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Uveal melanoma is the most common intraocular malignancy in adults. Despite the effective primary treatment, up to 50% of patients with uveal melanoma will develop metastatic lesions mainly in the liver, which are resistant to conventional chemotherapy and lead to patient's death. To date, no orthotopic murine models of uveal melanoma which can develop spontaneous metastasis are available for preclinical studies. Here, we describe a spontaneous metastatic model of uveal melanoma based on the orthotopic injection of human uveal melanoma cells into the suprachoroidal space of immunodeficient NSG mice. All mice injected with bioluminescent OMM2.5 ( n = 23) or MP41 ( n = 19) cells developed a primary tumor. After eye enucleation, additional bioluminescence signals were detected in the lungs and in the liver. At necropsy, histopathological studies confirmed the presence of lung metastases in 100% of the mice. Liver metastases were assessed in 87 and in 100% of the mice that received OMM2.5 or MP41 cells, respectively. All tumors and metastatic lesions expressed melanoma markers and the signaling molecules insulin-like growth factor type I receptor and myristoylated alanine-rich C-kinase substrate, commonly activated in uveal melanoma. The novelty of this orthotopic mouse xenograft model is the development of spontaneous metastases in the liver from the primary site, reproducing the organoespecificity of metastasis observed in uveal melanoma patients. The faster growth and the high metastatic incidence may be attributed at least in part, to the severe immunodeficiency of NSG mice. This model may be useful for preclinical testing of targeted therapies with potential uveal melanoma antimetastatic activity and to study the mechanisms involved in liver metastasis.

Chronic gut inflammation in Crohn’s disease (CD) is associated with an increase in oxidative stress and an imbalance of antioxidant enzymes. We have previously shown that catalase (CAT) activity is permanently inhibited by CD. The purpose of the study was to determine whether there is any relationship between the single nucleotide polymorphisms (SNPs) in the CAT enzyme and the potential risk of CD associated with high levels of oxidative stress. Additionally, we used protein and regulation analyses to determine what causes long-term CAT inhibition in peripheral white mononuclear cells (PWMCs) in both active and inactive CD. We first used a retrospective cohort of 598 patients with CD and 625 age-matched healthy controls (ENEIDA registry) for the genotype analysis. A second human cohort was used to study the functional and regulatory mechanisms of CAT in CD. We isolated PWMCs from CD patients at the onset of the disease (naïve CD patients). In the genotype-association SNP analysis, the CAT SNPs rs1001179, rs475043, and rs525938 showed a significant association with CD (p < 0.001). Smoking CD patients with the CAT SNP rs475043 A/G genotype had significantly more often penetrating disease (p = 0.009). The gene expression and protein levels of CAT were permanently reduced in the active and inactive CD patients. The inhibition of CAT activity in the PWMCs of the CD patients was related to a low concentration of CAT protein caused by the downregulation of CAT-gene transcription. Our study suggests an association between CAT SNPs and the risk of CD that may explain permanent CAT inhibition in CD patients together with low CAT gene and protein expression.

Crohn's disease (CD) is a complex and multifactorial illness. There are still considerable gaps in our knowledge regarding its pathophysiology. A transcriptomic approach could shed some light on little-known biological alterations of the disease. We therefore aimed to explore the ileal transcriptome to gain knowledge about CD. We performed whole transcriptome gene expression analysis on ileocecal resections from CD patients and inflammatory bowel disease-free controls, as well as on a CD-independent cohort to replicate selected results. Normalized data were hierarchically clustered, and gene ontology and the molecular network were studied. Cell cultures and molecular methods were used for further evaluations. Genome-wide expression data analysis identified a robust transmembrane immunoglobulin domain-containing 1 (TMIGD1) gene underexpression in CD tissue, which was even more marked in inflamed ileum, and which was replicated in the validation cohort. Immunofluorescence showed TMIGD1 to be located in the apical microvilli of well-differentiated enterocytes but not in intestinal crypt. This apical TMIGD1 was lower in the noninflamed tissue and almost disappeared in the inflamed mucosa of surgical resections. In vitro studies showed hypoxic-dependent TMIGDI decreased its expression in enterocyte-like cells. The gene enrichment analysis linked TMIGD1 with cell recovery and tissue remodeling in CD settings. involving guanylate cyclase activities. Transcriptomics may be useful for finding new targets that facilitate studies of the CD pathology. This is how TMIGD1 was identified in CD patients, which was related to multiciliate ileal epithelial cell differentiation. NEW & NOTEWORTHY This is a single-center translational research study that aimed to look for key targets involved in Crohn's disease and define molecular pathways through different functional analysis strategies. With this approach, we have identified and described a novel target, the almost unknown TMIGD1 gene, which may be key in the recovery of injured mucosa involving intestinal epithelial cell differentiation.

Patients with ulcerative colitis (UC) have an increased risk of colorectal cancer. Scarce data regarding the development of adenomas in these patients are available both for normal and colitic mucosa.The objective of this article is to evaluate the prevalence of adenomatous polyps and associated risk factors in patients with UC.Patients with UC were identified from the databases of two tertiary referral centers. Medical, endoscopic and histologic reports were reviewed.A total of 403 patients were included (53% male; 33% extensive colitis) and 1065 colonoscopies (median per patient, 2) were recorded and analyzed. Seventy-four adenomas in 47 patients (11.7%) and three cases of colorectal cancer were found during a median follow-up of 6.3 years. The cumulative risk of colorectal adenoma was 4.7%, 16.7%, 23.6% and 34.4% at 10, 20, 30 and 40 years from UC diagnosis, respectively. The cumulative risk of developing metachronous colorectal adenoma was 66.7%, 87.9%, and 90.9% at 5, 10, and 15 years from first adenoma detection. Older age at UC diagnosis and longer disease duration were independent risk factors for colorectal adenoma development.The prevalence of colorectal adenomas among UC patients seems to be higher than previously reported, although lower than in the background population.

