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Aberrant activation of the Hedgehog (Hh) signaling pathway, through which the GLI family of transcription factors (TF) is stimulated, is commonly observed in cancer cells. One well-established mechanism of this increased activity is through the inactivation of Suppressor of Fused (SUFU), a negative regulator of the Hh pathway. Relief from negative regulation by SUFU facilitates GLI activity and induction of target gene expression. Here, we demonstrate a novel role for SUFU as a promoter of GLI activity in pancreatic ductal adenocarcinoma (PDAC). In non-ciliated PDAC cells unresponsive to Smoothened agonism, SUFU overexpression increases GLI transcriptional activity. Conversely, knockdown (KD) of SUFU reduces the activity of GLI in PDAC cells. Through array PCR analysis of GLI target genes, we identified B-cell lymphoma 2 (BCL2) among the top candidates down-regulated by SUFU KD. We demonstrate that SUFU KD results in reduced PDAC cell viability, and overexpression of BCL2 partially rescues the effect of reduced cell viability by SUFU KD. Further analysis using as a model GLI1, a major TF activator of the GLI family in PDAC cells, shows the interaction of SUFU and GLI1 in the nucleus through previously characterized domains. Chromatin immunoprecipitation (ChIP) assay shows the binding of both SUFU and GLI1 at the promoter of BCL2 in PDAC cells. Finally, we demonstrate that SUFU promotes GLI1 activity without affecting its protein stability. Through our findings, we propose a novel role of SUFU as a positive regulator of GLI1 in PDAC, adding a new mechanism of Hh/GLI signaling pathway regulation in cancer cells., (© 2023 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Upon accumulation of improperly folded proteins in the Endoplasmic Reticulum (ER), the Unfolded Protein Response (UPR) is triggered to restore ER homeostasis. The induction of stress genes is a sine qua non condition for effective adaptive UPR. Although this requirement has been extensively described, the mechanisms underlying this process remain in part uncharacterized. Here, we show that p97/VCP, an AAA+ ATPase known to contribute to ER stress-induced gene expression, regulates the transcription factor GLI1, a primary effector of Hedgehog (Hh) signaling. Under basal (non-ER stress) conditions, GLI1 is repressed by a p97/VCP-HDAC1 complex while upon ER stress GLI1 is induced through a mechanism requiring both USF2 binding and increase histone acetylation at its promoter. Interestingly, the induction of GLI1 was independent of ligand-regulated Hh signaling. Further analysis showed that GLI1 cooperates with ATF6f to induce promoter activity and expression of XBP1, a key transcription factor driving UPR. Overall, our work demonstrates a novel role for GLI1 in the regulation of ER stress gene expression and defines the interplay between p97/VCP, HDAC1 and USF2 as essential players in this process., Competing Interests: Declaration of competing interest EC is a founding member of Thabor Tx (https://www.thabor-tx.com/). The other authors declare that they have no competing interests with the contents of this article., (Copyright © 2023. Published by Elsevier B.V.)

Many patients experiencing acute gastrointestinal bleeding (GIB) require iron supplementation to treat subsequent iron deficiency (ID) or iron-deficiency anemia (IDA). Guidelines regarding management of these patients are lacking. We aimed to identify areas of unmet need in patients with ID/IDA following acute GIB in terms of patient management and physician guidance. We formed an international working group of gastroenterologists to conduct a narrative review based on PubMed and EMBASE database searches (from January 2000 to February 2021), integrated with observations from our own clinical experience. Published data on this subject are limited and disparate, and those relating to post-discharge outcomes, such as persistent anemia and re-hospitalization, are particularly lacking. Often, there is no post-discharge follow-up of these patients by a gastroenterologist. Acute GIB-related ID/IDA, however, is a prevalent condition both at the time of hospital admission and at hospital discharge and is likely underdiagnosed and undertreated. Despite limited data, there appears to be notable variation in the prescribing of intravenous (IV)/oral iron regimens. There is also some evidence suggesting that, compared with oral iron, IV iron may restore iron levels faster following acute GIB, have a better tolerability profile, and be more beneficial in terms of quality of life. Gaps in patient care exist in the management of acute GIB-related ID/IDA, yet further data from large population-based studies are needed to confirm this. We advocate the formulation of evidence-based guidance on the use of iron therapies in these patients, aiding a more standardized best-practice approach to patient care., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

