Redefining the role of lymphocytes in gastroesophageal reflux disease and eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) and reflux esophagitis (RE) overlap clinically and histologically. RE is characterized by epithelial infiltration with small numbers of neutrophils and eosinophils, EoE by a prominent eosinophilic infiltrate. Lymphocytic esophagitis (LE), a new entity characterized by peripapillary lymphocytosis, questions the role lymphocytes play in esophageal inflammation. We test the hypothesis that lymphocyte infiltration in RE differs from EoE. One blinded pathologist read esophageal biopsies from 39 RE and 39 EoE patients. Both groups demonstrated significant numbers of lymphocytes (RE 22.7 +/- 2.2/HPF, EoE 19.8 +/- 1.8/HPF). Eosinophils/HPF in RE and EoE were 2.8 +/- 0.7 and 74.9 +/- 8.2, respectively (P < 0.001). Neutrophils were uncommon in RE (0.26 +/- 0.16/HPF) and EoE (0.09 +/- 0.04; P = 0.07). Eight of the 39 RE specimens had >or=50 lymphocytes in >or=1 HPF. Two were consistent with LE. There was an inverse correlation between numbers of eosinophils and lymphocytes in EoE (R = -0.47; P = 0.002), and no correlation between them in RE (R = 0.18; P = 0.36). The patients with EoE who used antireflux medications had fewer lymphocytes (16.3 +/- 1.3 vs 22.2 +/- 2.3/HPF; P = 0.030) and eosinophils (55.6 +/- 5.2 vs 76.0 +/- 8.7/HPF; P = 0.042) than those who did not. The pathological role of lymphocytes in RE and EoE may be underestimated. Our observation that 5% of the RE specimens meet histopathological criteria for LE potentially blurs the line between these entities. The observation that eosinophil counts are lower in EoE when antireflux meds are used supports the notion that reflux plays a role in the clinical expression of EoE.

Circadian patterns of gastric electrical and mechanical activity in dogs.

Gastric motor function assessment, in humans and animals, is typically performed for short recording periods. The aim of this article was to monitor gastric electrical and motor activity in the antrum and fundus simultaneously, for long periods, using a new implantable system. Ten dogs were implanted with fundic and antral electrodes for assessment of impedance and electrical activity. Dogs were studied while in cages, for periods of 22-26 h. From late evening and until feeding on the next day, slow wave (SW) rhythm demonstrated a distinct pattern of intermittent pauses (mean duration = 22.8 +/-4.1 s) that delineated groups of SW's. Phasic increases in fundic tone were seen mostly in association with SW pauses, and were highly correlated with antral contractions, R(2) = 0.652, P < 0.05. The SW rate (events per minute) in the postprandial period, fasting and night time was 4.2 +/- 0.2, 5 +/- 0.2 and 4.7 +/- 0.3, respectively, P < 0.05 postprandial vs other periods. Antral and fundic mechanical activities were highly correlated during fasting, particularly at night. This novel method of prolonged gastric recording provides valuable data on the mechanical and electrical activity of the stomach, not feasible by current methods of recording. During fasting, fundic and antral motor activities are highly correlated and are associated with periodic pauses in electrical activity.

Neural gastrointestinal electrical stimulation enhances colonic motility in a chronic canine model of delayed colonic transit.

Neural gastrointestinal electrical stimulation (NGES) induces sequential contractions and enhances emptying in acute canine gastric and colonic models. This study was set to determine (i) the effect of NGES in a chronic canine model of delayed colonic transit and (ii) possible mechanism of action. Four pairs of electrodes were implanted in the distal colon of nine mongrel dogs. Delayed colonic transit was induced by diphenoxylate/atropine and alosetron. Transit was fluoroscopically determined by the rate of evacuation of radiopaque markers, and was tested twice in each dog, in random order, on and off stimulation. Two stimulation sequences, separated by 1 min, were delivered twice a day via exteriorized electrodes. Colonic manometry during stimulation was performed before and after intravenous (i.v.) injection of 1 mg of atropine. Complete evacuation of all markers was significantly shortened by NGES, from 4 days to 2 days, interquartile range 3-4 days vs 2-3 days, respectively, P = 0.016. NGES induced strong sequential contractions that were significantly diminished by atropine: 190.0 +/- 14.0 mmHg vs 48.7 +/- 19.4 mmHg, respectively (P < 0.001). NGES induces strong sequential colonic contractions and significantly accelerates movement of content in a canine model of delayed colonic transit. The effect is atropine sensitive.

