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Background & Aims: Patients with systemic sclerosis (SSc) have impairments in gastrointestinal smooth muscle function. The disorder has been associated with circulating antibodies to cholinergic muscarinic the type-3 receptor (M(3)-R). We investigated whether it is possible to neutralize these antibodies with pooled human IgGs (pooledhIgG)., Methods: We studied the effects of IgGs purified from patients with SSc (SScIgGs) on cholinergic nerve stimulation in rat colon tissues. We also examined the effects of SScIgGs on M(3)-R activation by bethanechol (BeCh), M(3)-R occupancy, and receptor binding using immunofluorescence, immunoblot, and enzyme-linked immunosorbent analyses of human internal anal sphincter (IAS) smooth muscle cells, before and after administration of pooledhIgG. Functional displacement of M(3)-R occupancy by the SScIgGs was compared with that of other IgGs during the sustained phase of BeCh-induced contraction of intact smooth muscles from rats., Results: SScIgG significantly attenuated neurally mediated contraction and acetylcholine release in rat colon as well as BeCh-induced sustained contraction of the IAS smooth muscle. In immunofluorescence analysis, SScIgG co-localized with M(3)-R. In immunoblot and enzyme-linked immunosorbent analyses, M(3)-R loop-2 peptide and human IAS SMC membrane lysates bound significant amounts of SScIgG, compared with IgGs from healthy individuals and pooledhIgG. Binding was attenuated significantly by application of pooledhIgG, which by itself had no significant effect. Incubation of samples with pooledhIgG, or mixing pooledhIgG with SScIgG before administration to tissues, significantly reduced binding of SScIgG, indicating that pooledhIgG prevents SScIgG blockade of M(3)-R., Conclusions: In studies of rat and human tissues, pooled human IgG prevent and reverses the cholinergic dysfunction associated with the progressive gastrointestinal manifestations of SSc by neutralizing functional M(3)-R antibodies present in the circulation of patients with SSc., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

This is a report of a patient who manifests all of the features of Carney's syndrome, including gastrointestinal stromal tumors (GISTs), extra-adrenal paragangliomas, and pulmonary chondromas. The patient underwent surgical resection of a gastric GIST; a retroperitoneal, nonfunctional paraganglioma; and a mediastinal, catecholamine-secreting paraganglioma (pheochromocytoma). Recently, new gastric GISTs were diagnosed by endoscopic, ultrasound-guided, fine-needle aspiration (EUS-FNA) biopsy and were resected. Recurrence of stromal tumors following complete resection is common in Carney's syndrome and presents considerable management challenges. This case illustrates several important points: (1) Carney's syndrome, although rare, should be considered in patients with foregut GISTs; (2) GISTs associated with Carney's syndrome, like sporadic gastric GISTs, may have a more indolent clinical course; and (3) EUS-FNA may be useful for the diagnosis and management of GISTs in this syndrome.

Background & Aims: Previous studies have identified adrenergic receptor sites in the lower esophageal sphincter (LES) of animals and humans. A beta3 adrenoceptor has been identified and cloned. The binding site for this receptor has been found in the rat LES in vitro. The aim of the study was to assess the role of a specific beta3 agonist (CL316243) on LES pressure (LESP) in vivo., Methods: Anesthetized adult opossums were given CL316243 and isoproterenol intravenously as boluses before and after continuous infusion of L748337 (a specific beta3 antagonist), propranolol, and bethanechol. Blood pressure, heart rate, and LESP were continuously recorded., Results: CL316243 caused a dose-dependent maximal inhibition of LESP of 88.5% +/- 4.8%. The mean duration of inhibition was 62.2 +/- 9.2 minutes with minimal change in cardiovascular parameters. Isoproterenol caused dose-dependent maximal inhibition of 89.4% +/- 4.7% with mean duration of action of 5.1 +/- 0.9 minutes but was associated with significant hypotension and tachycardia. L748337 and propranolol significantly blocked the effects of CL316243 and isoproterenol, respectively. CL316243 and isoproterenol inhibited the bethanechol-mediated hypertensive LES., Conclusions: (1) A selective beta3 agonist, CL316243, caused significant, prolonged, and dose-dependent inhibition of LESP and, unlike isoproterenol, had minimal effect on heart rate and mean arterial pressure. (2) The beta3 antagonist, L748337, selectively inhibited CL316243 without altering the isoproterenol response. (3) CL316243 and isoproterenol both caused inhibition of cholinergic-mediated hypertensive LESP.

