OBJECTIVES:The aim of this study was to investigate the relationship between aquaporin (AQP) water channel expression and the pathological features of early untreated inflammatory bowel disease (IBD) in humans.METHODS:Patients suspected to have IBD on the basis of predefined symptoms, including abdominal pain, diarrhea, and/or blood in stool for more than 10 days, were examined at the local hospital. Colonoscopy with biopsies was performed and blood samples were taken. Patients who did not meet the diagnostic criteria for IBD and who displayed no evidence of infection or other pathology in the gut were included as symptomatic non-IBD controls. AQP1, 3, 4, 5, 7, 8, and 9 messenger RNA (mRNA) levels were quantified in biopsies from the distal ileum and colon by quantitative real-time polymerase chain reaction. Protein expression of selected AQPs was assessed by confocal microscopy. Through multiple alignments of the deduced amino acid sequences, the putative three-dimensional structures of AQP1, 3, 7, and 8 were modeled.RESULTS:AQP1, 3, 7, and 8 mRNAs were detected in all parts of the intestinal mucosa. Notably, AQP1 and AQP3 mRNA levels were reduced in the ileum of patients with Crohn's disease, and AQP7 and AQP8 mRNA levels were reduced in the ileum and the colon of patients with ulcerative colitis. Immunofluorescence confocal microscopy showed localization of AQP3, 7, and 8 at the mucosal epithelium, whereas the expression of AQP1 was mainly confined to the endothelial cells and erythrocytes. The reduction in the level of AQP3, 7, and 8 mRNA was confirmed by immunofluorescence, which also indicated a reduction of apical immunolabeling for AQP8 in the colonic surface epithelium and crypts of the IBD samples. This could indicate loss of epithelial polarity in IBD, leading to disrupted barrier function.CONCLUSION:AQPs 1 and 8 and the aquaglyceroporins AQPs 3 and 7 are the AQPs predominantly expressed in the lower intestinal tract of humans. Their expression is significantly reduced in patients with IBD, and they are differentially expressed in specific bowel segments in patients with Crohn's disease and ulcerative colitis. The data present a link between gut inflammation and water/solute homeostasis, suggesting that AQPs may play a significant role in IBD pathophysiology.

Objectives: The aim of this study was to define the composition of the gut bacterial flora in Norwegian patients with early stage Crohn’s disease (CD). Methods: By using a nonselective metagenomics approach, the general bacterial composition in mucosal biopsies from the ileum and the colon of five subjects, four patients with different phenotypes of CD, and one noninflammatory bowel disease control, was characterized. After partial 16S ribosomal RNA (rRNA) gene sequencing, BLAST homology searches for species identification and phylogenetic analysis were performed. Results: An overall biodiversity of 106 different bacterial operational taxonomic units (OTUs) was detected in the cloned libraries. Nearly all OTUs belonged to the phylae Bacteroidetes (42% in CD, 71% in the control) or Firmicutes (42% in CD, 28% in the control), except for some OTUs that belonged to the phylum Proteobacteria (15% in CD, 0% in the control) and a few OTUs that could not be assigned to a phylum (2% in CD, 1% in the control). Conclusion: Based on the high incidence of inflammatory bowel disease (IBD) in Norway, this pilot study represents a relevant determination of the gut microbiota in Norwegian patients compared to previous findings in other countries. The bacterial profile of Norwegian CD patients was found to be similar to that of CD patients in other countries. The findings do not support a particular bacterial composition as a predominant causative factor for the high incidence of IBD that exists in some countries.

Greenstein et al. have commented on the report “Paucity of mycobacteria in mucosal bowel biopsies from adults and children with early inflammatory bowel disease”,1 which negates the role of Mycobacterium avium subspecies paratuberculosis (MAP) in the early pathogenesis of Crohn's disease (CD), and suggest that this scenario opens up for an alternative mycobacterial species in the genesis of CD. We thank the Authors and the Editor for initiating such an illustrious discussion and would like to address two points, anti-inflammatory drugs in IBD and the potential role of mycobacteria other than MAP in the …

