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IBD
Kinds of IBD Terms modified by IBD Selected AbstractsPotential role of soluble angiopoietin-2 and Tie-2 in patients with inflammatory bowel diseaseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2 2006I. E. Koutroubakis Abstract Background, Angiogenesis has been suggested to play an important role in inflammatory bowel disease (IBD). The aim of the study was to evaluate the serum markers of angiogenesis angiopoietin-2 (Ang-2) and soluble angiopoietin receptor Tie-2 in patients with ulcerative colitis (UC) and Crohn's disease (CD). Materials and methods, Serum Ang-2 and Tie-2 serum levels were measured in 160 IBD patients (79 UC and 81 CD) and in 80 matched healthy controls using commercially available enzyme-linked immunosorbent assays. Serum Ang-2 and Tie-2 levels were correlated with the disease activity, as well as the type, localization and treatment of the disease. Results, Median serum Ang-2 and Tie-2 levels were significantly higher in both the UC patients and the CD patients compared with the healthy controls (P < 0·05 and P < 0·001, respectively). The IBD patients with early disease (diagnosis < 2 years) had significantly higher (P = 0·04) median serum Ang-2 levels but significantly lower (P = 0·02) median serum Tie-2 levels as compared with IBD patients with late disease (diagnosis > 2 years). The CD patients with active disease had significantly higher levels of Ang-2 compared with non-active disease (P = 0·02). Serum levels of both Ang-2 and Tie-2 were not correlated with laboratory markers such as ESR, CRP, white blood cell count, platelet count and albumin. Conclusions, Serum Ang-2 and Tie-2 levels are elevated in patients with IBD. These markers may mediate angiogenesis and vascular permeability in the mucosa of patients with IBD. [source] Paradox of simultaneous intestinal ischaemia and hyperaemia in inflammatory bowel diseaseEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 10 2005O. A. Hatoum Abstract This review has focused on evidence regarding intestinal perfusion of inflammatory bowel disease (IBD). Basic investigation has defined an altered microvascular anatomy in the affected IBD bowel, which corresponds with diminished mucosal perfusion in the setting of chronic, long-standing inflammation. Diminished perfusion is linked to impaired wound healing, and may contribute to the continued refractory mucosal damage, which characterizes IBD. Alterations in vascular anatomy and physiology in IBD suggests additional possible mechanisms by which micro-vessels may contribute to the initiation and perpetuation of IBD. This begs the following questions: will angiogenesis within the gut lead to sustained inflammation, does the growing vasculature generate factors that transform the surrounding tissue and does angiogenesis generate vascular anastomosis within the gut, with shunting of blood away from the mucosal surface, impairment of metabolism and potentiation of gut damage? Further studies are required to define the mechanisms that underlie the vascular dysfunction and its role in pathophysiology of IBD. [source] The role of MAPK in governing lymphocyte adhesion to and migration across the microvasculature in inflammatory bowel diseaseEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 1 2009Franco Scaldaferri Abstract Lymphocyte recruitment is a key pathogenic event in inflammatory bowel disease (IBD). Adhesion of T cells to human intestinal microvascular endothelial cells (HIMEC) is mediated by ICAM-1, VCAM-1 and fractalkine (FKN), but the signaling molecules that orchestrate this process have yet to be identified. Because MAPK play an important role in the response of many cell types to pro-inflammatory stimuli, we assessed the functional role of p38 MAPK, p42/44 MAPK and JNK in the regulation of lymphocyte adhesion to and chemotaxis across the microvasculature in IBD. We found that the MAPK were phosphorylated in the bowel microvasculature and human intestinal fibroblasts of patients with IBD but not of healthy individuals. Stimulation of HIMEC with TNF- , triggered phosphorylation of the MAPK, and up-regulation of VCAM-1, FKN and ICAM-1. Blockade of p38 decreased the expression of all MAPK by 50% (p<0.01), whereas inhibition of p42/44 decreased the expression of ICAM-1 and FKN by 50% (p<0.01). Treatment of human intestinal fibroblasts with TNF- , elicited production of IL-8 and MCP-1, which was reduced (p<0.05) by blockade of p38 and p42/44. Finally, blockade of p38 and p42/44 reduced lymphocyte adhesion to (p<0.05) and transmigration across (p<0.05) HIMEC monolayers. These findings suggest a critical role for MAPK in governing lymphocyte influx into the gut in IBD patients, and their blockade may offer a molecular target for blockade of leukocyte recruitment to the intestine. [source] CONTEMPORARY ISOLATION-BY-DISTANCE, BUT NOT ISOLATION-BY-TIME, AMONG DEMES OF EUROPEAN GRAYLING (THYMALLUS THYMALLUS, LINNAEUS) WITH RECENT COMMON ANCESTORSEVOLUTION, Issue 2 2009Nicola J. Barson The development of isolation by distance (IBD) and isolation by time (IBT) was contrasted among demes of European grayling (Thymallus thymallus) that have diverged within the last 25 generations following colonization of a lake (Lesjaskogsvatnet). We find low but significant levels of genetic differentiation among spawning tributaries and a pattern of IBD among them. We do not, however, find evidence for IBT despite an up to four-week difference in spawning date between "warm/early" and "cold/late" spawning demes and differences in the incubation temperatures experienced by offspring. It appears that IBD has developed more rapidly than IBT in this system and that adaptive divergence has been initiated in the absence of IBT. Although analysis of selected loci could reveal reduced recombination in parts of the genome associated with temporal divergence, our analysis of neutral genetic data suggests that IBD is a more important isolating mechanism in the early stages of adaptive divergence in European grayling. [source] ANTHROPOGENIC EFFECTS ON POPULATION GENETICS OF PHYTOPHAGOUS INSECTS ASSOCIATED WITH DOMESTICATED PLANTSEVOLUTION, Issue 12 2007Nadir Alvarez The hypothesis of isolation by distance (IBD) predicts that genetic differentiation between populations increases with geographic distance. However, gene flow is governed by numerous factors and the correlation between genetic differentiation and geographic distance is never simply linear. In this study, we analyze the