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This study evaluated the effects of various levels of dietary calcium on polyp formation, vitamin D homeostasis, and fecal bile acids in the Apcmin mouse. Female Apcmin mice were randomized to three groups and fed a purified diet with either half or double the level of calcium in control AIN-93G. Serum 25-OH-D and fecal bile acids were measured at weeks 0 and 12 of treatment. Mice were killed for polyp scoring by two observers blinded to treatment after 12 weeks. Results show there was no difference in polyp number or tumor load with dietary calcium in any treatment group. Serum 25-OH-D was reduced and total fecal bile acids were increased in animals that received the high calcium diet. We have previously shown that vitamin D supplementation diminishes polyp load; the lack of effect of an altered calcium diet seen here may be due to a disturbance in vitamin D homeostasis.

We tested the hypothesis that stimulation of intestinal mucosal afferent nerves produces an increase in superior mesenteric artery (SMA) but a decrease in mesenteric adipose tissue (MAT) blood flow. In anesthetized rats, blood flow in the SMA (pulsed Doppler flowmetry) and MAT (hydrogen gas clearance) was measured simultaneously before and after administration of 0.9% saline, 640 μM capsaicin, or 5% dextrose into the intestinal lumen. The changes in the SMA were 3.8 ± 3.0, 15.9 ± 4.0, and 18.8 ± 7.6%; and those in the MAT, 4.7 ± 4.0, −11.5 ± 3.4, and −0.07 ± 3.4% of baseline, respectively. The data indicate that exposure of the intestinal lumen to an afferent nerve stimulant or nutrient induced a dichotomous pattern of blood flow changes, an increase in the SMA and a reduction in MAT. The capsaicin-sensitive afferent nerves may be instrumental in mediating these energy responses.

The effects of aging on inhibitory neuropeptide concentrations and intrinsic inhibitory innervation of circular muscle were investigated using normal descending colon obtained at surgery. Immunoreactive vasoactive intestinal peptide, peptide histidine-methionine, met5-enkephalin, neuropeptide Y, and somatostatin were extracted from specimens of muscularis externa (patient ages: 19-84 years) and measured by radioimmunoassay. Intracellular electrical activity was recorded from strips of circular muscle (patients ages: 49-84 years) using glass microelectrodes; inhibitory junction potentials were evoked by electrical field stimulation. There were no significant differences (t tests: P greater than 0.05) between neuropeptide concentrations in patients less than 70 years old (N = 28) compared to patients greater than or equal to 70 years old (N = 12). However, the amplitude of inhibitory junction potentials declined with increasing patient age (r = -0.58, P = 0.02, N = 16), with no change in resting membrane potentials (r = 0.22; P greater than 0.05). The decline in amplitude in women (r = -0.68, P = 0.03, N = 9) preceded the decline in men (r = -0.62, P = 0.10, N = 7). Age-related decline in inhibitory junction potentials could be related to decreased: density of inhibitory nerves, release of inhibitory neurotransmitter, density of binding sites for inhibitory neurotransmitter on smooth muscle, or a combination thereof. Alternatively, this decline might represent a change in interaction of inhibitory neurotransmitter with the smooth muscle membrane, such as a change in coupling of binding site with the potassium channel, decreased number of potassium channels, or altered permeability of the potassium channel.

Use of dual-energy X-ray absorptiometry (DEXA) data to calculate the percent of body fat in the visceral (%VF) and subcutaneous (%SF) compartments and the mechanism of visceral fat vasoconstriction when intestinal mucosal afferent nerves are stimulated has not been reported. The aim of this study was to compare visceral fat weight determined by DEXA and direct weighing and determine whether enalapril attenuates visceral fat vasoconstriction induced by stimulation of intestinal mucosal afferent nerves. We performed two studies. Study 1: In euthanized mice, DEXA scans were obtained before and after visceral fat dissection. The dissected fat weight was determined by DEXA (VF) and by direct weighing. Study 2: In anesthetized rat preparations, visceral (mesenteric) fat blood flow was monitored by laser Doppler flowmetry (LDF). After baseline, vehicle or 3 mg/kg enalapril (angiotensin-converting enzyme inhibitor) was administered intravenously, followed by 2 ml/kg of 640 microm capsaicin intraduodenally. In study 1, there was agreement between visceral fat weight determined by the DEXA (y) and direct weighing (x): y = 0.98x, r = 0.99, n = 10. In study 2, LDF signals showed an instantaneous decline when capsaicin was administered into the duodenal lumen. After enalapril treatment, the reductions were significantly attenuated compared with those after vehicle treatment. DEXA results combined with visceral fat dissection permit determination of body fat distribution. The instantaneous decline in visceral fat blood flow suggests that the reduction is a neural- rather than a hormone-mediated event, and attenuation by enalapril suggests angiotensin II plays a role.

