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Environmental and lifestyle factors play an important role in the natural history of Crohn's disease and ulcerative colitis. A group of international experts from the International Organization for the Study of Inflammatory Bowel Diseases voted on a series of consensus statements to inform the management of inflammatory bowel disease (IBD). The recommendations include avoiding traditional cigarette smoking in patients with Crohn's disease or ulcerative colitis, screening for symptoms of depression, anxiety, and psychosocial stressors at diagnosis and during flares (with referral to mental health professionals when appropriate), and encouraging regular physical activity as tolerated. Patients using dietary approaches for treatment of their IBD should be encouraged to adopt diets that are best supported by evidence and involve monitoring for the objective resolution of inflammation. We recommend formal assessment for obesity and nutritional deficiencies, and patients should be encouraged to maintain a normal body-mass index. A shared decision-making approach to contraception should include the consideration of IBD-related factors, and risk factors for venous thromboembolism. Long-term or frequent use of high-dose non-steroidal anti-inflammatory drugs should be avoided. For primary prevention of disease in the offspring of patients with IBD, we recommend avoiding passive exposure to tobacco, using antibiotics judiciously, and considering breastfeeding when able.

Background & Aims: Bone loss is a common complication of human inflammatory bowel disease (IBD), but its mechanisms are not understood completely. We investigated bone metabolism in interleukin-10-deficient (IL-10-/-) mice, an animal model with IBD features. Methods:IL-10-/- male mice (8- and 12-weeks-old) and their age-matched wild-type counterparts (C57BL/6J) were studied. Bone mass of the femur was determined by ashing. Tibial cancellous and cortical bone mass and formation was measured by static and dynamic histomorphometry. Biomechanical strength of the femur was tested. Primary bone marrow stromal cell cultures were used to assess osteoblast generation. Serum levels of 25-OH vitamin D"3, insulin-like growth factor-1 (IGF-1), parathyroid hormone, osteocalcin, and deoxy-pyridinoline cross-links were measured. The presence of colitis was determined histologically, and by IL-12 and interferon-@c (IFN-@c) secretion from cultured colonic explants. Results: Eight- and 12-week-old IL-10-/- mice developed osteopenia of both cancellous and cortical bone, evidenced by lower femoral ash weight, cancellous bone area and surface, trabecular number, and decreased cortical bone area and width. Osteopenia was associated with mechanical fragility, manifested by decreased stiffness and mechanical load at fracture, and was caused by suppressed bone formation, indicated by decreased cancellous double-labeled surface, mineralizing surface, serum osteocalcin level, and mineralized nodule number in bone marrow stromal cell cultures. IL-10-/- mice with colitis had significantly less bone mass compared with IL-10-/- mice without colitis. Conclusions:IL-10-/- mice develop the hallmarks of osteoporosis, that is, reduced bone mass, increased mechanical fragility, and suppressed bone formation. The presence of colitis is an important contributor to osteoporosis in IL-10-/- mice.

Background & Aims: We tested whether the attenuation of experimental colitis by live probiotic bacteria is due to their immunostimulatory DNA, whether toll-like receptor (TLR) signaling is required, and whether nonviable probiotics are effective. Methods: Methylated and unmethylated genomic DNA isolated from probiotics (VSL-3), DNAse-treated probiotics and Escherichia coli (DH5@a) genomic DNA were administered intragastricly (i.g.) or subcutaneously (sc) to mice prior to the induction of colitis. Viable or @c-irradiated probiotics were administered i.g. to wild-type mice and mice deficient in different TLR or in the adaptor protein MyD88, 10 days prior to administration of dextran sodium sulfate (DSS) to their drinking water and for 7 days thereafter. Results: ntragastric and sc administration of probiotic and E. coli DNA ameliorated the severity of DSS-induced colitis, whereas methylated probiotic DNA, calf thymus DNA, and DNase-treated probiotics had no effect. The colitis severity was attenuated to the same extent by i.g. delivery of nonviable @c-irradiated or viable probiotics. Mice deficient in MyD88 did not respond to @c-irradiated probiotics. The severity of DSS-induced colitis in TLR2 and TLR4 deficient mice was significantly decreased by i.g. administration of @c-irradiated probiotics, whereas, in TLR9-deficient mice, @c-irradiated probiotics had no effect. Conclusions: The protective effects of probiotics are mediated by their own DNA rather than by their metabolites or ability to colonize the colon. TLR9 signaling is essential in mediating the anti-inflammatory effect of probiotics, and live microorganisms are not required to attenuate experimental colitis because nonviable probiotics are equally effective.