BACKGROUNDA patient-derived organoid (PDO) platform may serve as a promising tool for translational cancer research. In this study, we evaluated PDO's ability to predict clinical response to gastrointestinal (GI) cancers.METHODSWe generated PDOs from primary and metastatic lesions of patients with GI cancers, including pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma. We compared PDO response with the observed clinical response for donor patients to the same treatments.RESULTSWe report an approximately 80% concordance rate between PDO and donor tumor response. Importantly, we found a profound influence of culture media on PDO phenotype, where we showed a significant difference in response to standard-of-care chemotherapies, distinct morphologies, and transcriptomes between media within the same PDO cultures.CONCLUSIONWhile we demonstrate a high concordance rate between donor tumor and PDO, these studies also showed the important role of culture media when using PDOs to inform treatment selection and predict response across a spectrum of GI cancers.TRIAL REGISTRATIONNot applicable.FUNDINGThe Joan F. & Richard A. Abdoo Family Fund in Colorectal Cancer Research, GI Cancer program of the Mayo Clinic Cancer Center, Mayo Clinic SPORE in Pancreatic Cancer, Center of Individualized Medicine (Mayo Clinic), Department of Laboratory Medicine and Pathology (Mayo Clinic), Incyte Pharmaceuticals and Mayo Clinic Hepatobiliary SPORE, University of Minnesota-Mayo Clinic Partnership, and the Early Therapeutic program (Department of Oncology, Mayo Clinic).

Background: Periodontal diseases and inflammatory bowel diseases (IBD, ulcerative colitis [UC] and Crohn disease [CD]) have been reported to present with increased salivary and gingival crevicular fluid (GCF) concentrations of cytokines. The aim of this study was to evaluate the salivary and GCF levels of TNF-α, IL-1β, IL-10, and IL-17A and their associations with the periodontal statuses of UC, CD, and non-IBD patients, and to analyze the interrelationships among these cytokines, IBD conditions, and periodontal diseases., Methods: This cross-sectional study was performed with a total of 131 patients (62 women and 69 men, mean age 42.96±13.02 years). Patients were divided into three groups: UC, CD, and non-IBD. Periodontal status was defined according to the 2017 World Workshop Disease Classification. Salivary and GCF cytokine levels were analyzed using ELISA., Results: UC and CD patients diagnosed as having periodontitis and gingivitis presented with significantly higher levels of TNF-α and lower levels of IL-10 as compared with non-IBD patients (p<0.05). UC patients diagnosed with periodontitis exhibited significantly higher scores of bleeding on probing (p = 0.011) and increased salivary and GCF IL-1β levels as compared with CD patients (p = 0.005, and 0.012, respectively). Considering the active and remission status of IBD, salivary IL-1β was found to be correlated with the parameters representing the severity of periodontal diseases in active UC and CD patients., Conclusion: In the presence of periodontal diseases, UC and CD patients showed different expression levels of TNF-α, IL-1β, and IL-10 in oral secretions as compared with non-IBD patients., (© 2022 American Academy of Periodontology.)

Irritable bowel syndrome with diarrhoea (IBS-D) and functional diarrhoea (FDr) are the two major functional bowel disorders characterized by diarrhoea. In spite of their high prevalence, IBS-D and FDr are associated with major uncertainties, especially regarding their optimal diagnostic work-up and management. A Delphi consensus was performed with experts from 10 European countries who conducted a literature summary and voting process on 31 statements. Quality of evidence was evaluated using the grading of recommendations, assessment, development, and evaluation criteria. Consensus (defined as >80% agreement) was reached for all the statements. The panel agreed with the potential overlapping of IBS-D and FDr. In terms of diagnosis, the consensus supports a symptom-based approach also with the exclusion of alarm symptoms, recommending the evaluation of full blood count, C-reactive protein, serology for coeliac disease, and faecal calprotectin, and consideration of diagnosing bile acid diarrhoea. Colonoscopy with random biopsies in both the right and left colon is recommended in patients older than 50 years and in presence of alarm features. Regarding treatment, a strong consensus was achieved for the use of a diet low fermentable oligo-, di-, monosaccharides and polyols, gut-directed psychological therapies, rifaximin, loperamide, and eluxadoline. A weak or conditional recommendation was achieved for antispasmodics, probiotics, tryciclic antidepressants, bile acid sequestrants, 5-hydroxytryptamine-3 antagonists (i.e. alosetron, ondansetron, or ramosetron). A multinational group of European experts summarized the current state of consensus on the definition, diagnosis, and management of IBS-D and FDr., (© 2022 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: Patients with Crohn's disease experience major deterioration in work productivity and quality of life. We aimed to provide the long-term effects of anti-tumor necrosis factor agents on work productivity and activity impairment and quality of life in patients with Crohn's disease using the Inflammatory Bowel Disease Questionnaire and the Short-Form Health Survey-36., Methods: Patients with Crohn's disease and initiated an anti-tumor necrosis factor treatment were included and followed up for 12 months in this observational study., Results: A total of 106 patients were included in this study, and 64.2% of the patients were males. Mean [± standard deviation] age was 36.8 [± 10.9] years. At baseline, mostly perianal fistulas [65.7%] were observed [n = 23]. Intestinal stenosis was detected in 34.9% of the patients [n = 37], and most of the stenosis was located in the ileum [70.6%] followed by the colon [20.6%]. Extraintestinal symp- toms were observed in 24 patients [22.6%]. Most frequent extraintestinal symptom was arthritis with 71.4% [n = 15]. Mean time from first symptom to initiation of anti-tumor necrosis factor treatment was 6.3 [± 5.0] years. Improvements in work productivity and activ- ity impairment scores throughout 12 months were -24.1% [P = .003] for work time missed, -18.0% [P = .006] for impairment at work, -8.5% [P = .160] for overall work impairment, and -17.0% [P < .001] for daily activity impairment. Similarly, significant improvements [P < .001] were detected in all components of the Inflammatory Bowel Disease Questionnaire when compared to baseline. Statistically sig- nificant improvements [P < .05] were detected for all components of Short-Form Health Survey-36 except for mental health [P = .095]., Conclusion: Our study indicates the significant improvement in work productivity and activity impairment and quality of life of patients with Crohn's disease who receive long-term anti-tumor necrosis factor treatment.