Background: Onset during old age has been reported in upto 10% of total cases of inflammatory bowel disease (IBD). Aim: To evaluate phenotypic characteristics and the use of therapeutic resources in patients with elderly onset IBD. Methods: Case-control study including all those patients diagnosed with IBD over the age of 60 years since 2000 who were followed-up for >12 months, identified from the IBD databases. Elderly onset cases were compared with IBD patients aged 18 to 40 years at diagnosis, matched by year of diagnosis, gender and type of IBD (adult-onset). Results: One thousand three hundred and seventy-four elderly onset and 1374 adult-onset cases were included (62% ulcerative colitis (UC), 38% Crohn's disease (CD)). Among UC patients, elderly onset cases had a lower proportion of extensive disease (33% vs 39%; P < 0.0001). In CD, elderly onset cases showed an increased rate of stenosing pattern (24% vs 13%; P < 0.0001) and exclusive colonic location (28% vs 16%; P < 0.0001), whereas penetrating pattern (12% vs 19%; P < 0.0001) was significantly less frequent. Regarding the use of therapeutic resources, there was a significantly lower use of corticosteroids (P < 0.0001), immunosuppressants (P < 0.0001) and anti-TNFs agents (P < 0.0001) in elderly onset cases. Regarding surgery, we found a significantly higher surgery rate among elderly onset UC cases (8.3% vs 5.1%; P < 0.009). Finally, elderly onset cases were characterised by a higher rate of hospitalisations (66% vs 49%; P < 0.0001) and neoplasms (14% vs 0.5%; P < 0.0001). Conclusions: Elderly onset IBD shows specific characteristics and they are managed differently, with a lower use of immunosuppressants and a higher rate of surgery in UC.

Background: Ulcerative proctitis (UP) presents distinctive clinical characteristics, outcomes and therapeutic approaches as compared to left-sided and extensive ulcerative colitis (UC). Aim: To describe the current therapeutic requirements and clinical outcomes in patients with active UP. Methods: Retrospective observational study conducted in a referral IBD centre. Patients with UP in follow-up between 1989 and 2014 were included. The clinical characteristics, as well as the different treatments and drug formulations administered to treat flares, were recorded. Results: Out of 687 UC patients, 101 patients (15%) with UP were included. Median follow-up was 8 years (IQR 3-14) and 49% of patients presented disease activity during the study period. Topical mesalazine monotherapy (90%) was the most commonly administered treatment for disease activity (mostly as suppositories), followed by topical steroids (47%) and oral mesalazine (56%) in monotherapy or combination therapy. Only 14% and 16% of patients required oral prednisone and beclomethasone, respectively. Conclusions: In clinical practice, active UP presents mostly favourable outcomes. Mesalazine suppositories are by far the most used treatment for these patients. (C) 2017 Elsevier Espana, S.L.U., AEEH y AEG. All rights reserved.

This article takes a close look at La Borda, a housing cooperative being developed in Barcelona. The article encompasses the economic and social context in which the housing initiative emerged, the organisational features that define the cooperative, and its origins in the process of urban renewal of the former industrial site of Can Batllo. The article also analyses its current development and its potential for scalability. Drawing on Moulaert's definition of social innovation, the authors argue that La Borda goes beyond the mere provision of housing to include public participation as a key component of the model. The Andel Model for cooperative housing is presented as the main source of inspiration for La Borda's model, including its roots in the social and cooperative economy and the role of the cession of use housing tenure. The article concludes there are reasons to believe La Borda will succeed in providing long-term affordable housing while engaging its residents in its daily management. The author...

Nivolumab, a monoclonal antibody-targeting programmed cell death protein-1, is being increasingly used for the treatment of some advanced neoplasms. Several of its adverse effects are a result of the upregulation of T cells, with colitis as one of the most severe, and a challenging differential diagnosis with ulcerative colitis. However, few real-life clinical practice cases have been reported beyond trials. Our aim was to report a series of new cases, reviewing previously communicated endoscopic-proven nivolumab-induced colitis. All patients treated with nivolumab in three university centers were identified and those who developed immune-mediated colitis (defined as the presence of diarrhea and evidence of colitis demonstrated by colonoscopy) were described. Additionally, a review of case reports of nivolumab-induced colitis reported in the literature up to March 2018 was performed. Six new cases of nivolumab-induced colitis and 13 previously reported cases out of randomized clinical trials are described. Colonoscopy showed a mucosal pattern mimicking ulcerative colitis in a large proportion of patients. Clostridium difficile superinfection was observed in two out of 19 cases. All but three patients definitively discontinued nivolumab therapy. Most patients were initially managed with oral or intravenous corticosteroids, but five of them required rescue therapy with infliximab. Nivolumab-induced colitis may mimic ulcerative colitis. Steroid therapy (oral or intravenously) is often efficient, but one-fourth of patients need rescue therapy with anti-TNF. Intestinal superinfection with Clostridium difficile or cytomegalovirus should be ruled out before starting immunosuppressive therapy.

Background and Aims Steroid-refractoriness is a common and unpredictable phenomenon in ulcerative colitis [UC], but there are no conclusive studies on the molecular functions involved. We aimed to assess the mechanism of action related to steroid failure by integrating transcriptomic data from UC patients, and updated molecular data on UC and glucocorticoids. Methods MicroRNA [miRNA] and mRNA expression were evaluated by sequencing and microarrays, respectively, from rectal biopsies of patients with moderately-to-severe active UC, obtained before and on the third day of steroid treatment. The differential results were integrated into the mathematical models generated by a systems biology approach. Results This computational approach identified 18 proteins that stand out either by being associated with the mechanism of action or by providing a means to classify the patients according to steroid response. Their biological functions have been linked to inflammation, glucocorticoid-induced transcription and angiogenesis. All the selected proteins except ANP32E [a chaperone which has been linked to the exchange of H2A.z histone and promotes glucocorticoid receptor-induced transcription] had previously been related to UC and/or glucocorticoid-induced biological actions. Western blot and immunofluorescence assays confirmed the implication of this chaperone in steroid failure in patients with active UC. Conclusions A systems biology approach allowed us to identify a comprehensive mechanism of action of steroid-refractoriness, highlighting the key role of steroid-induced transcription and the potential implication of ANP32E in this phenomenon.

