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Video capsule endoscopy has revolutionized our ability to visualize the small bowel mucosa. This modality is a valuable tool for the diagnosis of suspected small bowel Crohn's disease, and it is increasingly used for the monitoring of disease activity in patients with established small bowel Crohn's. The purpose of the current article was to review the literature pertaining to the utilization of capsule endoscopy in established Crohn's disease, for monitoring of mucosal healing, postoperative recurrence, disease classification, and other indications.

Background: Objective monitoring of the severity of inflammation in patients with inflammatory bowel disease (IBD) is an essential part of disease management. However, repeat endoscopy to define extent and severity of inflammation is not practical. Fecal calprotectin (FC) is a biomarker that can be used as a surrogate test to distinguish inflammatory from noninflammatory gastrointestinal disease., Methods: A targeted search of the literature regarding FC, focusing primarily on the past three years, was conducted to develop practical clinical guidance on the current utility of FC in the routine management of IBD patients., Results: It is recommended that samples for FC testing be obtained from the first bowel excretion of the day. FC testing should be used as standard of care to accurately confirm inflammation and 'real-time' disease activity when a clinician suspects an IBD flare. Although FC is a reliable marker of inflammation, its role in routine monitoring in improving long-term outcomes has not yet been fully assessed. Based on available evidence, the authors suggest the following cut-off values and management strategies: when FC levels are <50 µg⁄g to 100 µg⁄g, quiescent disease is likely and therapy should be continued; when FC levels are >100 µg⁄g to 250 µg⁄g, inflammation is possible and further testing (eg, colonoscopy) is required to confirm inflammation; and when FC levels are >250 µg⁄g, active inflammation is likely and strategies to control inflammation should be initiated (eg, optimizing current therapies or switching to an alternative therapy)., Discussion: FC is a useful biomarker to accurately assess the degree of inflammation and should be incorporated into the management of patients with IBD.

Butyrate is a potent anticarcinogenic compound against colon cancer cells in vitro. However, its rapid metabolism is hypothesized to limit its anticancer benefits in colonic epithelial cells. Carnitine, a potent antioxidant, is essential to fatty acid oxidation. The aims of this study were to identify a colon cancer cell line capable of transporting carnitine. We evaluated the effect of carnitine and acetylcarnitine (ALCAR) on the response of colon carcinoma cells to butyrate. We explored the mechanisms underlying the anticarcinogenic benefit. SW480 cells were incubated with butyrate ± carnitine or ALCAR. Carnitine uptake was assessed using [3H]-carnitine. Apoptosis and cell viability were assessed using an ELISA kit and flow cytometry, respectively. Modulation of proteins implicated in carnitine transport, cell death and proliferation were assessed by western blotting. SW480 cells were found to transport carnitine primarily via the OCTN2 transporter. Butyrate induced SW480 cell death occurred at concentrations of 2 mM and higher. Cells treated with the combination of butyrate (3 mM) with ALCAR exhibited increased mortality. The addition of carnitine or ALCAR also increased butyrate-induced apoptosis. Butyrate increased levels of cyclin D1, p21 and PARP p86, but decreased Bcl-XL and survivin levels. Butyrate also downregulated dephospho-β-catenin and increased acetylated histone H4 levels. Butyrate and carnitine decreased survivin levels by ≥25%. ALCAR independently induced a 20% decrease in p21. These results demonstrate that butyrate and ALCAR are potentially beneficial anticarcinogenic nutrients that inhibit colon cancer cell survival in vitro. The combination of both agents may have superior anticarcinogenic properties than butyrate alone.

Background: Optimal management of obscure gastrointestinal bleeding (OGIB) remains unclear., Objective: To evaluate diagnostic yields and downstream clinical outcomes comparing video capsule endoscopy (VCE) with push enteroscopy (PE)., Methods: Patients with OGIB and negative esophagogastroduodenoscopies and colonoscopies were randomly assigned to VCE or PE and followed for 12 months. End points included diagnostic yield, acute or chronic bleeding, health resource utilization and crossovers., Results: Data from 79 patients were analyzed (VCE n=40; PE n=39; 82.3% overt OGIB). VCE had greater diagnostic yield (72.5% versus 48.7%; P<0.05), especially in the distal small bowel (58% versus 13%; P<0.01). More VCE-identified lesions were rated possible or certain causes of bleeding (79.3% versus 35.0%; P<0.05). During follow-up, there were no differences in the rates of ongoing bleeding (acute [40.0% versus 38.5%; P not significant], chronic [32.5% versus 45.6%; P not significant]), nor in health resource utilization. Fewer VCE-first patients crossed over due to ongoing bleeding (22.5% versus 48.7%; P<0.05)., Conclusions: A VCE-first approach had a significant diagnostic advantage over PE-first in patients with OGIB, especially with regard to detecting small bowel lesions, affecting clinical certainty and subsequent further small bowel investigations, with no subsequent differences in bleeding or resource utilization outcomes in follow-up. These findings question the clinical relevance of many of the discovered endoscopic lesions or the ability to treat most of these effectively over time. Improved prognostication of both patient characteristics and endoscopic lesion appearance with regard to bleeding behaviour, coupled with the impact of therapeutic deep enteroscopy, is now required using adapted, high-quality study methodologies.

