Metabolomic profiles are gender, disease and time specific in the interleukin-10 gene-deficient mouse model of inflammatory bowel disease.

Metabolomic profiling can be used to study disease-induced changes in inflammatory bowel diseases (IBD). The aim of this study was to investigate the difference in the metabolomic profile of males and females as they developed IBD. Using the IL-10 gene-deficient mouse model of IBD and wild-type mice, urine at age 4, 6, 8, 12, 16, and 20 weeks was collected and analyzed by nuclear magnetic resonance (NMR) spectroscopy. Multivariate data analysis was employed to assess differences in metabolomic profiles that occurred as a consequence of IBD development and severity (at week 20). These changes were contrasted to those that occurred as a consequence of gender. Our results demonstrate that both IL-10 gene-deficient and wild-type mice exhibit gender-related changes in urinary metabolomic profile over time. Some male-female separating metabolites are common to both IL-10 gene-deficient and control wild-type mice and, therefore, appear to be related predominantly to gender maturation. In addition, we were able to identify gender-separating metabolites that are unique for IL-10 gene-deficient and wild-type mice and, therefore, may be indicative of a gender-specific involvement in the development and severity of the intestinal inflammation. The comparison of the gender-separating metabolomic profile from IL-10 gene-deficient mice and wild-type mice during the development of IBD allowed us to identify changes in profile patterns that appear to be imperative in the development of intestinal inflammation, but yet central to gender-related differences in IBD development. The knowledge of metabolomic profile differences by gender and by disease severity has potential clinical implications in the design of both biomarkers of disease as well as the development of optimal therapies

Tiesuolalogistiikka

Tämän opinnäytetyön tilaajana toimii YIT Rakennus Oy. Opinnäytetyö on kehittämisprojekti, jonka tavoitteena on tuottaa tilaajalle visuaalinen hallintajärjestelmä tiesuolan materiaalivirtojen seuraamiseen. Työn lähteenä on käytetty Liikenneviraston julkaisemaa materiaalia teiden kunnossapidosta sekä YIT:n eri työmaiden tuottama dataa teiden kunnossapidosta. Kehittämisprojektin lähtötietoina käytetään olemassa olevaa dataa tiesuolasta, lisäksi projektissa kartoitetaan uusia tapoja hyödyntää olemassa olevaa dataa, yhdenmukaistetaan eri työmaiden käytäntöjä kerätä dataa sekä tuodaan mahdollisuus koko organisaatiolle hyödyntää kerättyä dataa. Työssä kerrotaan myös yleisten teiden kunnossapidosta, teiden hoitoluokista, liukkaudentorjunnasta suolaamalla sekä tiesuolan varastoinnista, kuljetuksesta sekä materiaalivirtojen hallinnasta yleisesti. Työn tuloksena on syntynyt uusi hallintajärjestelmä tiesuolan materiaalivirtojen hallintaan sekä uusia toimintatapaehdotuksia liukkaudentorjuntamateriaalien hallinnasta kerättävään dataan.This Bachelor´s thesis was commissioned by YIT Construction Ltd. The purpose of the thesis was to develop a visual control system to follow the materials flow of the ice-control salt. Another aim was to explore new ways to utilize the existing data, standardize the practice of different construction sites to collect data and provide the organization with the possibility to utilize the collected data. The sources used in the thesis were the existing data and studies on the topic including the material published by Finnish Transport Agency and the data provided by YIT´s various construction sites on road maintenance. This thesis also discusses general road maintenance, road maintenance classes, antiskid treatment through ice-control salt, storage of ice-control salt, transportation and general material flow management. As a result of the thesis a new management system for the management of road salt material flows was produced. The thesis also includes suggestions for the control of ice-control salt material

A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis.

