The incidence of Type 1 diabetes is growing yearly. Worryingly, the aetiology of the disease is inconclusive. What is known is that the total number of affected individuals, as well as the severity and number of associated complications are growing for this chronic disease. With increasing complications due to severity, length of exposure, and poor control, the disease is beginning to consume an increasingly major portion of healthcare costs to the extent that it poses major economic risks in several nations. Research has shown that intensive insulin therapy aimed at certain minimum glycosylated haemoglobin threshold levels reduces the incidence of complications by up to 76% compared to conventional insulin therapy. Moreover, the effects of such intensive therapy regimes over a 6.5y duration persists for at least 10y after, a so called metabolic memory. Thus, early intervention can slow the momentum of complications far more easily than later intervention. Early, safe, intensive therapy protocols offer potential solutions to the growing social and economic effects of diabetes. Since the 1970s, the artificial endocrine pancreas has been heralded as just this type of solution. However, no commercial product currently exists, and ongoing limitations in sensors and pumps have resulted in, at best, modest clinical advantages over conventional methods of insulin administration or multiple daily injection. With high upfront costs, high costs of consumables, significant complexity, and the extensive infrastructure and support required, these systems and devices are only used by 2-15% of individuals with Type 1 diabetes. Clearly, there is an urgent need to address the large majority of the Type 1 diabetes population using conventional glucose measurement and insulin administration. For these individuals, current conventional or intensive therapies are failing to deliver recommended levels of glycaemic control. This research develops an understanding of clinical glycaemic control using conventional insulin administration and glucose measurement techniques in Type 1 diabetes based on a clinically validated in silico virtual patient simulation. Based on this understanding, a control protocol for Type 1 diabetes that is relatively simple and clinically practical is developed. The protocol design incorporates physiological modelling and engineering techniques to adapt to individual patient clinical requirements. By doing so, it produces accurate, patient-specific recommendations for insulin interventions. Initially, a simple, physiological compartmental model for the pharmacokinetics of subcutaneously injected insulin is developed. While the absorption process itself is subject to significant potential variability, such models enable a real-time estimation of plasma insulin concentration. This information would otherwise be lacking in the clinical environment of outpatient Type 1 diabetes treatment due to the inconvenience, cost, and laboratory turnaround for plasma insulin measurements. Hence, this validated model offers significant opportunity to optimise therapy selection. An in silico virtual patient simulation tool is also developed. A virtual patient cohort is developed on patient data from a representative cohort of the broad diabetes population. The simulation tool is used to develop a robust, adaptive protocol for prandial insulin dosing against a conventional intensive insulin therapy, as well as a controls group representative of the general diabetes population. The effect on glycaemic control of suboptimal and optimal, prandial and basal insulin therapies is also investigated, with results matching clinical expectations. To gauge the robustness of the developed adaptive protocol, a Monte Carlo analysis is performed, incorporating realistic and physiological errors and variability. Due to the relatively infrequent glucose measurement in outpatient Type 1 diabetes, a method for identifying the diurnal cycle in effective insulin sensitivity and modelling it in retrospective patient data is also presented. The method consists of identifying deterministic and stochastic components in the patient effective insulin sensitivity profile. Circadian rhythmicity and sleep-wake phases have profound effects on effective insulin sensitivity. Identification and prediction of this rhythm is of utmost clinical relevance, with the potential for safer and more effective glycaemic control, with less frequent measurement. It is thus a means of further enhancing any robust protocol and making it more clinically practical to implement. Finally, this research presents an entire framework for the realistic, and rapid development and testing of clinical glycaemic control protocols for outpatient Type 1 diabetes. The models and methods developed within this framework allow rapid and physiological identification of time-variant, patient-specific, effective insulin sensitivity profiles. These profiles form the responses of the virtual patient and can be used to develop and robustly test clinical glycaemic control protocols in a broad range of patients. These effective insulin sensitivity profiles are also rich in dynamics, specifically those circadian in nature which can be identified, and used to provide more accurate glycaemic prediction with the potential for safer and more effective control.

