Background and Aims: Approximately 95% of bile acids (BAs) excreted into bile are reabsorbed in the gut and circulate back to the liver for further biliary secretion. Therefore, pharmacological inhibition of the ileal apical sodium-dependent BA transporter (ASBT/SLC10A2) may protect against BA-mediated cholestatic liver and bile duct injury. Methods: 8-week-old Mdr2-/- (Abcb4-/-) mice (model of cholestatic liver injury and sclerosing cholangitis) received either a diet supplemented with A4250 (0.01% w/w) – a highly potent and selective ASBT inhibitor – or a chow diet. Liver injury was assessed biochemically and histologically after 4 weeks of A4250 treatment. Expression profiles of genes involved in BA homeostasis, inflammation and fibrosis were assessed via RT-PCR from liver and ileum homogenates. Intestinal inflammation was assessed by RNA expression profiling and immunohistochemistry. Bile flow and composition as well as biliary BA profiles were analyzed after 1 week of ASBT inhibitor feeding. Results: Mdr2-/- mice treated with A4250 showed significantly decreased serum ALT, AP and BAs levels, reduced hepatic expression of pro-inflammatory (Tnf-α, Vcam1, Mcp-1) and pro-fibrogenic (Col1a1, Col1a2) genes and bile duct injury (mRNA and immunohistochemistry for CK19). Furthermore, A4250 significantly reduced bile flow and biliary BA output, which correlated with reduced Bsep transcription, while Ntcp and Cyp7a1 were induced. Importantly, biliary BA output was reduced while other components including protective bicarbonate did not change in A-4250 treated mice. Conclusions: Pharmacological ASBT inhibition attenuates cholestatic liver and bile duct injury by reducing biliary BA output.

BACKGROUND:Ulcerative colitis (UC) pathophysiology is characterized by an imbalance between pro- and anti-inflammatory cytokines. Interferon (IFN)-beta-1a has potent immunoregulatory properties, including stimulation of host defence mechanisms and thus represents a potential treatment.AIM:To extend pilot data and identify a suitable dose of IFN-beta-1a to achieve endoscopically confirmed remission (ECR) in patients with moderately active UC and to evaluate safety.METHODS:In this multicentre, double-blind, placebo-controlled trial, adults with moderately active UC were randomized to IFN-beta-1a 44 or 66 microg, or placebo, subcutaneously three times weekly for 8 weeks, with a 4-week follow-up.RESULTS:Endoscopically-confirmed remission was observed in 23.4% [95% confidence interval (CI): 13.8-35.7] of placebo patients, 29.2% (95% CI: 18.6-41.8) of the IFN-beta-la 44 microg group and 20.0% (950% CI: 11.1-31.8) of the 66 microg group (P = 0.45). Improvements with IFN-beta-1a 44 microg were greater than with placebo for most secondary efficacy outcomes, although significance was not achieved. Placebo response rates were higher than expected from previous trials. Adverse events were similar to the known safety profile of IFN treatment.CONCLUSIONS:Interferon-beta-1a was generally well tolerated at the doses tested, but a significant therapeutic benefit in patients with UC was not observed.

OBJECTIVE:Gastroesophageal reflux disease has been reported to be a common burden on health-care resources in the Western world, but its manifestations in the general population are as yet unclear. The aim of this study was to estimate the prevalence of, and to identify the risk factors for gastroesophageal reflux symptoms (GERS) and erosive esophagitis (EE) in the adult population of two Swedish municipalities.MATERIAL AND METHODS:A random sample (n =3000) of the adult population (20-81 years of age) of two Swedish municipalities (n =21,610) was surveyed using a validated postal questionnaire assessing gastrointestinal symptoms. The response rate was 74%. A subsample (n = 1000) of the responders was subsequently invited, in random order, for esophago-gastro-duodenoscopy with evaluation of GERS, risk factors and tests for Helicobacter pylori.RESULTS:GERS were reported by 40.0% and EE was found in 15.5% of the population that had undergone endoscopy. Of those with GERS, 24.5% had EE while 36.8% of those with EE reported no GERS. Hiatus hernia and obesity remained significant risk factors for GERS and/or EE, with or without symptoms in a main effect model (OR up to 14 at EE). Those with active H. pylori infection had a higher risk of GERS without EE than those without H. pylori infection (OR = 1.71 (1.23 2.38)).CONCLUSIONS:GERS and EE (of which one-third is asymptomatic) are highly prevalent in the Swedish adult population. H. pylori infection seems to play a role in the manifestations of gastroesophageal reflux.

