The <Emphasis Type="Italic">Helicobacter pylori</Emphasis> duodenal ulcer promoting gene, <Emphasis Type="Italic">dupA</Emphasis>in China

Background  

The prevalence of H. pylori is as high as 60–70% in Chinese population. Although duodenal ulcer and gastric cancer are both caused by H. pylori, they are at opposite ends of the spectrum and as such are considered mutually exclusive. Duodenal ulcer promoting (dupA) gene was reported to be associated with duodenal ulcer development. The aim of this study was to determine the prevalence of dupA gene of Helicobacter pylori in patients with various gastroduodenal diseases and to explore the association between the gene and other virulence factors.     

<Emphasis Type="Italic">Helicobacter pylori</Emphasis> in a Korean Isolate Expressed Proteins Differentially in Human Gastric Epithelial Cells

Purpose  

The proteins expressed in gastric epithelial cells infected with Helicobacter pylori (H. pylori) may determine the clinical outcome such as chronic gastritis, peptic ulcer, and gastric carcinoma. The present study aims to determine the differentially expressed proteins in human gastric epithelial AGS cells that were infected with H. pylori in a Korean isolate, a cagA+, vacA s1b m2 iceA1 H. pylori by proteomic analysis. The differentially expressed proteins, whose expression levels were more or less than twofold in H. pylori-infected cells, were analyzed.     

Associations of a PTPN11 G/A polymorphism at intron 3 with Helicobactor pylori seropositivity, gastric atrophy and gastric cancer in Japanese

Background  

Previous studies have revealed the significance of Helicobacter pylori (H. pylori) infection as a risk factor of gastric cancer. Cytotoxin-associated gene A (cagA) positivity has been demonstrated to determine the clinical outcome of H. pylori infection in the presence of SHP-2 (src homology 2 domain-containing protein tyrosine phosphatase-2). This study aimed to examine the formerly reported association of G/A PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) polymorphism (rs2301756) with gastric atrophy, as well as the association with gastric cancer in a Japanese population using a large sample size.     

Prevalence of non <Emphasis Type="Italic">Helicobacter pylori</Emphasis> species in patients presenting with dyspepsia

Background  

Helicobacter species associated with human infection include Helicobacter pylori, Helicobacter heilmannii and Helicobacter felis among others. In this study we determined the prevalence of H. pylori and non-Helicobacter pylori organisms H. felis and H. heilmannii and analyzed the association between coinfection with these organisms and gastric pathology in patients presenting with dyspepsia. Biopsy specimens were obtained from patients with dyspepsia on esophagogastroduodenoscopy (EGD) for rapid urease test, histology and PCR examination for Helicobacter genus specific 16S rDNA, H. pylori phosphoglucosamine mutase (glmM) and urease B (ureB) gene of H. heilmannii and H. felis. Sequencing of PCR products of H. heilmannii and H. felis was done.     

Elevated Serum Matrix Metalloproteinase-3 and -7 in <Emphasis Type="Italic">H. pylori</Emphasis>-Related Gastric Cancer Can Be Biomarkers Correlating with a Poor Survival

Background  

Helicobacter pylori (H. pylori) infection up-regulates the expression of matrix metalloproteinases (MMPs), which may be involved in chronic inflammation, ulceration, and even cancer development. This study aimed to test if serum levels of MMP-3, -7, and -9 are correlated with different clinical outcomes in H. pylori-infected subjects and if these are predictive of progression to H. pylori-related gastric cancer.     

The overmethylated genes in <Emphasis Type="Italic">Helicobacter pylori</Emphasis>-infected gastric mucosa are demethylated in gastric cancers

Background  

The transitional-CpG sites between weakly methylated genes and densely methylated retroelements are overmethylated in the gastric mucosa infected with Helicobacter pylori (H. pylori) and they are undermethylated in the gastric cancers depending on the level of loss of heterozygosity (LOH) events. This study delineated the transitional-CpG methylation patterns of CpG-island-containing and -lacking genes in view of the retroelements.     