The dorsal vagal complex (DVC), containing the nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus nerve (DMV), plays a pivotal role in autonomic regulation. Afferent fibers from peripheral organs and higher brain centers synapse in the NTS, which integrates these synaptic connections as well as information from systemically circulating hormones and metabolites. The integrated information is relayed to the dorsal motor nucleus of the vagus nerve (DMV), which in turn, projects motor fibers to elicit parasympathetic control of digestive and other viscera. Physiological functions mediated by the DVC are disrupted in diabetic patients and synaptic plasticity within the DVC has been linked to these complications. N-methyl-D-aspartic acid (NMDA) receptors have been extensively studied for their involvement in synaptic plasticity in a variety of central nervous system disorders; and their activation in the DVC modulates hepatic glucose production and feeding behavior. Although chronic disease can alter NMDA function, changes in DVC expression and/or sensitivity of NMDA receptors in diabetic states has not been addressed. Using whole cell electrophysiology, functional properties of the nuclei in the DVC were investigated in normoglycemic and type 1 diabetic mice. Preterminal NMDA (preNMDA) receptors were discovered to tonically modulate excitatory neurotransmission on terminals contacting DMV neurons. While these preNMDA receptors were not found to differentially modulate tonic excitatory neurotranmission, soma-dendritic NMDA receptor responses of NTS neurons were augmented in type 1 diabetic mice. Through the use single-cell PCR, increased NMDA receptor responses could be correlated to neurons that mediate excitatory neurotransmission and would argue that augmented NMDA receptor responses increase vagal output. In general, enhancing vagal output decreases activity of connected peripheral organs. Molecular approaches were employed to corroborate the observed functional NMDA receptors changes to their protein and mRNA expression levels. Overall, results argue that NMDA receptors are involved in synaptic plasticity in DVC of type 1 diabetic mice to enhance excitatory neurotransmission. This modulation may potentially serve as a physiological counter regulatory mechanism to control pathological disturbances of gastrointestinal homeostatic reflex responses.

Le diabète de type 1 (DT1) est une maladie auto-immune qui est caractérisée par la destruction des cellules R des îlots de pancréas. L'utilisation des modèles animaux comme la souris NOD a facilité la compréhension de la physiopathologie du DT1, car ces souris développent spontanément le diabète d'une façon similaire à l'homme. Les lymphocytes T auto-réactifs CD4 + et CD8+ jouent un rôle majeur dans le développement de cette maladie. Dans les conditions non pathologiques, les lymphocytes T auto-réactifs sont éliminés dans le thymus (tolérance centrale) ou maintenus en états d'anergie en périphérie (tolérance périphérique). En périphérie, les cellules dendritiques (CDs) de type tolérogènes induisent l'expansion et/ou la différenciation d'une population spécifique de lymphocyte T (Treg), qui contribue à la suppression de la prolifération et l'activation des lymphocytes T auto-réactifs. Certaines fonctions tolérogènes des CDs telle que la présentation d'antigènes est sous le contrôle de l'ubiquitine ligase MARCH I. MARCH I ubiquitine le CMH de classe II et les molécules de costimulation CD86 et prévient donc leurs expressions à la surface des cellules dendritiques, et ainsi l'inhibition de la stimulation de lymphocytes T. Le but de ce projet est: 1) de caractériser les niveaux d'expression de MARCH I dans les CDs tolérogènes générées en présence d'IL-10 en comparaison aux CDs immunogènes générées en absence d'IL-10, 2) de déterminer si la sur-expression