Tu1368 A Bioengineered Segment of Colonic Smooth Muscle Tissue Demonstrates the Capabilities of Expansion and Decompression Similar to Native Tissue

urge-initiated defecation (16 pts pre vs 22 post, p=0.09), abdominal pain (1.6 episodes/wk to 0.9/wk, p=0.06) or stool consistency (Bristol Stool Scale 4, 15% of pts pre vs 28% post, p=0.06). Both child-reported and parent-reported QOL improved significantly: Total PedsQL Scores, child-reported (64±22 vs 77±19; p<0.01) and parent-reported (61±19 vs 73±18; p<0.01). Colonic transit rate improved significantly (mean GC at 48 hours 3.3±0.7 pre vs 4.0±0.7 post; p=0.004). Good patient contact was needed to ensure understanding, proper use of the machine and good compliance. Conclusion: TES administered at home on top of existing treatment produced faster colonic transit, a significant reduction in soiling and improved QOL in STC children. Defecation frequency also increased in patients starting with <3BA/wk. TES is delivered across the skin and is non-invasive and home-based selfadministration is possible provided good education and contact is established. Additional studies are required to optimize the treatment.

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Introduction Irritable bowel syndrome (IBS) is associated with impaired health-related quality of life (HRQoL) (Agarwal & Spiegel 2011), but the relative contribution of different biopsychosocial factors remains unclear. Aim To test the association between HRQoL on the one hand and gastrointestinal (GI) sensorimotor function, psychosocial factors & somatic symptom severity on the other. Methods IBS patients (Rome II criteria) were consecutively recruited from a single tertiary care center. Rectal sensitivity and compliance was assessed using barostat. Small bowel manometry was performed to calculate motility index and oroanal transit time was measured using radio-opaque markers. Validated self-report questionnaires were used to measure disease-specific HRQoL (IBSQOL), anxiety & depression (HADS), GI-specific anxiety (VSI), GI symptom severity (GSRS), stool form & frequency (Bristol Stool Form) and somatization (SCL-90R). Bivariate associations between each of these variables and the 9 different IBS-QoL subscales were assessed using Pearson correlations. Variables showing significant bivariate associations were entered into general linear models (GLM) with the IBS-QoL subscales as the dependent variables, controlling for age and gender. Results Descriptive 116 patients were included and HRQoL impairment was similar to previous studies in IBS. Bivariate associations (details not shown) For the majority of HRQoL domains, moderate to strong correlations were found with psychosocial and somatic symptom variables. Weak though significant correlations were found with rectal sensory thresholds and/or compliance for some domains (emotional, energy, food, physical role). No significant association with GI motor function (motility index, oroanal transit time) was found for any of the HRQoL domains. General Linear Models The results of the full GLM analyses with the 9 IBS-QoL subscales as dependent variables and factors significantly associated with them in bivariate analysis as independent variables are shown schematically in Table 1. Conclusion In IBS, psychological and somatic symptom levels are more strongly associated with all disease-specific HRQoL domains compared to GI sensorimotor function, jointly explaining between 20 & 60% of the variance in HRQoL. These findings underline the importance of a careful biopsychosocial assessment when addressing HRQoL in IBS, rather than exclusively focusing on GI symptoms and function testing. Table 1 Summary of general linear models for each HRQoL domain

Tu1367 Impaired Alimentary Tract Secretion Viscosity Could Potentially Facilitate the Development of Chronic Constipation Juan Castro-Combs, Marek Majewski, Boguslawa Sochacka, Irene Sarosiek, Grzegorz Wallner, Jerzy Sarosiek The alimentary tract mucosa has a capacity to continuously release mucus-rich secretion into the lumen, one of the major components of the mucus-buffer layer protecting the underlying surface epithelium against injury by endogenous and exogenous aggressive factors (T, Jaworski, I. Sarosiek et al, DD&S, 50:357-65, 2005). Mucin, the major component of mucus, determines the viscosity of the alimentary tract secretion; therefore, it facilitates lubrication for the luminal content of indigestible food particles thus accelerating its propagation and the final evacuation in an effortless fashion. The role of potential mucin-related viscosity impairment in patients with chronic constipation remains to be explored. The Aim: Therefore, we decided to test the viscosity of gastric secretion in patients with chronic constipation and to compare these results with similar data obtained from asymptomatic volunteers. Subjects & Methods: The study was approved by IRB and conducted in 19 patients (15F, mean age of 41, 19-64 age range) with symptoms of chronic constipation (CC) diagnosed acc. to Rome III criteria and 19 normal controls (13F, mean age of 43, 1971 range). The viscosity of gastric secretion was assessed in gastric juice collected in basal and stimulated (1hr) conditions, mimicking ingested-food conditions using 6μg/kg b.wt. s.c. injections of pentagastrin (Cambridge Lab., UK). The viscosity of gastric secretion was measured using cone/plate digital viscometer, DV-II+Pro model (Brookfield Bioengineering Lab Inc, Boston, MA) employing the shear rate between 2 and 16/sec. Results are presented as Mean ±SEM for viscosity expressed as cP units. Statistical analysis was implemented using Σ-Stat Software (SyStat Inc. CA) Results: The viscosity value in basal conditions in controls was 48% higher than in patients with CC (9.41 ±1.74 cP vs. 6.34 ±1.01 cP, P<0.05) at the lowest shear rate (2/sec) and 55% higher (4.80 ±1.14 cP vs. 3.11 ±0.46 cP, P<0.05) at the middle shear rate value (8/sec). The viscosity value in pentagastrin-stimulated conditions in controls was 71% higher than in patients with CC (7.84 ±1.71 cP vs. 4.59 ±1.20 cP, P<0.01) at the lowest shear rate (2/sec) and 35% higher (3.04 ±0.52 cP vs. 2.26 ±0.38 cP, P<0.05) at the middle shear rate value (8/sec). Conclusions: 1.The significantly lower viscosity of gastric secretion in patients with CC vs. normal volunteers may imply a potential impairment in mucus-related lubrication within the alimentary tract. 2. This may potentially contribute to the development of symptoms related to chronic constipation and may open a new therapeutic avenue for this patient population in the future. Tu1368 A Bioengineered Segment of Colonic Smooth Muscle Tissue Demonstrates the Capabilities of Expansion and Decompression Similar to Native Tissue Elie Zakhem, Shreya Raghavan, Saranyaraajan Varadarajan, Sita Somara, Robert R. Gilmont, Khalil N. Bitar