interaction between the effects of geographic distance and of wild or domesticated status of the host plant on genetic differentiation in the bean beetle Acanthoscelides obvelatus. Geographic distance explained most of the among-population genetic differentiation. However, IBD varied depending on the kind of population pairs for which the correlation between genetic differentiation and geographic distance was examined. Whereas pairs of beetle populations associated with wild beans showed significant IBD (P < 10,4), no IBD was found when pairs of beetle populations on domesticated beans were examined (P= 0.2992). This latter result can be explained by long-distance migrations of beetles on domesticated plants resulting from human exchanges of bean seeds. Beetle populations associated with wild beans were also significantly more likely than those on domesticated plants to contain rare alleles. However, at the population level, beetles on cultivated beans were similar in allelic richness to those on wild beans. This similarity in allelic richness combined with differences in other aspects of the genetic diversity (i.e., IBD, allelic diversity) is compatible with strongly contrasting effects of migration and drift. This novel indirect effect of human actions on gene flow of a serious pest of a domesticated plant has important implications for the spread of new adaptations such as resistance to pesticides. [source] Detection of Helicobacter species DNA by quantitative PCR in the gastrointestinal tract of healthy individuals and of patients with inflammatory bowel diseaseFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 1 2004Xander W. Huijsdens Abstract In many animal species different intestinal Helicobacter species have been described and a few species are associated with intestinal infection. In humans, the only member of the Helicobacter family which is well described in literature is Helicobacter pylori. No other Helicobacter -associated diseases have definitely been shown in humans. We developed a sensitive quantitative PCR to investigate whether Helicobacter species DNA can be detected in the human gastrointestinal tract. We tested gastric biopsies (including biopsies from H. pylori positive persons), intestinal mucosal biopsies and fecal samples from healthy persons, and intestinal mucosal biopsies from patients with inflammatory bowel disease (IBD) for the presence of Helicobacter species. All gastric biopsies, positive for H. pylori by culture, were also positive in our newly developed PCR. No Helicobacter species were found in the mucosal biopsies from patients with IBD (n=56) nor from healthy controls (n=25). All fecal samples were negative. Our study suggests that Helicobacter species, other than H. pylori, are not present in the normal human gastrointestinal flora and our results do not support a role of Helicobacter species in IBD. [source] Calculation of IBD probabilities with dense SNP or sequence dataGENETIC EPIDEMIOLOGY, Issue 6 2008Jonathan M. Keith Abstract The probabilities that two individuals share 0, 1, or 2 alleles identical by descent (IBD) at a given genotyped marker locus are quantities of fundamental importance for disease gene and quantitative trait mapping and in family-based tests of association. Until recently, genotyped markers were sufficiently sparse that founder haplotypes could be modelled as having been drawn from a population in linkage equilibrium for the purpose of estimating IBD probabilities. However, with the advent of high-throughput single nucleotide polymorphism genotyping assays, this is no longer a reasonable assumption. Indeed, the imminent arrival of individual sequencing will enable high-density single nucleotide polymorphism genotyping on a scale for which current algorithms are not equipped. In this paper, we present a simple new model in which founder haplotypes are modelled as a Markov chain. Another important innovation is that genotyping errors are explicitly incorporated into the model. We compare results obtained using the new model to those obtained using the popular genetic linkage analysis package Merlin, with and without using the cluster model of linkage disequilibrium that is incorporated into that program. We find that the new model results in accuracy approaching that of Merlin with haplotype blocks, but achieves this with orders of magnitude faster run times. Moreover, the new algorithm scales linearly with number of markers, irrespective of density, whereas Merlin scales supralinearly. We also confirm a previous finding that ignoring linkage disequilibrium in founder haplotypes can cause errors in the calculation of IBD probabilities. Genet. Epidemiol. 2008. © 2008 Wiley-Liss, Inc. [source] Estimating the power of variance component linkage analysis in large pedigreesGENETIC EPIDEMIOLOGY, Issue 6 2006Wei-Min Chen Abstract Variance component linkage analysis is commonly used to map quantitative trait loci (QTLs) in general pedigrees. Large pedigrees are especially attractive for these studies because they provide greater power per genotyped individual than small pedigrees. We propose accurate and computationally efficient methods to calculate the analytical power of variance component linkage analysis that can accommodate large pedigrees. Our analytical power computation involves the approximation of the noncentrality parameter for the likelihood-ratio test by its Taylor expansions. We develop efficient algorithms to compute the second and third moments of the identical by descent (IBD) sharing distribution and enable rapid computation of the Taylor expansions. Our algorithms take advantage of natural symmetries in pedigrees and can accurately analyze many large pedigrees in a few seconds. We verify the accuracy of our power calculation via simulation in pedigrees with 2,5 generations and 2,8 siblings per sibship. We apply this proposed analytical power calculation to 98 quantitative traits in a cohort study of 6,148 Sardinians in which the largest pedigree includes 625 phenotyped individuals. Simulations based on eight representative traits show that the difference between our analytical estimation of the expected LOD score and the average of simulated LOD scores is less than 0.05 (1.5%). Although our analytical calculations are for a fully informative marker locus, in the settings we examined power was similar to what could be attained with a single nucleotide polymorphism (SNP) mapping panel (with >1 SNP/cM). Our algorithms for power analysis together with polygenic analysis are implemented in a freely available computer program, POLY. Genet. Epidemiol. 