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potentially increase the yield of diagnosing reflux in NERD patients. This technique can detect subtle mucosal changes which were not seen with conventional endoscopy. The abnormal NBI findings in NERD patients especially those with hypersensitive esophagus had lend support to Rome III concept that this phenotype is indeed part of NERD.

Background: The association between type 2 diabetes mellitus and intestinal neoplasia has been shown epidemiologically. It is also well known that a high fat diet (HFD) promotes insulin resistance which is a risk factor for intestinal neoplasia. Dipeptidyl peptidase-4 (DPP4) inhibitors are used clinically in diabetes therapy to prolong the effects of glucagon-like peptide-1 (GLP-1). However, because another derivative from proglucagon, the intestinotrophic hormone GLP-2, is also a substrate for DPP-4, DPP-4 inhibitionmay enhance intestinal carcinogenesis by increasing endogenous active GLP-2. We therefore conducted this study to investigate the influence of a DPP-4 inhibitor on intestinal tumorigenesis in Apc Min/+ mice fed a HFD. Material and Methods: Segmental differences in DPP-4, 8, and 9 mRNA expression and DPP enzyme activity were determined in the mice. The DPP-4 inhibitor, sitagliptin (0.3, 1 or 3 mg/kg), was given orally. Mucosal DPP activity and GLP concentrations were measured 24 hr after administration. Six-week-old male Apc Min/+ mice were randomized to either a HFD (60 kcal fat) group or control diet (10 kcal fat) group for 9 weeks. Each group was divided into two groups, which were either treated or not treated with sitagliptin (3 mg/kg/day, i.g.). The mice were sacrificed 9 weeks after the initiation of treatment. The small intestine was coiled up into a Swiss roll, which was used to determine the number, size, and localization of tumors. Results: DPP-4 mRNA was expressed at high levels in the jejunum and ileum, with high DPP-4 activity also being detected. Oral sitagliptin caused a dose-dependent suppression in mucosal DPP-4 activity. Although the mucosal concentration of total GLP-2 was not affected, the concentration of GLP-1(7-36) was significantly elevated in the mucosa of the ileum. From seven to eight weeks after the initiation of sitagliptin treatment, bloody and inconsistent stools were observed mainly in the control diet and sitagliptin-treated mice. These mice also showed significantly lower body weight gains. In the control diet group, daily treatment with sitagliptin caused a significant increase in the number of intestinal tumors compared with mice not treated with sitagliptin. Daily treatment with sitagliptin suppressed the number of intestinal tumors in the HFD group, although this change was not statistically significant. Conclusion: This study demonstrated that chronic treatment with sitagliptin increased endogenous mucosal GLPs in the intestine and promoted intestinal tumorigenesis in lean mice, whereas sitagliptin treatment tended to suppress tumorigenesis in mice fed a HFD. Because a HFD promotes insulin resistance and intestinal neoplasia, DPP-4 inhibition may also be useful as an agent for preventing cancer in obese or diabetic patients.

Background: Small intestinal lesions induced by NSAIDs are of great concern in clinical settings. Various hypotheses, mainly of which related to the inhibition of prostaglandin synthesis, have been proposed for the origin of these inflammatory responses, however, the precise mechanism is yet to be known. The cellular process of the lesions must involve upand down-regulations of a large number of proteins and complex interactions between them. To elucidate it, global and systematic identification of the proteins in intestinal cells affected by non-steroidal anti-inflammatory drugs (NSAIDs) is essential. Two-dimensional polyacrylamide gel electrophoresis allows the analysis of total proteins from both cells and tissues, so it can help to elucidate the complex interactions and mechanisms inside cells. Aims: To identify the proteins that play a critical role in NSAIDs toxicity in intestinal cells and to clarify the mechanism of intestinal mucosal injuries induced by NSAIDs. Materials and Methods: We performed 2-DE on IEC-6 rat normal intestinal cells that were treated with indomethacin (200 μΜ, 24 h) or a vehicle control. The differentially displayed proteins were identified through matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Results: We found 18 up-regulated and 8 down-regulated proteins that showed a statistically significant difference of p < 0.05 and a ≥1.5 average fold difference in spot volume as a result of indomethacin treatment. Among these, we found that collagen I and the proteins involved in collagen I synthesis and maturation were all down-regulated. Consistent with this, immunohistochemical analysis showed that the indomethacin-treated rat intestinal mucosal cells exhibits decreased collagen I expression on its apical surface. Furthermore, the cell-protective effect of collagen I on intestinal mucosal cells was demonstrated by the use of a collagen-synthesis inhibitor and cell cultivation on collagen-coated plates versus uncoated plates. Conclusions: For the first time in the literature, a proteomic approach was employed to identify the global proteome alterations of the intestinal mucosa using indomethacin-treated and untreated IEC-6 cells. These results show that collagen I may play an important role in cytoprotection against indomethacin-induced intestinal mucosal injury. Insights gained from the current study may facilitate the development of new therapeutic strategies against NSAID-induced intestinal injury.