Treatment of gastroparesis: a multidisciplinary clinical review.

This clinical review on the treatment of patients with gastroparesis is a consensus document developed by the American Motility Society Task Force on Gastroparesis. It is a multidisciplinary effort with input from gastroenterologists and other specialists who are involved in the care of patients with gastroparesis. To provide practical guidelines for treatment, this document covers results of published research studies in the literature and areas developed by consensus agreement where clinical research trials remain lacking in the field of gastroparesis.

Meal-induced secretion of gastrointestinal regulatory peptides is not affected by sleep.

UNLABELLED: The mechanisms responsible for the disruption of the migrating motor complex (MMC) by feeding are not fully understood. Sleep reduces the duration of the postprandial or fed pattern of motility in the intestine. This study was set out to determine if this effect is associated with sleep-induced changes in the secretion of regulatory peptides in response to food. METHODS: Duodenojejunal motility was studied in 15 healthy ambulant subjects for 2 consecutive days. On one day identical solid meals were consumed in the morning and late in the evening, the latter followed by sleep. On the other day, identical liquid meals were infused into the stomach and the duodenum in the morning and late in the evening, the latter after the onset of sleep. Plasma concentrations of gastrin, neurotensin, peptide YY (PYY), pancreatic polypeptide (PP), motilin and glucose were monitored before and after meals. Sleep significantly shortened the duration of the fed pattern after the solid meal and even more so after the liquid meal. The plasma concentrations of all peptides, except motilin, increased significantly following each meal. Blood glucose levels rose after each meal, the changes being similar with all meals. Food-induced gastrointestinal regulatory peptides secretion and intestinal absorption of glucose are not affected by sleep. The vagal response to a meal, as indicated by PP release, is intact during sleep. The results support the importance of neural mechanisms in the modulation of the postprandial pattern of intestinal motility.

Constipation: an approach to diagnosis, treatment, referral.

When a patient reports constipation, a careful history and physical examination may identify the underlying cause. In many patients, though, no underlying cause is identified. Empiric treatment with exercise, hydration, fiber supplementation, and mild laxatives is often effective. If constipation does not resolve with these measures, then the physician may refer the patient for further testing for slow colonic transit, pelvic floor dysfunction, or anatomical defects, and in difficult and recalcitrant cases for surgical treatment.

Diabetic gastropathy: a practical approach to a vexing problem.

The clinical presentation of diabetic gastropathy varies, and a diagnosis usually must be confirmed with tests that evaluate the structure and function of the upper gut. Although glucose control, dietary changes, and drug therapy are the current mainstays of treatment, they may not be effective. Gastric pacing, a new technique that stimulates gastric motility, may give physicians another management tool.

The role of short-term multilumen duodenojejunal manometry in patients with intestinal motor dysfunction.

Short-term duodenojejunal manometry, using a multilumen perfused tube, was performed in 12 patients with symptoms of motor dysfunction, 6 patients with irritable bowel syndrome and predominant diarrhea and 6 patients with chronic constipation. Ten healthy individuals served as controls. The durations, in minutes, of the various phases of the migratory motility complex in the three groups were: phase I: 24.4 +/- 22.1, 26.9 +/- 17.3, and 27.2 +/- 18.5; phase II: 86.7 +/- 25.2, 132 +/- 93, and 73.1 +/- 40.8, and those of phase III: 6 +/- 2.5, 6.8 +/- 5, and 6.4 +/- 1.7, respectively. The differences between patients and controls were not statistically significant. Variables of contractions of phase III in the different groups were: frequency (per minute): 10.9 +/- 0.8, 10.7 +/- 0.4, and 11.3 +/- 0.4; Summation of amplitudes per minute: 205.2 +/- 55.7, 288 +/- 57.9, and 337.8 +/- 76.5; Mean amplitude (mm Hg): 19.1 +/- 4.2, 28.6 +/- 5, and 33.5 +/- 7.1, respectively. Results in the patient groups were not significantly different from controls. Short-term duodenojejunal manometry was normal in patients with irritable bowel syndrome and in those with chronic constipation.

