Randomised clinical trial: rabeprazole improves symptoms in patients with functional dyspepsia in Japan.

BACKGROUND: The efficacy of proton pump inhibitors (PPIs) for treating functional dyspepsia (FD) is not well established. AIM: This study, named the SAMURAI study, aimed to assess the efficacy and dose-response relationship of rabeprazole in Japanese patients with FD in a multicentre, double-blinded, randomised, placebo-controlled trial. METHODS: Investigated FD was diagnosed using the Rome III criteria. Subjects who did not respond to 1 week of single-blind placebo treatment in a run-in period were randomly assigned to 8 weeks of double-blind treatment with rabeprazole 10 mg, 20 mg, 40 mg or placebo, once daily. Dyspeptic symptoms were assessed by a dyspepsia symptom questionnaire (7-point Likert scale) and symptom diary. RESULTS: Of 392 subjects entered into the run-in period, 338 were randomly assigned. Although there was no significant difference between placebo and rabeprazole groups in complete symptom relief for four major dyspeptic symptoms, the satisfactory symptom relief of rabeprazole 20 mg was significantly higher than placebo according to the dyspepsia symptom questionnaire (45.3% vs. 28.2%, P = 0.027) and the symptom diary assessment (48.7% vs. 30.0%, P = 0.016). The efficacy was not influenced by syndrome type or Helicobacter pylori status. No statistically significant differences in the incidence of adverse events were seen among treatment groups. CONCLUSIONS: Rabeprazole 20 mg once daily but not 10 or 40 mg significantly provides satisfactory symptom relief for functional dyspepsia (ClinicalTrials.gov, Number NCT01089543).

Clinical trial: irsogladine maleate, a mucosal protective drug, accelerates gastric ulcer healing after treatment for eradication of Helicobacter pylori infection--the results of a multicentre, double-blind, randomized clinical trial (IMPACT study).

BACKGROUND: Helicobacter pylori eradication therapy alone is not sufficient to heal all gastric ulcers. AIM: To verify the efficacy of treatment with irsogladine maleate between the termination and assessment of treatment for eradicating H. pylori in a double-blind study. METHODS: Three hundred and twenty-two patients with a single H. pylori-positive gastric ulcer were given eradication treatment, then assigned randomly to a treatment group [given 4 mg/day irsogladine maleate (n = 150)] or a control group [given a placebo (n = 161)]. The gastric ulcer healing rates were compared after 7 weeks of treatment. RESULTS: The healing rate was significantly higher in the irsogladine maleate group (83.0%) than in the placebo group (72.2%; chi2 test, P = 0.0276). In the subgroup analysis of cases of eradication failure, the gastric ulcer healing rate was significantly higher in the irsogladine maleate group (57.9%) than in the placebo group (26.1%; chi2 test, P = 0.0366). CONCLUSIONS: Irsogladine maleate was effective for treating gastric ulcer after H. pylori eradication. The high healing rates observed in patients with or without successful eradication demonstrate the usefulness of irsogladine maleate treatment regardless of the outcome of eradication.

Expression of SDF-1 alpha and nuclear CXCR4 predicts lymph node metastasis in colorectal cancer.

Although stromal cell-derived factor (SDF)-1 alpha and its receptor CXCR4 are experimentally suggested to be involved in tumorigenicity, the clinicopathological significance of their expression in human disease is not fully understood. We examined SDF-1 alpha and CXCR4 expression in colorectal cancers (CRCs) and their related lymph nodes (LNs), and investigated its relationship to clinicopathological features. Specimens of 60 primary CRCs and 27 related LNs were examined immunohistochemically for not only positivity but also immunostaining patterns for SDF-1 alpha and CXCR4. The relationships between clinicopathological features and SDF-1 alpha or CXCR4 expression were then analysed. Stromal cell-derived factor-1 alpha and CXCR4 expression were significantly associated with LN metastasis, tumour stage, and survival of CRC patients. Twenty-nine of 47 CXCR4-positive CRCs (61.7%) showed clear CXCR4 immunoreactivity in the nucleus and a weak signal in the cytoplasm (nuclear type), whereas others showed no nuclear immunoreactivity but a diffuse signal in the cytoplasm and at the plasma membrane (cytomembrane type). Colorectal cancer patients with nuclear CXCR4 expression showed significantly more frequent LN metastasis than did those with cytomembrane expression. Colorectal cancer patients with nuclear CXCR4 expression in the primary lesion frequently had cytomembrane CXCR4-positive tumours in their LNs. In conclusion, expression of SDF-1 alpha and nuclear CXCR4 predicts LN metastasis in CRCs.

Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with nonalcoholic fatty liver disease (NAFLD).

BACKGROUND: Liver fibrosis is the main predictor of the progression of nonalcoholic fatty liver disease. Transient elastography (FibroScan), which measures liver stiffness, is a novel, noninvasive method to assess liver fibrosis. AIM: We investigated the usefulness of liver stiffness measurement in the evaluation of liver fibrosis in nonalcoholic fatty liver disease patients. STUDY POPULATION: A total of 97 nonalcoholic fatty liver disease patients. METHODS: Transient elastography was performed for liver stiffness measurement in 97 nonalcoholic fatty liver disease patients. And the relationship between histological parameters and liver stiffness measurement was studied by multivariate analysis. Moreover, we investigated the relationship between liver stiffness measurement and the serum levels of hyaluronic acid and type IV collagen 7s domain. RESULTS: The liver stiffness was well correlated with the stage of liver fibrosis (Kruskal-Wallis test p < 0.0001). The areas under the receiver-operating characteristic curves were 0.927 for > or = F1, 0.865 for > or = F2, 0.904 for > or = F3, 0.991 for > or = F4. Only fibrosis stage was correlated significantly with liver stiffness measurement by multiple regression analysis. Liver stiffness was also strongly correlated with the serum levels of type IV collagen 7s domain (r = 0.525, p < 0.0001) and hyaluronic acid (r = 0.457, p < 0.0001). CONCLUSIONS: Our results show a significant correlation between liver stiffness measurement and fibrosis stage in nonalcoholic fatty liver disease patients, as confirmed by the results of liver biopsy, which remains the gold standard for evaluation of the severity of liver fibrosis in patients with nonalcoholic steatohepatitis.

Minimal change oesophagitis: a disease with characteristic differences to erosive oesophagitis.

BACKGROUND: The majority of gastro-oesophageal reflux disease (GERD) seems to be non-erosive reflux disease. Nonerosive reflux disease includes minimal change oesophagitis (whitish or reddish, oedematous change and erosion that is not regarded as mucosal break) and no endoscopic abnormalities. AIM: To investigate the accurate proportion of those with minimal change oesophagitis and to clarify its characteristics. In addition, we evaluated the effect of famotidine (40 mg/day) in those with minimal change. METHODS: Prospective endoscopic assessment was performed for consecutive 606 out-patients. Of the 582 patients suitable for analysis, 347 were non-treated. The latter were divided into those with erosive GERD or minimal change, and their endoscopic findings and characteristics were compared. RESULTS: Among 347 non-treated patients, 88 (25%) had erosive GERD and 249 (72%) had minimal change. Compared with patients who have erosive GERD and those with minimal change, the latter were less likely to have hiatal hernia or bile reflux, but more likely to have gastric atrophy. Symptomatic patients (n = 55) with minimal change oesophagitis were more likely to have hiatal hernia than those who were asymptomatic (n= 194). Most patients preferred taking famotidine on-demand, during a 4-week follow-up period. CONCLUSIONS: Most non-erosive reflux disease can be classified as minimal change oesophagitis, and that have different characteristics from erosive GERD. On-demand famotidine may be a suitable alternative treatment for patients with minimal change disease.

Effect of central corticotropin releasing factor on hepatic circulation in rats: the role of the CRF2 receptor in the brain.

BACKGROUND: Corticotropin releasing factor (CRF) is distributed in the central nervous system and acts as a neurotransmitter to regulate gastric functions through vagal-muscarinic pathways. We have recently demonstrated that central CRF aggravates experimental acute liver injury in rats. In the present study, the central effect of CRF on hepatic circulation was investigated. METHODS: Hepatic surface perfusion was determined by laser Doppler flowmetry in urethane anaesthetised rats. Portal pressure and portal blood flow was simultaneously monitored. CRF (0.1-4 nmol), urocortin II (a selective CRF2 receptor agonist 2.5-100 pmol), or saline vehicle was injected intracisternally, and changes in hepatic circulation were observed for 120 minutes. We examined the effects of various pretreatments with K41498, a selective CRF2 receptor antagonist, atropine, 6-hydroxydopamine, hepatic plexus denervation, or hepatic branch vagotomy, respectively. RESULTS: Intracisternal injection of CRF (0.2-4 nmol) caused a dose dependent decrease in hepatic surface perfusion with a maximum response occurring 60 minutes post injection. Portal pressure was dose dependently elevated and portal blood flow was decreased by intracisternal CRF concurrently with the decrease in hepatic surface perfusion. These changes in hepatic circulation by intracisternal CRF were abolished by 6-hydroxydopamine and hepatic plexus denervation, but not by atropine or hepatic vagotomy. Urocortin II injected intracisternally decreased hepatic surface perfusion and elevated portal pressure at doses within the picomolar range. Intracisternal preadministration of K41498 inhibited the effect of central CRF on the hepatic circulation. CONCLUSION: These data suggest that CRF acts in the brain to decrease hepatic surface perfusion and elevate portal pressure through central CRF(2) receptor and sympathetic-noradrenergic pathways.