OBJECTIVE:The present population based adult cohort was part of a new prospective study of patients with inflammatory bowel disease (IBD) in South-Eastern Norway, the Inflammatory Bowel South-Eastern Norway II study, investigating disease characteristics in an attempt to improve our knowledge regarding factors related to early clinical phenotype and disease activity.MATERIAL AND METHODS:Patients suspected to have IBD on the basis of predefined symptoms, including abdominal pain, diarrhea, and/or blood in stool for more than 10 days were examined at the local hospital. Colonoscopy with biopsies was performed and blood and stool samples were taken.RESULTS:In ulcerative colitis (UC) patients, the median Simple Clinical Colitis Activity Index (SCCAI) was 4 (range 0-10) in mild and 6 (range 0-14) in patients with moderate or severe endoscopic activity of inflammation (p = 0.002). The calprotectin concentration in feces was significantly related to the SCCAI (p = 0.034) and the Mayo endoscopic subscore (p = 0.031). There was a significant association between the C-reactive protein (CRP) value, leucocytes and thrombocytes and the SCCAI, but only leucocytes were significantly associated with the Mayo endoscopic subscore. In Crohn's disease (CD) patients, there was no statistical significant association between the Harvey-Bradshaw Index (HBI) and the endoscopic grade of mucosal inflammation (p = 0.8). The calprotectin concentration in feces was significantly related to the endoscopic activity score (p = 0.004), but not to the HBI (p = 0.5). HBI was significantly related to the CRP value (p = 0.047) and thrombocytes (p = 0.03).CONCLUSIONS:In UC, both biochemical and fecal markers are related to disease activity and extent of disease, whereas in CD, the fecal calprotectin concentration is a reliable marker of mucosal affection, but not for systemic disease activity.

Considered "negative" for MAP, these results would be very "positive" for tuberculoid leprosy Dear Sir,We would like to compliment Dr Ricanek and associates on their recent study published in the JCC 1 .It is a well conceived, planned, performed, analyzed and written contribution to a disparate and contradictory literature.Their comments were considered and non-contentious.Theirs is a thoughtful contribution that is in the laudable tradition of Norwegian mycobacterial investigation. 2 As investigators who are concerned that MAP is indeed zoonotic, and responsible for far more than just Crohn disease; we would like to make several specific comments.#1.Their MIGT and PCR concerns are well stated and cogent.Their caveats notwithstanding, their proceeding from a positive MGIT signal to IS 900 PCR may become standard for those attempting to culture MAP from humans.As costs fall and availability increases, whole organism genomic sequencing may eventually supercede their approach.#2.We were particularly impressed that they stated that their young patients were naive to (presumably) IBD therapy, even if not to some conventional antibiotics.However, unless specifically stated the authors ignore the increasing body of literature that, unknowingly, the medical profession has been using antiMAP antibiotics when they use "anti-inflammatories," "immune-suppressants" and "immunomodulators" in the therapy of IBD. 3,43.The significance of the increase in MAP detection rate in longstanding IBD may be open to an alternative interpretation.It is that in long standing IBD, MAP, a notoriously difficult mycobacterium to detect in humans, is somewhat easier to demonstrate as disease progresses!#4.Finally, we have long suggested that amongst mycobacterial diseases, there is greater commonality between MAP and leprosy than MAP with tuberculosis. 3,5If these results had been obtained in a tuberculosis study, the author's negative interpretations would be reasonable.In contrast, if this were a leprosy study, particularly the paucibacillary tuberculoid form, their results would be considered stunningly positive.Particularly sinceto this day-M.leprae has never been grown in culture. 6