Background Colonic cytomegalovirus [CMV] reactivation has been involved in steroid refractoriness in patients with active ulcerative colitis [UC]. The benefits of antiviral therapy in this clinical setting are still under debate, but the burden of viral reactivation has been associated with a poorer outcome in some studies. Our aim was to assess whether the burden of CMV reactivation measured by the number of viral inclusions by immunohistochemistry [IHC-CMV] is associated with a risk of colectomy. Methods Biopsy sets of UC patients with positive IHC-CMV were identified from the Pathology departments of three university hospitals. All biopsies were reviewed by expert pathologists, and the maximum number of IHC-CMV-positive cells in each biopsy set was re-assessed. Epidemiological and clinical features and clinical outcomes were recorded. Results Forty-six positive IHC-CMV cases with UC were included. At the time of CMV reactivation, 70% were receiving corticosteroids, 33% azathioprine, and 24% anti-tumour necrosis factor [TNF] agents. Thirty-two patients [70%] were treated with antiviral therapy. The median number of IHC-CMV-positive cells was 2 cells/biopsy [IQR 1-4]. Fourteen patients [30%] underwent colectomy, and 4 of them [29%] showed persistence of CMV in the surgical specimen. In the multivariate analysis, colectomy was only associated with >2 positive cells/biopsy [p = 0.048] and younger age [p = 0.023]. Conclusions The burden of CMV colonic reactivation in patients with active UC, as measured by IHC, seems to be related to the risk of colectomy, and more data is needed to understand whether antiviral therapy guided by CMV burden will alter the clinical outcome.

Background: Peculiarities of inflammatory bowel disease (IBD) have been explored in ethnic groups, such as Asians, Hispanics, and Afro-Americans, but not in other ethnic minorities, such as Roma/Gypsies. Methods: In a retrospective, hospital-based study, all adult Roma/Gypsy patients included in the IBD databases of seven Spanish centres were identified as cases. For each Roma/Gypsy patient, a Caucasian patient, matched for several demographic features, was searched as a control. Data on phenotypic features, therapeutic requirements, and familial aggregation were recorded. Results: Sixty-eight Roma/Gypsy patients were identified, 29 of them being women. The mean age at diagnosis of IBD was 24.9 +/- 9.5 years, and the mean time elapsed since diagnosis was 96.6 +/- 72.2 months. Roma/Gypsy IBD patients showed a significantly higher rate of familial aggregation (43%) than their Caucasian controls (9%) (p = 0.00001). CD in Roma/Gypsies had more often a complicated pattern (mainly penetrating) while UC patients showed a marked trend to more often developing extraintestinal manifestations. In addition, Roma/Gypsy IBD patients had a somewhat greater need for immunosuppressants, biological agents or surgery. Conclusions: These are the first data on IBD in Roma/Gypsy patients. Familial aggregation is the most prominent feature in these patients, suggesting a predominant role of genetics in its pathogenesis. (C) 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Background The convoluted relationship between obesity, bariatric surgery and inflammatory bowel disease (IBD) is of increasing interest. Aim To analyse evidence regarding the role of bariatric surgery in the development of de novo IBD and its impact on clinical outcomes and safety in patients with established IBD. Methods A PubMed/Medline search was performed to identify studies reporting the development of IBD after bariatric surgery and the outcomes of IBD patients after bariatric surgery. Results Eighty patients were reported to have developed de novo IBD after bariatric surgery (21% ulcerative colitis [UC], 75% Crohn's disease [CD]), mostly females. Roux-en-Y gastric bypass was the most frequent bariatric technique (80%). Symptoms related to IBD occurred within 1 month and 16 years after surgery. Regarding patients with known IBD undergoing bariatric surgery, 60 patients (35 CD, 24 UC, and 1 unclassified colitis) have been reported. Sleeve gastrectomy was the most frequent bariatric procedure, particularly in CD patients. Acute flares after surgery were observed in only four UC patients. In addition, two retrospective population-based studies described perioperative outcomes of bariatric surgery on IBD patients, demonstrating only a significant increase in small bowel obstruction in these patients. Conclusions Bariatric surgery in carefully selected patients with established IBD is technically feasible and probably safe. Development of de novo IBD should be taken into account in individuals with previous bariatric surgery who develop diarrhoea, anaemia or excessive weight loss.

Background & Aims Crohn's disease is a highly heterogeneous inflammatory bowel disease comprising multiple clinical phenotypes. Genome-wide association studies (GWASs) have associated a large number of loci with disease risk but have not associated any specific genetic variants with clinical phenotypes. We performed a GWAS of clinical phenotypes in Crohn's disease. Methods We genotyped 576,818 single-nucleotide polymorphisms in a well-characterized cohort of 1090 Crohn's disease patients of European ancestry. We assessed their association with 17 phenotypes of Crohn's disease (based on disease location, disease behavior, disease course, age at onset, and extraintestinal manifestations). A total of 57 markers with strong associations to Crohn's disease phenotypes ( P -4 ) were subsequently analyzed in an independent replication cohort of 1296 patients of European ancestry. Results We replicated the association of 4 loci with different Crohn's disease phenotypes. Variants in MAGI1 , CLCA2 , 2q24.1 , and LY75 loci were associated with a complicated stricturing disease course ( P combined = 2.01 × 10 -8 ), disease location ( P combined = 1.3 × 10 -6 ), mild disease course ( P combined = 5.94 × 10 -7 ), and erythema nodosum ( P combined = 2.27 × 10 -6 ), respectively. Conclusions In a GWAS, we associated 4 loci with clinical phenotypes of Crohn's disease. These findings indicate a genetic basis for the clinical heterogeneity observed for this inflammatory bowel disease.