Background: Clinical efficacy and risk of complications are associated with intracellular levels of thiopurine metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurines (6-MMP) in patients with Crohn's disease. Therapeutic monitoring of thiopurine metabolites is not widely available. Surrogate markers such as hematologic indices (MCV, leukopenia) have been proposed., Aims: To evaluate accuracy of hematologic indices for prediction of therapeutic levels of thiopurine metabolites., Methods: A retrospective cross-sectional study. We included patients treated with thiopurines for IBD between February 2008 and November 2013. Hematologic indices were correlated with thiopurine metabolites and compared to pre-treatment levels., Results: A total of 168 patients with 608 measurements were included. Macrocytosis was observed in 4.5 % of the patients. On multivariate analysis, macrocytosis was associated with 6-TGN levels >235 pmol/8 × 10(8) erythrocytes and 6-mmp levels >5,700 pmol/8 × 10(8) erythrocytes. Therapeutic 6-TGN levels were associated with MCV, ΔMCV, macrocytosis and lymphocyte count. Sensitivity and Spearman's r correlation for prediction of therapeutic metabolite levels were poor for all hematologic indices., Conclusion: Although macrocytosis and an elevated MCV are associated with therapeutic 6-TGN levels, the correlation is weak. None of the evaluated hematologic indices is a reliable surrogate marker for thiopurine metabolite levels.

Background: Multiple studies have established the superior diagnostic accuracy of video capsule endoscopy (VCE) for the diagnosis of small bowel (SB) Crohn's disease (CD). However, data on the clinical impact of VCE in patients with established CD are scarce. The aim of this study was to examine the impact and safety of VCE on the clinical management of patients with established CD., Methods: A retrospective, multicenter, cross-sectional study. The study cohort included consecutive patients with established SB CD who underwent VCE in 4 tertiary referral centers (1 Canada, 1 Sweden, and 2 United Kingdom) from January 2008 to October 2013. Patients were excluded if VCE was performed as a part of the initial diagnostic workup. The presence of SB mucosal inflammation was quantified using the Lewis score. Inflammatory biomarkers (C-reactive protein and fecal calprotectin) were measured and correlated with the Lewis score., Results: The study included 187 patients. No SB inflammation was observed in 28.4%, mild-to-moderate inflammation in 26.6%, and moderate-to-severe inflammation in 45% of the patients (median Lewis score, 662; range, 0-6400). A change in management was recommended in 52.3% of the patients based on VCE findings. Elevated C-reactive protein, fecal calprotectin, or the combination of both were poorly correlated with significant SB inflammation. SB capsule retention occurred in 4 patients (2.1%)., Conclusions: VCE in patients with established CD is safe, and the results often have a significant clinical impact. VCE should not be limited to CD patients with positive inflammatory markers because their predictive value for significant SB inflammation is poor.

Background and Aims: Combination therapy with infliximab and azathioprine has been shown to be superior to either treatment alone in Crohn's disease (CD). However, the benefit of combining adalimumab with an immunomodulator remains controversial. The aim of this study was to compare the efficacy of adalimumab monotherapy with combination therapy for induction and maintenance of response and remission in CD using a meta-analysis of the current literature., Methods: We performed a systematic literature search using Medline, Embase, Cochrane and several other databases. Prospective randomized controlled trials, retrospective cohort and case-controlled studies were included. The primary outcomes included induction of response and remission (up to week 12), maintenance of clinical response and remission (1 year) and the need for dose escalation. Several subgroup and sensitivity analyses were performed., Results: Eighteen out of 2743 retrieved studies were included. A meta-analysis of 7 studies assessing induction of remission (n=1984) showed that ADA monotherapy was inferior to combination therapy [OR=0.78 (0.64-0.96), p=0.02]. A meta-analysis of 4 studies revealed that combination therapy was not statistically different from ADA for maintenance of remission [OR=1.08 (0.79-1.48), p=0.48]. Combination therapy was also not different from ADA monotherapy in terms of requirement for dose escalation [OR=1.13 (0.69-1.85), p=0.62]., Conclusions: Combination therapy with ADA and immunomodulator was mildly superior to ADA monotherapy for induction of remission in CD. The rate of remission at 1 year and the need for dose escalation were similar in both groups. These findings should be interpreted with caution in view of possible confounders and should be further validated by randomized controlled trials., (Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Videocapsule endoscopy (VCE) has revolutionized our ability to visualize the small bowel mucosa. This modality is a valuable tool for the diagnosis of obscure small bowel Crohn's disease (CD), and can also be used for monitoring of disease activity in patients with established small-bowel CD, detection of complications such as obscure bleeding and neoplasms, evaluation of response to anti-inflammatory treatment and postoperative recurrence following small bowel resection. VCE could also be an important tool in the management of patients with unclassified inflammatory bowel disease, potentially resulting in reclassification of these patients as having CD. Reports on postoperative monitoring and evaluation of patients with ileal pouch-anal anastomosis who have developed pouchitis have recenty been published. Monitoring of colonic inflammatory activity in patients with ulcerative colitis using the recently developed colonic capsule has also been reported. Capsule endoscopy is associated with an excellent safety profile. Although retention risk is increased in patients with small bowel CD, this risk can be significanty decreased by a routine utilization of a dissolvable patency capsule preceding the ingestion of the diagnostic capsule. This paper contains an overview of the current and future clinical applications of capsule endoscopy in inflammatory bowel disease.

Vitamin D signaling through its nuclear vitamin D receptor has emerged as a key regulator of innate immunity in humans. Here we show that hormonal vitamin D, 1,25-dihydroxyvitamin D(3), robustly stimulates expression of pattern recognition receptor NOD2/CARD15/IBD1 gene and protein in primary human monocytic and epithelial cells. The vitamin D receptor signals through distal enhancers in the NOD2 gene, whose function was validated by chromatin immunoprecipitation and chromatin conformation capture assays. A key downstream signaling consequence of NOD2 activation by agonist muramyl dipeptide is stimulation of NF-kappaB transcription factor function, which induces expression of the gene encoding antimicrobial peptide defensin beta2 (DEFB2/HBD2). Pretreatment with 1,25-dihydroxyvitamin D(3) synergistically induced NF-kappaB function and expression of genes encoding DEFB2/HBD2 and antimicrobial peptide cathelicidin in the presence of muramyl dipeptide. Importantly, this synergistic response was also seen in macrophages from a donor wild type for NOD2 but was absent in macrophages from patients with Crohn disease homozygous for non-functional NOD2 variants. These studies provide strong molecular links between vitamin D deficiency and the genetics of Crohn disease, a chronic incurable inflammatory bowel condition, as Crohn's pathogenesis is associated with attenuated NOD2 or DEFB2/HBD2 function.