Effect of RANTES Promoter Genotype on the Severity of Intestinal Metaplasia in Helicobacter pylori-Infected Japanese Subjects

Background A complex interaction of host genetic and environmental factors may be relevant in the development of Helicobacter pylori (H. pylori)-related gastro-duodenal diseases. RANTES is a potent chemoattractant peptide for memory T lymphocytes and eosinophils, and has been shown to be enhanced in H. pylori-infected gastric mucosa. We aimed to clarify the effect of RANTES functional promoter polymorphism on the risk of gastro-duodenal diseases in a Japanese population. Methods Four hundred and eighty-three subjects, comprising 106 gastric ulcer, 52 duodenal ulcer, and 325 non-ulcer subjects, were included in this study. Restriction fragment length polymorphism (RFLP) analysis was performed for polymorphisms at −28 C/G in the RANTES gene promoter region. Gastritis scores of antral gastric mucosa were assessed according to the updated Sydney system. Results There were no significant differences in the RANTES promoter genotype distributions among non-ulcer subjects, ulcer patients, and gastric and duodenal ulcers. However, the degree of intestinal metaplasia was significantly lower among G carriers in H. pylori-infected subjects aged 60 years or older (C/C vs. G carriers; 1.28 ± 1.02 vs. 0.83 ± 0.89, P = 0.0357). In addition, we also found that the same genotype held a lower risk of more severe intestinal metaplasia in H. pylori-infected female subjects (C/C vs. G carriers; 0.91 ± 1.03 vs. 0.41 ± 0.73, P = 0.0443). Conclusion The polymorphism of RANTES promoter is not associated with the susceptibility to peptic ulcer diseases, but the −28 G carrier is associated with a reduced risk of developing more severe intestinal metaplasia in H. pylori-positive subjects aged 60 years and older and in female subjects.     

Characteristics and Interactions of <Emphasis Type="Italic">Helicobacter pylori</Emphasis> and <Emphasis Type="Italic">H. pylori</Emphasis>-Infected Human Gastroduodenal Epithelium in Peptic Ulcer: A Transmission Electron Microscopy Study

Helicobacter pylori (H. pylori) has been presumed to be an initiating factor in a previously recognized chain of events, starting with active chronic gastritis and leading to atrophy of the mucosal membrane, intestinal metaplasia, dysplasia (intraepithelial neoplasia), and finally culminating in gastric carcinoma. Adherence of H. pylori to the gastroduodenal epithelium is believed to be an important step in the induction of active chronic inflammation of the mucosal layer. However, it is not clear how the pathogen chronically colonizes the gastroduodenal epithelium. In this study, 30 biopsy specimens from H. pylori-positive peptic ulcer (15 for gastric ulcer, 15 for duodenal ulcer) patients were examined by transmission electron microscopy (TEM) to observe the structural adherence of H. pylori to gastroduodenal epithelium while ten healthy postulants were served as controls. We also investigated the interaction between H. pylori and gastroduodenal epithelial cells. Morphological appearances of both the pathogen and the cells as well as features of colonization, attachment, and internalization were observed. H. pylori exhibited both spiral and coccoid forms. Cytoplasmic vacuolar degeneration played by the vacuolating toxin (VacA) was apparent in gastroduodenal epithelial cells. Specially, a number of tumor cells were found in H. pylori-positive gastric intestinal metaplasia (IM) mucosa under TEM which provided an ultrastructural evidence of IM carrying a particularly high risk for the development of gastric cancer.     

