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1126 Neonatal Colonic Inflammation Modulates Molecular Nociceptive Pathways Resulting in Visceral Hypersensitivity When Re-Exposed to Adult Colon Inflammation
Table 1. Characteristics of pharyngeal stimulus induced pharyngo-esophageal and cardiorespiratory responses
AGA Abstracts
covariates history of lower gastrointestinal endoscopy (six months to 3 years prior to end of CRC diagnosis/ follow-up), frequency of health care visits and socio-economic status. Mutually exclusive competing outcomes included CRC (or death due to CRC) and colectomy prior to CRC diagnosis. Analyses were stratified for era of follow-up (1987-1993; 19942001 and 2002-2012) to assess time trends. Results: Of 9095 individuals with IBD, 175 (1.9%) were diagnosed with CRC, and of 86,948 individuals without IBD 886(1.0%) were diagnosed with CRC. Overall, in the multivariate models, there was an approximately two fold increase in CRC incidence and CRC mortality among individuals with IBD between 1987 and 2012 (Incidence: Hazard ratio (HR): 1.95; 95% Confidence interval (CI): 1.652.30). Mortality: HR 2.15; 95% CI: 1.60-2.89). In stratified analysis, there was no decrease in HR for CRC mortality in the later time periods (table 1). The increased risk for distal and proximal CRC incidence was very similar in the latest era. . Conclusions: This population-based study suggests that although the magnitude of increased CRC risk is smaller than that reported in the earlier studies, there is no time trend of lower magnitude of increased CRC mortality with IBD in North America. Surveillance for CRC should be continued to be performed for individuals with colonic IBD. Table 1
1125 Pharyngeal Provocation Induced Pharyngo-Esophageal and Cardio-Respiratory Rhythms in Dysphagic Human Neonates at Full Term Status Kathryn Hasenstab, Swetha Sitaram, Reza Shaker, Sudarshan Jadcherla *P<0.05 vs gavage for pairwise comparison, Pharyngo-esophageal reflexes includes pharyngeal reflexive swallow or pharyngo-upper-esophageal sphincter contractile reflex.
BACKGROUND: According to American Academy of Pediatrics, asymptomatic oral feeding among neonates is an expectation for safe discharge from the NICU. However, convalescing neonates frequently experience feeding difficulties and are unable to achieve full oral feeds by term status, and tube feeding becomes a necessity for maintenance of growth. Pharyngoesophageal and cardio-respiratory rhythm adaptations among neonates with oral feeding difficulties are unclear. AIMS: To test the hypothesis that pharyngeal provocation induced pharyngo-esophageal and cardio-respiratory adaptive reflex response characteristics are distinct among neonates with oral feeding difficulties. METHODS: Fifty-four convalescing neonates (32 male, 27.7 ± 3.4 wks gestation) were studied at 38.7 ± 1.2 wks postmenstrual age using concurrent pharyngo-esophageal manometry, ECG, respiratory inductance plethysmography, and nasal airflow thermistor to test pharyngo-esophageal and cardio-respiratory adaptive interactions during graded abrupt pharyngeal water stimuli (0.1, 0.3, and 0.5 mL). We measured the characteristics of pharyngeal reflexive swallow (recruitment, frequency, variability, and stability), esophageal peristaltic reflexes, cardiac rate modulations, and deglutition apnea and respiratory rhythm disturbances. Feeding method at time of manometric evaluation was exclusive gavage (N=12), transitional gavage (N=12), and exclusive oral (N= 30). Comparisons were made among the 3 types of feeding methods using linear mixed and GEE statistical models. Data presented as mean ± SEM or %. RESULTS: Response characteristics of reflexes of interest evoked upon abrupt graded pharyngeal infusions (N= 402) are classified into 1) pharyngeal reflexes, 2) esophageal reflexes, 3) cardiac rate modulations, 4) respiratory rhythm changes, and 5) volumetric response relationships (Table 1). The ratio (%) of solitary: multiple pharyngeal reflexive swallowing was 19:81 in exclusive gavage, 16:84 in transitional gavage, and 19:81 in exclusive oral feeding strategies (p=0.5). CONCLUSIONS: 1) Infants with exclusive gavage feeding at full term status have prolonged respiratory rhythm disturbances, prolonged esophageal waveform activity, and delayed onset of pharyngo-esophageal reflexes suggesting impairment of pharyngeal afferent and exaggeration of esophageal efferent activity, aberrant respiratory rhythm modulations. 