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© 2015 Susan Hutfless et al.Objectives. To assess the relationship between infections and the risk of pediatric-onset inflammatory bowel disease (IBD). Methods. We conducted a nested case-control study of 501 incident cases aged ≤17 years and 9,442 control

Background: We examined the sequences of clinical care leading to diagnoses of Alzheimer's disease and related dementias (ADRD) using electronic health records from a large academic medical center., Methods: We included patients aged 65+ with their first ADRD diagnoses from January 1, 2014 to December 31, 2019. Using state sequence analysis, care sequences were defined by the ordering of healthcare utilizations occurred in the 2 years before ADRD diagnosis., Results: Of 3621 patients (median age 80), nearly half followed a care sequence of having one primary care visit close to their ADRD diagnosis. Additional care sequences included periodic (n = 322, 8.9%) and multiple (n = 416, 11.5%) outpatient visits to primary care and having one (n = 395, 10.9%), multiple (n = 469, 13.0%), or highly frequent (n = 357, 10.7%) outpatient visits to other specialties. Patients' sociodemographic traits contributed to the variability in care sequences., Conclusions: Several distinct patterns of care leading to ADRD diagnoses were identified. Integrated care models are needed to promote early identification of ADRD., Highlights: Dementia patients followed distinct care pathways prior to their dementia diagnoses. Key sociodemographic traits contributed to the variation in the sequences of care. Racial differences in the sequencing of care were also found, but only in women., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Purpose of Review: To evaluate the clinical and nutritional significance of genetically determined lactase non-persistence and potential lactose and milk intolerance in 65-70% of the world's adult population., Recent Findings: Milk consumption is decreasing in the USA and is the lowest in countries with a high prevalence of lactase non-persistence. The dairy industry and Minnesota investigators have made efforts to minimize the influence of lactose intolerance on milk consumption. Some lactose intolerant individuals, without co-existent irritable bowel syndrome, are able to consume a glass of milk with a meal with no or minor symptoms. The high frequency of lactase persistence in offspring of Northern European countries and in some nomadic African tribes is due to mutations in the promoter of the lactase gene in association with survival advantage of milk drinking. Educational and commercial efforts to improve calcium and Vitamin D intake have focused on urging consumption of tolerable amounts of milk with a meal, use of lowered lactose-content foods including hard cheeses, yogurt, and lactose-hydrolyzed milk products.

Background and Aims: Serrated epithelial change (SEC) is a histologic finding in longstanding colitis that may be associated with dysplasia. Our primary aim was to determine the incidence of dysplasia and colorectal cancer (CRC) in inflammatory bowel disease (IBD) patients with SEC. Secondary aims were to determine the rate of location concordance between SEC and dysplasia/CRC and to identify other risk factors associated with dysplasia in IBD patients with SEC., Methods: A retrospective, descriptive, observational study was performed by searching the Pathology Data System at a single tertiary referral center for a histologic finding of "serrated epithelial change." The patient's first pathology specimen with SEC was designated the index SEC. All subsequent pathology reports were evaluated for the occurrence and location of dysplasia or CRC. Univariable and multivariable logistic regression were performed to identify predictors of dysplasia., Results: There were 187 patients with confirmed IBD and 1 or more histologic findings of SEC without prior dysplasia. Mean IBD duration was 16 years, and median follow-up time was 28 months. The rate of high-grade dysplasia or CRC was 17 per 1000 patient-years. Thirty-nine of 187 patients (21%) had synchronous or metachronous dysplasia or CRC. Location concordance was 68%. Multivariable analysis found SEC on follow-up examinations, older age at IBD diagnosis, male gender, and a first-degree relative with CRC were associated with dysplasia in IBD patients with SEC., Conclusions: This uncontrolled study describes a high frequency of dysplasia in patients with a histologic finding of SEC. SEC seen on successive endoscopic examinations further increased the risk of dysplasia. Further controlled studies are needed to determine if SEC is a precancerous lesion in IBD patients and if SEC can be endoscopically identified., (Copyright © 2016 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Objectives. To assess the relationship between infections and the risk of pediatric-onset inflammatory bowel disease (IBD). Methods. We conducted a nested case-control study of 501 incident cases aged ≤17 years and 9,442 controls who were members of Kaiser Permanente Northern California for at least one consecutive year between 1996 and 2006. IBD was confirmed and the incidence date was adjudicated by pediatric gastroenterologists. Hospitalized infections were identified from the principal diagnosis code of electronic inpatient records. Medications to treat infections were identified during the hospitalization. Conditional logistic regression was used to assess the associations between hospitalized infections, medications, and Crohn's disease and ulcerative colitis. Results. In the year prior to diagnosis, both hospitalized infection of any system (OR 6.3; 95% CI 1.6-23.9) and hospitalized intestinal infection (OR 19.4; 95% CI 2.6-143.2) were associated with CD. Hospitalized infections of any system were inversely associated with UC after excluding the year prior to diagnosis (OR 0.4; 95% CI 0.2-0.9). No UC case had a hospitalized gastrointestinal infection prior to diagnosis. Conclusion. Infections appear to play opposite roles prior to the diagnosis of CD and UC. Infections may be associated with an increased risk of CD and a decreased risk of UC.

