Tetsuo Arakawa

Osaka Medical College, Takatuki, Ōsaka, Japan

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Publications (656)2878.73 Total impact

  • N Iwakura, Y Fujiwara, T Arakawa
    Alimentary Pharmacology & Therapeutics 05/2015; 41(10):1024-5. DOI:10.1111/apt.13180 · 4.55 Impact Factor
  • PLoS ONE 04/2015; 10(4):e0122330. DOI:10.1371/journal.pone.0122330 · 3.53 Impact Factor
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    ABSTRACT: Barrett's esophagus (BE) is characterized by a distinct Th2-predominant cytokine profile. However, antigens that shift the immune response toward the Th2 profile are unknown. We examined the effects of rebamipide on the esophageal microbiome and BE development in a rat model. BE was induced by esophagojejunostomy in 8-week-old male Wistar rats. Rats were divided into control and rebamipide-treated group receiving either a normal or a 0.225 % rebamipide-containing diet, respectively, and killed 8, 16, 24, and 32 weeks after the operation. PCR-amplified 16S rDNAs extracted from esophageal samples were examined by terminal-restriction fragment length polymorphism (T-RFLP) analysis to assess microbiome composition. The dynamics of four bacterial genera (Lactobacillus, Clostridium, Streptococcus, and Enterococcus) were analyzed by real-time PCR. The incidences of BE in the control and rebamipide group at 24 and 32 weeks were 80 and 100, and 20 and 33 %, respectively. T-RFLP analysis of normal esophagus revealed that the proportion of Clostridium was 8.3 %, while that of Lactobacillales was 71.8 %. The proportions of Clostridium increased and that of Lactobacillales decreased at 8 weeks in both groups. Such changes were consistently observed in the control but not in the rebamipide group. Clostridium and Lactobacillus expression was lower and higher, respectively, in the rebamipide group than in the control group. Rebamipide reduced BE development and altered the esophageal microbiome composition, which might play a role in BE development.
    Digestive Diseases and Sciences 04/2015; DOI:10.1007/s10620-015-3662-4 · 2.55 Impact Factor
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    ABSTRACT: Mucosal healing is now the ideal treatment goal for patients with Crohn's disease (CD) and endoscopy is suitable for both visualizing the intestinal mucosa and optimizing treatment according to the objective endoscopic findings; however, passing through strictures with a conventional colonoscope is sometimes difficult. An ultrathin colonoscope (outer diameter 9.2 mm) has been developed for superior insertion performance. CD patients with strictures that could not be passed with a conventional colonoscope were eligible for entry into the study. We investigated the rate of passage of the ultrathin colonoscope beyond strictures. We also investigated the clinical impact of optimizing the treatment strategy according to the endoscopic findings beyond the stricture. Of 49 patients, the ultrathin colonoscope could pass the stricture in 59.2% (29/49). The main reason for failure compared with the "pass" group was anal stricture (P = 0.005). When including finger bougie for severe anal stricture, passage of the stricture was achieved in 83.7% (41/49) of cases and the oral mucosa beyond the stricture was visualized. In these cases, 56.1% (23/41) had treatment efficacy confirmed and 43.9% (18/41) required a change of treatment. Importantly, half (9/18) of them were in clinical remission. There were no complications of the study. The ultrathin colonoscope could provide optimized treatment based on objective findings of the activity of the oral-side mucosa in CD patients complicated with stricture. Selection of the appropriate endoscope to visualize the responsible lesion is essential to optimize the treatment strategy in each case of CD. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.
