Biomedical subjects

J B Meddings

Publications and source records attributed to J B Meddings.

At least 37 records · Page 2Linked to original sources

PubMed1999

Intravenous fish oil emulsion attenuates total parenteral nutrition-induced cholestasis in newborn piglets.

Total parenteral nutrition (TPN) causes intrahepatic cholestasis and membrane phospholipid changes. Fatty acid (FA) composition of bile and hepatocyte phospholipid is influenced by dietary FA composition. We hypothesized that altering FA composition of i.v. lipid emulsions modifies 1) severity of TPN-induced cholestasis; 2) hepatocyte membrane composition and function; 3) bile flow and composition. Newborn piglets received either sow's milk, TPN with i.v. soybean oil or TPN with i.v. fish oil (FO). After 3 wk, basal and stimulated bile flow were measured after bolus injections of 20, 50, and 100 micromol/kg of taurocholate (TCA). Bile was analyzed for bile acids, cholesterol, phospholipids, and phospholipid-FA. Sinusoidal and canalicular membrane PL-FA, fluidity, and Na+/K+-ATPase were measured. Although the soybean oil-fed animals developed cholestasis, the FO and milk group had similar liver and serum bilirubin. Basal and stimulated bile flow rates were impaired in the soybean oil but not in the FO group. Hepatocyte membrane FA composition reflected dietary FA. Changes in sinusoidal and canalicular membrane fluidity and sinusoidal Na+/K+-ATPase activity did not explain the effect of FO on TPN-induced cholestasis. Intravenous FO reduces TPN-induced cholestasis by unknown mechanisms.

Animals↗

PubMed1999

Bowel permeability and CD45RO expression on circulating CD20+ B cells in patients with ankylosing spondylitis and their relatives.

OBJECTIVE: Ankylosing spondylitis (AS) is reportedly associated with subclinical endoscopic gut inflammation in up to 57% of patients. Studies of bowel permeability, however, have not consistently revealed abnormalities in these patients. CD20+CD45RO+ expression is associated with increased antigen exposure, and previous work has shown increased expression in this B cell isoform in patients with Crohn's disease and their relatives, correlating with intestinal permeability abnormalities. We sought to re-examine intestinal permeability in patients with AS and their relatives, and relate any observed alterations in permeability with evidence of increased antigen presentation as assessed by the number of circulating B cells that were CD45RO positive. METHODS: We studied small intestinal and gastric permeability by measurement of excretion of lactulose, mannitol, and sucrose in 60 patients with AS and 24 of their first-degree relatives. We also studied expression of CD20+CD45RO+ by flow cytometry in these patients. RESULTS: Both patients and first-degree relatives had significantly increased small intestinal, but not gastric, permeability compared to controls. Among patients, current users of nonsteroidal anti-inflammatory drugs (NSAID) had significantly increased small intestinal permeability compared to nonusers, but relatives not using NSAID also had increased permeability. CD20+CD45RO+ expression was increased in one-third of patients but did not correlate with permeability abnormalities. CONCLUSION: Patients with AS have altered small intestinal, but not gastric, permeability. NSAID use cannot explain all the abnormality. Bowel permeability abnormalities, possibly genetically determined, may antedate development of bowel or joint symptoms. Increased CD20+CD45RO+ expression suggests increased antigen exposure, which may be related to previous or current intestinal permeability abnormalities.

Adult↗

PubMed1998

Discrimination of site-specific alterations in gastrointestinal permeability in the rat.

BACKGROUND & AIMS: Detection of gastrointestinal damage can be accomplished by permeability testing. However, current methodology presents several problems, including lack of site specificity and an inability to easily measure colonic damage. We hypothesized that probes of similar size could be used to simultaneously assess permeability along the length of the gastrointestinal tract. Differentiation of damage sites could be made, provided that probes were selectively destroyed at different levels. Class 1 probes should be destroyed after leaving the stomach, class 2 after leaving the small intestine, and class 3 not at all. In this manner, class 1 probes would report damage to the proximal gut, class 2 to the small intestine, and class 3 to the gut as a whole. METHODS: We defined saccharide probes with these characteristics and observed their permeability patterns in defined models of localized gastrointestinal damage. RESULTS: With gastric damage, permeability of only class 1 probes increased, whereas with colonic damage only permeation rates of class 3 probes was increased. Furthermore, the permeation rates of both class 2 and 3 probes increased in the presence of small intestinal disease. CONCLUSIONS: These techniques allow a single screening test that is sensitive to damage at any level of the gastrointestinal tract and may be used in either animals or humans.

