Background & Aims Patients with inflammatory bowel disease (IBD) who have been exposed to thiopurines might have an increased risk of skin cancer. We assessed this risk among patients in France. ...Methods We performed a prospective observational cohort study of 19,486 patients with IBD, enrolled from May 2004 to June 2005, who were followed up until December 31, 2007. The incidence of nonmelanoma skin cancer (NMSC) in the general population, used for reference, was determined from the French Network of Cancer Registries. Results Before the age of 50 years, the crude incidence rates of NMSC among patients currently receiving or who previously received thiopurines were 0.66/1000 and 0.38/1000 patient-years, respectively; these values were 2.59/1000 and 1.96/1000 patient-years for the age group of 50 to 65 years and 4.04/1000 and 5.70/1000 patient-years for patients older than 65 years. Among patients who had never received thiopurines, the incidence of NMSC was zero before the age of 50 years, 0.60/1000 for the ages of 50 to 65 years, and 0.84/1000 for those older than 65 years. A multivariate Cox regression model stratified by propensity score quintiles showed that ongoing thiopurine treatment (hazard ratio HR, 5.9; 95% confidence interval CI, 2.1–16.4; P = .0006) and past thiopurine exposure (HR, 3.9; 95% CI, 1.3–12.1; P = .02) were risk factors for NMSC. They also identified age per 1-year increase as a risk factor for NMSC (HR, 1.08; 95% CI, 1.05–1.11; P < .0001). Conclusions Ongoing and past exposure to thiopurines significantly increases the risk of NMSC in patients with IBD, even before the age of 50 years. These patients should be protected against UV radiation and receive lifelong dermatologic screening.
Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular pattern recognition receptor that senses bacterial peptidoglycan (PGN)-conserved motifs in cytosol and stimulates host immune ...response. The association of NOD2 mutations with a number of inflammatory pathologies, including Crohn disease (CD), Graft-versus-host disease (GVHD), and Blau syndrome, highlights its pivotal role in host-pathogen interactions and inflammatory response. Stimulation of NOD2 by its ligand (muramyl dipeptide) activates pro-inflammatory pathways such as nuclear factor-κB (NF-κB), mitogen-activated protein kinases (MAPKs), and Caspase-1. A loss of NOD2 function may result in a failure in the control of microbial infection, thereby initiating systemic responses and aberrant inflammation. Because the ligand of Nod2 is conserved in both gram-positive and gram-negative bacteria, NOD2 detects a wide variety of microorganisms. Furthermore, current literature evidences that NOD2 is also able to control viruses' and parasites' infections. In this review, we present and discuss recent developments about the role of NOD2 in shaping the gut commensal microbiota and pathogens, including bacteria, viruses, and parasites, and the mechanisms by which Nod2 mutations participate in disease occurrence.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Rodents are recognized as hosts for at least 60 zoonotic diseases and may represent a serious threat for human health. In the context of global environmental changes and increasing mobility of humans ...and animals, contacts between pathogens and potential animal hosts and vectors are modified, amplifying the risk of disease emergence. An accurate identification of each rodent at a specific level is needed in order to understand their implications in the transmission of diseases. Among the Muridae, the Rattini tribe encompasses 167 species inhabiting South East Asia, a hotspot of both biodiversity and emerging and re-emerging diseases. The region faces growing economical development that affects habitats, biodiversity and health. Rat species have been demonstrated as significant hosts of pathogens but are still difficult to recognize at a specific level using morphological criteria. DNA-barcoding methods appear as accurate tools for rat species identification but their use is hampered by the need of reliable identification of reference specimens. In this study, we explore and highlight the limits of the current taxonomy of the Rattini tribe.
We used the DNA sequence information itself as the primary information source to establish group membership and estimate putative species boundaries. We sequenced two mitochondrial and one nuclear genes from 122 rat samples to perform phylogenetic reconstructions. The method of Pons and colleagues (2006) that determines, with no prior expectations, the locations of ancestral nodes defining putative species was then applied to our dataset. To give an appropriate name to each cluster recognized as a putative species, we reviewed information from the literature and obtained sequences from a museum holotype specimen following the ancient DNA criteria.