    Journal of Gastroenterology and Hepatology 03/2015; 30 Suppl 1:66-70. DOI:10.1111/jgh.12739 · 3.63 Impact Factor
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    ABSTRACT: Approximately more than half of patients with non-erosive reflux disease (NERD) do not respond to proton pump inhibitor (PPI) therapy. Although NERD is a heterogeneous entity, previous study showed that multichannel intraluminal impedance (MII)-pH monitoring could distinguish reflux-related disease from PPI-refractory NERD. The aim of this study was to examine the usefulness of baseline impedance in PPI-refractory NERD patients. We used MII-pH monitoring to analyze reflux parameters, symptom index (SI), and baseline impedance in 37 PPI-refractory NERD patients on PPI. Reflux was divided into acid (nadir pH ≤ 4) and non-acid (nadir pH > 4). Subjects were classified as having reflux-related disease based on abnormal reflux parameters or positive SI (≥ 50%), or non-reflux-related disease, including functional heartburn, based on negative SI with normal reflux parameters. A total of 26 of the 37 subjects were diagnosed with reflux-related disease, including eight with acid-reflux type and 18 with non-acid-reflux type, and nine with functional heartburn and two with pseudohypersalivation. There were no significant differences in the clinical characteristics of the acid-reflux type, non-acid-reflux type, and functional heartburn groups. The baseline impedance value in the acid-reflux type (1245 ± 392 Ω) was significantly lower than that in the non-acid-reflux type (2824 ± 1160 Ω) and functional heartburn (3546 ± 1353 Ω) groups. Baseline impedance values inversely correlated with reflux percent time, acid-reflux time, and acid exposure time. Among patients with PPI-refractory NERD, acid-reflux type was associated with lower baseline impedance compared with non-acid-reflux type and functional heartburn. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.
    Journal of Gastroenterology and Hepatology 03/2015; 30 Suppl 1:36-40. DOI:10.1111/jgh.12743 · 3.63 Impact Factor
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    ABSTRACT: The features of proton pump inhibitor-responsive oesophageal eosinophilia (PPI-REE) are similar to those of eosinophilic oesophagitis (EoE), but PPI-REE demonstrates symptomatic and histological responses to PPI therapy. Several studies have shown that basophils play a crucial role in the pathogenesis of allergic diseases. To identify and compare basophil infiltration in the oesophageal epithelium in patients with EoE, PPI-REE, gastroesophageal reflux disease (GERD) and normal oesophagus (controls). Biopsy specimens from 43 patients, including 12 with EoE, 11 with PPI-REE, 10 with GERD and 10 normal oesophagus, were analysed. Immunohistochemistry was performed to quantify the number of basophils and mast cells in the oesophageal epithelium. Double immunofluorescence staining for thymic stromal lymphopoietin (TSLP) and basophils was performed. Patients with EoE were treated with swallowed fluticasone. There were no differences in clinical, endoscopic or histological features between patients with EoE and PPI-REE. There were more basophils and mast cells in patients with EoE and PPI-REE than in patients with GERD and control subjects. Basophil infiltration of the oesophageal epithelium in patients with EoE was higher than that in patients with PPI-REE (3.6 ± 2.8 per high power field vs. 1.2 ± 0.9 per high power field respectively; P = 0.02); however, there was no significant difference in mast cell infiltration between the two groups. TSLP was highly expressed in the oesophageal epithelium in areas infiltrated by basophils. Steroid therapy significantly decreased intraepithelial basophils in patients with EoE. Basophils may play an important role in the pathogenesis of eosinophilic oesophagitis. © 2015 John Wiley & Sons Ltd.
    Alimentary Pharmacology & Therapeutics 02/2015; 41(8). DOI:10.1111/apt.13141 · 4.55 Impact Factor
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    ABSTRACT: To determine the efficacy and safety of rapid induction therapy with oral tacrolimus without a meal in steroid-refractory ulcerative colitis (UC) patients. This was a prospective, multicenter, observational study. Between May 2010 and August 2012, 49 steroid-refractory UC patients (55 flare-ups) were consecutively enrolled. All patients were treated with oral tacrolimus without a meal at an initial dose of 0.1 mg/kg per day. The dose was adjusted to maintain trough whole-blood levels of 10-15 ng/mL for the first 2 wk. Induction of remission at 2 and 4 wk after tacrolimus treatment initiation was evaluated using Lichtiger's clinical activity index (CAI). The mean CAI was 12.6 ± 3.6 at onset. Within the first 7 d, 93.5% of patients maintained high trough levels (10-15 ng/mL). The CAI significantly decreased beginning 2 d after treatment initiation. At 2 wk, 73.1% of patients experienced clinical responses. After tacrolimus initiation, 31.4% and 75.6% of patients achieved clinical remission at 2 and 4 wk, respectively. Treatment was well tolerated. Rapid induction therapy with oral tacrolimus shortened the time to achievement of appropriate trough levels and demonstrated a high remission rate 28 d after treatment initiation. Rapid induction therapy with oral tacrolimus appears to be a useful therapy for the treatment of refractory UC.