de MARCH I chez CDs immunogènes de souris NOD rétablit leurs fonctions tolérogènes. Nos résultats montrent que les CDs de souris NOD générées en absence d'IL-10 expriment des niveaux très élevés de CMH de classe II et de molécules de costimulation (CD80 et CD86). Au contraire, les CDs générées en présence d'IL-10 résistent à la maturation, puisqu'une faible augmentation de l'expression du CMH II et des molécules de co-stimulation est observée suite à leur stimulation au LPS. Ces dernières produisent des quantités importantes d'IL-10 et des faibles quantités d'IL-12 et d'INF-y et expriment des niveaux très élèvés d'ARNm de MARCH I comparativement aux CDs générées en absence d'IL-10. Nous avons aussi montré que la transduction des CDs immunogènes par un lentivirus contenant le gène qui code pour MARCH I leur permet d'acquérir les propriétés des CDs tolérogènes. En effet, les CDs transduites par MARCH I expriment de faibles niveaux du CMH II, de CD80 et CD86 après stimulation au LPS. Nous avons aussi montré que les CDs transduites par le gène qui code pour MARCH I, dont la partie N-terminale 1 à 40 (? 1-40 ) ou 1 à 60 (?1-66 ) a été délétée, stabilisent l'expression de MARCH I tout en préservant leur capacité à diminuer l'expression du CMH de classe II et de CD86. Ainsi, ces conditions permettent d'obtenir des CDs tolérogènes qui pourront être utilisées comme thérapie cellulaire pour prévenir ou empêcher le développement du diabète chez la souris NOD. [Symboles non conformes]

Le diabète de type 1 (DT1) est une maladie auto-immune qui résulte en la destruction des cellules (ß des îlots de Langerhans par les cellules du système immunitaire. Des travaux précédents de notre laboratoire ont identifié la cytokine "Thymic Stromal Lymphopoietin" (TSLP) comme étant un stimulus tolérogénique pour les cellules dendritiques (DCs) chez le modèle murin du DT1, la souris "Non Obese Diabeiic" (NOD). Les DCs conditionnées à la TSLP (TSLP-DCs) présentent un phénotype semi-mature, sont capables d’induire une réponse Th2 ainsi qu’une conversion et une expansion des lymphocytes T régulateurs (Tregs) in vitro et protègent les souris NOD contre le DT1. Ces observations nous ont amené à investiguer les mécanismes qui entraînent cette protection contre le DT1. Les travaux décrits dans ce mémoire montrent que les TSLP-DCs injectées chez les souris NOD migrent vers la rate, de manière privilégiée. Ces observations nous ont amené à étudier l’influence des TSLP-DCs sur la réponse Th1/Th2 au niveau de la rate. Nous avons observé que les splénocytes CD4[indice supérieur +] et CD8[indice supérieur +] de souris injectées avec des TSLP-DCs exprimaient moins d’IFN? par rapport au souris témoins (splénocytes des souris injectées avec des LPS-DCs). Ces résultats suggèrent une diminution de la réponse Th1 chez ces splénocytes. Par contre, les résultats obtenus avec l’IL-10 ne nous ont pas permis de conclure quant à l’influence des TSLP-DCs sur la réponse Th2. Cependant, nous avons confirmé la capacité des TSLP-DCs à induire la conversion des lymphocytes T CD4[indice supérieur +]CD25[indice supérieur -] en Tregs CD4[indice supérieur +]CD25[indice supérieur +]Foxp3[indice supérieur +]. Nous avons aussi montré que ces Tregs partiellement convertis inhibent la prolifération de lymphocytes T 8.3-CD8[indice supérieur +] diabétogènes, et empêchent la production d’IFN?. Les Tregs convertis en présence de TSLP-DCs ou de LPS-DCs ont également été injectés à des souris 8.3-NOD.RAG2[indice supérieur -/-]. Les résultats ont révélé que seuls les Tregs différenciés en présence de TSLP-DCs ont la capacité d’empêcher le développement du DT1. Nos travaux suggèrent que la diminution de la réponse Th1 et l’induction d’une population efficiente de lymphocytes Tregs font partie des mécanismes utilisés par les TSLP-DCs pour protéger les souris NOD contre le DT1.

