Evaluation of treatment for gastro-oesophageal reflux disease with a proton pump inhibitor, and relationship between gastro-oesophageal reflux disease and Helicobacter pylori infection in Japan.

BACKGROUND: Effective therapy for gastro-oesophageal reflux disease (GERD) is associated with improvement in health-related quality of life. It remains unclear whether Helicobacter pylori infection protects against GERD. AIM: We evaluated the relationship between GERD and H. pylori, and whether the health-related quality of life score improved after medical treatment. METHODS: We enrolled 151 outpatients with upper abdominal symptoms; 81 patients received omeprazole 20 mg/day for 2 weeks. Health-related quality of life was assessed using the Gastrointestinal Symptom Rating Scale (GSRS) and the Psychological General Well-Being (PGWB) index. H. pylori infection was diagnosed by serum antibody or endoscopy and the relationship between GERD and H. pylori was evaluated. RESULTS: In GERD patients, the mean GSRS score improved from 2.20 to 1.67 following treatment (P < 0.01). The mean GSRS reflux symptom score improved from 2.96 to 1.67 (P < 0.01). The mean PGWB score improved from 96.36 to 107.34 (P < 0.01). All scores in GERD patients significantly improved compared with non-GERD patients. The H. pylori-positive ratio was 66.15% in GERD patients and 65.21% in non-GERD patients (P = 0.94). CONCLUSIONS: Health-related quality of life is useful for evaluation of proton pump inhibitor treatment in GERD. The presence of H. pylori was not associated with the prevalence of GERD.

The effects of cure of Helicobacter pylori infection on the signal transduction of gastric epithelial cells.

BACKGROUND: The CagA protein of Helicobacter pylori is directly injected from the bacteria into cells via the bacterial type IV secretion system and undergoes tyrosine phosphorylation in the gastric epithelial cells. Translocated CagA forms a physical complex with the SRC homology 2 domain (SH2)-containing tyrosine phosphatase SHP-2, which plays an important role in mitogenic signal transduction in the host cells. AIM: We examined the effect of eradication therapy on the signal transduction pathway of gastric epithelial cells induced by the CagA protein of H. pylori. METHODS: Gastric biopsy samples were obtained from 20 H. pylori-positive atrophic gastritis patients before, and 3 months after, H. pylori infection eradication therapy, and subjected to immunoblot analysis to detect tyrosine phosphorylated CagA protein and CagA co-immunoprecipitated endogenous SHP-2. RESULTS: Tyrosine phosphorylated CagA protein and CagA co-immunoprecipitated endogenous SHP-2 were detected in the gastric mucosa from H. pylori-positive atrophic gastritis patients. All H. pylori strains from these patients were cagA-positive type I strains. After curing H. pylori infection, the tyrosine phosphorylated CagA protein and CagA co-immunoprecipitated endogenous SHP-2 disappeared from the gastric mucosa. CONCLUSION: The cure of infection reduces the stimulated signal transduction of gastric epithelial cells by the translocated CagA protein of H. pylori, and may confer a beneficial effect on the reduction of cancer risk.

Association of the HLA-DRB1 gene locus with gastric adenocarcinoma in Japan.

BACKGROUND AND AIM: Helicobacter pylori infection is associated with gastric adenocarcinoma, however, the odds ratio is relatively low. The aim of the present study was to investigate host genetic factors that increase the risk of gastric adenocarcinoma among H. pylori-infected individuals. METHODS: A total of 70 patients with early gastric adenocarcinoma and 121 unrelated healthy controls were examined for H. pylori infection and HLA-DRB1 genotyping. The frequencies of HLA-DRB1 alleles were compared among groups. RESULTS: The allele frequency of DRB1*04051 was significantly higher in patients with gastric adenocarcinoma (17.9%) than in controls (7.9%) (P(correct) = 0.045). The odds ratio of gastric adenocarcinoma associated with the presence of the HLA-DRB1*04051 allele compared with its absence was 2.55 (95% confidence limits, 1.35-4.83). This genetic risk was not associated with H. pylori infection. There was no significant difference in the HLA-DRB1 allele frequency between H. pylori-positive and H. pylori-negative controls. The frequency of genotypes that possessed the DRB1*04051 allele in gastric adenocarcinoma patients (34.3%) was significantly higher than that in H. pylori-negative controls (11.9%) (p = 0.0089) and H. pylori-positive controls (15.2%) (p = 0.0066). CONCLUSION: These findings suggest that immunogenetic factors for susceptibility to gastric adenocarcinoma are present in the host, the HLA-DRB1*04051 allele is a host genetic risk factor for gastric adenocarcinoma, and that this genetic risk is independent of H. pylori infection.