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    ABSTRACT: This research was conducted is to assess the effect of booster doses of the trivalent influenza vaccine in adult inflammatory bowel disease (IBD) patients treated with anti-tumor necrosis factor (TNF)-α agents and/or immunomodulators. Adult IBD patients and healthy individuals were subcutaneously administered the trivalent influenza vaccine. They were randomized into two groups: the single vaccination group and the two vaccination booster group. Blood samples were collected, and the antibody titers against each influenza strain were determined by hemagglutination inhibition at 3 different time points (pre-vaccination, 3 weeks post-vaccination, and after the flu season) in the single vaccination group and at 4 time points (pre-vaccination, 3 weeks post-first vaccination, 3 weeks post-second vaccination, and after the flu season) in the booster vaccination group. Seventy-eight IBD patients and 11 healthy controls were randomized into the single vaccination group and the booster vaccination group. Twenty-nine patients received immunomodulators; 21 received anti-TNF-α agents; and 28 received a combination of both. No significant differences were observed in the evaluated immune response parameters between 3 weeks post-vaccination in the single vaccination group and 3 weeks post-second vaccination in the booster vaccination group (geometric mean titers: H1N1, p = 0.09; H3N2: p = 0.99; B: p = 0.94). A higher pre-vaccination titer was significantly associated with sufficient seroprotection rate after vaccination for the H1N1 strain (odds ratio 11.93, p = 0.03). The second booster of trivalent influenza vaccination did not improve the immune response in adult IBD patients who were treated with immunomodulators and/or anti-TNF-α agents.
    Journal of Gastroenterology 02/2015; DOI:10.1007/s00535-015-1042-7 · 4.02 Impact Factor
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    ABSTRACT: Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Although the mechanisms of this association have not been fully elucidated, nighttime reflux plays a central role. However, the detailed characteristics of nighttime reflux occurring during sleep are unknown. The aim of the present study was to examine the characteristics and prevalence of nighttime reflux in the natural sleep environment of GERD patients. Seventeen patients experiencing daily moderate-to-severe heartburn and/or regurgitation were studied using multichannel intraluminal impedance pH monitoring and electroencephalography off-proton pump inhibitor treatment. Nighttime reflux was divided based on reflux type (liquid or gas), acidity (acidic, weakly acidic, or alkaline) and extent (distal only or proximal migration) according to the standard criteria. Nighttime phases were divided as follows: recumbent-awake before falling asleep, nonrapid eye movement, rapid eye movement, awakening from sleep, and post-awakening in the morning. Among 184 nighttime refluxes, 43 (23%) occurred during recumbent-awake before falling asleep, 28 (15%) during nonrapid eye movement, 14 (8%) during rapid eye movement, 86 (46%) during awakening from sleep, and 13 (7%) during post-awakening in the morning. Liquid reflux was more common in awakening during sleep (92%), nonrapid eye movement (100%), and rapid eye movement (100%) compared with awakening before falling asleep (68%). The prevalence of proximal migration was significantly lower in nonrapid eye movement and rapid eye movement than in the other phases. There were no differences in acidity and bolus clearance time among the phases. Thirteen (65%) of 20 events with GERD symptoms had nighttime reflux, suggesting that only 7.1% (13 of 184) of nighttime refluxes were symptomatic. Nighttime reflux was observed in 48 (11%) of 425 awakening episodes during sleep. Different reflux patterns at each phase during nighttime might explain the pathogenesis of GERD and its related sleep disturbances. © 2015 International Society for Diseases of the Esophagus.
