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The effect of the putative enteric neurotransmitters neurokinin A and substance P were investigated on human small intestinal motility. Either neurokinin A, at doses of 6-25 pmol/kg/min, or substance P at doses of 1-6 pmol/kg/min were administered intravenously to healthy volunteers over 4 hr. Neurokinin A dose-dependently increased the fraction of phase II of the migrating motor complex, contraction frequency, motility index, and amplitude of contractions. At the highest dose, neurokinin A induced a phase II-like pattern, disrupting the migrating myoelectric complex. Substance P dose-dependently increased phase II of the migrating motor complex. The contraction frequency increased slightly at the highest dose, but neither motility index nor contraction amplitude changed. It is concluded that neurokinin A and substance P stimulate small intestinal motility in man, and it can be speculated that they play a role in the control of human small intestinal motility. [ABSTRACT FROM AUTHOR]

Tissue concentrations of malondialdehyde in the gastrointestinal tract of the rat were quantified as indicators of lipid peroxidation and tissue damage after challenge with tachykinins and after pretreatment with allopurinol. Neurokinin A, neurokinin B, and substance P given intravenously during 30 min increased the production of malondialdehyde in the stomach, duodenum, jejunum, and colon in a dose-dependent manner at doses from 100 to 400 pmol/kg/min (P < 0.05-0.01). However, the stomach seemed less responsive to the tachykinin challenge. For comparison, a similar dose-dependent increase of malondialdehyde was found in the liver and lung, with more pronounced effects of neurokinin B (P < 0.05-0.01). Pretreatment with allopurinol, 10 mg/kg, significantly reduced malondialdehyde responses to tachykinin challenge in intestinal tissues (P < 0.001). In conclusion, elaboration of malondialdehyde is suggested to reflect the ability of gastrointestinal tissues to react to tachykinins at high concentrations with liberation of free radicals as part of an inflammatory reaction. [ABSTRACT FROM AUTHOR]