Background: It has been suggested that acute histological activity has a prognostic value in the outcome of ulcerative colitis (UC) patients in clinical and endoscopic remission. Our aim was to assess the role of histology as a risk factor for clinical relapse (CR) in patients in both clinical and endoscopic remission. Methods: Patients with left-sided or extensive UC in clinical and endoscopic remission (Mayo endoscopic subscore

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a little known entity that can affect the oropharyngeal mucosa, the gastrointestinal tract and the skin. The main risk factor for the development of this lesion is immunosuppression. Because its features are similar to other Epstein-Barr virus-associated lymphoproliferative disorders, a differential diagnosis can sometimes prove challenging. Here, we report the case of a man diagnosed with Crohn's disease and treated with azathioprine and infliximab who developed ulceration at the rectum that was refractory to conventional medical treatment. Although the histological characteristics were suggestive of an EBVMCU, lymphoproliferative disease could not be ruled out. The patient did not improve after discontinuation of the treatment, a proctectomy was performed and the diagnosis of this disease was confirmed. Although very few cases of EBVMCU affecting the colon have been reported, its diagnosis should be always considered in refractory cases of inflammatory bowel disease with patients undergoing immunosuppressive treatment.

Use of probiotic therapy is an active area of investigation to treat intestinal disorders. The clinical benefits of the I3.1 probiotic formula (Lactobacillus plantarum (CECT7484, CECT7485) and P. acidilactici (CECT7483)) were demonstrated in irritable bowel syndrome (IBS) patients in a randomized, double-blind, placebo-controlled clinical trial. The aim of this study was to evaluate the therapeutic effects of I3.1 in two experimental models of colitis, a dextran sulfate sodium (DSS)-induced colitis model and an interleukin (IL)-10-deficient mice model. Colitis was induced in 32 8-week-old Balb/c mice by administering 3% (w/v) DSS in drinking water for 5 days. Probiotics were administered orally (I3.1 or VSL#3, 1 x 109 CFU daily) for 10 days before the administration of DSS. Also, probiotics (I3.1 or VSL# 3, 1 x 109 CFU daily) were administered orally to 36 6-week-old C57B6J IL-10(-/-) mice for 10 weeks. Body weight was recorded daily. Colon samples were harvested for histological examination and cytokine measurements. Body weight after DSS administration did not change in the I3.1 group, whereas the VSL#3 group had weight loss. Also, I3.1 normalized IL-6 to levels similar to that of healthy controls and significantly increased the reparative histologic score. In the IL-10-deficient model, both VSL# 3 and I3.1 reduced the severity of colitis compared to untreated controls, and I3.1 significantly reduced the levels of IFN-gamma compared to the other two groups. In conclusion, I3.1 displays a protective effect on two murine models of experimental colitis. Results suggest that the mechanism of action could be different from VSL#3.

Background & aims: The early hospital readmission of patients with decompensated cirrhosis is a current problem. A study is presented on the incidence, the impact on mortality, and the predictive factors of early hospital readmission. Patients and methods: On the study included 112 cirrhotic patients, discharged after some decompensation between January 2013 and May 2014. Multivariate analyses were performed to identify predictors of early readmission and mortality. Results: The early readmission rate was 29.5%. The predictive factors were male gender (OR: 2.81; 95% CI: 1.07-7.35), Model for End-Stage Liver Disease-sodium score >= 15 (OR: 3.79; 95% CI 1.48-9.64), and Charlson index >= 7 (OR: 4.34, 95% CI 1.65-11.4). This model enabled patients to be classified into low or high risk of early readmissions (13.6% vs. 52.2%). The mortality rate was significantly higher among patients with early readmission (73% vs. 35%) (p= 15, and Charlson index >= 7 are predictors of early readmission. These results could be used to develop future strategies to reduce early readmission. (C) 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Background and Aim Thiopurines prevent Crohn's disease (CD) endoscopic recurrence (ER) at least in 50% of patients 1 year after surgery. This study aimed to evaluate the value of adding mesalazine in patients with subclinical ER despite preventive thiopurine therapy. Methods Crohn's disease patients with ileocecal resection treated with thiopurines for postsurgical recurrence prevention in whom mesalazine was added (cases) to treat ER without clinical recurrence (CR) were identified and compared with those in whom no treatment was added to thiopurines (controls). All patients were followed up for at least 1 year from the index endoscopy. Development of CR as well as evolution of mucosal lesions was evaluated. Results Thirty-seven patients were included (19 cases and 18 controls). Initial Rutgeerts' score was i2 in 16 patients (9 cases and 7 controls), and i3 in 21 patients (10 cases and 11 controls). After a median clinical follow-up of 59 months (interquartile range 22–100) from the index endoscopy, six cases (32%) and two controls (11%) developed CR (P = 0.2). After a median time to last endoscopic follow-up of 23 months (interquartile range 17–71), 18 patients (49%) showed improvement in Rutgeerts' score, 11 patients (30%) demonstrated progression of mucosal lesions, and 8 (22%) had no changes, with no differences between study groups. Conclusions The addition of mesalazine seems to be of no benefit in patients with subclinical endoscopic recurrence while on thiopurine prevention. Moderate endoscopic postsurgical recurrence while on thiopurines may even revert with no additional therapy in some patients.