Background: Small intestinal lesions induced by NSAIDs are of great concern in clinical settings. Various hypotheses, mainly of which related to the inhibition of prostaglandin synthesis, have been proposed for the origin of these inflammatory responses, however, the precise mechanism is yet to be known. The cellular process of the lesions must involve upand down-regulations of a large number of proteins and complex interactions between them. To elucidate it, global and systematic identification of the proteins in intestinal cells affected by non-steroidal anti-inflammatory drugs (NSAIDs) is essential. Two-dimensional polyacrylamide gel electrophoresis allows the analysis of total proteins from both cells and tissues, so it can help to elucidate the complex interactions and mechanisms inside cells. Aims: To identify the proteins that play a critical role in NSAIDs toxicity in intestinal cells and to clarify the mechanism of intestinal mucosal injuries induced by NSAIDs. Materials and Methods: We performed 2-DE on IEC-6 rat normal intestinal cells that were treated with indomethacin (200 μΜ, 24 h) or a vehicle control. The differentially displayed proteins were identified through matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Results: We found 18 up-regulated and 8 down-regulated proteins that showed a statistically significant difference of p < 0.05 and a ≥1.5 average fold difference in spot volume as a result of indomethacin treatment. Among these, we found that collagen I and the proteins involved in collagen I synthesis and maturation were all down-regulated. Consistent with this, immunohistochemical analysis showed that the indomethacin-treated rat intestinal mucosal cells exhibits decreased collagen I expression on its apical surface. Furthermore, the cell-protective effect of collagen I on intestinal mucosal cells was demonstrated by the use of a collagen-synthesis inhibitor and cell cultivation on collagen-coated plates versus uncoated plates. Conclusions: For the first time in the literature, a proteomic approach was employed to identify the global proteome alterations of the intestinal mucosa using indomethacin-treated and untreated IEC-6 cells. These results show that collagen I may play an important role in cytoprotection against indomethacin-induced intestinal mucosal injury. Insights gained from the current study may facilitate the development of new therapeutic strategies against NSAID-induced intestinal injury.

Background and Aim: Non-steroidal anti-inflammatory drugs (NSAIDs) is known to cause mucosal injury in not only the upper gastrointestine but also the small intestine. Proton pump inhibitors(PPIs) are useful for the treatment of upper gastrointestinal mucosal injuries induced by NSAIDs. However, it was reported that some kinds of PPI exacerbate NSAIDsinduced small intestinal injury. The mechanism of NSAIDs-induced small intestinal injury is unclear and acid is not related to its mucosal injury. In this study, we confirmed effects of each PPIs which suppress gastric acid secretion for indomethacin(IM)-induced small intestinal mucosal injury and investigated the molecular mechanism of PPI which protected small intestinal injury induced by indomethacin. Methods: (In vivo study) Male SD rats were orally administered IM (10 mg/kg) and their small intestines were resected 24 hours later. We measured the ulcer index, MPO activity, iNOS-mRNA expression, and bacterial count. PPIs were orally administered 30 min before IM administration:lansoprazole (30 mg/ kg or 100 mg/kg) or omeprazole (30 mg/kg or 100 mg/kg). In addition, we investigated the effects of lansoprazole or omeprazole on heme oxygenase-1(HO-1), which is deeply involved in mucosal protection. (in vitro study) We confirmed the expression of HO-1 by realtime PCR andWestern Blotting in IEC-6 stimulated lansoprazole, IM, or lansoprazole+IM. We also confirmed how these drugs affect cell mass culturing by MTT assay and examined participation of NF-E2 related factor 2(Nrf2). Results: (1)Among PPIs, only lansoprazole inhibited small intestinal lesions. (2)Lansoprazole inhibited iNOS-mRNA expression, MPO activity, and the bacterial count in the infiltrated intestinal mucosa. (3) The amount of HO1 protein in the intestinal mucosa was significantly increased by lansoprazole but not by omeprazole. Prior administration of carbonmonoxide (CO)-releasingmolecule-2 significantly reduced the severity of these lesions, suggesting that lansoprazole ameliorates small intestinal ulceration through upregulation of HO-1/CO. (4) IM induced the expression of HO-1 at maximum 6hours, lansoprazole at 12hours, and lansoprazole+IM at 12hours after administration of drugs in IEC-6. Lansoprazole induced the expression Nrf2 at 6hours later. Knock down of Nrf2 decreased the preventive effect of lansoprazole in IEC-6. Conclusion: Among PPIs, only lansoprazole suppressed IM-induced small intestinal injury. Lansoprazole induced the expression of HO-1 and the protective effect of lansoprazole against IM-induced small intestinal injury was related to HO-1 inducted by Nrf2.