2) Volume dependent pharyngo-esophageal and cardio-respiratory responses occur. 3) Volume-dependent deceleration of heart rate was evident. These findings implicate mal-adaptation of vagovagal reflexes involving pharyngeal-esophageal and cardio-respiratory regulatory neural circuitry. *Supported in part by P01 DK068051 (Jadcherla/Shaker)
1126 Neonatal Colonic Inflammation Modulates Molecular Nociceptive Pathways Resulting in Visceral Hypersensitivity When Re-Exposed to Adult Colon Inflammation Jose Aguirre, John Winston, Don W. Powell, Sushil K. Sarna Background and Aim: Inflammatory bowel disease (IBD) patients experience abdominal pain during inflammatory flare and while in remission. The etiology and pathophysiology of this biological pain remain unknown, though evidence suggests an important role for visceral hypersensitivity (VHS). Epidemiological findings suggest early-life infections are a risk factor for the development of pediatric and adult IBD and adolescent or adult gastrointestinal infections may trigger the onset of IBD or its relapse. We tested the hypothesis that neonatal colonic inflammation (NCI) modulates molecular conditions in nociceptive pathways resulting in VHS, as measured by colorectal distention (CRD), when exposed to subsequent colonic inflammation through modulation of central norepinephrine release and expression of specific spinal cord neurotrophins. Methods: We studied four groups of animals: 1) saline control rats (Ctr. rats); 2) rats subjected only to NCI on post-natal day 10 by colonic administration of trinitrobenzene sulfonic acid (TNBS, 130 mg/kg) (NCI rats); 3) 8 to 12 weeks old naive rats subjected to adult colon inflammation (ACI) for the first time (ACI rats); and 4) 8 to 12 weeks old adult NCI rats subjected to adult colon inflammation by TNBS (68 mg/kg) (NCI+ACI rats). Tissues were collected 7 days following adult TNBS administration. Results: NCI by itself had no significant effect on VHS measured by visceromotor response (VMR) CRD compared to control rats. When compared to all groups, NCI+ACI rats showed a significant (p<0.05) increase of VMR to CRD. Plasma epinephrine and norepinephrine were increased 2-fold (p<0.05) in NCI+ACI rats compared to ACI rats. Heart rate variability analysis was consistent with increased sympathetic and decreased vagal tone in NCI+ACI rats compared to the other experimental groups. Expression of tyrosine hydroxylase (TH) mRNA was increased in the locus ceruleus (3 fold, p<0.05) and TH protein was increased in the adrenal gland (1.5 fold, p<0.05). Enhanced visceral hypersensitivity in NCI+ACI rats was significantly decreased by systemic administration of b2 adrenergic receptor (AR) antagonist propranolol. BDNF protein expression was upregulated 35% (p<0.05) in the LSand 30% ( p<0.05) in TL-spinal cord dorsal horn of NCI+ACI rats vs. the other groups. Compared to controls, BDNF mRNA expression in colon projecting neurons from NCI+ACI rats in S1 DRG was elevated 7-fold but only 3 fold in ACI rats. Intrathecal administration of BDNF antagonist trkBFc significantly reduced VHS in NCI+ ACI rats. Conclusion: These findings support the hypothesis that early-life colonic inflammation triggers epigenetic programming that upregulates TH in the LC and the adrenal medulla as well as BDNF in DRG neurons and spinal cord. The resulting increase of central and peripheral norepinephrine (NE) and spinal cord BNDF enhance VHS.
