Masatsugu Shiba

Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent

Background: Enterobacteria and cytokines both play roles in the pathophysiology of NSAID-induced enteropathy. Toll-like receptor (TLR) 4 recognises lipopolysaccharide (LPS), resulting in activation of an inflammatory cascade via the accessory protein MyD88. Aims: To investigate role of TLR4 in inflammatory responses in indomethacin-induced enteropathy. Methods: Indomethacin was administered p.o. to non-fasting rats and mice to induce small intestinal damage. The extent of such damage was evaluated by measuring the injured area stained dark blue with Evans blue. Rats were given antibiotics (ampicillin, aztreonam or vancomycin) p.o., or intraperitoneal LPS (a TLR4 ligand) or neutralising antibodies against neutrophils, tumour necrosis factor (TNF)-α, or monocyte chemotactic protein (MCP)-1. Furthermore, the intestinal ulcerogenicity of indomethacin was examined in TLR4-mutant, TLR4−/−, and MyD88−/− mice. Results: Indomethacin induced small intestinal damage with an increase in expression of TNF-α and MCP-1 in both rats and mice. Antibodies against neutrophils, TNF-α and MCP-1 inhibited the damage by 83%, 67% and 63%, respectively, in rats. Ampicillin and aztreonam also inhibited this damage, and decreased the number of Gram-negative bacteria in the small intestinal contents of the rat. However, vancomycin, which exhibited no activity against Gram-negative bacteria, had no preventive effect against this damage. Administration of LPS 1 h after indomethacin aggravated the damage, whereas LPS pretreatment inhibited it with reduction of expression of TLR4 and cytokines. In TLR4-mutant mice, the damage and cytokine expression were markedly inhibited. TLR4−/− and MyD88−/− mice were also resistant to the damage. Conclusions: Indomethacin may injure the small intestine through a TLR4/MyD88-dependent pathway.

Prevalence of overlaps between GERD, FD and IBS and impact on health-related quality of life.

Objective:  Gastroesophageal reflux disease (GERD), functional dyspepsia (FD), and irritable bowel syndrome (IBS) are common, and have negative impacts on health‐related quality of life (HR‐QOL). Several studies demonstrated a significant overlap between two of these three diseases. The purpose of this study was to examine the prevalence of GERD, FD, and IBS, their overlap rates, and HR‐QOL for each disease and each overlap compared with healthy controls in the Japanese general population.

Effect of chronic stress on gastric emptying and plasma ghrelin levels in rats

Chronic stress is associated with gastrointestinal functional diseases. Although the pathophysiology seems to be associated with gastrointestinal motility, their mechanisms remain unclear. We investigated gastric emptying and chemical mediators under conditions of continuous stress, which were produced using 8-week-old male Wistar rats kept in a cage filled with water to 2 cm height for 5 days. We examined gastric emptying by the phenol red method and chemical mediators at 4, 8, and 24 h and 3 and 5 days after initiation of stress restraint. Plasma ACTH level was significantly higher in the stress throughout the period of measurement. Continuous stress delayed gastric emptying until 24 h: peak delay was observed at 8 h, whereas gastric emptying was accelerated on days 3 and 5. Plasma noradrenalin level was significantly elevated at every time point until 24 h. Guanethidine pretreatment eliminated the delay in gastric emptying at 8 h. Active ghrelin was significantly increased on days 3 and 5 after peak (at 24 h) plasma total and desacyl ghrelin in the stress group. Number of ghrelin-immunoreactive cells and level of preproghrelin mRNA expression in the gastric body increased in parallel with plasma active ghrelin level. Pretreatment with growth hormone secretagogue receptor antagonist at 5 days partially inhibited the stress-induced acceleration of gastric emptying. Delayed gastric emptying at acute phase of continuous stress was mediated via sympathetic pathway, while acceleration at chronic phase was mediated via increased active ghrelin release from the stomach.

Prevalence of gastroesophageal reflux disease and gastroesophageal reflux disease symptoms in Japan.

Background and Aim:  Epidemiological studies have shown that 10–48% of people in developed countries have gastroesophageal reflux disease (GERD) symptoms such as heartburn and acid regurgitation. The present study aimed to examine the prevalence of GERD symptoms and GERD in Japanese subjects.