Dietary capsaicin reduces rodent visceral fat weight. We tested the hypothesis that intact intestinal mucosal afferent nerve function is necessary for fat deposition in visceral adipose tissue sites. Rats were treated daily for 2 weeks with intragastric (chronic treatment) vehicle or capsaicin. Superior mesenteric artery blood flow and mesenteric and inguinal fat blood flow were measured before and after capsaicin was administered into the duodenum (acute treatment). Fat from all sites was dissected and weighed. Chronic capsaicin significantly attenuated acute capsaicin-induced mesenteric hyperemia but did not abolish the reflex wiping of the eye exposed to capsaicin, indicating that functional ablation was limited to the intestinal mucosal afferent nerves. The associated vasoconstriction in adipose tissue was inhibited at the visceral (mesenteric) site and maintained but attenuated at the subcutaneous (inguinal) site. The onset of vasoconstriction was instantaneous, indicating a reflex mechanism. There was a redistribution of fat from visceral to subcutaneous sites, reflected by a decrease and an increase in the percentage of body fat in the visceral and subcutaneous sites, respectively. These pilot studies reveal for the first time that normal intestinal mucosal afferent nerve function is necessary for the physiologic accumulation of fat in visceral adipose tissue sites.

This study evaluated the effects of various levels of dietary calcium on polyp formation, vitamin D homeostasis, and fecal bile acids in the Apcmin mouse. Female Apcmin mice were randomized to three groups and fed a purified diet with either half or double the level of calcium in control AIN-93G. Serum 25-OH-D and fecal bile acids were measured at weeks 0 and 12 of treatment. Mice were killed for polyp scoring by two observers blinded to treatment after 12 weeks. Results show there was no difference in polyp number or tumor load with dietary calcium in any treatment group. Serum 25-OH-D was reduced and total fecal bile acids were increased in animals that received the high calcium diet. We have previously shown that vitamin D supplementation diminishes polyp load; the lack of effect of an altered calcium diet seen here may be due to a disturbance in vitamin D homeostasis.

Our aims were to examine the influence of neural isolation of the jejunoileum on postprandial pancreatobiliary secretion. In four dogs, duodenal perfusion and aspiration catheters were implanted, and serosal electrodes were placed along the proximal small bowel. Control studies of gastric emptying, output of bile acids and amylase, and plasma concentrations of peptide YY and neurotensin were performed on three occasions following ingestion of a 340-kcal mixed-nutrient liquid meal. The dogs then underwent our model of in situ jejunoileal neural isolation, and the meal studies were repeated. Neural isolation, when compared to control, did not affect either postprandial conversion of intestinal myoelectric activity to the "fed" pattern, gastric emptying (T1/2, X +/- SE of the liquid meal (74 +/- 6 vs 79 +/- 7 min; P greater than 0.05), or cumulative amylase output (373 +/- 59 vs 305 +/- 66 kU; P greater than 0.05). Neural isolation decreased cumulative postprandial bile acid output from 6.6 +/- 0.9 mM to 3.4 +/- 1.1 mM (P less than 0.05) and increased postprandial plasma concentrations of peptide YY and neurotensin. Our findings suggest that the jejunoileal denervation that accompanies the in situ neural isolation of the jejunoileum is not associated with changes in postprandial motility patterns, gastric emptying, or pancreatic amylase secretion. Loss of this innervation, however, may decrease postprandial output of bile acids and lead to a compensatory increase in the postprandial release of neurotensin and peptide YY.

Concentrations of the candidate endocrine and paracrine peptide, peptide YY, were measured by specific radioimmunoassay in tissue extracts prepared from normal ileum, normal colon, Crohn's disease, and ulcerative colitis. In both the ascending and descending colon, there were significantly decreased mean concentrations of peptide YY in Crohn's colitis and ulcerative colitis, compared to mean concentrations in normal colon. There was no age-related decrease of concentrations of peptide YY in normal colon. The decrease in concentrations of peptide YY in colon obtained from patients with inflammatory bowel disease did not appear related either to the duration of the clinical symptoms of the disease or to the severity of colonic inflammation. Further studies of the physiological function of peptide YY in man are needed to determine whether these findings might be useful in understanding a component of the pathophysiology of idiopathic inflammatory bowel disease.

Information concerning bowel habits was gathered from a representative sample of 14,407 United States adults in the first National Health and Nutrition Examination Survey in 1971-1975 and approximately 10 years later among the same individuals. The prevalence of self-reported constipation, diarrhea, infrequent defecation (three or fewer bowel movements per week), and frequent defecation (two or more bowel movements per day) increased with aging. Women were more likely than men (P less than 0.05) to report constipation (20.8% compared to 8.0%) and infrequent defecation (9.1% compared to 3.2%). Blacks were more likely than whites to report infrequent defecation (P less than 0.05). Older respondents reporting constipation were more likely to use laxatives or stool softeners than younger respondents reporting constipation, but they were also less likely to have infrequent defecation. To evaluate factors predictive of impaired bowel function, case definitions were created using information concerning complaint of constipation, laxative use, frequency of defecation, and stool consistency. Female gender, black race, fewer years of education, low physical activity, and symptoms of depression were independent risk factors for impaired bowel function. This study provides national estimates of bowel complaints and their natural history and examines possible risk factors for constipation.