Background and Aims: Despite numerous shared susceptibility loci between Crohn's disease and ulcerative colitis, the prevalence of family history among ulcerative colitis patients is not well-established and considered to be less prevalent. A systemic review and meta-analysis were conducted to estimate the prevalence of family history of inflammatory bowel disease in ulcerative colitis patients, and its effect on disease outcomes., Methods: PubMED was searched to identify studies reporting the prevalence of family history of inflammatory bowel disease among ulcerative colitis patients. Definitions of family history, study type, and subtypes of family history prevalence were abstracted, as were disease outcomes including age at ulcerative colitis diagnosis, disease location, surgery and extraintestinal manifestations. Pooled prevalence estimates were calculated using random effects models., Results: Seventy-one studies (86,824 patients) were included. The prevalence of a family history of inflammatory bowel disease in ulcerative colitis patients was 12% (95% confidence interval [CI] 11 to 13%; range 0-39%). Family history of ulcerative colitis (9%; 22 studies) was more prevalent than Crohn's disease (2%; 18 studies). Patients younger than 18years of age at time of diagnosis had a greater family history of inflammatory bowel disease (prevalence 15%, 95% CI: 11-20%; 13 studies). There were no differences in disease location, need for surgery, or extraintestinal manifestations among those with a family history, although very few studies reported on these outcomes., Conclusions: Overall, 12% of ulcerative colitis patients have a family history of inflammatory bowel disease, and were more likely to have a family history of ulcerative colitis than Crohn's disease. Pediatric-onset ulcerative colitis patients were more likely to have a family history of inflammatory bowel disease., (Copyright © 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Background: In the northern hemisphere, the incidence of inflammatory bowel diseases (IBD) has a north-south gradient, suggesting a link between ultraviolet (UV) exposure or vitamin D status and the pathogenesis of IBD., Aim: To test the association of UV exposure with the rates and severity of IBD hospitalisation., Methods: We conducted a retrospective nationwide analysis of 649 932 Crohn's disease (CD), 384 267 ulcerative colitis (UC), and 288 894 297 non-IBD hospitalisations in the US between 1998 and 2010. Mean UV exposure was assigned to each hospitalisation using surface measures from the National Oceanic and Atmospheric Administration. Relative rates across UV exposures were estimated for IBD hospitalisations, prolonged hospitalisations, bowel surgeries and deaths., Results: Among IBD patients, lower UV exposures had increased hospitalisation rates for CD (217.8 vs. 182.5 per 100 000 overall hospitalisations with low and very high UV, respectively; P trend <0.001) and UC (123.2 vs. 113.8 per 100 000; P trend = 0.033). Low UV groups had greater relative rates of prolonged hospitalisations [CD: 1.13, 95% confidence interval (CI) 1.07-1.19; UC: 1.21, 95% CI 1.13-1.30], bowel surgeries (CD: 1.24, 95% CI 1.16-1.32; UC: 1.21, 95% CI 1.09-1.33), and CD deaths (CD: 1.76, 95% CI 1.14-2.71; UC: 1.24, 95% CI 0.92-1.67). Among non-IBD patients, low UV was associated with prolonged hospitalisations (1.09; 95% CI 1.07-1.11) and deaths (1.13; 95% CI 1.09-1.17), but not bowel surgeries (1.01; 95% CI 0.99-1.03)., Conclusions: Lower ultraviolet exposure is associated with greater rates of hospitalisation, prolonged hospitalisation and the need for bowel surgery in IBD. This trend for bowel surgery was not seen with non-IBD encounters., (© 2014 John Wiley & Sons Ltd.)

Background: The development of colon cancer represents a major complication in patients with inflammatory bowel disease (IBD). The importance of microRNAs (miRs) in carcinogenesis is becoming clearer because miRs have been implicated in the regulation of cancer-related cellular processes to include apoptosis, differentiation, cell cycle progression, and immune function. In the current study, we sought to identify miR dysregulation specific to progression along the normal-inflammation-cancer axis in colonic specimens from patients with IBD., Methods: MiR microarrays and quantitative reverse transcription PCR were used to detect and confirm dysregulated miRs. Receiver operating characteristic curve analysis was applied to evaluate the potential use of miR-224 as a neoplastic disease marker in IBD. For miR-224 target messenger RNA (mRNA) identification, mRNA microarrays were employed in combination with bioinformatic analyses, Western blotting, and luciferase activity measurements., Results: We identified 30 miRs that were differentially expressed between chronically inflamed mucosae and cancers arising from IBD tissues. MiR-224 levels increased successively at each stage of IBD progression and accurately discriminated cancers from normal or chronically inflamed IBD tissues. Moreover, mRNA arrays combined with bioinformatic analyses suggested the participation of miR-224 in cell cycle regulation. Subsequently, cell cycle experiments indicated that miR-224 regulates the G1-S checkpoint. Finally, in silico prediction analyses, confirmed by Western blotting and luciferase assays, identified p21 as a specific direct mRNA target of miR-224., Conclusions: These findings reveal miR dysregulation specific to IBD-associated colorectal carcinoma. MiR-224 is overexpressed in IBD cancers and targets p21, a key cell cycle regulator. Moreover, these results establish the participation of miR-224 in IBD carcinogenesis.