Background: Ustekinumab (UST) is an anti-interleukin-12/23 antibody used in the treatment of inflammatory bowel disease. This study includes patients treated at four hospitals in Stockholm to provide long-term real-world data., Methods: Retrospective study including patients diagnosed with ulcerative colitis and treated with UST between the years 2019 and 2021. Patients were followed until withdrawal of treatment, or until a predefined end of study, 31 July 2021. Disease activity was assessed with Physician Global Assessment (PGA); Ulcerative Colitis Endoscopic Index of Severity (UCEIS), laboratory parameters, and drug persistence. The primary outcome was steroid-free remission (PGA = 0) and response (decrease PGA ≥ 1 from baseline) at 3 and 12 months, respectively., Results: A total of 96 patients, 44 women and 52 men were included. The patients had either extensive colitis (69%), left-sided colitis (29%), or proctitis (3%). All but two patients were anti-TNF-experienced; 94 (98%) had failed ≥1, 59 (61%) ≥ 2, and 34 (35%) had failed ≥ 3 anti-TNF drugs. In addition, 28 (29%) had failed vedolizumab. At inclusion, 92/96 patients (96%) had active disease and four patients were in remission. Among patients who were treated with UST, 9/71 (13%) were in steroid-free remission at 3 months, and 26/33 (78%) were at 12 months. Withdrawal rates at 3 and 12 months, were 12 and 26%, respectively, mainly due to persisting disease activity (20%)., Conclusion: In this group of patients with difficult-to-treat ulcerative colitis, UST was shown to be effective in the majority, with high drug persistence at 12 months in combination with a favorable safety profile., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Ustekinumab is used to treat inflammatory bowel disease mainly in patients failing anti-tumour necrosis factor (TNF)-agents., Objectives: To provide real-world data in unselected patients with Crohn's disease (CD), treated with ustekinumab., Design: Longitudinal retrospective study at four hospitals in Stockholm, Sweden., Methods: Disease activity (Harvey-Bradshaw index and physician global assessment), laboratory parameters, endoscopic findings and drug persistence were assessed. Follow-up data were obtained in patients that stopped ustekinumab., Results: In total, 322 patients (median age 38 years, 48% women) were included. All had luminal disease and 22% also fistulizing disease. A total of 271 (84%) had failed ⩾1 and 148 (46%) ⩾2 anti-TNF drugs; 34% failed vedolizumab. At inclusion, 93% had active disease; 28% were on oral corticosteroids and 18% on thiopurines. The median follow-up on treatment was 13.5 months; overall 67% were followed at least 24 months. By intention to treat analysis, response rate at 3 and 12 months was 43% and 42%, respectively. Among patients with ongoing ustekinumab, 19% were in steroid-free remission at 3 months and 64% at 12 months. The median faecal calprotectin level decreased from 460 µg/g at baseline to 156 µg/g at 3 months and was 182 µg/g at 12 months. C-reactive protein remained stable at 4 mg/L whereas serum albumin increased slightly. About 31% of patients were withdrawn during the first 12 months, mainly due to persisting disease activity 21%, adverse events 5%, bowel surgery 0.6% or malignancy 0.3%. The overall persistence on ustekinumab was 88%, 51%, 34% and 20% at 3, 12, 24 and 36 months, respectively. Within 12 months following withdrawal of ustekinumab in 121 patients, 64% had active disease most of the time, 68% needed another biologic and 24% underwent surgery., Conclusion: Among difficult-to-treat patients with CD, ustekinumab was effective in the majority, with high drug persistence at 12 and 24 months in combination with a favourable safety profile., Competing Interests: FB, HS and AB performed part of the work during their internship in gastroenterology at Region Stockholm. FB: Speaker: Janssen, Research: Janssen. CH: speaker: Janssen, Vifor-Pharma, Takeda. OF and CW are employees of Janssen Cilag AB. SA: Scientific committee/Advisory board: Pharmacosmos, Janssen, Takeda, Consultant: Takeda, Janssen, Speaker: Galapagos, Janssen, Tillotts, Research: Janssen. The other authors have nothing to declare., (© The Author(s), 2024.)

Background: Despite the increasing use of biologics in patients with inflammatory bowel disease (IBD), real-world data about outcomes in the era of biologics remain inconclusive., Aims: To investigate trends in surgeries, hospitalisations and medication use in patients with IBD in a multinational, population-based cohort METHODS: We included 42,894 patients with ulcerative colitis (UC) and 24,864 with Crohn's disease (CD) who were diagnosed between 2010 and 2017 in Denmark, Norway and Sweden. We extracted data about surgeries, hospitalisations and medications from national registries and compared across countries and diagnosis years., Results: Between 2010 and 2017, 2-year surgery rates were 4-7% in UC and 10-15% in CD and were stable over time. Two-year hospitalisation rates increased in Denmark (UC: 20% to 35%; CD: 27% to 32%) but were stable in Norway and Sweden (fluctuating between 33% and 37% in UC, and 46% and 52% in CD). Two-year rates of biologic use increased in both UC (7% to 16% in Denmark, 8% to 18% in Norway) and CD (22% to 26% in Denmark; 21% to 35% in Norway). Two-year rates of immunomodulator use increased in Norway (from 14% to 23% in UC; 37% to 45% in CD) and Sweden (from 41% to 52% in CD), but were stable in Denmark (between 17% and 21% in UC; 39% to 46% in CD)., Conclusion: Between 2010 and 2017, surgery rates among Scandinavian patients with IBD remained stable, with no clear changes in hospitalisation rates despite the increasing use of immunomodulators and biologics., (© 2022 John Wiley & Sons Ltd.)