    Diseases of the Esophagus 01/2015; 146(5). DOI:10.1111/dote.12324 · 2.06 Impact Factor
  • The American Journal of Gastroenterology 01/2015; 110(1):194-5. DOI:10.1038/ajg.2014.375 · 9.21 Impact Factor
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    ABSTRACT: Sociocultural factors are important because their different effects on the features of irritable bowel syndrome (IBS) between countries will provide clues towards solving this problem. The aims of this study were to depict the clinical realities of IBS in East Asian countries and test the hypothesis that the diagnosis and treatment of IBS differ between countries. Study participants were 251 physicians involved in the clinical practice of IBS at major institutions in Japan, South Korea, China, the Philippines, Indonesia and Singapore. The questionnaire contained 45 questions focused on the clinical practice of IBS. Subjects in Japan, South Korea, China, Indonesia, the Philippines and Singapore accounted for 55.4, 17.9, 8.8, 8.0, 6.4 and 3.6% of the study cohort, respectively. Amongst East Asian physicians, the most important symptom was considered to be abdominal pain by 33.4%, whilst 24.3% regarded alternating diarrhea and constipation to be the most important symptoms. Total colonoscopy and histopathology use showed no difference among countries. Prescriptions given for mild (p < 0.0001), moderate (p < 0.0001), severe (p < 0.0001), intractable (p = 0.002), diarrheal (p < 0.0001) and constipating (p < 0.0001) patients with IBS significantly differed between the countries. Except for several minor points, IBS specialists showed no significant difference in their diagnosis and treatment of IBS when compared to nonspecialists. This survey provided data on the clinical treatment of IBS among East Asian countries. The results supported the hypothesis that the diagnosis and treatment of IBS differs between countries. © 2015 S. Karger AG, Basel.
    Digestion 01/2015; 91(1):99-109. DOI:10.1159/000369078 · 2.03 Impact Factor
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    Kazunari Tominaga, Tetsuo Arakawa
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    ABSTRACT: Gastroenterological reflux disease and functional dyspepsia are usually treatable using Western medical practices. Nonetheless, some cases present with intractable symptoms that are not amenable to these therapies. Treatment with kampo, a traditional Japanese medicine, recently has been proposed as an alternative therapy for use in combination with the Western practices. In general, traditional Japanese medicines have been used empirically for intractable symptoms correctively designated as "general malaises." Accumulating lines of evidence, including basic and clinical researches, have demonstrate detailed mechanisms where traditional Japanese medicines exert pharmacological action to improve symptoms. Therefore, traditional Japanese medicines have been gaining use by various medical doctors as the specific modes of pharmacological action are recognized. This review covers both the pharmacological functions and the clinical efficacies of rikkunshito for use in treating disorders of the gastrointestinal tract.
    Frontiers in Pharmacology 01/2015; 6:7. DOI:10.3389/fphar.2015.00007
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    ABSTRACT: Objective Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Although treatment with proton pump inhibitors (PPIs) helps to improve GERD symptoms and subjective sleep parameters, the effects of PPI therapy on objective sleep parameters are conflicting. The aim of this study was to examine the effects of esomeprazole treatment on GERD symptoms and sleep parameters assessed using actigraphs and questionnaires. Methods Thirteen patients with GERD received 20 mg of esomeprazole once daily for two weeks. The patients wore actigraphs from three days before the initiation of PPI treatment to the end of therapy. They were also asked to answer the following self-reported questionnaires: Frequency Scale for the Symptoms of GERD (FSSG), Pittsburg Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS). Objective sleep parameters were evaluated using actigraphy. Results Treatment with esomeprazole significantly decreased the total FSSG score, including the scores for reflux and dysmotility, as well as the ESS score, although it had no effect on the PSQI score. After the second week of treatment, esomeprazole significantly decreased the wake time (from 47.5±39.6 min to 36.0±27.1 min) and sleep latency period (from 19.5±19.8 min to 9.9±10.2 min) and increased the percentage of sleep time (from 89.1±8.8% to 91.9±6.3%); however, improvements were not noted in all objective parameters. Conclusion Esomeprazole treatment significantly improves various objective sleep parameters in Japanese patients with GERD. Further placebo-controlled randomized trials are needed to obtain detailed results.
    Internal Medicine 01/2015; 54(6):559-65. DOI:10.2169/internalmedicine.54.3718 · 0.97 Impact Factor
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    ABSTRACT: Loss of response (LOR) to infliximab (IFX) has become an important clinical issue for patients with Crohn's disease (CD). Elemental diet (ED) therapy has been established as a nutrition therapy for CD in Japan. ED therapy can reduce antigen exposure and is both efficacious and safe. To evaluate the efficacy of concomitant ED therapy in maintaining regular IFX infusion in patients with CD. We retrospectively studied 125 patients with luminal CD treated with scheduled IFX maintenance therapy with a regular dosage. Patients were classified into two groups: the ED group with intake ≥900 kcal/day and the non-ED group with intake <900 kcal/day. When clinical LOR was detected on the basis of disease activity, laboratory parameters, or endoscopic findings, the physician discontinued the infusion schedule of IFX. We investigated the efficacy of ED therapy for sustaining the scheduled IFX maintenance therapy. With the exception of ED intake, no significant differences were found in patient characteristics between the ED group and the non-ED group. The ED group was significantly superior to the non-ED group (p = 0.049) in sustaining scheduled IFX maintenance therapy. It is well known that ED therapy is more effective for small bowel lesions than colonic lesions in CD. When comparing ileitis and ileocolitis patients with CD, the ED group was significantly superior to the non-ED group (p = 0.015). Concomitant ED therapy is effective in maintaining scheduled IFX maintenance therapy in patients with luminal CD in order to prevent LOR.