Background & aims: Disease outcome has been found to be poorer in familial inflammatory bowel disease (IBD) than in sporadic forms, but assessment of phenotypic concordance in familial IBD provided controversial results. We assessed the concordance for disease type and phenotypic features in IBD families. Methods: Patients with familial IBD were identified from the IBD Spanish database ENEIDA. Families in whom at least two members were in the database were selected for concordance analysis (K index). Concordance for type of IBD [Crohn's disease (CD) vs. ulcerative colitis (UC)], as well as for disease extent, localization and behaviour, perianal disease, extraintestinal manifestations, and indicators of severe disease (i.e., need for immunosuppressors, biological agents, and surgery) for those pairs concordant for IBD type, were analyzed. Results: 798 out of 11,905 IBD patients (7%) in ENEIDA had familial history of IBD. Complete data of 107 families (231 patients and 144 consanguineous pairs) were available for concordance analyses. The youngest members of the pairs were diagnosed with IBD at a significantly younger age (p < 0.001) than the oldest ones. Seventy-six percent of pairs matched up for the IBD type (kappa = 0.58; 95%CI: 0.42-0.73, moderate concordance). There was no relevant concordance for any of the phenotypic items assessed in both diseases. Conclusions: Familial IBD is associated with diagnostic anticipation in younger individuals. Familial history does not allow predicting any phenotypic feature other than IBD type. (C) 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Background: Active smoking has been associated with a higher risk of developing Crohn's disease (CD). However, its impact on clinical outcomes has been controversial among studies. Aims: To evaluate the influence of active smoking on initial manifestations of CD, the development of disease-related complications, and therapeutic requirements. Methods: Patients diagnosed with CD within a ten-year period (1994-2003) were identified. Clinical and therapeutic features until October 2008 or loss of follow-up were recorded. Smoking status was assessed at each major disease-related event (e.g. penetrating and stricturing complications, perianal disease, intestinal resection, introduction of immunomodulators or biological agents). Results: A total of 259 patients were included in the study with a median follow-up period of 91 months. At diagnosis, 50.5% were active smokers and only 12% of them quit smoking during follow-up, mostly after a major disease-related event occurred. Smoking at diagnosis was not associated with a particular CD presentation. Active smoking did not influence the development of strictures, intraabdominal and perianal penetrating complications, or increased resectional surgery, biological therapy or immunomodulators requirements. Conclusions: Patients who develop CD while smoking seem to have a similar disease course to those who never smoked. (c) 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Background and aim: Intravenous corticosteroids remain the first line therapy for severe attacks of ulcerative colitis although up to 30-40% of patients do not respond to treatment. The availability of alternative therapies to colectomy and the knowledge of early predictors of response to corticosteroids should have improved the clinical outcomes of patients with severe refractory ulcerative colitis. The aim of the study is to describe the current need, way of use, and efficacy of rescue therapies, as well as colectomy rates in patients with severe ulcerative colitis flares. Methods: Between January 2005 and December 2011, all patients admitted in three referral centres for a severe ulcerative colitis flare who received intravenous corticosteroids were identified and clinical and biological data were accurately collected. Patients were followed-up until colectomy, death, or date of data collection. Results: Sixty-two flares were included. Initial efficacy of intravenous corticosteroids (mild activity or inactive disease without rescue treatment, at day 7 after starting intravenous corticosteroids) was achieved in 50% of flares, and rescue therapies were used in 27 episodes (43%). After a median follow-up of 18 months, the colectomy rate was 6.5%. Failed oral corticosteroids for the index flare were the only baseline feature that predicted the need for rescue therapy and colectomy. Conclusions: There is a marked reduction in the colectomy rate and an increased use of medical rescue therapies as compared to historical series. Patients worsening while on oral corticosteroids for a moderate flare are at high risk of rescue therapy and colectomy and, therefore, should be directly treated with rescue therapies instead of attempting intravenous corticosteroids. (C) 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Background: Fecal calprotectin (FC) is the best noninvasive biomarker of disease activity in inflammatory bowel disease. Its correlation with endoscopic mucosal lesions could save inconvenient, expensive, and repeated endoscopic examinations in particular clinical settings. Patients and Methods: To assess the correlation between FC and the existence and severity of endoscopic postoperative recurrence (POR), a group of clinically stable outpatients with Crohn's disease for whom an ileocolonoscopy was routinely planned to assess POR were invited to collect a stool sample before starting bowel cleansing to measure FC. POR was graded by means of Rutgeerts endoscopic score. Results: One hundred nineteen ileocolonoscopies were included, 42% with endoscopic POR. FC was significantly lower in the absence of endoscopic POR and in the absence of any endoscopic lesion. The area under the receiver operating characteristic curve was 0.76 (95% confidence interval, 0.68-0.85) for the diagnosis of the absence of lesions and 0.75 (95% confidence interval, 0.66-0.84) for endoscopic POR. Better sensitivity and negative predictive value were observed when combining FC and serum C-reactive protein (CRP), leading to a sensitivity of 82%, a specificity of 53%, and negative and positive predictive values of 81% and 54%, respectively, for the prediction of endoscopic POR with a combination of FC 100 mu g/g and CRP 5 mg/L cutoff values. Conclusions: FC correlates closely with endoscopic POR in clinically stable postoperative patients with Crohn's disease and, when used in combination with CRP, might save endoscopic examinations and allow for a high-grade suspicion of endoscopic POR in the long-term monitoring of these patients.

Sexuality is important when assessing quality of life (QoL), which is often disturbed in inflammatory bowel disease (IBD). However, sexuality is not addressed in most QoL questionnaires. To evaluate the prevalence and predisposing factors of sexual dysfunction among IBD patients, and their own perception. A postal survey was conducted in IBD patients 25–65 years of age from two tertiary centres. Patients were asked to provide a control of the same gender and age without IBD. The questionnaire assessed patient perception of the impact of IBD on their sexuality, and also allowed calculation of the Erectile Function International Index or the Female Sexual Function Index. A total of 355 patients and 200 controls were available for the final analysis. Both groups were comparable except for a higher proportion of individuals who had been treated for depression among patients. Half of the female and one-third of the male patients considered that both sexual desire and satisfaction worsened after IBD diagnosis. As compared to controls, both men and women with IBD showed significantly lower scores in sexual function indexes, but a higher prevalence of sexual dysfunction was only noticed among women. Independent predictors of sexual dysfunction among IBD patients were the use of corticosteroids in women, and the use of biological agents, depression and diabetes in men. Sexuality is often disturbed in IBD patients, particularly among women. Many factors seem to contribute to worsened intimacy. Sexuality should be considered when QoL is assessed in these patients.

Background & Aim: Despite their well known anti-inflammatory actions, the clinical usefulness of omega-3 PUFA in inflammatory bowel disease is controversial. We aimed to systematically review the available data on the performance of omega-3 PUFA as therapeutic agents in these patients. Methods: Electronic databases were systematically searched for RCT of fish oil or omega-3 PUFA therapy in both active and inactive ulcerative colitis or Crohn's disease, without limitation on either the length of therapy or the form it was given, including nutritional supplements and enteral formula diets. Eligible articles were assessed for methodological quality on the basis of the adequacy of the randomisation process, concealment of allocation, blinding of intervention and outcome, possible biases, and completeness of follow-up. The five-point Oxford quality score was calculated. Results: A total of 19 RCT were finally selected for this review. Overall, available data do not allow to support the use of omega-3 PUFA supplementation for the treatment of both active and inactive inflammatory bowel disease. Negative results are quite consistent in trials assessing the use of omega-3 PUFA to maintain disease remission, particularly ulcerative colitis, and to a lesser extent Crohn's disease. Trials on their use in active disease do not allow to draw firm conclusions mainly because the heterogeneity of design (ulcerative colitis) or their short number (Crohn's disease). In most trials, the appropriateness of the selected placebo is questionable. Conclusion: The present systematic review does not allow to make firm recommendations about the usefulness of omega-3 PUFA in inflammatory bowel disease.

