Development of a uniform, very aggressive disease phenotype in all homozygous carriers of the NOD2 mutation p.Leu1007fsX1008 with Crohn's disease and active smoking status resulting in ileal stenosis requiring surgery

Background: NOD2variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value ofNOD2on an individual patient level remains controversial. We aimed to define the predictive power of the majorNOD2mutations regarding complicated CD in a large single center cohort. Methods 1076 CD patients were prospectively genotyped for the three common CD-associatedNOD2mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotype-phenotype analyses. Results Overall, 434 CD patients (40.3%) carried at least one of the three mainNOD2mutations. A significantly higher minor allele frequency (15.6%) of theNOD2frameshift mutation p.Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10(-5)). Moreover, a total of 54 CD patients (5.0%) were homozygous for thisNOD2frameshift mutation. 100% of these patients had ileal disease compared to 82% ofNOD2wild-type carriers (p<0.0001). In homozygous carriers of theNOD2frameshift mutation, 87% presented with ileal stenosis, 68.5% had fistulas, and 72.2% required CD-related surgery despite immunosuppressive therapy in 87% of these patients. All homozygous carriers of the 1007fs mutation who were active smokers had ileal stenosis and required CD-related surgery. Conclusion Homozygosity for Leu1007fsX1008 is an excellent biomarker for predicting complicated CD on an individual patient level. Active smoking and homozygosity for this mutation is associated with a 100% risk for developing ileal stenosis requiring CD-related surgery. In these patients, smoking cessation and early initiation of immunosuppressive strategies may be beneficial

The NOD2 Single Nucleotide Polymorphisms rs2066843 and rs2076756 Are Novel and Common Crohn's Disease Susceptibility Gene Variants

Background: The aims were to analyze two novel NOD2 variants (rs2066843 and rs2076756) in a large cohort of patients with inflammatory bowel disease and to elucidate phenotypic consequences. Methodology/Principal Findings: Genomic DNA from 2700 Caucasians including 812 patients with Crohn's disease (CD), 442 patients with ulcerative colitis (UC), and 1446 healthy controls was analyzed for the NOD2 SNPs rs2066843 and rs2076756 and the three main CD-associated NOD2 variants p.Arg702Trp (rs2066844), p.Gly908Arg (rs2066847), and p.Leu1007fsX1008 (rs2066847). Haplotype and genotype-phenotype analyses were performed. The SNPs rs2066843 (p = 3.01×10−5, OR 1.48, [95% CI 1.23-1.78]) and rs2076756 (p = 4.01×10−6; OR 1.54, [95% CI 1.28-1.86]) were significantly associated with CD but not with UC susceptibility. Haplotype analysis revealed a number of significant associations with CD susceptibility with omnibus p values 0.9). However, in CD, SNPs rs2066843 and rs2076756 were more frequently observed than the other three common NOD2 mutations (minor allele frequencies for rs2066843 and rs2076756: 0.390 and 0.380, respectively). In CD patients homozygous for these novel NOD2 variants, genotype-phenotype analysis revealed higher rates of a penetrating phenotype (rs2076756: p = 0.015) and fistulas (rs2076756: p = 0.015) and significant associations with CD-related surgery (rs2076756: p = 0.003; rs2066843: p = 0.015). However, in multivariate analysis only disease localization (p<2×10−16) and behaviour (p = 0.02) were significantly associated with the need for surgery. Conclusion/Significance: The NOD2 variants rs2066843 and rs2076756 are novel and common CD susceptibility gene variants

