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Mo2002 A Prospective Study in Human Subjects Evaluating the Safety and Efficacy of a Novel Balloon-Colonoscope
AGA Abstracts
available components, requires no additional hardware, and can be used for real-time closedloop control of a robot controlled magnetic endoscopic system. Our method represents a first step toward enabling technology to redefine endoscopy. In-vivo animal studies focused on validating the method are in progress.
Mo2003 Effects of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin on IndomethacinInduced Intestinal Mucosal Injury in Rats Kaori Fujiwara, Takuya Inoue, Ken Narabayashi, Taisuke Sakanaka, Toshihiko Okada, Sadaharu Nouda, Kazuki Kakimoto, Takanori Kuramoto, Kumi Ishida, Ken Kawakami, Yosuke Abe, Toshihisa Takeuchi, Satoshi Tokioka, Kazuhide Higuchi
Mo2002
Background: The gut incretin glucagon-like peptide-1 (GLP-1) and the intestinotropic hormone GLP-2 are released from enteroendocrine L cells in response to ingested nutrients. Exogenous GLP-2 analogue treatment increases intestinal villous mass, exerts anti-apoptotic effects, and prevents intestinal injury. Although non-steroidal anti-inflammatory drug (NSAID)-induced intestinal ulcers are increasingly diagnosed, they have no known effective therapy. Since GLP-2 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4), DPP-4 inhibition may potentiate the effects of endogenous GLP-2 and provide a novel approach for the treatment of mucosal injury in the intestine. However, the effect of DPP-4 inhibitors on intestinal ulcers is unknown. Material and Methods: Segmental differences in DPP-4, 8, and 9 mRNA expression and DPP enzyme activity were determined in BALB/c mice. The DPP4 inhibitor sitagliptin (0.3, 1 or 3 mg/kg) was given orally. Mucosal DPP activity and GLP concentrations were measured 24 hr after administration. Small intestinal ulcers were induced by indomethacin injections (10.0 mg/kg/day, s.c. for the prevention study, 8.0 mg/kg/day, sc for 2 days for the ulcer healing study) in fed rats. For the prevention study, sitagliptin (3 mg/kg, i.g.) was given before (24 hours, and on Day 0) indomethacin treatment. For the ulcer healing study, sitagliptin (3 mg/kg, i.g.) and/or an elemental diet (ED) (free access to a powdered ED) were given orally from Days -2 to 7 after indomethacin treatment. Apoptosis was evaluated by immunohistochemistry for single-stranded DNA (ssDNA) and by Western blotting for cleaved caspase-3. Results: In mice, DPP-4 mRNA was highly expressed in the jejunum and ileum, and high DPP-4 activity was detected. DPP-8 and 9 were predominantly expressed in the colon. Oral sitagliptin dose-dependently suppressed mucosal DPP-4 activity, especially in the ileum and proximal colon, without affecting plasma DPP-4 activity. Although the mucosal concentration of total GLP-2 was not affected, the mucosal concentration of GLP-1(7-36) was significantly elevated in the ileum and proximal colon. In rats, pretreatment with oral sitagliptin suppressed apoptosis and significantly reduced total ulcer length assessed on Day 1. The combination of sitagliptin and an ED accelerated intestinal ulcer healing on Day 7. Conclusion: The DPP-4 inhibitor, sitagliptin, suppressed mucosal DPP-4 activity and increased mucosal concentrations of GLP-1(7-36) in the ileum and proximal colon in mice, and prevented the formation and promoted the healing of indomethacin-induced intestinal ulcers in rats. These findings suggest that sitagliptin may be a useful therapeutic option for intestinal injuries.
