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OBJECTIVE: Cytochrome P450 2C19 (CYP2C19) polymorphisms play an important role in the metabolism of proton pump inhibitors. Rabeprazole is primarily metabolized via non-enzymatic pathways. In this study, we determined whether rabeprazole- and pantoprazole- based eradication treatments were influenced by CYP2C19 polymorphisms. PATIENTS AND METHODS: A total of 200 patients infected with Helicobacter pylori were treated with either 40 mg of pantoprazole or 20 mg of rabeprazole plus 500 mg of clarithromycin, 1000 mg of amoxicillin twice daily for 2 weeks. CYP2C19 genotype status was determined by Polymerase Chain Reaction (PCR)- restriction-fragment-length polymorphism. The genotypes of cytochrome P450 2C19 were classified as homozigote extensive metabolizer (HomEM), heterozigote metabolizer (HetEM) and poor metabolizer (PM). The CYP2C19 genotype of all patients, the effectiveness of the treatment, the effect of the genotypic polymorphism on the treatment were assessed. RESULTS: The frequencies of HotEM, HetEM, PM were 78%, 19.5% and 2.5%, respectively. 48% (n = 96) of the patients received treatment with rabeprazole and 52% (n = 104) with pantoprazole. The eradication rate was 64.7% for HomEM, 79.4% for HetEM, 100% for PM (p = 0.06). In HetEM, PM, are considered as a single group, the eradication rates were higher in patients with the HetEM and PM (HetEM+PM) genotypes than in those with the wild-type genotype (81.8 vs. 64.7% p = 0.031). Among the patients treated with rabeprazole, the eradication rates were significantly lower in those with the HomEM genotype than in those with the Het- EM+PM genotypes (60% vs. 85.7% p = 0.023). CONCLUSIONS: The genotypic polymorphism is effective on the rate of eradication. Eradication treatment rate with rabeprazole is influenced by CYP2C19 genotype. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Patients with inflammatory bowel disease (IBD) show increased the prevalence of cytomegalovirus (CMV) infection due to the severity of the disease and the immunosuppressive treatments they receive. The aim of this study was to determine the prevalence of CMV infection in IBD patients and identify the risk factors for CMV infection with different demographic characteristics in IBD patients. PATIENTS AND METHODS: We enrolled 85 patients diagnosed with IBD (43 with ulcerative colitis (UC) and 42 with Crohn's disease (CD)) in this prospective study. The clinical disease activities of UC and CD were assessed using Truelove- Witts and Crohn's disease activity index (CDAI). CMV infection was assessed by detection of DNA using real-time polymerase chain reaction (PCR) in blood samples and quantitative PCR in colonic biopsy specimens and by detection of inclusion bodies using hematoxylineosin staining. RESULTS: Thirteen patients with IBD exhibited concomitant CMV infection. CMV infection was not detected in any of the patients in remission. Viral loads measured in the colonic mucosa of infected patients ranged from 800-7000 genome copies/mL total extracted DNA. The mean serum CMV DNA level was 1694 ± 910 copies/mL (range: 800-3800). The rate of steroid resistance in CMV-positive cases was significantly higher than that in CMV-negative cases (p = 0.001). CD with acute exacerbation was a risk factor for CMV disease (p = 0.04). All of the CMV-positive patients received immunosuppressive treatments. CONCLUSIONS: CMV infection should be suspected in steroid-resistant UC and CD. Antiviral treatment improved the clinical outcome in steroid-resistant IBD cases with serum CMV DNA levels above 1000 copies/mL. [ABSTRACT FROM AUTHOR]

Background The fine balance of immunoglobulins ( Ig) E, Ig G1, Ig G4 and Ig A in healthy production is maintained by the interaction of B cells with adaptive and innate immune response. The regulation of toll-like receptors ( TLRs)-driven innate and adaptive immune effector B-cell response and the role of mammalian telomeric TTAGGG repeat elements represent an important research area. Methods Human PBMC and purified naive and memory B cells were stimulated with specific ligands for TLR2, TLR3, TLR4, TLR5, TLR7, TLR8 and TLR9 in the presence or absence of telomeric oligonucleotides. B-cell proliferation, differentiation and antibody production were determined. Results TLR9 ligand directly activates naive and memory B cells, whereas TLR7 can stimulate them in the presence of plasmacytoid dendritic cells. Human B cells proliferate and turn into antibody-secreting cells in response to TLR3, TLR7 and TLR9, but not to TLR2, TLR4, TLR5 and TLR8 ligands. Stimulation of B cells with intracellular TLR3, TLR7 and TLR9 induced an activation cascade leading to memory B-cell generation and particularly Ig G1, but also Ig A, Ig G4 and very low levels of Ig E production. Mammalian telomeric oligodeoxynucleotide ( ODN) significantly inhibited all features of TLR ligand-induced events in B cells including B-cell proliferation, Ig E, Ig G1, Ig G4, Ig A production, class switch recombination, plasma cell differentiation induced by TLR3, TLR7 and TLR9 ligands. Conclusion B cells require specific TLR stimulation, T-cell and plasmacytoid dendritic cell help for distinct activation and Ig production profiles. Host-derived telomeric ODN suppress B-cell activation and antibody production demonstrating a natural mechanism for the control of overexuberant B-cell activation, antibody production and generation of memory. [ABSTRACT FROM AUTHOR]

