Positive effect of abdominal breathing exercise on gastroesophageal reflux disease: a randomized, controlled study.

OBJECTIVES: The lower esophageal sphincter (LES), surrounded by diaphragmatic muscle, prevents gastroesophageal reflux. When these structures become incompetent, gastric contents may cause gastroesophageal reflux disease (GERD). For treatment, lifestyle interventions are always recommended. We hypothesized that by actively training the crura of the diaphragm as part of the LES using breathing training exercises, GERD can be positively influenced. METHODS: A prospective randomized controlled study was performed. Patients with non-erosive GERD or healed esophagitis without large hernia and/or previous surgery were included. Patients were randomized and allocated either to active breathing training program or to a control group. Quality of life (QoL), pH-metry, and on-demand proton pump inhibitor (PPI) usage were assessed at baseline and after 4 weeks of training. For long-term follow-up, all patients were invited to continue active breathing training and were further assessed regarding QoL and PPI usage after 9 months. Paired and unpaired t-test was used for statistical analysis. RESULTS: Nineteen patients with non-erosive GERD or healed esophagitis were randomized into two groups (10 training group and 9 control group). There was no difference in baseline patient characteristics between the groups and all patients finished the study. There was a significant decrease in time with a pH<4.0 in the training group (9.1±1.3 vs. 4.7±0.9%; P<0.05), but there was no change in the control group. QoL scores improved significantly in the training group (13.4±1.98 before and 10.8±1.86 after training; P<0.01), but no changes in QoL were seen in the control group. At long-term follow-up at 9 months, patients who continued breathing exercise (11/19) showed a significant decrease in QoL scores and PPI usage (15.1±2.2 vs. 9.7±1.6; 98±34 vs. 25±12 mg/week, respectively; P<0.05), whereas patients who did not train had no long-term effect. CONCLUSIONS: We show that actively training the diaphragm by breathing exercise can improve GERD as assessed by pH-metry, QoL scores and PPI usage. This non-pharmacological lifestyle intervention could help to reduce the disease burden of GERD.

Mycophenolate mofetil for Crohn's disease: short-term efficacy and long-term outcome.

AIM: To assess the long-term efficacy of the antimetabolite agent mycophenolate mofetil in patients with Crohn's disease. METHODS: Twenty patients with complicated Crohn's disease were treated with mycophenolate mofetil, 1 g b.d., for up to 7 years. Twelve patients were intolerant to azathioprine, seven were resistant to azathioprine and one had a history of mesalazine-induced pancreatitis. The response to mycophenolate mofetil was determined by calculation of the Harvey-Bradshaw index, the ability to taper steroids and the grading of fistula activity. RESULTS: After 6 months, 11 of the 20 patients had responded. Seven of the 11 responders relapsed after a median of 18 months, three have an ongoing response at month 17, 19 and 82, and one discontinued mycophenolate mofetil owing to toxicity. After initial treatment failure, mycophenolate mofetil was continued in 12 of 17 patients for a further 2-41 months without inducing a stable remission. Mycophenolate mofetil was of benefit in nine of the 12 patients intolerant to azathioprine and in two of the seven patients resistant to azathioprine. Perianal fistulas improved in seven of eight patients; five of the seven subsequently deteriorated, but only one due to reactivated perianal disease. CONCLUSIONS: Mycophenolate mofetil was initially effective in a sizeable fraction of patients with complicated Crohn's disease, but relapse within 18 months was common. Nevertheless, mycophenolate mofetil could be a useful alternative in patients intolerant to azathioprine.

Effect of oral tacrolimus (FK 506) on steroid-refractory moderate/severe ulcerative colitis.

BACKGROUND: Steroid refractory ulcerative colitis is most commonly treated with intravenous ciclosporin to avoid colectomy. In search for an alternative drug that can be administered orally we investigated oral tacrolimus (FK 506) for this indication. METHODS: Nine patients with active, moderate/severe steroid refractory UC were treated with oral tacrolimus with a daily dose of 0.15 mg/kg body weight. After patients had responded azathioprine was added for long-term immunosuppression. RESULTS: All patients responded within 1-2 weeks. After 12 weeks of tacrolimus therapy six patients (67%) were in complete remission, two patients (22%) had mild to moderate disease activity, and one patient (11%) underwent colectomy. After a mean follow up of 21 months six of the nine patients (67%) had their colon in situ. Two patients developed severe side-effects, one thrombopenia with intestinal bleeding, and one bicytopenia. Mild side-effects were common. CONCLUSION: Oral tacrolimus may be an effective alternative to intravenous ciclosporin for the therapy of steroid-refractory ulcerative colitis. Patients receiving tacrolimus need to be watched carefully for side-effects.