Background/aims: Aspiration pneumonia is one of the most serious complications of gastrostomy tube feeding, with a reported incidence of 10%-20% in nursing home patients. The aims of this prospective study were to examine lower esophageal sphincter (LES) pressure before and after placement of gastrostomy tubes and to examine the effects of rapid intragastric bolus and slow, continuous feeding on LES pressure., Methods: Ten subjects were enrolled in the study. Basal LES pressure was measured before and after placement of gastrostomy tubes. Thereafter, LES pressure was measured for 15 minutes during rapid intragastric infusion of 250 mL of an enteral feeding formula and 100 mL water and continuous infusion of the enteral feeding formula at 80 mL/h. Scintigrams evaluating gastroesophageal reflux were obtained during each method of feeding., Results: Placement of gastrostomy tubes had no effect on basal LES pressure. Rapid intragastric bolus infusion led to a reduction in LES pressure to incompetent levels at 2.1 +/- 2.0 mm Hg (P < 0.001). Free gastroesophageal reflux to the sternal notch was shown by scintigraphy. Slow, continuous gastrostomy feedings did not alter LES pressure (P > 0.05) or show free gastroesophageal reflux by scintigraphy., Conclusions: Gastroesophageal reflux and aspiration in patients fed via the gastrostomy tube may be caused by LES relaxation secondary to gastric distention caused by distention of the stomach.

The purpose of this study was to investigate the mechanism of action of metoclopramide on the lower esophageal sphincter (LES) muscle of the opossum. Metoclopramide gave a dose-related increase in LES muscle active tension. A peak response of 12.5 +/- 2.1 g (mean +/- SEM) was achieved at 3.1 X 10(-4) M. The maximal and submaximal LES muscle response to metoclopramide could not be antagonized by atropine, hyoscine, hexamethonium, tetrodotoxin, phentolamine, diphenhydramine, or propranolol. Metoclopramide did not augment the submaximal muscle responses to gastrin I, acetylcholine, or norepinephrine. These studies suggest that in the opossum, metoclopramide acts through a direct action on the smooth muscle.

Lower esophageal sphincter (LES) pressure was evaluated in response to oral or intravenous metoclopramide in normal subjects and in patients with symptomatic gastroesophageal reflux. Both the oral and intravenous administration of metoclopramide gave a dose-related increase in LES pressure. Complete dose-response curves to the oral compound showed greater absolute responsiveness in normals as compared to patients with LES incompetence. The generally accepted oral dose of 10.0 mg of metoclopramide gave a slight increase in LES pressure which was not consistent in all symptomatic patients. These studies suggest that higher doses of metoclopramide may be required for treating symptomatic gastroesophageal reflux secondary to LES incompetence.

Most benign strictures of the esophagus can be successfully dilated with conventional bougienage techniques. Occasionally strictures are so severe, lengthy, or irregular that these techniques fail, and surgery is required. We describe 2 patients with such severe esophageal strictures that conventional techniques were initially unsuccessful. However, esophageal dilatation of both strictures was successful using the Grüntzig balloon catheter. A torqueable guide wire was initially directed through the stricture under fluoroscopic control. The balloon catheter was then passed over the guide wire and inflated sequentially to a maximum diameter of 9 mm. Subsequent dilatations using conventional techniques were successful. The technique of negotiating severe, irregular esophageal strictures with a torqueable guide wire followed by Grüntzig balloon catheter dilatation may be valuable in the management of severe esophageal strictures.