Background: Small intestinal lesions induced by NSAIDs are of great concern in clinical settings. Various hypotheses, mainly of which related to the inhibition of prostaglandin synthesis, have been proposed for the origin of these inflammatory responses, however, the precise mechanism is yet to be known. The cellular process of the lesions must involve upand down-regulations of a large number of proteins and complex interactions between them. To elucidate it, global and systematic identification of the proteins in intestinal cells affected by non-steroidal anti-inflammatory drugs (NSAIDs) is essential. Two-dimensional polyacrylamide gel electrophoresis allows the analysis of total proteins from both cells and tissues, so it can help to elucidate the complex interactions and mechanisms inside cells. Aims: To identify the proteins that play a critical role in NSAIDs toxicity in intestinal cells and to clarify the mechanism of intestinal mucosal injuries induced by NSAIDs. Materials and Methods: We performed 2-DE on IEC-6 rat normal intestinal cells that were treated with indomethacin (200 μΜ, 24 h) or a vehicle control. The differentially displayed proteins were identified through matrix-assisted laser desorption/ionization-time of flight mass spectrometry. Results: We found 18 up-regulated and 8 down-regulated proteins that showed a statistically significant difference of p < 0.05 and a ≥1.5 average fold difference in spot volume as a result of indomethacin treatment. Among these, we found that collagen I and the proteins involved in collagen I synthesis and maturation were all down-regulated. Consistent with this, immunohistochemical analysis showed that the indomethacin-treated rat intestinal mucosal cells exhibits decreased collagen I expression on its apical surface. Furthermore, the cell-protective effect of collagen I on intestinal mucosal cells was demonstrated by the use of a collagen-synthesis inhibitor and cell cultivation on collagen-coated plates versus uncoated plates. Conclusions: For the first time in the literature, a proteomic approach was employed to identify the global proteome alterations of the intestinal mucosa using indomethacin-treated and untreated IEC-6 cells. These results show that collagen I may play an important role in cytoprotection against indomethacin-induced intestinal mucosal injury. Insights gained from the current study may facilitate the development of new therapeutic strategies against NSAID-induced intestinal injury.

and by final histology. RESULTS: After ISS-ODN injection, IDO-C but not IDO-KO mice demonstrated increased anxiety behavior as evidenced by less total time in the light box (IDO-C: from 184 to 101 seconds [p=.04] vs. IDO-KO: from 200 to 214 seconds [p=NS]) and less entries into the light box (IDO-C: from 17 to 10.1 entries [p ,.01] vs. IDO-KO from 18.1 to 16.5 entries [p=NS]). Similarly, in response to colitis induction IDO-C mice demonstrated increased anxiety behavior whereas the IDO-KO mice did not. This included fewer entries into the light box (IDO-C: 12.9 vs. IDO-KO: 19.6 entries, p=0.02) and less time in the light box (IDO-C: 224 vs. IDO-KO: 335 seconds, p,0.01). Locomotor differences were not statistically different between groups. These differences in anxiety behaviors were observed even though colitis severity was modestly worse in the IDO-KO group after the third, but not first and second, cycles of DSS. CONCLUSIONS: Increased activity of IDO1 in the gut is associatedwith heightened anxiety behavior patterns in the setting of experimental colitis or after pharmacologic induction. Further investigation to determine the mechanism underlying this observation (decreased serotonin substrate vs. elevated neuroactive kynurenines) is warranted as it may have therapeutic implications for IBD patients affected by disease-activity-related mood disturbance.