Animals↗

PubMed1998

Sucrose permeability as a means of detecting diseases of the upper digestive tract.

The healthy gastric epithelium will not allow easy permeation of a disaccharide-sized molecule such as sucrose. However, during gastric damage, intact sucrose can pass the gastric epithelium and ultimately appear in the urine. We examined the relationship between total urinary sucrose excretion and various diseases. We used 149 patients (105 had upper gastrointestinal disease, 12 had gastric cancer and 32 were normal). Subjects were given a solution containing 100 g sucrose in 450 c.c. water. All urine was collected for 7.5 h. The urinary sucrose concentration was determined by anion exchange high-performance liquid chromatography. Total urinary sucrose excretion was significantly higher in patients with gastric ulcer and those with gastric cancer than in endoscopically normal controls. In the 34 patients with gastric ulcer, the total sucrose excretion was closely correlated with ulcer size. Ulcer location did not affect urinary sucrose excretion. A strong correlation was also observed between sucrose excretion and lesion size in the 12 patients with gastric cancer. The sucrose permeability test may be a relatively sensitive method to detect gastric disease.

Case-Control Studies↗

PubMed1998

The utility of endoscopy in the management of patients with gastroesophageal reflux symptoms.

OBJECTIVE: The utility of endoscopy in the management of patients with symptoms of gastroesophageal reflux disease (GERD) is unclear. The purpose of this prospective study was to assess the impact of endoscopy on the subsequent management of patients with uncomplicated reflux symptoms. METHODS: A total of 742 patients underwent endoscopy for symptoms of GERD. Endoscopists recorded the therapy before endoscopy, the findings of endoscopy, and the treatment recommendations after endoscopy. RESULTS: There was no difference in pre-endoscopy therapy or grade of esophagitis in subjects undergoing endoscopy for failed therapy versus GERD symptoms alone. After endoscopy, the most common strategy for patients taking omeprazole was to maintain or increase the dose. For those taking an H2 blocker before endoscopy, the most common outcome was to switch the patient to omeprazole, independent of the grade of esophagitis. CONCLUSIONS: Most patients undergoing endoscopy for symptoms of GERD were switched to omeprazole regardless of the endoscopic findings. No esophageal cancer was identified and the incidence of Barrett's esophagus was low. It appears that endoscopy itself did not change the management of patients receiving H2-blocker therapy. A trial of a proton pump inhibitor before endoscopy should be considered.

Adolescent↗

PubMed1998

Vagal involvement in dietary regulation of nutrient transport.

In omnivores, gradual alterations in dietary nutrient composition are observed. To efficiently absorb dietary nutrients these animals alter intestinal nutrient transporter expression to match the pattern of nutrient intake. This often involves reprogramming the crypt cell to express greater numbers of the relevant transport system. The aim of this study was to determine whether vagal afferents are involved in this adaptive process. Guinea pigs were habituated to a low-carbohydrate diet and then switched to a high-carbohydrate diet. The resultant increase in glucose transporter expression was assessed by determining rates of glucose transport in jejunal brush-border membrane vesicles. Ablation of vagal afferents was accomplished by application of capsaicin to exposed cervical vagi and confirmed using Fast blue tracer studies. We found that animals in which vagal afferents were ablated with capsaicin were unable to alter rates of glucose transport in response to an increase in dietary carbohydrate. This suggests that vagal afferents are involved in this adaptive process. These findings support a role for the vagus nerve in regulating intestinal transport function, which may be important to consider in clinical disease that involves the vagus nerve.

Adaptation, Physiological↗

PubMed1998

GLP-2 augments the adaptive response to massive intestinal resection in rat.

