Cheng Chan Lu

Esomeprazole 40 mg twice daily in triple therapy and the efficacy of Helicobacter pylori eradication related to CYP2C19 metabolism

Aim : To determine whether an increased dosage of esomeprazole 40 mg twice daily in triple therapy improved the Helicobacter pylori eradication rate for patients with different genotypes of S‐mephenytoin 4′‐hydroxylase (CYP2C19).

Genetic susceptibility to nasopharyngeal carcinoma within the HLA-A locus in Taiwanese

NPC is an epithelial tumor that is highly prevalent among the southern Chinese. Numerous studies have indicated that specific HLA haplotypes and genes within the HLA complex are associated with NPC. As a first effort to localize the gene responsible for susceptibility, the HLA‐A, ‐B, and ‐A2 subtypes were examined for their association to NPC. Consistent with previous reports, frequencies of HLA‐A2 [OR = 2.50, pc = 0.020 (study population); OR = 3.73, pc = 0.0030 (≥40 years old)] were significantly higher in patients with NPC than in healthy controls. Two‐locus analysis indicated that A2+B46+ individuals are at greater risk for NPC than A2−B46− individuals in both the population studied and the ≥40‐year‐old group. This, however, may be due to the close linkage of these 2 genes. Moreover, A2+B38+ individuals were at higher risk than A2−B38− individuals in both the population studied and the ≥40‐year‐old group; A2 and B38 are not genetically linked. These findings suggest that B38 or B46 alone cannot confer a high risk of NPC but that, in conjunction with A2, B38 or B46 positivity greatly increases risk. None of 5 A2 subtypes identified from studied populations was significantly associated with NPC. Microsatellite marker D6S211, located 97 kb telomeric to HLA‐A, was analyzed for its association with NPC. Allele 4 of D6S211 was significantly associated with NPC (OR = 3.97, pc = 0.0042). These results strongly support the hypothesis that genes associated with susceptibility to NPC in the HLA region are within the HLA‐A locus.

Lactobacillus acidophilus ameliorates H. pylori-induced gastric inflammation by inactivating the Smad7 and NFκB pathways.

BackgroundH. pylori infection may trigger Smad7 and NFκB expression in the stomach, whereas probiotics promote gastrointestinal health and improve intestinal inflammation caused by pathogens. This study examines if probiotics can improve H. pylori-induced gastric inflammation by inactivating the Smad7 and NFκB pathways.ResultsChallenge with H. pylori increased IL-8 and TNF-α expressions but not TGF-β1 in MKN45 cells. The RNA levels of Smad7 in AGS cells increased after H. pylori infection in a dose-dependent manner. A higher dose (MOI 100) of L. acidophilus pre-treatment attenuated the H. pylori-induced IL-8 expressions, but not TGF-β1. Such anti-inflammatory effect was mediated via increased cytoplasmic IκBα and depletion of nuclear NFκB. L. acidophilus also inhibited H. pylori-induced Smad7 transcription by inactivating the Jak1 and Stat1 pathways, which might activate the TGF-β1/Smad pathway. L. acidophilus pre-treatment ameliorated IFN-γ-induced Smad7 translation level and subsequently reduced nuclear NF-κB production, as detected by western blotting.ConclusionsH. pylori infection induces Smad7, NFκB, IL-8, and TNF-α production in vitro. Higher doses of L. acidophilus pre-treatment reduce H. pylori-induced inflammation through the inactivation of the Smad7 and NFκB pathways.

Nasopharyngeal carcinoma-susceptibility locus is localized to a 132 kb segment containing HLA-A using high-resolution microsatellite mapping.

Nasopharyngeal carcinoma (NPC) is an epithelial tumor uniquely prevalent in southern Chinese. HLA‐A2 is associated with NPC. In a previous study, we showed that the genes associated with susceptibility to NPC are primarily located within the HLA‐A locus in Taiwanese NPC patients. However, the pathogenic genes causing NPC susceptibility remain unknown. Here, 8 polymorphic microsatellite markers distributed over a 1 megabase region surrounding the HLA‐A locus were subjected to genetic analysis for the NPC‐susceptibility locus. Statistical studies of associated alleles detected on each microsatellite locus showed that the NPC‐ susceptibility genes are most likely located between the D6S510 and D6S211 markers within a 132 kb segment containing the HLA‐A locus. These results undoubtedly would facilitate the further positional cloning of the NPC‐susceptibility locus, which has been elusive for the past 30 years.

