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Aim: To evaluate the efficacy and safety of esomeprazole-based triple therapy compared with lansoprazole therapy as first-line eradication therapy for patients with Helicobacter pylori (H. pylori) in usual post-marketing use in Japan, where the clarithromycin (CAM) resistance rate is 30%., Methods: For this multicenter, randomized, open-label, non-inferiority trial, we recruited patients (≥ 20 years of age) with H. pylori infection from 20 hospitals in Japan. We randomly allocated patients to esomeprazole therapy (esomeprazole 20 mg, CAM 400 mg, amoxicillin (AC) 750 mg for the first 7 d, with all drugs given twice daily) or lansoprazole therapy (lansoprazole 30 mg, CAM 400 mg, AC 750 mg for the first 7 d, with all drugs given twice daily) using a minimization method with age, sex, and institution as adjustment factors. Our primary outcome was the eradication rate by intention-to-treat (ITT) and per-protocol (PP) analyses. H. pylori eradication was confirmed by a urea breath test from 4 to 8 wk after cessation of therapy., Results: ITT analysis revealed the eradication rates of 69.4% (95%CI: 61.2%-76.6%) for esomeprazole therapy and 73.9% (95%CI: 65.9%-80.6%) for lansoprazole therapy (P = 0.4982). PP analysis showed eradication rate of 76.9% (95%CI: 68.6%-83.5%) for esomeprazole therapy and 79.8% (95%CI: 71.9%-86.0%) for lansoprazole therapy (P = 0.6423). There were no differences in adverse effects between the two therapies., Conclusion: Esomeprazole showed non-inferiority and safety in a 7 day-triple therapy for eradication of H. pylori compared with lansoprazole.

Objective: MicroRNAs (miRNAs) act as tumour suppressor genes or oncogenes in the regulation of multiple carcinogenic processes. Aberrant miRNA expression is reported in Helicobacter pylori (H pylori)-related gastritis and gastric cancer. The cytotoxin-associated gene A (CagA) of H pylori has a pathophysiologically important role in gastric carcinogenesis. A study was undertaken to evaluate the effect of CagA on miRNA expression and its regulatory mechanism., Methods: The effect of CagA on miRNA expression was assessed by comprehensive miRNA microarray. The mechanisms of the in vitro and in vivo effects of CagA on histone modification and DNA methylation and the involvement of CagA-dysregulated signal transduction on let-7, an important representative miRNA in gastric carcinogenesis, were investigated., Results: In in vitro experiments, CagA significantly attenuated let-7 expression leading to Ras pathway activation. CagA enhanced c-myc, DNA methyltransferase 3B (DNMT3B) and Enhancer of Zeste homologue 2 (EZH2) expression and attenuated miR-26a and miR-101 expression, which resulted in the attenuation of let-7 expression by histone and DNA methylation. Experiments performed in CagA transgenic mice revealed that c-myc, EZH2 and DNMT3B expression were enhanced and let-7 expression was attenuated to induce Ras oncoprotein expression in the stomach, with no associated inflammation., Conclusions: H pylori CagA induces aberrant epigenetic silencing of let-7 expression, leading to Ras upregulation.

Musashi-1 (Msi-1), a mammalian neural RNA-binding protein, has been found to play important roles in the maintenance of stem cell states and differentiation in neural stem cells and mouse intestinal cells. We explored Msi-1 expression and its potential implications in the human stomach. Reverse transcription-PCR revealed that Msi-1 levels were significantly higher in the corpus than in antrum in Helicobacter pylori (Hp)-infected patients (n = 49) (P < 0.00001) in paired biopsy samples, whereas they were low and comparable at these two sites in Hp-negative patients (n = 31). Msi-1 levels were significantly higher in the Hp-infected corpus (n = 107) than in the Hp-negative corpus (n = 69) (P < 0.00000001). Immunohistochemistry and in situ hybridization demonstrated that Msi-1 was expressed at the base and neck/isthmus region of the fundic glands and partly co-expressed in Ki-67-positive cells in the corpus and antrum. Msi-1 levels correlated with Hp density (P < 0.05). Based on these results, we conclude that Hp infection strongly induces Msi-1 in the corpus. Given its expression in dividing cells, Msi-1 may modulate the state of gastric progenitor cells.