A Prospective Study in Human Subjects Evaluating the Safety and Efficacy of a Novel Balloon-Colonoscope Ian M. Gralnek, Alain Suissa, Sveta Domanov Background: Colonoscopy is the "criterion standard" for detecting colorectal adenomas and cancers. Yet, multiple studies have shown significant numbers of adenomas are missed at colonoscopy. This is primarily due to inadequate visualization of the proximal aspect of colonic folds & flexures. The use of a cap fitted on the tip of the colonsocope, so as to mechanically straighten haustral folds on colonoscope withdrawal, has shown promise in improving adenoma detection rates. However, full circumferential colon lumen evaluation is limited with the cap technique. Thus the NaviAid™ G-EYE™ (SMART Medical Systems Ltd, Ra'anana, Israel) is a novel, balloon-colonoscope comprising a standard, commerciallyavailable colonoscope with a reprocessable, permanently integrated, inflatable balloon at the distal tip of the scope. Figure 1. The balloon is inflated / deflated (endoscopist selected inflation levels, Figure 2) through the endoscope internally, without any external mounted accessories. The balloon-colonoscope is advanced just like a traditional colonoscope, and with the balloon deflated. Upon reaching the cecum, the balloon is inflated to engage the colon walls and the scope is then withdrawn. Withdrawal of the inflated balloon-colonoscope causes mechanical straightening of haustral folds and flexures, thereby allowing the proximal side of the folds to be viewed. Aims/Methods: To establish the feasibility, usability and safety of a novel balloon-colonoscope in a prospective cohort of human subjects (ages 40-75 years) referred for CRC screening, polyp surveillance or diagnostic evaluation. Primary study endpoint was cecal intubation, additional endpoints included: time to cecal intubation, withdrawal time, total procedure time, polyps identified, success of polypectomies, and adverse events (AE). Telephone follow up with subjects was performed. This was Helsinki committee approved and informed consent obtained. Results: From 1/11/12 to 25/11/12, n=25 consecutive subjects (mean age 59.3 years, 13 male) were entered at Elisha Hospital, Haifa, Israel. One subject was excluded due to inadequate colon prep, thus 24 subjects are analyzed. A 24/24 (100%) cecal intubation rate was achieved. Mean time (minutes) to the cecum was 5.05, withdrawal time 7.44, and total procedure time 17.52. There were 20 polyps identified in 14 subjects, a 58.3% polyp detection rate (compared to 30-35% polyp detection rates reported per published literature). There were 16 polyps (1-5mm), 2 polyps (6-9mm) and 2 polyps (≥10mm) in size. All identified polyps were removed by cold or hot snare polypectomy. There were no AEs reported at patient follow up. Conclusions: The NaviAid™ G-EYE™ balloon-colonoscope appears feasible, usable, and safe. There was 100% cecal intubation, a 58% polyp detection rate, and no AEs. Comparative human studies are now underway.
Mo2004 Development of Obesity, Insulin Resistance and Metabolic Derangements in Mice Overexpressing Sar1b Whose Mutation Causes Chylomicron Retention Disease Schohraya Spahis, Carole Garofalo, Lea Emonnot, Valerie Marcil, Alain Montoudis, Edgard Delvin, Rocio Sanchez, Daniel Sinnett, Ernest G. Seidman, Alain T. Sane, Emile Levy Background: Mutations of SARA2 gene coding for Sar1B lead to Chylomicron Retention Disease (CRD) characterized by varying degrees of chronic fat malabsorption, hypocholesterolemia, fat-soluble vitamin deficiency, failure to thrive, chronic diarrhea and neurological manifestations. Objectives: The main aim of this study was to assess whether Sar1B overexpression, under a hypercaloric diet, accelerated lipid production and chylomicron (CM) secretion, as well as alters metabolic status. Methods: To this end, we generated transgenic mice overexpressing human Sar1B (Sar1B+/+) using pBROAD3-mcs that features the ubiquitous mouse ROSA26 promoter. Results: Sar1B+/+ mice with high-fat feeding significantly displayed increased body weight and adiposity compared with wild-type (WT) mice under the same diet or Sar1B+/+ mice under chow diet. Furthermore, Sar1B+/+ mice were prone to liver steatosis as revealed by significantly elevated hepatic triglycerides (TG) and cholesterol in comparison with WT animals. They