Background: Anti-glycan antibody serologic markers may serve as a useful adjunct in the diagnosis/prognosis of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). This meta-analysis/systemic review aimed to evaluate the diagnostic value, as well as the association of anti-glycan biomarkers with IBD susceptible gene variants, disease complications, and the need for surgery in IBD., Methods: The diagnostic odds ratio (DOR), 95% confidence interval (CI), and sensitivity/specificity were used to compare the diagnostic value of individual and combinations of anti-glycan markers and their association with disease course (complication and/or need for surgery)., Results: Fourteen studies were included in the systemic review and nine in the meta-analysis. Individually, anti-Saccharomyces cervisiae antibodies (ASCA) had the highest DOR for differentiating IBD from healthy (DOR 21.1; 1.8-247.3; two studies), and CD from UC (DOR 10.2; CI 7.7-13.7; seven studies). For combination of ≥2 markers, the DOR was 2.8 (CI 2.2-3.6; two studies) for CD-related surgery, higher than any individual marker, while the DOR for differentiating CD from UC was 10.2 (CI 5.6-18.5; three studies) and for complication was 2.8 (CI 2.2-3.7; two studies), similar to individual markers., Conclusions: ASCA had the highest diagnostic value among individual anti-glycan markers. While anti-chitobioside carbohydrate antibody (ACCA) had the highest association with complications, ASCA and ACCA associated equally with the need for surgery. Although in most individual studies the combination of ≥2 markers had a better diagnostic value as well as higher association with complications and need for surgery, we found the combination performing slightly better than any individual marker in our meta-analysis., (Copyright © 2012 Crohn's & Colitis Foundation of America, Inc.)

Background: The majority of studies that report early life risk factors for pediatric-onset inflammatory bowel disease (IBD) do not account for potential confounding, which can lead to spurious associations and incorrect inferences., Aims: To assess the relationship between prenatal and perinatal characteristics and the risk of pediatric-onset IBD accounting for potential confounding., Methods: We conducted a nested case-control study of 189 cases aged ≤18 years and 3,080 age- and membership-matched controls born at a Kaiser Permanente Northern California facility between 1984 and 2006. The cases were diagnosed with IBD between 1996 and 2006 and diagnosis was confirmed by chart review. We obtained prenatal and perinatal characteristics from the electronic clinical records of the mother and child. Conditional logistic regression was used to assess the associations between these factors and risk of incident IBD, Crohn's disease, and ulcerative colitis., Results: In analyses accounting for confounding, maternal IBD (odds ratio [OR] 5.1, 95 % confidence interval [CI] 2.0-12.9) and white race (OR 2.3, 95 % CI 1.6-3.2) were the only factors statistically associated with pediatric-onset IBD. Maternal respiratory infection during pregnancy (OR 2.0, 95 % CI 1.0-4.0), age < 20 years (OR 2.0, 95 % CI 0.8-4.7) and gestational hypertension (OR 1.7, 95 % CI 1.0-2.7) were associated with pediatric-onset IBD, but did not achieve statistical significance., Conclusions: Maternal history of IBD and race were the only characteristics of those that we examined that were associated with the development of pediatric IBD in this well-documented population of cases and matched controls.

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Background: Crohn's disease (CD) and ulcerative colitis (UC) result from pathophysiologically distinct dysregulated immune responses, as evidenced by the preponderance of differing immune cell mediators and circulating cytokine expression profiles. MicroRNAs (miRNAs) are small, noncoding RNAs that act as negative regulators of gene expression and have an increasingly recognized role in immune regulation. We hypothesized that differences in circulating immune cells in CD and UC patients are reflected by altered miRNA expression and that miRNA expression patterns can distinguish CD and UC from normal healthy individuals., Methods: Peripheral blood was obtained from patients with active CD, inactive CD, active UC, inactive UC, and normal healthy adults. Total RNA was isolated and miRNA expression assessed using miRNA microarray and validated by mature miRNA quantitative reverse-transcription polymerase chain reaction., Results: Five miRNAs were significantly increased and two miRNAs (149* and miRplus-F1065) were significantly decreased in the blood of active CD patients as compared to healthy controls. Twelve miRNAs were significantly increased and miRNA-505* was significantly decreased in the blood of active UC patients as compared to healthy controls. Ten miRNAs were significantly increased and one miRNA was significantly decreased in the blood of active UC patients as compared to active CD patients., Conclusions: Peripheral blood miRNAs can be used to distinguish active CD and UC from healthy controls. The data support the evidence that CD and UC are associated with different circulating immune cells types and that the differential expression of peripheral blood miRNAs may form the basis of future diagnostic tests for inflammatory bowel disease., (Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.)