Objective: The etiopathogenesis of spondyloarthropathies (SpA) is still unclear. Recently, anti-CD74 antibody has been suspected to play a role in SpA etiopathogenesis. This study aimed to examine the levels of anti-CD74 antibody in patients with SpA and investigate their association with disease activity., Methods: This study was conducted using data from patients who were treated at the departments of rheumatology and gastroenterology between June 2013 and November 2013. The demographic and clinical characteristics of the participants and their serum IgG-type antibodies against anti-CD74 were analyzed., Results: We analyzed 111 patients with ankylosing spondylitis (AS), 108 patients with inflammatory bowel disease (IBD), and 101 healthy controls. The rate of human leukocyte antigen-B27 positivity was 86.5% in patients with AS and 21.3% in patients with IBD. The mean levels of anti-CD74 antibodies in the AS, IBD, and control groups were 6.99±3.24 ng/mL, 6.25±3.34 ng/mL, and 7.83±4.72 ng/mL, respectively. Anti-CD74 levels were higher in healthy controls than in patients with IBD (p=0.009). There was no significant difference in anti-CD74 levels between the AS and IBD groups and the AS and control groups. In addition, there was no correlation between anti-CD74 levels and disease activity., Conclusion: This study could not find an association between anti-CD74 levels and SpA in Turkish patients.

Background and Goals: The aims of the present study were to investigate the natural history of cirrhosis and to determine trends in the etiology of cirrhosis., Methods: Between January 2001 and January 2018, a total of 1,341 patients had been diagnosed with cirrhosis and were included., Results: A total of 898 cirrhotic patients, who were followed up for at least 6 months were included into the analysis. The median age was 54 years. The median Child-Pugh and MELD scores were 7.5 and 11, respectively. Ascites (51%) was the most common causes of decompensation. Chronic viral hepatitis was the most frequent cause of cirrhosis (58%). Hepatitis B virus (HBV) infection was the main etiology (34%), followed by hepatitis C virus (HCV) infection (18%). Among 129 patients with cryptogenic cirrhosis (CC), 60 had metabolic abnormalities. If these 60 patients with CC were considered to have nonalcoholic fatty liver disease (NAFLD)-related cirrhosis, the proportion of NAFLD-related cirrhosis increased from 1.8 to 8.0%. At admission, 74 patients (8%) had been diagnosed with hepatocellular carcinoma (HCC). A new HCC developed in 80 patients during the follow-up period. The probability of developing HCC was 3.9% at 12 months. Logistic regression analysis showed that the development of HCC was significantly associated with older age (p < 0.001), male gender (p < 0.001), viral etiology (p = 0.026), and baseline high aspartate aminotransferase level (p = 0.01). Overall, 104 cirrhotic patients died., Conclusion: HBV and HCV remain the leading causes of etiology in cirrhosis and HCC. However, NAFLD-related cirrhosis is recognized as a growing burden., (© 2020 S. Karger AG, Basel.)

Pancreatic cancer remains among the deadliest forms of cancer with a 5 year survival rate less than 10%. With increasing numbers being observed, there is an urgent need to elucidate the pathogenesis of pancreatic cancer. While both contribute to disease progression, neither genetic nor environmental factors completely explain susceptibility or pathogenesis. Defining the links between genetic and environmental events represents an opportunity to understand the pathogenesis of pancreatic cancer. Epigenetics, the study of mitotically heritable changes in genome function without a change in nucleotide sequence, is an emerging field of research in pancreatic cancer. The main epigenetic mechanisms include DNA methylation, histone modifications and RNA interference, all of which are altered by changes to the environment. Epigenetic mechanisms are being investigated to clarify the underlying pathogenesis of pancreatic cancer including an increasing number of studies examining the role as possible diagnostic and prognostic biomarkers. These mechanisms also provide targets for promising new therapeutic approaches for this devastating malignancy., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

