Better disease care behaviors in youth with type 1 diabetes (T1D) are strongly related to better metabolic control (HbA1c). However, HbA1c results are only available, on average, every three months, and may not accurately capture intricacies of blood glucose fluctuations. Youth then must rely on blood glucose levels obtained throughout the day to determine which disease care behaviors to perform to maintain optimal metabolic control. Youth may have difficulty performing these disease care behaviors properly or consistently, which makes parental monitoring a crucial aspect of the diabetes regimen. Additionally, youth who experience frequent or severe hypoglycemia may develop a fear of hypoglycemia, which may impact their disease care behaviors and blood glucose levels directly. Average blood glucose levels strongly related to HbA1c which verifies HbA1c as a good indicator of average blood glucose levels. The Average Daily Risk Range (ADRR) index had a stronger relation to HbA1c than Mean Amplitude of Glycemic Excursions (MAGE) index; however, the percentage of blood glucose levels below, within, and above range may be the best indicator of glycemic variability, as it is more easily calculated and understood. More parental monitoring related to more diabetes prevention behaviors but not intervention behaviors or less glycemic variability.

The psychometric properties of two measures of diabetes disease care, the Diabetes Behavior Rating Scale (DBRS) and the 24-hr Diabetes Interview (24-hr) were evaluated. The 24-hr is a widely used, structured interview while the DBRS is a self-administered, fixed-choice questionnaire. Both measures were administered to 250 youth with Type 1 Diabetes (aged 11–14 years) and their parents. Overall, both measures demonstrate adequate psychometric properties. The DBRS and the 24-hr demonstrated good incremental validity and low convergent validity with each adding significant additive value. Both measures demonstrated good concurrent validity with HbA1c. As expected, scores on the 24-hr demonstrated less than adequate test-retest reliability and both measures demonstrated low parent/youth agreement. Interestingly, external validity analyses demonstrated DBRS scores were moderately related to HbA1c in non-pump but not pump regimens, while the 24-hr displayed acceptable external validity. Only three subscales significantly contributed to HbA1c suggesting a more parsimonious assessment measure. This novel, brief combination could prove efficacious for clinical practice.

Individual growth curve (IGC) modeling evaluated longitudinal trajectories of glycemic control and diabetes care of youth with Type 1 Diabetes (T1D) over three years. IGC modeling allowed comparison of confounded sociodemographic predictors of disease outcomes that included ethnicity, SES, parent marital status, family structure, as well as disease duration, to determine the relative impact of these factors in the evolution of HbA1c and diabetes care throughout adolescence. At baseline, participants recruited from two pediatric endocrinology clinics included 198 youth, ages 9-15 (M age = 12.65, 77% Caucasian, 74% lived with married biological parents, M SES = 45.70) with average HbA1c of 8.43% and reported diabetes care behaviors consistent with ADA recommendations. Glycemic control did not deteriorate significantly, but IGC modeling detected a trend of a steady decline in HbA1c of .01% each year. Youth with married biological parents had HbA1c levels approximately 1.23% lower than youth with alternative parent marital status throughout adolescence, t = 4.03, p < .001, although an age by marital status interaction, t = -2.34, p < .05, indicated the impact of parent marital status on HbA1c decreased at age 17. Analyses revealed significant annual declines in blood glucose monitoring frequency, t = -7.61, p < .001, eating frequency, t = -9.04, p < .001, and exercise frequency, t = -7.87, p < .001. Alternatively, the consumption of carbohydrates and fats remained relatively stable throughout adolescence. Consideration of sociodemographic predictors and disease duration further clarified trajectories of disease care behaviors. Throughout adolescence, African American youth reported lower blood glucose monitoring frequency than Caucasian youth. Youth with lower SES exercised less frequently and demonstrated poorer dietary consumption than youth with higher SES. Youth from families with alternative parent marital status ate and exercised less frequently compared to youth from married biological families. However, youth from single-parent homes exercised more frequently than those from two-parent homes. Longer disease duration related to declines in blood glucose monitoring frequency, yet better dietary consumption. Results may inform development of interventions for youth at risk of poor glycemic control and diabetes management across ethnicity, SES, and parent marital status groups.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Le cancer du sein triple négatif (TNBC) représente entre 15-20% des cancers du sein et est l'un des types les plus agressifs. De plus, un sous-groupe de ces patientes est résistant à la radiothérapie (RT) et développe fréquemment une récidive hâtive de la maladie. Des études précédentes ont démontré que l’inflammation induite par la RT accélère la progression du cancer et le développement des métastases. Cette hypothèse a donc été validée dans un modèle pré-clinique de TNBC en implantant les cellules de carcinome de souris triple négatives D2A1 dans les glandes mammaires de la souris Balb/c. Premièrement, la tumeur primaire à été irradiée à une dose sous-curative une semaine post-implantation des cellules. En deuxième lieu, le tissu mammaire de la souris a été pré-irradié avant d'implanter les cellules cancéreuses afin de bien discerner l'effet du microenvironnement irradié sur celles-ci. Ces deux modèles ont mené à une augmentation significative des cellules tumorales circulantes ainsi que du nombre de métastases pulmonaires. Plusieurs molécules inflammatoires dont l'interleukine-1 bêta (IL-1β), l'interleukine-6 (IL-6) ou encore la cyclooxygénase 2 (COX-2) ont été identifiées comme facteurs clés impliqués dans la migration radio-induite des cellules cancéreuses du sein. Conséquemment, un inhibiteur large-spectre comme la chloroquine (CQ), entre autres utilisé comme traitement anti-malarien et anti-inflammatoire, a su prévenir ces effets secondaires associés à la RT. Étant donné que l'action de la CQ est peu sélective, une répression de l'expression de l'ARNm de la métalloprotéinase (MMP) de membrane de type 1 (MT1-MMP), une MMP de surface impliquée notamment dans la migration cellulaire, l'invasion tumorale et l'angiogenèse, a été réalisée afin d'éclaircir le mécanisme d'inhibition des métastases radio-induites. Cette répression de la MT1-MMP prévient la formation des métastases pulmonaires radio-induites, démontrant ainsi un des mécanisme important de l'invasion radio-induite. Ce résultat confirme donc l'importance de la MT1-MMP dans ce phénomène et son potentiel comme biomarqueur de prédiction de l'efficacité des traitements de RT, particulièrement chez les patientes atteintes de TNBC.