OBJECTIVE:Rebound acid hypersecretion after withdrawal of proton pump inhibitor (PPI) may lead to symptom aggravation and difficulties in withdrawing anti-reflux medication. The aim was to investigate pathophysiological and clinical consequences of on-demand treatment with PPI in patients with endoscopy-negative reflux disease.MATERIAL AND METHODS:Twenty-six patients with endoscopy-negative reflux disease were investigated for rebound effects of lansoprazole 15 mg, used on-demand, maximum 4 capsules daily during a 6-month period. P-CgA and s-gastrin were measured before, at termination and 2 weeks after stopping treatment. Symptom score was performed the week before and the second week after treatment, 24-h pH-metry after both periods.RESULTS:Median daily consumption of lansoprazole was 15.1 mg (95% CI: 10.5; 18.8). S-gastrin before treatment was 31.2 pmol/l, 54.8 at the end (p < 0.01), 31.7 two weeks after withdrawal. P-CgA was 16.7 u/l before treatment, 37.5 at the end (p < 0.01), 17.7 two weeks after withdrawal (p = 0.35). A positive correlation was found between total consumption of lansoprazole and CgA increase during treatment (r = 0.44 p = 0.03). There was a reduction in symptom score during the treatment period from 30 (24-38) before, to 20 (15-36) the second week after treatment, p = 0.06. 32% had increase in symptoms.CONCLUSIONS:Rebound acid hypersecretion is probably an infrequent problem in on-demand treatment with PPI in patients with endoscopy-negative reflux disease. A significant increase in p-CgA and s-gastrin was found after 6 months treatment. Fourteen days after withdrawal, CgA and gastrin returned to pretreatment levels. Overall, no aggravation of symptoms was found, but 1/3 experienced increased symptoms.

BACKGROUND:Patients with inflammatory bowel disease (IBD) are at increased risk of colorectal cancer (CRC). Recently, new phenotypes of CRC in IBD have been suggested. Studies of the prognosis of CRC in IBD have shown conflicting results. The aim of the study was to analyze factors for prognosis in CRC-IBD, including the impact of the new phenotypes.METHODS:By using the nationwide, population-based Cancer Registry of Norway, we compared survival of a CRC-IBD cohort with CRC in the background population (all-CRC), adjusting for the topographical distribution of dysplasia at cancer diagnosis (widespread versus localized neoplasia in IBD) and other factors. We also analyzed prognostic factors within CRC-IBD.RESULTS:The mean age at CRC diagnosis was 43 years in widespread, 52 years in localized neoplasia IBD, and 70 years in all-CRC (P < 0.05). Adjusted for cofactors, prognosis of CRC-IBD was poorer compared to all-CRC (mortality rate ratio [MRR] 3.71, 95% confidence interval [CI]: 2.54-5.42, P < 0.001). Prognosis of widespread neoplasia IBD was poorer compared to all-CRC (MRR 4.27, 95% CI: 2.83-6.44, P < 0.001) and compared to localized neoplasia IBD (MRR 3.58, 95% CI: 0.87-14.72, P = 0.076). Survival was not significantly different between localized neoplasia IBD and all-CRC (P = 0.132).CONCLUSIONS:The results demonstrate lower age and poorer survival of CRC in IBD compared to CRC in the background population. The unfavorable effect of IBD on prognosis of CRC was pronounced in widespread neoplasia IBD. The diagnosis of this phenotype seems to be an important prognostic sign in patients with CRC in IBD.

Background The presence of Mycobacterium avium subspecies paratuberculosis (MAP) has previously been inferred in the genesis of Crohn's disease (CD), and a higher incidence of MAP PCR positivity has been demonstrated in the gut and peripheral blood of CD patients than in healthy individuals. The objective of this prospective study was to assess the potential etiological role of MAP in the pathogenesis of CD. Methods The presence of mycobacteria was assessed in bowel biopsies from newly diagnosed, treatment naïve Norwegian patients with IBD, including CD and ulcerative colitis (UC), as compared to a hospital-based cohort of CD and UC patients. Biopsies were collected from the small and large bowel in 354 individuals with suspected IBD. Detection of mycobacteria was performed by long-term cultivation in combination with direct detection by MAP IS900-specific PCR. Results Among the specimens included from the patients with early IBD, samples from only two of the patients with CD (2.7%) and two of the non-IBD controls (1.5%) exhibited a positive growth signal. None of the CD patients and only one of the non-IBD controls was MAP PCR positive. Only the single PCR positive non-IBD control was also mycobacterial culture positive with Mycobacterium avium subsp. hominissuis. In the referral patients with long-term IBD, the prevalence of growth signal and MAP PCR positivity was higher (52 and 9%, respectively). Conclusions These findings demonstrate the paucity of MAP in the gut of treatment naïve CD patients. This study does not provide evidence for a role of MAP in early IBD.