To determine whether treatment with a potent protease-resistant analog of human glucagon-like peptide 2 (GLP-2) might augment the adaptive response to massive intestinal resection, rats were divided into resected, which had 75% of the midjejunoileum removed, sham-resected, and nonsurgical groups. Within each group, animals were assigned to 21 days of treatment with the drug (0.1 micrograms/g of the GLP-2 analog in phosphate-buffered saline) or vehicle alone subcutaneously twice daily. Food intake; weight gain; jejunal and ileal diameters, total and mucosal wet weights per centimeter, crypt depths, and villus heights; mucosal sucrase activity, milligrams of protein per centimeter, and micrograms of DNA per centimeter; and D-xylose absorption were measured. There was a significant increase in diameter, total and mucosal wet weights per centimeter, crypt-villus height, sucrase activity, milligrams of protein per centimeter and micrograms of DNA per centimeter in both the jejunum and ileum in response to resection and a significant additive response to the GLP-2 analog in the jejunum but not in the ileum. The ratio of milligrams of protein per centimeter to micrograms of DNA per centimeter of mucosa was not different among groups, consistent with hyperplasia. D-Xylose absorption was significantly reduced in response to resection; however, the GLP-2 analog enhanced the absorptive capacity in control animals and restored the absorptive capacity in resected animals. Thus the GLP-2 analog induces mucosal hyperplasia and enhances the rate and magnitude of the proximal intestinal adaptive response to massive resection.

Adaptation, Physiological↗

PubMed1998

Increased intestinal permeability is associated with the development of multiple organ dysfunction syndrome in critically ill ICU patients.

We conducted a prospective, observational cohort study designed to compare intestinal permeability (IP) and development of multiple organ dysfunction syndrome (MODS) in a subset of critically ill patients in an intensive care unit (ICU). All patients with an expected ICU stay of 72 h or more were entered into the study, and IP was determined on a daily basis whenever possible from the urinary fractional excretion of orally administered lactulose and mannitol (LMR). Forty-seven consecutive patients were studied, and 28 developed MODS either at the time of admission or during their ICU course. These patients, as a group, had significantly worse IP at admission than did a non-MODS cohort (LnLMR: -2.10 +/- 1.10 versus -3.26 +/- 0.83). Those patients who developed MODS following admission also had a significantly greater admission IP than did the non-MODS group (-2.51 +/- 0.85). Differences in IP between cohorts could not be explained by differences in the incidence of systemic inflammatory response syndrome (SIRS)/sepsis or shock. With multivariate regression analysis, the only parameter present on admission that was predictive of subsequent MODS was IP. Differences in IP and the severity of organ dysfunction were also present (MODS severity mild: -3.01 +/- 0.72; moderate: -1.97 +/- 0.69; and severe: -1.12 +/- 0.96). Patients who developed MODS had a persistently abnormal IP during their ICU stay, and a significantly delayed improvement in their IP compared with the non-MODS cohort. We conclude that the development of MODS is associated with an abnormal and severe derangement of IP that is detectable prior to the onset of the syndrome. This observation lends credence to the premise that gastrointestinal (GI) dysfunction may be causally associated with the development of MODS in the critically ill patient.

Adult↗

PubMed1997

Gastrointestinal permeability in celiac disease.

BACKGROUND & AIMS: Intestinal permeability is increased in patients with active celiac disease. The measurement of sucrose permeability is proposed as a novel means to detect upper gastrointestinal damage, with potentially greater use than conventional methods. The aim of this study was to evaluate the effectiveness of sucrose in the detection of celiac disease. METHODS: Permeability tests were performed in 27 newly diagnosed patients, at diagnosis, after upper gastrointestinal endoscopies were performed to exclude macroscopic gastric lesions, and after 2 months on a gluten-free diet. Results were compared with those obtained in 30 healthy subjects and 7 patients with chronic diarrhea but no evidence of celiac disease. RESULTS: At diagnosis, 25 of 27 patients had increased urinary excretion of sucrose. Mean sucrose excretion in patients with untreated celiac disease was significantly increased compared with healthy controls and controls with disease. Sucrose excretion decreased significantly after treatment and completely normalized in 60% of patients. The lactulose-mannitol ratio was abnormal in 26 of 27 patients, with a mean value significantly greater than that observed in healthy controls. This ratio also significantly declined after treatment; however, no values returned to the normal range. CONCLUSIONS: Increased sucrose permeability is a sensitive marker for advanced celiac disease. Moreover, it decreases rapidly in response to a gluten-free diet and therefore is potentially useful to follow response to therapy.

Adolescent↗

PubMed1997

Effects of altered cardiac membrane fluidity on beta-adrenergic receptor signalling in rats with cirrhotic cardiomyopathy.