2006. © 2006 Wiley-Liss, Inc. [source] Linkage mapping methods applied to the COGA data set: Presentation Group 4 of Genetic Analysis Workshop 14GENETIC EPIDEMIOLOGY, Issue S1 2005E. Warwick Daw Abstract Presentation Group 4 participants analyzed the Collaborative Study on the Genetics of Alcoholism data provided for Genetic Analysis Workshop 14. This group examined various aspects of linkage analysis and related issues. Seven papers included linkage analyses, while the eighth calculated identity-by-descent (IBD) probabilities. Six papers analyzed linkage to an alcoholism phenotype: ALDX1 (four papers), ALDX2 (one paper), or a combination both (one paper). Methods used included Bayesian variable selection coupled with Haseman-Elston regression, recursive partitioning to identify phenotype and covariate groupings that interact with evidence for linkage, nonparametric linkage regression modeling, affected sib-pair linkage analysis with discordant sib-pair controls, simulation-based homozygosity mapping in a single pedigree, and application of a propensity score to collapse covariates in a general conditional logistic model. Alcoholism linkage was found with ,2 of these approaches on chromosomes 2, 4, 6, 7, 9, 14, and 21. The remaining linkage paper compared the utility of several single-nucleotide polymorphism (SNP) and microsatellite marker maps for Monte Carlo Markov chain combined oligogenic segregation and linkage analysis, and analyzed one of the electrophysiological endophenotypes, ttth1, on chromosome 7. Linkage was found with all marker sets. The last paper compared the multipoint IBD information content of several SNP sets and the microsatellite set, and found that while all SNP sets examined contained more information than the microsatellite set, most of the information contained in the SNP sets was captured by a subset of the SNP markers with ,1-cM marker spacing. From these papers, we highlight three points: a 1-cM SNP map seems to capture most of the linkage information, so denser maps do not appear necessary; careful and appropriate use of covariates can aid linkage analysis; and sources of increased gene-sharing between relatives should be accounted for in analyses. Genet. Epidemiol. 29(Suppl. 1):S29,S34, 2005. © 2005 Wiley-Liss, Inc. [source] Case-control single-marker and haplotypic association analysis of pedigree dataGENETIC EPIDEMIOLOGY, Issue 2 2005Sharon R. Browning Abstract Related individuals collected for use in linkage studies may be used in case-control linkage disequilibrium analysis, provided one takes into account correlations between individuals due to identity-by-descent (IBD) sharing. We account for these correlations by calculating a weight for each individual. The weights are used in constructing a composite likelihood, which is maximized iteratively to form likelihood ratio tests for single-marker and haplotypic associations. The method scales well with increasing pedigree size and complexity, and is applicable to both autosomal and X chromosomes. We apply the approach to an analysis of association between type 2 diabetes and single-nucleotide polymorphism markers in the PPAR-, gene. Simulated data are used to check validity of the test and examine power. Analysis of related cases has better power than analysis of population-based cases because of the increased frequencies of disease-susceptibility alleles in pedigrees with multiple cases compared to the frequencies of these alleles in population-based cases. Also, utilizing all cases in a pedigree rather than just one per pedigree improves power by increasing the effective sample size. We demonstrate that our method has power at least as great as that of several competing methods, while offering advantages in the ability to handle missing data and perform haplotypic analysis. Genet. Epidemiol. 28:110,122, 2005. © 2004 Wiley-Liss, Inc. [source] Simultaneous localization of two linked disease susceptibility genesGENETIC EPIDEMIOLOGY, Issue 1 2005Joanna M. Biernacka Abstract For diseases with complex genetic etiology, more than one susceptibility gene may exist in a single chromosomal region. Extending the work of Liang et al. ([2001] Hum. Hered. 51:64,78), we developed a method for simultaneous localization of two susceptibility genes in one region. We derived an expression for expected allele sharing of an affected sib pair (ASP) at each point across a chromosomal segment containing two susceptibility genes. Using generalized estimating equations (GEE), we developed an algorithm that uses marker identical-by-descent (IBD) sharing in affected sib pairs to simultaneously estimate the locations of the two genes and the mean IBD sharing in ASPs at these two disease loci. Confidence intervals for gene locations can be constructed based on large sample approximations. Application of the described methods to data from a genome scan for type 1 diabetes (Mein et al. [1998] Nat. Genet. 19:297,300) yielded estimates of two putative disease gene locations on chromosome 6, approximately 20 cM apart. Properties of the estimators, including bias, precision, and confidence interval coverage, were studied by simulation for a range of genetic models. The simulations demonstrated that the proposed method can improve disease gene localization and aid in resolving large peaks when two disease genes are present in one chromosomal region. Joint localization of two disease genes improves with increased excess allele sharing at the disease gene loci, increased distance between the disease genes, and increased number of affected sib pairs in the sample. Genet. Epidemiol. © 2004 Wiley-Liss, Inc. [source] Multipoint analysis using affected sib pairs: Incorporating linkage evidence from unlinked regionsGENETIC EPIDEMIOLOGY, Issue 2 2001Kung-Yee Liang Abstract In this paper, we proposed a multipoint method to assess evidence of linkage to one region by incorporating linkage evidence from another region. This approach uses affected sib pairs in which the number of alleles shared identical by descent (IBD) is the primary statistic. This generalized estimating equation (GEE) approach is robust in that no assumption about the mode of inheritance is required, other than assuming the two regions being considered are unlinked and that there is no more than one susceptibility gene in each region. The method proposed here uses data from all available families to simultaneously test the hypothesis of statistical interaction between regions and to estimate the location of the susceptibility gene in the target region. As an illustration, we have applied this GEE method to an asthma sib pair study (Wjst et al. [1999] Genomics 58:1,8), which earlier reported evidence of linkage to chromosome 6 but showed no evidence for chromosome 20. Our results yield strong evidence to chromosome 20 (P value = 0.0001) after incorporating linkage information from chromosome 6. Furthermore, it estimates with 95% certainty that the map location of the susceptibility gene is flanked by markers D20S186 and D20S101, which are approximately 16.3 cM apart. Genet. Epidemiol. 