Escherichia coli est une espèce bactérienne à multiples facettes. En effet, certaines souches sont présentes à l’état commensal au niveau intestinal, ou sont utilisées comme probiotiques. À l’inverse, d’autres souches sont responsables d’infections intestinales ou extra-intestinales chez l’Homme et les animaux à sang chaud. Les souches d’E. coli pathogènes extra-intestinales (ExPEC) sont responsables de nombreuses maladies infectieuses (méningites néo-natales, infections urinaires, septicémies ou infections respiratoires). Plusieurs facteurs de virulence ont été identifiés chez les souches ExPEC (adhésines, invasines…) et notamment la protéine IbeA, mise en évidence dans une souche isolée d’un cas de méningite néo-natale humaine. Le gène ibeA est retrouvé chez différentes souches ExPEC, dont certaines d’origine aviaire. Il est localisé au sein de l’îlot génomique GimA, sur un des quatre opérons de cet îlot, entre ibeR codant un potentiel régulateur et ibeT codant un potentiel antiporteur. La protéine IbeA a été décrite comme jouant un rôle dans l’invasion bactérienne des cellules endothéliales microvasculaires de cerveau humain (HBMEC). Afin de mieux comprendre le rôle d’IbeA dans le processus infectieux et l’invasion cellulaire, nous avons étudié l’implication d’IbeA dans l’adhésion de la souche ExPEC d’origine aviaire BEN2908 puis tenté de déterminer la localisation de cette protéine et son lien avec la protéine IbeT. L’étude phénotypique comparative de la souche BEN2908 et de son mutant ?ibeA nous a montré qu’IbeA intervenait dès le stade de l’adhésion aux HBMEC. Des tests d’adhésion en absence des fimbriae de type 1 (adhésine majeure de notre souche) nous ont montré que dans ce contexte, IbeA n’avait pas d’action sur l’adhésion. Ce résultat nous a suggéré qu’il pouvait y avoir une baisse d’expression des fimbriae de type 1 à la surface bactérienne dans un mutant ?ibeA, ce que nous avons montré par dots blots. Pour comprendre comment IbeA entraînait une modification de l’expression des fimbriae de type 1, nous nous sommes intéressés au contrôle de l’expression des gènes de l’opéron fim. Nous avons ainsi montré que le promoteur de ces gènes, localisé sur un élément invertible, était préférentiellement dans une orientation ne permettant pas la transcription des gènes fim dans un mutant ?ibeA. Nous avons ensuite mis en évidence chez le mutant ?ibeA une baisse de l’expression des gènes fimB et fimE qui codent pour deux recombinases participant au contrôle de l’orientation de l’élément invertible. Ces baisses d’expression de fimB et fimE pourraient expliquer la diminution d’expression des fimbriae de type 1 dans le mutant ?ibeA. Enfin, des phénotypes similaires à ceux du mutant ?ibeA ont été observés chez un mutant ?ibeT. La localisation d’IbeA est indispensable pour comprendre comment cette protéine peut agir sur l’expression des recombinases FimB et FimE. Nous avons localisé IbeA dans le compartiment cytoplasmique, mais l’incertitude sur la fonctionnalité d’IbeA dans les constructions génétiques utilisées nécessite de confirmer ces premiers résultats. Enfin, nous avons recherché un rôle métabolique pour IbeA et IbeT étant données les homologies d’IbeT avec des transporteurs de composés carbonés. Nous avons observé qu’un mutant ?ibeT présentait un retard de croissance par rapport à la souche sauvage et au mutant ?ibeA dans des cultures en milieu minimum avec du fumarate, du succinate, du malate ou de l’aspartate comme seule source de carbone. Ces résultats suggèrent un lien entre le métabolisme de certains dicarboxylates, l’expression des fimbriae de type 1 et les protéines IbeA et IbeT. Ils ouvrent de nombreuses perspectives pour la compréhension du mécanisme d’action d’IbeA et IbeT. / Escherichia coli is bacterial species with multiple facets. Indeed, some strains are present at a commensal state in the intestinal tract of humans and warm-blooded animals, or are used as probiotics. Conversely, other strains are responsible for intestinal or extra-intestinal infections in Humans and warm-blooded animals. Extra-intestinal pathogenic E. coli (ExPEC) strains are responsible for multiple infectious diseases (neonatal meningitis, urinary tract infections, septicaemias or respiratory infections). Several virulence factors have been identified in ExPEC strains (adhesins, invasins,…) and notably the IbeA protein, originally identified in a strain isolated from a case of human neonatal meningitis. The ibeA gene is found in different ExPEC strains, of including strains avian origin. It is located on one of the four operon of the GimA genomic island, between ibeR coding a putative regulator and ibeT coding a putative antiporter. The IbeA protein is known for its role in bacterial invasion of human brain microvascular endothelial cells (HBMEC). In order to better understand the role of IbeA in the infectious process and cellular invasion, we have studied the involvement of IbeA in adhesion of the avian pathogenic E. coli strain BEN2908 and attempted to determine the localisation of this protein and its link with the IbeT protein. The comparative henotypic study of strain BEN2908 and its ?ibeA mutant showed that IbeA was involved in the adhesion to HBMEC. Adhesion tests in the absence of type 1 fimbriae ( the major adhesin of our strain) showed that IbeA did not have a direct role in adhesion in this context. This result suggested there could be a decrease in type 1 fimbriae expression at the bacterial surface in the ?ibeA mutant. This was demonstrated by dot blots. To understand how IbeA led to a modification of type 1 fimbriae, we investigated the role of IbeA in the control of the expression of genes that belong to the fim operon. Thus we showed that the promoter of these genes, located on an invertible element, was preferentially in an orientation preventing transcription of the fim genes in the ?ibeA mutant. Then, we highlighted in the ?ibeA mutant, a decrease of expression of the fimB and fimE genes encoding two recombinases involved in the orientational control of invertible element. These decreases of fimB and fimE expression could explain the reduction of type 1 fimbriae expression in the ?ibeA mutant. Lastly, phenotypes similar to that of the ?ibeA mutant were observed in a ?ibeT mutant. The localisation of IbeA is necessary to understand how this protein can act on fimB and fimE expression. We localised IbeA in the bacterial cytoplasm, but the doubt on the functionality of IbeA in the genetic constructions used demands that these results be confirmed. Finally, we have looked for a metabolic role for IbeA and IbeT, given the IbeT homology with carbon compound transporters. We have observed that, in minimal broth with fumarate, succinate, malate or aspartate as sole carbon sources, the ?ibeT mutant presented a lower growth rate than the wild type strain and ?ibeA mutant. Altogether, these results suggest a link between metabolism of dicarboxylates, type 1 fimbriae expression and IbeA and IbeT proteins. They open numerous perspectives for the comprehension of IbeA and IbeT mechanisms.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 152-175).