Background: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has been shown to induce colon cancer cell apoptosis in the presence of interferon-gamma. We hypothesized that co-treatment using TWEAK with other pro-apoptosis agents could sensitize death receptor-resistant colon cancer cells., Materials and Methods: The effects of chemopreventive agents and TWEAK on cell death and apoptosis were determined using propidium iodide (PI) exclusion and M30 CytoDEATH., Results: We found that 15d-PGJ(2) sensitizes colon cancer cells to TWEAK-induced apoptosis. Caspase inhibition reduced 15d-PGJ(2)-, but not 15d-PGJ(2)+TWEAK-induced apoptosis. 15d-PGJ(2) promoted reactive oxygen species (ROS) production and dissipation of mitochondrial potential (DeltaPsi(m)) that were more marked with combined treatment. ROS, DeltaPsi(m) and cell death were partially normalized by the antioxidant N-acetylcysteine. TWEAK induced nuclear factor-kappa B activation, which was attenuated by 15d-PGJ(2). 15d-PGJ(2) reduced the expression of the anti-apoptotic proteins BCL-X(L) and MCL-1, while increasing BAX and translocation of cytochrome c and apoptosis-inducing factor., Conclusion: 15d-PGJ(2) sensitized cancer cells to TWEAK-induced apoptosis through an ROS-dependent cell death pathway and may have chemotherapeutic utility as an apoptosis-enhancing agent.

Standard laboratory indicators of inflammation such as erythrocyte sedimentation rate and C-reactive protein are of little value in the diagnosis of inflammatory bowel disease. Serologic markers for anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies have been available for some time but are not sufficiently specific or sensitive for use in first-line screening. The second- and third-generation serologic panels have increased sensitivity and specificity, and the addition of assays for anti-outer membrane porin protein C immunoglobulin A and anti-CBir1 have led to the identification of unique subsets of Crohn's disease patients at risk for more complicated and severe forms of disease. This may prove useful in determining whether early aggressive therapy is warranted. Tests are also available for genotyping patients before starting azathioprine and for monitoring clinical response once the patients are receiving the immunomodulator. For patients on anti-tumor necrosis factor-alfa therapy, a dual test measuring serum levels of infliximab and antibodies against infliximab can aid physicians in determining dose and infusion intervals, as well as alert them to the possibility of infusion reactions and/or a reduced duration of efficacy.

Background: An adolescent boy aged 17 years presented with sudden onset of visual impairment, which was rapidly diagnosed as bilateral anterior uveitis by an ophthalmologist. A systemic review noted episodes of nonbloody diarrhea, weight loss of 3 kg and a diminished appetite during the previous 10 months. The patient's family history revealed an older brother with Crohn's disease., Investigations: Visual acuity test, slit-lamp examination, ophthalmologic fundoscopy and endoscopic evaluation of the upper and lower gastrointestinal tract with biopsy., Diagnosis: Multifocal Crohn's disease, involving the terminal ileum and cecum, in addition to the stomach and duodenum., Management: Treatment with topical corticosteroids, in the form of ophthalmic drops and oral budesonide ileal-release capsules. Once remission was achieved, it was maintained with mercaptopurine.

Background and Objectives: The role of dietary factors in the etiology of Crohn's disease (CD) is inconsistent largely due to difficulties in acquiring valid information on consumption habits. We examined the impact of diet on new onset CD in children using a validated food-frequency questionnaire (FFQ)., Methodology: A case-control study was carried out. Children < or =20 yr, newly diagnosed with CD, were recruited from 3 pediatric gastroenterology clinics across Canada. Population or hospital controls were selected matched to cases for time of diagnosis (+/-6 months) and area of residence. Dietary consumption 1 yr prior to disease diagnosis was evaluated using a validated FFQ, administered within 1 month of diagnosis. Conditional logistic regression analysis adjusting for potential confounding variables (energy intake, age, gender, body mass index) was carried out., Results: A total of 130 CD patients and 202 controls were studied. Mean age at diagnosis (+/-SD) was 14.2 (2.7). There were more male patients (59%). Comparing the highest to the lowest levels of consumption, higher amounts of vegetables (OR 0.69, 95% CI 0.33-1.44, P= 0.03), fruits (OR 0.49, 95% CI 0.25-0.96, P= 0.02), fish (OR 0.46, 95% CI 0.20-1.06, P= 0.02), and dietary fiber (OR 0.12, 95% CI 0.04-0.37, P < 0.001) protected from CD. Consumption of long-chain omega-3 fatty acids (LCN-omega-3) was negatively associated with CD (OR 0.44, 95% CI 0.19-1.00, P < 0.001). A higher ratio of LCN-omega-3/omega-6 fatty acids was significantly associated with lower risks for CD (OR 0.32, 95% CI 0.14-0.71, P= 0.02)., Conclusions: Our findings indicate that an imbalance in consumption of fatty acids, vegetables, and fruits is associated with increased risks for CD among Canadian children.