Eradication of Helicobacter pylori infection induces an increase in body mass index.

BACKGROUND: The relationship between H. pylori infection and body mass indices is controversial. AIM: To investigate the relationship between H. pylori infection and body indices, and to examine the effect of H. pylori eradication therapy on body indices. METHODS: Nine-hundred and thirty-two employees of an industrial corporation were examined for H. pylori infection and body mass indices. Three hundred and two H. pylori-positive cases diagnosed with chronic gastritis by upper gastrointestinal endoscopy or radiography underwent eradication therapy. Body mass indices, serum total cholesterol levels and symptom scores were obtained before and at 12 months after eradication therapy. RESULTS: There was no significant difference in body weight, body mass index (BMI) or serum total cholesterol level between the H. pylori-positive and H. pylori-negative groups. However, body weight and BMI increased significantly 12 months after eradication of H. pylori infection. In contrast, there was no significant difference in body weight and BMI 12 months after eradication therapy in the non-eradication group. Serum total cholesterol levels did not change after eradication therapy in either the eradication or non-eradication groups. CONCLUSION: Eradication of H. pylori infection induced an increase in BMI in industrial workers with chronic gastritis in Japan.

Gastric leptin and Helicobacter pylori infection.

BACKGROUND: Leptin regulates feeding behaviour and therefore may be a mediator of anorexia associated with acute and chronic inflammation. Recently, leptin mRNA and leptin protein were found in the gastric epithelium. AIM: The aim of the present study was to examine the effect of Helicobacter pylori infection on gastric leptin expression to investigate the pathophysiological role of gastric leptin. METHODS: Surgically resected human stomach tissues were subjected to immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) to check for the presence of leptin in the human gastric epithelium. A total of 201 H pylori positive patients with chronic gastritis underwent eradication therapy for H pylori and were examined for the effect of infection cure in terms of body mass index (BMI) and serum leptin levels. Biopsy specimens from the gastric fundic mucosa were obtained from 40 of the 201 patients before and three months after eradication therapy. These samples were subjected to quantitative RT-PCR to examine the effect of eradication therapy on leptin expression in the gastric fundic mucosa. RESULTS: Leptin immunoreactive cells were detected in the lower half of the gastric fundic glands and a leptin PCR product was also found in the gastric fundic mucosa. H pylori infection significantly increased gastric leptin expression. In addition, cure of H pylori infection significantly reduced gastric leptin expression, with a concomitant increase in BMI. In contrast, serum leptin levels did not change significantly after cure of H pylori infection. CONCLUSION: Leptin is present in the human gastric mucosa. Gastric leptin may play a role in weight gain after eradication of H pylori infection. Gastric leptin may have a local rather than systemic action.

Cibenzoline has an inhibitory effect on vasorelaxation mediated by adenosine triphosphate-sensitive K(+) channels in the rat carotid artery.