Using a recently developed methodology, this study succeeds in refining the taxonomy of one of the most difficult groups of mammals. Most of the species expected within the area were retrieved but new putative species limits were also indicated, in particular within Berylmys and Rattus genera, where future taxonomic studies should be directed. Our study lays the foundations to better investigate rodent-born diseases in South East Asia and illustrates the relevance of evolutionary studies for health and medical sciences.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has ...been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent studies reported a role for more than 70 genes or loci in the susceptibility to Crohn's disease (CD). However, the impact of these associations in clinical practice remains to be defined. The ...aim of the study was to analyse the relationship between genotypes and phenotypes for the main 53 CD-associated polymorphisms.
A cohort of 798 CD patients with a median follow up of 7 years was recruited by tertiary adult and paediatric gastroenterological centres. A detailed phenotypic description of the disease was recorded, including clinical presentation, response to treatments and complications. The participants were genotyped for 53 CD-associated variants previously reported in the literature and correlations with clinical sub-phenotypes were searched for. A replication cohort consisting of 722 CD patients was used to further explore the putative associations.
The NOD2 rare variants were associated with an earlier age at diagnosis (p = 0.0001) and an ileal involvement (OR = 2.251.49-3.41 and 2.77 1.71-4.50 for rs2066844 and rs2066847, respectively). Colonic lesions were positively associated with the risk alleles of IL23R rs11209026 (OR = 2.25 1.13-4.51) and 6q21 rs7746082 (OR = 1.60 1.10-2.34 and negatively associated with the risk alleles of IRGM rs13361189 (OR = 0.29 0.11-0.74) and DEFB1 rs11362 (OR = 0.50 0.30-0.80). The ATG16L1 and IRGM variants were associated with a non-inflammatory behaviour (OR = 1.75 1.22-2.53 and OR = 1.50 1.04-2.16 respectively). However, these associations lost significance after multiple testing corrections. The protective effect of the IRGM risk allele on colonic lesions was the only association replicated in the second cohort (p = 0.03).
It is not recommended to genotype the studied polymorphisms in routine practice.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hirschsprung's disease (HSCR) is a serious congenital bowel disorder with a prevalence of 1/5000. Currently, there is a lack of systematically developed guidelines to assist clinical decision-making ...regarding diagnostics and management.
This guideline aims to cover the diagnostics and management of rectosigmoid HSCR up to adulthood. It aims to describe the preferred approach of ERNICA, the European Reference Network for rare inherited and congenital digestive disorders.
Recommendations within key topics covering the care pathway for rectosigmoid HSCR were developed by an international workgroup of experts from 8 European countries within ERNICA European Reference Network from the disciplines of surgery, medicine, histopathology, microbiology, genetics, and patient organization representatives. Recommendation statements were based on a comprehensive review of the available literature and expert consensus. AGREE II and GRADE approaches were used during development. Evidence levels and levels of agreement are noted.
Thirty-three statements within 9 key areas were generated. Most recommendations were based on expert opinion.
In rare or low-prevalence diseases such as HSCR, there remains limited availability of high-quality clinical evidence. Consensus-based guidelines for care are presented.
Crohn disease (CD) is a multifactorial disease in which an abnormal immune response in the gastrointestinal (GI) tract leads to chronic inflammation. The small intestine, particularly the ileum, of ...patients with CD is colonized by adherent-invasive E. coli (AIEC)--a pathogenic group of E. coli able to adhere to and invade intestinal epithelial cells. As the earliest inflammatory lesions are microscopic erosions of the epithelium lining the Peyer's patches (PPs), we investigated the ability of AIEC bacteria to interact with PPs and the virulence factors involved. We found that AIEC bacteria could interact with mouse and human PPs via long polar fimbriae (LPF). An LPF-negative AIEC mutant was highly impaired in its ability to interact with mouse and human PPs and to translocate across monolayers of M cells, specialized epithelial cells at the surface of PPs. The prevalence of AIEC strains harboring the lpf operon was markedly higher in CD patients compared with controls. In addition, increased numbers of AIEC, but not LPF-deficient AIEC, bacteria were found interacting with PPs from Nod2(-/-) mice compared with WT mice. In conclusion, we have identified LPF as a key factor for AIEC to target PPs. This could be the missing link between AIEC colonization and the presence of early lesions in the PPs of CD patients.