BACKGROUND/AIMS: The relationship between cardiac plasma membrane physical properties and beta-adrenergic receptor signalling function in cirrhotic cardiomyopathy remains unclear. We aimed to clarify this issue by examining the effect of altering membrane fluidity on beta-adrenergic receptor signalling in cirrhotic rats. METHODS: Cirrhosis was induced by chronic bile duct ligation, while controls were sham-operated. Left ventricular papillary muscle contractility was measured in an organ bath containing 95% oxygen saturated Tyrode's buffer. Cardiac plasma membrane physical properties, represented by membrane fluidity, were evaluated by fluorescent depolarization, using 1,6-diphenyl-1,3,5,-hexatriene as a probe. Membrane cAMP levels were measured after stimulation at the beta-adrenoceptor level by isoproterenol (10(-4) mol/l), the G-protein level with AIF(-4) (10 mmol/l) and the adenylyl cyclase level with forskolin (100 micromol/l) before and after membrane fluidization with 2-(2-methoxyethoxy)ethyl 8-(cis-2-n-octylcyclopropyl)octanoate (A2C). RESULTS: Maximum papillary muscle contractile force under isoproterenol stimulation was 0.48+/-0.05 and 0.34+/-0.03 N/cm2 in sham-operated and bile duct ligated rats, respectively (p<0.05). Cardiac membranes from cirrhosis were rigid and this was associated with diminished cAMP generation. After the fluidity of membranes from cirrhotic rats was restored to control values with A2C, cAMP production stimulated with isoproterenol was significantly increased. However, cAMP production stimulated by AIF(-4) and forskolin did not differ before and after membrane fluidization. CONCLUSIONS: The blunted cardiac contractility of cirrhosis was associated with decreased membrane fluidity and diminished beta-adrenergic receptor signalling. The results suggest that in cirrhotic cardiomyopathy, the rigid plasma membrane interferes with the beta-adrenoceptor and G-protein coupling process.

Animals↗

PubMed1997

Increased gastrointestinal permeability in patients with Plasmodium falciparum malaria.

Sequential gastrointestinal permeability in patients with Plasmodium falciparum malaria was determined by measuring the permeation of sucrose, lactulose, and mannitol to assess both gastric and small intestine permeability. Sucrose absorption (gastroduodenal permeability) was increased in patients with severe malaria (defined as either >5% parasitemia or a serum bilirubin level of >50 micromol/L) and became normal by day 2 following treatment. A similar proportion of patients with uncomplicated malaria had increased gastroduodenal permeability initially, which resolved by day 7 of treatment. During acute malarial illness, the lactulose: mannitol (L:M) ratio in urine was increased and was found to be higher in patients with severe malaria than in those with uncomplicated malaria and in controls, but this ratio reverted to normal during convalescence. At the time of admission, the L:M ratios in patients with uncomplicated malaria were increased but became normal by day 2 after treatment. Conversely, the duration of increased L:M ratios in patients with severe malaria was longer. By day 7, the L:M ratios in patients with severe malaria were higher than those in patients with uncomplicated malaria and in controls. We conclude that gastrointestinal permeability is increased during severe and uncomplicated falciparum malaria but reverts to normal during convalescence.

Adolescent↗

PubMed1997

Review article: Intestinal permeability in Crohn's disease.

Measurements of intestinal permeability (IP) may help in determining susceptibility for the development of Crohn's disease or for imminent relapse in patients with the disease. It is now apparent that a subset of patients at high risk for the development of Crohn's disease have either increased baseline IP or an exaggerated response to environmental agents that increase IP. These, coupled with observations that increased IP in patients at risk for the development of Crohn's disease is associated with an abnormal immunological phenotype, lend support to the hypothesis that increased IP is a very early event in the genesis of Crohn's disease.

Animals↗

PubMed1997

Endoscopists' opinions of indications for upper gastrointestinal endoscopy.