Background: Infliximab (IFX) is used in active Crohn's disease for induction and maintenance of remission. There are scanty data on weight gain in IBD-patients under anti-TNF treatment. We investigated changes in weight and blood chemistry in anti-TNF-naïve Crohn's disease patients during their first course of IFX., Methods: Retrospective analysis of 110 patients (77 men, 33 women) aged 34 years (range 14-73), 54 with luminal and 56 with fistulising disease, given at least 3 infusions of IFX (range 3-11). Data regarding body weight, height, C-reactive protein (CRP), haemoglobin and S-albumin at baseline, before the third infusion, at three months and at 12 months were collected., Results: At 6 weeks, 65 (59%) increased in weight, 73% and 76% at three and 12 months, respectively. There was an increase in median weight (1.7 kg, IQR = 3.1 kg) and BMI (0.5 kg/m 2 , IQR = 1.2 kg/m 2 ) at 6 weeks, which persisted at three and 12 months (all p  < .001). There was no difference between men and women. Young patients, patients with underweight or fistulising disease increased most in weight. Disease activity assessed by PGA and SES-CD decreased at all time points ( p  < .05). Increases in weight and BMI correlated with an increase in serum albumin and a decrease in CRP., Conclusion: Approximately 60% of Crohn's disease patients experience weight gain within the first six weeks of infliximab treatment. The weight increment correlates with improvements in inflammatory markers and disease activity. The causes of weight gain may be related to treatment induced metabolic changes and reduced inflammatory burden.

Objectives: Anti-TNF treatment is established for patients with severe inflammatory bowel disease (IBD) refractory to conventional medication. However, long-term real-life observations are limited. We have monitored 200 patients with primary response to infliximab (Remicade ® ). Methods: Patients with either Crohn's disease (CD) or ulcerative colitis (UC) who started IFX and had clinical response at 1 year were prospectively followed. C-reactive protein (CRP), albumin, fecal calprotectin (FCP), Harvey Bradshaw index (HBI) in CD cases, and Quality of Life index were monitored. Concomitant medications, surgery and hospitalisation were assessed. Results: Out of the 200 patients, 164 suffered from CD. Median disease duration was 5.0 (0.2-44.0) years and the observation time was 3.4 (1.0-13.9) years. Steroid use was reduced from 51% to 10%. HBI in CD patients decreased from 8.0 ± 0.40 to 2.7 ± 0.26. Disease activity in UC patients was only assessed by biochemical markers. CRP decreased from 29.0 ± 6.2 to 8.0 ± 7.1 mg/L. FCP showed a decrease from 1918 (1837) to 191 (646) mg/kg. Hospitalization showed similar tendency and quality of life was improved. Twenty-seven percent had been operated before IFX introduction compared to 11% during the observation period. Loss of response was seen in 42 patients, of which 20 patients needed intestinal surgery. Conclusion: Two-thirds of the patients demonstrated stable clinical benefit from maintenance IFX. The results show steroid-sparing efficacy as well as improved quality of life and reduced need for surgery.

Intestinal fatty acid binding protein (I-FABP) indicates barrier integrity., Aims: determine if I-FABP is elevated in active Crohn's disease (CD) and if I-FABP parallels anti-TNF α antibody (infliximab) induced lowering of TNF α and Harvey-Bradshaw Index (HBI) as potential indicator of mucosal healing. I-FABP distribution along human gut was determined. Serum from 10 CD patients collected during first three consecutive infliximab treatments with matched pretreatment and follow-up samples one week after each treatment and corresponding HBI data were analyzed. I-FABP reference interval was established from 31 healthy subjects with normal gut permeability. I-FABP and TNF α were measured by ELISA; CRP was measured by nephelometry. Healthy tissue was used for I-FABP immunohistochemistry. Pretreatment CD patient TNF α was 1.6-fold higher than in-house reference interval, while I-FABP was 2.5-fold higher, which lowered at follow-ups. Combining all 30 infusion/follow-up pairs also revealed changes in I-FABP. HBI followed this pattern; CRP declined gradually. I-FABP was expressed in epithelium of stomach, jejunum, ileum, and colon, with the highest expression in jejunum and ileum. I-FABP is elevated in active CD with a magnitude comparable to TNF α . Parallel infliximab effects on TNF α , HBI, and I-FABP were found. I-FABP may be useful as an intestine selective prognostic marker in CD.