Background: Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer. Aberrant microRNA (miR) expression has been linked to carcinogenesis; however, no reports document a relationship between IBD-related neoplasia (IBDN) and altered miR expression. In the current study we sought to identify specific miR dysregulation along the normal-inflammation-cancer axis., Methods: miR microarrays and quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) were used to detect dysregulated miRs. Receiver operating characteristic curve analysis was employed to test for potential usefulness of miR-31 as a disease marker of IBDNs. In silico prediction analysis, Western blot, and luciferase activity measurement were employed for target identification., Results: Several dysregulated miRs were identified between chronically inflamed mucosae and dysplasia arising in IBD. MiR-31 expression increases in a stepwise fashion during progression from normal to IBD to IBDN and accurately discriminated IBDNs from normal or chronically inflamed tissues in IBD patients. Finally, we identified factor inhibiting hypoxia inducible factor 1 as a direct target of miR-31., Conclusions: Our study reveals specific miR dysregulation as chronic inflammation progresses to dysplasia. MiR-31 expression levels increase with disease progression and accurately discriminates between distinct pathological entities that coexist in IBD patients. The novel effect of miR-31 on regulating factor inhibiting hypoxia inducible factor 1 expression provides a new insight on the pathogenesis of IBDN., (Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.)

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.

Background: Crohn's disease (CD) and ulcerative colitis (UC) are associated with expression differences in genes involved in immune function, wound healing, and tissue remodeling. MicroRNAs (miRNAs) are small, noncoding RNAs that act as potent negative regulators of gene expression and are differentially expressed in chronic inflammatory diseases, including UC. We examined the expression of miRNAs in tissues from different intestinal regions and in patients with active ileal and colonic CD., Methods: Colonoscopic pinch biopsies were obtained from the terminal ileum, cecum, transverse colon, sigmoid colon, and rectum of normal, healthy adults and from the ileum and sigmoid colon of patients with active ileal and colonic CD. miRNA expression was assessed using miRNA microarray and validated by mature miRNA quantitative reverse-transcription polymerase chain reaction (RT-PCR)., Results: Ten intestine region-specific miRNAs were identified. Three miRNAs were increased and one miRNA was decreased in the terminal ileum as compared to the colon. Six other miRNAs expressed varying levels of expression among the colon regions. Five miRNAs were found to be differentially expressed in tissues of patients with active colonic CD, with three increased and two decreased as compared to normal, healthy controls. Similarly, four miRNAs were found to be significantly increased in tissues of patients with active ileal CD., Conclusions: The expression differences between ileal CD, colonic CD, and previously identified UC-associated miRNAs support the likelihood that miRNAs influence differing inflammation-related gene expression in each inflammatory bowel disease (IBD) subtype and may form the basis for future diagnostic tests and therapeutic targets for IBD.

Background & Aims: Lymphocytic enterocolitis is a malabsorptive syndrome characterized by severe small-bowel villous abnormality and crypt hyperplasia and dense infiltrate of lymphocytes throughout the gastrointestinal tract., Methods: We present 2 patients with lymphocytic enterocolitis refractory to usual medical therapy who were treated with tumor necrosis factor antagonists., Results: Both patients had clinical improvement in diarrheal symptoms and intestinal histologic abnormalities., Conclusions: Tumor necrosis factor-alpha antagonists such as infliximab or adalimumab may be a new treatment option for patients with severe refractory lymphocytic enterocolitis not responding to corticosteroids., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: NOD2 mutations and anti-Saccharomyces cerevisiae antibodies (ASCAs) are established risk factors of Crohn's disease (CD) in whites but have not been assessed in African-American (AA) adults with CD., Methods: AAs with CD and controls were recruited by the Mid-Atlantic African-American IBD Study as part of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) IBD Genetics Consortium. Genotyping for the three common CD NOD2 mutations (Leu1007fsinsC, G908R/2722g>c, and R702W/2104c>t) and ASCA enzyme-linked immunosorbent assays were performed in 183 AA CD patients and in 143 controls. Logistic regression was used to calculate adjusted odds ratios (ORs) for the association between ASCA and disease phenotype., Results: ASCA sensitivity and specificity values were 70.5 and 70.4%, respectively. On univariate analysis, ASCA was significantly associated with younger age at diagnosis, ileal involvement, and complicated (stricturing/penetrating) behavior. On multivariate analysis, ASCA titer (per 25 Units) was associated with ileal involvement (OR 1.18, 95% confidence interval (CI): 1.04-1.34), complicated behavior (OR 1.13, 95% CI: 1.01-1.28), and surgery (hazard ratio: 1.11, 95% CI: 1.02-1.21). Cigarette smoking and CD family history were also significantly associated with surgery. NOD2 carriers (all heterozygotes) were more common among CD cases than controls (8.2 vs. 2.1%; OR 4.17%, 95% CI: 1.18-14.69). The NOD2 mutation population attributable risk was 6.2%., Conclusions: In comparison with whites, ASCA in AAs has a similar sensitivity but a lower specificity for CD. ASCA is associated with ileal involvement, complicated behavior, and surgery in AAs with CD. NOD2 is a risk gene for AA CD, although mutation frequency and population attributable risk are much lower than in whites.