Background & aims: This analysis of Crohn's disease patients treated with infliximab in ACCENT I compared episodic and scheduled treatment strategies under conditions that simulate clinical practice. Methods: After 5 mg/kg infliximab at week 0, 573 patients were randomized to infusions at weeks 2 and 6 and every 8 weeks until week 46 of placebo (episodic), infliximab 5 mg/kg at weeks 2 and 6 followed by 5 mg/kg (5 mg/kg scheduled) every 8 weeks, or infliximab 5 mg/kg at weeks 2 and 6 followed by 10 mg/kg (10 mg/kg scheduled) every 8 weeks. At or after week 14, treatment could be given with a dose of infliximab 5 mg/kg higher upon loss of response. Results: The efficacy of scheduled infliximab therapy was better than episodic treatment. Crohn's Disease Activity Index (CDAI) scores were consistently significantly better in the 10 mg/kg scheduled maintenance group from weeks 10 to 54, and response and remission rates (combined scheduled) were significantly higher from weeks 10 to 30. A greater proportion of patients achieved complete mucosal healing at week 54 (P = 0.041). A lower proportion developed antibodies to infliximab in the scheduled groups than in the episodic group (9% [5 mg/kg], 6% [10 mg/kg], 28% [episodic], respectively). Scheduled strategy patients had fewer Crohn's disease-related hospitalizations (P = 0.014) and surgeries (P = 0.01) than episodic strategy patients. Conclusions: The scheduled infliximab groups, particularly the 10 mg/kg group, had better CDAI and Inflammatory Bowel Disease Questionnaire (IBDQ) responses than those in the episodic group. Both scheduled groups had fewer hospitalizations, higher rates of mucosal healing, and fewer developed antibodies than those in the episodic group, with no increase in side effects.

Background & Aims: Impaired mucosal barrier, cytokine imbalancE. and dysregulated CD4^+ T cells play important roles in the pathogenesis of experimental colitis and human inflammatory bowel disease. Immunostimulatory DNA sequences (ISS-DNA) and their synthetic oligonucleotide analogs (ISS-ODNs) are derived from bacterial DNA. are potent activators of innate immunity at systemic and mucosal sites, and can rescue cells from death inflicted by different agents. We hypothesized that these combined effects of ISS-DNA could inhibit the damage to the colonic mucosa in chemically induced colitis and thereby limit subsequent intestinal inflammation. Methods: The protective and the anti-inflammatory effect of ISS-ODN administration were assessed in dextran sodium sulfate-induced colitis and in 2 models of hapten-induced colitis in Balb/c mice. SimilarlY. these effects of ISS-ODN were assessed in spontaneous colitis occurring in IL-10 knockout mice. Results: In all models of experimental and spontaneous colitis examineD. ISS-ODN administration ameliorated clinical, biochemical, and histologic scores of colonic inflammation. ISS-ODN administration inhibited the induction of colonic proinflammatory cytokines and chemokines and suppressed the induction of colonic matrix metaIloproteinases in both dextran sodium sulfate- and hapten-induced colitis. Conclusions: As the colon is continuously exposed to bacterial DNA. these findings suggest a physiologic, anti-inflammatory role for immunostimulatory DNA in the GI tract. Immunostimulatory DNA deserves further evaluation for the treatment of human inflammatory bowel disease.

GASTROENTEROLOGY 1999;117:1008-1011

A randomized, double-blind, placebo-controlled study was conducted to determine whether concomitant administration of ranitidine reduces gastroduodenal mucosal damage associated with 1 week of indomethacin treatment. One hundred ten subjects with acute muculoskeletal conditions and who received indomethacin 150 mg/ day completed the trial: 55 were treated with ranitidine 150 mg b.i.d. and 51 subjects received placebo b.i.d. Endoscopic gastric and duodenal injury were assessed before and after one week of treatment. There was no statistically significant difference in the percentage of patients with gastroduodenal damage or in the severity of the lesions in both treatment groups. Ranitidine did not ameliorate indomethacin-induced gastrointestinal symptoms and there was no correlation between upper gastrointestinal symptoms and endoscopic findings.

We examined 27 patients with portal hypertension admitted because of acute UGI bleeding endoscopically within 24 hours. We identified esophageal-gastric varices as the bleeding source in 22 patients, and found no acute mucosal lesions in any of them. In only four patients was chronic liver disease due to alcohol consumption. We therefore suggest that acute mucosal lesions as a cause of UGI bleeding in patients with portal hypertension are common only in those with alcoholic cirrhosis.