A prospective, single-blind trial comparing wireless capsule endoscopy and double-balloon enteroscopy in patients with obscure gastrointestinal bleeding

BackgroundWireless capsule endoscopy (CE) and double-balloon enteroscopy (DBE) are new methods enabling diagnostic endoscopy of the entire small intestine. However, which of the two is superior is unclear. We therefore prospectively compared the clinical efficacy of CE and DBE.MethodsWe prospectively examined 32 patients with obscure gastrointestinal bleeding. CE preceded DBE by 1–7 days, and all patients underwent DBE twice, by antegrade and retrograde approaches, to evaluate the entire small intestine. Physicians evaluating the results of CE and DBE were blind to the results of the other method. We evaluated diagnosis, diagnostic yield of the two methods, and clinical outcomes.ResultsCE revealed abnormal findings in 29 (90.6%) of 32 patients. CE definitively or probably detected the sources of bleeding in 23 (71.9%) of the 32 patients, including angioectasias (eight), erosions (seven), ulcers (five), tumor (one), and hemorrhagic polyps (two). DBE definitely or probably detected the sources of bleeding in 21 (65.6%) of the 32 patients, including angioectasias (seven), erosions (four), ulcers (five), tumor (one), hemorrhagic polyps (two) and diverticula (two). CE yielded more abnormal findings than DBE (CE 90.6%, DBE 65.6%) (P = 0.032), although there were no significant differences in diagnostic yield between the methods. We were able to perform additional treatment or biopsy with DBE in 13 patients, including coagulation therapy (ten), endoscopic mucosal resection (one), biopsy (seven), and extraction of retained CE (two).ConclusionsOur results demonstrate the superiority of CE in detecting abnormal lesions, and the superiority of DBE in endoscopic management.

Differences in clinical characteristics between patients with endoscopy-negative reflux disease and erosive esophagitis in Japan

OBJECTIVE:Helicobacter pylori infection and atrophic gastritis are inversely related to erosive esophagitis. Whether these factors affect the pathogenesis of endoscopy-negative reflux disease is not clear. We aimed to elucidate the differences in clinical characteristics between endoscopy-negative erosive disease and erosive esophagitis.METHODS:253 subjects (89 with endoscopy-negative reflux disease and 164 with erosive esophagitis) were studied. Gastric atrophy was assessed by measurement of serum pepsinogen. Logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI) of endoscopy-negative reflux disease compared with erosive esophagitis.RESULTS:Among GERD patients, female gender (OR = 2.27, 95% CI, 1.25–4.10), smoking (OR = 0.45, 95% CI, 0.22–0.91), and the presence of hiatal hernia (OR = 0.30, 95% CI, 0.17–0.56) were significantly associated with endoscopy-negative reflux disease compared with male gender, not smoking, and absence of hiatal hernia, respectively. Body mass index (BMI) was also significantly associated with a decreased OR for endoscopy-negative reflux disease. Although H. pylori infection and gastric atrophy were significantly more common in patients with endoscopy-negative reflux disease, these associations did not persist in a multiple-adjustment model. After adjustment for gender, BMI, smoking, and hiatal hernia, a decrease in serum pepsinogen I/II ratio was significantly associated with an increased OR for endoscopy-negative reflux disease (p for trend = 0.018).CONCLUSIONS:Female gender, low BMI, not smoking, absence of hiatal hernia, and severity of gastric atrophy were positively associated with endoscopy-negative reflux disease compared with erosive esophagitis among Japanese patients.