    Digestive Diseases and Sciences 12/2014; DOI:10.1007/s10620-014-3493-8 · 2.55 Impact Factor
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    ABSTRACT: Background and aim The clinical significance of minimal changes in non-erosive reflux disease (NERD) is controversial. Multichannel intraluminal impedance–pH (MII-pH) monitoring enables classification of NERD. The aim of this study was to evaluate associations between endoscopic findings and functional assessment via MII-pH monitoring in patients with proton-pump inhibitor (PPI)-refractory NERD. Methods Thirty-four PPI-refractory NERD patients were retrospectively analyzed. On the basis of the MII-pH monitoring results, cases were classified as acid reflux, non-acid reflux, and functional heartburn. Minimal changes such as white turbidity, erythema, loss of fine vascular network pattern at the esophagogastric junction, hyperplasia of vascular network at the middle esophagus, hernia, flap valve grade, and atrophic gastritis were evaluated endoscopically. Results Among 34 patients, 8 were categorized with acid reflux, 17 with non-acid reflux, and 9 with functional heartburn. There were no differences in the prevalence of minimal changes among the groups, but all cases showing white turbidity of the entire esophageal circumference involved non-acid reflux. The prevalence of hiatal hernia and abnormal flap valve did not differ among the three groups, but the presence of atrophic gastritis was significantly more common in patients with functional heartburn than in those with acid and non-acid reflux. The prevalence of hyperplasia of the vascular network at the middle esophagus was significantly higher in patients with proximal migration than in those without. Conclusion There are associations between endoscopic findings and functional assessment via MII-pH monitoring. Future studies should pay more attention to the endoscopic findings at the middle esophagus.
    Esophagus 12/2014; DOI:10.1007/s10388-014-0480-2 · 0.74 Impact Factor
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    ABSTRACT: New strategies for the care of irritable bowel syndrome (IBS) are developing and several novel treatments have been globally produced. New methods of care should be customized geographically because each country has a specific medical system, life style, eating habit, gut microbiota, genes and so on. Several clinical guidelines for IBS have been proposed and the Japanese Society of Gastroenterology (JSGE) subsequently developed evidence-based clinical practice guidelines for IBS. Sixty-two clinical questions (CQs) comprising 1 definition, 6 epidemiology, 6 pathophysiology, 10 diagnosis, 30 treatment, 4 prognosis, and 5 complications were proposed and statements were made to answer to CQs. A diagnosis algorithm and a three-step treatment was provided for patients with chronic abdominal pain or abdominal discomfort and/or abnormal bowel movement. If more than one alarm symptom/sign, risk factor and/or routine examination is positive, colonoscopy is indicated. If all of them, or the subsequent colonoscopy, are/is negative, Rome III or compatible criteria is applied. After IBS diagnosis, step 1 therapy consisting of diet therapy, behavioral modification and gut-targeted pharmacotherapy is indicated for four weeks. Non-responders to step 1 therapy proceed to the second step that includes psychopharmacological agents and simple psychotherapy for four weeks. In the third step, for patients non-responsive to step 2 therapy, a combination of gut-targeted pharmacotherapy, psychopharmacological treatments and/or specific psychotherapy is/are indicated. Clinical guidelines and consensus for IBS treatment in Japan are well suited for Japanese IBS patients; as such, they may provide useful insight for IBS treatment in other countries around the world.