21:105,122, 2001. © 2001 Wiley-Liss, Inc. [source] Detection of Enterohepatic and Gastric Helicobacter Species in Fecal Specimens of Children with Crohn's DiseaseHELICOBACTER, Issue 4 2008Si Ming Man Abstract Background: Although there is compelling evidence to support the role of bacteria in Crohn's disease (CD), there is currently no solid evidence to support the role of any one specific bacterial causative agent. Recent studies have suggested that members of the Helicobacteraceae may play a role in the development of CD. The aim of this study was to further investigate the presence of members of the Helicobacteraceae in children with and without CD. Materials and methods: Fecal specimens from 29 children with CD, 11 healthy, normal controls, and 26 symptomatic controls with non-inflammatory bowel disease (IBD) pathology were obtained for DNA extraction and subjected to Helicobacteraceae -specific polymerase chain reaction (PCR). All PCR-positive samples were sequenced. The association between the presence of members of the Helicobacteraceae and each study group was statistically analysed using the Fisher's exact test. Results: Based on Helicobacteraceae -specific PCR analysis, 59% (17 of 29) of the children with CD were positive, which was significantly higher than that in asymptomatic healthy children [9% (1 of 11); p = .01] and that in symptomatic children with non-IBD pathology [0% (0/26); p < .0001]. Sequencing of the 16S rRNA gene of positive samples revealed the presence of both enterohepatic Helicobacter species and Helicobacter pylori in fecal specimens. Conclusions: For the first time, enterohepatic and gastric Helicobacter species have been identified in fecal specimens from children diagnosed with CD using PCR. Our data suggest that Helicobacter species may have a pathogenic role in the development of CD in a considerable proportion of children. [source] Primary sclerosing cholangitis in children: A long-term follow-up studyHEPATOLOGY, Issue 1 2003Ariel E. Feldstein Primary sclerosing cholangitis (PSC) is increasingly diagnosed in children and adolescents, but its long-term prognosis remains uncertain. The aim of this longitudinal, cohort study was to determine the long-term outcome of children with PSC. Fifty-two children with cholangiography-proven PSC (34 boys and 18 girls; mean age 13.8 ± 4.2 years; range, 1.5-19.6 years) who were seen at our institution over a 20-year period were followed-up for up to 16.7 years. Two thirds presented with symptoms and/or signs of PSC and 81% had concomitant inflammatory bowel disease (IBD). Twenty-five percent had total alkaline phosphatase activity within the normal range for the age group, but all of them had elevated ,-glutamyl transpeptidase levels. Autoimmune hepatitis overlapping with PSC was present in 35% of children. A positive but transient clinical and/or biochemical response occurred under therapy with ursodeoxycholic acid, alone or in combination with immunosuppressive medications. During follow-up, 11 children underwent liver transplantation for end-stage PSC and 1 child died. The median (50%) survival free of liver transplantation was 12.7 years. Compared with an age- and gender-matched U.S. population, survival was significantly shorter in children with PSC (P < .001). In a Cox regression model, lower platelet count, splenomegaly, and older age were associated with shorter survival. Presence of autoimmune hepatitis overlapping with PSC (P = .2) or medical therapy (P = .2) did not affect survival. In conclusion, PSC significantly decreases survival in this child population. Although pharmacologic therapy may improve symptoms and liver test results initially, it does not seem to impact the long-term outcome. [source] Diagnostic difficulties in inflammatory bowel disease pathologyHISTOPATHOLOGY, Issue 2 2006R K Yantiss This review summarizes some of the common diagnostic problems encountered by pathologists when evaluating patients with chronic colitis and in whom inflammatory bowel disease (IBD) is either suspected or within the differential diagnosis. Both ulcerative colitis (UC) and Crohn's disease (CD) show characteristic, but non-specific, pathological features that may overlap and result in a diagnosis of ,indeterminate colitis' (IC). However, other reasons why pathologists may entertain a diagnosis of IC include failure to recognize or accept certain ,hardcore' histological features as indicative of CD, an attempt to classify cases of chronic colitis based on mucosal biopsy material or in the absence of adequate clinical and radiographic information, and the presence of other disease processes that mask, or mimic, IBD. In addition, some cases of UC may show unusual CD-like features, such as discontinuous or patchy disease, ileal inflammation, extracolonic inflammation, granulomatous inflammation in response to ruptured crypts, aphthous ulcers, or transmural inflammation. Furthermore, other forms of colitis, such as microscopic colitis, diverticulitis and diversion colitis may, on occasion, also show IBD-like changes. The clinical and pathological features that aid in the distinction between these entities, and others, are covered in detail in this review. [source] Regulatory T cells and intestinal homeostasisIMMUNOLOGICAL REVIEWS, Issue 1 2005Janine L. Coombes Summary:, Murine models of inflammatory bowel disease (IBD) are useful tools for the study of the pathogenesis and regulation of intestinal inflammation. Colitis can be induced in immune-deficient mice following transfer of populations of T cells or following infection with Helicobacter hepaticus and other intestinal pathogens. In these situations, colitis occurs as a result of the absence of a specialized population of regulatory cells, as transfer of CD4+CD25+ T cells prevents disease. Importantly, from a clinical perspective, CD4+CD25+ T cells can also