Background and Aims: Crohn's disease [CD] and ulcerative colitis [UC] are chronic diseases associated with a substantial utilisation of healthcare resources. We aimed to estimate the prevalence of inflammatory bowel disease [IBD], CD, and UC and to describe and compare healthcare utilisation and drug treatment in CD and UC patients., Methods: This was a cross-sectional study of all patients with a recorded IBD diagnosis in Stockholm County, Sweden. Data on outpatient visits, hospitalisations, surgeries, and drug treatment during 2013 were analysed., Results: A total of 13 916 patients with IBD were identified, corresponding to an overall IBD prevalence of 0.65% [CD 0.27%, UC 0.35%, inflammatory bowel disease unclassified 0.04%]; 49% of all IBD patients were treated with IBD-related drugs. Only 3.6% of the patients received high-dose corticosteroids, whereas 32.4% were treated with aminosalicylates [CD 21.2%, UC 41.0%, p < 0.0001]. More CD patients were treated with biologicals compared with UC patients [CD 9.6%, UC 2.9%, p < 0.0001] and surgery was significantly more common among CD patients [CD 3.0%, UC 0.8%, p < 0.0001]., Conclusions: This study indicates that patients with CD are the group with the highest medical needs. Patients with CD utilised significantly more healthcare resources [including outpatient visits, hospitalisations, and surgeries] than UC patients. Twice as many CD patients received immunomodulators compared with UC patients and CD patients were treated with biologicals three times more often. These results highlight that CD remains a challenge and further efforts are needed to improve care in these patients., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The present study tested the hypothesis that patients with Crohn's disease (CD) have a higher prevalence and risk for caries compared to people without CD., Material and Methods: Patients with CD were divided into groups; 71 patients (50.7 ± 13.9 years) who had gone through resective intestinal surgery and 79 patients (42.0 ± 14.4 years) who had not. The patients were compared to 75 controls (48.6 ± 13.4 years) regarding DMF-T and DMF-S, Lactobacilli (LB), Streptococcus mutans (SM), salivary flow and dental plaque. Statistical methods including ANOVA or Chi-square test for calculation of demographic differences between groups, analysis of covariance (ANCOVA) to compare the clinical variable and Post hoc analyses were done with Fischers Least Significant Difference test or Chi-square. Non-parametric Spearman's correlation matrix coefficient was estimated between clinical variables and disease duration., Results: CD patients who had been subjected to resective surgery had a higher DMF-S score (50.7 versus 36.5; p = 0.01) compared to the control group after adjusting for age, gender and smoking. These patients had higher counts of SM (1.5 versus 0.9; p = 0.04) and LB (10000.0 versus 1000.0; p = 0.01), and more dental plaque (53.7 versus 22.6; p = 0.001). CD patients reported a more frequent consumption of sweetened drinks between meals compared to controls (p = 0.001)., Conclusions: The present study shows that patients with CD who had undergone resective surgery had a higher DMFs score, and higher salivary counts of Lactobacilli and Streptococcus mutans compared to the control group.