Proton pump inhibitors (PPI) metabolism and pharmacokinetics are regulated by cytochrome P450 enzymes in the liver. Cytochrome P450 2C19 (CYP2C19) polymorphism plays an import role in the metabolism of PPIs. The three possible genotypes for CYP2C19 each has a distinct effect on the pharmacodynamics of PPIs. Homozygote extensive metabolizers (HomEM) are the most frequent genotype and have two wild-types (non-mutant) (*1/*1) alleles. HomEM is associated with increased enzyme activity, which increases the rate of PPI metabolism. Intragastric pH, which is required for eradication, is lowest in HomEM. In HomEMs, an insufficient increase in intragastric pH results in decreased anti-Helicobacter pylori (HP) efficacy of the antibiotics and, therefore, lower eradication rates. We determined whether the HP eradication rate would increase after high-dose PPI treatment of extensive PPI metabolizers who had been treated unsuccessfully with a standard PPI dose. In our report, increasing the PPI dosage in patients with genotype polymorphisms may be effective on eradication rates. Eradication rates are directly affected by CYP2C19 polymorphisms, and eradication treatments should be planned considering such genotypic polymorphisms. Hence, CYP2C19 genotyping prior to treatment may facilitate determination of the optimum PPI dose to improve the therapeutic outcome. However, further researches are required to confirm this hypothesis. [ABSTRACT FROM AUTHOR]

Background: The number of Sp1–Egr1 binding tandem repeats at the ALOX5 promoter influences gene transcription and may modify the response to anti-leukotriene treatment. The relationship of ALOX5 variants to asthma severity and leukotriene production by eosinophils is unknown. Objective: To characterize ALOX5 mRNA expression and cysteinyl-leukotriene production by eosinophils from individuals bearing ALOX5 promoter deletional variants and their association with the severity of childhood asthma. Methods: Eosinophils from adult asthmatics bearing only variant alleles (with other than five tandem repeats on both chromosomes, non5/non5) or no variant alleles (5/5) were cultured in vitro and ALOX5 expression and leukotriene secretion were measured. A total of 621 children with mild or moderate-severe asthma were genotyped at the ALOX5 core promoter. Results: Asthmatics with non5/non5 genotype expressed less ALOX5 mRNA and produced less LTC4 into culture supernatants than 5/5 individuals (6.4 ± 2.0 and 20.0 ± 5.0 pg/ml, n = 5; P < 0.05). More asthmatic children bearing non5/non5 genotype had moderate-severe asthma than children with the 5/5 genotype (5.3% vs. 1.4%, P = 0.008). Multivariate logistic regression identified ALOX5 promoter genotype as a significant predictor of disease severity (OR = 3.647, 95% CI: 1.146–11.608, P = 0.03). Consistent with these findings, children bearing the non5/non5 genotype had greater bronchomotor response to exercise as measured by the maximum fall after exercise and the area under the exercise curve ( P < 0.05 for both). Conclusion: Our results suggest that children who express the asthma phenotype despite having a genetic variant that impairs their ability to express ALOX5 have more severe disease and thus are more likely to have asthma symptoms. [ABSTRACT FROM AUTHOR]

Abstract Background The ability to predict the function and structure of complex molecular mechanisms underlying cellular behaviour is one of the main aims of systems biology. To achieve it, we need to understand the evolutionary routes leading to a specific response dynamics that can underlie a given function and how biophysical and environmental factors affect which route is taken. Here, we apply such an evolutionary approach to the bacterial chemotaxis pathway, which is documented to display considerable complexity and diversity. Results We construct evolutionarily accessible response dynamics starting from a linear response to absolute levels of attractant, to those observed in current-day Escherichia coli. We explicitly consider bacterial movement as a two-state process composed of non-instantaneous tumbling and swimming modes. We find that a linear response to attractant results in significant chemotaxis when sensitivity to attractant is low and when time spent tumbling is large. More importantly, such linear response is optimal in a regime where signalling has low sensitivity. As sensitivity increases, an adaptive response as seen in Escherichia coli becomes optimal and leads to 'perfect' chemotaxis with a low tumbling time. We find that as tumbling time decreases and sensitivity increases, there exist a parameter regime where the chemotaxis performance of the linear and adaptive responses overlap, suggesting that evolution of chemotaxis responses might provide an example for the principle of functional change in structural continuity. Conclusions Our findings explain several results from diverse bacteria and lead to testable predictions regarding chemotaxis responses evolved in bacteria living under different biophysical constraints and with specific motility machinery. Further, they shed light on the potential evolutionary paths for the evolution of complex behaviours from simpler ones in incremental fashion.