Correlation between expression of MMP-9 and MMP-3 in Helicobacter pylori infected patients with different gastroduodenal diseases

Background and study aims

Helicobacter pylori (H. pylori) has been implicated in the pathogenesis of most important gastro-duodenal diseases, such as gastritis, peptic ulcer disease (PUD) and gastric cancer. H. pylori upregulates the expression and activity of several matrix metalloproteinases (MMPs) in the gastric mucosa, but the role of MMP-3 and MMP-9 in infected patients with H. pylori have not been clearly defined yet. We examined mucosal MMP-3 and MMP-9 mRNA levels in gastric mucosa of H. pylori infected patients and evaluated the effects of virulence factors cagA and vacA allelic variants on these levels. We also determined correlation between mucosal MMP-3 and MMP-9 mRNA levels and types of disease.

Molecular and histological evaluation of tumor necrosis factor-alpha expression in <Emphasis Type="Italic">Helicobacter pylori</Emphasis>-mediated gastric carcinogenesis

Purpose  

Helicobacter pylori (H. pylori) is considered to be a major factor contributing to gastric mucosal damage by stimulating mucosal macrophage production of inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), but the inflammatory responses within the gastric mucosa in vivo are not well known. Therefore, this study was designed to investigate the expression of TNF-α induced by H. pylori infection which is involved in the tumor initiation and promotion of gastric carcinogenesis.     

Evaluation for <Emphasis Type="Italic">Helicobacter pylori</Emphasis> in Meckel’s Diverticulum by Using Real-Time PCR

Background  

Although Helicobacter pylori (H. pylori) has been identified in heterotopic gastric mucosa of Meckel’s diverticulum, controversial results are reported in the pertinent literature.     

Systematic review and meta-analysis: the relationship between the Helicobacter pylori dupA gene and clinical outcomes

Background

In 2005, the first disease-specific Helicobacter pylori virulence factor that induced duodenal ulcer and had a suppressive action on gastric cancer has been identified, and was named duodenal ulcer promoting gene (dupA). However, the importance of the dupA gene on clinical outcomes is conflicting in subsequent studies. The aim of this study was to estimate the magnitude of the risk for clinical outcomes associated with dupA gene.

Methods

A meta-analysis of case-control studies which provided raw data on the infection rates with the dupA -positive H. pylori detected by polymerase chain reaction was performed.

Results

Seventeen studies with a total of 2,466 patients were identified in the search. Infection with the dupA -positive H. pylori increased the risk for duodenal ulcer by 1.41-fold (95% confidence interval [CI], 1.12-1.76) overall. Subgroup analysis showed that the summary odds ratio (OR) was 1.57 (95% CI, 1.19-2.06) in Asian countries and 1.09 (95% CI, 0.73-1.62) in Western countries. There was no association between the presence of the dupA gene and gastric cancer and gastric ulcer. Publication bias did not exist.

Conclusion

Our meta-analysis confirmed the importance of the presence of the dupA gene for duodenal ulcer, especially in Asian countries.     

The prevalence of <Emphasis Type="Italic">Helicobacter pylori</Emphasis> in Japanese children with gastritis or peptic ulcer disease

Background Although Helicobacter pylori infection is typically acquired in childhood, the role of H. pylori infection in gastroduodenal diseases in childhood remains to be defined. The purpose of this study was to evaluate the prevalence of H. pylori infection in children with gastritis, duodenal ulcer, and gastric ulcer.Methods This was a retrospective analysis of 283 Japanese children (mean age, 11.5 years) with non-nodular gastritis (n = 73), nodular gastritis (n = 67), duodenal ulcer (n = 100), and gastric ulcer (n = 43). H. pylori status was based on biopsy tests. Clinical symptoms at the time of endoscopy were analyzed with regard to a possible association with the infection.Results The prevalence of H. pylori in non-nodular gastritis, nodular gastritis, duodenal ulcer, and gastric ulcer was 28.8%, 98.5%, 83.0%, and 44.2%, respectively. H. pylori was significantly linked to duodenal ulcer and gastric ulcers in the age group of 10–16 years, but not in the age group of 9 years and under. In children with H. pylori infection, nodular gastritis was observed in 26.3% of gastric ulcer patients and in 74.7% of duodenal ulcer patients (P < 0.001). H. pylori infection was significantly associated with the prevalence of anemia (P < 0.05).Conclusions H. pylori is the most important causal factor for the development of duodenal ulcer in childhood. While H. pylori infection appears to be a risk factor in gastric ulcer, other causes are responsible for most cases. Nodular gastritis is the most common type of H. pylori gastritis in childhood. Chronic infection with H. pylori is associated with anemia.     