Background: Vaccines have been hypothesized in the etiology of autoimmune diseases including type 1 diabetes. There are cases of diabetes reported in the Vaccine Adverse Event Reporting System (VAERS) following the administration of the human papillomavirus (HPV) vaccine, however this potential association has yet to be investigated. The objective of this thesis was to determine whether there is an association between immunization against HPV and the development of type 1 diabetes mellitus in grade 8 girls eligible for Ontario’s vaccination program. Methods: A retrospective, population-based, cohort study of girls residing within an Ontario health unit and eligible for the province’s publicly funded school-based HPV vaccination program between 2007 and 2010 was executed using provincial administrative health databases and the Immunization Recording Information System (IRIS) database. To control for known, unknown and unmeasured time-independent confounders, a self-controlled case series analysis was conducted. The relative incidence and 95% confidence interval were estimated using conditional Poisson regression. Results: The study cohort was comprised of 3465 girls with a mean age of 13.2 years at cohort entry (range 12.7 to 13.6 years). The mean duration of follow up was 2.7 years and ranged from 1.6 to 3.6 years. The proportion of girls who received at least one dose of the qHPV vaccine during the observation period was 58.3% (n=2020). During the study follow-up 15 cases of new onset type 1 diabetes were observed, six of which were classified as etiologically exposed to the qHPV vaccine. Using an indefinite risk window, immunization with the qHPV vaccine was not associated with an increased risk of developing type 1 diabetes (age and season-adjusted RI 0.15; 95% CI 0.02-1.32). Conclusions: The results of this thesis regarding the risk of type 1 diabetes following immunization with the qHPV vaccine are inconclusive as a consequence of the small number of cases identified. However, the random distribution of cases across time and across exposure status suggests that there is no association. Before a definitive conclusion is reached the analysis must be re-conducted on a larger cohort. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2012-05-28 10:39:00.73

Type 1 diabetes (T1D) is an autoimmune disease that occurs when T lymphocyte cells attack and destroy beta cells in the pancreas.1 The cause of T1D is considered to be a combination of genetic predisposition and environmental or lifestyle risk factors. Early introduction of diet is thought to play a role in the development of T1D as it is less common in people who were breastfed and who were introduced to solid foods at later ages. The protection that breastfeeding can offer against the development of childhood obesity and T1D in children at risk for T1D is unknown and may be related to many different factors. The purpose of this project is to review the literature on the association between infant diet, including breastfeeding and complementary foods, and the development of obesity and T1D. This information will be used to prepare a secondary analysis proposal to examine the association between length of exclusive breastfeeding and obesity risk in children at risk for T1D for submission to the Presentations and Publications Committee of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study.

Indiana University-Purdue University Indianapolis (IUPUI) / Bone disease and degradation is a ubiquitous problem, the complexity and treatment of which humanity has only begun to understand. Diabetes Mellitus is a disease which, in all forms, profoundly effects the organs of the body, bone included. As is often the case in biology, there are inherent differences between the sexes when considering skeletal development and disease progression and outcome. Although there are several reported mouse models for diabetes, until now there has been no characterization of bone disease in any model where diabetes occurs with equal frequency in males and females in greater than 90% of animals. In this study, a protocol for reliable induction of diabetes in both sexes using intraperitoneal injections of Streptozotocin was developed. The resulting bone phenotype in male and female mice was characterized and compared to weight and age matched control groups. In this model female diabetic mice exhibited a robust deficit in bone quality, while both sexes experienced loss of beta-cell mass and increased glycation of hemoglobin rendering the diabetic mice unable to produce insulin endogenously. Further, these mice were unable to metabolize exogenous insulin injected during insulin tolerance testing. This model is a strong candidate for future exploration of osteoporotic bone disease, Diabetes Mellitus, and the link between estrogen and glucose sensitivity.