In this double-blind, parallel-group multicenter study, patients with endoscopically proven gastric ulcers were randomly allocated to treatment with either 50 µg or 200 µg of misoprostol or 300 mg of cimetidine, each given four times daily for four weeks. Endoscopic, clinical and laboratory assessments were made before treatment and after four weeks; clinical and laboratory assessments were repeated at two weeks. In the Korean center, assessments were also made after six weeks and at eight weeks of treatment. Six hundred and thirty patients were studied. The three treatment groups were similar in age and occupation. However, the proportion of men in the misoprostol 50-µg, 200-µg and cimetidine 300-mg groups was 67%, 63%, and 59%, respectively. Therapeutic success was defined as complete healing of all ulcers, judged endoscopically. On an intent-to-treat basis, which includes all losses to follow-up and withdrawals as treatment failures, ulcer healing rates in the misoprostol 50-µg, 200-µg and cimetidine 300-mg groups were 39%, 51%, and 58%, respectively. In the Korean center, the healing rates were 38%, 64%, and 70%, respectively, after eight weeks of treatment. There was no statistically significant difference in the healing rates at four weeks between the misoprostol 200-µg and cimetidine 300-mg groups (P=0.16). The healing rate with the misoprostol 200-µg dose was significantly better than with the 50-µg dose (P=0.008). Cimetidine 300 mg relieved global pain significantly better than misoprostol 200 µg at two weeks (P=0.047) but not at four weeks. The 200-µg dose of misoprostol relieved pain significantly better than the 50-µg dose at four weeks (P=0.019), but not at two weeks. All three treatments were well tolerated. Severe adverse events were rare.

Systemic administration of capsaicin aggravates ethanol-induced injury of rat gastric mucosa. We evaluated the effect of subcutaneous administration of capsaicin on the gastric mucosa and on inflammatory mediators in saline- and ethanol-treated rats. Functional ablation of primary afferent C-fibers by capsaicin (total 100 mg/kg subcutaneous) tripled ethanol-induced damage. Pretreatment with ketotifen, a mast cell stabilizer (1 mg/kg) protected rat gastric mucosa from the amplified injury induced by capsaicin and ethanol. Tempol, a selective nontoxic cell-permeable nitroxide, completely prevented the amplified gastric ulceration induced by capsaicin and ethanol. This was accompanied by a significant decrease in leukotriene B4 and C4 generation. It is therefore suggested that mast cells and free radicals contribute to the amplified injury observed in rats pretreated with capsaicin and ethanol and that the pharmacological modulation of mast cell release and scavenging of free radicals may be of therapeutic efficacy in the prevention of gastric injury.

Thein vivo effect of substance P and related peptide analogs on gastrointestinal transit in unanesthetized rats was studied. Fasted male rats were given intragastrically 0.5 ml of a powdered charcoal (BaSo4·H2O) meal and were concomitantly injected intraperitoneally with 8 ?g/kg of substance P or a related peptide. In control rats, the percentage of small intestine traversed by the meal 15 min after feeding was 44.9±1.4 (N = 12). Substance P, [Glu6]SP6–11, [pGlu6, gPhe6, mGly9]SP6–11 and [pGlu5,N-MePhe8,N-MeGly9SP6–11, significantly accelerated intestinal transit: 59.5±3.1% (N=7); 66.0±3.8% (N=14), 66.8±2.4% (N=25), and 58.4±4.4% (N=4), respectively. Concomitant injection of [pGlu6SP6–11 and BOC-Phe-Phe-Gly-NHOH, an inhibitor of enzyme degradation at a dose of 800 ?g/kg lowered by 10-fold the dose of [pGlu6]SP6–11 needed to induce the same degree of intestinal transit acceleration. These results indicate that in rats, substance P and related peptides accelerate gastrointestinal transit.

Two approaches to the recruitment of subjects for screening for fecal occult blood were tested in two middleclass neighborhoods in Jerusalem. After invitations were mailed to 2,909 persons aged 40 and older, 855 (29) requested the special “Colo-Screen” packet of slides; and 496, one-sixth of those contacted originally, ultimately returned stool specimens for examination. In a parallel campaign by family doctors, invitations were distributed personally to 324 patients visiting a Sick Fund Clinic; 225 (69) requested Colo-Screen slides and 137 (42 of the persons invited) sent in stool specimens. Males and females responded equally. Of the 633 specimens received, 29 (4.6) were positive for occult blood; two cancers and seven adenomatous polyps were found and resected. Screening programs for colorectal cancer should encourage greater personal participation of family doctors in the recruitment process.