Effect of Interlukin-1β on proliferation of gastric epithelial cells in culture

Background  

Helicobacter pylori is the main risk factor for the development of non-cardia gastric cancer. Increased proliferation of the gastric mucosa is a feature of H. pylori infection. Mucosal interkeukin-1β production is increased in H. pylori infection and IL-1β genotypes associated with increased pro-inflammatory activity are risk factors for the development of gastric cancer. The effect of IL-1β on gastric epithelial cell proliferation has been examined in this study.     

Endoscopic characteristics and Helicobacter pylori infection in NSAID-associated gastric ulcer

Background and Aim: Helicobacter pylori infection and non‐steroidal anti‐inflammatory drugs (NSAIDs) are deeply involved in the etiology of gastric ulcers. The aim of our study was to clarify the endoscopic characteristics and H. pylori infection status of NSAID‐associated gastric ulcers. Methods: The study group comprised 50 patients (23 men, 27 women; mean age 66.5 years) with NSAID‐associated gastric ulcers and 100 sex‐ and age‐matched patients with gastric ulcer associated with other factors (control group). Ulcer morphology, size and number of lesions, onset site and incidence of hemorrhagic ulcers were investigated endoscopically in both groups. H. pylori infection was diagnosed by serology, histology and ¹³C‐urea breath test. Results: Multiple lesions (68% vs 20%, P < 0.001), occurrence in the antrum (56% vs 6%, P < 0.001), and hemorrhagic ulcer (34% vs 4%, P < 0.001) were significantly more prevalent in patients with NSAID‐associated gastric ulcers than in patients with non‐NSAID‐associated gastric ulcer. The H. pylori infection rate was significantly lower in NSAID‐associated gastric ulcer patients than in non‐NSAID‐associated gastric ulcer patients (48% vs 96%, P < 0.001). In the NSAID‐associated gastric ulcer group, the prevalence of H. pylori infection was significantly lower in patients with ulcers in the antrum than in those with ulcers in the angulus or corpus (25% vs 77.3%, P < 0.001). Conclusions: In contrast to non‐NSAID‐associated gastric ulcers, NSAID‐associated gastric ulcers frequently occur in the antrum with bleeding. The rate of H. pylori infection in NSAID‐associated gastric ulcers is significantly lower than that in non‐NSAID‐associated gastric ulcers.     

Helicobacter pylori cagA Status and Peptic Ulcer Disease in Iran

Helicobacter pylori contributes to the development of peptic ulcers and atrophic gastritis. Furthermore, H. pylori strains carrying the cagA gene are more virulent than cagA -negative strains and are associated with the development of gastric adenocarcinoma. The cagA gene is a putative H. pylori virulence factor of unknown function. The aim of this study was to determine the prevalence of the cagA gene among H. pylori isolates and its relationship with peptic ulcer disease in 128 Iranian patients. A total of 107 (83.6%) samples were positive, including 40 (95%) of the 42 patients with duodenal ulcer, 43 (86%) of the 50 patients with gastric ulcer, and 24 (66.6%) of the 36 patients with gastritis. cagA was present in 32 (80%) of 40 strains from duodenal ulcer patients, 33 (77%) of 43 strains from gastric ulcer patients, and 11 (46%) of 24 from gastritis patients. We also attempted to investigate the subtypes of 3′ region of cagA gene in H. pylori strains isolated from Iranian patients and their relation to H. pylori-associated gastroduodenal diseases. The PCR product of cagA positive strains obtained with primer set CAG1/CAG2 differed in size, varying from 642 to 651 bp (subtype A) in 33 isolates to 756 bp (subtype B/D) in 13 isolates. This does not support the view that subtypes of the 3′ region of cagA gene in H. pylori isolated from Iran correlate with the clinical outcomes of H. pylori, but colonization with cagA positive strains was significantly higher among duodenal ulcer than gastritis patients in Iran.     