Cigarette Smoking and Alcohol Consumption Associated with Gastro-Oesophageal Reflux Disease in Japanese Men

Background: Associations between lifestyle factors and gastro-oesophageal reflux disease (GORD) have been conflicting. We aimed to examine these associations in Japanese men. Methods: We performed a cross-sectional study of Japanese male workers who visit a clinic for a routine health check-up and asked them to fill out a self-report questionnaire. Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for GORD, defined as heartburn and/or acid regurgitation at least twice weekly. Results: Of the 4095 eligible subjects, 276 (6.7%) were diagnosed as having GORD. Current smoking was significantly associated with GORD compared with non-smoking (OR r = r 1.35, 95% CI, 1.01-1.82). Moderate drinking (16-37 r mL/day) and heavy drinking ( S 38 r mL/day) were also associated with GORD, while age and body mass index were not. After adjustment for age, daily alcohol consumption and body mass index, an increase in number of pack-years of cigarette smoking was significantly associated with an increased OR of GORD ( P for trend r = r 0.034), and the OR for persons whose number of pack-years of cigarette smoking was more than 20.1 was 1.45 (CI 1.04-2.04) compared with non-smokers. Conclusion: Cigarette smoking and alcohol consumption are associated with an increased odds ratio for GORD in Japanese men.BACKGROUND Associations between lifestyle factors and gastro-oesophageal reflux disease (GORD) have been conflicting. We aimed to examine these associations in Japanese men. METHODS We performed a cross-sectional study of Japanese male workers who visit a clinic for a routine health check-up and asked them to fill out a self-report questionnaire. Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for GORD, defined as heartburn and/or acid regurgitation at least twice weekly. RESULTS Of the 4095 eligible subjects, 276 (6.7%) were diagnosed as having GORD. Current smoking was significantly associated with CORD compared with non-smoking (OR = 1.35, 95% CI, 1.01-1.82). Moderate drinking (16-37 mL/day) and heavy drinking (> or = 38 mL/day) were also associated with GORD, while age and body mass index were not. After adjustment for age, daily alcohol consumption and body mass index, an increase in number of pack-years of cigarette smoking was significantly associated with an increased OR of GORD (P for trend = 0.034), and the OR for persons whose number of pack-years of cigarette smoking was more than 20.1 was 1.45 (CI 1.04-2.04) compared with non-smokers. CONCLUSION Cigarette smoking and alcohol consumption are associated with an increased odds ratio for GORD in Japanese men.

Covered self-expandable metal stents with an anti-migration system improve patency duration without increased complications compared with uncovered stents for distal biliary obstruction caused by pancreatic carcinoma: a randomized multicenter trial.

OBJECTIVES:The requirements of biliary stents used in the palliation of malignant biliary obstruction are a long duration of patency and minimal adverse effects. Covered self-expandable metal stents (SEMSs) have been shown to prevent tumor ingrowth, which is the most frequent complication of uncovered SEMSs. However, because they are prone to migration, the superiority of covered SEMS has yet to be convincingly demonstrated. The aim of this study was to evaluate the superiority of covered over uncovered SEMSs in the palliation of distal biliary obstruction due to unresectable pancreatic carcinoma, using both stent types with relatively low axial force and uncovered flared ends to prevent their migration.METHODS:From April 2009 to December 2010, 120 patients who were admitted to 22 tertiary-care centers because of distal biliary obstruction from unresectable pancreatic carcinomas were enrolled in this prospective randomized multicenter study. Patients were randomly assigned to receive a covered or uncovered SEMS deployed at the site of the biliary stricture during endoscopic retrograde cholangiopancreatography. Stent patency time, patient survival time, patient survival time without stent dysfunction (time to stent dysfunction or patient death), cause of stent dysfunction (ingrowth, overgrowth, migration, or sludge formation), and serious adverse events were compared between covered and uncovered SEMS groups.RESULTS:Patient survival time in the two groups did not significantly differ (median: 285 and 223 days, respectively; P=0.68). Patient survival time without stent dysfunction was significantly longer in the covered than in the uncovered SEMS group (median: 187 vs. 132 days; P=0.043). Stent patency was also significantly longer in the covered than in the uncovered SEMS group (mean±s.d.: 219.3±159.1 vs. 166.9±124.9 days; P=0.047). Reintervention for stent dysfunction was performed in 14 of 60 patients with covered SEMSs (23%) and in 22 of 60 patients with uncovered SEMSs (37%; P=0.08). Stent dysfunction was caused by tumor ingrowth, tumor overgrowth, and sludge formation in 0 (0%), 3 (5%), and 11 (18%) patients in the covered SEMSs group, and in 15 (25%), 2 (3%), and 6 (10%) patients in the uncovered SEMSs group, respectively. Stent migration was not observed in either group. Rates of tumor overgrowth and sludge formation did not significantly differ between the two groups, whereas the rate of tumor ingrowth was significantly lower in the covered than in the uncovered SEMS group (P<0.01). Acute pancreatitis occurred in only one patient in the covered SEMS group. Acute cholecystitis occurred in one patient in the covered SEMS group and in two patients in the uncovered SEMS group. There was no significant difference between the two groups in the incidence of serious adverse events.CONCLUSIONS:By preventing tumor ingrowth and migration, covered SEMSs with an anti-migration system had a longer duration of patency than uncovered SEMSs, which recommends their use in the palliative treatment of patients with biliary obstruction due to pancreatic carcinomas.