Background/aims: Toll-like receptor 4 (TLR4), which requires a helper molecule, MD-2, is a main receptor for lipopolysaccharide (LPS) from gram-negative bacteria. The expression of TLR4 in H. pylori infection in human gastric mucosa, however, is unclear. The aim of this study was to determine the effect of H. pylori infection on the TLR4 and MD-2 expression in human gastric mucosa., Methodology: Biopsy samples from the antrum and corpus were obtained from 45 patients (25 patients without H. pylori infection including 5 patients with successful eradication of H. pylori, and 20 patients with H. pylori infection). These samples were used for TLR4, MD-2 mRNA expression study and immunohistochemical study., Results: In patients without H. pylori infection, the expressions of TLR4 and MD-2 were bigger in the corpus mucosa than in the antral mucosa. In patients with H. pylori infection, the expressions of TLR4 and MD-2 significantly increased in the antral and corpus mucosa. Immunohistochemical study revealed similar results as the TLR4 mRNA expression. After the eradication of H. pylori, the expressions of TLR4 and MD-2 were the same levels in both sites as those in patients without H. pylori infection., Conclusions: The results indicated that H. pylori infection significantly increased TLR4 and MD-2 expressions in the antral and corpus mucosa.

Numerous cellular and molecular events have been described in development of gastric cancer. In this article, we overviewed roles of Helicobacter pylori (H pylori) infection on some of the important events in gastric carcinogenesis and discussed whether these cellular and molecular events are reversible after cure of the infection. There are several bacterial components affecting gastric epithelial kinetics and promotion of gastric carcinogenesis. The bacterium also increases risks of genetic instability and mutations due to NO and other reactive oxygen species. Epigenetic silencing of tumor suppressor genes such as RUNX3 may alter the frequency of phenotype change of gastric glands to those with intestinal metaplasia. Host factors such as increased expression of growth factors, cytokines and COX-2 have been also reported in non-cancerous tissue in H pylori-positive subjects. It is noteworthy that most of the above phenomena are reversed after the cure of the infection. However, some of them including overexpression of COX-2 continue to exist and may increase risks for carcinogenesis in metaplastic or dysplastic mucosa even after successful H pylori eradication. Thus, H pylori eradication may not completely abolish the risk for gastric carcinogenesis. Efficiency of the cure of the infection in suppressing gastric cancer depends on the timing and the target population, and warrant further investigation.

Background: Biliary tract cancer is a highly fatal disease with poor prognosis, but the aetiology is poorly understood., Aim: We aimed to identify Helicobacter bilis infection in the gallbladder in patients with biliary tract disease., Methods: Archival gallbladder specimens from 34 patients (14 males and 20 females) with an average age of 61.4 +/- 12.2 years (mean +/- SE) were retrieved, consisting of 11 cases of gallbladder cancer, three of bile duct cancer, 16 of cholecystolithiasis and four of pancreatic cancer. DNA was extracted and nested PCR using primers specific for 16S rRNA of H. bilis was performed., Results: Amplification was observed in 3 of 11 gallbladder cancer cases (27.2%) and one of three cases with biliary duct cancer (33.3%). In total, four of 14 cases with biliary tract cancer were positive for H. bilis (28.6%). In addition, the presence of H. bilis was shown in two of 16 cases (12.5%) with cholecystolithiasis. Notably, although the number of cases examined was small, none of the four cases with pancreatic cancer showed the presence of H. bilis infection in the gallbladder without apparent abnormalities., Conclusion: H. bilis infection may play a role in biliary tract disease, particularly in biliary tract cancer.

