M1834 E-Cadherin Cleavage in Gastroesophageal Reflux Disease (GERD)

M1834 E-Cadherin Cleavage in Gastroesophageal Reflux Disease (GERD)

immunohistochemical staining of FOXP3 and CD45. Furthermore, mucosal transcript levels of TGF-beta1 and IL-10 were studied and all data were correlate...

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immunohistochemical staining of FOXP3 and CD45. Furthermore, mucosal transcript levels of TGF-beta1 and IL-10 were studied and all data were correlated with histopathological values according to the updated Sydney classification. Results: GERD was associated with a chronic inflammation (P=0.065) and reduced FOXP3-mRNA in the cardiac mucosa (84%) as compared to controls, whereas H. pylori-positive patients revealed a 25.1-fold (P= 0.03) increase of FOXP3 gene expression. These results were confirmed by immunohistochemical analysis of intramucosal FOXP3+ Tregs. The absolute number [0.78+/-0.15 versus 2.65+/-0.44, P<0.001] as well as their proportion among all infiltrating immune cells [2.65+/0.61% versus 8.14+/-1.38%, P<0.001] were significantly reduced in patients with GERD than those infected with H. pylori. Conclusion: The GERD-associated chronic inflammation at the cardia is not associated with an infiltration of FOXP3+ Tregs. The regulation of chronic inflammation in GERD is distinct from the common involvement of FOXP3+ Tregs in other chronic inflammatory diseases of the GI tract as presented for H. pylori infection.

M1832

Background & Aim: An occupation-related susceptibility of several categories of orchestral musicians, as the wind instruments players, to experience gastro-esophageal reflux was hypothesized. We investigated a series of professional orchestral musicians, comparing reflux symptoms referred from wind instruments players with those from players of other instruments (control). Methods: A structured questionnaire was distrubuted to 1083 musicians (414 wind instruments players and 669 players of other instruments) of 21 orchestras of 15 Italian towns in order to obtain information on reflux symptoms in the year preceding the survey together with selected individual characteristics and life style habits. Prevalence rate ratios, adjusted for the type of instrument played, gender, age, body mass index, smoking status, alcohol consumption and other confounding factors, were computed. Results: Wind instrument players reported a statistically significant higher prevalence of heartburn and regurgitation than the other instrument players, with adjusted prevalent rate ratios of 1.23 (CI 95% 1.04-1.46) and 1.23 (CI=0.97-1.55). Conclusions: Wind instrument players among orchestral musicians reported a higher prevalence of reflux symptoms than other instruments players. Future studies will be needed to clarify whether reflux symptoms in professional opera choristers are stress-induced and therefore may be considered as a work-related discomfort.

M1830 Modulation of Salivation and Heartburn in Response to the Site of Acid Infusion in Human Esophagus Sudhir K. Dutta, Kireet Agrawal, Mitchell Mah'moud Introduction: Gastroesophageal reflux disease (GERD) is associated with a variety of clinical manifestations ranging from heartburn (HB) to chest pain (Gastroenterol. Clin. North Am. 2008; 37:845). Salient factors in the pathogenesis of this disorder include amount of acid reflux (frequency, duration and extent of mucosal exposure), salivation, and esophageal peristalsis. Several clinical observations suggest that there may be a differential expression of the disease depending on its magnitude of mucosal exposure to the acid reflux. Aim/ Objective: We postulated that salivation and heartburn in response to intraluminal acid exposure may vary according to site of acid infusion in human esophagus. Materials/Methods: To test this hypothesis, twelve healthy subjects were enrolled in this study after obtaining informed consent. Each study subject received infusions of Hydrochloric acid (HCl) (100mmol/L) in the upper {20cm above lower esophageal sphincter (LES)} and the lower esophagus (10cm above LES). HCl was infused for 20 minutes and parotid saliva was collected periodically. HB severity score was tabulated using a standardized and validated scale. Standard statistical methods were used to determine the significance of difference between the various groups. Results: Intraluminal perfusion of HCl in the upper esophagus was associated with greater mean Parotid saliva flow rate (PSFR) (0.75±0.03ml/min) as compared to the lower half (10cm above LES) (0.54±0.05 ml/min) (p<0.05). The heartburn score per unit of time was also significantly elevated in the upper esophagus (8±1) as compared to the lower esophagus (5.5±1) with acid infusion (p<0.05). There was no heartburn at all upon acid infusion in the stomach. Summary: Our data suggest that intraluminal HCl infusion in the upper esophagus is associated with greater parotid salivary secretion and higher HB score (p<0.05). These observations may be related greater number of Hydrogen ion receptor exposure in the esophageal mucosa and/or increased density of sensory innervations by the vagus nerve in the upper esophagus. Keywords: Acid infusion, Heartburn, salivation.