Examination, prevention and treatment of osteoporosis in patients with inflammatory bowel disease: recommendations and reality.

BACKGROUND: Patients with inflammatory bowel disease (IBD) are at increased risk of developing osteopenia and osteoporosis. Our aim was to evaluate the current practices of examination, prevention and treatment of osteoporosis in IBD patients in a routine clinical setting. METHODS: A total of 154 consecutive patients with IBD (63 female, 91 male; 36 ulcerative colitis, 115 Crohn's disease, 3 indeterminate colitis), referred to two gastroenterological units for scheduled follow-up examinations, were included. Patient charts were evaluated regarding bone densitometry already performed and any prophylactic or therapeutic interventions in cases of low bone mineral density. RESULTS: Bone mineral density (BMD) measurements had been performed only in 38 patients (25%). BMD was abnormally low in 27 of the examined patients (71%), 20 of whom had osteopenia and seven had osteoporosis. Among the subgroup of patients on long-term steroid therapy (77 patients), 30 had been referred to bone densitometry during the course of disease, and 21 of them were found to have low bone mineral density. Preventive measures were prescribed in 12 patients (9% of the whole study population). In the majority of the patients with low bone mineral density, calcium and vitamin D were used as treatment. CONCLUSIONS: Despite the high prevalence of osteopenia and osteoporosis in patients with IBD, only a minority of these patients were included in a structured program in accordance with modern guidelines for diagnosing and preventing this extraintestinal complication in a routine clinical setting.

Mesalazine 4 g daily given as prolonged-release granules twice daily and four times daily is at least as effective as prolonged-release tablets four times daily in patients with ulcerative colitis.

BACKGROUND: High doses of mesalazine usually result in an inconvenient dosage schedule and reduced compliance. The goal of this trial was to compare the effects of mesalazine 4 g daily given as prolonged-release granules in packets of 1 g with that of prolonged-release tablets of 0.5 g. METHODS: Two hundred twenty-seven patients with mild-to-moderate ulcerative colitis were randomized to treatment with two packets twice daily (Gr-b.i.d.), 1 packet four times daily (Gr-q.i.d.) or 2 tablets four times daily (Ta-q.i.d.) for 8 weeks. A disease activity index (ulcerative colitis disease activity index: UC-DAI) was calculated, and the granules were defined as noninferior to the tablets if the lower limit of the 95% CI for the differences was more than -1 UC-DAI score unit. RESULTS: Noninferiority of the granules compared with the tablets was demonstrated. The mean improvement in the UC-DAI in the treatment groups Gr-b.i.d., Gr-q.i.d., and Ta-q.i.d. were 3.2, 2.9, and 2.4, respectively; the proportion of complete responders in the three groups 39%, 37%, and 31%, respectively. There were no differences in side effects. CONCLUSION: Mesalazine 4 g daily given as prolonged-release granules twice and four times daily is at least as effective as prolonged-release tablets four times daily in patients with mild to moderate ulcerative colitis. The patients preferred the twice daily dosing.

Gastric adenocarcinoma mimicking achalasia in a 15-year-old patient: a case report and review of the literature.

Although adenocarcinoma of the cardia is extremely rare in adolescent patients, the endoscopist should be alert to this disease in patients of any age with dysphagia, even if symptoms, and results of a barium study, upper endoscopy, and esophageal manometry are suggestive of primary achalasia, especially if family history is negative for achalasia. In addition, secondary achalasia should be suspected in patients who do not respond to therapy with botulinum toxin within 2 months. Because none of the mentioned tests can distinguish between primary achalasia and secondary forms due to carcinoma of the cardia, biopsy specimens should be obtained. It appears that, although there is a minimal risk for complications, a diagnostic procedure such as biopsy would be appropriate when the information obtained could be essential. In some cases EUS can be an additional diagnostic tool, because lesions of the submucosa and the surrounding area can be identified by EUS.

Anti-cardiolipin antibodies in patients with inflammatory bowel disease.