Background & Aims: Celiac disease may be associated with autoimmune diseases. The aims of the present study were to determine in celiac patients which factors modulate the risk of autoimmune disease ...and to evaluate the effect of the gluten-free diet. Methods: The occurrence of autoimmune disease and compliance to gluten-free diet were specified retrospectively in 924 celiac patients recruited from 27 French pediatric and adult gastroenterology centers. Results: One or several autoimmune diseases had developed in 178 patients. The cumulative risk of autoimmune disease was 8.1% ± 1% at age 15, and 15.7% ± 1.5% at age 30. Factors associated with an increased risk were family history of autoimmunity (hazard ratio, 2.36; 95% confidence interval, 1.71–3.31) and diagnosis of celiac disease before 36 years of age (hazard ratio, 2.65; 95% confidence interval, 1.79–3.85). After diagnosis of celiac disease, 55 of 788 patients developed an autoimmune disease. The cumulative risk of subsequent autoimmune disease was lower in patients compliant to a gluten-free diet versus noncompliant patients (at 10 years, 6% ± 2% vs 15.6% ± 5.9%, respectively; P = .02). The incidence of autoimmune diseases was 5.4 per 1000 patient-years during adherence to a gluten-free diet versus 11.3 per 1000 patient-years during nonadherence to the diet ( P = .002). Results were similar in both the pediatric and the adult populations. Conclusions: Celiac patients most at risk for autoimmune disease are those diagnosed early in life and having a family history of autoimmunity. The gluten-free diet has a protective effect.
The incidence of inflammatory bowel diseases (IBDs) tended to increase for several decades. Diet is suspected to be a major determinant of the occurrence of these diseases. This prospective study ...aimed to assess the associations among occurrence of IBD, dietary patterns, and ultra-processed food in the French NutriNet-Santé cohort.
Participants of the NutriNet-Santé cohort who completed at least three 24-hour dietary records were included. Incident IBD cases were identified from 3 questionnaires and confirmed by phone or email interview. Major dietary patterns (DPs) were computed using a principal component analysis (PCA) based on 29 food groups' consumption, whereas proportions of ultra-processed foods (UPFs) were obtained using the NOVA classification. Multivariable Poisson models were performed to evaluate associations among DP quintiles, UPF proportion (UPFp) in the diet, and incident IBD.
A total of 105,832 participants were included, contributing 238,924 person-years in a mean follow-up of 2.3 ± 2.2 years. Among them, 75 participants reported an incident IBD. Three major DPs were retained: "healthy," "traditional," and "western." No significant association was found for DPs and UPFp after adjustments for covariates.
In this study, neither DPs nor UPF proportion in the diet were significantly associated with the risk of incident IBD after adjustments for covariates. Further studies are needed to investigate the long-term association between diet and IBD.
ABSTRACT
Objective:
Infliximab (IFX) is a frequent therapeutic option for Crohn disease (CD) patients. Early detection of responders to IFX is critical for the management of CD in order to avoid ...long‐term exposure to the drug without benefit. This retrospective study aimed at analysing which early parameters recorded during the induction period are able to predict response to IFX during the maintenance period in pediatric CD.
Patients and Methods:
Medical records of all CD patients ages from 2 to 18 years who received IFX at a tertiary IBD center were retrospectively analyzed. Children were classified in 3 groups according to their response at week 14 (W14) (1) remission, (2) clinical response or (3), no response. The factors recorded at W0, W2, and W6, which were associated with remission at W14 were analyzed using a logistic regression.
Results:
Among the 111 patients included, 74.8% patients were responders to IFX at W14, including 38.7% in clinical remission and 36% with partial clinical response. Clinical remission at W14 was associated with normal growth (P < 0.01), and normal albuminemia (P = 0.01) at baseline, It was also associated with trough levels to IFX >8.3 μg/ml at week 6 (P < 0.01).
Conclusion:
Trough levels to IFX >8.3 μg/ml at week 6 are predictive of remission at W14 for luminal disease.
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