Background: Incidence of inflammatory bowel disease (IBD) is increasing in newly industrialised countries (NICs); however, data on suboptimal response to anti-tumor necrosis factor (anti-TNF) agents are limited., Objectives: To assess incidence and indicators of suboptimal response to first anti-TNF therapy in IBD patients in NICs., Methods: A chart review was conducted in ten countries from Asia-Pacific (APAC), Latin America (LatAm), and Russia and the Middle East (RME) regions among patients diagnosed with ulcerative colitis (UC) or Crohn's disease (CD), initiating anti-TNF therapy in 2010-2015. The cumulative incidence of suboptimal response to anti-TNF therapy was assessed using the following indicators: dose escalation or discontinuation, augmentation with non-biologic therapy, IBD-related hospitalization, or surgery., Results: The study included 1,674 patients (570 UC; 1,104 CD). At 24 months, 32.9% of UC (APAC: 45.1%; LatAm: 38.2%; RME: 23.8%) and 41.2% of CD patients (APAC: 54.1%; LatAm: 42.5%; RME: 29.5%) had experienced suboptimal response. The most frequent first indicator was non-biologic therapy augmentation in LatAm (41.7%), IBD-related hospitalization in RME (UC: 50.7%; CD:37.3%) and in APAC for CD (39.1%), and anti-TNF discontinuation in APAC for UC (38.3%)., Conclusion: Suboptimal response to anti-TNF agents is common in IBD patients in NICs. Observed regional differences in the incidence and indicators may reflect local practice and anti-TNF restrictions in IBD management., Nct Registration Number: NCT03090139., Competing Interests: Declaration of Competing Interests Qasim M Rana Khan, Olga Fadeeva and Dirk Demuth are employees of Takeda Pharmaceuticals Company Ltd. Morgane Guennec and Cecilia Sison are employees of IQVIA, which was funded by Takeda Pharmaceuticals Company Ltd to conduct this study. Jesús K. Yamamoto-Furusho is an advisory committee/board member for Takeda Pharmaceuticals Company Ltd; has received honoraria from AbbVie, Takeda, Janssen, Farmasa, Ferring, Alfasigma, Hospira, UCB, Danone, Almirall and Pfizer as a speaker, key opinion leader, and member of national and international advisory boards; has received research funds from Bristol, Shire, Pfizer and Takeda and former President of the Pan American Crohn's and Colitis organisation (PANCCO). Othman Al Harbi is a consultant or advisory committee/board member for AbbVie, Janssen, Pfizer and Takeda Pharmaceuticals Company Ltd. Alessandro Armuzzi is a consultant or advisory/board member for AbbVie, Allergan, Amgen, Biogen, Celgene, Celltrion, Ferring, Hospira, Janssen, Lilly, MSD, Mundipharma, Mylan, Pfizer, Roche, Samsung Bioepis, Sofar, and Takeda Pharmaceuticals Company Ltd; has received lecture fees from AbbVie, Amgen, AstraZeneca, Chiesi, Ferring, Hospira, Janssen, Medtronic, MSD, Mitsubishi Tanabe, Mundipharma, Nikkiso, Otsuka, Pfizer, Samsung Bioepis, Takeda, Tigenix, and Zambon; and research funding from MSD, Pfizer and Takeda. Webber Chan indicated no relevant financial relationships. Enrique Ponce de Leon is a consultant or advisory/board member for AbbVie, Janssen and Takeda Pharmaceuticals Company Ltd. Jiaming Qian is an advisory committee/board member for Takeda Pharmaceuticals Company Ltd. Marina Shapina is an advisory committee/board member for Takeda Pharmaceuticals Company Ltd. Murat Toruner is an advisory committee/board member for Takeda Pharmaceuticals Company Ltd; has received consulting fees from AbbVie Turkey, MSD Turkey, Janssen Turkey, Takeda Turkey and has received lecture fees from AbbVie Turkey, MSD Turkey, Janssen Turkey, Takeda Turkey, Ferring Turkey and UCB Turkey. Chia-Hung Tu is an advisory committee/board member for Takeda Pharmaceuticals Company Ltd. Byong Duk Ye has received a research grant from Celltrion and Pfizer Korea; is a consultant or advisory/board member for AbbVie Korea, Celltrion, Chong Kun Dang Pharm., Daewoong Pharma., Ferring Korea, Janssen Korea, Kangstem Biotech, Kuhnil Pharm., Medtronic Korea, Shire Korea, Takeda Korea, IQVIA, Cornerstones Health, Robarts Clinical Trials Inc. and Takeda; has received lecture fees from AbbVie Korea, Celltrion, Ferring Korea, Janssen Korea, Shire Korea, Takeda Korea, and IQVIA., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Epidemiological studies demonstrate an increased risk of colorectal cancer in patients with inflammatory bowel disease (IBD). A detailed literature review was conducted on epidemiology, risk factors, pathophysiology, chemoprevention and outcomes of colorectal cancer (CRC) in IBD as part of the 3rd ECCO scientific pathogenesis workshop., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