Body mass index can determine the healing of reflux esophagitis with Los Angeles Grades C and D by esomeprazole.

AIMS:This study assessed the endoscopic healing rates of reflux esophagitis with Los Angeles grades C and D (RE-CD) using a 6-month esomeprazole and the demographic factors or genotypes of S-mephenytoin 4′-hydroxylase (CYP2C19) that correlated with the healing of RE-CD.METHODS:One hundred thirteen patients with RE-CD received esomeprazole 40 mg daily for 6 months and completed serial follow-ups regarding healing by endoscopies at the 1st month and the 6th month, respectively. In each patient, demographic factors, including body mass index (BMI), and the CYP2C19 genotypes were checked.RESULTS:The endoscopic healing rates of RE-CD were similar among patients with different genotypes of CYP2C19 at the 1st month and the 6th month, respectively (P > 0.05). A lower healing rate of RE-CD at the 1st month was independently related to a higher BMI > 25 kg/m2, coffee drinking, and the presence of hiatus hernia (P < 0.05), but not with the CYP2C19 genotypes. A higher BMI > 25 kg/m2 independently had a 2.32-fold decrease of the healing of RE-CD (P < 0.001), but a net decrease of BMI > 1.5 kg/m2 independently had a 3.65-fold increase of the healing of RE-CD at the 6th month (P = 0.014).CONCLUSIONS:Esomeprazole 40 mg daily can be effective for RE-CD patients with different CYP2C19 genotypes. BMI > 25 kg/m2 is an independent risk factor to determine the healing of RE-CD by esomeprazole. Reducing BMI > 1.5 kg/m2, especially for those with an initial BMI > 25 kg/m2, could be promising to improve the healing of RE-CD by esomeprazole.

Host TNF-α -1031 and -863 promoter single nucleotide polymorphisms determine the risk of benign ulceration after H. pylori infection

OBJECTIVES:This study tested whether host genotypes of the tumor necrosis factor-alpha (TNF-α) promoter single nucleotide polymorphism (SNP) could determine clinical and histological outcomes after Helicobacter pylori infection.METHODS:A total of 524 dyspeptic patients, 424 with and 100 without H. pylori infection, were checked for TNF-α promoter SNP over the locus on −1031(T/C), −863(C/A), −857(C/T), −806(C/T), and −308(G/A) by sequence-specific oligonucleotide probe. Each patient received panendoscopy to take gastric biopsy to detect H. pylori infection and its related histology using the updated Sydneys system. Gastric TNF-α expressions were stained by immunohistochemistry.RESULTS:In H. pylori-infected patients, −1031C or −863A carriers of TNF-α promoter had more severe gastric neutrophil infiltration and TNF-α gastric staining than individuals with −1031TT or −863CC genotype, respectively (p < 0.05). The multivariate logistic regression verified both −1031C and −863A carriers were independent risk factors to have duodenal ulcers and gastric ulcer without IM in the H. pylori-infected hosts (p < 0.05). As compared to −863CC and −1031TT genotype combinations, the ulcer risk after H. pylori infection was 2.46 (95% CI: 1.32–4.59, p≤ 0.00001) for the carriers with either −1031C or −863A allele, and even elevated to 6.06 (95% CI: 3.57–10.21, p≤ 0.00001) for the individuals harboring both −863A and −1031C alleles. For patients with gastric ulcer, the 863CC genotype had a higher rate to have intestinal metaplasia than −863A carrier (p≤ 0.005).CONCLUSIONS:TNF-α−1031 and −863 promoter SNP should be novel host factors to determine the gastric inflammation and risk of peptic ulceration upon H. pylori infection.