reverse an established colitis. CD4+CD25+ T cells proliferate both in the secondary lymphoid organs and at the site of inflammation, suggesting that regulation occurs both locally and systemically. CD4+CD25+ T cells are not only capable of regulating other T cells but are also capable of suppressing components of the innate immune system. Control of colitis is dependent on the presence of the immunosuppressive cytokines interleukin-10 and transforming growth factor-,, although their roles are divergent and complex. Regulatory T cells represent one of the host's mechanisms to prevent immune pathology during chronic immune stimulation. Enhancement of regulatory T-cell activity may be useful to control autoreactive T-cell responses and inhibit harmful inflammatory diseases such as asthma and IBD. [source] The role of T-regulatory cells and Toll-like receptors in the pathogenesis of human inflammatory bowel diseaseIMMUNOLOGY, Issue 2 2008Megan E. Himmel Summary Two related chronic inflammatory diseases, Crohn's disease and ulcerative colitis, are together often referred to as inflammatory bowel disease (IBD). Current treatment options are not curative, and patients face lifelong therapy and debilitation. IBD is thought to be the product of a combination of genetic and environmental factors that result in the abnormal regulation of immune responses. Experimental models have demonstrated that normal CD4+ T-regulatory (Treg) cell responses and commensal bacteria are required for the maintenance of gut immune homeostasis. Recent evidence that CD4+ T cells express Toll-like receptors (TLRs) and respond directly to TLR ligands, suggests that signals from commensal bacteria may directly affect T-cell responses in the gut. In this review, we focus on evidence that defects in Treg cells may underlie IBD in humans. In addition, we discuss evidence that direct signaling via TLRs to T cells can affect IBD and that T-cell-dependent responses to bacterial proteins, such as flagellin, are central to the aetiology of this disease. [source] Nitric oxide in inflammatory bowel disease: a universal messenger in an unsolved puzzleIMMUNOLOGY, Issue 4 2004George Kolios Summary In recent years, nitric oxide (NO), a gas previously considered to be a potentially toxic chemical, has been established as a diffusible universal messenger that mediates cell,cell communication throughout the body. Constitutive and inducible NO production regulate numerous essential functions of the gastrointestinal mucosa, such as maintenance of adequate perfusion, regulation of microvascular and epithelial permeability, and regulation of the immune response. Up-regulation of the production of NO via expression of inducible nitric oxide synthase (iNOS) represents part of a prompt intestinal antibacterial response; however, NO has also been associated with the initiation and maintenance of inflammation in human inflammatory bowel disease (IBD). Recent studies on animal models of experimental IBD have shown that constitutive and inducible NO production seems to be beneficial during acute colitis, but sustained up-regulation of NO is detrimental. This fact is also supported by studies on mice genetically deficient in various NOS isoforms. However, the mechanism by which NO proceeds from being an indispensable homeostatic regulator to a harmful destructor remains unknown. Furthermore, extrapolation of data from animal colitis models to human IBD is questionable. The purpose of this review is to update our knowledge about the role of this universal mediator and the enzymes that generate it in the pathogenesis of IBD. [source] Preliminary evidence supporting a framework of psychological adjustment to inflammatory bowel disease,INFLAMMATORY BOWEL DISEASES, Issue 10 2010Jennifer L. Kiebles PhD Abstract Background: Adjustment to chronic disease is a multidimensional construct described as successful adaptation to disease-specific demands, preservation of psychological well-being, functional status, and quality of life. Inflammatory bowel disease (IBD) can be particularly challenging due to the unpredictable, relapsing and remitting course of the disease. Methods: All participants were patients being treated in an outpatient gastroenterology clinic at a university medical center. Participants completed a survey of questionnaires assessing illness perceptions, stress, emotional functioning, disease acceptance, coping, disease impact, and disease-specific and health-related quality of life. Adjustment was measured as a composite of perceived disability, psychological functioning, and disease-specific and health-related quality of life. Results: Participants were 38 adults with a diagnosis of either Crohn's disease (45%) or ulcerative colitis (55%). We observed that our defined adjustment variables were strongly correlated with disease characteristics (r = 0.33,0.80, all P < 0.05), an emotional representation of illness (r = 0.44,0.58, P < 0.01), disease acceptance (r = 0.34,0.74, P < 0.05), coping (r = 0.33,0.60, P < 0.05), and frequency of gastroenterologist visits (r = 0.39,0.70, P < 0.05). Better adjustment was associated with greater bowel and systemic health, increased activities engagement and symptom tolerance, less pain, less perceived stress, and fewer gastroenterologist visits. All adjustment variables were highly correlated (r = 0.40,0.84, P < 0.05) and demonstrated a cohesive composite. Conclusions: The framework presented and results of this study underscore the importance of considering complementary pathways of disease management including cognitive, emotional, and behavioral factors beyond the traditional medical and psychological (depression and anxiety) components. (Inflamm Bowel Dis 2010) [source] N-3 polyunsaturated fatty acid diet therapy for patients with inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 10 2010Kan Uchiyama MD Abstract Background: N-3 polyunsaturated fatty acids (PUFA) are considered important pharmaconutrients for modulating mucosal immunity and therapeutic responses in patients with inflammatory bowel disease (IBD). We investigated the influence of diet therapy involving the use of an "n-3 PUFA food exchange table" (n-3DP) on the fatty acid composition of the erythrocyte membranes of IBD patients and its remission-maintaining effects. Methods: We analyzed the fatty acid composition of the erythrocyte membrane before and after n-3DP intervention in 20 initial-onset IBD patients who had not undergone any dietary intervention. We then analyzed it again