Purpose of review To describe the evidences for the usefulness of dietary manipulations (including the use of probiotics and prebiotics) in the management of irritable bowel syndrome (IBS). Recent findings Exclusion diets do not have a role in the management of these patients except in the case of malabsorbed sugars (lactose, fructose). However, recent work suggests that excluding these sugars is more effective in non-IBS than in IBS patients. Also, the first small open series on the use of very low (20 g/day) carbohydrate diet (VLCD) in IBS has been published with promising results. However, safety concerns do not allow us to recommend them. In the period of review, further evidence has been provided on the role of psyllium in IBS. Also, the available evidence on the use of probiotics in IBS has been meta-analyzed. Summary IBS patients should eat a balanced diet without restrictions, and (except for malabsorbed sugars) exclusion diets are not useful in most of them. The role of VLCD remains to be established. The concept that increasing fiber intake is useful for IBS may not be true for all patients, and hydrophilic colloids (e.g. psyllium) are preferred. There is growing evidence for the effectiveness of probiotics in IBS.

Psoas abscess is a rare condition and is usually related to diseases of the gastrointestinal tract. The clinical presentation is often nonspecific, frequently delaying diagnosis. In our environment, Crohn's disease is the most common underlying condition in psoas abscess, although its occurrence in the course of Crohn's disease is also considered to be rare. We present a series of three patients with Crohn's disease who developed psoas abscess at different time points (at diagnosis of Crohn's disease, within the first year of disease, and years after diagnosis). We review the literature and focus on the clinical factors associated with the occurrence of these abscesses and the therapeutic approach to both this septic complication and the underlying disease.

Parenteral nutrition (PN) offers the possibility to increase or to ensure nutrient intake in patients, in whom sufficient nutrition by oral or enteral alone is insufficient or impossible. Complementary to the ESPEN guideline on enteral nutrition of liver disease (LD) patients the present guideline is intended to give evidence-based recommendations for the use of PN in LD. For this purpose three paradigm conditions of LD were chosen: alcoholic steatohepatitis (ASH), liver cirrhosis and acute liver failure. The guideline was developed by an interdisciplinary expert group in accordance with officially accepted standards and is based on all relevant publications since 1985. The guideline was presented on the ESPEN website and visitors’ criticism and suggestions were welcome and included in the final revision. PN improves nutritional state and liver function in malnourished patients with ASH. PN is safe and improves mental state in patients with cirrhosis and severe HE. Perioperative (including liver transplantation) PN is safe and reduces the rate of complications. In acute liver failure PN is a safe second-line option to adequately feed patients in whom enteral nutrition is insufficient or impossible.

Background Capsule endoscopy (CE) has proven efficacy in detecting mucosal lesions of the upper gastrointestinal tract and it has been widely evaluated for assessing small-bowel lesions in patients with suspected or established Crohn’s disease (CD). Aims To evaluate the impact of CE on the management of patients with established CD. Methods All patients with known CD that underwent CE were identified from IBD and endoscopy databases. Baseline characteristics of the study population, CE findings, changes in therapy, and patient outcome were recorded. Patients were followed for 18 months after CE. Results CE was performed in 14 CD patients for iron deficiency anemia (n = 5) or abdominal pain of unknown origin (n = 3), or re-evaluation of disease location (n = 6). The overall diagnostic yield was 85.7%. As a result of the CE findings, CD therapy was changed in 64% of cases. Clinical outcome changed in three out of five patients with iron deficiency anemia and in two out of three patients with abdominal pain. Conclusions CE has a high diagnostic yield even in patients with previously known CD, and its findings may influence disease management and clinical outcome.

Background: Cytomegalovirus (CMV) infection has been reported in ulcerative colitis (UC), especially in severe, steroid-refractory disease. However, its role in steroid-refractoriness remains unknown. Our goals were to evaluate the prevalence of CMV disease in UC, the best diagnostic strategy, and the influence of disease activity and/or treatment in its development. Methods: Prospective, observational study including 114 subjects with active UC requiring intravenous steroids, steroid-refractory UC, inactive UC on mesalamine, inactive UC on azathioprine, and healthy controls. CMV antibodies, pp65-antigenemia, and rectal biopsies for hematoxylin and eosin staining, immunohistochemistry, and CMV-pp67 mRNA were performed. These procedures were repeated after medical treatment only in patients with active UC. CMV disease was defined by the presence of inclusion bodies and/or positive immunohistochemistry in colonic biopsies. Results: CMV disease was found in 6 steroid-refractory, CMV-IgG-positive UC patients but not among controls, inactive UC, or steroid-responding UC patients. In 5 out of the 6 patients, CMV disease was diagnosed after 7–10 days on cyclosporine. Conclusions: CMV disease in UC only affects seropositive, steroid-refractory UC patients. Steroid/cyclosporine treatment together with disease activity may predispose to latent colonic CMV reactivation. The impact of antiviral therapy on the clinical outcome of these patients remains to be elucidated. (Inflamm Bowel Dis 2008)

The use of immunomodulators for the treatment of inflammatory bowel disease is increasing. One of the most common adverse effects associated with this kind of drugs are infectious complications. In recent years, special attention has been paid to certain latent infections which, in patients under immunomodulatory therapy, can be reactivated and prove lethal. Consequently, preventive actions have been adopted, such as screening for hepatitis B virus and tuberculosis infection before starting these treatments. Primary infection with the Epstein-Barr herpesvirus is usually asymptomatic. However, this virus can have an aggressive course and even lead to the development of lymphoma. We report two cases of atypical infectious mononucleosis in patients with inflammatory bowel disease under azathioprine therapy and review the available evidence on the most appropriate therapeutic approach in this subset of patients.