Association Between Dinner-to-Bed Time and Gastro-Esophageal Reflux Disease

OBJECTIVE:It is generally recommended that patients with gastro-esophageal reflux disease (GERD) refrain from eating within 3 h of going to sleep. In addition to a remarkable lack of supporting clinical evidence, whether GERD patients have shorter dinner-to-bed time is unknown. This study was designed to determine a possible association between dinner-to-bed time and GERD, compared with healthy adults.METHODS:In a matched case-control study, we enrolled 147 GERD patients, and age- and sex-matched 294 controls without GERD symptoms such as heartburn and acid regurgitation during the previous year. Dinner-to-bed time, defined as the time intervals until going to bed after finishing eating dinner, was examined by a self-report questionnaire. Logistic regression was used to calculate odds ratio (OR) and 95% confidence intervals (CI) for GERD.RESULTS:After adjustment for smoking habits, drinking habits, and body mass index, shorter dinner-to-bed time was significantly associated with an increased OR of GERD (p < 0.0001) and the OR for patients whose dinner-to-bed time was less than 3 h was 7.45 (95% CI 3.38–16.4) compared with patients whose dinner-to-bed time was 4 h or more. These observations were consistent in both patients with nonerosive GERD and erosive esophagitis, and there was no significant difference in dinner-to-bed time intervals between nonerosive GERD and erosive esophagitis.CONCLUSION:In this matched case-control study, shorter dinner-to-bed time was significantly associated with an increased OR for GERD.

Increased expression of cytokines and adhesion molecules in rat chronic esophagitis.

Background/Aims: Cytokines and adhesion molecules regulate many inflammatory processes in several gastrointestinal diseases. The dynamics of cytokines and adhesion molecules in reflux esophagitis are unknown in detail. We examined the expression and dynamics of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), MIP-2, GRO/cytokine-induced neutrophil chemoattractant-2α (CINC-2α), intercellular adhesion molecule-1 (ICAM-1), leukocyte function-associated antigen 1 (LFA-1; CD11a/CD18), and Mac-1 (CD11b/CD18) in rat chronic reflux esophagitis. Methods: Chronic acid reflux esophagitis was induced in Wistar rats by ligating the transitional region between the forestomach and the glandular portion and wrapping the duodenum near the pylorus with a small piece of an 18-Fr Nélaton catheter. Rats were killed 3 or 21 days after operation. The levels of mRNA expression of cytokines and ICAM-1 were determined by real-time quantitative RT-PCR. Localization of adhesion molecules and cytokines was investigated by immunohistochemical staining, and numbers of LFA-1- or Mac-1-positive cells were quantified. Results: IL-1β, TNF-α, MCP-1, MIP-1α, MIP-2, CINC-2α, and ICAM-1 mRNA expression was significantly increased in esophageal lesions compared with normal esophagus. There were few these cytokines- or adhesion molecule-positive cells in normal esophagus. In regions of esophagitis, numerous inflammatory leukocytes in lamina propria and the submucosal layer exhibited positive reactions for these cytokines and endothelial cells were intensely stained for ICAM-1. Numbers of LFA-1- and Mac-1-positive cells were significantly increased in rat chronic esophagitis. Treatment with rabeprazole almost completely inhibited development of chronic acid reflux esophagitis and significantly decreased expression of cytokines and ICAM-1 mRNA in esophageal tissue compared with control. Conclusion: Cytokines and adhesion molecules play important roles in the pathogenesis of chronic reflux esophagitis in this rat model.