    Journal of Gastroenterology 12/2014; 50(1). DOI:10.1007/s00535-014-1017-0 · 4.02 Impact Factor
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    ABSTRACT: Glucagon-like peptide (GLP)-2, secreted by L cells in the small intestine, has anti-inflammatory effects in the gastrointestinal tract. A GLP-2 analogue has been an effective treatment for Crohn disease (CD). G-protein-coupled receptor (GPR) 40 and GPR120 are probably involved in GLP-2 production, the mechanisms of which remain unclear. In our experiments, normal ileal mucosa expressed GPR40, but rarely expressed GPR120. However, both GPRs were overexpressed in the L cells of the inflamed ileal mucosa of CD patients. Mucosal inflammation induced the overexpression of GPR40, GPR120, and several inflammatory cytokines, with correlations between ileal concentrations of tumor necrosis factor (TNF)-α and GPR expression levels; however, inflammation did not induce the expression of proglucagon, a precursor of GLP-2 in CD patients. In rat L cells and GLUTag cells, TNF-α treatment increased GPR120 mRNA expression without affecting GPR40 mRNA expression. Dual agonists of GPR40 and GPR120, GW9508 and linoleic acid, respectively, increased GLP-2 production from L cells, but these agonists decreased it in the presence of TNF-α. The GPR40 antagonist, GW1100, inhibited the GW9508-induced increase in GLP-2 production, and silencing GPR120 resulted in further elevation of GLP-2 production. Thus, GPR120-dependent signaling inhibited the stimulatory effects of GPR40 on GLP-2 expression, and TNF-α treatment decreased GLP-2 expression by up-regulating GPR120 expression in L cells. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
    American Journal Of Pathology 11/2014; 185(1). DOI:10.1016/j.ajpath.2014.09.010 · 4.60 Impact Factor
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    ABSTRACT: Comparisons between the acid inhibitory effects of rabeprazole and esomeprazole after single oral administration with standard doses have not been previously presented. We examined intra-gastric pH after oral administrations of these two proton pump inhibitors using 24-h pH monitoring. Fifty-four normal volunteers not infected by Helicobacter pylori were investigated. Using a cross-over design, we administered 10 mg of rabeprazole or 20 mg of esomeprazole in 27 at 30 min after supper and in the remaining 27 subjects at 15 min before supper, and performed 24-h pH monitoring. Intra-gastric pH data were nearly identical when the proton pump inhibitors were taken after meals. Even if the data were compared in different CYP2C19 genotypes, rabeprazole and esomeprazole did not show the difference. In poor metabolizer, both of the drugs showed stronger acid inhibition. When taken before meals, intra-gastric pH after esomeprazole administration was slightly but not significantly higher than that observed after rabeprazole administration not only in daytime but also in nighttime period. In conclusion, rabeprazole and esomeprazole were similarly effective when administered after a meal.
    Journal of Clinical Biochemistry and Nutrition 11/2014; 55(3):178-83. DOI:10.3164/jcbn.14-41 · 2.29 Impact Factor
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    ABSTRACT: We report that odd-skipped related 1 (OSR1) gene encoding a zinc-finger transcription factor was preferentially methylated in gastric cancer by genome-wide methylation screening. OSR1 expression was frequently silenced or downregulated in gastric cancer cell lines. OSR1 expression was also significantly downregulated at both mRNA and protein levels in primary gastric cancer tissues compared with adjacent normal tissues. The silencing or downregulation of OSR1 was closely associated with promoter hypermethylation. Overexpression of OSR1 significantly inhibited cell growth, arrested cell cycle, and induced apoptosis in gastric cancer cell lines AGS, MKN28, and MGC803. Conversely, knockdown of OSR1 by OSR1-short hairpin RNA significantly enhanced cell growth, promoted cell cycle, and inhibited apoptosis in normal gastric epithelial cell line GES1. The dual-luciferase reporter assay revealed that OSR1 activated the p53 transcription and repressed the T-cell factor (TCF)/lymphoid enhancer factor (LEF). Complementary DNA expression array and Western blotting showed that OSR1 increased the expression of nuclear p53, p21, Fas, and death receptor-5 and suppressed the expression of cyclin D1 and cyclin-dependent kinase 4 in p53 signaling pathway. In addition, OSR1 suppressed the expression of cytoplasmic β-catenin, TCF-1, and LEF1 in Wnt/β-catenin signaling pathway. OSR1 methylation was detected in 51.8% of primary gastric cancer patients (85 of 164) by bisulfite genomic sequencing. Multivariate Cox regression analysis showed that OSR1 methylation was an independent predictor of poor survival. Kaplan-Meier survival curves revealed that OSR1 methylation was associated with shortened survival in TNM stages I-III patients. In conclusion, OSR1 acts as a functional tumor suppressor through the transcriptional activation of p53 and repression of TCF/LEF in gastric cancer. Detection of OSR1 methylation may serve as a potential biomarker of early stage of gastric cancer.