Les cellules dendritiques (DC) jouent un rôle central dans l’orchestration de la réponse immunitaire cellulaire spécifique, et des anomalies dans leur développement et/ou leur fonction peuvent être à l’origine de maladies auto-immunes. Le diabète de type 1 est une maladie auto-immune qui résulte de la destruction spécifique des cellules ? du pancréas par les lymphocytes T auto-réactifs. Chez la souris NOD, modèle animal d’étude du diabète de type 1, la fonction des DC est altérée, et résulte en partie d’un défaut de la voie de signalisation JAK-STAT5. En effet, le facteur de transcription STAT5 est essentiel à la signalisation du Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) et de la Thymie Stromal Lymphopoietin (TSLP), qui confèrent une fonction tolérogène aux DC in vitro et in vivo. De plus, les souris déficientes en STAT5b se caractérisent par une auto-immunité sévère, soulignant le rôle fondamental de STAT5b dans la tolérance immunitaire. Chez l’homme, des cas de mutations récessives du gène stat5b ont été rapportés, entraînant des maladies auto-immunes systémiques. Nous avons généré des souris NOD transgéniques exprimant de façon constitutive la forme active de STAT5b de souris C57BL/6 spécifiquement au sein des DC. Nos résultats ont montré que toutes les souris transgéniques sont protégées contre le diabète. Les analyses par cytométrie de flux ont montré une maturation plus importante des DC de souris transgéniques, ainsi qu'une augmentation de la proportion de lymphocytes T régulateurs, associée à une baisse de la population de lymphocytes T CD8+ dans la rate et les ganglions pancréatiques (PLN) et mésentériques (MLN). Les tests de prolifération in vitro ont montré une prolifération plus important de lymphocytes T CD4+ et CD8+ des souris transgéniques, et présentent un profil immunorégulateur de type TH2 et TC2 respectivement. En outre, les DC de souris transgéniques induisent une déviation immune vers un profil TH2 des lymphocytes T BDC2.5-CD4+ diabétogènes, ainsi que la conversion peptide-spécifique de lymphocytes T BDC2.5-CD4+Foxp3- diabétogènes en lymphocytes T régulateurs Foxp3+ in vitro. In vivo, les splénocytes de souris transgéniques ne transfèrent pas le diabète chez les souris NOD.SCID. De plus, le transfert de DC de souris transgéniques à des souris NOD prédiabétiques ont montré une résistance au diabète chez les souris receveuses. En conclusion, les DC exprimant de façon constitutive la forme activée de STAT5b acquièrent des propriétés tolérogènes, et protègent les souris NOD contre le diabète. Cette résistance au diabète est médiée en périphérie par l'augmentation du pool de lymphocytes T régulateurs et par l'induction d'une réponse immunorégulatrice de type TH2.

Bakgrund: I Sverige insjuknar årligen 800 barn i typ 1 diabetes. Sjukdomen är kronisk och kännetecknas av stor urinmängd, överdriven törst, viktminskning och trötthet. Behandlingen är livslång vilket leder till livsstilsförändringar för barnet. Sjukdomen påverkar samtidigt hela familjen känslomässigt och en stor omställning krävs för att få livet att gå ihop. Omhändertagandet av hela familjen är viktigt då det påverkar dem i hur de ser på sjukdomen och klarar av att gå vidare i livet. Syfte: Att belysa hur familjer till barn med typ 1 diabetes upplever sin situation. Metod: En litteraturöversikt baserad på elva studier med kvalitativ ansats. Resultat: Resultatet i denna studie sammanfattas med två huvudteman och nio underkategorier: Förändringar i det dagliga livet – Anpassning, Delaktighet och engagemang, Egenvård, Gå vidare i livet; Känslomässiga upplevelser – Oro och rädsla, Förnekelse, Utanförskap, Sorg och förlust, Betydelse av kunskap. Slutsats: Familjer till barn med typ 1 diabetes drabbas av olika känslor vid diagnos och hanteringen av sjukdomen kräver stor förändring i livet för barnet och dennes familj. Kunskap, engagemang och delaktighet är viktiga faktorer för att främja hälsa hos familjen. Klinisk betydelse: Studien har betydelse och klinisk relevans för att öka kunskapen bland de som berörs så att omvårdnaden och bemötandet kan bli bättre i framtiden för de familjer med barn som drabbas av typ 1 diabetes. / Background: Every year 800 children in Sweden get the diagnosis type 1 diabetes. The disease is chronic and is characterized by a large amount of urine, excessive thirst, weight loss and fatigue. Treatment is life long, which leads to lifestyle changes for the child. At the same time the disease affects the whole family emotionally, and they need to change their life in order to make ends meet. It is important to take care of the entire family as it affects them in the way they look at the disease and are able to move on in life. Aim: To illuminate how families of children with type 1 diabetes experiences their situation. Method: A literature review based on eleven studies involving qualitative approach. Results: The results in this study are summarized in two themes and nine subthemes: Changes in daily life – Adaptation, Participation and commitment, Self-care, Move on after diagnosis; Emotional experiences – Anxiety and fear, Denial, Exclusion, Grief and loss, Importance of knowledge. Conclusion: At diagnosis families of children with type 1 diabetes suffer from mixed emotions and the management of the disease requires great change in the life of the child and their family. Knowledge, commitment and involvement are important factors to promote health of the family. Clinical implications: The study has significance and clinical relevance to increase knowledge among those who are affected so that the care and treatment can be improved in the future for those families with children who suffer from type 1 diabetes.