exhibited augmented levels of plasma TG and saturated fatty acids (FAs) along with alterations in FA composition. They also showed greater susceptibility to developing insulin sensitivity in view of the high values of plasma glucose, insulin and HOMA-IR index in the fasting state. Finally, Sar1B+/+ mice responded more efficiently to oral fat tolerance tests as reflected by the rise in plasma TG and CM concentrations, which reflects enhanced intestinal fat absorption. Conclusions: These results suggest that Sar1B overexpression under alimentary fat can induce cardiometabolic traits as revealed by incremental weight gain, fat deposition, circulating lipids, hepatic steatosis, insulin sensitivity and intestinal fat absorption. Acknowledgment: This study was supported by the Canadian Institutes of Health Research and the J.A. DeSève Research Chair in Nutrition
Balloon-Colonoscope showing integrated, inflated ballon at scope tip
Mo2005 Gut Indoleamine 2,3 Dioxygenase-1 Activity Expression Contributes to Colitis-Associated Anxiety Heba Iskandar, Jeffrey M. Marinshaw, Emily Vivio, Suprada Rao, Matthew A. Ciorba BACKGROUND: In active Crohn's disease and experimental colitis, serum tryptophan levels can be severely depressed while kynurenine levels are elevated. This finding reflects increased expression of the immunomodulatory enzyme indoleamine 2,3 dioxygenase (IDO1). IDO1 activity has recently been postulated to be an important biologic link between inflammation and mood disturbance. As inflammatory bowel disease (IBD) patients commonly experience disease-activity-associated mood disorders, we HYPOTHESIZED that elevated gut IDO1 expression could be a contributing factor. METHODS: Age-, sex-, and housing-matched C57/Bl6 mice (N≥8/group) were compared based on IDO1 activity (Competent (IDO-C) vs. Knockout (IDO-KO)). Gut IDO1 activity was induced either pharmacologically by ISSODN (a TLR9 agonist) or by colitis induction (4% DSS x 3 cycles). Behavior was filmed for precise scoring of anxiety with the light-dark preference test. Locomotor activity was tested at each time-point to rule out potential physical impairment prior to behavioral testing.
Bllaoon inflation system providing endoscopist selected controlled pressure level
AGA Abstracts
S-716
available components, requires no additional hardware, and can be used for real-time closedloop control of a robot controlled magnetic endoscopic system. Our method represents a first step toward enabling technology to redefine endoscopy. In-vivo animal studies focused on validating the method are in progress.
Mo2003 Effects of the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin on IndomethacinInduced Intestinal Mucosal Injury in Rats Kaori Fujiwara, Takuya Inoue, Ken Narabayashi, Taisuke Sakanaka, Toshihiko Okada, Sadaharu Nouda, Kazuki Kakimoto, Takanori Kuramoto, Kumi Ishida, Ken Kawakami, Yosuke Abe, Toshihisa Takeuchi, Satoshi Tokioka, Kazuhide Higuchi
Mo2002
Background: The gut incretin glucagon-like peptide-1 (GLP-1) and the intestinotropic hormone GLP-2 are released from enteroendocrine L cells in response to ingested nutrients. Exogenous GLP-2 analogue treatment increases intestinal villous mass, exerts anti-apoptotic effects, and prevents intestinal injury. Although non-steroidal anti-inflammatory drug (NSAID)-induced intestinal ulcers are increasingly diagnosed, they have no known effective therapy. Since GLP-2 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4), DPP-4 inhibition may potentiate the effects of endogenous GLP-2 and provide a novel approach for the treatment of mucosal injury in the intestine. However, the effect of DPP-4 inhibitors on intestinal ulcers is unknown. Material and Methods: Segmental differences in DPP-4, 8, and 9 mRNA expression and DPP enzyme activity were determined in BALB/c mice. The DPP4 inhibitor sitagliptin (0.3, 1 or 3 mg/kg) was given orally. Mucosal DPP activity and GLP concentrations were measured 24 hr after administration. Small intestinal ulcers were induced by indomethacin injections (10.0 mg/kg/day, s.c. for the prevention study, 8.0 mg/kg/day, sc for 2 days for the ulcer healing study) in fed rats. For the prevention study, sitagliptin (3 mg/kg, i.g.) was given before (24 hours, and on Day 0) indomethacin treatment. For the ulcer healing study, sitagliptin (3 mg/kg, i.g.) and/or