bold=significant, italic=trend, n/s=not significant, blank cells indicate that this variable was not entered into the model because of a lack of significant bivariate association

Introduction: Many gut disorders/cancers require intestinal resectioning leading to shorter bowels. There is a significant need for functional intestinal replacement (segments of intestine capable of distention and recovery). We have previously bioengineered colonic circular smooth muscle ring constructs. These rings maintained their functionality after being placed around a tubular chitosan scaffold. Objective: To tissue-engineer a mechanically stable and physiologically functional cylindrical intestinal smooth muscle segment. Methods: (1) Several circumferentially-oriented circular smooth muscle tissue constructs were bioengineered using a fibrin-based model with an internal diameter of 5mm. (2) A hollow tubular chitosan scaffold was also manufactured with the following dimensions: 2.5cm length, 7.25mm outer diameter, 3.25mm luminal diameter and 2mm thickness. (3) The constructs were placed around the scaffold in close proximity. (4) Surgical glue was applied between the junctions of the constructs and along their circumference. The composite tubular construct was maintained in culture for >1 month. (5) The integrity of the muscle tissue was tested by pipetting media through the lumen and flow and leakage were monitored. Results: The bioengineered colon segment was 2cm in length. The construct had a uniform tubular structure similar to native colon. The new bioengineered 2cm-long circular smooth muscle tubular construct maintained its structural integrity In Vitro >1 month. The tubular chitosan scaffold maintained its luminal opening and supported the bioengineered tubular colon around it. Pipetting media through the scaffold from one end, while the other end was clamped, caused an expansion of the cylindrical colon tube at the midsection followed by emptying of the liquid on the opposite end and decompression of the midsection enlargement. The construct was able to withstand a volume 4-5 times the capacity of the relaxed cylinder. There was no sign of leakage from the tissue. The pressure applied several times by pipetting did not cause any leakage and the flow of media was unidirectional without any backflow. Summary: We show the production of a continuous piece of intestinal smooth muscle, using colonic circular smooth muscle constructs that maintained its integrity during the culture period. There was no leakage through the muscle tissue. Conclusion: We manufactured a continuous tubular intestinal smooth muscle construct. This construct demonstrated the properties of expansion followed by decompression similar to the mechanical properties of native intestinal tissue. This could be suitable for intestinal replacement. This work was supported by NIH/NIDDK RO1DK042876.

Tu1370 Effects of Ono-2952, a Novel Translocator Protein 18kda Antagonist, on Stress-Induced Rectal Hyperalgesia and Defecation in Rats Katsukuni Mitsui, Takashi Sasamura, Seishi Katsumata, Tomohiro Niwa, Yuji Kawahara, Noriko Morimoto, Ken Yoshikawa, Shinji Nakade Background/Aim: Translocator protein 18kDa (TSPO) localized on the outer mitochondrial membrane regulates cholesterol transport from intracellular stores into mitochondria, a rate limiting step of neurosteroidgenesis. Neurosteroids are known to act as allosteric modulators of excitatory and/or inhibitory neurotransmitter receptors. ONO-2952 is a novel potent and selective TSPO antagonist produced by ONO Pharmaceutical Co., Ltd. We have hypothesized that ONO-2952 has a potential in the treatment of stress-related disorders like irritable bowel syndrome (IBS). The aim of this study was to investigate the effects of ONO-2952 on stress-induced disturbance of bowel movement, abdominal pain/discomfort and anxietyrelated behavior in rats. Methods: To determine bowel movement, weight of feces during 1 hour restraint stress was measured in rats. ONO-2952 or a vehicle was orally administered 2 hours before restraint stress loading. In the experiments of abdominal nociception, ONO2952 or a vehicle was orally administered 1 hour before forelimb restraint stress loading followed by a rectal balloon-distension which was applied at 5 minute interval for 1 hour from 5 minutes after 1 hour stress exposure. The nociceptive threshold was determined by abdominal electromyogram. To demonstrate the effects of ONO-2952 on stress-induced anxiety, rats were conditioned 15 times at 1 minute intervals by a 3 second warning beep followed by a 5 second 2 mA foot shock and flash of light. On the following day, rats were again placed in the apparatus 2 hours after oral administration of ONO-2952 or a vehicle. Freezing time under the 30 minutes stress without exposure to foot shock was measured. We also evaluated the influence of ONO-2952 on normal defecation and visceral nociceptive threshold in non-stressed rats. Results: ONO-2952 prevented the defecation induced by restraint stress at doses of 0.3 mg/kg or higher. ONO-2952 also prevented the decrease of

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AGA Abstracts

AGA Abstracts

Relative Contribution of Gastrointestinal Sensorimotor Function, Psychosocial Factors & Somatic Symptom Severity to Health-Related Quality of Life in Irritable Bowel Syndrome Katarina Wilpart, Hans Törnblom, Jan F. Tack, Magnus Simren, Lukas Van Oudenhove