Background & Aims: Osteoporosis frequently occurs in Crohn's disease, often because of corticosteroids. Budesonide as controlled release capsules is a locally acting corticosteroid with low systemic bloavailability. We investigated its effects on bone compared with prednisolone.Methods: In 34 international centers, 272 patients with Crohn's disease involving ileum and/or colon ascendens were randomized to once daily treatment with budesonide or prednisolone for 2 years at doses adapted to disease activity. One hundred eighty-one corticosteroid-free patients had active disease (98 had never received corticosteroids, corticosteroid naive; 83 had received corticosteroids previously, corticosterold exposed), and 90 had quiescent disease, receiving long-term low doses of corticosteroids, corticosteroid-dependent; in 1 patient, no efficacy data were obtained. Bone mineral density and fractures were assessed in a double-blinded fashion; disease activity, side effects, and quality of life were monitored.Results: Neither the corticosteroid-free nor the corticosteroid-dependent patients treated with budesonide differed significantly in bone mineral density from those receiving prednisolone. However, corticosteroid-naive patients receiving budesonide had smaller reductions in bone mineral density than those on prednisolone (mean, -1.04% vs -3.84%; P =.0084). Treatment-emergent corticosteroid side effects were less frequent with budesonide. Efficacy was similar in both groups.Conclusions: Treatment with budesonide is associated with better preserved bone mass compared with prednisolone in only the corticosteroid-naive patients with active ileocecal Crohn's disease. In both the corticosteroid-free and corticosteroid-dependent groups, budesonide and prednisolone were equally effective for up to 2 years, but budesonide caused fewer corticosteroid side effects.

SummaryBackground : Cross‐sectional studies indicate that gastro‐oesophageal reflux disease symptoms have a prevalence of 10–20% in Western countries and are associated with obesity, smoking, oesophagitis, chest pain and respiratory disease.Aim : To determine the natural history of gastro‐oesophageal reflux disease presenting in primary care in the UK.Methods : Patients with a first diagnosis of gastro‐oesophageal reflux disease during 1996 were identified in the UK General Practice Research Database and compared with age‐ and sex‐matched controls. We investigated the incidence of gastro‐oesophageal reflux disease, potential risk factors and comorbidities, and relative risk for subsequent oesophageal complications and mortality.Results : The incidence of a gastro‐oesophageal reflux disease diagnosis was 4.5 per 1000 person‐years (95% confidence interval: 4.4–4.7). Prior use of non‐steroidal anti‐inflammatory drugs, smoking, excess body weight and gastrointestinal and cardiac conditions were associated with an increased risk of gastro‐oesophageal reflux disease diagnosis. Subjects with gastro‐oesophageal reflux disease had an increased risk of respiratory problems, chest pain and angina in the year after diagnosis, and had a relative risk of 11.5 (95% confidence interval: 5.9–22.3) of being diagnosed with an oesophageal complication. There was an increase in mortality in the gastro‐oesophageal reflux disease cohort only in the year following the diagnosis.Conclusions : Gastro‐oesophageal reflux disease is a disease associated with a range of potentially serious oesophageal complications and extra‐oesophageal diseases.

Until now, the development of effective therapies for the treatment of functional disorders such as irritable bowel syndrome (IBS) has been thwarted by a general lack of knowledge about how events in the intestine are detected by visceral afferent neurones. There are considerable gaps in our knowledge of the anatomy as well as the function and modulation of visceral afferent projections, in particular about what causes visceral hypersensitivity or abnormal sensory perception of stimuli in the gut. The field is advancing …

p = 0.30) and 2.0 mg/kg-36.9%(placebo vs. 2.0 mg/kg p = 0.04) whereas the corresponding response rates were 41.4%, 49.2% (placebo vs. 0.5mg/kg p=0.36), and 53.1% (placebo vs. 2.0 mg/kg p=0.14)Pharmacokinetic data indicated the antibody had a half-life of approximately 12 days.Pharmacodynamic data suggested that complete saturation of ct4137 was not achieved over the duration of treatment.Subgroup analysis showed that patients who obtained consistent and sustained saturation of a4J37 on PBLs were more likely to enter remission than those who did not.No important differences in adverse events were noted among the three treatment groups.Conclusion MLN-02, administered at 2.0 mg/kg, is a biologically active therapy for the treatment of active CD.Future trials to evaluate higher doses of MLN02 and the relation of higher doses to sustained saturation are under consideration.