Elevated levels of anti-cardiolipin antibodies are associated with an increased risk for venous and arterial thrombosis. In patients with inflammatory bowel disease thrombosis is a well known complication. We determined the prevalence of elevated anti-cardiolipin antibodies in 136 patients with inflammatory bowel disease compared with 136 healthy controls and analyzed thromboembolic complications in patients with increased anti-cardiolipin antibody levels. Anti-cardiolipin antibody titers were significantly elevated in patients with Crohn's disease (5.7 units/ml) and ulcerative colitis (5.3 units/ml) compared to the control group (2.5 units/ml). We found no correlation between disease activity and anti-cardiolipin antibody levels. Seven patients had deep venous thrombosis in their history, in three of them this was complicated by pulmonary embolism. In only two of the seven patients with deep venous thrombosis were anti-cardiolipin antibody levels increased. In conclusion, anti-cardiolipin antibody titers were significantly increased in patients with inflammatory bowel disease. Elevated anti-cardiolipin antibody levels appear to play no role in the pathogenesis of thromboembolic events in patients with inflammatory bowel disease.

Mycophenolate mofetil in patients with Crohn's disease.

OBJECTIVE: Intolerance to azathioprine is a rare but important problem in treating chronically active Crohn's disease. We performed this study to evaluate mycophenolate mofetil as an alternative immunosuppressive therapy for patients with Crohn's disease who did not tolerate azathioprine. METHODS: Four patients with highly active perianal Crohn's disease and two patients with chronically active, steroid-dependent Crohn's disease were included. All patients consumed 2 g/day of mycophenolate mofetil for a median of 8 months (range, 6-12 months). Disease activity was measured by the Perianal Crohn's Disease Activity Index in patients with perianal disease and by the Crohn's Disease Activity Index in patients with chronically active Crohn's disease. RESULTS: Azathioprine-induced side effects disappeared after the drug was discontinued. All patients improved during treatment with mycophenolate mofetil, as shown by a remarkable reduction in the respective clinical scores. Five patients showed no side effects during treatment with mycophenolate mofetil. After 4 months' treatment one patient developed diarrhea that was probably not due to mycophenolate mofetil. CONCLUSION: Mycophenolate mofetil could be an alternative therapy to azathioprine in patients with Crohn's disease.

Successful steroid treatment of idiopathic thrombocytopenic purpura after orthotopic liver transplantation for primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver frequently associated with extrahepatic autoimmune phenomena. Specific antibodies against platelet glycoproteins may play an important role in the pathogenesis of thrombocytopenia associated with PBC. This is the first report of life-threatening idiopathic thrombocytopenic purpura successfully treated with steroids in a 62-yr-old woman 2 yr after liver transplantation for PBC.

Short-term efficacy and long-term outcome of cyclosporine treatment in patients with severe ulcerative colitis.

Cyclosporine A (CyA) has been recommended for the treatment of severe steroid-resistant ulcerative colitis, however, long-term results are scarce. We prospectively followed a treatment plan in 14 patients with severe ulcerative colitis receiving intravenous CyA after failure to respond to at least eight days of standard therapy with prednisolone (1-1.5 mg/kg/day). CyA was delivered in a daily dose of 5 mg/kg i.v. for a mean of 14 days (range 7-28) in addition to ongoing medical therapy. CyA whole blood levels were monitored by HPLC and maintained between 100 ng/ml and 400 ng/ml. Responders were switched to oral CyA (5-7.5 mg/kg/day) for a mean of two months, and steroids were gradually tapered. Eleven patients (79%) initially responded to i.v. CyA, three patients failed to respond and underwent urgent colectomy. Time until response averaged seven days (range 3-13). Four of the eleven responders underwent colectomy because of severe relapse after one, eleven, twelve and 13 months of follow-up. The remaining seven patients were followed for a median of 48 months. During the first year of follow-up three out of seven had a severe relapse and responded to steroids (two patients) or to a further course of i.v. CyA (one patient). During CyA therapy one patient developed staphylococcal sepsis, other adverse events were mild and reversible. The results confirm that CyA is effective in severe steroid-refractory ulcerative colitis. Severe relapse and colectomy are uncommon after the first year of follow-up and the colon preserving effect of CyA can be maintained in up to 50% of patients over a period of four years.

Acetorphan prevents cholera-toxin-induced water and electrolyte secretion in the human jejunum.