Aim: To study the association between inflammatory bowel disease (IBD) and genetic variations in eosinophil protein X (EPX) and eosinophil cationic protein (ECP)., Methods: DNA was extracted from ethylene diamine tetraacetic acid blood of 587 patients with Crohn's disease (CD), 592 with ulcerative colitis (UC) and 300 healthy subjects. The EPX405 (G > C, rs2013109), ECP434 (G > C, rs2073342) and ECP562 (G > C, rs2233860) gene polymorphisms were analysed, by the 5'-nuclease allelic discrimination assay. For determination of intracellular content of EPX and ECP in granulocytes, 39 blood samples was collected and extracted with a buffer containing cetyltrimethylammonium bromide. The intracellular content of EPX was analysed using an enzyme-linked immunosorbent assay. The intracellular content of ECP was analysed with the UniCAP(®) system as described by the manufacturer. Statistical tests for calculations of results were χ(2) test, Fisher's exact test, ANOVA, Student-Newman-Keuls test, and Kaplan-Meier survival curve with Log-rank test for trend, the probability values of P < 0.05 were considered statistically significant., Results: The genotype frequency for males with UC and with an age of disease onset of ≥ 45 years (n = 57) was for ECP434 and ECP562, GG = 37%, GC = 60%, CC = 4% and GG = 51%, GC = 49%, CC = 0% respectively. This was significantly different from the healthy subject's genotype frequencies of ECP434 (GG = 57%, GC = 38%, CC = 5%; P = 0.010) and ECP562 (GG = 68%, GC = 29%,CC = 3%; P = 0.009). The genotype frequencies for females, with an age of disease onset of ≥ 45 years with CD (n = 62), was for the ECP434 and ECP562 genotypes GG = 37%, GC = 52%, CC = 11% and GG = 48%, GC = 47% and CC = 5% respectively. This was also statistically different from healthy controls for both ECP434 (P = 0.010) and ECP562 (P = 0.013). The intracellular protein concentration of EPX and ECP was calculated in μg/10(6) eosinophils and then correlated to the EPX 405 genotypes. The protein content of EPX was highest in the patients with the CC genotype of EPX405 (GG = 4.65, GC = 5.93, and CC = 6.57) and for ECP in the patients with the GG genotype of EPX405 (GG = 2.70, GC = 2.47 and CC = 1.90). ANOVA test demonstrated a difference in intracellular protein content for EPX (P = 0.009) and ECP (P = 0.022). The age of disease onset was linked to haplotypes of the EPX405, ECP434 and ECP562 genotypes. Kaplan Maier curve showed a difference between haplotype distributions for the females with CD (P = 0.003). The highest age of disease onset was seen in females with the EPX405CC, ECP434GC, ECP562CC haplotype (34 years) and the lowest in females with the EPX405GC, ECP434GC, ECP562GG haplotype (21 years). For males with UC there was also a difference between the highest and lowest age of the disease onset (EPX405CC, ECP434CC, ECP562CC, mean 24 years vs EPX405GC, ECP434GC, ECP562GG, mean 34 years, P = 0.0009). The relative risk for UC patients with ECP434 or ECP562-GC/CC genotypes to develop dysplasia/cancer was 2.5 (95%CI: 1.2-5.4, P = 0.01) and 2.5 (95%CI: 1.1-5.4, P = 0.02) respectively, compared to patients carrying the GG-genotypes., Conclusion: Polymorphisms of EPX and ECP are associated to IBD in an age and gender dependent manner, suggesting an essential role of eosinophils in the pathophysiology of IBD.

Objective: To reveal specific gene activation in nitric oxide (NO)-related inflammation we studied differential gene expression in inflammatory bowel disease (IBD)., Methods: Total RNA was isolated from 20 biopsies of inflamed mucosa from Crohn's disease (CD) and ulcerative colitis (UC) patients each as well as from six controls, labeled with (32)P-dCTP and hybridized to a human NO gene array. Significant genes were analyzed for functional gene interactions and heatmaps generated by hierarchical clustering. A selection of differentially expressed genes was further evaluated with immunohistochemical staining., Results: Significant gene expression differences were found for 19 genes in CD and 23 genes in UC compared to controls, both diseases with high expression of ICAM1 and IL-8. Correlation between microarray expression and corresponding protein expression was significant (r = 0.47, p = 0.002). Clustering analysis together with functional gene interaction analysis revealed clusters of coregulation and coexpression in CD and UC: transcripts involved in angiogenesis, inflammatory response mediated by the transcription factor hypoxia-inducible factor 1, and tissue fibrosis. Also, a fourth cluster with transcripts regulated by the transcription factor Sp1 was found in UC., Conclusions: Expression analysis in CD and UC revealed disease-specific regulation of NO-related genes, which might be involved in perpetuating inflammatory disease activity in IBD.