Butyrate (NaBu), a product of intestinal microbial metabolism, has been proposed as an anti-inflammatory agent for treating inflammatory bowel diseases. However, the molecular mechanisms implicated in the modulation of intestinal epithelial cell inflammatory response to NaBu remain unknown. Here, microarray analysis performed on nontransformed human crypt intestinal epithelial cells (HIEC) shows that NaBu regulated specifically the short-term IL-1beta -dependent induction of different inflammatory genes. While NaBu significantly increased the IL-1beta -induction of genes like SAA2, C3, and IL-1alpha , other inflammatory genes like CXCL5, CXCL11, and IL-1beta were decreased. Induction of various genes such as CXCL8, CCL20, and IL-6 was unaffected by NaBu. We show that, compared to genes that are upregulated or downregulated by NaBu, genes that are unaffected by NaBu were induced more rapidly after IL-1beta treatment and contained a higher concentration of transcription factor binding sites in their promoter region. In addition, transient treatment with IL-1beta was sufficient for subsequent induction of NaBu-upregulated and NaBu-unaffected classes of genes, while a continuous presence of IL-1beta was required for NaBu-downregulated gene expression. In conclusion, our results suggest that fundamental differences predispose inflammatory genes to specific regulation by NaBu in intestinal epithelial cells, thereby allowing precise control of inflammation.

Capsule endoscopy (CE) is an innovative technological breakthrough that for the first time provides a noninvasive method to obtain high-resolution imaging of the entire small bowel. Since its recent inception, the diagnostic utility of CE has become well established for the evaluation of diverse ulcerative and inflammatory disorders of the jejunum and ileum. The incredible resolution of its lens (0.1 mm) detects focal villous edema or atrophy, denuded, as well as ulcerated mucosal lesions missed by other imaging techniques. CE has been shown by meta-analysis to be a more sensitive method to investigate patients for small bowel Crohn's disease, with an incremental yield above 30% versus other imaging modalities. In patients with indeterminate colitis, CE is useful in distinguishing between ulcerative and Crohn's colitis. Among patients with established Crohn's disease, CE may be employed to determine: (1) the extent and severity of small bowel involvement, (2) postoperative recurrence, (3) post-therapy mucosal healing, and (4) whether active small bowel inflammatory lesions exist in the clinical setting of functional bowel disorder. Complications are rare and include capsule retention at stricture sites. The new patency capsule can diminish the risk of the latter problem in at-risk patients. CE can also serve as a guide to sites that require biopsies or dilatation by push or double-balloon enteroscopy. However, other causes of small bowel lesions may mimic Crohn's disease. A standard terminology system has thus been developed, and a CE Crohn's disease severity scoring index is currently undergoing validation studies.

cDNA microarray technology enables detailed analysis of gene expression throughout complex processes such as differentiation. The aim of this study was to analyze the gene expression profile of normal human intestinal epithelial cells using cell models that recapitulate the crypt-villus axis of intestinal differentiation in comparison with the widely used Caco-2 cell model. cDNA microarrays (19,200 human genes) and a clustering algorithm were used to identify patterns of gene expression in the crypt-like proliferative HIEC and tsFHI cells, and villus epithelial cells as well as Caco-2/15 cells at two distinct stages of differentiation. Unsupervised hierarchical clustering analysis of global gene expression among the cell lines identified two branches: one for the HIEC cells versus a second comprised of two sub-groups: (a) the proliferative Caco-2 cells and (b) the differentiated Caco-2 cells and closely related villus epithelial cells. At the gene level, supervised hierarchical clustering with 272 differentially expressed genes revealed distinct expression patterns specific to each cell phenotype. We identified several upregulated genes that could lead to the identification of new regulatory pathways involved in cell differentiation and carcinogenesis. The combined use of microarray analysis and human intestinal cell models thus provides a powerful tool for establishing detailed gene expression profiles of proliferative to terminally differentiated intestinal cells. Furthermore, the molecular differences between the normal human intestinal cell models and Caco-2 cells clearly point out the strengths and limitations of this widely used experimental model for studying intestinal cell proliferation and differentiation.

Wireless capsule endoscopy represents an extraordinary technical innovation in diagnostic gastrointestinal endoscopy. As in adult patients, it opens new horizons that permit an accurate and noninvasive approach to identifying occult lesions in the small bowel in children and adolescents. A limitation in the pediatric age group is the size of the capsule, precluding its use in infants and small toddlers. In children unable to swallow the capsule, "front loading" the gastroscope to introduce it into the duodenum is a suitable alternative approach. Capsule endoscopy is highly useful to evaluate for inflammatory changes in patients suspected to have small bowel Crohn's disease in whom conventional imaging failed to confirm the diagnosis. It is now the method of first choice to assess for small bowel polyps or tumors, to find a source of blood loss in obscure intestinal bleeding, and for undiagnosed malabsorptive conditions such as intestinal lymphangiectasia. Capsule retention is the one major potential adverse effect of capsule endoscopy. In patients suspected to have a small bowel stenosis, consideration should be given to using the patency capsule prior to using the real videocapsule so as to decrease the risk of capsule retention.