and then had received scheduled maintenance IFX. Similarly, in the Re-set IFX group, patients received scheduled maintenance IFX immediately following surgery to eliminate active CD lesions. Both groups were followed for 3 to 5 years during which patients’ disease profiles were monitored with a keen interest in mucosal healing. Results: During 1, 2 and 5 years of follow up, remission maintenance rates were 58.3%, 37.5%, and 16.2%, respectively in the RIFX group. The corresponding maintenance remission rates in the Re-set IFX group were 91.7%, 69.5% and 51.7%. Likewise, complete mucosal healing rate at 3 years was 29.6% in the RIFX group and 75.0% in the Re-set IFX group, reflecting vastly better maintenance efficacy rates in the Re-set IFX group vs RIFX group. Readmission rate was 50.0% in the RIFX group vs 21.2% in the Re-set IFX group, while re-operation rate was 23.3% in the RIFX group and 12.1% in the Re-set IFX group. Conclusions: In the clinical settings described above, scheduled maintenance IFX therapy appeared to produce improved efficacy outcomes when initiated immediately after resections of active CD lesions. More notably, the efficacy of IFX to induce mucosal healing was better in the Re-set treatment setting vs routine setting.

Evaluation of Additive Effects of Narrow Band Imaging (NBI) Magnification in Borderline Gastric Cancer Diagnosis: Randomized Comparative Study of Conventional/Dye Endoscopy With and Without NBI-Magnification Toshihisa Takeuchi*, Eiji Umegaki, Yuichi Kojima, Ken Narabayashi, Yukiko Yoda, Akira Imoto, Sadaharu Nouda, Kumi Ishida, Yosuke Abe, Daisuke Masuda, Takuya Inoue, Satoshi Tokioka, Kazuhide Higuchi 2nd Dep of Internal Medicine, Osaka Medical Collage, Takatsuki, Japan Introduction: Endoscopic submucosal dissection (ESD) is used globally for early gastric cancer, and accurate borderline lesion diagnosis is important. Current qualitative gastric cancer diagnosis involves magnification NBI. Distinguishing benign and malignant tumors by surface microstructural and capillary patterns, and diagnosing excavated gastric cancer histotypes, are reported to be possible, but there is no firm position on NBI-magnification borderline gastric cancer diagnosis. Objectives: To investigate additive effects of NBI-magnification for borderline diagnosis of ESD-target gastric cancer, and pathological characteristics of lesions not diagnosable even with NBI-magnification. Subjects and Methods: ESD-target gastric cancer cases were randomly allocated, 250 lesions each, to borderline diagnosis by conventional/dye endoscopy, with and without NBImagnification. The former used maximum magnification, structural reinforcement B8, and an Evis Lucera magnifying endoscope with a slit-tip transparent hood. Cancer and other tissues were distinguished by Yao’s VS classification system, and lesion border demarcation lines were determined. With each group, three endoscopists performed or attended pre-ESD borderline lesion diagnosis, marking approx. 5 mm outside lesions, and ESD. Preoperative borderline diagnosis and ESD specimens were compared pathologically, and the rate of failing borderline diagnosis (lateral margin positivity), and causative factors, were evaluated. Results: There were no significant inter-group differences in lesion size, shape, or position, or ESD duration. Conventional/dye endoscopy borderline diagnosis failure rate was significantly lower with than without NBImagnification, at 1.6% (4/250) and 5.6% (14/250; p 0.05). Lesions failing borderline diagnosis are (a) well-differentiated adenoma with mucosal surface layer replacement-type growth; (b) moderately differentiated adenoma dominated by mucosal middle layer invasion, with little surface layer atypia; or (c) undifferentiated cancer with mucosal middle layer invasion. Conclusions: In borderline gastric cancer diagnosis in ESD-target patients, addition of NBImagnification to conventional/dye endoscopy significantly increased diagnostic accuracy, showing the method’s additive effects. However, in histological evaluation of lesions (well-differentiated adenoma with little mucosal surface layer atypia, low-atypia cancer with mucosal middle layer invasion, etc) failing borderline diagnoses even with NBI-magnification, identification of the demarcation line was considered to be difficult.