Factors implicated in the pathogenesis of gastric ulcer were studied simultaneously in seven patients with strictly defined type 1 gastric ulcer (single benign ulcer above the incisura of the stomach) and in six healthy controls. After ingestion of an ordinary solid-liquid meal, patients with gastric ulcer demonstrated gastric hyposecretion of acid, pepsin, and water; delayed gastric emptying of solids with normal emptying of liquids; and increased intragastric concentrations of bile acids. These functional abnormalities appear to be interrelated. Metoclopramide, administered orally in a double-blind fashion, ameliorated the defect in the emptying of solids and the high concentrations of bile acid in the gastric contents. The ability of this drug to break this interdependent cycle suggests the need for further clinical investigation.

Radioscintiscanning techniques and the pattern of serum gastrin responses to secretin and calcium infusions, and to ingestion of a test meal, correctly identified the presence of an isolated retained antrum in a patient with prior gastric surgery. This well documented case report shows that such a diagnostic approach is feasible and practical.

To further assess the molar ratio of branched-chain to aromatic amino acids as a measure of disease activity, we correlated results of this test with histologic features of inflammation, standard biochemical tests, and prognosis in 68 patients with severe chronic active hepatitis. An abnormal molar ratio (less than 3.0) reflected histologic findings of chronic active hepatitis in 26 of 35 instances. A normal molar ratio (greater than or equal to 3.0), however, was associated with histologic features of chronic active hepatitis in nine of 14 instances. Molar ratio abnormalities occurred more frequently in patients with cirrhosis than without cirrhosis (95% vs 45%, P less than 0.01). Only one of 20 patients with cirrhosis had a normal ratio, and none of 12 followed serially during therapy improved the ratio to normal. No correlation was seen between the molar ratio and severity of inflammation or serum levels of aspartate aminotransferase, albumin, bilirubin, and gamma globulin. When corticosteroids were discontinued, relapse occurred as frequently in patients with a normal molar ratio as in others (80% vs 71%), and the presence of an abnormal ratio did not preclude a sustained remission after treatment. We conclude that the plasma molar ratio does not reflect histologic activity, correlate with standard liver function tests, or indicate disease behavior after treatment withdrawal. A normal molar ratio during or after treatment, however, may exclude cirrhosis.

We have compared responses to an ordinary solid-liquid (S) meal and to a homogenized (H) meal of identical composition (sirloin steak, bread, butter, ice cream with chocolate syrup, and water) by measuring simultaneously postprandial gastric, pancreatic, and biliary functions by marker-perfusion techniques. Responses to each (S or H) meals differed strikingly both in magnitude and pattern. S meals elicited a stronger early gastric secretory response (acid, pepsin, and volume) which compensated for faster initial emptying and resulted in higher gastric acidity and volume than after H meals. Further, nutrients ingested with S meals were emptied at a slower rate than H (as evidenced by a more gradual decline in intragastric buffer and osmolality, as well as time required for complete emptying of the meal). This, in turn, prolonged pancreatic and biliary responses since stimulation of these organs continued for as long as meal was delivered into the duodenum. However, early biliary outputs (gallbladder response) were less after S than H, probably because nutrients entered the duodenum more slowly and were initially diluted by rapidly emptying water. The physical characteristics of each meal (encompassing appearance, taste, and form of ingestion) probably accounted for early differences in digestive responses. Later, interactions between gastric (motor and secretory), pancreatic, and biliary functions played a major role. Our findings suggest that gastric, pancreatic, and biliary responses to liquid test meals introduced into the stomach may differ substantially from the presumably more physiological response to ordinary solid-liquid meals.

Regulation of the exocrine pancreatic secretion elicited by a meal in man is incompletely understood. In this study, we attempted to localize in the gastrointestinal tract areas that control postprandial trypsin secretion and to determine the effects of individual components of jejunal chyme on the meal-stimulated trypsin secretion. Trypsin outputs elicited by ingesting a mixed-nutrient meal and diverting it at the ligament of Treitz proximal to an occlusive balloon were compared with those occurring when the same meal was ingested, diverted at the ligament of Treitz, and immediately reinfused distal to the balloon, a procedure that exposed the entire gastrointestinal tract to chyme. Two different meals, one of semielemental and one of complex nutrients, were used with similar results. Trypsin outputs were similar whether or not jejunal chyme was diverted. In addition, no component--exogenous nutrients or endogenous secretions--of chyme reaching the jejunum after a meal further modified the trypsin secretion elicited by the gastroduodenal segment. This finding suggests that the gastroduodenal segment is sufficient to elicit the entire postprandial trypsin output and is the physiologic determinant of meal-stimulated trypsin secretion.

The purpose of our interdisciplinary meeting is to provide a forum for the communication of recent research in gastrointestinal hormones. The Fifth International Symposium will cover a broader scope than before: i t will include chemistry, morphology, evolution, pharmacology and physiology, as well as receptors and clinical application of all endocrine, paracrine and neuronal peptides of the gastrointestinal tract.