Background and Objectives: Evidence for the hygiene hypothesis in the etiology of Crohn's disease (CD) is unclear. We investigated the relationship between infection-related exposures and risk for CD in children., Methods: A hospital-based case-control was carried out. Newly-diagnosed cases of CD (n = 194), less than 20 yr of age were recruited from the gastroenterology clinic of a large-pediatric inflammatory bowel disease (IBD) center in Montreal, Canada. Orthopedic patients pair-matched (n = 194) for timing of diagnosis and area of residence were recruited as controls. Information on infection-related exposures between birth and disease diagnosis was ascertained by administering a structured questionnaire to the mother and the index subject. The relationship between the frequency and timing of infection-related exposures with CD was studied., Results: The mean age (SD) at diagnosis was 12.3 (5.1). CD was more common after 10 yr of age. Gender distribution was similar between comparison groups. In multivariate conditional logistic regression, family history of IBD (odds ratio (OR) = 4.6; 95% confidence interval (CI) = 1.6-13.3), age (OR = 1.2; 95% CI = 1.1-1.3), and owning a pet (OR = 2.0; 95% CI = 0.9-4.5) were associated with risk for CD, whereas regular use of a personal towel (OR = 0.5; 95% CI = 0.2-0.9) and lesser crowding in homes (OR = 0.3; 95% CI = 0.1-0.8) were protective. Day-care attendance during the first 6 months of life and "physician-diagnosed infections" between 5 and 10 yr of age were associated with increased risks for CD., Conclusions: Infection-related exposures seem to enhance risk for CD in children. The timing of these exposures during early childhood may be relevant to the etiology of pediatric CD.

Background and Objectives: Many Crohn's disease (CD) patients develop complications (fistulae and abscesses), and require surgery, often repeatedly and at variable instances. Identifying serological markers that determine their early or repeated manifestation can enable implementing more aggressive preventive strategies. Our objective was to study the ability of serological markers for predicting development of early (first) and recurrent complications or requirement for surgery., Methods: Serum anti-Saccharomyces cervisiae (ASCA) (IgA & IgG) and perinuclear antineutrophil cytoplasmic antibodies (pANCA) were assayed close to diagnosis in a pediatric cohort of CD patients identified between 1996 and 1998. At diagnosis and follow-up, information was acquired on demographic and clinical features of disease. Relation between ASCA and clinical events was studied using adjusted Cox-proportional hazards modeling. The relative rates of recurrent clinical events according to the marker measures were compared., Results: The mean age (SD) at diagnosis was 11.2 (3.4) yr. Among 139 patients, 35 (25.9%) and 31 (22.3%) acquired one or more CD related surgery or complication, respectively. Time to occurrence of the first complication was lower among patients ASCA+ (IgA or IgG) (hazards ratio (HR) = 2.33; 95% confidence interval (CI) = 0.99-5.50) and among those with higher ASCA-IgA titers (HR = 1.20; 95% CI = 1.08-1.34). The rates of recurrent complications were higher among those positive or with higher ASCA titers. ASCA did not predict time to undergoing surgery independent of complications, and was unrelated to the occurrence of recurrent surgeries., Conclusions: Our study shows that serum ASCA measured close to diagnosis can determine the occurrence of early complications in pediatric CD. Preventive treatment targeted toward these susceptible patients could potentially modify the disease course.

Background and Aims: Obscure small-bowel disorders are jejunal and ileal lesions undiagnosed by traditional imaging techniques (endoscopic, radiologic). We evaluated the diagnostic usefulness and safety of capsule endoscopy for obscure small-bowel disorders in children and adolescents., Methods: Comparative, prospective, self-controlled trials in patients (age, 10-18 y) suspected to have either small-bowel Crohn's disease, polyps, or obscure gastrointestinal (GI) bleeding. Capsule results were compared with the diagnostic imaging studies normally used in this age group., Results: Among 20 patients suspected of Crohn's disease, multiple lesions consistent with this diagnosis were observed by capsule endoscopy in 50%. Small-bowel Crohn's disease was ruled out in 8 patients. Eosinophilic enteropathy was found in 2 others. For polyp detection (n = 6), capsule endoscopy yielded 100% concordance with the control studies when analyzed per patient. However, capsule endoscopy revealed a greater number (50%) of polyps. Among patients with obscure bleeding (n = 4), the capsule examination confirmed a diagnosis of vascular malformations in 3. Capsule endoscopy more accurately identified the precise source of bleeding compared with angiography. All 30 capsule studies were well tolerated, although 1 capsule was retained owing to an inflammatory stenosis. The capsule eventually was expelled after corticosteroid therapy., Conclusions: Capsule endoscopy correctly diagnosed or excluded a bleeding source, small-bowel polyps, or Crohn's disease of the small bowel in 29 of 30 patients. Capsule endoscopy permits an accurate, noninvasive approach for diagnosing obscure small bowel lesions in children over the age of 10.

Background: Interleukin (IL)-15 is overexpressed in intestinal tissue with active Crohn's disease (CD). However, its role in the pathogenesis of the disease remains uncertain. We studied the effects of IL-15 on colonic mucosal proinflammatory cytokine response in vitro using organ culture of human colonic explants., Methods: Colonic tissue was obtained from (1) resections in pediatric CD patients (inflamed and noninflamed) and (2) rectal biopsies in patients with CD undergoing colonoscopy (n = 31) and controls (n = 9). In preliminary experiments, explants from the resections were cultured in the presence or absence of a simulated T(H)1 stimulation using ionomycin (Io) and phorbol-myristate-acetate (PMA), with or without IL-15, or in medium alone. Rectal biopsies were cultured in the same conditions as above, with or without adding a monoclonal anti-IL-15 neutralizing antibody (mAb). Levels of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and IL-2R alpha were measured by enzyme-linked immunosorbent assay., Results: IL-15, in the absence of Io + PMA, did not induce the expression of IFN-gamma, TNF-alpha, or IL-2R alpha. Only inflamed explants from resections stimulated with Io + PMA expressed IFN-gamma, TNF-alpha, and IL-2R alpha. This T(H)1 stimulatory effect was inhibited by IL-15 in a dose-dependent fashion. In rectal biopsy explants, inflamed, noninflamed CD, and control tissue responded to stimulation with Io + PMA (P < 0.05) with increased IFN-gamma and TNF-alpha (P < 0.05). This response was again inhibited by IL-15. The inhibitory effect of IL-15 was specifically reversed by anti-IL-15 mAb (P < 0.05). The data for the CD group were also analyzed according to the severity of colonic inflammation and medication use., Conclusions: Our results suggest a possible anti-inflammatory role for IL-15 in CD. We postulate that its overexpression in CD potentially represents a protective mechanism against the exaggerated T(H)1 immune response.

Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. It occurs in children and adolescents with gastrointestinal symptoms, dermatitis herpetiformis, dental enamel defects, osteoporosis, short stature, delayed puberty and persistent iron deficiency anemia and in asymptomatic individuals with type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, selective immunoglobulin (Ig)A deficiency and first degree relatives of individuals with celiac disease. The Celiac Disease Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has formulated a clinical practice guideline for the diagnosis and treatment of pediatric celiac disease based on an integration of a systematic review of the medical literature combined with expert opinion. The Committee examined the indications for testing, the value of serological tests, human leukocyte antigen (HLA) typing and histopathology and the treatment and monitoring of children with celiac disease. It is recommended that children and adolescents with symptoms of celiac disease or an increased risk for celiac disease have a blood test for antibody to tissue transglutaminase (TTG), that those with an elevated TTG be referred to a pediatric gastroenterologist for an intestinal biopsy and that those with the characteristics of celiac disease on intestinal histopathology be treated with a strict gluten-free diet. This document represents the official recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition on the diagnosis and treatment of celiac disease in children and adolescents.

Dendritic cells (DCs) are thought to play an important role in the pathogenesis of autoimmune inflammation, including Crohn's disease (CD). We investigated the distribution and state of maturation of DCs in the colon in relation to the severity of inflammation and therapy. Using archival specimens from colonic resections in 19 pediatric patients with CD and 14 controls, we identified and characterized the DCs within the lamina propria, submucosa, and muscularis compartments using morphologic and quantitative immunohistochemical methods. The distribution of CD11c+CD83+CD68+DC-SIGN+ and immature CD11c+CD83-CD68-DC-SIGN+ DCs within the different compartments varied according to the presence or absence of CD as well as to the severity of inflammation and systemic corticoid treatment. Immature DCs were only found in non-inflamed control colonic tissue. Marked reductions (60% and 30%) in total CD11c and CD83 DC numbers were observed in CD tissue samples compared with controls (P < 0.05). CD samples from patients on corticosteroid therapy were significantly more depleted than in tissue from untreated patients or those on other drugs. Colonic tissue with severe inflammation had reduced numbers of CD11c+ and CD83+ DCs in the lamina propria and submucosal compartments (80% and 76% for CD11c; 75% and 76% for CD83, respectively, P < 0.05), with a concomitant increase (525% for CD11c and 700% for CD83 P < 0.05) of DCs in the muscularis compartment, compared to moderately inflamed and non-inflamed CD tissue. Our data suggest that an imbalance in intestinal DC subpopulations may play a role in the initiation and/or the maintenance of chronic inflammation in CD. Corticosteroid therapy is associated with colonic DC depletion., (Copyright 2004 Lippincott Williams & Wilkins)

Background and Aims: The utility of serial measurements of anti-Saccharomyces cerevisiae (ASCA) and perinuclear antineutrophil cytoplasmic (p-ANCA) antibodies in Crohn's disease (CD) evolution is unknown. We aimed to study the pattern of antibody change and the prognosis of selected outcomes by baseline (at time of diagnosis) and serial antibody measurements in pediatric CD patients., Methods: Serum ASCA and p-ANCA antibodies were measured at baseline (n = 154) and repeated during follow-up (n = 61) using standard techniques in a cohort of patients identified at Hôpital Sainte-Justine between 1996 and 1998. Clinical information was abstracted from medical charts. Antibody patterns were examined using mixed modeling techniques. The prognostic ability of antibodies for selected outcomes was evaluated using logistic regression., Results: Fifteen (24.5%), 18 (29.5%), and 11 (18%) patients with serial antibody measurements changed their ASCA-IgA, ASCA-IgG, and p-ANCA status (positivity), respectively. No distinct patterns in the evolution of antibody titers were noted. Baseline ASCA-IgA positivity significantly predicted relapses during disease course (IgA: odds ratio [OR], 2.9; 95% confidence interval [CI], 1.33-6.35). Serial antibody measurements did not predict the occurrence of clinical outcomes., Conclusions: Baseline serum antibodies were predictive of a more relapsing disease course in pediatric CD. However, the limited variability in the antibodies over time and the inability of serial measurements to predict clinical outcomes may limit their use in the establishment of intervention strategies.

The mucosal immune system is overactivated in Crohn disease (CD) and viral infections have been associated with clinical exacerbations. To investigate the potential association between mucosal inflammation and the cytokines involved in the early response to viruses, we analyzed colonic tissue levels of IL-2Ralpha, interferon-alpha, and IL-15 in CD. Patients undergoing diagnostic colonoscopy were classified into controls (n = 22) and three CD groups based on the histologic severity of inflammation and clinical activity: a) severely active CD (n = 3); b) mild to moderately active CD (n = 14); and c) quiescent CD (n = 23). Rectal biopsies (two per patient) were homogenized and cytokine levels determined by ELISA kits. Statistical analysis was performed by ANOVA with Tukey and Scheffé tests. IL-2Ralpha levels were increased in the active CD group compared with the quiescent CD group: a) 405 +/- 87, b) 159 +/- 31, and c) 33 +/- 15 pg/mg DNA (p < 0.001). The latter group was similar to controls (39 +/- 20 pg/mg DNA). Furthermore, a linear correlation (r = 0.98) between IL-2Ralpha and disease activity (Van Hees index) was observed. IL-15 levels were also higher in active compared with quiescent CD and controls: a) 0.69 +/- 0.23 and b) 0.72 +/- 0.31 versus c) 0.28 +/- 0.21 and 0.28 +/- 0.14 pg/mg DNA for controls (p < 0.05). Interferon-alpha levels were undetectable in all samples. Our data suggest that IL-2Ralpha tissue levels correlate with CD activity. IL-15 is also overproduced in inflamed CD tissue. The lack of a parallel elevation of interferon-alpha does not support a role for viral induction of IL-15 in inflamed CD samples.