A review of diabetic gastropathy.

Diabetes mellitus affects various organs, including the gastrointestinal tract. The stomach is commonly affected, and symptoms related to the upper GI tract are frequently reported. Management of diabetic gastropathy involves dietary modifications, pharmacological agents, and occasionally, alternative feeding methods.

Review article: the impact of bariatric surgery on gastrointestinal motility.

BACKGROUND: Obesity is a major medical problem worldwide. Different treatment modalities have emerged to treat obese patients, but the best long-term results are achieved with bariatric surgery. Currently, the interventions most commonly performed are laparoscopic adjustable gastric banding (LAGB), Roux-en-Y- gastric bypass (RYGB) and sleeve gastrectomy. AIM: To review the gastrointestinal motor complications associated with each of these types of bariatric interventions and the clinical implications of such complications. METHODS: Search of medical database (PubMed) on English-language articles from January 1996 to March 2011. The search terms used were laparoscopic adjustable gastric banding (LAGB), sleeve gastrectomy (LSG), roux-en-Y-gastric bypass (RYGB), using the AND operator with the terms: complications, motility, GERD, reflux, gastric emptying, esophagitis, dysphagia. RESULTS: Of the three bariatric interventions reviewed, LAGB was the most studied. Most studies reported short follow-up, of ≤ 1 year. Oesophageal motor dysfunction is the most common motility complication following the bariatric interventions that were reviewed and is mainly observed after LAGB. Some data suggest that oesophageal motor function testing predicts development of post-operative symptoms and oesophageal dilation. RYGB offers protection from gastro-oesophageal reflux. Sleeve gastrectomy was the least studied and was associated with an acceleration of gastric emptying. CONCLUSIONS: The effects of these interventions on GI motility should be considered when selecting patients for bariatric surgery. There is scant information regarding the overall effect of sleeve gastrectomy on gastro-oesophageal reflux patterns and oesophageal motility.

Efficacy of the glucagon-like peptide-1 agonist exenatide in the treatment of short bowel syndrome.

BACKGROUND: Short bowel syndrome (SBS) is a serious clinical disorder characterized by diarrhea and nutritional deprivation. Glucagon-like peptide-1 (GLP-1) is a key hormone, produced by L-cells in the ileum, that regulates proximal gut transit. When extensive ileal resection occurs, as in SBS, GLP-1 levels may be deficient. In this study, we test whether the use of GLP-1 agonist exenatide can improve the nutritional state and intestinal symptoms of patients with SBS. METHODS: Five consecutive patients with SBS based on ≤90 cm of small bowel and clinical evidence of nutritional deprivation were selected. Baseline SBS symptoms, demographic and laboratory data were obtained. Antroduodenal manometry was performed on each subject. Each patient was then started on exenatide and over the following month, the baseline parameters were repeated. KEY RESULTS: The subjects consisted of four males and one female, aged 46-69 years. At baseline, all had severe diarrhea that ranged from 6 to 15 bowel movements per day, often occurring within minutes of eating. After exenatide, all five patients had immediate improvement in bowel frequency and form; bowel movements were no longer meal-related. Total parenteral nutrition was stopped successfully in three patients. Antroduodenal manometry revealed continuous low amplitude gastric contractions during fasting which completely normalized with exenatide. CONCLUSIONS & INFERENCES: Exenatide is a novel and safe treatment option for SBS. It produced substantial improvement in the bowel habits, nutritional status and quality of life of SBS patients. Successful treatment with exenatide may significantly reduce the need for parenteral nutrition and small bowel transplant.

