-thirds were females, and the mean age at disease onset was 81.97 ± 46.63 months. The most common initial presentations were Gottron's papule (82.1%) and muscle weakness (82.1%). After excluding one patient with an incomplete record, the remaining 31 patients who had muscle weakness were analyzed; among them, 22 (70.97%) achieved complete clinical response, but only six (19.4%) achieved complete clinical remission. Multivariate analysis showed that female sex, negative Gowers' sign at disease onset, and positive photosensitivity at disease onset were favorable factors to achieve complete clinical remission. Moreover, covariate-adjusted survival curves were drawn for making predictions of complete clinical remission. Only 13 (33.33%) patients were symptom free at the end of follow up, whereas the other 26 suffered from different kinds of complications. None of them developed malignancy, but two (5.13%) patients died during the follow-up period.ConclusionFactors such as male sex and Gowers' sign were unlikely to favor the achievement of complete clinical remission in juvenile dermatomyositis. Certain complications cannot be avoided, and thus more effective treatments and monitoring strategies are needed for better control of juvenile dermatomyositis

Simultaneous block and I/O buffer floorplanning for flip-chip design

The flip-chip package gives the highest chip density of any packaging method to support the pad-limited ASIC design. One of the most important characteristics of flip-chip designs is that the input/output buffers could be placed anywhere inside a chip. In this paper, we first introduce the floorplanning problem for the flip-chip design and formulate it as assigning the positions of input/output buffers and first-stage/last-stage blocks so that the path length between blocks and bump balls as well as the delay skew of the paths are simultaneously minimized. We then present a hierarchical method to solve the problem. We first cluster a block and its corresponding buffers to reduce the problem size. Then, we go into iterations of the alternating and interacting global optimization step and the partitioning step. The global optimization step places blocks based on simulated annealing using the B*-tree representation to minimize a given cost function. The partitioning step dissects the chip into two subregions, and the blocks are divided into two groups and are placed in respective subregions. The two steps repeat until each subregion contains at most a given number of blocks, defined by the ratio of the total block area to the chip area. At last, we refine the floorplan by perturbing blocks inside a subregion as well as in different subregions. Compared with the B*-tree based floorplanner alone, our method is more efficient and obtains significantly better results, with an average cost of only 51.8 % of that obtained by using the B*-tree alone, based on a set of real industrial flip-chip designs provided by leading companies

The effect of caffeic acid phenethyl ester on the functions of human monocyte-derived dendritic cells

<p>Abstract</p> <p>Background</p> <p>Propolis, an ancient herbal medicine, has been reported the beneficial effect both in asthma patients and murine model of asthma, but the mechanism was not clearly understood. In this study, the effect of caffeic acid phenethyl ester (CAPE), the most extensively studied components in propolis, on the functions of human monocyte-derived dendritic cells (MoDCs) was investigated.</p> <p>Results</p> <p>CAPE significantly inhibited IL-12 p40, IL-12 p70, IL-10 protein expression in mature healthy human MoDCs stimulated by lipopolysaccharides (LPS) and IL-12 p40, IL-10, IP-10 stimulated by crude mite extract. CAPE significantly inhibited IL-10 and IP-10 but not IL-12 expression in allergic patients' MoDCs stimulated by crude mite extract. In contrast, the upregulation of costimulatory molecules in mature MoDCs was not suppressed by CAPE. Further, the antigen presenting ability of DCs was not inhibited by CAPE. CAPE inhibited IκBα phosphorylation and NF-κB activation but not mitogen-activated protein kinase (MAPK) family phosphorylation in human MoDCs.</p> <p>Conclusion</p> <p>These results indicated that CAPE inhibited cytokine and chemokine production by MoDCs which might be related to the NF-κB signaling pathway. This study provided a new insight into the mechanism of CAPE in immune response and the rationale for propolis in the treatment of asthma and other allergic disorders.</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

Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis

X-linked juvenile retinoschisis (XLRS), linked to mutations in the RS1 gene, is a degenerative retinopathy with a retinal splitting phenotype. We generated human induced pluripotent stem cells (hiPSCs) from patients to study XLRS in a 3D retinal organoid in vitro differentiation system. This model recapitulates key features of XLRS including retinal splitting, defective retinoschisin production, outer-segment defects, abnormal paxillin turnover, and impaired ER-Golgi transportation. RS1 mutation also affects the development of photoreceptor sensory cilia and results in altered expression of other retinopathy-associated genes. CRISPR/Cas9 correction of the disease-associated C625T mutation normalizes the splitting phenotype, outer-segment defects, paxillin dynamics, ciliary marker expression, and transcriptome profiles. Likewise, mutating RS1 in control hiPSCs produces the disease-associated phenotypes. Finally, we show that the C625T mutation can be repaired precisely and efficiently using a base-editing approach. Taken together, our data establish 3D organoids as a valid disease model