Background: Iron deficiency is a common and undertreated problem in inflammatory bowel disease (IBD)., Aim: To develop an online tool to support treatment choice at the patient-specific level., Methods: Using the RAND/UCLA Appropriateness Method (RUAM), a European expert panel assessed the appropriateness of treatment regimens for a variety of clinical scenarios in patients with non-anaemic iron deficiency (NAID) and iron deficiency anaemia (IDA). Treatment options included adjustment of IBD medication only, oral iron supplementation, high-/low-dose intravenous (IV) regimens, IV iron plus erythropoietin-stimulating agent (ESA), and blood transfusion. The panel process consisted of two individual rating rounds (1148 treatment indications; 9-point scale) and three plenary discussion meetings., Results: The panel reached agreement on 71% of treatment indications. 'No treatment' was never considered appropriate, and repeat treatment after previous failure was generally discouraged. For 98% of scenarios, at least one treatment was appropriate. Adjustment of IBD medication was deemed appropriate in all patients with active disease. Use of oral iron was mainly considered an option in NAID and mildly anaemic patients without disease activity. IV regimens were often judged appropriate, with high-dose IV iron being the preferred option in 77% of IDA scenarios. Blood transfusion and IV+ESA were indicated in exceptional cases only., Conclusions: The RUAM revealed high agreement amongst experts on the management of iron deficiency in patients with IBD. High-dose IV iron was more often considered appropriate than other options. To facilitate dissemination of the recommendations, panel outcomes were embedded in an online tool, accessible via http://ferroscope.com/., (© 2013 John Wiley & Sons Ltd.)

Background/aims: The effect of exogenous hypergastrinemia on esophageal motor function has been well documented. However, it is not known whether chronic endogenous hypergastrinemia influences esophageal motility and lower esophageal sphincter pressure. The purpose of this study was to investigate the effect of chronic hypergastrinemia on lower esophageal sphincter pressure and esophageal motility in patients with significantly elevated serum gastrin levels., Methodology: 37 patients (28 women; mean age, 53.7 years) with autoimmune gastritis and 35 functional dyspepsia patients participated in this study. Esophageal motility testing was performed by using an eight-lumen water-perfused catheter. Ten wet swallows were given and each contraction was analysed for lower esophageal sphincter pressure, lower esophageal sphincter relaxation, contraction amplitude and peak velocity., Results: Mean serum fasting gastrin level was 1382.8±731.9pg/mL in patients with autoimmune gastritis and 107±83.9pg/mL in the control group (p=0.000). Mean lower esophageal sphincter pressure (31.6±14.42mmHg vs. 20.5±8.05mmHg, p=0.000) and mean contraction amplitude (82.48±35.0mmHg vs. 58.11±21.75mmHg, p=0.001), in hypergastrinemic patients were significantly higher than in the control group., Conclusions: These results suggest that in patients with autoimmune gastritis, prolonged and significant elevation of serum gastrin levels, increases lower esophageal sphincter pressure and esophageal body contraction amplitude. However, this increase in lower esophageal sphincter pressure does not cause upper gastrointestinal symptoms in patients with autoimmune gastritis.

Background: Helicobacter pylori infection is a known risk factor for gastric cancer. The aim of the study was to determine the effect of H. pylori and age on gastric epithelial cell kinetics., Methods: One hundred and fifty-seven patients (92 men, median age: 58.5 years, range: 18-85) who had undergone upper gastrointestinal endoscopy due to dyspeptic symptoms were enrolled into the study. Six antral biopsy samples were obtained for flow cytometric DNA analysis (expressed as proliferative index [PI], S+G2/M phase), presence of H. pylori (CLO-test, culture and histology), and histopathologic examination., Results: Eighty-four (53.5%) patients were H. pylori positive and 93.3% of patients had diploid pattern and 6.7% expressed aneuploid pattern. The mean PI was 4.8 ± 0.2 for the whole group studied. PI were 5.14 ± 0.33 and 4.26 ± 0.36 for H. pylori (+) and H. pylori (-) patients respectively (P = 0.017). When age groups were taken into account, PI was found higher in patients over 75 years of age (n = 14, PI = 6.66 ± 1.3) compared to patients under 35 years of age (n = 25, PI = 3.83 ± 0.41, P = 0.014). There was no correlation between histological changes and PI. H. pylori (P = 0.045) and age (P = 0.082) were independent factors for PI., Conclusion: PI of gastric antral mucosa increases in patients with H. pylori infection. Although PI increases by age, H. pylori is the only factor that significantly and independently influences the rate of epithelial cell proliferation., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Background and Goals: The aim of this cohort study was to determine the characteristics and clinical outcome of 170 patients with drug-induced liver injury (DILI) in a single center., Study: Between January 2001 and June 2007, a total of 170 individuals who were diagnosed with DILI were retrospectively analyzed. The median follow-up period was 110.0 days., Results: During the study period, a total of 5471 new patients were assessed for liver test abnormalities. Of those, 170 patients (3.1%) fulfilled the criteria of DILI. A total of 83 different drugs were considered to be related to the hepatotoxicity; a single drug was suspected in 57.6% of individuals. The median interval between the suspicious drug intake and DILI recognition was 15.0 days. Hepatocellular pattern was observed in 50.0% of patients with a mean alanine aminotransferase level of 952.2+/-907.0 U/L. The main causative group of drugs was antibiotics. Sixty-two patients required hospitalization; acute liver failure developed in 14 (8.2%), chronicity was observed in 19 (11.2%), and 7 died (4.1%). Overall, complete recovery occurred in 82% of patients. The presence of jaundice on admission and shorter interval period between drug intake and DILI recognition were identified as risk factors for the development of acute liver failure., Conclusions: DILI is an important cause of liver test abnormalities in outpatient clinics, and antibiotics represent the most common drug group. Overall, complete recovery after the withdrawal of the suspicious drug occurred in the majority of patients, but DILI may progress to acute liver failure, chronicity, and death.