and evaluated disease activity after 12,18 months intervention in 230 IBD patients (168 ulcerative colitis, 62 Crohn's disease; follow-up group) in whom n-3DP was introduced after remission had been achieved. The follow-up group was divided into remission and relapse groups. Results: In the 20 initial-onset patients, the mean n-3/n-6 ratio significantly increased after intervention (0.41 ± 0.16 versus 0.70 ± 0.20; P < 0.001). In the follow-up group the ratio in the remission group (n = 145) was significantly higher than that in the relapse group (n = 85) (0.65 ± 0.28 versus 0.53 ± 0.18; P < 0.001). The ratio significantly decreased in those who suffered a relapse after the beginning of treatment (P < 0.01). Conclusions: N-3DP significantly increased the erythrocyte membrane n-3/n-6 ratio in IBD patients, and this ratio was significantly higher in the remission group, suggesting that n-3DP alters the fatty acid composition of the cell membrane and influences clinical activity in IBD patients. (Inflamm Bowel Dis 2010) [source] Hepatopancreatobiliary manifestations and complications associated with inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 9 2010Udayakumar Navaneethan MD Abstract Abstract: Diseases involving the hepatopancreatobiliary (HPB) system are frequently encountered in patients with inflammatory bowel disease (IBD). Hepatobiliary manifestations constitute some of the most common extraintestinal manifestations of IBD. They appear to occur with similar frequency in patients with Crohn's disease or ulcerative colitis. HPB manifestations may occur in following settings: 1) disease possibly associated with a shared pathogenetic mechanism with IBD including primary sclerosing cholangitis (PSC), small-duct PSC/pericholangitis and PSC/autoimmune hepatitis overlap, acute and chronic pancreatitis related to IBD; 2) diseases which parallel structural and physiological changes seen with IBD, including cholelithiasis, portal vein thrombosis, and hepatic abscess; and 3) diseases related to adverse effects associated with treatment of IBD, including drug-induced hepatitis, pancreatitis (purine-based agents), or liver cirrhosis (methotrexate), and reactivation of hepatitis B, and biologic agent-associated hepatosplenic lymphoma. Less common HPB manifestations that have been described in association with IBD include autoimmune pancreatitis (AIP), IgG4-associated cholangitis (IAC), primary biliary cirrhosis (PBC), fatty liver, granulomatous hepatitis, and amyloidosis. PSC is the most significant hepatobiliary manifestation associated with IBD and poses substantial challenges in management requiring a multidisciplinary approach. The natural disease course of PSC may progress to cirrhosis and ultimately require liver transplantation in spite of total proctocolectomy with ileal-pouch anal anastomosis. The association between AIP, IAC, and elevated serum IgG4 in patients with PSC is intriguing. The recently reported association between IAC and IBD may open the door to investigate these complex disorders. Further studies are warranted to help understand the pathogenesis of HPB manifestations associated with IBD, which would help clinicians better manage these patients. An interdisciplinary approach, involving gastroenterologists, hepatologists, and, in advanced cases, general, colorectal, and transplant surgeons is advocated. (Inflamm Bowel Dis 2010) [source] Cytomegalovirus in inflammatory bowel disease: Pathogen or innocent bystander?INFLAMMATORY BOWEL DISEASES, Issue 9 2010Garrett Lawlor MD Abstract The role of cytomegalovirus (CMV) in exacerbations of inflammatory bowel disease (IBD) remains a topic of ongoing debate. Current data are conflicting as to whether CMV worsens inflammation in those with severe colitis, or is merely a surrogate marker for severe disease. The interpretation of existing results is limited by mostly small, retrospective studies, with varying definitions of disease severity and CMV disease. CMV colitis is rare in patients with Crohn's disease or mild-moderate ulcerative colitis. In patients with severe and/or steroid-refractory ulcerative colitis, local reactivation of CMV can be detected in actively inflamed colonic tissue in about 30% of cases. Where comparisons between CMV+ and CMV, steroid-refractory patients can be made, most, but not all, studies show no difference in outcomes according to CMV status. Treatment with antiviral therapy has allowed some patients with severe colitis to avoid colectomy despite poor response to conventional IBD therapies. This article reviews the immunobiology of CMV disease, the evidence for CMV's role in disease severity, and discusses the outcomes with antiviral therapy. (Inflamm Bowel Dis 2010) [source] Dipeptidyl peptidase expression during experimental colitis in miceINFLAMMATORY BOWEL DISEASES, Issue 8 2010Roger Yazbeck PhD Abstract Background: We have previously demonstrated that inhibition of dipeptidyl peptidase (DP) activity partially attenuates dextran sulfate sodium (DSS) colitis in mice. The aim of this study was to further investigate the mechanisms of this protection. Materials and Methods: Wildtype (WT) and DPIV,/, mice consumed 2% DSS in drinking water for 6 days to induce colitis. Mice were treated with saline or the DP inhibitors Ile-Pyrr-(2-CN)*TFA or Ile-Thia. DP mRNA and enzyme levels were measured in the colon. Glucagon-like peptide (GLP)-2 and GLP-1 concentrations were determined by radioimmunoassay, regulatory T-cells (Tregs) by fluorescence activated cell sorting (FACS) on FOXp3+T cells in blood, and neutrophil infiltration assessed by myeloperoxidase (MPO) assay. Results: DP8 and DP2 mRNA levels were increased (P < 0.05) in WT+saline mice compared to untreated WT mice with colitis. Cytoplasmic DP enzyme activity was increased (P < 0.05) in DPIV,/, mice at day 6 of DSS, while DP2 activity was increased (P < 0.05) in WT mice with colitis. GLP-1 (63%) and GLP-2 (50%) concentrations increased in WT+Ile-Pyrr-(2-CN)*TFA mice compared to day-0 controls. MPO activity was lower in WT+Ile-Thia and WT+Ile-Pyrr-(2-CN)*TFA treated mice compared to WT+saline (P < 0.001) at day 6 colitis. Conclusions: DP expression and activity are differentially regulated during DSS colitis, suggesting a pathophysiological role for these enzymes in human inflammatory bowel disease (IBD). DP inhibitors impaired neutrophil recruitment and maintenance of the Treg population during DSS-colitis, providing further preclinical evidence for the potential therapeutic use of these inhibitors