The use of gastric electrical signals for algorithm for automatic eating detection in dogs.

Food ingestion increases fundic impedance (FI) and reduces antral slow wave rate (SWR). Our aim was to determine if such changes can be integrated into an algorithm for automatic eating detection (AED). When incorporated in implantable medical devices, AED can time treatment to food intake without need for patient input. Four dogs were implanted with fundic and antral electrodes, connected to an implantable recording device. Changes in FI and SWR induced by fixed meals of different weights were determined, and were used to build an AED algorithm. Its performance was then tested on the same animals given an ad libitum access to food. The effects of gastric balloon distension and nitroglycerin on SWR and FI were also tested. Fixed meals reduced SWR in a weight-dependent manner, R(2) = 0.936, P < 0.05 baseline compared to 50, 100, 200 and 400 g. Meals increased FI above baseline in a weight-dependent manner; R(2) = 0.994, P < 0.05 baseline compared to 200 and 400 g. During ad libitum intake, the AED algorithm detected 86% of all meals > or =15 g. Gastric distension reduced SWR and increased FI. Nitroglycerin reduced SWR. AED, using changes in FI and gastric SWR is feasible. Changes in FI and SWR are induced primarily by the presence of food in the stomach.

Distribution of interstitial cells of Cajal and nitrergic neurons in normal and diabetic human appendix.

The objective of this study was to determine the distribution of enteric nerves and interstitial cells of Cajal (ICC) in the normal human appendix and in type 1 diabetes. Appendixes were collected from patients with type 1 diabetes and from non-diabetic controls. Volumes of nerves and ICC were determined using 3-D reconstruction and neuronal nitric oxide synthase (nNOS) expressing neurons were counted. Enteric ganglia were found in the myenteric plexus region and within the longitudinal muscle. ICC were found throughout the muscle layers. In diabetes, c-Kit positive ICC volumes were significantly reduced as were nNOS expressing neurons. In conclusion, we describe the distribution of ICC and enteric nerves in health and in diabetes. The data also suggest that the human appendix, a readily available source of human tissue, may be useful model for the study of motility disorders.

Small bowel motility: ready for prime time?

The primary function of the small bowel is the absorption of nutrients, and the motor patterns of the healthy bowel are intended to promote that function. The motor patterns of the small bowel are the result of close interaction between the enteric nervous system, extrinsic nerves, regulatory peptides, and the intestinal smooth muscle. The basic electrical rhythm governing intestinal contractions is determined by specialized pacemaker cells called the interstitial cells of Cajal. Diseases affecting any of these components may result in intestinal dysmotility and its associated symptoms. Although transit studies and intestinal manometry are helpful in the diagnosis of dysmotility, our understanding of pathophysiology is hampered by the difficulties involved in obtaining and analyzing intestinal tissue. Treatment of intestinal dysmotility relies on dietary manipulations and nutritional support (enteral or parenteral) because there is no drug therapy that can effectively enhance the propulsive function of the small bowel. Small bowel transplantation remains a life-saving intervention for patients who fail to respond to other therapies.

Fecal incontinence: a practical approach to evaluation and treatment.

Fecal incontinence is a common problem and can have a major impact on the quality of life of those affected. Various disease processes affecting stool consistency, rectal sensitivity, or the anal sphincters can cause fecal incontinence. Obstetric trauma is now known to be a major cause of sphincter dysfunction. The evaluation of the patient with incontinence helps to determine the choice of therapy-medical or surgical. The two most important tests are anorectal manometry, which provides information on sphincter pressures, and rectal sensation, and anal endosonography, which is currently the test of choice for defining the anatomy of the anal sphincters. The choice of therapy depends on the etiology of incontinence, the anatomy of the sphincters, and also on the effect of incontinence on the quality of life of the patient. Control of diarrhea, regardless of the cause, should be attempted first. Biofeedback therapy is effective in the majority of patients and is particularly attractive because it is safe and well tolerated. Surgery is offered when medical therapy is unsuccessful or when the etiology is thought to respond best to surgery, such as in postobstetric trauma. Sphincter repair, for treatment of selective sphincter defects, is the best surgical option. Neoanal sphincters and implanted artificial sphincters are far less attractive because of technical difficulties and low success rate.