OBJECTIVE: To determine whether endoscopists and general internists agreed with the characterization of appropriateness for endoscopy of various clinical scenarios, as previously reported by the RAND Corporation. DESIGN: Mail survey. STUDY SAMPLE: All endoscopists in western Canada and a random sample of general internists who did not perform endoscopy. METHODS: Questionnaires were sent to 179 endoscopists in western Canada who were asked to rate the 53 scenarios for endoscopy on a nine-point scale ranging from most appropriate to most inappropriate. A similar questionnaire was sent to 39 general internists practising in the province of Alberta. RESULTS: Response rate was 72% of endoscopists (n = 128) and 64% of general internists (n = 25). Among the endoscopists, there was agreement with the RAND classification for 32 scenarios. All 18 indications previously thought to be appropriate were considered to be appropriate. However, endoscopists agreed with only six of 16 equivocal and eight of 19 indications considered inappropriate. Discrepancies were reviewed by five experienced endoscopists and most appeared to be related to a concern regarding possible malignancy linked in part with the definition of failure to respond to medical therapy; and to a refusal to request a barium meal before endoscopy. Among general internists, there was agreement with RAND in 26 scenarios. When the appropriateness rankings of endoscopists and general internists were compared, there was agreement in 40 of 53 scenarios. Significant discrepancies in ratings were identified in scenarios in which barium studies were described as being normal, known or not done. CONCLUSIONS: The equivocal and inappropriate ratings developed by the RAND Corporation are not uniformly accepted by the endoscopy community or general internists. Use of the RAND indications for assessing quality assurance can be challenged.

Adult↗

PubMed1996

Opioid receptors on guinea-pig intestinal crypt epithelial cells.

1. Opioid peptides promote net intestinal absorption via two mechanisms: stimulation of Na+ and Cl- absorption and inhibition of Cl- secretion. Although these transport changes are predominantly mediated by submucosal neurones, it is currently unclear whether opioid peptides can regulate enterocyte function directly. We therefore tested the hypothesis that enterocytes have specific opioid receptors. 2. Villus and crypt jejunal epithelial cells were isolated by the distended sac method from anaesthetized guinea-pigs. Flow cytometry was used to resolve enterocytes from other cell types and to determine whether binding of a fluorescently labelled opioid antagonist, naltrexone-FITC, could be prevented by unlabelled mu- and delta-opioid receptor agonists. A population of crypt enterocytes (approximately 21%) exhibited high-affinity naltrexone-FITC binding to both mu- and delta-type binding sites that was stereoselective and sodium dependent. Villus enterocytes did not exhibit any of these characteristics. 3. Basal cAMP production was elevated in both villus and crypt cells treated with IBMX (3-isobutyl-1-methylxanthine). Villus cells did not respond to 100 nM vasoactive intestinal peptide (VIP), nor were they affected by opioid peptides. In contrast, 100 nM VIP significantly increased cAMP production in crypt epithelial cells, which was significantly reduced by both morphiceptin and D-Ser2-Leu-Enk-Thr. This opioid-mediated effect was stereoselective and blocked by the opioid receptor antagonist naltrexone. 4. These experiments suggest that enterocytes isolated from the crypt epithelium of guineapigs have both mu- and delta-types of opioid receptors. It is possible that these cells participate in opioid-mediated regulation of intestinal secretion.

1-Methyl-3-isobutylxanthine↗

PubMed1996

The anti-oxidant properties of 5-aminosalicylic acid.

Oxidative damage to biological membranes is an important cause of tissue injury in inflammatory bowel disease. 5-Aminosalicylic Acid (5ASA) has therapeutic efficacy in Ulcerative colitis, which may be based on its antioxidant properties. We used Parinaric acid as a fluorescent marker of oxidation in an intestinal microvillous brush border membrane preparation. Various concentrations of the antioxidants 5ASA, ascorbate, and tocopherol were added, and oxidation was initiated from within the membrane by 2,2' azobis (2.4-dimethylvaleronitrile) (AMVN) and from solution by 2,2' azobis (2-amidinopropane) hydrochloride (AAPH). Tocopherol was able to inhibit oxidation from either source. Ascorbate was only able to inhibit oxidation initiated from solution. 5ASA was able to inhibit oxidation initiated from either site, and was more effective than tocopherol against AAPH, but similarly effective against AMVN. We postulate that water soluble 5ASA preferentially associates with membrane surface, allowing chain-breaking antioxidant activity when peroxidation is initiated within the membrane. Likewise, it is effective against aqueous oxidants because its position allows it to interact with AAPH before lipid peroxidation can be initiated as well as breaking the lipid peroxidation chain once it is initiated. This dual capacity may be important for therapeutic effect of 5ASA and may suggest other candidate antioxidants for clinical trials.

Amidines↗

PubMed1996

Intravenous ursodeoxycholic acid reduces cholestasis in parenterally fed newborn piglets.