Unlabelled: We preoperatively determined the accuracy of (18)F-FDG PET/CT for differentiating fixed muscle hypertrophy and fibrotic stenoses from acute transmural inflammatory stenoses in patients with Crohn's disease (CD) scheduled to undergo surgical resection for obstructive symptoms., Methods: Seventeen patients with known CD prospectively underwent (18)F-FDG PET/CT before already-planned surgery for obstructive symptoms. Image interpretation was by consensus of 2 readers with knowledge of patient participation in the study but not of other clinical history. Lesions were qualitatively graded on a 5-point scale for the presence of increased (18)F-FDG uptake consistent with active inflammation. Maximum lean standardized uptake value (SUL(max)) was determined for lesions scored 1 or more. Imaging results were compared with the pathologic grading of inflammation and predominant histopathologic subtype for each patient's surgical specimen, whether mainly inflammation, fibrosis, or muscle hypertrophy., Results: Thirteen of the 17 patients underwent surgery (median, 28 d after PET/CT; range, 2-148 d), and 12 of these 13 had histopathologic correlation. Despite the predominant histopathologic subtype (inflammation, 5; fibrosis, 4; and muscle hypertrophy, 3), acute and chronic inflammation, fibrosis (median, 50%; range, 40%-90%), and muscle hypertrophy (median, 20-fold thickening; range, 9- to 40-fold thickening) were found in all patients. SUL(max) was significantly higher in severe than in mild-to-moderate chronic inflammation (8.2 +/- 2.8 vs. 4.7 +/- 2.5, P = 0.04). No patient with predominantly fibrosis or muscle hypertrophy (n = 7) had an SUL(max) greater than 8. Visually, 10 of 12 patients on PET/CT were considered to have active inflammation of the bowel., Conclusion: Patients with CD who undergo surgery for obstructive symptoms have histopathologically mixed findings of inflammation, fibrosis, and muscle hypertrophy. Qualitative PET interpretations were quite sensitive, but additional semiquantitative analyses using SUL(max) helped identify patients with active inflammation. This information may be beneficial for referring gastroenterologists considering medical therapy versus surgery for patients with CD who present with obstructive symptoms.

Specific antimicrobial antibodies present in the sera of patients with inflammatory bowel disease (IBD) have been proven to be valuable serological biomarkers for diagnosis/prognosis of the disease. Herein we describe the use of a whole Escherichia coli proteome microarray as a novel high throughput proteomics approach to screen and identify new serological biomarkers for IBD. Each protein array, which contains 4,256 E. coli K12 proteins, was screened using individual serum from healthy controls (n = 39) and clinically well characterized patients with IBD (66 Crohn disease (CD) and 29 ulcerative colitis (UC)). Proteins that could be recognized by serum antibodies were visualized and quantified using Cy3-labeled goat anti-human antibodies. Surprisingly significance analysis of microarrays identified a total of 417 E. coli proteins that were differentially recognized by serum antibodies between healthy controls and CD or UC. Among those, 169 proteins were identified as highly immunogenic in healthy controls, 186 proteins were identified as highly immunogenic in CD, and only 19 were identified as highly immunogenic in UC. Using a supervised learning algorithm (k-top scoring pairs), we identified two sets of serum antibodies that were novel biomarkers for specifically distinguishing CD from healthy controls (accuracy, 86 +/- 4%; p < 0.01) and CD from UC (accuracy, 80 +/- 2%; p < 0.01), respectively. The Set 1 antibodies recognized three pairs of E. coli proteins: Era versus YbaN, YhgN versus FocA, and GabT versus YcdG, and the Set 2 antibodies recognized YidX versus FrvX. The specificity and sensitivity of Set 1 antibodies were 81 +/- 5 and 89 +/- 3%, respectively, whereas those of Set 2 antibodies were 84 +/- 1 and 70 +/- 6%, respectively. Serum antibodies identified for distinguishing healthy controls versus UC were only marginal because their accuracy, specificity, and sensitivity were 66 +/- 5, 69 +/- 5, and 61 +/- 7%, respectively (p < 0.04). Taken together, we identified novel sets of serological biomarkers for diagnosis of CD versus healthy control and CD versus UC.