1127 Sacral Nerve Stimulation for Treatment of Constipation in Children: LongTerm Outcomes, Patient Benefit, and Parent Satisfaction Peter L. Lu, Ilan J. Koppen, Danielle Orsagh-Yentis, Karen Leonhart, Erica J. Ambeba, Katherine J. Deans, Peter C. Minneci, Karen A. Diefenbach, Seth A. Alpert, Marc A. Benninga, Desale Yacob, Carlo Di Lorenzo Background: Treatment options for children with constipation refractory to medical treatment are limited. Recent studies suggest that sacral nerve stimulation (SNS) is an effective treatment option for children with defecation disorders. However, the long-term outcomes
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AGA Abstracts
AGA Abstracts
covariates history of lower gastrointestinal endoscopy (six months to 3 years prior to end of CRC diagnosis/ follow-up), frequency of health care visits and socio-economic status. Mutually exclusive competing outcomes included CRC (or death due to CRC) and colectomy prior to CRC diagnosis. Analyses were stratified for era of follow-up (1987-1993; 19942001 and 2002-2012) to assess time trends. Results: Of 9095 individuals with IBD, 175 (1.9%) were diagnosed with CRC, and of 86,948 individuals without IBD 886(1.0%) were diagnosed with CRC. Overall, in the multivariate models, there was an approximately two fold increase in CRC incidence and CRC mortality among individuals with IBD between 1987 and 2012 (Incidence: Hazard ratio (HR): 1.95; 95% Confidence interval (CI): 1.652.30). Mortality: HR 2.15; 95% CI: 1.60-2.89). In stratified analysis, there was no decrease in HR for CRC mortality in the later time periods (table 1). The increased risk for distal and proximal CRC incidence was very similar in the latest era. . Conclusions: This population-based study suggests that although the magnitude of increased CRC risk is smaller than that reported in the earlier studies, there is no time trend of lower magnitude of increased CRC mortality with IBD in North America. Surveillance for CRC should be continued to be performed for individuals with colonic IBD. Table 1
1125 Pharyngeal Provocation Induced Pharyngo-Esophageal and Cardio-Respiratory Rhythms in Dysphagic Human Neonates at Full Term Status Kathryn Hasenstab, Swetha Sitaram, Reza Shaker, Sudarshan Jadcherla *P<0.05 vs gavage for pairwise comparison, Pharyngo-esophageal reflexes includes pharyngeal reflexive swallow or pharyngo-upper-esophageal sphincter contractile reflex.
BACKGROUND: According to American Academy of Pediatrics, asymptomatic oral feeding among neonates is an expectation for safe discharge from the NICU. However, convalescing neonates frequently experience feeding difficulties and are unable to achieve full oral feeds by term status, and tube feeding becomes a necessity for maintenance of growth. Pharyngoesophageal and cardio-respiratory rhythm adaptations among neonates with oral feeding difficulties are unclear. AIMS: To test the hypothesis that pharyngeal provocation induced pharyngo-esophageal and cardio-respiratory adaptive reflex response characteristics are distinct among neonates with oral feeding difficulties. METHODS: Fifty-four convalescing neonates (32 male, 27.7 ± 3.4 wks gestation) were studied at 38.7 ± 1.2 wks postmenstrual age using concurrent pharyngo-esophageal manometry, ECG, respiratory inductance plethysmography, and nasal airflow thermistor to test pharyngo-esophageal and cardio-respiratory adaptive interactions during graded abrupt pharyngeal water stimuli (0.1, 0.3, and 0.5 mL). We measured the characteristics of pharyngeal reflexive swallow (recruitment, frequency, variability, and stability), esophageal peristaltic reflexes, cardiac rate modulations, and deglutition apnea and respiratory rhythm disturbances. Feeding method at time of manometric evaluation was exclusive gavage (N=12), transitional gavage (N=12), and exclusive oral (N= 30). Comparisons were made among the 3 types of feeding methods using linear mixed and GEE statistical models. Data presented as mean ± SEM or %. RESULTS: Response characteristics of reflexes of interest evoked upon abrupt graded pharyngeal infusions (N= 402) are classified into 1) pharyngeal reflexes, 2) esophageal reflexes, 3) cardiac rate modulations, 4) respiratory rhythm changes, and 5) volumetric response relationships (Table 1). The ratio (%) of solitary: multiple pharyngeal reflexive swallowing was 19:81 in exclusive gavage, 16:84 in transitional gavage, and 19:81 in exclusive oral feeding strategies (p=0.5). CONCLUSIONS: 1) Infants with exclusive gavage feeding at full term status have prolonged respiratory rhythm disturbances, prolonged esophageal waveform activity, and delayed onset of pharyngo-esophageal reflexes suggesting impairment of pharyngeal afferent and exaggeration of esophageal efferent activity, aberrant respiratory rhythm modulations. 