UNLABELLED: Studies in cardiac myocytes have shown that cibenzoline reduces adenosine triphosphate (ATP)-sensitive K(+) currents, suggesting that this class Ia antiarrhythmic drug may modify the activity of ATP-sensitive K(+) channels in these preparations. The effects of class Ia antiarrhythmic drugs on vasodilation mediated by ion channels have not been studied. Therefore, we designed this study to examine whether cibenzoline may produce changes in vasorelaxation in response to a selective ATP-sensitive K(+) channel opener, levcromakalim, in the isolated rat carotid artery. Rings of rat carotid arteries without endothelium were suspended for isometric force recording. Concentration-response curves were obtained in a cumulative fashion. During submaximal contraction to phenylephrine (3 x 10(-7) M), vasorelaxation in response to levcromakalim (10(-8) to 10(-5) M) or 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7; 10(-10) to 10(-5) M) was obtained. During contraction to phenylephrine, levcromakalim induced concentration-dependent vasorelaxation. A selective ATP-sensitive K(+) channel antagonist, glibenclamide (5 x 10(-6) M), completely abolished vasorelaxation in response to levcromakalim, whereas a selective Ca(2+)-dependent K(+) channel antagonist, iberiotoxin (5 x 10(-8) M), did not affect the relaxation. Cibenzoline (10(-6) to 10(-5) M) significantly reduced vasorelaxation to levcromakalim in a concentration-dependent fashion. In contrast, cibenzoline (10(-5) M) did not alter vasorelaxation to a nitric oxide donor, NOC-7. These results suggest that from the clinically relevant concentrations, a novel class Ia antiarrhythmic drug, cibenzoline, impairs carotid vasodilation mediated by ATP-sensitive K(+) channels. IMPLICATIONS: In isolated rat carotid artery, cibenzoline (10(-6) to 10(-5) M) reduced vasorelaxation to levcromakalim in a concentration-dependent fashion. These results suggest that from the clinically relevant concentrations, a novel class Ia antiarrhythmic drug, cibenzoline, impairs carotid vasodilation mediated by adenosine triphosphate-sensitive K(+) channels.

Mild alkalinization and acidification differentially modify the effects of lidocaine or mexiletine on vasorelaxation mediated by ATP-sensitive K+ channels.

BACKGROUND: The previous study by the authors showed that the class Ib antiarrhythmic drug lidocaine impairs but mexiletine augments vasorelaxation mediated by adenosine triphosphate-sensitive K+ channels. Lidocaine and mexiletine have different values of the negative logarithm of the drug-proton dissociation constant, indicating that the ion channel-blocking effects of these drugs under different pH levels may vary. However, the role of pH in the effects of lidocaine and mexiletine on vasodilation mediated by K+ channels has not been studied. Therefore, the current study was designed to examine whether the inhibition and augmentation of vasorelaxation in response to an adenosine triphosphate-sensitive K+ channel opener, levcromakalim, by the clinically relevant concentrations of lidocaine or mexiletine are modified by mild alkalinization or acidification in the isolated rat aorta. METHODS: Rings of the rat aorta without endothelium were suspended for isometric force recording. Three types of modified Krebs-Ringer solutions (pH 7.2, 7.4, and 7.6) were prepared by changing the composition of NaCl and NaHCO3. During contractions in response to phenylephrine (3 x 10(-7) M), relaxations in response to levcromakalim (10(-8) to 10(-5) M) were obtained. Lidocaine (10(-5) to 10(-4) M), mexiletine (10(-5) to 10(-4) M), or glibenclamide (10(-5) M) was applied 15 min before addition of phenylephrine. RESULTS: Relaxations in response to levcromakalim, which are abolished by the selective adenosine triphosphate-sensitive K+ channel antagonist glibenclamide (10(-5) M), were not different among the three pH groups. In the normal Krebs-Ringer solution of pH 7.4, lidocaine significantly reduced these relaxations in a concentration-dependent fashion. Alkalinization of pH 7.6 augmented the inhibitory effect of lidocaine on these relaxations, whereas acidification of pH 7.2 substantially abolished this effect. In contrast, mexiletine pH independently augmented relaxations in response to levcromakalim. Glibenclamide (10(-5) M) abolished these relaxations in arteries treated with mexiletine (10(-4) M) in any pH group. CONCLUSIONS: These results suggest that even under conditions of such mild alkalosis or acidosis, vasorelaxation via adenosine triphosphate-sensitive K+ channels is dependent on pH in the presence of clinically relevant concentrations of lidocaine but not mexiletine.

The effect of Helicobacter pylori eradication therapy on dyspepsia symptoms in industrial workers in Japan.