Indometacin up-regulates TFF2 expression in gastric epithelial cells.

BACKGROUND: Trefoil factor family peptides are expressed in gastrointestinal epithelial cells and play a critical role in maintaining mucosal integrity. Although non-steroidal anti-inflammatory drugs (NSAIDs) are important causative agents of gastric mucosal lesions, few data are available about the effect of NSAIDs on trefoil family peptides in gastric mucosa. AIM: To examine whether indometacin, a widely used NSAID, affects trefoil factor family expression in gastric epithelial cells. METHODS: MKN45, a cell line derived from human gastric cancer, was used. TFF1, TFF2, and TFF3 mRNA expression was assessed by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). TFF2 gene transcription was also examined by luciferase reporter gene assay. RESULTS: Relative expression level of TFF1, TFF2, TFF3 mRNA was 616: 12: 1 in unstimulated MKN45 cells. Although indometacin (1-250 micro mol/L) had no significant effect on the expression of TFF1 and TFF3 mRNA, it up-regulated TFF2 mRNA expression in a dose- and time-dependent manner. Luciferase reporter gene assay confirmed the up-regulation of TFF2 gene transcription by indometacin. Indometacin-induced up-regulation of TFF2 expression was not antagonized by externally applied prostaglandin E2. CONCLUSION: These results suggest that indometacin up-regulates gastric epithelial cell TFF2 expression through a COX-independent mechanism. Since TFF peptides play an important role in gastric mucosal protection, indometacin-induced TFF2 may reduce the degree of gastric mucosal damage induced by indometacin.

Clinical evaluation of granulocyte/monocyte apheresis therapy for active ulcerative colitis.

BACKGROUND: Recent evidence suggests that peripheral blood granulocytes and monocytes/macrophages have a major role in the exacerbation of ulcerative colitis. AIMS: Our objective was to investigate if selective granulocyte and monocyte adsorptive apheresis with Adacolumn promotes remission of active ulcerative colitis and spares corticosteroid. SUBJECTS: Sixty patients with active ulcerative colitis were studied, of whom 39 had relapsing-remitting ulcerative colitis, 15 had chronic continuous and 6 had their first episode of ulcerative colitis. METHODS: Granulocytapheresis was done with an Adacolumn filled with cellulose acetate beads as apheresis carriers that adsorb FcgammaR and complement receptors bearing leucocytes (granulocytes, monocytes and a small fraction of lymphocytes). Patients received up to 10 Adacolumn sessions over 12 weeks, one session was 60-90 min at 30 mL/min. No additional medication was given. Efficacy was assessed with Seo's activity index (AI) [Seo M, Okada M, Yao T. An index of disease activity in patients with ulcerative colitis. Am J Gastroenterol 1992;87:971-6]. The mean AL was 197.5 and range 154.4-277.7. AI < 150 was considered significant improvement and AI < 100 was considered clinical remission. RESULTS: Of 60 patients, 50 (83.3 %) improved, 14 achieved remission, granulocytapheresis was most effective in steroid-dependent patients. At entry, the mean dose of prednisolone was 15.3 mg/day per patient and was reduced to 3.6 mg/day after 10 sessions. Granulocytapheresis was well tolerated and no serious side-effects were observed. CONCLUSION: Based on our experience in patients with diverse ulcerative colitis disease expression and long-term exposure to conventional drug therapy, we believe that granulocytapheresis is an effective adjunct to conventional medication for promoting remission and sparing steroids in patients with active ulcerative colitis.

Pathophysiology of gastric acid secretion in patients with chronic renal failure: influence of Helicobacter pylori infection.