2) Volume dependent pharyngo-esophageal and cardio-respiratory responses occur. 3) Volume-dependent deceleration of heart rate was evident. These findings implicate mal-adaptation of vagovagal reflexes involving pharyngeal-esophageal and cardio-respiratory regulatory neural circuitry. *Supported in part by P01 DK068051 (Jadcherla/Shaker)
1126 Neonatal Colonic Inflammation Modulates Molecular Nociceptive Pathways Resulting in Visceral Hypersensitivity When Re-Exposed to Adult Colon Inflammation Jose Aguirre, John Winston, Don W. Powell, Sushil K. Sarna Background and Aim: Inflammatory bowel disease (IBD) patients experience abdominal pain during inflammatory flare and while in remission. The etiology and pathophysiology of this biological pain remain unknown, though evidence suggests an important role for visceral hypersensitivity (VHS). Epidemiological findings suggest early-life infections are a risk factor for the development of pediatric and adult IBD and adolescent or adult gastrointestinal infections may trigger the onset of IBD or its relapse. We tested the hypothesis that neonatal colonic inflammation (NCI) modulates molecular conditions in nociceptive pathways resulting in VHS, as measured by colorectal distention (CRD), when exposed to subsequent colonic inflammation through modulation of central norepinephrine release and expression of specific spinal cord neurotrophins. Methods: We studied four groups of animals: 1) saline control rats (Ctr. rats); 2) rats subjected only to NCI on post-natal day 10 by colonic administration of trinitrobenzene sulfonic acid (TNBS, 130 mg/kg) (NCI rats); 3) 8 to 12 weeks old naive rats subjected to adult colon inflammation (ACI) for the first time (ACI rats); and 4) 8 to 12 weeks old adult NCI rats subjected to adult colon inflammation by TNBS (68 mg/kg) (NCI+ACI rats). Tissues were collected 7 days following adult TNBS administration. Results: NCI by itself had no significant effect on VHS measured by visceromotor response (VMR) CRD compared to control rats. When compared to all groups, NCI+ACI rats showed a significant (p<0.05) increase of VMR to CRD. Plasma epinephrine and norepinephrine were increased 2-fold (p<0.05) in NCI+ACI rats compared to ACI rats. Heart rate variability analysis was consistent with increased sympathetic and decreased vagal tone in NCI+ACI rats compared to the other experimental groups. Expression of tyrosine hydroxylase (TH) mRNA was increased in the locus ceruleus (3 fold, p<0.05) and TH protein was increased in the adrenal gland (1.5 fold, p<0.05). Enhanced visceral hypersensitivity in NCI+ACI rats was significantly decreased by systemic administration of b2 adrenergic receptor (AR) antagonist propranolol. BDNF protein expression was upregulated 35% (p<0.05) in the LSand 30% ( p<0.05) in TL-spinal cord dorsal horn of NCI+ACI rats vs. the other groups. Compared to controls, BDNF mRNA expression in colon projecting neurons from NCI+ACI rats in S1 DRG was elevated 7-fold but only 3 fold in ACI rats. Intrathecal administration of BDNF antagonist trkBFc significantly reduced VHS in NCI+ ACI rats. Conclusion: These findings support the hypothesis that early-life colonic inflammation triggers epigenetic programming that upregulates TH in the LC and the adrenal medulla as well as BDNF in DRG neurons and spinal cord. The resulting increase of central and peripheral norepinephrine (NE) and spinal cord BNDF enhance VHS.
1127 Sacral Nerve Stimulation for Treatment of Constipation in Children: LongTerm Outcomes, Patient Benefit, and Parent Satisfaction Peter L. Lu, Ilan J. Koppen, Danielle Orsagh-Yentis, Karen Leonhart, Erica J. Ambeba, Katherine J. Deans, Peter C. Minneci, Karen A. Diefenbach, Seth A. Alpert, Marc A. Benninga, Desale Yacob, Carlo Di Lorenzo Background: Treatment options for children with constipation refractory to medical treatment are limited. Recent studies suggest that sacral nerve stimulation (SNS) is an effective treatment option for children with defecation disorders. However, the long-term outcomes
S-227
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AGA Abstracts