    The Journal of Pathology 11/2014; 234(3). DOI:10.1002/path.4391 · 7.33 Impact Factor
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    ABSTRACT: Toll-like receptor 2 (TLR2) recognizes conserved molecular patterns associated with both gram-negative and gram-positive bacteria, and detects some endogenous ligands. Previous studies demonstrated that in ischemia-reperfusion (I/R) injury of the small intestine, the TLR2-dependent signaling exerted preventive effects on the damage in young mice, but did not have a significant effect in neonatal mice. We investigated the role of TLR2 in adult ischemia-reperfusion injury in the small intestine. Wild-type and TLR2 knockout mice at 16 weeks of age were subjected to intestinal I/R injury. Some wild-type mice received anti-Ly-6G antibodies to deplete circulating neutrophils. In wild-type mice, I/R induced severe small intestinal injury characterized by infiltration by inflammatory cells, disruption of the mucosal epithelium, and mucosal bleeding. Compared to wild-type mice, TLR2 knockout mice exhibited less severe mucosal injury induced by I/R, with a 35%, 33%, and 43% reduction in histological grading score and luminal concentration of hemoglobin, and the numbers of apoptotic epithelial cells, respectively. The I/R increased the activity of myeloperoxidase (MPO), a marker of neutrophil infiltration, and the levels of mRNA expression of tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and cyclooxygenase-2 (COX-2) in the small intestine of the wild-type mice by 3.3-, 3.2-, and 13.0-fold, respectively. TLR2 deficiency significantly inhibited the I/R-induced increase in MPO activity and the expression of mRNAs for TNF-α and ICAM-1, but did not affect the expression of COX-2 mRNA. I/R also enhanced TLR2 mRNA expression by 2.9-fold. TLR2 proteins were found to be expressed in the epithelial cells, inflammatory cells, and endothelial cells. Neutrophil depletion prevented intestinal I/R injury in wild-type mice. These findings suggest that TLR2 may mediate I/R injury of the small intestine in adult mice via induction of inflammatory mediators such as TNF-α and ICAM-1.
    PLoS ONE 10/2014; 9(10):e110441. DOI:10.1371/journal.pone.0110441 · 3.53 Impact Factor

Publication Stats

5k Citations
2,878.73 Total Impact Points

Institutions

  • 2008–2015
    • Osaka Medical College
      • Second Department of Internal Medicine
      Takatuki, Ōsaka, Japan
  • 1989–2015
    • Osaka City University
      • • Department of Gastroenterology
      • • Graduate School of Medicine
      • • Third Department of Internal Medicine
      Ōsaka, Ōsaka, Japan
  • 2007
    • Sonoda Women's University
      Amagasaki, Hyōgo, Japan
    • Osaka Prefectural Medical Center for Respiratory and Allergic Diseases
      Ōsaka, Ōsaka, Japan
  • 2004
    • Teikyo University
      Edo, Tōkyō, Japan
  • 2003
    • Aichi Medical University
      • Department of Gastroenterology
      Koromo, Aichi, Japan
  • 2001
    • Kitasato University
      • Medical Department
      Edo, Tōkyō, Japan
  • 1998–2001
    • Osaka City General Hospital
      Ōsaka, Ōsaka, Japan
  • 2000
    • California State University, Long Beach
      Long Beach, California, United States
  • 1999
    • Tsumura & Co.
      Edo, Tōkyō, Japan
    • Otsuka Pharmaceutical Group
      Edo, Tōkyō, Japan
  • 1993–1998
    • University of California, Irvine
      Irvine, California, United States
  • 1996
    • Osaka University
      • Department of Internal Medicine
      Suika, Ōsaka, Japan
  • 1990–1996
    • Long Beach Memorial Medical Center
      Long Beach, California, United States
    • Zeria Pharmaceutical Co.
      Edo, Tōkyō, Japan
  • 1992
    • Tohoku University
      Miyagi, Japan
    • The University of Tokyo
      Tōkyō, Japan