Background: neuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02)., Principal Findings: we identified one promoter SNP (rs2530547 [-103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk., Significance: these findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance., (© 2011 Anedda et al.)

Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan, comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis.

Objectives: Crohn's disease (CD) is characterized by overproduction of proinflammatory cytokines like interleukin (IL)-1beta. Production of mature IL-1beta is dependent on a caspase-1-activating protein complex called the NALP3 inflammasome, composed of NALP3, ASC, and CARD8. NALP3 shares structural similarities with Nod2, and both of these proteins are required for bacteria-induced IL-1beta secretion. The combination of the polymorphisms CARD8 (C10X)and NALP3 (Q705K) was recently shown to be associated with rheumatoid arthritis.Our aim was to investigate whether these combined polymorphisms play a role in the susceptibility to CD., Methods: The study included 498 CD patients in two cohorts from different regions and 742 control individuals from a Swedish population. DNA was isolated from whole blood. Polymorphisms of (Q705K) NALP3 and (C10X) CARD8, as well as the Nod2 variants, R702W and G908R, were genotyped using the Taqman single nucleotide polymorphism assay. The Nod2 frameshift mutation, L1007fs, was detected by Megabace SNuPe genotyping., Results: Our results show that men who have both the C10X and Q705K alleles in CARD8 and NALP3, and who express wild-type alleles of Nod2 are at an increased risk of developing CD (odds ratio, OR: 3.40 range: 1.32-8.76); P = 0.011). No association with these polymorphisms was found in women (OR: 0.89 (range: 0.44-1.77); P = 0.74)., Conclusions: We suggest a role for combined polymorphisms in CARD8 and NALP3 in the development of CD in men, with obvious sex differences in the genetic susceptibility pattern. These findings give further support to the importance of innate immune responses in CD.

Objective: Recent data have controversially suggested that variants of the organic cation transport genes SLC22A4 (OCTN1) and SLC22A5 (OCTN2) are responsible for the contribution of IBD5 to disease susceptibility in Crohn's disease (CD). The objective of this study was to assess the contribution of the SLC22A4 variant (1672T) and SLC22A5 variant (-207C) together with three IBD5 haplotype markers in the previously uninvestigated Swedish CD population., Material and Methods: The study comprised 178 CD patients and 143 healthy controls (HC). Genotyping for IBD5 single nucleotide polymorphisms (SNPs) IGR2096a&#95;1, IGR2198a&#95;1, IGR2230a&#95;1, SLC22A4 1672T and SLC22A5 -207C was carried out using the TaqMan system. Associations with disease susceptibility and disease phenotype were investigated., Results: Strong linkage disequilibrium was observed between the investigated SNPs (D prime >0.92). IGR2096a&#95;1 allelic frequency and homozygosity rates were associated with CD (44% CD versus 33.8% HC, p=0.008, OR=1.55 and 20% CD versus 12% HC, p=0.04, OR=1.93, respectively). Variant allelic frequency of SLC22A4, 1672T (44% versus 36%, p=0.03, OR=1.4) and homozygosity for the SLC22A4, SLC22A5 TC haplotype (1672T, -207C) (21.3% versus 12%, p=0.03, OR=1.78, population attributable risk (PAR)=11%) were associated with CD. There was no association between the allelic frequency of SLC22A5 and CD (46.6% CD versus 41.5% HC, p=0.82). The association of the TC haplotype with CD was not independent of the SNPs representing the extended IBD5 linkage interval., Conclusions: The IBD5 locus is associated with CD in the Swedish population. The strongest association is with the marker SNP IGR2096a&#95;1, lying p-telomeric to SLC22A4 and SLC22A5. The effect of the TC haplotype was not an independent determinant in this population.