In contrast to ulcerative colitis and pouchitis, benefits of probiotic therapy in preventing recurrence/relapse in Crohn's disease (mostly involving the ileum) are far from being proven. The lack of response in this setting does not seem attributable to a lower relevance of dysbiosis in ileal Crohn's disease, since this – or at least the presence of increased mucosal amounts of potentially pathogen bacteria – has been proven to occur in the ileum of Crohn's disease patients. Available data indicate that whereas in ulcerative colitis (and to a lesser extent in colonic Crohn's disease) the innate immune response is enhanced, it is constitutively depressed in ileal Crohn's disease. Therefore, attempts to modify the composition of intestinal microflora in colonic IBD or pouchitis by means of probiotics do make sense. In contrast, supplying additional bacteria (even being probiotics) to an ileum with decreased antibacterial defence does not seem reasonable. In fact, the presence of intestinal contents has been reported to be related to postoperative recurrence in ileo-caecal Crohn's disease, and antibiotic treatment in effective to prevent its development.

INTRODUCTION The aim of the abstracts presented at scientific meetings is their publication in a peer-review journal. In this study, we analysed the publication rates of the abstracts submitted to the 24th AEEH meeting (1999) and also to see if this was stable over time. MATERIAL AND METHODS We assessed the publication rates of the abstracts presented at the 24th AEEH meeting in journals included in MEDLINE. As a comparison tool, we did the same with the abstracts submitted to the 34th Annual Meeting of the European Association for the Study of the Liver (EASL). The same procedure was carried out on the three subsequent editions of AEEH meetings to evaluate the continuity in the long term. RESULTS Of the abstracts submitted at the 24th AEEH meeting, 52.8% (93/176) were published: 71.4% of those had been accepted for oral presentation, 54% as a poster and 41% were non-accepted abstracts. From the 34th EASL Annual Meeting, 27.1% (248/913) of the submitted abstracts were published (p < 0.001 compared to AEEH), 52.5% of those were accepted for oral communication, 33.1% accepted as a poster communication and 18.1% from non-accepted abstracts. Moreover, this high publication rate of the abstracts of AEEH meeting at 1999, was maintained during the following three years (47.55 and 54%, respectively). CONCLUSIONS a) The publication rate of abstracts presented at 24th AEEH meeting was excellent and superior in comparison to the EASL rate of the same year; b) almost three quarters of abstracts accepted for oral presentation and more than half of those accepted as a poster were finally published, and c) high publication rates seem to be maintained over time.

Altres ajuts: Marie Curie Career Integration Grant i una beca Fundació Dexeus Salut de la Dona Efforts to develop vaccines that can elicit mucosal immune responses in the female genital tract against sexually transmitted infections have been hampered by an inability to measure immune responses in these tissues. The differential expression of adhesion molecules is known to confer site-dependent homing of circulating effector T cells to mucosal tissues. Specific homing molecules have been defined that can be measured in blood as surrogate markers of local immunity (e.g. α4β7 for gut). Here we analyzed the expression pattern of adhesion molecules by circulating effector T cells following mucosal infection of the female genital tract in mice and during a symptomatic episode of vaginosis in women. While CCR2, CCR5, CXCR6 and CD11c were preferentially expressed in a mouse model of Chlamydia infection, only CCR5 and CD11c were clearly expressed by effector T cells during bacterial vaginosis in women. Other homing molecules previously suggested as required for homing to the genital mucosa such as α4β1 and α4β7 were also differentially expressed in these patients. However, CD11c expression, an integrin chain rarely analyzed in the context of T cell immunity, was the most consistently elevated in all activated effector CD8+ T cell subsets analyzed. This molecule was also induced after systemic infection in mice, suggesting that CD11c is not exclusive of genital tract infection. Still, its increase in response to genital tract disorders may represent a novel surrogate marker of mucosal immunity in women, and warrants further exploration for diagnostic and therapeutic purposes.

Background Fecal calprotectin (FC) is considered the best noninvasive way to assess disease activity in ulcerative colitis (UC). However, it is not known which is the more suitable moment for stool sampling in patients with increased stool frequency. The aims of this study were to assess the intraindividual variation of FC within day and to evaluate if the first bowel movement in the morning is the more suitable sample for FC measurement in patients with acute flares of UC. Patients and methods Patients admitted because of active UC were invited to collect samples from several bowel movements (including the first in the morning) during the same day providing their ordinal chronology. FC was measured by means of a quantitative rapid point-of-care test based on lateral flow assay immunochromatography. Results Eighteen patients were included for a total of 56 stool samples. Most patients had extensive UC and severe disease activity. Within-day FC values varied widely, and the median coefficient of variation was 40% (5%-114%) with a median range of variation of FC values of 3887 mg/kg (69-9946). The sample from the first stool in the morning obtained the highest individual FC within-day value in 33.3% of cases and the lowest in 38.9%. Conclusions FC values widely vary between motions in patients with active UC. Stool sample collection from the first bowel movement in the morning does not ensure the highest or lowest within-day FC value. In patients with overt active UC, a single FC determination should not be used as the basis for therapeutic strategies.

Altres ajuts: 2012 Spanish Gastroenterological Association i CIBER G0034 Glucocorticosteroids are the first line therapy for moderate-severe flare-ups of ulcerative colitis. Despite that, up to 60% of patients do not respond adequately to steroid treatment. Previously, we reported that low IL-10 mRNA levels in intestine are associated with a poor response to glucocorticoids in active Crohn's disease. Here, we test whether IL-10 can favour the response to glucocorticoids by improving the TNFα-induced intestinal barrier damage (assessed by transepithelial electrical resistance) in Caco-2 monolayers, and their possible implications on glucocorticoid responsiveness in active ulcerative colitis. We show that the association of IL-10 and glucocorticoids improves the integrity of TNFα-treated Caco-2 cells and that p38 MAPK plays a key role. In vitro, IL-10 facilitates the nuclear translocation of p38 MAPK-phosphorylated thereby modulating glucocorticoids-receptor-α, IL-10-receptor-α and desmoglein-2 expression. In glucocorticoids-refractory patients, p38 MAPK phosphorylation and membrane desmoglein-2 expression are reduced in colonic epithelial cells. These results suggest that p38 MAPK-mediated synergism between IL-10 and glucocorticoids improves desmosome straightness contributing to the recovery of intestinal epithelium and reducing luminal antigens contact with lamina propria in ulcerative colitis. This study highlights the link between the intestinal epithelium in glucocorticoids-response in ulcerative colitis.