ObjectiveEtrolizumab (rhuMAb β7, anti-β7, PRO145223) is a humanised monoclonal antibody targeting the β7 subunit of the heterodimeric integrins α4β7 and αEβ7, which are implicated in leucocyte migration and retention in ulcerative colitis (UC). This randomised phase I study evaluated the safety and pharmacology of etrolizumab in patients with moderate to severe UC.DesignIn the single ascending dose (SAD) stage, etrolizumab (0.3, 1.0, 3.0, 10 mg/kg intravenous, 3.0 mg/kg subcutaneous (SC) or placebo) was administered 4:1 (n=25) in each cohort. In the multiple dose (MD) stage, new patients received monthly etrolizumab (0.5 mg/kg SC (n=4), 1.5 mg/kg SC (n=5), 3.0 mg/kg SC (n=4), 4.0 mg/kg intravenous (n=5)) or placebo (n=5). The pharmacokinetics was studied and Mayo Clinic Score evaluated at baseline, day 29 (SAD), and days 43 and 71 (MD).ResultsIn the SAD stage, there were no dose limiting toxicities, infusion or injection site reactions. Two impaired wound healing serious adverse events occurred in two patients receiving etrolizumab. In the MD stage, there were no dose limiting toxicities, and no infusion or injection site reactions. Headache was the most common adverse event, occurring more often in etrolizumab patients. Antietrolizumab antibodies were detected in two subjects. The duration of β7 receptor full occupancy was dose related. A clinical response was observed in 12/18 patients, and clinical remission in 3/18 patients treated with etrolizumab in the MD stage, compared with 4/5 and 1/5 placebo patients, respectively.ConclusionEtrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted

Patients with Inflammatory Bowel Disease Exhibit Dysregulated Responses to Microbial DNA

Background: A critical role for the gut epithelium lies in its ability to discriminate between pathogens and commensals and respond appropriately. Dysfunctional interactions between microbes and epithelia are believed to have a role in inflammatory bowel disease (IBD). In this study, we analyzed microbiota and gene expression in IBD patients and examined responses of mucosal biopsies to bacterial DNA. Methods: Biopsies were taken from non-inflamed areas of the colon in healthy controls (HC) and Crohn’s disease (CD) and ulcerative colitis (UC) patients in remission. Biopsies were snap-frozen or cultured with DNA from Lactobacillus plantarum (LP) or Salmonella dublin (SD). Gene expression was analyzed under basal conditions and in response to DNA. Gene networks were analyzed using Ingenuity Pathways software. Mucosal-associated microbiota was analyzed using terminal restriction fragment length polymorphism. Frequency of single nucleotide polymorphisms in NOD2 and TLR9 was assessed. Results: Patients with IBD had altered microbiota, enhanced expression of inflammatory genes, and increased correlations between specific gene expression and microbes. Principle component analysis showed CD and UC patients to cluster independently from healthy controls in both gene expression and microbial analysis. DNA from LP stimulated anti-inflammatory pathways in controls and UC patients, but induced an upregulation of IL17A in CD patients. There were no differences in SNP frequencies of TLR9 or NOD2 in the groups

Increased Epithelial Gaps in the Small Intestine Are Predictive of Hospitalization and Surgery in Patients With Inflammatory Bowel Disease

Objectives: Epithelial gaps resulting from intestinal cell extrusions can be visualized with confocal laser endomicroscopy (CLE) during colonoscopy and increased in normal-appearing terminal ileum of inflammatory bowel disease (IBD) patients. Cell-shedding events on CLE were found to be predictive of disease relapse. The aim of this study was to assess the prognostic value of epithelial gap densities for major clinical events (hospitalization or surgery) in follow-up. Methods: We prospectively followed IBD patients undergoing colonoscopy with probe-based CLE (pCLE) for clinical events including symptom flares, medication changes, hospitalization, or surgery. Survival analysis methods were used to compare event times for the composite outcome of hospitalization or surgery using log-rank tests and Cox proportional hazards models. We also examined the relationship of gap density with IBD flares, need for anti-tumor necrosis factor therapy, disease duration, gender and endoscopic disease severity, and location. Results: A total of 21 Crohn's disease and 20 ulcerative colitis patients with a median follow-up of 14 (11–31) months were studied. Patients with elevated gap density were at significantly higher risk for hospitalization or surgery (log-rank test P=0.02). Gap density was a significant predictor for risk of major events, with a hazard ratio of 1.10 (95% confidence interval=1.01, 1.20) associated with each increase of 1% in gap density. Gap density was also correlated with IBD disease duration (Spearman's correlation coefficient rho=0.44, P=0.004), and was higher in male patients (9.0 vs. 3.6 gaps per 100 cells, P=0.038). Conclusions: Increased epithelial gaps in the small intestine as determined by pCLE are a predictor for future hospitalization or surgery in IBD patients