Aim: To study the effect of oral steroids upon clinical response and rectal mucosa secretion of eosinophil cationic protein (ECP), myeloperoxidase (MPO), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and albumin in patients with collagenous colitis (CC)., Methods: A segmental perfusion technique was used to collect perfusates from rectum of CC patients once before and twice (one and four weeks) after the start of steroid treatment. Clinical data was monitored and ECP, MPO, bFGF, VEGF and albumin concentrations were analyzed by immunochemical methods in perfusates and in serum., Results: Steroids reduced the number of bowel movements by more than five times within one week and all patients reported improved subjective well-being at wk 1 and 4. At the same time, the median concentrations of ECP, bFGF, VEGF and albumin in rectal perfusates decreased significantly. MPO values were above the detection limit in only 3 patients before treatment and in none during treatment. VEGF, bFGF, ECP and albumin concentrations correlated with each other with the exception of ECP and albumin. A decrease of serum ECP and VEGF concentrations was also seen even if the overtime reduction was not significant., Conclusion: Oral steroid treatment in CC patients induced a simultaneous reduction of bowel movements and rectal release of ECP, bFGF, VEGF and albumin, suggesting that these polypeptides and increased mucosal permeability are important components of the pathophysiology in collagenous colitis.

Objective: Crohn's disease (CD) is a chronic inflammatory bowel disorder caused by environmental and genetic factors. Mutations in the CARD15 gene have been associated with CD. No previous case-control CARD15 study has been performed in the Swedish population., Material and Methods: The study comprised of 321 individuals: 178 with CD and 143 healthy controls (HCs), all from Stockholm County. All were genotyped for the three main CD-associated CARD15 variants (R702W, G908R and 1007fs) and phenotypic associations were investigated., Results: The allele frequencies of the R702W variant (4.5% CD versus 0.7% HC, p=0.008, OR = 6.8) and the G908R variant (2.0% CD versus 0% HC, p=0.045) were more common in CD patients than in controls. No significant difference in1007fs variant allele frequency was found between CD patients and controls (2.0% CD versus 1.7% HC, p = 0.8, OR = 1.1). Carriage of CARD15 variants was more common in the CD patients than in controls (15.2% CD versus 4.2% HC, p = 0.001, OR = 4.1, population attributable risk (PAR) = 11.4%). Genotype-phenotype analysis demonstrated that CARD15 variants were associated with ileal disease (p=0.0006, OR = 9.3, CI = 2.2-34) and protective for colonic CD (p = 0.01, OR = 0.18). An association between CARD15 variants and ileal CD (p=0.004, OR = 6.6) was confirmed by multivariate analyses., Conclusions: The CARD15 variants R702W and G908R, but not 1007fs, are associated with susceptibility to CD in Stockholm County. Genotype-phenotype analysis shows an association with ileal CD. The contribution of these CARD15 mutations in Swedish CD patients overall is low in relation to studies elsewhere in Central Europe and North America, but is consistent with emerging data from elsewhere in Scandinavia and in Northern Europe.