The effect of duodenal ulcer healing induced by omeprazole on gastroduodenal generation of eicosanoids, platelet-activating factor (PAF), pepsinogen A, and gastrin was evaluated. Sixty patients with endoscopically proven duodenal ulcer were randomized to receive 20 mg omperazole once daily or 300 mg ranitidine at bedtime for 2 weeks. Patients whose ulcers did not heal were treated for an additional 2 weeks. Endoscopic biopsy specimens and serum samples were obtained before and after treatment. There was no significant difference in the healing rate between the two treatment modalities. At 2 weeks healing rates were 60% and 56% in the omperazole and ranitidine groups, respectively, whereas at 4 weeks the respective healing rates were 96% and 86%. Ulcer healing induced by omeprazole and ranitidine was not accompanied by significant changes in mucosal leukotriene B4 or C4 generation. Mucosal PAF significantly decreased in patients treated with omeprazole for 4 weeks. In omperazole-treated patients there was a trend towards increase in mucosal prostaglandin E2 generation which was significant in the fundus after 4 weeks of treatment. After 2 weeks of omeprazole treatment, serum gastrin and pepsinogen A levels almost doubled when compared with their pretreatment levels. In conclusion, duodenal ulcer healing with 20 mg omeprazole daily is not superior to healing rates with 300 mg ranitidine at bedtime after both 2 and 4 weeks of treatment. In omeprazole-treated subjects ulcer healing was accompanied by a significant decrease in mucosal PAF generation and increased levels of serum gastrin and pepsinogen A.

Platelet-activating factor (PAF), leukotriene B4 (LTB4), and leukotriene C4 (LTC4) generation by gastroduodenal mucosa was assessed in duodenal ulcer patients and in normal subjects, to elucidate their possible role in the pathogenesis of peptic ulcer disease. Endoscopic fundic, antral, and duodenal biopsy specimens were obtained from 35 duodenal ulcer patients on the day the diagnosis was established and from 42 normal controls. In duodenal ulcer patients PAF generation, determined by platelet aggregation, was two- to three-fold higher than its respective generation by normal subjects. LTB4 and LTC4 synthesis by cultured antral and duodenal mucosa obtained from duodenal ulcer patients was twofold higher than their synthesis by normal subjects. Fundic LTB4 and LTC4 generation was similar in ulcer patients and controls. In 11 patients PAF, LTB4, and LTC4 generation was also assessed after 4 weeks of treatment resulting in ulcer healing and found to be significantly reduced when compared with their synthesis when the ulcer was active. These results thus suggest that PAF, LTB4, and LTC4 may have a role in the pathogenesis of duodenal ulcer, and therefore their modulation may have therapeutic benefits.

The effect of immunosuppressive drugs, 4-aminosalicylic acid (4-ASA), acetyl 5-aminosalicylic acid (S-ASA), and ketotifen on human colonic eicosanoid accumulation was evaluated in view of enhanced accumulation in patients with active ulcerative colitis. Azathioprine (100 üg/ml), cyclosporin (100 üg/ml), and methotrexate (100 üg/ml) significantly inhibited, by 25-35%, prostaglandin E, (PGE,) accumulation by organ-cultured colonic mucosa of ulcerative colitis patients. Methotrexate was the only immunosuppressive drug that inhibited leukotriene B4 (LTB4) accumulation (50%), whereas azathioprine inhibited the accumulation of leukotriene C4 (LTC,) (25%). 5-ASA and its metabolite, acetyl 5-ASA, inhibited by 20-70% PGE2, LTB, and LTC4 accumulation in the culture, supporting the contention that acetyl 5-ASA is as active as 5-ASA in these respects. 4-ASA had no effect on any of the eicosanoids. Ketotifen, a mast cell stabilizer, significantly inhibited the accumulation of PGE2, LTB4, and LTC4 by 33-60%. These results suggest a potential, new, unrecognized mode by which the immuno-modulators induce part of their therapeutic effects in inflammatory bowel disease and support the contention that acetyl 5-ASA is as active as 5-ASA. The results obtained also indicate that ketotifen, used effectively in the prevention of bronchial asthma, inhibits the accumulation of colonic eicosanoids and, thus, may be of value in the treatment of inflammatory bowel disease.