M1833 Strong Correlation Between Squamocolumnar Junction Position and Age in Healthy Volunteers John P. Seenan, Angela A. Wirz, Alan T. Clarke, Andrew W. Kelman, Kenneth E. McColl INTRODUCTION: The gastric cardia is an important site of pathology with a high incidence of inflammation, metaplasia and neoplasia. However this complex area is poorly understood and it has been proposed that cardia mucosa itself may be pathological, arising from columnar metaplasia of the distal esophageal squamous mucosa. Previous autopsy studies show a near absence of cardia epithelium in neonates and an increase in length with age. AIMS & METHODS: Aim: To determine if the position of the squamocolumnar junction (SCJ) within the lower esophageal high pressure zone (HPZ) changes with age in healthy subjects. Methods:15 Helicobacter pylori negative subjects (9 males) were studied. Each underwent upper GI endoscopy with clipping of a radio-opaque endoclip at the squamocolumnar junction. On a separate study day, synchronized 36 sensor high resolution manometry and videofluoroscopy was performed with subjects fasted and in a semi-recumbent position. A 10 second analysis period of stable sphincter tone (out with sphincter relaxations) was selected. The proximal high pressure zone was identified from manometry data as a stepdown in pressure to the intrathoracic pressure. The location of the SCJ was determined using image analysis software with the measured distance of a pH sensor (known to be 1cm) used as a scale. The distance between the position of the SCJ and the proximal HPZ was calculated for each individual. RESULTS: The median age of the subjects was 25 years (Range 20-59). The median distance between SCJ position and proximal HPZ position for the group was 3.59cm (Range 0.31-4.46) . There was a strong negative correlation between age and distance between SCJ and proximal HPZ ,(r = -0.831, p<0.001) with the squamocolumnar junction closer to the proximal HPZ with increasing age. The correlation was even stronger in males alone (r = -0.961, p<0.001). In multiple regression analysis the combination of both increasing age and body mass index was significantly associated with movement of the SCJ closer to the proximal HPZ (R2=73.6%, P<0.001) with a strong trend towards significance for both individual variables (p=0.053 and p=0.088 respectively). CONCLUSION: The position of the squamocolumnar junction relative to the proximal high pressure zone is strongly correlated to age in healthy subjects. This is consistent with proximal migration of the squamocolumnar junction due to columnar metaplasia of the distal esophageal squamous mucosa.