OBJECTIVES: Acetorphan is an orally administered inhibitor of enkephalinase in the wall of the digestive tract. It prevents inactivation of endogenous opioid peptides released by submucosal and myenteric neurons. The aim of this study was to examine the effect of acetorphan on jejunal water and electrolyte transport in healthy volunteers under basal conditions and in a state of intestinal secretion induced by a bacterial enterotoxin. DESIGN: Ten volunteers in two groups were studied in an open trial. For the experimental design an intestinal perfusion technique was used. METHODS: Cholera toxin was used to induce intestinal secretion in a model employing segmental perfusion of the human proximal jejunum. Acetorphan was given orally prior to intrajejunal administration of cholera toxin; its effect on intestinal transport was measured over a period of four hours after exposure to cholera toxin. Serum levels of methylthioether of thiorphan as the main metabolite were measured throughout three experiments to assure sufficient drug absorption. RESULTS: Acetorphan had no influence on basal water and electrolyte absorption (133 vs. 140 ml/30 cm x h). In a control group with cholera toxin alone, significant water secretion was induced (131 ml/30 cm x h). Acetorphan completely prevented this secretion by leaving an absorption rate of 27 ml/30 cm x h. Intestinal electrolyte transport was also significantly changed towards absorption by acetorphan. CONCLUSION: Acetorphan can prevent jejunal water and electrolyte secretion induced by cholera toxin. Enkephalins may thus protect the small intestine from enterotoxin-induced secretion.

Combination of cyclosporine, azathioprine and prednisolone for perianal fistulas in Crohn's disease.

OBJECTIVES: Fistulas in Crohn's disease remain a difficult clinical challenge. Rapid improvement with cyclosporine followed by deterioration after discontinuation of this drug has been reported. This study aimed to determine whether fast remission and long-term improvement could be achieved when cyclosporine was administered concurrently with azathioprine and low-dose prednisolone and then be discontinued. METHODS: Nine patients with fistulas were enrolled in this open study. For the first two weeks cyclosporine was administered intravenously at a dose of 5 mg/kg/day. Azathioprine and low-dose prednisolone were also given during this period. After two weeks cyclosporine was administered orally for a further ten weeks while azathioprine and a tapered dose of prednisolone were continued. Effectiveness was evaluated clinically, by a scoring system and by magnetic resonance imaging. RESULTS: With intravenous cyclosporine as part of this regimen, all nine patients went into remission within days. There were no recurrences after changing from intravenous to oral cyclosporine. Cyclosporine was terminated after three months while azathioprine and low-dose prednisolone were continued. Thereafter, four patients did not deteriorate, three deteriorated slightly, and two patients had a recurrence. The CDAI (Crohn's Disease Activity Index) improved from 200 (range 85-350) to 136 (range 26-200) by the end of the third month. Serological markers remained stable after discontinuation of cyclosporine. There were no serious side effects during this triple drug regimen. CONCLUSIONS: The combination of cyclosporine, azathioprine and low-dose prednisolone leads to marked improvement of perianal fistulas in Crohn's disease. Remission occurs quickly under cyclosporine. These remissions can be maintained with azathioprine in a majority of patients.

Platelet-activating factor contributes to immune cell and oxidant-mediated intestinal secretion.

The sensitivity of the Ussing-chambered rat colon to stimulation of Cl- secretion (as measured by the change in short-circuit current) by exogenous platelet-activating factor (PAF) was increased significantly by washing the colon in vitro with Ringer's solution containing fatty acid-free albumin. When the wash solution was extracted with chloroform/methanol and the lipid extract was added back to Ussing-chambered colons, inhibition of PAF-stimulated short-circuit current was observed, whereas short-circuit current responses to bradykinin or vasoactive intestinal peptide were not affected. Hypoxia appears to be an important trigger for the down-regulation of the PAF response. These data suggest that hypoxia releases PAF or an endogenous lipid PAF inhibitor that desensitizes PAF receptors on colonic epithelial or mucosal cells. The short-circuit current response of rabbit colon to the chemotactic peptide formyl-methionyl-leucyl-phenylalanine was not inhibited by any PAF antagonist devoid of cyclooxygenase inhibitory activity but was strongly inhibited by indomethacin. In contrast, anti-IgE- or H2O2-stimulated short-circuit current in rat colon was inhibited by specific PAF antagonists, and this inhibition was additive with indomethacin. Both anti-IgE and H2O2 significantly increased PAF production by rat colon. These data suggest that PAF plays an important role in oxidant (H2O2)- and anti-IgE-mediated colonic Cl- secretion but not in Cl- secretion mediated by formyl-methionyl-leucyl-phenylalanine-stimulated phagocytes.