Background & Aims: We sought to identify and quantify the clinical factors that were associated with opportunistic infections in inflammatory bowel disease patients., Methods: We identified 100 consecutive IBD patients with opportunistic infections. For each case, 2 matched IBD patients who did not have a history of opportunistic infection were selected as controls. Conditional logistic regression was used to assess associations between putative risk factors and opportunistic infections, presented as odds ratios (OR) and 95% confidence intervals (CIs)., Results: In univariate analysis, use of corticosteroids (OR, 3.4; 95% CI, 1.8-6.2), azathioprine/6-mercaptopurine (OR, 3.1; 95% CI, 1.7-5.5), and infliximab (OR, 4.4; 95% CI, 1.2-17.1) were associated individually with significantly increased odds for opportunistic infection. Multivariate analysis indicated that use of any one of these drugs yielded an OR of 2.9 (95% CI, 1.5-5.3), whereas use of 2 or 3 of these drugs yielded an OR of 14.5 (95% CI, 4.9-43) for opportunistic infection. The relative risk of opportunistic infection was greatest in IBD patients seen at older than 50 years of age (OR, 3.0; 95% CI, 1.2-7.2, relative to those 24 years or younger). No patient died from opportunistic infection., Conclusions: Immunosuppressive medications, especially when used in combination, and older age are associated with increased risk of opportunistic infections. The absolute risk of opportunistic infection in IBD patients remains to be determined, as does any potential benefit of any preventive strategy.

The transcription factor, nuclear factor-kappaB (NF-kappaB), is a dominant regulator of the expression of hundreds of genes, many of which play important roles in the regulation of inflammation and programmed cell death (apoptosis). Since the discovery of NF-kappaB in the mid 1980s, this transcription factor has been the subject of intense investigation. Excess or inappropriate activation of NF-kappaB has been observed in human inflammatory bowel disease and in a host of other inflammatory diseases and type of cancer. Functional studies in animals have shed light on the role of NF-kappaB in broader pathophysiological contexts. From such studies, it has become quite clear that NF-kappaB plays unique and distinct functions in different cell types. Because of the importance of NF-kappaB in signaling inflammation, and in inhibiting programmed cell death, many pharmaceutical companies are developing small-molecule inhibitors of this pathway. In this article, we evaluate the relative pros and cons of blocking NF-kappaB as a therapeutic approach for inflammatory bowel disease. On the basis of the results of studies in animals that have primarily used genetic approaches to inhibit NF-kappaB activity, we suggest that there are certain niche indications for blocking NF-kappaB in inflammatory bowel disease that offer particular promise.

To determine the prevalence, clinical and radiological characteristics of spondyloarthropathy (SpA) in patients with inflammatory bowel disease (IBD), to assess the association between HLA B27 and B51 and the extraintestinal symptoms and to evaluate whether IBD is associated with Behçet's disease (BD). One hundred and sixty-two consecutive adult patients with established diagnosis of IBD as either Crohn's disease (CD) or ulcerative colitis (UC) were evaluated. All the patients including those previously diagnosed with or without SpA had a complete rheumatologic examination and they were evaluated according to the European Spondyloarthropathy Study Group (ESSG) criteria for SpA and The International Study Group for Behçet's disease criteria for BD. The demographic and clinical data were recorded on a standardized form. The radiographies were obtained in all the patients and computed tomography (CT) was performed in the patients with suspected pelvic radiographies and/or low back pain in the physical examination. Radiological evaluation was made according to the Modified New York criteria. HLA B27, B51 and anti-neutrophile cytoplasmic antigen (ANCA) were searched in all the patients. Of the 162 patients with IBD (mean age 41.48+/-11.63 years, male 60, female 102), 78 were CD and 84 were UC. The mean of the IBD duration was 54.92+/-50.32 months and SpA duration was 20.63+/-34.37 months. The prevalence of SpA and AS in IBD was 45.7 and 9.9%, respectively. Frequencies of SpA and AS, the difference between UC and CD were not significant. Spondylitis, enthesitis, peripheral arthritis, oral ulcer and uveitis were not different between UC and CD, but erythema nodosum was found significantly more common in the CD patients compared with UC patients (P=0.005). The duration of IBD and SpA was similar in both groups. As the IBD duration increased, the prevalence of SpA development decreased (rr=0.991, P=0.009). Of the IBD patients, 13.6% were asymptomatic for musculoskeletal manifestations of SpA and their sacroiliac radiographies and CTs showed grade 2 sacroiliitis. HLA B27, B51 and ANCA positivities were not different between the patients with UC and CD. HLA B27 was significantly more common in the patients with sacroiliitis, spondylitis, enthesitis, peripheral arthritis, erythema nodosum, uveitis (P<0.001) and oral ulcer (P=0.025). BD was diagnosed in none of the patients. ANCA positivity was found to be related with the presence of erythema nodosum and uveitis (P=0.001 and P=0.005). The prevalence of SpA and AS is higher in the prospectively evaluated patients with radiological studies than those in the previously published studies. There is a high prevalence of asymptomatic sacroiliitis in IBD. An early diagnosis of inflammatory arthritis in IBD patients may prevent a disability due to SpA and AS.

