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.

Effect of central urocortin on carbon tetrachloride-induced acute liver injury in rats.

The effect of intracisternal injection of urocortin, an endogenous ligand for corticotropin-releasing factor (CRF) 2 receptor, on carbon tetrachloride (CCl4)-induced acute liver injury was investigated in rats. Intracisternal injection of urocortin dose-dependently enhanced elevation of serum alanine aminotransferase and aspartate aminotransferase levels induced by CCl4. Intracisternal urocortin also aggravated CCl4-induced histological changes of the liver. The aggravating effect of central urocortin on CCl4-induced acute liver injury was abolished by chemical sympathectomy, but not by vagotomy. These data demonstrate that urocortin acts in the brain to exacerbate acute liver injury through the sympathetic nervous system and suggest a possible involvement of the CRF2 receptor in the central CRF-induced exacerbation of acute liver injury in rats.

Interaction of syntaxin with alpha-fodrin, a major component of the submembranous cytoskeleton.

The soluble N-ethyl maleimide-sensitive factor attachment protein receptor machinery is involved in membrane docking and fusion. In this machinery, the syntaxin family is a central coordinator and participates in multiple protein-protein interactions. In this study we have shown that alpha-fodrin, nonerythroid spectrin, is a new binding partner of the syntaxin family. alpha-Fodrin bound to syntaxin-1a, -3, and -4, all of which are localized on the plasma membrane. Syntaxin-3 interacted with alpha-fodrin in dose-dependent and saturable manners but not with alpha-spectrin, erythroid spectrin. Syntaxin-3 interacted with alpha-fodrin through its C-terminal coiled-coil region. Binding of Munc18 or SNAP-25 to syntaxin-1a inhibited the interaction of alpha-fodrin with syntaxin-1a. Available evidence indicates that alpha-fodrin is implicated in exocytosis, but a precise mode of action of alpha-fodrin in exocytosis remains unclear. Our results suggest that alpha-fodrin regulates exocytosis through the interaction with members of the syntaxin family.

Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: a pilot study.

BACKGROUND: Non-alcoholic steatohepatitis is a distinct entity, characterized by fatty change, lobular inflammation and fibrosis of the liver. Some cases of non-alcoholic steatohepatitis progress to cirrhosis, but it is not easy to distinguish this disease from non-alcoholic fatty liver by non-invasive examinations. No proven therapy for non-alcoholic steatohepatitis exists. Transforming growth factor-beta1 is implicated in the development of liver fibrosis, and is inhibited by alpha-tocopherol (vitamin E) in the liver. Therefore, in this study, the significance of the measurement of the level of plasma transforming growth factor-beta1 and the effect of alpha-tocopherol on the clinical course of non-alcoholic steatohepatitis were investigated. METHODS: Twelve patients with non-alcoholic steatohepatitis and 10 patients with non-alcoholic fatty liver, with a diagnosis confirmed by liver biopsy, were studied. None of the patients had a history of alcohol abuse, habitual medicine or malignant or inflammatory diseases. All patients were negative for hepatitis B, C and G virus. Patients were given dietary instruction for 6 months, and then alpha-tocopherol (300 mg/day) was given for 1 year. Blood chemistries, measurement of plasma transforming growth factor-beta1 level and liver biopsies were undertaken before and after the 1-year alpha-tocopherol treatment. RESULTS: The serum alanine transaminase level decreased in non-alcoholic fatty liver patients, but not in non-alcoholic steatohepatitis patients, after 6 months of dietary therapy. Although the serum alanine transaminase level in non-alcoholic steatohepatitis patients was reduced during the 1-year alpha-tocopherol treatment, alpha-tocopherol had no effect on the serum alanine transaminase level in non-alcoholic fatty liver patients. The histological findings, such as steatosis, inflammation and fibrosis, of the non-alcoholic steatohepatitis patients were improved after alpha-tocopherol treatment. The plasma transforming growth factor-beta1 level in non-alcoholic steatohepatitis patients was significantly elevated compared with that in non-alcoholic fatty liver patients and healthy controls, and decreased, accompanied by an improvement in serum alanine transaminase level, with alpha-tocopherol treatment. CONCLUSIONS: Our data suggest that the measurement of the level of plasma transforming growth factor-beta1 represents a possible method of distinguishing between non-alcoholic steatohepatitis and non-alcoholic fatty liver. Long-term alpha-tocopherol treatment may be safe and effective for non-alcoholic steatohepatitis. A randomized, controlled, double-blind trial is needed to confirm the full potential of alpha-tocopherol in the management of non-alcoholic steatohepatitis.

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.

Central regulation of hepatic function by neuropeptides.

In addition to classical neurotransmitters, such as acetylcholine and noradrenaline, neuropeptides have been recognized as new neurotransmitters and neuromodulators. Neuropeptides are widely distributed in the central nervous system as well as in peripheral nerves, and act as neurotransmitters to regulate various physiological functions. The digestive organs are no exception, and several neuropeptides in the central nervous system are shown to act in specific brain sites and control gastrointestinal functions, such as gastric acid secretion, and gastrointestinal motility, through the autonomic nervous system. Recently, a relationship between central neuropeptides and hepatic function through the autonomic nervous system has been revealed in animal models. Thyrotropin-releasing hormone acts in the medulla, in particular in the left dorsal vagal complex, to induce stimulation of hepatic blood flow and hepatic proliferation, and protect against experimental liver injury through vagal and cholinergic pathways. Corticotropin-releasing factor injected intracisternally elicits inhibition of the hepatic blood flow and exacerbates experimental liver injury through sympathetic and noradrenergic pathways. Neuropeptide Y acts in the left dorsal vagal complex, in particular in regard to the Y1 receptor subtype, to stimulate bile secretion. Other neuropeptides such as beta-endorphin and bombesin in the brain modulate hepatic proliferation and bile secretion. Through the use of neuropeptides, new knowledge of the central and peripheral mechanisms underlying brain regulation of hepatic function will be revealed. Further studies in regard to the physiological relevance of the central action of neuropeptides on specific brain sites should be performed to unravel the underlying pathways that mediate brain-liver interaction.

[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.