Development of pre-school children

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 7 uppsatser.

INTRODUCTION: Acute Severe Ulcerative Colitis (ASUC) is a life threatening condition which requires urgent and aggressive medical therapy to reduce mortality, morbidity and avoid surgery; the mainstay of treatment is intravenous corticosteroids. To facilitate this process it is essential to identify patients at high risk of poor outcomes and emergency colectomy. Numerous risk factors predicting the need for surgery have described in the Western literature both at presentation and on day 3 of intravenous therapy, however there are no local data addressing this issue. As such it is unclear if these predictors are applicable in our setting. The aim of this study is thus to identify risk factors for emergency colectomy in patients admitted to Groote Schuur Hospital with ASUC. METHODS: A retrospective cohort study of 98 patients admitted with ASUC between January 2003 and January 2013 was performed. Clinical, demographic, laboratory, radiological and endoscopic factors on admission and 3 days thereafter were analysed as predictors of colectomy by univariate and multivariate analysis. Patients were followed up retrospectively for 90 days RESULTS: Twenty five percent of the cohort underwent emergency colectomy, 80% within 15 days of presentation. On univariate analysis factors on admission which predicted colectomy were exposure to oral corticosteroids (p=0.01), megacolon (p=0.049) or mucosal islands (p=0.04) on abdominal Xray, and a short duration from UC diagnosis until presentation with ASUC (p=0.04). There was no significant association between ethnicity, age at UC diagnosis, gender, family history of IBD, or smoking status. There was also no association with baseline haemoglobin or CRP. The only day 3 variable that significantly predicted colectomy was serum albumin (p=0.01).This was also the only variable to remain significant on multivariate analysis (OR 0.79, 95% CI 0.65-0.97, p=0.01). CONCLUSION: ASUC is a medical emergency, predicting which patients will likely require colectomy is a very valuable tool in guiding therapeutic management. In our study the only variable significantly associated with colectomy was hypoalbuminaemia on day 3. However given the small study numbers a larger prospective study would be of value in identifying additional risk factors.

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The human gut microbiome is believed to play an integral role in host health and disease. In a microbial community, associations between constituent members play an important role in determining the overall structure and function of the community. To understand the nature of bacterial associations at the species level in healthy human gut microbiomes, we analyzed previously published collections of whole-genome shotgun sequence data, from fecal samples obtained from four different healthy human populations. Using a Random Forest Classifier, we identified bacterial species that were prevalent in these populations and whose relative abundances could be used to accurately distinguish between the populations. Bacterial association networks were also constructed using these signature species revealed conserved bacterial associations across populations and a dominance of positive associations over negative associations, with this dominance being driven by associations between species that are closely related either taxonomically or functionally. Functional analysis using protein families suggests that much of the taxonomic variation across human populations does not foment substantial functional differences. Next, multiple external healthy controls from the same geographical regions (American population) were compared to Inflammatory Bowel Disease (IBD) samples from the American population using shotgun sequencing data. We identified 34 bacterial species that were significantly elevated in IBD samples, relative to all control groups. These species elevated in IBD appear to play important roles in the healthy control groups, but it is possible that their over-abundance has deleterious effects on the host, possibly due to many of these bacteria being involved in mucin degradation, immune modulation, antibiotic resistance, and inflammation. We also identified differences in functional capacities between IBD and healthy controls and linked the changes in the functional capacity to previously published clinical research and to symptoms that commonly occur in IBD, such as rectal bleeding, diarrhea, vitamin K deficiency, and inflammation.