Background: Adherence plays an important role in the therapeutic effectiveness of medical therapy in inflammatory bowel disease (IBD). We assessed whether trust-in-physician and Black race were predictors of adherence., Methods: We performed a cross-sectional study of Black (n = 120) and White (n = 115) IBD patients recruited from an outpatient IBD clinic. Self-reported adherence to taking medication and keeping appointments, trust-in-physician, and health-related quality of life were measured using the validated instruments, the modified Hill-Bone Compliance Scale (HBCS), the Trust-in-Physician Scale (TIPS), and the Short IBD Questionnaire (SIBDQ), respectively., Results: Overall adherence was 65%. Higher adherence correlated with greater trust-in-physician (r = -0.30; P < 0.0001), increasing age (r = -0.19; P = 0.01), and worsening health-related quality of life (r = -0.18; P = 0.01). Adherence was also higher among White IBD patients compared to Blacks (HBSC: 15.6 versus 14.0, P < 0.0001). Trust-in-physician, race, and age remained predictors of adherence to medical management after adjustment for employment, income, health insurance, marital and socioeconomic status, and immunomodulator therapy. The adjusted odds ratio for adherence in Blacks compared to Whites was 0.29 (95% confidence interval: 0.13-0.64). Every half standard deviation increase in trust-in-physician and every incremental decade in age were associated with 36% and 47% higher likelihood of adherence, respectively., Conclusions: Trust-in-physician is a potentially modifiable predictor of adherence to IBD medical therapy. Black IBD patients exhibited lower adherence compared to their White counterparts. Understanding the mechanisms of these racial differences may lead to better optimization of therapeutic effectiveness.

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29).

Background & Aims: Chronic inflammatory bowel diseases such as ulcerative colitis (UC) are associated with differential expression of genes involved in inflammation and tissue remodeling. MicroRNAs (miRNAs), which direct mRNA degradation and translational inhibition, influence a number of disease processes. We examined whether miRNAs are differentially expressed in UC tissues and are associated with expression of genes that regulate inflammation., Methods: miRNA expression was assessed in patients with active UC, inactive UC, Crohn's disease, irritable bowel syndrome, infectious colitis, and microscopic colitis, as well as in healthy subjects by microarray, quantitative reverse transcription-polymerase chain reaction and in situ hybridization analyses. Colonic epithelial cell (HT29) expression of miRNAs was assessed. Regulation of gene expression by miRNAs was assessed by luciferase reporter construct assays and transfection of specific miRNA mimics., Results: Active UC was associated with the differential expression of 11 miRNAs; 3 were significantly decreased and 8 were significantly increased in UC tissues. In situ hybridization analysis indicated that miR-192, an miRNA with decreased expression in active UC, was predominantly localized to colonic epithelial cells. Macrophage inflammatory peptide (MIP)-2 alpha, a chemokine expressed by epithelial cells, was identified as a target of miR-192. In colon epithelial cells, induction of MIP-2 alpha expression by tumor necrosis factor-alpha was accompanied by a concomitant reduction in miR-192 expression and miR-192 was observed to regulate the expression of MIP-2 alpha., Conclusions: These findings expand the known roles of miRNAs, indicating that tissues from patients with UC, and possibly other chronic inflammatory diseases, have altered miRNA expression patterns. These findings also demonstrate that miRNAs regulate colonic epithelial cell-derived chemokine expression.

Our objective was to determine whether there are dominating racial differences in patient preferences for surgery that may explain the disparities in proctocolectomy utilization between African Americans (AA) and whites. We used the time trade-off technique to measure health preferences for undergoing ileal pouch anal anastomosis (IPAA) and ileostomy among a community sample of 23 white and 16 AA participants who were unaffected by colorectal disease. Our results show that African Americans were similar to whites with respect to baseline quality of life and comorbidities. There were no differences in health utility ratings for IPAA between AA and whites (0.49 +/- 0.34 vs 0.51 +/- 0.31, P = 0.95). The health preference for ileostomy among AA (0.52 +/- 0.32) was also similar to that in whites (0.54 +/- 0.32). We conclude that patient preferences for proctocolectomy are unlikely to be a dominant contributing factor to racial disparities in total proctocolectomy for diseases of the colon.

Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score=3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score=3.5) and 3q29 (peak LOD score=3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score=2.57) and Jewish UC on chromosome 2q24 (peak LOD score=2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score=4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score=2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.