Colonic biopsy specimens from patients with active ulcerative colitis and controls were incubated for four hours in the presence or absence of calcium ionophore or antihuman immunoglobulin E (IgE). Platelet-activating factor (PAF) was determined in the tissue by aggregation assay after extraction with 80% ethanol. PAF was not detected in normal mucosa, whereas A23187 and antihuman IgE stimulated its activity: mean ±SE, 43.2±8.6 and 33.0±6.1 pg/10 mg wet weight, respectively. In active ulcerative colitis, A23187 and antihuman IgE induced significantly higher stimulation of PAF synthesis compared to their effects on normal mucosa. The enhanced stimulation of PAF induced by A23187 was dose-dependently inhibited by sulphazalazine, 5-aminosalicylic acid and prednisolone, but not by sulfapyridine. Colonic interleukin-1 content and release during 24 h of culture were significantly higher in patients with active ulcerative colitis and Crohn's disease compared to normal subjects. Prednisolone significantly and dose-dependently inhibited interleukin-1 release. These results suggest that colonic generation of PAF and interleukin-1 are elevated in patients with inflammatory bowel disease and, thus, may have a role in its pathogenesis. Pharmacological suppression of colonic PAF and interleukin-1 production may have beneficial therapeutic effects.

The hypothesis that bisacodyl induces intestinal fluid accumulation by increasing mucosal PGE2 content, inhibiting (Na+K) ATPase, and stimulating adenyl cyclase activities was tested in rats. Eighteen hours after its intragastric administration, bisacodyl (5.0 mg/kg body wt) decreased significantly jejunal and colonic (Na+K) ATPase activity: 36.4±1.4 (se) and 28.3±1.4, respectively, as compared to 42.1±1.6 and 37.0±2.9 µmol/mg protein/hr in saline-treated rats. Bisacodyl administration increased significantly jejunal and colonic PGE2 content and stimulated jejunal and colonic adenyl cyclase activity as compared to those in control rats. Jejunal and colonic cAMP content was not significantly increased by bisacodyl. Four hours after its administration, bisacodyl increased intestinal PGE2 content but failed to stimulate adenyl cyclase activity. Pretreatment with indomethacin prevented the increase in PGE2 content and the stimulation of adenyl cyclase induced by bisacodyl. Only jejunal phosphodiesterase activity was stimulated by bisacodyl (10 mg/kg body wt). The results reported thus suggest that intestinal inhibition of (Na+K) ATPase activity, increase of mucosal PGE2 content, and possibly also stimulation of adenyl cyclase activity might contribute to the net water accumulation induced by bisacodyl. It is also suggested that the stimulation of adenyl cyclase activity is mediated by increase in mucosal PGE2 content.

A familial study of 189 Jewish Crohn's disease patients was conducted in order to evaluate the risk for inflammatory bowel disease (IBD) in relatives of the patients and to try to understand better the genetic component in the etiology of the disease among Jews. One hundred fifty-seven patients filled out questionnaires that were verified by personal interviews. In 10 families (6.6%), a first-degree relative of the propositus was found to have IBD, seven Crohn's disease and three ulcerative colitis. Among first-degree relatives, siblings were more frequently affected: of 400, five had Crohn's disease and one ulcerative colitis. Among 304 parents, two had Crohn's disease and two ulcerative colitis, while none of the propositi's children had IBD. The prevalence of first-degree relatives with Crohn's disease was similar in the 98 and 45 families of Ashkenazi and non-Ashkenazi origin: 5.1% and 4.4%, respectively. The risk for siblings of the probands to be affected were also similar in the two groups: 1.5% and 1.8%; while parents of the probands were affected only in the group of Ashkenazi Jews.

Capsaicin-sensitive afferent neurons are involved in maintaining the integrity of the gastro-intestinal mucosa. These neurons are closely apposed to mast cells and could, therefore, lead to their activation. In the present study, the role of capsaicin-sensitive neurons in the pathogenesis of experimental colitis and the possible involvement of mast cells and nitric oxide were evaluated. Rats were treated with capsaicin subcutaneously, 20, 30, and 50 mg/kg, on three consecutive days, a regimen shown to ablate primary afferent neurons. Colitis was induced two weeks later by flushing 2 ml 5% acetic acid into the proximal colon. Control rats received saline, acetic acid, or capsaicin alone. Another group of rats received ketotifen (100 µg/100 g body wt × 2/day) intragastrically 48 hr prior to damage induction and thereafter. Rats were sacrificed 24 hr after damage induction, the colon isolated, damage assessed, explants were organ-cultured for 24 hr for determination of nitric oxide generation, and mucosa extracted for determination of leukotriene B4 generation and nitric oxide synthase activity. Significant increases in colonic weight, nitric oxide synthase activity, and nitric oxide and leukotriene B4 generation accompanied the near tripling of acetic acid-induced damage in capsaicin-pretreated rats. Ketotifen pretreatment significantly decreased the macroscopic damage and the increase in colonic weight. The protection provided by ketotifen was accompanied by a significant decrease in leukotriene B4 generation and nitric oxide synthase activity (80%). The correlation between the extent of colonic damage, nitric oxide synthase activity, and nitric oxide generation in acetic acid-induced colitis in capsaicin-pretreated rats suggests possible involvement of nitric oxide in its pathogenesis. The protective effect of ketotifen in capsaicin-pretreated rats indicates that mast cell activation is not prevented by ablation of afferent neurons.