Background: The histological variability in colitis-associated colorectal cancer (CRC in inflammatory bowel disease [IBD]) and the association to clinical factors is unknown.Methods: in population-based material including 67 patients with CRC in IBD, histopathology of the cancers and tissue samples from different colorectal localizations were reevaluated, and relationships to clinical factors analyzed.Results: Forty-three of 60 patients (75%) showed dysplasia in the colorectum apart from the cancer. while 17 (25%) had no dysplasia at cancer diagnosis. Mean age at onset of IBD wits 22) years in patients with and 34 years in patients without dysplasia (P = 0.01). The mean duration of colitis-CRC interval was 21 years in patients with and 16 years in patients without dysplasia (P = 0.02). The latter group included all patients with a colitis-CRC interval <10 years. Active inflammation wits more likely to occur in patients with dysplasia (odds ratio [OR] 14.2). The 2 groups were not discriminated by gender. family history of CRC or IBD, diagnosis of PSC, medical treatment, active symptoms, or histological features like type of cancer and differentiation. In Multiple logistic regression analysis the age at onset of IBD was the strongest predictive variable for dysplasia at cancer diagnosis (P = 0.025).Conclusions: Widespread neoplasia occurs in the majority of cases with CRC in IBD and is associated with early onset of IBD. Localized neoplasia occurs in about a quarter of the patients and shows an association with late-onset IBD. The 2 groups probably shows all association with late-onset IBD. The 2 groups probably represent different pathogenetic entities of neoplasia in IBD. This might have consequences for surveillance strategies.

Objective. Owing to rising incidence rates in inflammatory bowel disease (IBD), there has been increased interest in causal relationships in pediatric disease. The present population-based inception cohort was recruited in the Oslo area from 2005 to 2007, with the aim of conducting a detailed characterization of treatment-naive patients at diagnosis. Material and methods. After an invitation was extended to all general practitioners in the catchment area, patients aged 18 years with suspected IBD were diagnosed by proximal and distal endoscopy, MRI, demographic, clinical, and histological and molecular characteristics. Symptomatic non-IBD patients served as controls. Results. Of 100 pediatric patients, 62 had IBD (39 Crohn's disease (CD), 19 ulcerative colitis (UC), 4 IBD unclassified (IBDU)) and 38 other diseases. Median age at diagnosis for IBD was 13.1 years (56.4% males), median symptom duration 6 months, and 69% L3 (Vienna classification). With 195,000 children aged 18 years in the catchment area, the incidence rate of IBD per 100,000/years inhabitants was 10.9 (6.8 for CD, 3.6 for UC, and 0.6 IBDU) and for those aged 16 years (178,500) the incidence rate was 10.6. The higher NOD2 allele frequency among children may partly contribute to the increase. Conclusions. The results indicate a marked rise in the incidence of CD in contrast to no increase in UC in South-Eastern Norway, compared with the figures from the last 15 years. Time from onset of symptoms to diagnosis still represents a challenge for early characterization in IBD.