BACKGROUND: The relationship between Helicobacter pylori infection and non-ulcer dyspepsia is still controversial. The potential benefits and risks of the treatment could depend on local conditions, such as the prevalence of the infection and the local rates of gastric cancer. AIM: To evaluate the effects of H. pylori eradication therapy on non-ulcer dyspepsia symptoms in industrial workers in Japan. METHODS: A total of 615 employees of an industrial corporation were examined for H. pylori infection and symptom scores; 215 H. pylori-positive non-ulcer dyspepsia cases underwent eradication therapy. Symptom scores were also analysed 12 months after the eradication therapy. Serum pepsinogen A and pepsinogen C levels were analysed and chronic atrophic gastritis was serologically diagnosed on the basis of the criteria of a pepsinogen A < 70 ng/mL and pepsinogen A : pepsinogen C ratio < 3.0. RESULTS: The symptom score improved significantly in the cured cases, but not in the non-cured cases. The effect of the cure of H. pylori infection on symptoms was analysed according to the serological diagnosis of chronic atrophic gastritis. In both groups, cases with atrophic gastritis and cases with chronic gastritis only, the cure of infection was effective in improving symptoms. CONCLUSION: The cure of H. pylori infection was effective in reducing non-ulcer dyspepsia symptoms in industrial workers in Japan.

Helicobacter pylori infection induces hyperammonaemia in Mongolian gerbils with liver cirrhosis.

BACKGROUND AND AIMS: We previously reported the effect of Helicobacter pylori eradication on hyperammonaemia in patients with liver cirrhosis. However, the role of H pylori as a cause of hyperammonaemia is controversial. We developed an animal model with liver cirrhosis and investigated the effect of H pylori infection on hyperammonaemia. MATERIALS AND METHODS: Five week old male Mongolian gerbils were inoculated orally with broth culture of H pylori. Forty eight gerbils were divided into four groups. Gerbils not inoculated with H pylori were fed a commercial rodent diet (group A) or a choline deficient diet (group C). Gerbils inoculated with H pylori were fed the commercial rodent diet (group B) or the choline deficient diet (group D). Blood ammonia levels of the femoral vein and portal vein were measured 30 weeks later. RESULTS: All gerbils fed the choline deficient diet developed liver cirrhosis with fatty metamorphosis. The survival rate of group D was significantly lower than that of the other groups. Systemic and portal blood ammonia levels in group D were significantly higher than those in the other groups. CONCLUSIONS: H pylori infection induces hyperammonaemia in gerbils with liver cirrhosis.

Effects of CYP2C19 gene polymorphism on cure rates for Helicobacter pylori infection by triple therapy with proton pump inhibitor (omeprazole or rabeprazole), amoxycillin and clarithromycin in Japan.

BACKGROUND: Omeprazole is mainly metabolized by cytochrome P450 2C19 (CYP2C19) in the liver. Rabeprazole, on the other hand, is mainly metabolized to thioether-rabeprazole via a non-enzymatic pathway and partially metabolized to demethylated-rabeprazole by CYP2C19 in liver CYP2C19 status may affect cure rate for Helicobacter pylori infection with proton pump inhibitor triple therapy. AIM: To investigate whether genetic polymorphism of CYP2C19 and selected proton pump inhibitors (omeprazole or rabeprazole) were associated with cure rate for Helicobacter pylori infection using triple therapy with omeprazole or rabeprazole, amoxicillin, and clarithromycin. METHODS: A total of 170 Helicobacter pylori-positive patients with chronic gastritis were randomized to receive one of the following Helicobacter pylori eradication regimens; OAC (omeprazole 20 mg bd, amoxycillin 750 mg bd and clarithromycin 400 mg bd for 1 week) and RAC (rabeprazole 20 mg bd, amoxycillin 750 mg bd and clarithromycin 400 mg bd for 1 week). The CYP2C19 genotype; wild-type or two mutant genes (ml in exon 5 and m2 in exon 4), or both, were identified by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: In DAC regimen, cure rate (per protocol analysis) was 73.3% in homozygous extensive metabolizers, 86.1% in heterozygous extensive metabolizers, and 85.0% in poor metabolizers. In RAC regimen, the cure rate was 81.0% in homozygous extensive metabolizers, 82.9% in heterozygous extensive metabolizers, and 87.5% in poor metabolizers. Cure rate was not significantly different between the CYP2C19 genotypes in both regimens. CONCLUSION: Triple therapy with proton pump inhibitor (omeprazole or rabeprazole), amoxycillin, and clarithromycin is sufficiently effective in cure of Helicobacter pylori infection regardless of CYP2C19 status.