in IBD. Finally, DPIV appears to play a critical role in mediating the protective effect of DP inhibitors. Inflamm Bowel Dis 2010 [source] Mechanisms by which inflammation may increase intestinal cancer risk in inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 8 2010Pamela M. O'Connor PhD Abstract Patients with ulcerative colitis and Crohn's disease are at increased risk of developing intestinal cancers via mechanisms that remain incompletely understood. However, chronic inflammation and repeated events of inflammatory relapse in inflammatory bowel disease (IBD) expose these patients to a number of signals known to have tumorigenic effects including persistent activation of the nuclear factor-,B and cyclooxygenase-2/prostaglandin pathways, release of proinflammatory mediators such as tumor necrosis factor-, and interleukin-6, and enhanced local levels of reactive oxygen and nitrogen species. These inflammatory signals can contribute to carcinogenesis via 3 major processes: 1) by increasing oxidative stress, which promotes DNA mutagenesis thus contributing to tumor initiation; 2) by activating prosurvival and antiapoptotic pathways in epithelial cells, thereby contributing to tumor promotion; and 3) by creating an environment that supports sustained growth, angiogenesis, migration, and invasion of tumor cells, thus supporting tumor progression and metastasis. The present review integrates clinical and basic research observations in an attempt to provide a comprehensive understanding of how inflammatory processes may contribute to intestinal cancer development in IBD patients. (Inflamm Bowel Dis 2010) [source] In vivo analysis of gut function and disease changes in a zebrafish larvae model of inflammatory bowel disease: A feasibility studyINFLAMMATORY BOWEL DISEASES, Issue 7 2010Angeleen Fleming PhD Abstract Background: The aim of this study was to develop a model of inflammatory bowel disease (IBD) in zebrafish larvae, together with a method for the rapid assessment of gut morphology and function in vivo thereby enabling medium-throughput compound screening. Methods: Assays were performed using larval zebrafish from 3,8 days postfertilization (d.p.f.) in 96-well plates. Gut morphology and peristalsis were observed in vivo using fluorescent imaging following ingestion of fluorescent dyes. IBD was induced by addition of 2,4,6-trinitrobenzenesulfonic acid (TNBS) to the medium within the well. Pathology was assessed in vivo using fluorescent imaging and postmortem by histology, immunohistochemistry, and electron microscopy. Therapeutic compounds were evaluated by coadministration with TNBS. Results: A novel method of investigating gut architecture and peristalsis was devised using fluorescent imaging of live zebrafish larvae. Archetypal changes in gut architecture consistent with colitis were observed throughout the gut. Significant changes in goblet cell number and tumor necrosis factor alpha (TNF-,) antibody staining were used to quantify disease severity and rescue. Prednisolone and 5-amino salicylic acid treatment ameliorated the disease changes. Candidate therapeutic compounds (NOS inhibitors, thalidomide, and parthenolide) were assessed and a dissociation was observed between efficacy assessed using a single biochemical measure (TNF-, staining) versus an assessment of the entire disease state. Conclusions: Gut physiology and pathology relevant to human disease state can be rapidly modeled in zebrafish larvae. The model is suitable for medium-throughput chemical screens and is amenable to genetic manipulation, hence offers a powerful novel premammalian adjunct to the study of gastrointestinal disease. (Inflamm Bowel Dis 2010) [source] New proteomic approaches for biomarker discovery in inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 7 2010Giulia Roda MD Abstract There is an increasing interest in the discovery of new inflammatory bowel disease (IBD) biomarkers able to predict the future patterns of disease and to help in diagnosis, treatment, and prognosis. A biomarker is a substance that can be measured biologically and is associated with an increased risk of the disease. Biomarkers can be a genetic testing factor or proteins in biological samples such as serum, plasma, and cellular subpopulations. All of them should be studied to find out their utility in the management of IBD. Ulcerative colitis and Crohn's disease are relapsing and remitting chronic IBDs characterized by a global immune defect. The gold standard of their diagnosis is histological evaluation performed during endoscopic procedures. Several studies have focused on the identification and combination of less invasive diagnostic serum biomarkers. Nowadays, diagnostic serum tests are not able either to determine whether and when the relapse will occur once the disease is in remission state or to select a patient phenotype more responsive to a specific therapy and more susceptible to different types of complication. In this review we analyze and report the current understanding in IBD biomarkers and discuss potential future biomarkers and new developments of proteomics, such as subproteomics, as an innovative approach for the classification of patients according to their pattern of protein expression. (Inflamm Bowel Dis 2010) [source] Health-related quality of life of youth with inflammatory bowel disease: A comparison with published data using the PedsQL 4.0 generic core scalesINFLAMMATORY BOWEL DISEASES, Issue 6 2010Jennifer Hauser Kunz PhD Abstract Background: This study compared youth and parent-proxy reports of health-related quality of life (HRQoL) among youth with inflammatory bowel disease (IBD) to published comparison group data and examined concordance between youth and parent-proxy reports of HRQoL. Methods: One hundred thirty-six youth and parent-proxy reports on the PedsQL 4.0 Generic Core Scales were compared to published data from chronically ill, acutely ill, and healthy comparison groups using independent samples t -tests. Reporter agreement was examined using paired samples t -tests and intraclass correlations (ICCs). Results: Youth with IBD reported lower psychosocial functioning than the healthy comparison group, higher physical and social functioning than the chronically ill group, and lower school functioning than all published comparison groups. Parent-proxy reports of youth HRQoL were higher than the chronically ill group, but lower than the healthy group on all scales except psychosocial functioning. Youth with active IBD reported