This report takes an approach of laying the first steps to create an artificial pancreassystem as treatment for type 1 diabetes. This includes a thoroughly performedanalysis of the most intrusive physical factors, such as hormonal activity, time offset,errors of measurement and metabolism. Such factors raise a need forcompensation. A compensation that will enable the development of the link betweena continuous glugose monitoring(CGM)-device and an insulin infusion pump,a system that can be described as an Artificial Pancreas.Through analysis of measured glucose series, a mathematicalapproximation is presented to solve the time offset of CGM.The approximation gives sufficient results but with room for improvementFrom the analysis of affecting factors, a compensation model isdeveloped. The model is designed as a closed loop which is suitable for timecontinuous systems. The output of the compensation model equation presented here is adirective that would be read by an insulin pump.

Several epidemiological and clinical studies have indicated a possible role of Enterovirus (EV) infection in type 1 diabetes (T1D) development. However, the exact casual mechanism of these viruses in T1D development is not known. The aim of this thesis is to study various EVs that have been shown to differ in their immune phenotype, lytic ability, association with induction of islet autoantibodies, ability to replicate, cause islet disintegration and induce innate antiviral pathways in infected pancreatic cells in vitro. Furthermore, EV presence and pathogenic process in pancreatic tissue and isolated islets of T1D patients was also studied. Studies in this thesis for first time show the detection of EV RNA and protein in recent onset live T1D patients supporting the EV hypothesis in T1D development. Further all EV serotypes studied were able to replicate in islets, causing variable amount of islet disintegration ranging from extensive islet disintegration to not affecting islet morphology at all. However, one of the EV serotype replicated in only two out of seven donors infected, highlighting the importance of individual variation between donors. Further, this serotype impaired the insulin response to glucose stimulation without causing any visible islet disintegration, suggesting that this serotype might impaired the insulin response by inducing a functional block. Infection of human islets with the EV serotypes that are differentially associated with the development of islet autoantibodies showed the islet cell disintegration that is comparable with their degree of islet autoantibody seroconversion. Suggesting that the extent of the epidemic-associated islet autoantibody induction may depend on the ability of the viral serotypes to damage islet cells. Furthermore, one of the EV strains showed unique ability to infect and replicate both in endo and exocrine cells of the pancreas. EV replication in both endo and exocrine cells affected the genes involved in innate and antiviral pathways and induction of certain genes with important antiviral activity significantly varied between different donors. Suggesting that the same EV infection could result in different outcome in different individuals. Finally, we compared the results obtained by lytic and non lytic EV strains in vitro with the findings reported in fulminant and slowly progressing autoimmune T1D and found some similarities. In conclusion the results presented in this thesis further support the role of EV in T1D development and provide more insights regarding viral and host variation.  This will improve our understanding of the possible causative mechanism by EV in T1D development.

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Type 1 diabetes is a condition which affects the lives of thousands of young people throughout the UK. Existing research has recognised the difficulties that adolescents have in managing their diabetes, and a large amount of research has focused on glycaemic control, and influential factors. This project attempted to establish what is known about young people’s experiences of living with type 1 diabetes, and to further develop this knowledge pertaining particularly to the school environment through qualitative research. Method A systematic review of the literature in relation to young people’s views of their life with type 1 diabetes was conducted and a synthesising thematic analysis was carried out. A qualitative research study was then carried out involving 7 adolescents aged 13-16 years who had a diagnosis of type 1 diabetes. Semi-structured interviews were carried out with the focus being on the young people’s experiences of type 1 diabetes within the school environment. Interview sessions were transcribed and Interpretative Phenomenological Analysis (IPA) was used to analyse the data. Results Five themes emerged from the systematic review. Analysis of the studies led to the emerging themes of: Normal/Different, Control/Management, Relationships, Health– care and Educational experiences. The articles revealed that the experiences of adolescents varied, and were frequently dependent upon the actions of others. Four major themes emerged from the analysis of the research study: Support, Knowledge and Understanding, Standing out, and Adjusting and Accepting. Discussion Systematic review of the articles revealed that the experiences of adolescents varied, and were frequently dependent upon the actions of others. A sense of normalcy was important, and the strict routine and activities of diabetes management impacted upon their ability to achieve it. The support of friends and family was valued, but could at times become overwhelming and educational and health professionals made a difference to their ability to successfully fit diabetes into their lives. The suggestions made by individuals within the studies were generally consistent, and have implications for healthcare providers, friends and families, and schools in relation to facilitating successful diabetic management. Many of the young people taking part in the present research study had encountered negative experiences within the school environment in relation to both peers and staff. However, they described elements of helpful practice and made suggestions for improvements that could be made within school to facilitate a more positive experience.