BACKGROUND & AIMS: Cholestasis complicates total parenteral nutrition (TPN) in preterm infants. Ursodeoxycholic acid (UDCA) is used for several cholestatic problems. The hypothesis of this study was that intravenous UDCA prevents TPN-induced cholestasis by (1) maintaining normal basal and stimulated bile flow, (2) altering bile composition, and (3) changing hepatocyte membrane composition and Na+,K(+)-adenosine triphosphatase (ATPase) activity. METHODS: Three groups of piglets were studied: group 1 received sow's milk, groups 2 and 3 received TPN, and group 3 also received 100 mumol.kg-1.day-1 UDCA intravenously. After 3 weeks, basal and stimulated bile flow were measured. Cholesterol, bile acids, phospholipids, and phospholipid fatty acids were analyzed in bile, and fluidity, phospholipid fatty acid composition, and Na+,K(+)-ATPase were analyzed in hepatocyte membranes. RESULTS: Bile acid secretion and basal and stimulated bile flow were similar in control and UDCA-treated animals but reduced to < 50% in the TPN group. Bile acid-dependent and -independent bile flow were lower in the TPN group. UDCA did not normalize abnormalities in TPN-induced bile composition. Sinusoidal but not canalicular membrane fluidity was different in TPN than in control and UDCA-treated animals. UDCA also increased Na+,K(+)-ATPase activity. Bile and membrane phospholipid fatty acids reflected dietary fatty acids. CONCLUSIONS: Intravenous UDCA improves bile flow and reduces bilirubin levels in the serum and liver in piglets with TPN-induced cholestasis.

Animals↗

PubMed1996

Substrates for hypothalamic PGE2 synthesis are not decreased in cholestatic rats.

We have recently described impaired IL-1 beta-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis in cholestatic rats and have implicated defective IL-1 beta-mediated hypothalamic generation of PGE2 in this finding. Since patients with obstructive cholestasis have decreased levels of PGE2 precursor fatty acids in their red blood cell membranes (arachidonic acid) we speculated that a similar deficiency of membrane prostaglandin percursor fatty acids in the hypothalamus of cholestatic rats may contribute to the defective cytokine-mediated PGE2 generation we have previously described. Therefore, in this study we determined red blood cell and hypothalamic membrane fatty acid composition in rats with obstructive cholestasis due to bile duct resection and in non-cholestatic sham resected controls 5 days after operation. To do this red blood cell membrane and hypothalamic membrane fatty acids were extracted, methyl esterified and quantified by gas liquid chromatography. Similar to results found in patients with obstructive cholestasis, bile duct resected rats had significantly reduced levels of red blood cell membrane arachidonic acid compared to levels in sham resected controls (p < or = 0.02). However, bile duct resected and sham resected rats had similar levels of hypothalamic membrane arachidonic acid. Therefore, these results suggest that the impaired IL-1 beta-induced HPA axis activation in cholestatic rats cannot be explained by lower hypothalamic membrane levels of the PGE2 substrate arachidonic acid in these animals. Furthermore, our results suggest that the brain in cholestasis appears to be protected from membrane fatty acid composition alterations which are seen outside the blood-brain-barrier.

Animals↗

PubMed1996

Intestinal permeability changes in response to acetylsalicylic acid in relatives of patients with Crohn's disease.

BACKGROUND & AIMS: Presence of a familial intestinal permeability defect in Crohn's disease remains controversial despite numerous studies. The purpose of this study was to determine whether detection of a permeability defect in first-degree relatives of patients with Crohn's disease can be enhanced using an acetylsalicylic acid provocation test. METHODS: Lactulose-mannitol ratio, a measure of intestinal permeability, and total sucrose excretion, a measure of gastroduodenal permeability, were determined before and after ingestion of acetylsalicylic acid in healthy controls, in patients with Crohn's disease, and in the first-degree relatives of patients with Crohn's disease. Subjects were classified as hyperresponders if their results were above the mean of + 2SD of the controls. RESULTS: First-degree relatives had a 110% increase in intestinal permeability after acetylsalicylic acid compared with an increase of 57% in controls (P = 0.001). Thirty-five percent of relatives were classified as hyperresponders. There was no significant difference in the change in sucrose excretion between relatives and controls (259% vs 198%; P < 0.05). CONCLUSIONS: First-degree relatives of patients with Crohn's disease have an exaggerated increase in intestinal but not gastroduodenal permeability in response to acetylsalicylic acid. This study supports a familial permeability defect in Crohn's disease, which may not be present in all families.

Adult↗