OBJECTIVES: The incidence of gastroduodenal diseases is high in patients with chronic renal failure (CRF). However, gastric acidity in CRF has been reported to range in level from low to high. Moreover, it remains unknown whether Helicobacter pylori infection influences gastric acidity in such patients. Thus, we aimed to clarify the pathophysiological perturbation in gastric acidity and to determine the influence of H. pylori infection in CRF. DESIGN: Case-control study. SETTING: A university hospital. SUBJECTS: Twenty-seven patients with CRF and 24 control patients, presenting with either gastrointestinal symptoms, positive faecal occult blood, or anaemia (haemoglobin <10 g dL(-1)). MEASURES: The patients underwent gastroduodenal endoscopy with simultaneous determination of H. pylori infection. Gastric ammonium concentration, serum pepsinogen I and II, and basal gastrin level were measured. Thereafter, gastric acid secretion was monitored by 24-h intragastric acidity measurement with calculation of pH-3 holding time (%) (hours showing pH>3/24 h). RESULTS: In the CRF group, pH-3 holding time of H. pylori (+) subgroup was significantly greater than that of H. pylori (-) subgroup (71.2 +/- 32.4% vs. 32.8 +/- 30.0%, mean +/- SD; P=0.03). Pepsinogen I/II ratio was inversely correlated with pH-3 holding time in the control and CRF groups. Gastric ammonium concentration in CRF/H. pylori (+) subgroup (14.1 +/- 9.2 mmol L(-1)) was significantly higher than in CRF/H. pylori (-) (2.5 +/- 2.7 mmol L(-1); P=0.002) and control/H. pylori (+) subgroups (6.1 +/- 4.2 mmol L(-1); P=0.01). Serum gastrin level was significantly higher in the CRF group than in the control group (297 +/-343 pg mL(-1) vs. 116 +/- 69 pg mL(-1); P=0.02) as a whole. However, there was no significant correlation between serum creatinine and gastrin levels in the CRF group. Gastrin level in CRF/H. pylori (+) subgroup was significantly higher than in CRF/H. pylori (-), control/H. pylori (+), and control/H. pylori (-) subgroups (423 +/-398 pg mL(-1) vs. 113 +/- 79, 124 +/- 78, and 96 +/-43 pg mL(-1), respectively; P=0.01-0.03). Significant positive correlations amongst pH-3 holding time, ammonium and gastrin concentrations were found in the CRF group, but not in the control group. CONCLUSIONS: CRF without H. pylori infection primarily shows a tendency for high gastric acidity, but without hypergastrinaemia. Persistent H. pylori infection in CRF leads to decreased acidity and, consequently, to fasting hypergastrinaemia via a feedback mechanism. The hypoacidity in CRF with H. pylori infection appears to result from neutralization of acid by ammonia as well as from gastric atrophy. Thus, H. pylori infection status critically determines perturbation in gastric acidity and fasting gastrin level in CRF.

Up-regulation of TFF expression by PPARgamma ligands in gastric epithelial cells.

BACKGROUND: Although trefoil factor family peptides (TFF peptides) are assumed to play important roles in gastric mucosal protection, the regulatory mechanism of gastric TFF expression has not been fully understood yet. Recent reports showed gastric expression of peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear receptor known to be involved in the regulation of cell growth and differentiation in other cell types, such as adipocytes. AIM: To determine whether PPARgamma affects the expression of TFF in gastric epithelial cells. METHODS: MKN45 gastric cells were used as a model of gastric epithelial cells. DNA synthesis of the cells was determined by the measurement of BrdU incorporation. The effects of PPARgamma ligands, 15-deoxy-Delta12,14-prostaglandin J2 (15d-PGJ2) and troglitazone (TGZ) on TFF expression were assessed by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: MKN45 cells expressed a significant amount of PPARgamma. Both 15d-PGJ2 and TGZ suppressed DNA synthesis of the cells in a dose-dependent manner. In the control condition, MKN45 cells most abundantly expressed TFF1 and the relative expression level of TFF1, TFF2, and TFF3 mRNA was 1700:32:1. TFF1 and TFF2 mRNA levels were significantly up-regulated by the incubation of the cells with 15d-PGJ2 (10 micro m) or TGZ (30 micro m), whereas TFF3 mRNA level was not affected. CONCLUSION: The results of the present study suggest a possible role of PPARgamma in the regulation of TFF expression in gastric epithelial cells.

Effect of PPARgamma ligands on the viability of gastric epithelial cells.