Epithelial cells undergo a form of apoptosis termed anoikis when they lose extracellular attachments. We evaluated the role of transcription factor NF-kappaB in the regulation of anoikis susceptibility of intestinal epithelial cells. Culture of rat intestinal epithelial cells in suspension induced NF-kappaB activation, which blocked the anoikis of those cells, as assessed by internucleosomal DNA fragmentation and caspase-3 cleavage. Activation of NF-kappaB after the loss of extracellular attachments required focal adhesion kinase tyrosine 397 phosphorylation. This triggered a signaling cascade through phosphatidylinositol 3-kinase and AKT, to induce DNA binding of the RelA/p65 NF-kappaB polypeptide. NF-kappaB activated in this manner induced the up-regulated expression of a distinct program of genes that included osteoprotegerin, BCL-2, and IAP-1 (inhibitor of apoptosis protein-1). Chromatin immunoprecipitation experiments revealed that NF-kappaB directly regulated the promoters of these 3 genes. Knock-down of the expression of osteoprotegerin, BCL-2, or inhibitor of apoptosis protein-1 by RNA interference showed that these factors inhibit anoikis, and genetic reconstitution of their expression alone or in combination restored normal levels of anoikis to NF-kappaB-inactive intestinal epithelial cells. Together, these findings have identified the molecular components of a previously unrecognized antianoikis pathway in intestinal epithelial cells.

Background: Surveillance colonoscopy in inflammatory bowel diseases (IBDs) is advocated for early diagnosis of neoplasia but is imperfect because some patients develop cancer despite surveillance. We sought to determine if any endoscopic factors during surveillance colonoscopy were associated with the diagnosis of colorectal dysplasia before the development of cancer., Methods: We reviewed the Mayo Clinic endoscopic database and medical records of patients with IBD who underwent surveillance colonoscopy between January 2002 and November 2003. Associations were sought between endoscopic factors and the diagnosis of dysplasia. Among 635 IBD patients, 24 (3.8%) had flat dysplasia and 12 (1.9%) had IBD-related polypoid dysplasia. In 28 patients (4.4%), sporadic tubular adenoma was identified. Colonoscopies in which flat dysplasia was identified varied in duration from 7 to 81 minutes (median, 24.5 min) compared with 3 to 70 minutes (median, 22 min) for those in which dysplasia was not found., Results: Using logistic regression analysis, we found that every additional minute in total colonoscopy time increased the flat dysplasia diagnosis rate by 3.5% (P = 0.0157). There was a significant correlation between median surveillance colonoscopy duration per endoscopist and flat dysplasia diagnosis rate (P = 0.0066). The number of biopsies taken during the procedures with flat dysplasia ranged from 6 to 36 (median, 28) compared with 2 to 54 (median, 25) in those without flat dysplasia. There was no significant effect of biopsy number of dysplasia diagnosis., Conclusions: Our results show that the practice of surveillance colonoscopy varies greatly among endoscopists, and longer procedure duration is significantly associated with the likelihood of dysplasia diagnosis.

EGF receptor (EGFR) promotes intestinal epithelial restitution, an important early process in the reepithelialization of ulcers. During epithelial restitution, the mechanism of EGFR activation is not known. We evaluated the role of TNF-converting enzyme (TACE), a metalloprotease disintegrin that proteolytically processes plasma membrane-anchored EGFR ligand precursors into their mature active forms, in wound-induced EGFR activation and epithelial restitution. With the use of scrape-wounded rat intestinal epithelial-1 (RIE-1) cell monolayers to model epithelial ulceration and restitution, we observed the rapid wound-dependent release of EGFR ligands into culture medium. RIE-1 cells express TACE, and treatment with phorbol ester, an established TACE stimulus, triggered the extracellular release of an EGFR ligand, transforming growth factor-alpha. Blockade of TACE using TNF processing inhibitor (TAPI-1), a specific hydroxamate inhibitor of metalloprotease disintegrins, prevented release of EGFR ligands from wounded RIE-1 cell monolayers. The restitution of wounded RIE-1 cell monolayers was also dose-dependently inhibited by TAPI-1, establishing the role of metalloprotease disintegrins in this process. These results have established a mechanism of EGFR activation in wounded intestinal epithelium and show an important functional role for metalloprotease disintegrin-mediated ectodomain shedding during intestinal epithelial restitution. Therefore, activation of the TACE-EGFR system might promote the healing of intestinal tract ulcers in patients.