Cross-sectional analysis of overall dietary intake and Mediterranean dietary pattern in patients with crohn's disease

The primary objective of this study was to explore the macro- and micro-nutrient intakes and dietary patterns of patients with Crohn’s disease (CD). Secondary objectives were to (a) compare the micronutrient intakes of CD patients with a representative sample of individuals, (b) describe the macro- and micronutrient intakes of male and female CD patients, and (c) describe Mediterranean diet scores (P-MDS) of male and female CD patients in remission that were recruited from an inflammatory bowel disease (IBD) clinic in Calgary, AB. Consecutive patients with ileal and/or colonic CD in endoscopic remission were recruited for participation in this cross-sectional study. Sixty-seven patients were enrolled with a mean age of 45, and a Body Mass Index (BMI) ≥ 25. Compared with the representative sample, patients with CD had similar energy, protein, carbohydrate, and total fat intake. However, polyunsaturated fats (PUFA), omega-6 and 3, and monounsaturated fats (MUFA) were lower in CD patients and dietary fiber intake was higher (p < 0.05). Vitamins C, D, thiamin, niacin, magnesium, phosphorus, zinc, and potassium were all significantly lower in all CD patients when compared to the representative sample (p < 0.05). Few patients with CD met the P-MDS criteria and overall scores were low (mean 4.5, Standard Deviation (SD) = 1.1 in males and 4.7, SD = 1.8 in females). The CD patients in this study had suboptimal dietary intakes and patterns and these data may be used to inform future dietary interventions in this population to improve intake

The NOD2-Smoking Interaction in Crohn's Disease is likely Specific to the 1007fs Mutation and may be Explained by Age at Diagnosis:A Meta-Analysis and Case-Only Study

Background: NOD2 and smoking are risk factors for Crohn's disease. We meta-analyzed NOD2-smoking interactions in Crohn's disease (Phase 1), then explored the effect of age at diagnosis on NOD2-smoking interactions (Phase 2). Methods: Phase 1: MEDLINE and EMBASE were searched for studies (n = 18) providing data on NOD2 and smoking in Crohn's disease. NOD2-smoking interactions were estimated using odds ratios (ORs) and 95% confidence intervals (CIs) calculated using random effects models. Phase 2: A case-only study compared the proportion of smokers and carriers of the 1007 fs variant across ages at diagnosis (≤16, 17–40, >40 years). Findings: Phase 1: Having ever smoked was less common among carriers of the 1007 fs variant of NOD2 (OR 0.74, 95%CI:0.66–0.83). There was no interaction between smoking and the G908R (OR 0.96, 95%CI:0.82–1.13) or the R702W variant (OR 0.89, 95%CI:0.76–1.05). Phase 2: The proportion of patients (n = 627) carrying the 1007 fs variant decreased with age at diagnosis (≤16 years: 15%; 17–40: 12%; >40: 3%; p = 0.003). Smoking was more common in older patients (≤16 years: 4%; 17–40: 48%; >40: 71%; p < 0.001). Interpretation: The negative NOD2-smoking interaction in Crohn's disease is specific to the 1007 fs variant. However, opposing rates of this variant and smoking across age at diagnosis may explain this negative interaction