Background: Racial disparities in utilization of major surgical procedures have been well documented in the United States over the last decade. Crohn's disease (CD) is a chronically relapsing disorder that leads to significant morbidity and, in most cases, surgery. Our objective was to characterize health disparities in CD-related bowel resection among hospitalized CD patients., Methods: We analyzed discharge records from the Nationwide Inpatient Sample, the largest nationally representative database of acute-care hospitals throughout the United States. A total of 41,918 discharges with CD from 1998 to 2003 were included. Bowel resection and in-hospital mortality rates for non-Hispanic whites, African Americans, Hispanics, and non-Hispanic Asians were calculated., Results: After adjusting for age, sex, health insurance, comorbidity, median neighborhood income, and hospital characteristics, the relative rate ratio of undergoing bowel resection for African Americans, Hispanics, and Asians compared to whites was 0.68 (95% confidence interval [CI]: 0.61-0.76), 0.70 (95% CI: 0.60-0.83), and 0.31 (95% CI: 0.16-0.59), respectively. Compared to those with private insurance, the relative risk of surgery for those with Medicare, those with Medicaid, and those who were "self-pay" was 0.48 (95% CI: 0.44-0.54), 0.52 (95% CI: 0.46-0.59), and 0.67 (95% CI: 0.58-0.77), respectively. Women were less likely than men to undergo bowel resection (incidence rate ratio [IRR] = 0.80; 95% CI: 0.76-0.85). The in-hospital mortality of individuals who resided in neighborhoods whose median income was above the national median was lower (IRR = 0.71; 95% CI: 0.50-0.99)., Conclusions: Bowel resection among hospitalized CD patients varies by race, health insurance, and sex. Further mechanistic studies are needed to elucidate the social and biological underpinnings of these variations.

Background: Ulcerative colitis (UC) and Crohn's disease (CD) are inflammatory bowel diseases (IBD) with variable, overlapping clinical features and complex pathophysiologies., Methods: To identify pathogenic processes underlying these disease subtypes, we used single endoscopic pinch biopsies to elucidate patterns of gene expression in active and inactive areas of UC and CD and compared these to infectious colitis and healthy control samples., Results: Unsupervised classification of a total of 36 samples yielded promising separation between the affected IBD, unaffected IBD, non-IBD colitis, and normal control samples, suggesting each sample type had a distinctive gene expression pattern. Genes differentially expressed in the CD samples compared to in the controls were related to IFNgamma-inducible TH1 processes (IFITM1, IFITM3, STAT1, and STAT3) and antigen presentation (TAP1, PSME2, PSMB8). The most noticeable change in the UC samples was reduced expression of genes regulating biosynthesis, metabolism, and electrolyte transport (HNF4G, KLF5, AQP8, ATP2B1, and SLC16A). Twenty-five percent of genes down-regulated in the UC samples were also down-regulated in the infectious colitis samples. Unaffected biopsy samples of IBD patients also registered differences expression of genes compared to in the normal controls. Of these differentially expressed genes, only 2 were up-regulated, PSKH1, a regulator of mRNA processing, and PPID, a suppressor of apoptosis., Conclusions: The study shows that the gene expression patterns of IBD, CD in particular, are quite different from those of infectious colitis, highlighting distinctive expression of genes and pathways in UC and CD.

Background: Both antibodies to Saccharomyces cerevisiae (ASCA) and carriage of two mutated NOD2/CARD15 alleles are associated with ileal Crohn's disease (CD) and complications requiring bowel surgery. We assessed the ASCA titer as a marker of CD clinical behavior., Methods: In a cross-sectional study, we phenotyped 117 unrelated CD patients. Titers (Units, U) of ASCA IgG and IgA were measured and patients were genotyped for three high-risk NOD2/CARD15 alleles. Multiple logistic regression and Cox regression analyses were used to assess the association of factors to CD phenotype and time to surgery., Results: ASCA seropositivity was associated with younger age at diagnosis, ileal disease, and complicated (stricturing or penetrating) behavior. There was a dose-response between the number of mutant NOD2/CARD15 alleles and the prevalence and titers of ASCA. The ASCA titer and tobacco use were associated with ileal disease independently of NOD2/CARD15 status. The ASCA titer (odds ratio (OR): 2.7 per 25 U, 95% confidence interval (CI): 1.5-46.7) and ileal disease were associated with stricturing/penetrating behavior, independently of NOD2/CARD15 status. Patients with ileal CD and ASCA titers of 41 U and 60 U needed 10 and 5 years of disease, respectively, to accumulate a 50% risk of complications., Conclusions: ASCA+ patients had a greater frequency of mutant NOD2/CARD15 alleles. Nonetheless, higher ASCA titers were associated with higher probabilities of ileal CD and stricturing/penetrating behavior independently of NOD2/CARD15 status. Higher ASCA titers were associated with more rapid development of complications. This quantitative marker may prove useful in risk-stratifying patients to more aggressive antiinflammatory therapies.