lower physical health domain scores than youth with inactive disease. Concordance between youth and parent-proxy reports was moderate, with the lowest agreement in school and social functioning. Conclusions: Youth with IBD and their parents rate HRQoL as lower than healthy youth but do not perceive the impact of IBD to be as limiting as in other chronic conditions. Youth report suggests that IBD may be particularly detrimental to HRQoL in the school functioning domain. Moderate agreement between parent and youth reports substantiates continued use of multiple informants in studies of pediatric HRQoL. Inflamm Bowel Dis 2010 [source] Inflammatory bowel disease in young people: The case for transitional clinicsINFLAMMATORY BOWEL DISEASES, Issue 6 2010J. Goodhand MRCP Abstract Background: The incidence of inflammatory bowel disease (IBD) is increasing among adolescents. In all, 25% of patients are diagnosed before the age of 16, when they are traditionally transferred from the pediatric to the adult service. Methods: We conducted a retrospective case-controlled study to characterize patients treated in a novel transitional adolescent,young adult IBD clinic. This compared disease extent, radiation exposure, therapeutic strategy, and requirement for surgery in 100 adolescents with controls from our adult IBD clinic matched for disease duration. Results: The median (range) ages for the adolescent and adult population was 19 (16,28) and 43 (24,84), with a median age at diagnosis of 15 (3,26) and 39 (13,82) respectively (P < 0.001). Crohn's disease was significantly more common in the adolescents. Disease distribution was ileocolonic in 69% of adolescents and 28% of adults, restricted to the ileum in 20% of adolescents and 47% of adults, and colonic only in 11% and 22%, respectively. Upper gastrointestinal involvement occurred in 23% of adolescents, but was not seen in adults (P < 0.01). Total ulcerative colitis was seen in 67% of adolescents and 44% of adults (P < 0.01). Contrary to previous data adolescents did not receive more ionizing radiation than adults. Requirement for immunosuppressive therapy was higher in the adolescent group (53% versus 31%, respectively, P < 0.01). Likewise, 20% of adolescents had required biological therapy compared to only 8% in the adult cohort (P < 0.05). Conclusions: Gastroenterologists should recognize that IBD is more complex when presenting in adolescence and our data support the creation of specific adolescent transitional clinics. Inflamm Bowel Dis 2009 [source] Angiopoietin-2 in experimental colitisINFLAMMATORY BOWEL DISEASES, Issue 6 2010Vijay C. Ganta PhD Abstract Background: The pathophysiology of inflammatory bowel disease (IBD) includes leukocyte infiltration, blood and lymphatic remodeling, weight loss and protein enteropathy. The roles of angiopoietin-2 (Ang-2) in initiating gut inflammation, leukocyte infiltration and angiogenesis are not well understood. Methods: Disease activity index, histopathological scoring, myeloperoxidase assay, immunohistochemistry and sodium dodecyl sulphate- polyacrylamide gel electrophoretic methods were employed in the present study to addess the roles of Ang-2 in experimental colitis. Results: Several important differences were seen in the development of experimental IBD in Ang-2,/, mice. Although weight change and disease activity differ only slightly in WT and Ang-2,/, + DSS treated mice, leukocyte infiltration, inflammation and blood and lymphatic vessel density is significantly attenuated compared to WT + DSS mice. Gut capillary fragility and water export (stool blood and form) appear significantly earlier in Ang-2,/, + DSS mice vs. WT. Colon lengths were also significantly reduced in Ang-2,/, and gut histopathology was less severe in Ang-2,/, compared to WT + DSS. Lastly, the decrease in serum protein content in WT + DSS was less severe in Ang-2,/, + DSS, thus protein losing enteropathy (PLE) a feature of IBD is relieved by Ang-2,/,. Conclusion: These data demonstrate that in DSS colitis, Ang-2 mediates inflammatory hemangiogenesis, lymphangiogenesis and neutrophil infiltration to reduce some, but not all clinical features of IBD. The implications for Ang-2 manipulation in the development of IBD and other inflammatory diseases and treatments involving Ang-2 are discussed. (Inflamm Bowel Dis 2009) [source] Targeting TGF-,1 by employing a vaccine ameliorates fibrosis in a mouse model of chronic colitisINFLAMMATORY BOWEL DISEASES, Issue 6 2010Yanbing Ma MSc Abstract Background: Intestinal fibrosis and stricture formation are major complications of inflammatory bowel disease (IBD), for which there are currently few effective treatments. We sought to investigate whether targeting transforming growth factor-beta1 (TGF-,1), a key profibrotic mediator, with a peptide-based virus-like particle vaccine would be effective in suppressing intestinal fibrosis by using a mouse model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced chronic colitis. Methods: The vaccine was prepared by inserting a peptide derived from mouse TGF-,1 into a carrier hepatitis B core antigen using gene recombination methods. Chronic colitis was induced in BALB/c mice by 8 weekly TNBS administrations. Mice were subcutaneously injected with vaccine, carrier, or phosphate-buffered saline (PBS) in 2 separate studies: either before or after acute inflammatory responses commenced. Results: Sera from vaccinated mice exhibited significantly elevated levels of TGF-,1-specific immunoglobulin G (IgG), which inhibited TGF-,1-induced luciferase production in mink lung epithelial cells. In the chronic colitis model, mice receiving vaccine showed improved body weight gain and significantly reduced colonic collagen deposition. Hematoxylin and eosin staining and semiquantitative scoring indicated that vaccination even ameliorated colonic inflammation. Cytokine profile analysis revealed that levels of TGF-,1, interleukin (IL)-17, and IL-23 in vaccinated mouse colon tissues were decreased, and that percentages of IL-17-expressing CD4+ lymphocytes in mesenteric lymph node cells were reduced. Furthermore, Smad3 phosphorylation, a key event in TGF-, signaling, was decreased in colonic tissue in vaccinated mice. Conclusions: This TGF-,1 peptide-based vaccine, which suppressed excessive TGF-,1 bioactivity, may prevent the development of intestinal fibrosis and associated complications, presenting a novel approach in the treatment of IBD. (Inflamm Bowel Dis 2010) [source] | |||||||||||||||||||||||||||||||||||||