Impact of pepsinogen C polymorphism on individual susceptibility to gastric cancer and its precancerous conditions in a Northeast Chinese population

Purpose  Human pepsinogen C (PGC) is an aspartic protease produced specifically by the gastric mucosa, and is considered as a mature marker of gastric epithelium. This study examined the contributions of PGC polymorphisms and the Helicobacter pylori (H. pylori) infection to the risk of gastric cancer (GC), and its precancerous conditions in a Northeast Chinese population. Methods  The PGC insertion/deletion polymorphism was evaluated by polymerase chain reaction analysis, followed by direct DNA sequencing in 564 cases of GC, atrophic gastritis (AG), gastric ulcer (GU) and superficial gastritis (as control). All cases were frequency-matched 1:1 by gender and age (±5). H. pylori infection was identified by serum anti-H. pylori IgG measurement through enzyme-linked immunosorbent assay. Results  Patients with a homozygous PGC allele 1 genotype had a significant risk of AG [adjusted odds ratio (OR) 3.11; 95% confidence interval (CI) 1.44–6.71] or of GC (OR 3.00; 95% CI 1.38–6.51), and a significantly elevated risk of intestinal metaplasia (OR 1.90, 95% CI 1.11–3.27). PGC polymorphism with H. pylori infection increased risk of GU (OR 8.69; 95% CI 1.01–74.69), and AG (OR 11.12; 95% CI 1.37–90.84) or GC (OR 10.61; 95% CI 1.28–87.79) in a super-multiplicative manner. The S value was 5.40, 6.48 and 4.34; and the AP value was 72.09, 7.00 and 69.69%, respectively. Conclusions  The PGC gene polymorphism increases an individual’s susceptibility to GC and its precancerous conditions. Moreover, the PGC gene polymorphism shows a positive link to H. pylori infection in the development of GC.     

No Protective Role of Helicobacter pylori in the Pathogenesis of Reflux Esophagitis in Patients with Duodenal or Benign Gastric Ulcer in Korea

Little is known about the relationship between H. pylori infection and reflux esophagitis. To evaluate whether or not H. pylori plays a protective role in the pathogenesis of reflux esophagitis, the prevalence rates of reflux esophagitis depending on H. pylori status in consecutively diagnosed duodenal ulcer or benign gastric ulcer patients were evaluated. In addition, the incidence rates of reflux esophagitis depending on H. pylori status were evaluated for those patients who received follow-up endoscopy at least 6 months after eradication treatment. The prevalence rates of reflux esophagitis were 8.0% (2 patients) in the 25 H. pylori-negative duodenal ulcer group patients and 6.5% (36 patients) in the 555 H. pylori-positive duodenal ulcer group patients, and there was no statistical difference. Similarly, that of gastric ulcer patients was 9.4% (32 patients) in the 340 H. pylori-positive group patients, slightly higher than that in the 41 H. pylori-negative group patients 4.9% (2 patients), but without statistical significance. After eradication treatment the reflux esophagitis incidence rates were 2.5% (2 patients) in the 81 H. pylori-eradicated duodenal ulcer group patients and 7.7% (3 patients) in the 39 noneradicated duodenal ulcer group patients, and there was no statistical difference. Similarly, those of gastric ulcer patients were 6.8% (3 patients) in the 44 H. pylori-eradicated and 8.7% (2 patients) in the 23 noneradicated group patients again without statistical difference. These results suggest that H. pylori does not play a protective role in the pathogenesis of reflux esophagitis in patients with duodenal or gastric ulcer in Korea.     