1. MEN 11420 (nepadutant) is a potent, selective and competitive antagonist of tachykinin NK2 receptors. 2. The objective of the present study was to assess the capability of the drug to antagonize the stimulatory effects of neurokinin A (NKA) on gastrointestinal motility, as well as to change the fasting migrating motor complex (MMC). 3. Thirty-four male volunteers were randomized to treatment with either placebo or MEN 11420 in a double-blinded manner. Effects of MEN 11420 (8 mg intravenously) were evaluated as changes in phases I, II and III of MMC, as well as contraction frequency, amplitude and motility index during baseline conditions and during stimulation of motility using NKA (25 pmol kg(-1) min(-1) intravenously). 4. NKA preceded by placebo increased the fraction of time occupied by phase II, increased contraction frequency, amplitude and motility index. 5. MEN 11420 effectively antagonized the motility-stimulating effects of NKA. MEN 11420 reduced the phase II-stimulating effect of NKA. In addition, the stimulatory effect of NKA on contraction frequency and amplitude, as well as motility index were inhibited by MEN 11420. MEN 11420 did not affect the characteristics of MMC during saline infusion. 6. Plasma levels of MEN 11420 peaked during the first hour after infusion and decreased to less than half during the first 2 h. 7. In conclusion, intravenous MEN 11420 effectively inhibited NKA-stimulated, but not basal gastrointestinal motility, and was well tolerated by all subjects.

We have investigated the effect of 5-hydroxytryptamine (5-HT) and different 5-HT-receptor antagonists and atropine on the migrating myoelectric complex in the rat small intestine. Infusion of 5-HT dose-dependently shortened the interval between phase III of the migrating myoelectric complex (MMC). In untreated animals the interval in upper jejunum was 19.1 (16.0-22.1) min. At doses of 10 and 20 nmol kg-1 min-1, the interval decreased to 15.2 (12.0-18.4) and 10.2 (9.4-11.0) min, respectively. The 5-HT3-receptor antagonist ondansetron (0.5 mg kg-1) alone increased the MMC interval from 20.8 (15.1-26.5) to 33.9 (19.4-48.4) min. Neither methiothepin (0.5 mg kg-1) nor ketanserin (0.5 mg kg-1), selective for 5-HT1/5-HT2- and 5-HT2-receptors, respectively, changed the MMC interval. The 5-HT4-receptor antagonist GR 113808 (0.5 mg kg-1) disrupted the MMC and induced irregular spiking activity. Ondansetron and atropine antagonized the 5-HT-induced shortening of the MMC interval. Neither methiothepin nor ketanserin affected the response to 5-HT. GR 113808 did not block the response to 5-HT in half of the animals; however, in the remaining ones MMC was disrupted and irregular spiking induced. In conclusion, these results show that 5-HT dose-dependently stimulates the cycling of the MMC in the small intestine via 5-HT3-receptors and a cholinergic final pathway. Our findings encourage further studies on the role of the 5-HT3-receptor in the control of gastrointestinal motility.

1. The influence of circulating 5-hydroxytryptamine (serotonin) on small intestinal motility was investigated in healthy volunteers. 2. Small intestinal motility was studied by means of a constantly perfused multi-channel manometry tube, connected to a computer system. 3. Intravenous infusions of either 5-hydroxytryptamine at increasing doses or saline were given over a period of 4 h. 4. 5-Hydroxytryptamine infusion dose-dependently increased plasma 5-hydroxytryptamine from approximately 2 to 10 and 25 nmol/l respectively, as well as urinary excretions of 5-hydroxytryptamine and 5-hydroxyindole acetic acid, a major 5-hydroxytryptamine metabolite. 5. The number of phase III of the migrating motor complex originating in the small intestine was dose-dependently increased by 5-hydroxytryptamine, and found to correlate to the plasma concentration of 5-hydroxytryptamine. The fraction of phase III also increased at the expense of phase II activity. In addition, 5-hydroxytryptamine increased the motility index, propagation velocity of phase III activity and the amplitude of contractions during phase III. 6. Whereas the low dose of 5-hydroxytryptamine (15 nmol.min-1.kg-1) had no haemodynamic effects, an increase in heart rate by approximately 20 beats/min, without change in blood pressure, was observed at the higher dose (60 nmol.min-1.kg-1). Respiratory parameters did not change during infusion of 5-hydroxytrytamine at either dose. 7. In conclusion, elevation of circulating 5-hydroxytryptamine by intravenous infusion results in more frequent and faster propagating migrating motor complexes in the human small intestine during the inter-digestive period.