Although treatment of Crohn's disease (CD) with TNFa monoclonal antibodies is beneficial, many patients stop responding over time and become at risk of acquiring infections. This study investigated an alternative approach to attenuate the release of excess TNFα by silencing iRHOMs 1/2 with the intention of restoring TGFβ-mediated Immunosuppression through Mitigation of TNFα converting enzyme (TACE) Trafficking. TACE, a transmembrane metalloprotease involved in signaling of receptors/cytokines/growth factors/adhesion proteins, is upregulated in CD, resulting in a marked increase of membranous TNFα cleavage and inflammation. Initially, we measured TGFβRII shedding in plasma from CD patients and healthy controls (N=40 per group). We also measured the expression and production of TGFβ ligand, TGFβRII shedding, TNFα, IL-6, IL-1β, IL-10, and global versus membranous TACE production in CD-like macrophages during infection. Furthermore, we transfected CD-like macrophages with iRHOM siRNA during infection and measured the phosphorylation of Smad3, and the expression and production of key cytokines, and plasminogen activator inhibitor-1 (PAI-1). The impact of TNFα release and TGFβRII shedding in co-cultured Caco-2 monolayers was measured via Dihydroethidium (DHE) staining, NOX-1 gene expression analysis, and NADP/NADPH quantification. TGFβRII shedding was significantly higher in CD plasma compared to healthy controls [515.52 ± 54.23 pg/mL vs 310.81 ± 43.16 pg/mL, respectively]. Plasma from CD patients infected with Mycobacterium avium subspecies paratuberculosis (MAP) had significantly more TGFβRII shedding (601.83 ± 49.56 pg/mL) than MAP-negative CD samples (430.37 ± 45.73 pg/mL). TACE production, TGFβ expression and production, and TGFβRII shedding were also higher in MAP-infected macrophages compared to the controls. Following iRHOMs siRNA transfection, TACE expression, production, and membrane localization were significantly decreased. There was significant decrease in the expression and production of TGFβRII shedding, TNFα, IL-6, and IL-1β, and PAI-1; and an increase in IL-10 and Smad3 phosphorylation. Overall, there was decrease in inflammation and Caco-2 oxidative stress. The data clearly demonstrated that silencing iRHOMs 1 and 2 has significantly reduced TACE membrane trafficking, restored TGFβ-mediated immunosuppression, reduced the inflammatory response, and ultimately reversed tissue damage. The study provides a framework for new and safer therapeutic options to treat autoimmune disease including CD and Rheumatoid Arthritis.

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Fatty liver has previously often been associated with excessive alcohol consumption. During the last two decades, the interest in fatty liver occurring in non-drinkers i.e. non-alcoholic fatty liver disease (NAFLD) has increased dramatically. Today, NAFLD is considered as the most common liver disease in the developed world. It is strongly associated with obesity, insulin resistance, and hypertension. Thus, NAFLD is considered as the hepatic manifestation of the metabolic syndrome. The spectrum of NAFLD includes: simple fatty liver without necroinflammatory activity; non-alcoholic steatohepatitis (NASH), a condition characterised by hepatocellular injury, inflammation, and fibrosis; cirrhosis; and in some individuals hepatocellular carcinoma. The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the pathologist uses a four-graded scale: 0–3 or none, slight, moderate and severe. In this thesis we show that there is a considerable inter- and intraindividual variation in such scoring methods and that a more standardised and quantitative approach is preferable. The area/volume of fat in liver biopsies is greatly overestimated when assessed semiquantitatively. Moreover, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis. The long-term clinical and histopathological course of 129 consecutively enrolled NAFLD patients was studied. Mean follow-up (SD) was 13.7 (1.3) years. Survival of NASH patients was reduced compared with a matched reference population. These subjects more often died from cardiovascular and liver-related causes. Seven patients (5.4%) developed end-stage liver disease, including 3 patients with hepatocellular carcinoma. Most NAFLD patients will develop diabetes or impaired glucose tolerance in the long term. Progression of liver fibrosis is associated with more pronounced insulin resistance and significant weight gain. During follow-up, 17 patients had been prescribed a statin. At follow-up, patients on medication with statins had significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Although patients under statin treatment exhibited a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage. It is concluded that statins can be prescribed safely in patients with elevated liver enzymes because of NAFLD. Alcohol consumption was evaluated with a validated questionnaire combined with an oral interview. In a multivariate analysis moderate alcohol consumption, particularly when frequency of heavy episodic drinking was analysed, consistent with the diagnosis of NAFLD to be set, was independently associated with fibrosis progression in NAFLD. The NAFLD activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. We evaluated the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in our cohort of NAFLD patients. Although the NAS was independently associated with future risk of progressive fibrosis in NAFLD, the clinical usefulness of the score was limited due to significant overlap in clinical development between NAS-score groups.

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