Objective. Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC), but more knowledge is needed about the possible relationship between clinical parameters and the time to development of cancer in IBD. The aim of the study was to determine the variability of the colitis-CRC interval and to analyze the association with clinical variables in an attempt to gain information on predictive factors of time to cancer within a relatively large cohort of CRC patients. Material and methods. Patients diagnosed with IBD prior to 1 May 2005 at three university hospitals in Oslo were matched against the CRC files at the Cancer Registry of Norway. Only histological re-confirmed IBD and adenocarcinoma of the colorectum were included. Results. Sixty-one patients with CRC in ulcerative colitis and 6 in Crohn's disease, including 13 CRC in primary sclerosing cholangitis (PSC), covering a follow-up of 1625 patient years, were identified. The median time from diagnosis of IBD to CRC was 17 years. Seven of 58 patients (12%) developed CRC within 10 years from onset of IBD symptoms and 14/67 (21%) within 10 years after the diagnosis of IBD. The colitis-CRC interval decreased by a factor of 0.154 (p = 0.018) when age at onset of IBD increased by one year. Mean age at onset of IBD was 30 years in patients with Dukes' stage C or D compared with 20 years in Dukes' stage A or B patients (p = 0.017). The colitis-CRC interval decreased by a factor of 0.138 (p = 0.003) when the percentage of the colitis-CRC interval with active symptoms increased by 1%. Patients with PSC were significantly younger at onset of IBD symptoms (+ PSC: 19 years versus no PSC: 29 years, p = 0.04), but the colitis-CRC interval was similar to IBD without PSC (17 years versus 20 years, p = 0.236). Mean duration of the colitis-CRC interval was not related to family history or drug consumption prior to CRC. Conclusions. In the present cohort, for whom the median time from diagnosis of IBD to CRC was 17 years, 21% of the cancers developed before 10 years of disease, which is before colonoscopic screening is usually recommended. High age at onset of IBD may be related to a more aggressive development of CRC in IBD and early inclusion in screening programs might be considered for this group of patients. Symptom activity but not the diagnosis of PSC, family history of CRC or IBD or drug treatment seems to have an effect on the colitis-CRC interval.

time from year of diagnosis until the development of CRC from time starting 5-ASA for each group was calculated.For the short time, low dose (mean 7.89, std 6.19, median 7), short time, high dose (mean 8.94, std 9.5, median 7), long time, low dose (mean 24.7, std 11.6, median 24), and long time, high dose (mean 18.9, std 12.4, median 15).Comparing the duration until development of CRC revealed a significant difference (P=0.0014.)There was a significant difference between short time, low dose (or high dose) and long time, low dose (or high dose).Conclusion: The length of time a patient is on a 5-ASA may be more significant than the dose of 5-ASA in decreasing the risk of development of CRC in patients with UC.

Objective. The results of recent research suggest that there is an increasing incidence of inflammatory bowel disease (IBD) among children. Newly diagnosed IBD was compared between two consecutive 6-year periods in the same catchment area of southeastern Norway. Material and methods. Children subjected to endoscopy from 1993 to 2004 were recorded retrospectively in the first 6-year period and prospectively for the subsequent period. The mean size of the child population under 16 years in the area was 70,500. The study reports on incidence numbers, age at diagnosis, disease distribution and clinical presentation at diagnosis. Results. There were 23 incident cases of IBD in the first period and 25 in the subsequent period. The rates of Crohn's disease (CD) for the two periods were, respectively, 1.95 and 3.64, and for ulcerative colitis (UC) 3.67 and 2.05/100,000 children/year. Total incidence rates of IBD for the two periods were 5.6 and 5.7, respectively, similar to the findings of the IBSEN study of 1990-94. The change in CD and UC rates from the first to the second period can be explained by better methods of diagnosis. Conclusions. The total incidence of IBD was not changed between time periods, whereas a trend towards an increase in CD and a reduction in UC was recorded. The incidence rates are in accordance with previously reported national and international data from the past decade. The extent of disease in CD and UC may indicate a serious prognosis of IBD among children.

Background Rebound acid hypersecretion might occur after treatment with proton pump inhibitors. This study looks for a rebound aggravation of symptoms after short-term treatment with lansoprazole. Study Sixty-two patients (19 men and 43 women; mean age, 54 years; range, 32–77 years) with heartburn and regurgitation and normal upper endoscopy findings were studied in a randomized, double-blind, placebo-controlled trial with a crossover design. There were two 5-day treatment periods with lansoprazole 60 mg once daily or placebo in random order, separated by a 9-day washout period. Reflux, total, and antacid scores were calculated for each of the treatment periods. Higher scores during the placebo period in the group given lansoprazole first than in the group given placebo first indicated a rebound aggravation of symptoms. Results The mean symptom scores during the placebo period in the groups given lansoprazole first and placebo first were as follows: reflux score, 21.5 and 17.6, respectively (not significant); total score, 11.2 and 10.3, respectively (not significant); and antacid score, 8.2 and 7.2, respectively (not significant). Conclusions There is no indication of a rebound aggravation of symptoms 12 to 14 days after a 5-day treatment with lansoprazole 60 mg once daily in patients with reflux symptoms.