Diabetes typ 1 (DM typ 1) är en av de mest förekommande kroniska sjukdomarna och drabbar främst barn och tonårningar. DM typ 1 kräver en livslång övervakning och behandling med insulininjektioner vilket ställer höga ansvarskrav på den drabbade. Barn- och tonåren karaktäriseras av olika stadium. För att främja utvecklandet av en god patientdelaktighet under hela mognadsprocessen är det viktigt att sjuksköterskan besitter fördjupad kunskap om barns upplevelser av att leva med DM typ 1. Syftet med litteraturstudien var att beskriva barn i åldrarna 10-18 års upplevelser av att leva med DM typ 1. Metoddelen var en litteraturstudie som bestod av tio vetenskapliga artiklar. Resultatet framfördes genom tre huvudteman och tre underkategorier: Upplevelsen av egenvård, upplevelsen av stöd med underkategorierna; stöd genom föräldrar, stöd genom vänner och stöd genom sjukvårdsteamet och skolan. Det sista temat beskrev upplevelsen av sjukdomens påverkan på vardagen. Över tid upplevdes förståelsen och kunskapen av sjukdomen öka vilket genererade i förbättrad egenvård. Barn upplevde att en god problemlösningsförmåga var nyckeln till en välfungerande vardag. Varje patientmöte måste på en djupare nivå anpassas efter individen för att optimera vardagsupplevelsen för en person med DM typ 1. Sjuksköterskans roll i förbättringen av den unge individens vardagsupplevelser bör därför diskuteras mer. / Diabetes type 1 (DM type 1) is one ofe the most common chronical diseases and affects mainly children and adolescents. DM type 1 requires a lifelong monitoring and treatment with insulin injections, which sets high standards of responsibility on the affected person. Childhood and adolescence is characterized by different phases. To foster the development of a good patient participation thoughout the maturation process, it is important that nurses possess indepth knowledge about youth´s experiences. The aim of this study was to describe children´s, in the age of 10-18, experiences of livning with DM type 1. The method was a literature study which consisted of ten scientific articles. The findings was performed by three main themes and three sub-categories: the experience of self-care, the experience of support with the sub-categories: support from parents, support from friends and support through the healtcare team and the school. The last theme described the experience of the diseases impact on everyday life. Over time the experienced understanding and knowledge of the disease increased, which generated in improved self-care. Children experienced that good problem solvning skills were the key to a functioning everyday life. Each meeting with a patient must in a deeper way be adapted to the individual to optimize the experience of everyday life for a young person with DM type 1. The nurses role in improvning young people´s experiences of everyday life should therefore be discussed further.