Mouse model of gastric infection with cytotoxin-expressing strain of Helicobacter pylori in studying of pathogenesis of chronic gastric ulcer

Abstract Helicobacter pylori is a major risk factor for peptic ulcer, but studies on the role of H. pylori infection in gastric pathology are limited due to lack of convenient models resembling H. pylori infection in humans. We studied the effects of inoculation of conventional BALB/c mice with a toxigenic (cytotoxin associated gene A (cagA)+ and vacuolating cytotoxin gene A (vacA+) H. pylori strain on the course of healing of gastric ulcers. Following inoculation of toxigenic H. pylori or vehicle, gastric ulcers were produced in mice, which were then killed either at day 0 or after 2, 4, 7, 14 or 28 days and ulcer area and gastric blood flow (GBF) were determined. Gastric secretions from mice with chronic gastric fistulae were studied before and after inoculation with toxigenic H. pylori or vehicle (saline). The area (7 mm²) of ulcers in control mice decreased gradually and disappeared almost completely after 14 or 28 days. The ulcers in H. pylori-infected mice were present at all test days, showing a larger area than in vehicle control animals. The GBF in control mice rose gradually with decreasing ulcer size, being significantly higher at the ulcer margin than the ulcer crater. In contrast, the GBF in H. pylori-infected mice was significantly lower at the ulcer area than that in the vehicle controls but, again, the GBF at the ulcer margin was always higher than at the ulcer crater. Gastric acid output was reduced by more than 50% immediately after H. pylori inoculation and was accompanied by a significant increase in plasma gastrin release and a fall in gastric luminal somatostatin content. These secretory changes persisted at all test days. Oedema/congestion of surface epithelium appeared after 7 days and mucosal inflammatory infiltration appeared after 14 days, to further increase after 28 days, upon the induction of ulcer. Plasma interleukin (IL)-Iß and IL-12 were significantly elevated above the initial values compared with controls. Conventional mice with gastric ulcers can be successfully infected with an H. pylori strain expressing cagA and vacA cytotoxin and this infection markedly delays healing of the ulcers, probably due to the fall in GBF in the ulcer area, mucosal inflammation, cytokine release and impairment of the gastrin-somatostatin link.     

A Follow-up Study on the Effect of <Emphasis Type="Italic">Helicobacter pylori</Emphasis> Eradication on the Severity of Gastric Histology

Helicobacter pylori genetic diversity and geographic distribution affect the severity of gastric histology; while eradication heals gastritis, the improvement of atrophy and intestinal metaplasia (IM) is still controversial. We investigated whether H. pylori infection and genotypes (cagA–vacA) influence the histological changes and whether eradication resolves these changes. Twenty-one patients (11 duodenal ulcer, 2 gastric ulcer, 8 gastritis) received treatment. Biopsies for CLO, PCR, histology, and culture were collected before and at 1 and 12 months after treatment, and serum samples at 0, 1, 2, 6, and 12 months. H. pylori eradication was achieved in 71% of the patients. Histological scores for H. pylori densities were significantly higher in the antrum and incisura angularis. Scores for mononuclear cell and neutrophil infiltration were significantly higher in regions with a high H. pylori density and improved progressively after eradication. Eight patients with atrophy including five with IM showed no significant changes 12 months after eradication. The cagA gene, detected in 13 (62%), the vacA-s1a gene, in 20 (95%), and the vacA-m1 gene, in 12 (57%) of 21 patients were significantly associated with duodenal ulcer. A gradual decline in antibody titer reached an average of 67% 12 months after eradication. H. pylori infection and the associated genotypes (cagA of Western type) affect the severity of the gastric histology (mild forms of atrophy and IM) and the disease outcome. Eradication of H. pyloriresulted in healing of gastritis, but with no significant improvement in atrophy or IM.