Sa1735 Prophylactic Effect of Gastromucoprotective Drugs on NSAIDsInduced Esophageal, Gastric, Duodenal, and Small Intestinal Mucosal Injury in Healthy Subjects: A Prospective Randomized Study Eiji Umegaki*, Yuichi Kojima, Yukiko Yoda, Takanori Kuramoto, Sadaharu Nouda, Toshihisa Takeuchi, Kumi Ishida, Takuya Inoue, Satoshi Tokioka, Kazuhide Higuchi 2nd Department of Internal Medicine, Osaka Medical College, Takatsuki, Japan Introduction: A variety of factors are involved in the formation of lesions induced by non-steroidal anti-inflammatory drugs (NSAIDs) in the small intestine, considered unaffected by acid, including intestinal flora, bile, and mucus, and as yet there are no established preventive or therapeutic measures. Gastromucoprotective agent such as geranylgeranylacetone (GGA), irsogladine (IG), and rebamipide (REB), is used in the treatment of gastritis and gastric ulcers, and prevented NSAID-induced small intestinal lesions in rats (Gastroenterology 2010;138:A-528). Recently there was the report that proton pump inhibitors exacerbate NSAID-induced small intestinal injury by iducing dysbiosis (Gastroenterology 2011;141:1314). In this study, we investigated whether gastromucoprotective agent monotherapy can protect against NSAIDinduced esophageal, gastric, duodenal, and small intestinal mucosal injury. Subjects and Methods: We randomly allocated healthy volunteers(each group: n 15), aged 20 years, to take (1) diclofenac 75mg plus famotidine 20mg daily or diclofenac 75mg plus GGA 150mg daily, (2) diclofenac 75mg plus omeprazole 10mg or diclofenac 75mg plus IG 4mg, (3) aspirin 100mg plus omeprazole 10mg, aspirin 100mg plus REB 300mg or aspirin 100mg plus REB 900mg. All subjects underwent upper gastrointestinal endoscopy and video capsule endoscopy(VCE) before and 2 weeks after the treatment period, and were evaluated for gastric and small intestinal lesions. Upper gastrointestinal mucosal injury was evaluated using the Modified Lanza Score(MLS), and small intestinal changes were scored for the number of 6 lesion types of: erythema, haemorrhage, erosions, ulcers, edema, and strictures. In addition, we measured fecal calprotectin levels, as a marker of digestive tract mucosal permeability. Results: 1)No significant differences were seen between gastromucoprotective agent groups and acid suppressive agent groups in the background of volunteers, and in the mean increase in esophageal, gastric and duodenal mucosal lesions. 2)When examining the total number of small intestinal mucosal injury, lesion development was suggested after administration in acid suppressive agent groups. However, there was no development in gastromucoprotective agent groups. 3)GGA/IG/REB significantly inhibited an increase in the fecal calprotectin level in comparison with acid suppressive agent in patients with NSAIDs-related digestive tract mucosal injury. Conclusions: A similar protective effect against NSAID-induced acute esophageal, gastric and duodenal mucosal injury was seen for gastromucoprotective agent and acid suppressive agent. The protective effect in the small intestine was clearly superior for gastromucoprotective agent, however, indicating that GGA/IG/REB monotherapy can protect against NSAID-induced acute mucosal injury to the esophagus, stomach, duodenum and small intestine.

treatment of dysplastic BE. Methods: All patients referred to our centre for endoscopic management of dysplastic BE were reassessed with Olympus HD 180 endoscopes and narrow band imaging. An EMR was performed in patients with a visible mucosal abnormality that harboured dysplastic BE, at a second endoscopy prior to commencement of HALO RFA. Results: 51 patients were referred for assessment. Median age 70 years (range 41-86 yrs). There were 45 males and 6 females in the cohort. The median duration of follow up was 10 months (range 1-24 mths). 29/51 patients had an EMR performed. Technique: 24/29 procedures performed with Duette system, 5/29 cap and snare technique. Complications: 1/29 oesophageal perforation successfully surgically managed. In 13/29 (45%) EMR was considered necessary for optimal treatment, (6 patients found to have sub-mucosal invasion, were unsuitable for endoscopic therapy. In addition, 6 patients with intra-mucosal cancer and invasion to muscularis mucosa (M3) and 1 patient with invasion into lamina propria (M2) would probably not have been adequately treated by HALO ablation alone). 16/29 in whom dysplasia was confined to epithelium (M1), EMR would not have changed outcome. Conclusions: 1. EMR of visible mucosal abnormalities that harbour dysplastic BE is critical prior to HALO ablation to ensure both adequate clearance of invasive cancers and to exclude those with submucosal invasion. References: Pouw, R.E., et al., Efficacy of radiofrequency ablation combined with endoscopic resection for barrett’s esophagus with early neoplasia. Clin Gastroenterol Hepatol, 2010.8(1): p. 23-9