Acute Budd-Chiari syndrome with fulminant hepatic failure in a pregnant woman with factor V Leiden mutation.

Budd-Chiari syndrome during pregnancy has rarely been reported. This report presents a case of acute hepatic failure in a 20-year-old pregnant woman attributable to Budd-Chiari syndrome with underlying resistance to activated protein C caused by factor V Leiden mutation. The patient delivered a healthy girl by cesarean section in the 31st week of pregnancy. Acute hepatic failure in the 6th week postpartum was successfully treated by emergency liver transplantation, and the patient and her child were doing well at 8-month follow-up. Liver transplantation was lifesaving; normal factor V production by the transplant corrected the underlying coagulopathy. In this patient, latent thrombophilia attributable to activated protein C resistance was apparently aggravated by the hypercoagulable state of pregnancy leading to acute Budd-Chiari syndrome. Activated protein C resistance should be sought as an etiologic factor in patients with Budd-Chiari syndrome.

IL-1 stimulates intestinal myofibroblast COX gene expression and augments activation of Cl- secretion in T84 cells.

Because interleukin-1 (IL-1) is an important mediator in the inflamed intestine, its effects on enterocyte-subepithelial myofibroblast (SEMF) interaction were investigated in vitro. Acutely juxtaposing T84 cells with 18Co or P2JF SEMF preincubated with IL-1 alpha significantly enhanced T84 short-circuit current (Isc) responsiveness to secretagogues in comparison to SEMF not activated by IL-1 alpha. The sensitivity of T84 cell Isc to Ca(2+)-dependent, but not adenosine 3',5'-cyclic monophosphate-dependent, secretagogues was augmented by IL-1 alpha-treated SEMF. These effects of IL-1 alpha are directly correlated with SEMF prostaglandin E2 (PGE2) production. Both IL-1 alpha augmentation of Cl secretagogue responsiveness and PGE2 formation were inhibited by IL-1 receptor antagonist. Within 5 h, IL-1 alpha stimulated a 10-fold increase in cyclooxygenase (COX)-2 steady-state mRNA levels in 18Co cells. In contrast, COX-1 message levels increased more slowly to two- to threefold above control levels after 24 h incubation. These results demonstrate that the proinflammatory cytokine IL-1 alpha accentuates intestinal SEMF augmentation of enterocyte responsiveness to Ca(2+)-dependent CI-secretagogues. PGE2 is an important mediator of SEMF-enterocyte interaction. The effects of IL-1 alpha on SEMF PGE2 productions are, at least in part, due to stimulation of COX gene expression.

Effect of 5-hydroxytryptamine antagonists on cholera toxin-induced secretion in the human jejunum.

In rats, the combined administration of the 5-HT2 antagonist ketanserin and the 5-HT3 antagonist tropisetron inhibits cholera toxin-induced intestinal secretion. We investigated whether these agents and the 5-HT3 antagonist ondansetron can inhibit cholera toxin-induced secretion in the human jejunum using a segmental perfusion technique. In a first control period the subjects' jejunums were perfused continuously with a plasma-like electrolyte solution. In a second control period they either received a combination of tropisetron plus ketanserin, or tropisetron or ondansetron alone. Cholera toxin 6.25 micrograms was then administered intrajejunally and the experiments were continued for 4 h. Net water movements during the 4th hour after CT administration minus net water movement during the first control period was used for further calculation and was referred to as net luminal gain. In perfusion studies with tropisetron plus ketanserin resp. ondansetron the net luminal gain of water (+ 161 +/- 26 resp. 189 +/- 28 ml 30 cm-1 h-1, mean +/- SEM) was significantly higher compared to perfusion studies with cholera toxin alone (+ 94 +/- 30). Treatment with tropisetron did not change the CT-induced net luminal gain of water (+ 108 +/- 41). Movements of sodium, chloride, bicarbonate and potassium paralleled the movement of water. In agreement with these observations we found a deterioration of clinical parameters after the end of the perfusion studies in four of five subjects treated with CT 25 micrograms plus ketanserin and tropisetron.(ABSTRACT TRUNCATED AT 250 WORDS)