M1831 Gastroesophageal Reflux Disease Is Inversely Related with Glycemic Control in Morbidly Obese Patients Carlos Augusto S. Madalosso, Richard R. Gurski, Liana O. Ruas, Priscila Santini, Fernando Fornari Background: Recent evidence has linked metabolic syndrome with reflux esophagitis. The aim of this study was to assess the relation between glycemic control (GC) and gastroesophageal reflux disease (GERD) in morbidly obese patients. Methods: Eighty six patients (25 males, aging 38 ± 12 years, BMI 45 ± 8 kg/m2) underwent solid-state esophageal manometry, 24-h esophageal pH-metry, endoscopy and barium swallow X-ray after responding a GERD symptom questionnaire [heartburn ranging 0 (best) to 30 (worst)] and dosing both fasting plasma glucose (FPG in mg/dL) and glycosylated hemoglobin (HbA1c in %). Patients with poor GC (HbA1c 6.1-10 and FPG < 140) and those with very poor GC (HbA1c > 10 or FPG > 140) were compared. Results: Six patients were excluded due to normal HbA1c (< 6.1) with FPG < 140. Out of 80 patients, 63 composed the group poor GC (15 male, aging 38 ± 12 years, BMI 45 ± 7 kg/m2, HbA1c 7.7 ± 0.8) and 17 patients the group very poor GC (8 male, aging 42 ± 11 years, BMI 47 ± 9 kg/m2, HbA1c 10.5 ± 1.3). Patients with very poor GC showed better scores for heartburn [0 (0-4) vs. 8 (0-12); P = 0.003] but similar rates of reflux esophagitis (41% vs. 48%; P = 0.364). Total esophageal acid exposure [median (IQR)] was significantly lower in patients with very poor GC [2.3% (0.8-7.5%) vs. 5.2% (2.5-10.5%); P = 0.041]. Distal esophageal amplitude (134 ± 63 vs. 105 ± 38 mm Hg; P = 0.019) and lower esophageal sphincter pressure (29 ± 11 vs. 23 ± 13 mm Hg; P = 0.025) were both higher in the group of patients with very poor GC. These patients showed significantly less hiatal hernia at X-ray (6% vs. 38%; P = 0.016), as well as lower expiratory gastroesophageal pressure gradient (GEPG: 5.2 ± 3 vs. 7 ± 3.4 mm Hg; P = 0.050) and higher ventilatory gradient (inspiratory - expiratory GEPG: 13.6 ± 4.1 vs. 10.9 ± 3.8 mm Hg; P = 0.012) than patients with poor GC. Conclusions: This study suggests an inverse relation between glycemic control and GERD in morbidly obese patients. This finding seems to be related with lower rates of hiatal hernia in patients with very poor glycemic control. In these patients, increased ventilatory gradient might be a marker of higher abdominal complacence and diaphragm integrity.

M1834 E-Cadherin Cleavage in Gastroesophageal Reflux Disease (GERD) Biljana Jovov, Nicholas J. Shaheen, Zorka Djukic, Roy C. Orlando Background: The presence of dilated intercellular spaces within esophageal squamous epithelium of GERD patients, both erosive and nonerosive forms, suggests the presence of damage to the apical junctional complex (AJC), i.e. zonula occludens and zonula adherens, since the AJC regulates permeability via the intercellular space in this tissue. Methods: For detection of such damage, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and immunoblots were performed on esophageal biopsies from GERD patients (n=12) and healthy controls (n=4) for zonula occludens-1 (ZO-1), multiple claudins, occludin, and e-cadherin. Immunofluorescence (IF) detection was used to determine localization of proteins of interest, and enzyme-linked immunosorbent assay (ELISA) for quantification of soluble e-cadherin in plasma. Results: qRT-PCR demonstrated prominent down regulation of claudin-4 in GERD patients. Immunoblots, using a C-terminus monoclonal anti e-cadherin antibody, showed cleavage of e-cadherin in GERD patients. Two bands were detected, one of 120 kDa band corresponds to intact e-cadherin, and the other of 38 kDa band corresponds to C-terminus fragment. Interestingly, using an N-terminus antibody, increased levels of a soluble 80 kDa fragment of e-cadherin was detected by ELISA in the plasma of GERD patients (20.5 ± 2.1 μg/ml; n=10), compared to healthy controls 11.74 ± 0.9 μg/ml; n=10. Moreover, since the size of the cleaved e-cadherin fragment suggests possible proteolysis by a disintegrin and metalloprotease10 (ADAM10), Western blot and IF analysis were performed, and those analysis demonstrated increased levels of ADAM10 in GERD patients biopsies. Conclusions: These findings suggest that dysfunction of the AJC in GERD involves both down regulation of claudin-4 and proteolytic cleavage of e-cadherin. Since the product of e-cadherin cleavage is detectable in plasma and at higher levels in GERD patients than controls, consideration should be given to its possible use as a diagnostic or prognostic plasma marker in GERD. (Support: NIH grants DK036013 and DK063669).

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AGA Abstracts

AGA Abstracts

Reflux Symptoms in Orchestral Wind Instrument Players Giovanni Cammarota, Giovanna Masala, Rossella Cianci, Domenico Palli, Benedetta Bendinelli, Gianluca Ianiro, Raffaele Landolfi, Giovanni Gasbarrini, Antonio Gasbarrini