Background and Aims: Helicobacter pylori infection is associated with peptic ulcers; however, it is unclear whether the bacterium delays ulcer healing. We investigated the influence of H. pylori on ulcer healing in mice. We also examined the influence of H. pylori infection on angiogenesis., Methods: An acetic acid ulcer was made in male BALB/c mice. Three days later (day 0), the animals were inoculated with H. pylori SS1 strain. The healing process of the ulcer was examined macroscopically and microscopically on days 0, 6 and 9. The index of angiogenesis was also determined using carmine dye injection., Results: On day 0, angiogenesis began at the ulcer margin while the mucosal epithelia had not yet regenerated. On days 6 and 9, angiogenesis and epithelial regeneration developed and ulcer size reduced. These phenomena were significantly suppressed in mice infected with H. pylori., Conclusion: Helicobacter pylori infection significantly suppressed angiogenesis and delayed ulcer healing. These results indicate that H. pylori plays an important role in ulcer healing., (Copyright 2002 Blackwell Publishing Asia Pty Ltd)

Objective: The accuracy of the PyloriTek test (a 1-h rapid urease test) used after eradication therapy of Helicobacter pylori (H. pylori) has not been well clarified. This study was done to evaluate the accuracy of the PyloriTek test results for cases with and without eradication therapy, using culture and histology as gold standard methods, and to establish the suitable timing of the PyloriTek test after eradication treatment., Methods: One hundred sixty-three patients undergoing upper endoscopy were randomly selected; 100 patients had not received eradication therapy and 63 had. Three biopsy specimens each were obtained from the gastric antrum and the body for examination by PyloriTek, culture, and histology. The absence of H. pylori was established with negative results from both culture and histology., Results: In cases without eradication therapy, PyloriTek, correctly identified 66 of 67 H. pylori-positive cases and 30 of 33 H. pylori-negative cases, yielding 98.5% sensitivity and 90.9% specificity. In cases with eradication therapy, PyloriTek gave correct diagnoses in 10 of 17 H. pylori-positive cases and in 45 of 46 H. pylori-negative cases, for 58.8% sensitivity and 97.8% specificity. However, when PyloriTek was used more than 4 months after the end of eradication therapy, both the sensitivity and the specificity increased to 100%., Conclusion: Considering time and cost, the use of PyloriTek alone may be satisfactory for detecting H. pylori infection in cases without eradication therapy. When patients are examined more than 4 months after intervention, the use of PyloriTek alone may be sufficient for correctly diagnosing H. pylori infections.

This article consists of three independent studies regarding Helicobacter pylori-related gastric carcinogenesis. Ammonia, a Helicobacter product, promoted chemically induced gastric carcinogenesis in animals. Moreover, an extract of Helicobacter stimulated inflammatory production of nitric oxide (NO), a potent mutagen that causes G:C-->A:T transition. Meta-analysis of recent studies demonstrated that G:C-->A:T transition is one of the most common mutations in the p53 tumor suppressor gene in early phases of human gastric carcinogenesis. Therefore, bacterial factors such as ammonia and host factors, including inflammatory NO production, might play important roles in H. pylori-induced gastric carcinogenesis.

To elucidate the role of Helicobacter pylori infection in the pathogenesis of gastric ulcer, we investigated the intracellular mucin content by measuring the periodic acid-Schiff-Alcian blue (PAS-AB)-stained substances, by means of computer, in the biopsy sample of gastric mucosa from patients with and without H. pylori infection. In the antral mucosa the intracellular PAS-AB-stained mucin content was significantly smaller in patients with infection than in patients without infection, whereas in the oxyntic gland mucosa the intracellular mucin content showed no significant change between patients with and without infection. In an animal study we investigated the effect of ammonia, which might be produced by H. pylori in the presence of urea. The ammonia, administered orally, caused a greater decrease of intracellular PAS-AB-stained mucin content in the gastric antral mucosa than in the body mucosa, in a dose-dependent manner. The results suggested that H. pylori infection had a different effect on the gastric mucosal intracellular PAS-AB-stained mucin and lowered specifically the antral intracellular PAS-AB-stained mucin content, possibly due to generation of ammonia by H. pylori.