an elemental diet (ED) (free access to a powdered ED) were given orally from Days -2 to 7 after indomethacin treatment. Apoptosis was evaluated by immunohistochemistry for single-stranded DNA (ssDNA) and by Western blotting for cleaved caspase-3. Results: In mice, DPP-4 mRNA was highly expressed in the jejunum and ileum, and high DPP-4 activity was detected. DPP-8 and 9 were predominantly expressed in the colon. Oral sitagliptin dose-dependently suppressed mucosal DPP-4 activity, especially in the ileum and proximal colon, without affecting plasma DPP-4 activity. Although the mucosal concentration of total GLP-2 was not affected, the mucosal concentration of GLP-1(7-36) was significantly elevated in the ileum and proximal colon. In rats, pretreatment with oral sitagliptin suppressed apoptosis and significantly reduced total ulcer length assessed on Day 1. The combination of sitagliptin and an ED accelerated intestinal ulcer healing on Day 7. Conclusion: The DPP-4 inhibitor, sitagliptin, suppressed mucosal DPP-4 activity and increased mucosal concentrations of GLP-1(7-36) in the ileum and proximal colon in mice, and prevented the formation and promoted the healing of indomethacin-induced intestinal ulcers in rats. These findings suggest that sitagliptin may be a useful therapeutic option for intestinal injuries.
A Prospective Study in Human Subjects Evaluating the Safety and Efficacy of a Novel Balloon-Colonoscope Ian M. Gralnek, Alain Suissa, Sveta Domanov Background: Colonoscopy is the "criterion standard" for detecting colorectal adenomas and cancers. Yet, multiple studies have shown significant numbers of adenomas are missed at colonoscopy. This is primarily due to inadequate visualization of the proximal aspect of colonic folds & flexures. The use of a cap fitted on the tip of the colonsocope, so as to mechanically straighten haustral folds on colonoscope withdrawal, has shown promise in improving adenoma detection rates. However, full circumferential colon lumen evaluation is limited with the cap technique. Thus the NaviAid™ G-EYE™ (SMART Medical Systems Ltd, Ra'anana, Israel) is a novel, balloon-colonoscope comprising a standard, commerciallyavailable colonoscope with a reprocessable, permanently integrated, inflatable balloon at the distal tip of the scope. Figure 1. The balloon is inflated / deflated (endoscopist selected inflation levels, Figure 2) through the endoscope internally, without any external mounted accessories. The balloon-colonoscope is advanced just like a traditional colonoscope, and with the balloon deflated. Upon reaching the cecum, the balloon is inflated to engage the colon walls and the scope is then withdrawn. Withdrawal of the inflated balloon-colonoscope causes mechanical straightening of haustral folds and flexures, thereby allowing the proximal side of the folds to be viewed. Aims/Methods: To establish the feasibility, usability and safety of a novel balloon-colonoscope in a prospective cohort of human subjects (ages 40-75 years) referred for CRC screening, polyp surveillance or diagnostic evaluation. Primary study endpoint was cecal intubation, additional endpoints included: time to cecal intubation, withdrawal time, total procedure time, polyps identified, success of polypectomies, and adverse events (AE). Telephone follow up with subjects was performed. This was Helsinki committee approved and informed consent obtained. Results: From 1/11/12 to 25/11/12, n=25 consecutive subjects (mean age 59.3 years, 13 male) were entered at Elisha Hospital, Haifa, Israel. One subject was excluded due to inadequate colon prep, thus 24 subjects are analyzed. A 24/24 (100%) cecal intubation rate was achieved. Mean time (minutes) to the cecum was 5.05, withdrawal time 7.44, and total procedure time 17.52. There were 20 polyps identified in 14 subjects, a 58.3% polyp detection rate (compared to 30-35% polyp detection rates reported per published literature). There were 16 polyps (1-5mm), 2 polyps (6-9mm) and 2 polyps (≥10mm) in size. All identified polyps were removed by cold or hot snare polypectomy. There were no AEs reported at patient follow up. Conclusions: The NaviAid™ G-EYE™ balloon-colonoscope appears feasible, usable, and safe. There was 100% cecal intubation, a 58% polyp detection rate, and no AEs. Comparative human studies are now underway.