Background and Aim: Barrett's metaplasia is a premalign condition which plays a pivotal role in the development of esophageal adenocarcinoma. It is considered a complication of chronic gastroesophageal reflux disease. Although esophageal adenocarcinoma is an uncommon cancer, its incidence is rapidly increasing. The aims of the present study were to determine the prevalence of Barrett's metaplasia in outpatients referred for gastroscopy for upper gastrointestinal symptoms, and to clarify the relationship between Barrett's metaplasia and upper gastrointestinal symptoms., Methods: Three-hundred and ninety-five consecutive dyspeptic patients, never previously investigated, underwent gastroscopy and were enrolled into the study., Results: Barrett's metaplasia was detected in 29 patients (7.4%). The age-specific prevalence of Barrett's metaplasia increased with age. In multivariate analysis, Barrett's metaplasia was independently and positively related to age, sex and duration of symptoms, but not with upper gastrointestinal symptoms. In univariate analysis, Barrett's metaplasia was significantly more common in patients with antral intestinal metaplasia (24%) and presence of hiatal hernia (65.5%), compared with those with normal endoscopic findings (6.2% and 39.2%, respectively, p = 0.001)., Conclusion: Symptoms do not predict Barrett's metaplasia. Barrett's metaplasia is age-related and more common in patients with a longer duration of symptoms, presence of hiatal hernia and antral intestinal metaplasia.

Background & Aims: A reduction in nitric oxide (NO) has been implicated as a cause of intrahepatic vasoconstriction in cirrhosis, but the regulatory mechanisms remain undefined. The aim of this study was to examine a contributory role for caveolin-1, a putative negative regulator of endothelial NO synthase, in mediating deficient intrahepatic NO production in the intact cirrhotic liver., Methods: Cirrhosis was induced by carbon tetrachloride inhalation. Flow regulation of NO production and perfusion pressure was examined in the perfused rat liver. Protein expression of endothelial NO synthase (eNOS), caveolin, and calmodulin was examined by Western blotting and immunohistochemistry. NOS activity and NO production were assessed by citrulline generation and chemiluminescence, respectively. Protein-protein interactions were examined using whole tissue protein immunoprecipitation., Results: In response to incremental increases in flow, cirrhotic animals produced significantly less NO(x) than control animals. NOS activity was significantly reduced in liver tissue from cirrhotic animals compared with control animals in the presence of similar eNOS protein levels. Deficient eNOS activity was associated with a severalfold increase in binding of eNOS with caveolin. Protein levels of caveolin-1 were markedly increased in the cirrhotic liver., Conclusions: These studies provide evidence that enhanced expression and interaction of caveolin with eNOS contribute to impaired NO production, reduced NOS activity, and vasoconstriction in the intact cirrhotic liver.

Increased intrahepatic resistance in cirrhotic livers is in part caused by increased vascular tone. Several morphological abnormalities have been described in the sinusoidal endothelial cells of cirrhotic livers, but the functional impact of these abnormalities on the intrahepatic vascular tone has not been studied. The aim of this study was to investigate the intrahepatic endothelial function and the role of nitric oxide (NO) with regard to vascular tone in cirrhotic livers. Isolated rat liver perfusions were performed in cirrhotic rats (induced by chronic carbon tetrachloride inhalation) and weight-matched normal controls. After preconstricting the intrahepatic microcirculation with methoxamine (10(-4) mol/L), response to cumulative doses of receptor-mediated endothelial agonist, acetylcholine (10(-7) mol/L-10(-5) mol/L), was obtained. In another series, response to the receptor-independent endothelial agonist, calcium ionophore A23187 (10(-7) mol/L and 3 x 10(-7) mol/L), was obtained in the absence and presence of Nomega-nitro-L-arginine (NNA) and indomethacin. In a third series of rats, nitrate and nitrite production was measured in the perfusate of perfused normal and cirrhotic livers. There was significantly less vasorelaxation in cirrhotic livers as compared with normal livers in response to acetylcholine and calcium ionophore A23187 (P < .0001). The impaired vasorelaxation was a result of a decrease in both NO-mediated and non-NO-mediated components of vasorelaxation. Cirrhotic livers from ascitic rats had significantly less vasorelaxation as compared with livers from nonascitic rats (P < .005). There was significantly less production of nitrates and nitrites in cirrhotic livers (P < .05). The liver microcirculation of cirrhotic livers is characterized by endothelial dysfunction that results in impaired release of endothelial relaxing factors including NO.