The incidence and prevalence of Crohn's disease (CD) among children in developed countries is increasing. Although extensive progress has been made in the elucidation of the pathogenesis of the disease, its mechanism remains unknown. CD is likely to be the result of a complex interplay of both genetic and environmental factors (G x E). However, the specific elements underlying these interactions have not been defined. We propose that the underlying pathology of CD may be related to interactions between infections acquired either during intrauterine life and/or early childhood and DNA variants in the cytokine and the NOD2 genes. DNA variants in the latter could confer susceptibility by altering immune development and response to infectious agents. We present a molecular and epidemiological perspective on possible mechanisms underlying G x E. Investigating these and other pathways will be paramount for the appropriate identification of susceptible populations, so that preventive and/or therapeutic interventions could be adequately targeted.

Objective: To discuss current therapeutic modalities for cow's milk allergy and its prevention., Data Sources and Study Selection: The sources of data include original clinical studies carried out at Ste. Justine Hospital, as well as a systematic search of the published English and French language scientific literature restricted to human subjects using computerized searches (National Public Library of Medicine, Cochrane Database Systems Review) from 1997 to 2002. Search terms for article retrieval included food allergy, milk allergy, therapy, and prevention., Conclusions: The therapy of food allergies depends upon an accurate diagnosis, which remains a challenge in non--IgE-mediated cases. Dietary exclusion remains the mainstay of therapy, with medications reserved for exceptional patients. Preliminary evidence suggests that pancreatic enzyme supplementation may be of benefit for cases with multiple food allergies and severe eczema. Hydrolysate formula use is currently recommended for dietary allergy prevention in infants at an increased risk when maternal milk is insufficient or unavailable. The use of partially hydrolyzed formulas to prevent allergic disorders, including atopic dermatitis, is supported by clinical studies, but cannot be used in the already sensitized, milk-allergic child. Probiotics show enormous potential in preventing food allergic disorders as well.

Transitioning an adolescent patient to an internist/gastroenterologist's care requires an understanding of the specific issues and challenges involved in the diagnosis and management of paediatric inflammatory bowel disease (IBD). Even though diagnostic criteria, as well as methods are the same in children and adults, younger patients may experience more insidious presentations. A high level of suspicion is necessary for an early and accurate diagnosis. Management of IBD in the paediatric population begins with the assessment of disease extent and activity as well as the identification of potentially serious complications (such as malnutrition, growth/sexual retardation and osteoporosis), which are often present at the time of diagnosis. Treatment includes not only medical, nutritional or surgical therapy but also a multidisciplinary or holistic approach taking into consideration the psychological as well as social impact of the disease on the patient and family.

Background: Membrane lipid peroxidation may play a role in immune-mediated bowel diseases., Objective: We examined the effects of lipopolysaccharide (LPS), a ubiquitous endotoxin mediator of gram-negative bacteria, alone and in combination with iron-ascorbate, on enterocyte function. Furthermore, we assessed the antioxidant capacity of butylated hydroxytoluene (BHT) and butyric acid, which are known to play a significant role in the welfare of intestinal mucosa., Design: Differentiated intestinal Caco-2 cells were used to study the induction of membrane peroxidation by LPS (100 micro g/mL) and iron-ascorbate (0.2 and 2 mmol/L, respectively) and to examine the beneficial effects of BHT and butyric acid., Results: A significant dose-dependent increase in malondialdehyde, accompanied by lower apical membrane fluidity and significantly decreased sucrase activity, was observed when Caco-2 cells were incubated with LPS. LPS also augmented paracellular permeability ([(14)C]polyethylene glycol flux), prostaglandin E(2) production, and cyclooxygenase-2 (EC 1.14.99.1) expression. These abnormalities were exacerbated by the coadministration of iron-ascorbate, but most of them were suppressed by butyric acid and BHT., Conclusion: Bacterial endotoxin and prooxidants may overwhelm antioxidant defenses and become deleterious to enterocyte function, whereas butyric acid and BHT may provide antioxidant protection.

6-mercaptopurine (6-MP) and its parent drug azathioprine (AZA) have been proven to be effective for both steroid-dependent and chronically active, or steroid-resistant inflammatory bowel disease, as well as for the prevention of relapse. Concerns about toxicity, delayed onset of action, and therapeutic failure (1 out of 3 patients) have restricted their use. Recent pharmacogenetic advances have led to the development of novel strategies to optimize and individualize therapy with AZA and 6-MP, maximizing efficacy while minimizing toxicity. We have defined a range of optimal therapeutic 6-MP metabolite levels, as well as an association of metabolite levels with medication-induced toxicity and the genotype of the main catabolic enzyme, thiopurine methyltransferase (TPMT). Measurement of 6-MP metabolite levels and TPMT molecular analysis provide clinicians with useful tools for optimizing therapeutic response to 6-MP/AZA, as well as for identifying individuals at increased risk for drug-induced toxicity.