BACKGROUND:A high prevalence of osteoporosis has been noted in Crohn's disease, but data about fractures are scarce.METHODS:The relationship between low bone mineral density and the prevalence of vertebral fractures was studied in 271 patients with ileo-caecal Crohn's disease in a large European/Israeli study. One hundred and eighty-one currently steroid-free patients with active Crohn's disease (98 completely steroid-naive) and 90 steroid-dependent patients with inactive or quiescent Crohn's disease were investigated by dual X-ray absorptiometry scan of the lumbar spine, a standardized posterior/anterior and lateral X-ray of the thoracic and lumbar spine, and an assessment of potential risk factors for osteoporosis.RESULTS:Thirty-nine asymptomatic fractures were seen in 25 of 179 steroid-free patients (14.0%; 27 wedge, 12 concavity), and 17 fractures were seen in 13 of 89 steroid-dependent patients (14.6%; 14 wedge, three concavity). The prevalence of fractures in steroid-naive patients was 12.4%. The average bone mineral density, expressed as the T-score, of patients with fractures was not significantly different from that of those without fractures (-0.759 vs. -0.837; P=0.73); 55% of patients with fractures had a normal T-score. The bone mineral density was negatively correlated with lifetime steroids, but not with previous bowel resection or current disease activity. The fracture rate was not correlated with the bone mineral density (P=0.73) or lifetime steroid dose (P=0.83); in women, but not in men, the fracture rate was correlated with age (P=0.009).CONCLUSIONS:The lack of correlation between the prevalence of fractures on the one hand and the bone mineral density and lifetime steroid dose on the other necessitates new hypotheses for the pathogenesis of the former.

The gut flora is a vast interior ecosystem whose nature is only beginning to be unravelled, due to the emergence of sophisticated molecular tools. Techniques such as 16S ribosomal RNA analysis, polymerase chain reaction amplification and the use of DNA microarrays now facilitate rapid identification and characterization of species resistant to conventional culture and possibly unknown species. Life-long cross-talk between the host and the gut flora determines whether health is maintained or disease intervenes. An understanding of these bacteria-bacteria and bacteria-host immune and epithelial cell interactions is likely to lead to a greater insight into disease pathogenesis. Studies of single organism-epithelial interactions have revealed the large range of metabolic processes that gut bacteria may influence. In inflammatory bowel diseases, bacteria drive the inflammatory process, and genetic predisposition to disease identified to date, such as the recently described NOD2/CARD15 gene variants, may relate to altered bacterial recognition. Extra-intestinal disorders, such as atopy and arthritis, may also have an altered gut milieu as their basis. Clinical evidence is emerging that the modification of this internal environment, using either antibiotics or probiotic bacteria, is beneficial in preventing and treating disease. This natural and apparently safe approach holds great appeal.

% (n=31) in the calcium-vitamin D-fluoride and calcium-vitamin D-placebo groups, respectively (p

SUMMARY 1. Joint pain is a frequent manifestation of Crohn’s disease. Budesonide controlled ileal release (CIR) is a predominantly topically acting glucocorticosteroid, which is effective in treating active ileal or ileocaecal Crohn’s disease. 2. Therefore, it was of interest to study the effect of this predominantly topically acting therapy on the treatment of an extra‐intestinal symptom of Crohn’s disease by analysing data collected from budesonide CIR (Entocort ® ; Astra Draco AB, Lund, Sweden) trials. 3. Three large studies of budesonide CIR treatment in active Crohn’s disease provided a reliable source of clinical data. Of the 611 patients treated in the prospective double‐blind controlled trials, 291 had joint pain (arthritis/arthralgia) at entry, which was recorded as part of the Crohn’s Disease Activity Index. Statistical analysis was based on all patients treated, provided that the patient had joint pain at the start of treatment. 4. Daily oral budesonide CIR (9 mg) resulted in clinical remission of joint pain in 74% (95% confidence intervals (CI) 67–82%) of patients. This outcome was nearly twice as good as placebo (41%; 95% CI 34–57%) and as good as the outcome effected by daily oral prednisolone (40 mg; 72%; 95% CI 60–84%). The favourable response to budesonide CIR (9 mg) did not correlate with glucocorticosteroid‐associated side effects or with adrenal suppression, which were half those in the prednisolone (40 mg/day) group. 5. The favourable outcome may relate to restitution of normal intestinal immune function.

Smokers show higher rates of peptic ulcer disease (PUD) than nonsmokers, probably due to detrimental effects on the gastric mucosa. Surface-active phospholipids (SPL) are believed to play a key part in gastric cytoprotection. The aim of this study was to determine the chronic effects of smoking on the gastric SPL and to relate them to H. pylori (Hp) -induced effects. Gastric juice was aspirated in 52 patients, with normal findings at planned upper gastrointestinal endoscopy, and concentrations of seven phospholipid subclasses were analyzed. Concentrations of lysophosphatidylethanolamine (l-PE) were increased (P = 0.006) in smokers compared to nonsmokers in non-Hp-infected samples. Nonsmokers infected with Hp showed increased levels of l-PE (P = 0.01) and phosphatidylinositol (PI) (P = 0.02) compared to subjects not infected. In human gastric juice PI seems to be the dominating PL subclass, in contrast to the composition in biopsy specimens. We also found both Hp-infected and smoking subjects to have higher concentrations of more polar phospholipid subclasses, ie, l-PE, making the mucosa more vulnerable to acid attack as the gastric surfactant becomes less hydrophobic.