BACKGROUND: [corrected] Peroxisome proliferator-activated receptors (PPAR) are a family of three nuclear receptors (PPARalpha, PPARdelta, and PPARgamma). Although recent evidence suggests a role for PPARgamma in the regulation of colonic epithelial cell growth, the role for PPARgamma in the stomach has not been established. AIM: To examine the expression of PPARgamma and the effects of PPARgamma ligands on the viability of gastric epithelial cells. METHODS: MKN45 cells and primary cultured rat gastric epithelial cells were used. Troglitazone (TGZ) and 15-deoxy-Delta12, 14-prostaglandin J2 (15d-PGJ2) were used as PPARgamma ligands. Expression of PPARgamma was examined by RT-PCR and Western blot analysis. Cell viability was measured by WST-1 assay and TUNEL assay was performed to detect apoptosis. RESULTS: MKN45 cells expressed all subtypes of PPAR. PPARgamma ligands decreased cell viability and induced cell death in a dose-dependent manner, whereas ligands for PPARalpha and PPARdelta had no significant effect. TUNEL assay showed that this cell death is apoptosis. Primary cultured rat gastric epithelial cells also expressed PPARgamma and activation of PPARgamma decreased cell viability. CONCLUSION: These results suggest that PPARgamma plays an important role in the regulation of cell growth and cell death in gastric epithelial cells.

Characteristics of the peroxisome proliferator activated receptor gamma (PPARgamma) ligand induced apoptosis in colon cancer cells.

BACKGROUND: Involvement of peroxisome proliferator activated receptor gamma (PPARgamma) in the growth response of colon cancer cells has been suggested. AIMS: To investigate the characteristics of PPARgamma induced apoptosis in colon cancer cells. METHODS: The effects of ligands for each of the PPAR subtypes (alpha, delta, and gamma) on DNA synthesis and cell viability were examined in HT-29 colon cancer cells. Modulation of apoptosis related gene expression by PPARgamma ligands was screened with cDNA arrays, and the results were confirmed by quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis. RESULTS: PPARalpha, PPARdelta, and PPARgamma were all expressed in HT-29 cells. PPARgamma ligands, 15-deoxy-delta(12,)(14)-prostaglandin J2 (15d-PGJ2) and troglitazone (TGZ), suppressed DNA synthesis of HT-29 cells whereas ligands for PPARalpha and PPARdelta had no significant effects. Both 15d-PGJ2 and TGZ induced HT-29 cell death in a dose dependent manner which was associated with an increase in fragmented DNA and was sensitive to a caspase inhibitor. Among several genes selected by cDNA array screening, quantitative RT-PCR analysis confirmed downregulation of c-myc expression and upregulation of c-jun and gadd153 expression by 15d-PGJ2 and TGZ. PPARgamma induced apoptosis was antagonised by the presence of serum in the culture medium, and interaction between PPARgamma signalling and cell survival signalling through the phosphatidylinositol 3-kinase pathway was suggested. CONCLUSIONS: As c-myc is an important target gene of the adenomatous polyposis coli (APC)/beta-catenin and/or APC/gamma-catenin pathway, activation of PPARgamma signalling appears to compensate for deregulated c-myc expression caused by mutated APC. The present results suggest the potential usefulness of PPARgamma ligands for chemoprevention and treatment of colon cancers.

Cell culture model for antiulcerogenic agents.

To elucidate the mechanisms of antiulcerogenic agents, we established the cell culture model derived from rat gastric epithelium. The cultured cells were identified as mucus-producing cells by using histological analysis. This culture model is useful for investigating the untiulcer effect of various agents and to reveal the mechanisms of the drug action. In particular, the ulcer-healing model using the cultured monolayer is promising and convenient for the study of several growth factors such as HGF as well as antiulcerogenic agents. The effect of polaporezinc in the cultured model is introduced.

[Diagnosis of H. pylori infection by PCR].

Because of its high sensitivity, polymerase chain reaction (PCR) method can be used to detect the presence of very few numbers of H. pylori organisms in gastric biopsy materials or gastric juice samples. PCR has also been applied to the detection of H. pylori organisms in the oral cavity, in stools, and in the environment. RT-PCR is useful to study the expression of H. pylori pathogenic genes and gene expression of gastric mucosal cells in response to H. pylori infection. Other PCR-based techniques, such as PCR-RFLP or real-time quantitative PCR, are now providing important information on H. pylori and pathophysiology of H. pylori infection.