Intestinal dysmotility in patients with sphincter of Oddi dysfunction. A reason for failed response to sphincterotomy.

Sphincter of Oddi dysfunction (SOD) is associated with abdominal pain and is treated by sphincterotomy. Of 215 patients who underwent biliary sphincterotomy for SOD in our institution, 26 reported no improvement and 25 of those were found to have pancreatic sphincter dysfunction and subsequently underwent pancreatic septotomy. Nine patients remained symptomatic after the second intervention. Six of those nine patients, and seven of the 16 patients who improved after the septotomy, agreed to undergo an ambulatory duodenojejunal (DJ) manometry. DJ manometry was abnormal in four of the six symptomatic patients but only in one of seven patients who became asymptomatic after endoscopic treatment. We conclude that the persistence of symptoms after endoscopic ablation of the biliary and pancreatic sphincters is associated with abnormal intestinal motility, which may explain in part the lack of response to the endoscopic treatment.

Effect of misoprostol on postprandial intestinal motility and orocecal transit time in humans.

We measured the effect of misoprostol (M), a PGE1 analog, on duodenojejunal postprandial motor activity and orocecal transit in eight healthy volunteers. Intestinal motility was studied by an intraluminal catheter with three strain gauge transducers connected to a solid-state datalogger, and transit time was measured by a hydrogen breath test. Subjects were studied for two consecutive days and fed twice a day with a similar, 600-kcal meal. Misoprostol (M) at 800, 400, or 200 micrograms or placebo were taken orally before every one of the four meals. Transit time was measured after the morning meal on both days, after ingestion of either 800 micrograms of M or placebo. On four occasions, following M, the normal fed pattern was not established and the migrating motor complex (MMC) was not interrupted by the meal. In all other occasions, when the higher doses of M were given, the first 1-2 hr after the meal revealed a hypoactive bowel. This effect was inconsistently seen following 200 micrograms of M. Orocecal transit time was consistently and significantly shorter after M than placebo: 48.3 +/- 9.5 min vs 104.4 +/- 4.8 min, P < 0.0001. Four subjects had diarrhea during the study. We conclude that misoprostol, particularly at higher doses, has a profound effect on intestinal postprandial motility and results in accelerated transit time. The motility changes induced by M may be responsible, in part, for its effect on transit.

Effect of meal composition and sham feeding on duodenojejunal motility in humans.

The disruptive effect of meals of different fat content and caloric value and of sham feeding on the interdigestive migrating motor complex (IDMMC) was studied in eight healthy subjects using an ambulatory recording system that allowed continuous monitoring of small bowel motility for three consecutive days. The durations of fed pattern were not significantly different between meals of 800 kcal/50% fat, 400 kcal/50% fat, and 800 kcal/25% fat, but were significantly longer compared to IDMMC cycle length and sham feeding. The latter two were not significantly different. On a separate day, five subjects consumed a meal of 400 kcal/9% fat and a second one of 800 kcal/50% fat. The duration of the fed pattern following the high fat meal was significantly longer than the low fat one. Sham feeding significantly increased plasma concentrations of gastrin and neurotensin (NT), but did not affect those of cholecystokinin (CCK), insulin, and peptide YY (PYY). The various variables of the IDMMC were not different during the two nights of the study, and velocity of migration of phase III during the first day and both nights was similar. We conclude that the duration of the fed pattern depends, in part, on the composition of the meal. Sham feeding, resulting in an increase in both plasma gastrin and NT concentrations, does not disrupt the IDMMC. When using thin probes, IDMMC is stable during prolonged recording.