Background: Bisacodyl and colchicine affect smooth-muscle contractility, intestinal water, and electrolyte transport. Nitric oxide (NO) stimulates intestinal electrolyte secretion and has an important role as a mediator of intestinal motility. We therefore studied, in rats, the effects of these agents on nitric oxide synthase (NOS) activity and gastrointestinal transit. Methods: Rats were treated with bisacodyl (10 mg/kg intragastrically) or colchicine (5 mg/kg intraperitoneally) with or without pretreatment with ketotifen (1 mg/kg intragastrically). Rats were killed after 1, 2, and 4h. The intestine was isolated and rinsed, the mucosa scraped, and NOS activity determined. In all rats small-intestinal transit was measured 15 min after intragastric administration of charcoal. Results: Bisacodyl (10 mg/kg) and colchicine (5 mg/kg) induced a significant decrease in jejunal NOS activity. Pretreatment with the mast cell stabilizer ketotifen, which has been shown to attenuate the increased permeability induced by NO inhibition, prevented the decrease in colonic and jejunal NOS activity induced by bisacodyl and colchicine. Bisacodyl and colchicine significantly decreased intestinal transit time. Their effect on transit time was similar to that induced by intravenous administration of NG-nitro-L-arginine methyl ester (10 mg/kg). Conclusions: It is suggested that the effect of bisacodyl and colchicine on intestinal transport is, at least partly, mediated through NO inhibition.

Colonic biopsy specimens from patients with active ulcerative colitis and controls were incubated for four hours in the presence or absence of calcium ionophore or antihuman immunoglobulin E (IgE). Platelet-activating factor (PAF) was determined in the tissue by aggregation assay after extraction with 80% ethanol. PAF was not detected in normal mucosa, whereas A23187 and antihuman IgE stimulated its activity: mean ±SE, 43.2±8.6 and 33.0±6.1 pg/10 mg wet weight, respectively. In active ulcerative colitis, A23187 and antihuman IgE induced significantly higher stimulation of PAF synthesis compared to their effects on normal mucosa. The enhanced stimulation of PAF induced by A23187 was dose-dependently inhibited by sulphazalazine, 5-aminosalicylic acid and prednisolone, but not by sulfapyridine. Colonic interleukin-1 content and release during 24 h of culture were significantly higher in patients with active ulcerative colitis and Crohn's disease compared to normal subjects. Prednisolone significantly and dose-dependently inhibited interleukin-1 release. These results suggest that colonic generation of PAF and interleukin-1 are elevated in patients with inflammatory bowel disease and, thus, may have a role in its pathogenesis. Pharmacological suppression of colonic PAF and interleukin-1 production may have beneficial therapeutic effects.

Diarrhea is one of the important clinical symptoms in patients suffering from celiac disease and is attributed mainly to malabsorption. We determined pros tanoid content in small intestinal mucosa of five patients with active celiac disease and in a control group consisting of six patients. Prostaglandin E2and thromboxane B2content in duodenal mucosa of patients with active celiac disease was 1,581 ± 161 and 118 ± 40 pg/mg wet wt, respectively, significantly higher than their content in duodenal mucosa of the control group, 378 ± 86 and 8 ± 8, p<0.001 and p<0.02, respectively. 6‐Ketoprostaglandin Flacontent in celiac patients was not significantly different from its content in the control group: 908 ± 437 and 124 ± 53 pg/mg wet wt, respectively. It is possible that, in celiac disease, increased mucosal prostanoid content may contribute, at least in part, to intestinal electrolyte and fluid secretion and consequent diarrhea.