CEACAM6 Gene Variants in Inflammatory Bowel Disease

The carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) acts as a receptor for adherent-invasive E. coli (AIEC) and its ileal expression is increased in patients with Crohn's disease (CD). Given its contribution to the pathogenesis of CD, we aimed to investigate the role of genetic variants in the CEACAM6 region in patients with inflammatory bowel diseases (IBD). In this study, a total of 2,683 genomic DNA samples (including DNA from 858 CD patients, 475 patients with ulcerative colitis (UC), and 1,350 healthy, unrelated controls) was analyzed for eight CEACAM6 SNPs (rs10415946, rs1805223 = p.Pro42Pro, rs4803507, rs4803508, rs11548735 = p.Gly239Val, rs7246116 = pHis260His, rs2701, rs10416839). In addition, a detailed haplotype analysis and genotype-phenotype analysis were performed. Overall, our genotype analysis did not reveal any significant association of the investigated CEACAM6 SNPs and haplotypes with CD or UC susceptibility, although certain CEACAM6 SNPs modulated CEACAM6 expression in intestinal epithelial cell lines. Despite its function as receptor of AIEC in ileal CD, we found no association of the CEACAM6 SNPs with ileal or ileocolonic CD. Moreover, there was no evidence of epistasis between the analyzed CEACAM6 variants and the main CD-associated NOD2, IL23R and ATG16L1 variants. This study represents the first detailed analysis of CEACAM6 variants in IBD patients. Despite its important role in bacterial attachment in ileal CD, we could not demonstrate a role for CEACAM6 variants in IBD susceptibility or regarding an ileal CD phenotype. Further functional studies are required to analyze if these gene variants modulate ileal bacterial attachment

Broadband Multi-wavelength Properties of M87 during the 2017 Event Horizon Telescope Campaign

Abstract: In 2017, the Event Horizon Telescope (EHT) Collaboration succeeded in capturing the first direct image of the center of the M87 galaxy. The asymmetric ring morphology and size are consistent with theoretical expectations for a weakly accreting supermassive black hole of mass ∼6.5 × 109 M ⊙. The EHTC also partnered with several international facilities in space and on the ground, to arrange an extensive, quasi-simultaneous multi-wavelength campaign. This Letter presents the results and analysis of this campaign, as well as the multi-wavelength data as a legacy data repository. We captured M87 in a historically low state, and the core flux dominates over HST-1 at high energies, making it possible to combine core flux constraints with the more spatially precise very long baseline interferometry data. We present the most complete simultaneous multi-wavelength spectrum of the active nucleus to date, and discuss the complexity and caveats of combining data from different spatial scales into one broadband spectrum. We apply two heuristic, isotropic leptonic single-zone models to provide insight into the basic source properties, but conclude that a structured jet is necessary to explain M87’s spectrum. We can exclude that the simultaneous γ-ray emission is produced via inverse Compton emission in the same region producing the EHT mm-band emission, and further conclude that the γ-rays can only be produced in the inner jets (inward of HST-1) if there are strongly particle-dominated regions. Direct synchrotron emission from accelerated protons and secondaries cannot yet be excluded

Linguistic and cultural adaptation of user documentation : approaches and challenges

Since user documentation is an extension of the interface between a product and its users, compilers cannot afford to ignore its intercultural aspects. The paper identifies the localization variables which could influence the quality of user documentation and indicates related safety issues concerning the use of technical products in the respective cultural environment

Technical documentation for the elderly

Using examples from applied research conducted at the School of Applied Linguistics, Zurich University of Applied Sciences, this paper demonstrates which specific requirements technical documentation must consider for the target group of senior citizens. Various approaches are presented to show how the needs of this target group can be met

Specific requirements for technical communication in the development of a medical device user interface

How can technical communication, as part of applied linguistics, contribute to developing a medical device user interface so that devices can be used safely? Which particular requirements must be considered? This paper examines and illustrates selected aspects of this topic by presenting examples from applied research and offering related solutions

Synthesis, Swelling, and Exfoliation of Microporous Lamellar Titanosilicate AM-4

7 páginas, 10 figuras, 2 tablas.AM-4 is a layered porous titanosilicate built from TiO6 and SiO4 polyhedra. An improved synthesis of AM-4 crystalsenabling control of particle size by secondary growth and reducing synthesis time is presented. A new material, UZAR-S2, has been obtained by exfoliation of the smaller AM-4. The exfoliation consists of proton exchange with acetic acid, intercalation with nonylamine, and final activation by washing with HCl/water/ethanol. Besides XRD, TEM, N2 adsorption, FTIR, and UV/Vis characterization highlighting the delaminated character of UZAR-S2, CO2 adsorption was also measured.Financing from the Spanish Ministry of Science and Innovation (MAT2007-61028, CIT-420000-2009-32) and the Government of Aragón (PI035/09) is gratefully acknowledged. C. C. also thanks the Ministry for the “Juan de la Cierva” programme.Peer reviewe