Recent studies have shown a low adherence rate to maintenance treatment in patients with inflammatory bowel disease (IBD). We sought to assess the medication-taking behavior in a cohort of patients with IBD. We prospectively included IBD patients from the outpatient clinic who agreed to answer a questionnaire about prescribed treatment and adherence. Physicians registered clinical data including prescribed medications. Two hundred fourteen patients (115 Crohn's disease/99 ulcerative colitis) were included. The most prescribed medications were oral mesalazine (56.5%) and immunomodulators (41.1%). Forty-three percent of patients admitted to occasionally forgetting to take their medication but only 7.5% of them did it voluntary. Oral mesalazine and azathioprine were the drugs with the poorest compliance, with nonadherence rates of 45% and 25% of the total prescribed doses, respectively. The only factor associated with a better adherence was a more complicated course of the disease-steroid dependency, steroid refractoriness, need for infliximab treatment, hospitalization, or surgery (P=.02). Twenty percent of patients admitted to self-medicating. An important proportion of patients with IBD admit to forget some doses of the prescribed medication in the setting of a specialized unit of a referral centre.

Summary Background: Few data are available regarding the evolution of Crohn's disease after discontinuing a successful course of infliximab. Aim: To evaluate clinical outcome of Crohn's disease after induction of remission with three infliximab infusions (luminal disease) and after maintenance of remission with 1-year course of infliximab every 8 weeks (luminal and perianal). Methods: Twenty-three patients with active luminal Crohn's disease who responded to three infusions of infliximab (0, 2, and 6 weeks), and 23 patients with sustained response to infliximab every 8 weeks during 1 year, were included. Patients were followed-up until relapse or for at least 6 months after infliximab discontinuation. Clinical outcomes and factors associated to relapse were evaluated. Results: In luminal Crohn's disease, a three-infusion infliximab regimen achieved a sustained response in most patients, especially if a complete response occurred at the time of the third infusion. In patients treated for 1-year, infliximab discontinuation was also successful, with a cumulative probability of being free of relapse of 69% at 12 months. In perianal disease, early relapse was the rule after stopping infliximab treatment, with only 34% of patient maintaining remission at 1 year. Conclusions: Short regimens of infliximab might be evaluated in patients with luminal Crohn's disease. However, infliximab discontinuation is not recommended in perianal Crohn's disease, because of a high rate of early relapse.

BACKGROUND In rats, 30-70% of dietary fatty acids (FAs) are absorbed through the portal vein. Whether this occurs in humans is unknown, but it may occur in persons with cirrhosis, who show a blunted chylomicronemic response to dietary fat without significant steatorrhea. OBJECTIVE The objective was to investigate whether portal FA absorption occurs in humans with cirrhosis. DESIGN Six control subjects and 10 patients with (n = 5) and without (n = 5) cirrhotic ascites were fed [1-(13)C]palmitic and oleic acids in a test meal. Samples were drawn before and 30, 60, 90, 120, 240, 360, 480, and 720 min afterward for plasma [1-(13)C]-labeled FAs and breath (13)CO(2) assay. Fecal [1-(13)C]-labeled FAs were also measured. RESULTS [1-(13)C]-Labeled FAs increased in chylomicrons in all groups, but less in ascitic cirrhotic patients, because their median area under the curve from 120 to 720 min was significantly lower than in the control subjects for labeled palmitate [520 (interquartile range: 192-1137) compared with 2862 (2674-4175) micromol . min/L] and oleate [829 (781-1263) compared with 3119 (2939-4986) micromol . min/L]. [1-(13)C]-Labeled FA enrichment of VLDL was also lower in cirrhotic patients. [1-(13)C]-Labeled FA in free FAs peaked earlier in ascitic than in nonascitic patients and control subjects, mainly for [1-(13)C]oleate, and the median area under the curve from 0 to 120 min was significantly higher in ascitic patients than in control subjects [301 (255-400) compared with 48 (34-185) micromol . min/L]. Fecal excretion of [1-(13)C]-labeled FA was negligible and not significantly different between groups. CONCLUSIONS The low [1-(13)C]-labeled FA concentrations in chylomicrons and VLDL, without increased fecal losses, confirm previous data in cirrhotic patients with the use of an unlabeled fat load. The earlier [1-(13)C]-labeled FA appearance in free FAs supports the portal absorption of dietary fat in patients with advanced cirrhosis with spontaneous portal-systemic shunting.

Summary The use of fibre-supplemented enteral nutrition has been clinically assessed only for a few purposes, such as improving G–I tolerance to short-term enteral feeding (particularly in critically ill patients), preventing constipation in long-term enteral nutrition, and improving the glycaemic control in diabetic or carbohydrate-intolerant patients. Randomized trials have yielded divergent results regarding the ability of fibre to prevent enteral nutrition-associated diarrhea, suggesting that fermentability is a sine qua non for this purpose. Partially hydrolyzed guar gum seems to be effective, but more trials with this and other fermentable fibres are required. In contrast, non-fermentable fibre should be preferred to prevent constipation in long-term enterally fed patients. Soy polysaccharide has been the most extensively investigated fibre source for this purpose in healthy subjects on a short-term basis, but its usefulness in the clinical setting needs to be confirmed. The ability of fibre to decrease postprandial glycaemic response mostly depends of its viscosity, a property which is lost in the manufacturing process (hydrolysis) for its incorporation into enteral solutions for tube feeding. Although disease-specific enteral diets for diabetics appear to be better than standard formulas for metabolic control, it is difficult to ascertain to what extent fibre supplementation contributed to their beneficial effects.