Mo2004 Development of Obesity, Insulin Resistance and Metabolic Derangements in Mice Overexpressing Sar1b Whose Mutation Causes Chylomicron Retention Disease Schohraya Spahis, Carole Garofalo, Lea Emonnot, Valerie Marcil, Alain Montoudis, Edgard Delvin, Rocio Sanchez, Daniel Sinnett, Ernest G. Seidman, Alain T. Sane, Emile Levy Background: Mutations of SARA2 gene coding for Sar1B lead to Chylomicron Retention Disease (CRD) characterized by varying degrees of chronic fat malabsorption, hypocholesterolemia, fat-soluble vitamin deficiency, failure to thrive, chronic diarrhea and neurological manifestations. Objectives: The main aim of this study was to assess whether Sar1B overexpression, under a hypercaloric diet, accelerated lipid production and chylomicron (CM) secretion, as well as alters metabolic status. Methods: To this end, we generated transgenic mice overexpressing human Sar1B (Sar1B+/+) using pBROAD3-mcs that features the ubiquitous mouse ROSA26 promoter. Results: Sar1B+/+ mice with high-fat feeding significantly displayed increased body weight and adiposity compared with wild-type (WT) mice under the same diet or Sar1B+/+ mice under chow diet. Furthermore, Sar1B+/+ mice were prone to liver steatosis as revealed by significantly elevated hepatic triglycerides (TG) and cholesterol in comparison with WT animals. They exhibited augmented levels of plasma TG and saturated fatty acids (FAs) along with alterations in FA composition. They also showed greater susceptibility to developing insulin sensitivity in view of the high values of plasma glucose, insulin and HOMA-IR index in the fasting state. Finally, Sar1B+/+ mice responded more efficiently to oral fat tolerance tests as reflected by the rise in plasma TG and CM concentrations, which reflects enhanced intestinal fat absorption. Conclusions: These results suggest that Sar1B overexpression under alimentary fat can induce cardiometabolic traits as revealed by incremental weight gain, fat deposition, circulating lipids, hepatic steatosis, insulin sensitivity and intestinal fat absorption. Acknowledgment: This study was supported by the Canadian Institutes of Health Research and the J.A. DeSève Research Chair in Nutrition
Balloon-Colonoscope showing integrated, inflated ballon at scope tip
Mo2005 Gut Indoleamine 2,3 Dioxygenase-1 Activity Expression Contributes to Colitis-Associated Anxiety Heba Iskandar, Jeffrey M. Marinshaw, Emily Vivio, Suprada Rao, Matthew A. Ciorba BACKGROUND: In active Crohn's disease and experimental colitis, serum tryptophan levels can be severely depressed while kynurenine levels are elevated. This finding reflects increased expression of the immunomodulatory enzyme indoleamine 2,3 dioxygenase (IDO1). IDO1 activity has recently been postulated to be an important biologic link between inflammation and mood disturbance. As inflammatory bowel disease (IBD) patients commonly experience disease-activity-associated mood disorders, we HYPOTHESIZED that elevated gut IDO1 expression could be a contributing factor. METHODS: Age-, sex-, and housing-matched C57/Bl6 mice (N≥8/group) were compared based on IDO1 activity (Competent (IDO-C) vs. Knockout (IDO-KO)). Gut IDO1 activity was induced either pharmacologically by ISSODN (a TLR9 agonist) or by colitis induction (4% DSS x 3 cycles). Behavior was filmed for precise scoring of anxiety with the light-dark preference test. Locomotor activity was tested at each time-point to rule out potential physical impairment prior to behavioral testing.
Bllaoon inflation system providing endoscopist selected controlled pressure level
AGA Abstracts
S-716