Background & Aims: Ulcerative colitis is a debilitating disease for which colectomy is curative. Racial disparities have been described for a wide spectrum of surgical procedures. The goal of this study was to characterize racial and geographic differences in colectomy rates among hospitalized ulcerative colitis (UC) patients., Methods: We analyzed discharge records from the Nationwide Inpatient Sample, the largest representative sample of acute care hospitals throughout the United States. A total of 23,389 discharges with UC from 1998-2003 were included for analysis. Colectomy rates, in-hospital mortality, and length of stay were calculated for non-Hispanic whites, African Americans, and Hispanics., Results: After adjustment for age, gender, health insurance, comorbidity, and hospital characteristics, the colectomy rate ratios for African Americans and Hispanics compared with whites were 0.46 (95% confidence interval, 0.35-0.60) and 0.74 (95% confidence interval, 0.59-0.93), respectively. African Americans experienced a longer interval between admission and colectomy than whites (8.8 vs 5.6 days, P=.02). There were also significant geographic variations in colectomy, with the West and Midwest regions yielding rates 3-fold higher than the Northeast. Although adjusted in-hospital mortality did not differ by race, Medicaid patients had 3.3-fold higher mortality than those with private insurance. Between 1998 and 2003, the colectomy rate decreased among whites but not African Americans and Hispanics. A temporal narrowing of geographic variation in colectomy was also observed., Conclusions: The rate of colectomy among hospitalized UC patients varies significantly by race and geographic location. Further studies are needed to elucidate the social and biologic underpinnings of these variations.

Basal Cell Nevus Syndrome (BCNS) is an autosomal dominant disease. PTCH1 gene mutations have been found responsible in many but not all pedigrees. Inflammatory Bowel Disease (IBD) is a complex genetic disorder, disproportionate in Ashkenazim, and characterized by chronic intestinal inflammation. We revisited a large Ashkenazim pedigree, first reported in 1968, with multiple diagnoses of BCNS and IBD, and with a common genetic cause for both disorders proposed. We expanded the pedigree to four generations and performed a genome-wide linkage study for BCNS and IBD traits. Twelve members with BCNS, seven with IBD, five with both diagnoses and eight unaffected were genotyped. Both non-parametric (GENEHUNTER 2.1) and parametric (FASTLINK) linkage analyses were performed and a validation through simulation was performed. BCNS linked to chromosome 9q22 (D9S1120) just proximal to the PTCH1 gene (NPL=3.26, P=0.003; parametric two-point LOD=2.4, parametric multipoint LOD=3.7). Novel IBD linkage evidence was observed at chromosome 1p13 (D1S420, NPL 3.92, P=0.0047; parametric two-point LOD=1.9). Linkage evidence was also observed to previously reported IBD loci on 4q, (D4S2623, NPL 3.02, P=0.012; parametric two-point LOD=2.15), 10q23 (D10S1225 near DLG5, NPL 3.33, P=0.0085; parametric two-point LOD=1.3), 12 overlapping the IBD2 locus (D12S313, NPL 2.6, P=0.018; parametric two-point LOD=1.52), and 7q (D7S510 and D7S3046, NPL 4.06, P=0.0035; parametric two-point LOD=2.18). In this pedigree affected by both BCNS and IBD, the two traits and their respective candidate genetic loci segregate independently; BCNS maps to the PTCH1 gene and IBD maps to several candidate regions, mostly overlapping previously observed IBD loci.

Objectives: The complete elucidation of genetic variants that contribute to inflammatory bowel disease (IBD) will likely include variants that increase risk to both Crohn's disease and ulcerative colitis as well as variants that increase risk for particular phenotypic subsets. The purpose of this study was to assess phenotypic subsets that contribute to the major IBD susceptibility loci., Methods: This linkage study encompassed 904 affected relative pairs, representing the largest combined phenotyped cohort to date, and allowing for meaningful subset analyses. Genetic linkage data were stratified by disease location and age at diagnosis., Results: We establish that some loci, notably the IBD3 and chromosome 3q linkage regions demonstrate contributions from both small intestine and colon cohorts, whereas others, notably the IBD1 (NOD2/CARD15) and IBD2 regions increase risk for small intestine or colon inflammation, respectively. The strongest linkage evidence in this study was for the subset of extensive ulcerative colitis in the region of IBD2 (lod 3.27; p < 0.001). Evidence for linkage in the region of NOD2/CARD15 (IBD1) was stronger for the subset of Crohn's patients with ileal disease (lod 2.56; p= 0.035) compared to the overall Crohn's group, consistent with previous findings that NOD2/CARD15 variants are associated with ileal disease., Conclusions: Analyses incorporating disease location in IBD increase the power and enhance the accuracy of genomic localization. Our data provide strong evidence that extensive ulcerative colitis represents a pathophysiologic subset of IBD.