An association between the release of histamine and chondroitin sulfate E proteoglycan (PG) was demonstrated in human colonic mucosa (HCM). Colonic biopsy samples incorporated [35S]sulfate (2.7 X 10(6) +/- 188 X 10(3) cpm/mg of wet tissue; mean +/- SEM, n = 5) into PG, which was partially released into the culture medium during the incubation period. Ascending thin-layer chromatography of the released 35S-labeled PG after its digestion by chondroitin ABC lyase (chondroitinase, EC 4.2.2.4) followed by autoradiography yielded three products that migrated in the position of monosulfated disaccharides of N-acetylgalactosamine 4-sulfate and N-acetylgalactosamine 6-sulfate and of an oversulfated disaccharide possessing N-acetylgalactosamine 4,6-disulfate. Cultured colonic mucosa released 23.6 +/- 3.7 ng of histamine per mg of wet tissue (mean +/- SEM, n = 16) without any specific trigger. Comparison by linear regression analysis of the release of histamine and chondroitin [35S]sulfate E PG revealed a correlation coefficient (r) of 0.7 (n = 16; P less than 0.005). Histological examination of the colonic biopsies revealed the presence of many mast cells in various degrees of degranulation in the mucosa and submucosa, most of which were found in the submucosa. Incubation of the HCM biopsies in the presence of anti-human IgE revealed 58% +/- 12% (mean +/- SEM, n = 3) enhancement in the release of chondroitin [35S]sulfate E PG and 64% +/- 10% (mean +/- SEM, n = 4) of histamine release. The above correlation, the observation that most of the mast cells showed various degrees of degranulation, and the lack of heparin synthesis as opposed to the synthesis and immunological release of chondroitin sulfate E strongly suggest that the E mast cell exists in the human colon.

Diarrhea is one of the important clinical symptoms in patients suffering from celiac disease and is attributed mainly to malabsorption. We determined pros tanoid content in small intestinal mucosa of five patients with active celiac disease and in a control group consisting of six patients. Prostaglandin E2and thromboxane B2content in duodenal mucosa of patients with active celiac disease was 1,581 ± 161 and 118 ± 40 pg/mg wet wt, respectively, significantly higher than their content in duodenal mucosa of the control group, 378 ± 86 and 8 ± 8, p<0.001 and p<0.02, respectively. 6-Ketoprostaglandin Flacontent in celiac patients was not significantly different from its content in the control group: 908 ± 437 and 124 ± 53 pg/mg wet wt, respectively. It is possible that, in celiac disease, increased mucosal prostanoid content may contribute, at least in part, to intestinal electrolyte and fluid secretion and consequent diarrhea.

Cultured duodenal mucosa obtained from normal subjects synthesized and secreted significantly less prostaglandin E2(PGE2), 6-keto-PGF1α, and thromboxane B2(TXB2) than cultured gastric mucosa obtained from the same subjects. Accumulation of PGE2, 6-keto-PGF1α, and TXB2–the stable metabolites of prostacyclin I2and thromboxane A2, respectively–by cultured gastric mucosa obtained from 21 untreated patients with active duodenal ulcer was significantly lower than their respective accumulation by cultured gastric mucosa obtained from 14 normal subjects. Accumulation of all three prostanoids by cultured duodenal mucosa obtained from patients with active duodenal ulcer and from normal subjects was not significantly different. PGE2, 6-keto-PGF1α, and TXB2accumulation was five to six times higher than their respective content in fresh tissue before culture and was inhibited by flufenamic acid. These results suggest that a decrease in endogenous gastric prostanoid synthesis may have a role in the pathogenesis of peptic ulcer disease.

The activity of (2''-5'')oligoadenylate synthetase, an enzyme induced by and mediating the antiviral action of interferon, was measured in extracts of intestinal mononuclear and epithelial cells isolated from patients with Crohn's disease, ulcerative colitis, and a control group. No significant differences were detected among (2''-5'')oligoadenylate synthetase activities of lamina propria mononuclear cells derived from inflammatory bowel disease-involved and histologically normal control mucosa. Similarly, epithelial cells from inflammatory bowel disease and control patients expressed comparable levels of the enzyme, but these were significantly higher (p < 0.01) than those found in autologous mononuclear cells. These results indicate that interferon is locally produced along the human intestinal mucosa under normal and inflammatory conditions. While this study supports the contention that induction of an antiviral state does not play a significant role in the pathogenesis of inflammatory bowel disease, it does not exclude the activation of the interferon system for other immunologic functions.

Somatostation has been postulated to have a paracrine modulating role in gastrin and gastric acid secretion. We applied the organ culture technique to examine somatostatin release by explants of human gastric mucosa taken from patients with active duodenal ulcer, from control subjects, and from patients with pernicious anemia. Somatostatin was found to be released at a constant rate by antral explants during 3 h of incubation. In active duodenal ulcer antral and fundic 2-h somatostatin release (18.7 ± 2.6 pg/mg tissue (x¯+ SE), n = 75; and 27 ± 3 pg/mg tissue, n = 94, respectively) was significantly lower than release by control antral and fundic mucosa (83 ±17 pg/mg tissue, n = 39, and 72 ±16 pg/mg tissue, n = 42, respectively) (P<0.01). Somatostatin release by antral and fundic mucosa of patients with pernicious anemia was also significantly decreased (20 ± 8 pg/mg tissue, n = 12, and 7.6 ± 2 pg/mg tissue, n = 12, respectively) (P<0.05). These results imply possible impairments of the paracrine release of somatostatin in peptic ulcer disease and in pernicious anemia.