Bakgrund: Barn och ungdomar med typ 1diabetes har en kronisk sjukdom. En överförflyttning från barn-och ungdomsvård till vuxenvård är därmed oundviklig. Övergången emellan vårdorganisationerna tar vid under en ömtålig period i livet när ytterligare förändringar sker för de unga personerna, exempelvis inträdandet in i vuxenlivet. Syfte: Syftet var att beskriva unga personers erfarenheter av överförflyttningen från barn- och ungdomsvård till vuxenvård. Metod: Uppsatsen baseras på en litteraturöversikt av tio artiklar. Kvantitativa samt kvalitativa artiklar inhämtades från databaserna Cinahl och Medline. Resultat: Via analysen av artiklarna uppkom tre teman. Det första temat ”Ett möte   med två världar” skildrar de unga personernas erfarenheter av barn- och ungdomsvårdens samt vuxenvårdens varierande miljöer och de olika vårdorganisationernas strukturer. Det andra temat ”Ett ökat egenansvar” beskriver hur vårdnadshavarnas avsaknad och nya rutiner inom vuxenvården påverkar de unga personerna. Det tredje temat ”Ett sökande efter information” visar på att informationsbrist inför och om överförflyttningen förekommer. Det leder till att de unga   personerna känner sig vilsna och svikna inom vårdorganisationen. Diskussion: För unga personer med typ 1 diabetes kan det vara mycket svårt att balansera vardagen med arbete/studier och ta ansvar för sin egenvård. Efter övergången till vuxenvården förväntas den unga personen ta fullt ansvar för sin sjukdom och är personen inte förberedd på förändringen kan resultatet leda till utebliven närvaro. Sjuksköterskan kan stödja den unga personen med aktuell kunskap om sjukdomen och informera tidigt om vad överförflyttningen innebär. Resultatdiskussionen har Afaf Meleis omvårdnadsteori om transition som grund. / Background: Children and adolescents with type 1 diabetes, have a chronic disease. A transfer from the child and youth to adult care is therefore inevitable. The transition between healthcare organizations take place during a delicate period of life when further changes occur to the young people, such as the transition into adulthood. Aim: The aim was to describe young people's experiences of transition from child and youth to adult care. Methods: The essay is based on a literature review of ten articles. Quantitative and qualitative articles were obtained from the databases Cinahl and Medline. Results: Via the analysis of the articles emerged three themes. The first theme "A meeting of two worlds" describes the young people’s experiences of the child and youth care and adult care different environments, and the various healthcare organizations' structures. The second theme "An increasing responsibility" describes how guardian’s absence and procedures in adult care affects young people’s transition. The third theme "A search for information" indicates that the lack of information for and about the transfer occurs. The result is that the young people feel lost and deceived within the healthcare organization. Discussions: For young people with type 1 diabetes it may be very difficult to balance everyday life with work / study and take responsibility for their own self-care. After the transition to adult care the young person is expected to take full responsibility for the disease, and if the person is not prepared for the change the result may lead to loss of presence. The nurse can support the young person with current knowledge of the disease and inform early about what the transfer means. The result discussion has Afaf Meleis nursing theory of transition as a basis.

No description available.

This thesis contributes to the research area of causal inference, where estimation of the effect of a treatment on an outcome of interest is the main objective. Some aspects of the estimation of average causal effects in observational studies in general, and case-control studies in particular, are explored. An important part of estimating causal effects in an observational study is to control for covariates. The first paper of this thesis concerns the selection of minimal covariate sets sufficient for unconfoundedness of the treatment assignment. A data-driven implementation of two covariate selection algorithms is proposed and evaluated. A common sampling scheme in epidemiology, and when investigating rare events, is the case-control design. In the second paper we study estimators of the marginal causal odds ratio in matched and independent case-control designs. Estimators that, under a logistic regression model, utilize information about the known prevalence of being a case is examined and compared through simulations. The third paper investigates the particular situation where case-control sampled data is reused to estimate the effect of the case-defining event on an outcome of interest. The consequence of ignoring the design when estimating the average causal effect is discussed and a design-weighted matching estimator is proposed. The performance of the estimator is evaluated with simulation experiments, when matching on the covariates directly and when matching on the propensity score. The last paper studies the effect of type 1 diabetes mellitus (T1DM) on school achievements using data from the Swedish Childhood Diabetes Register, a population-based incidence register. We apply theoretical results from the second and third papers in the estimation of the average causal effect within the T1DM population. A matching estimator that accounts for the matched case-control design is used.