Leukocytes are implicated in the pathogenesis of diarrhea-associated hemolytic uremic syndrome (D(+) HUS). We hypothesized that increased circulating levels of granulocyte colony-stimulating factor (G-CSF), and the chemokines epithelial cell-derived neutrophil-activating protein-78 (ENA-78), growth related oncogen-alpha (GRO-alpha), macrophage inflammatory protein-1beta (MIP-1beta), and monocyte chemotactic protein-1 (MCP-1) are related to the severity of illness in Escherichia coli O157:H7 infections. We compared the circulating concentrations of these mediators in the course of E. coli O157:H7 enteritis, hemorrhagic colitis, and HUS. Our data show that, on admission, children with HUS presented 10-fold abnormally increased levels of G-CSF (p < 0.007), 3-fold increased MIP-1beta concentrations (p < 0.001), and 2-fold lower values of ENA-78 (p < 0.0001). One week later, a further 4-fold decrease in ENA-78 concentration was noted (p < 0.0001) whereas MIP-1beta levels returned to normal. HUS patients requiring peritoneal dialysis showed 6-fold increased G-CSF (p < 0.001) and 5-fold decreased ENA-78 (p < 0.001) levels. On admission, children with uncomplicated O157:H7 hemorrhagic colitis (HC) presented 3-fold abnormally increased concentrations of G-CSF (p < 0.001) and MIP-1beta (p < 0.0001). Those with O157:H7 enteritis but no bloody stools showed higher rates of abnormal GRO-alpha, MIP-1beta, and MCP-1 measurements than children with O157:H7 HC or HUS: GRO-alpha (50% enteritis, 36% HC, 17% HUS; p < 0.06), MIP-1beta (40% enteritis, 22% HC, 11% HUS; p < 0.02), MCP-1 (77% enteritis, 20% HC, 18% HUS; p < 0.0001). The data indicates that GRO-alpha, MIP-1beta, and MCP-1 are produced during E. coli O157:H7 enteritis, whether or not HC or HUS develops. Our data suggest that children with O157:H7 associated HUS may present abnormally increased circulating levels of G-CSF and decreased ENA-78 concentrations. The mechanisms responsible for leukocytes recruitment in O157:H7 infections are unclear and await further studies.

Objectives: The suspicion of IBD in patients presenting with nonspecific abdominal pain and diarrhea results in the extensive use of invasive diagnostic testing in patients likely to have a functional GI disorder. Noninvasive serodiagnostic tests, however, accurately identify IBD and may serve as effective screening tools. The objective of this study was to examine the cost-effectiveness of initial serodiagnostic screening followed by standard invasive testing, compared to standard invasive testing alone, in patients presenting with uninvestigated symptoms suggestive of IBD., Methods: Decision analysis was performed to compare the costs and outcomes of competing diagnostic strategies. Probability estimates were derived from the medical literature and expert opinion. Costs estimates were obtained from the Medicare Fee schedule and the cost-analysis was done from a third party payer perspective. The target population was patients with uninvestigated symptoms suggestive of IBD. The outcome measure was cost per correct diagnosis in competing strategies and was assessed at 1 yr., Results: In the base case analysis, the serodiagnostic strategies were dominant; they were less costly and more accurate than the standard invasive strategies. Sequential serodiagnostic strategies resulted in the largest cost savings ($550 per average patient) with an average cost per correct diagnosis of $1640 compared to $2188 for standard invasive testing. Cost savings were attributable to a 39% reduction in the use of invasive tests. The results were robust to varying model estimates over prespecified ranges in the sensitivity analyses. When costs of invasive testing are reduced by 80% or the prevalence of IBD is at least 83%, serodiagnostic strategies are no longer the most cost-effective., Conclusions: Initial serodiagnostic screening strategies may represent a cost-effective alternative to standard invasive diagnostic strategies. The economic benefits seem to be achieved by avoiding invasive evaluations in patients without IBD. Confirmation of these findings in a prospective comparative trial seems to be warranted.

We describe the course of 7 patients younger than 2 years with Crohn's disease. Prolonged remission was achieved medically (5) or surgically (1), whereas one patient died of disseminated adenovirus. Three had malnutrition and growth failure. Crohn's disease very early in life does not always imply a poor prognosis; however, significant morbidity and mortality are encountered.

Background & Aims: Approximately 40% of inflammatory bowel disease (IBD) patients fail to benefit from 6-mercaptopurine (6-MP)/azathioprine (AZA). Recent reports suggest 6-thioguanine nucleotide (6-TGN) levels (>235) independently correlate with remission. An inverse correlation between 6-TGN and thiopurine methyltransferase (TPMT) has been described. The objectives of this study were to determine whether dose escalation optimizes both 6-TGN levels and efficacy in patients failing therapy because of subtherapeutic 6-TGN levels and its effect on TPMT., Methods: Therapeutic efficacy and adverse events were recorded at baseline and upon reevaluation after dose escalation in 51 IBD patients. 6-MP metabolite levels and TPMT activity were recorded blinded to clinical information., Results: Fourteen of 51 failing 6-MP/AZA at baseline achieved remission upon dose escalation, which coincided with significant rises in 6-TGN levels. Despite increased 6-MP/AZA doses, 37 continued to fail therapy at follow-up. Dose escalation resulted in minor changes in 6-TGN, yet a significant increase in 6-methylmercaptopurine ribonucleotides (6-MMPR) (P < or = 0.01) and 6-MMPR:6-TGN ratio (P < 0.001). 6-MMPR rises were associated with dose-dependent hepatotoxicity in 12 patients (24%). TPMT was not influenced by dose escalation., Conclusions: Serial metabolite monitoring identifies a novel phenotype of IBD patients resistant to 6-MP/AZA therapy biochemically characterized by suboptimal 6-TGN and preferential 6-MMPR production upon dose escalation.