The abdominal wall is a common and often overlooked source of pain. Three obese patients with pain that proved to come from an abdominal wall hernia are described. The hernias were not found on physical examination, and extensive workup of the digestive tract did not disclose the diagnosis. Computed tomography directed at the abdominal wall demonstrated the hernias. We review the literature on the use of computed tomography in the diagnosis of abdominal wall lesions.

The effects of misoprostol 200 µg q.i.d. and cimetidine 300 mg q.i.d. on gastric cell turnover were investigated in duodenal ulcer patients before and after four weeks of therapy. Endoscopic biopsies were incubated with3H-thymidine. Glandular column length (number of cells per column) and the number of labelled cells per column were determined by autoradiography. There were no significant treatment effects on column length of the gastric pits of either the antrum or fundus. However, misoprostol and cimetidine had opposing effects on cell turnover. Misoprostol significantly decreased the number of labelled cells in antral (P<0.01) and fundic (P<0.001) gastric pits. However cimetidine significantly increased (P<0.01) the number of labelled cells in antral and fundic columns. The increased gastric cell turnover caused by cimetidine may contribute to its activity in peptic ulcer disease. The decreased cell turnover induced by misoprostol does not appear to be a mechanism responsible for its well-established cytoprotective activity.

The objective of the present study was to determine the efficacy of ketotifen (Zaditen®), an effective antiasthmatic drug, in preventing indomethacin-induced gastroduodenal mucosal injury in a two-arm prospective, randomized, double-blind, controlled and open study. Thirty healthy volunteers with endoscopic normal-appearing mucosa were randomly treated, double-blindly, for 1 week with either placebo or ketotifen, 2mg twice daily. On day 7 indomethacin, 50 mg three times daily, was added. Two subjects, one from each group, were withdrawn from the study owing to non-compliance. Ten additional subjects received ketotifen, 2 mg twice daily, 24 h before indomethacin administration, in an open manner. A second endoscopy was performed 24 h after indomethacin was initiated. Mucosal damage in the stomach and duodenum (hemorrhages, erosions, ulcers) was scored in accordance with Lanza et al. or counted numerically. Adverse reactions were documented. Ketotifen reduced indomethacin-induced gastric mucosal damage, reducing the mean gastric lesion score from 2.85 ± 0.20 in the placebo-treated group to 1.86 ± 0.36 and in the subjects pretreated with ketotifen for 7 days. Ketotifen protected (lesion score ≤1) 6 of 14 subjects pretreated for 7 days, whereas none of the 14 placebo-treated subjects were protected. Ketotifen had no statistically significant protective effects in the duodenum. In the open study lesion scores of patients pretreated with ketotifen for 24 h were similar to those pretreated for 7 days. Ketotifen is effective in the reduction of indomethacin-induced acute gastric mucosal injury. Further studies are required to verify these data in a more relevant clinical setting.

Release of platelet-activating factor (PAF) by cultured colonic mucosa of patients with ulcerative colitis and healthy controls was determined. Before stimulation with calcium ionophore or antihuman IgE, no PAF release by control mucosa and minimal PAF release by mucosa of the colitis patients were detected. After stimulation with calcium ionophore, PAF release was four to five times higher by colonic mucosa of the colitis patients than of the controls. After stimulation with antihuman IgE, PAF release was twice as high by colonic mucosa of colitis patients as by control mucosa. Prednisolone, sulphasalazine, and mesalazine inhibited PAF activity stimulated by calcium ionophore in a dose-dependent manner. The results suggest that the use of PAF antagonists in the treatment of ulcerative colitis should be investigated.

To the Editor.—Patients suffering from gastric fistula or patients in whom gastrostomy is established temporarily are usually fed via feeding jejunostomy or by total parenteral hyperalimentation. Feeding jejunostomy can be established only at surgery, and total parenteral hyperalimentation is expensive and can be complicated by infections.We have recently introduced a nasojejunal tube for prolonged alimentation of a patient with gastrostomy complicated by pancreaticgastric fistula. Our technique might be useful for prolonged feeding of patients suffering from similar conditions.Report of a Case.—A 35-year-old woman suffered from blunt abdominal injury following a car accident. A transection of the body of the pancreas was diagnosed at laparotomy, and distal pancreatectomy was performed with gastrostomy. The postoperative course was complicated by massive bleeding from the margins of the gastrostomy. In a second operation the gastrostomy was closed following resection of its margins. Two weeks later the gastrostomy spontaneously reopened, and