The association between tumor necrosis factor, HLA-DR alleles, and IgE-mediated asthma in Taiwanese adolescents

Background: Human leukocyte antigen (HLA) DR genes and the tumor necrosis factor (TNF) gene locus are associated with asthma and IgE production. TNFα‐308G/A frequencies between Japanese and Caucasians in the UK have been found to be different. The roles of HLA‐DRB1 and TNF genotypes are unknown in Taiwanese adolescents with IgE‐mediated asthma (I‐asthma).

Transgenic Expression of Entire Hepatitis B Virus in Mice Induces Hepatocarcinogenesis Independent of Chronic Liver Injury

Hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide, is most commonly caused by chronic hepatitis B virus (HBV) infection. However, whether HBV plays any direct role in carcinogenesis, other than indirectly causing chronic liver injury by inciting the host immune response, remains unclear. We have established two independent transgenic mouse lines expressing the complete genome of a mutant HBV (“preS2 mutant”) that is found at much higher frequencies in people with HCC than those without. The transgenic mice show evidence of stress in the endoplasmic reticulum (ER) and overexpression of cyclin D1 in hepatocytes. These mice do not show any evidence of chronic liver injury, but by 2 years of age a majority of the male mice develop hepatocellular neoplasms, including HCC. Unexpectedly, we also found a significant increase in hepatocarcinogenesis independent of necroinflammation in a transgenic line expressing the entire wildtype HBV. As in the mutant HBV mice, HCC was found only in aged—2-year-old—mice of the wildtype HBV line. The karyotype in all the three transgenic lines appears normal and none of the integration sites of the HBV transgene in the mice is near an oncogene or tumor suppressor gene. The significant increase of HCC incidence in all the three transgenic lines—expressing either mutant or wildtype HBV—therefore argues strongly that in absence of chronic necroinflammation, HBV can contribute directly to the development of HCC.

The corpus-predominant gastritis index may serve as an early marker of helicobacter pylori-infected patients at risk of gastric cancer

To eradicate Helicobacter pylori before the occurrence of precancerous changes is important to prevent gastric carcinogenesis.

Eradication of Helicobacter pylori increases childhood growth and serum acylated ghrelin levels

AIM To determine whether Helicobacter pylori (H. pylori)-infected children have reduced body weight (BW) and height (BH) growth, and if H. pylori eradication may restore growth while improving serum acylated ghrelin. METHODS This longitudinal cohort study with one-year follow-up enrolled 1222 children aged 4 to 12 years old into an observation cohort (18 with and 318 without H. pylori) and intervention cohort (75 with and 811 without). The 7-d triple therapy was used for eradication in the intervention cohort. The net increases of BW and BH as well serum acylated ghrelin after one-year follow-up were compared between successful eradicated H. pylori-infected children and controls. RESULTS In the observation cohort, the H. pylori-infected children had lower z score of BW (-1.11 ± 0.47 vs 0.35 ± 0.69, P = 0.01) and body mass index (BMI) (0.06 ± 0.45 vs 0.44 ± 0.73, P = 0.02) at enrollment and lower net BW gain after one-year follow-up (3.3 ± 2.1 kg vs 4.5 ± 2.4 kg, P = 0.04) than the non-infected controls. In the intervention cohort, the H. pylori-infected children had lower z score of BMI (0.25 ± 1.09 vs 0.68 ± 0.87, P = 0.009) and serum acylated ghrelin levels (41.8 ± 35.6 pg/mL vs 83.6 ± 24.2 pg/mL, P < 0.001) than the non-infected controls. In addition to restoring decreased serum ghrelin levels (87.7 ± 38.0 pg/mL vs 44.2 ± 39.0 pg/mL, P < 0.001), the H. pylori-infected children with successful eradication had higher net gains (P < 0.05) and increase of z scores (P < 0.05) of both BW and BH as compared with non-infected controls after one-year follow-up. CONCLUSION H. pylori-infected children are associated with low serum acylated ghrelin and growth retardation. Successful eradication of H. pylori restores ghrelin levels and increases growth in children.