SAMMANFATTNING Bakgrund: Att vara förälder till ett barn som insjuknar i diabetes kan innebära svår stress. Även om den akuta stressen vid diagnosen avtar, så upplever många föräldrar en pågående psykisk stress som kan leda till utbrändhet. Syfte: Syftet med studien var att beskriva hur föräldrar till barn med typ1 diabetes upplever stress minst ett och ett halvt år efter diagnos samt vilket stöd de önskar att sjukvården kunde bistå med. Metod: För att utföra studien valdes en kvalitativ design. Författaren genomförde semistrukturerade intervjuer med sex mammor vars barn var i åldrarna tre till arton år. Intervjudata analyserades med en deduktiv innehållsanalys. Karasek och Theorells kravkontroll-stödmodell användes som en teoretisk referensram för studien. Resultat: Studien resulterade i tre kategorier samt elva subkategorier och det övergripande temat Arbetet Diabetes. Kravet att hantera de oförutsägbara och instabila aspekterna med barnets sjukdom kunde orsaka oro och stress hos föräldrarna, liksom sömnbrist samt omgivningens oförståelse och okunskap. Att lämna över kontrollen över behandlingen till barnet självt eller förskola och skola var också något som kunde medföra en belastning och stress hos föräldrarna. Partnern och sjukvården utgjorde ett viktigt stöd i vardagen. Tekniska hjälpmedel upplevdes som ett avlastande stöd, men som även kunde bidra till ytterligare stress. Föräldrarna var i regel nöjda med sjukvården men önskade mer förståelse på vissa områden samt en obligatorisk uppföljning hos psykolog. Det fanns även en önskan om att syskon skulle inkluderas mer i vården. Slutsats: Upplevelsen av stress hos föräldrar till barn med typ 1 diabetes varierade och påverkades av faktorer som krav, kontroll och stöd. Oro för situationer man inte kunde påverka och förutse liksom osäkerheten i att lämna över kontrollen till andra bidrog till upplevelsen av stress. Stöd från partner, sjukvård, tekniska hjälpmedel och sociala medier hade betydelse för upplevd stress och belastning. En ökad förståelse och förebyggande insatser behövs för att förbättra sjukvårdens omhändertagande av föräldrarna till barn med diabetes / ABSTRACT Background: To be a parent of a child type 1 Diabetes can be severally stressful. Even if the initial stress at diagnosis recedes, many parents experience a persistent psychological stress which can lead to burnout symptoms. Aim: The aim of the study was to describe how parents of children with type 1 diabetes experienced stress at least 1.5 years after receiving the diagnosis and what support they wanted from healthcare providers. Method: A qualitative design was used conducting semi structured interviews with six mothers whose children were between the ages of three to eighteen. The collected data was analysed by using deductive content analysis. Karasek and Theorell’s demands-controlsupport model was used as a theoretical framework for the study. Results: The study resulted in three main categories and eleven subcategories with the work Diabetes as an underlying theme. The demands of handling the unpredictable and unstable aspects of the child’s disease caused stress, as well as sleep deprivation and handling other people’s ignorance. Handing over the control of care to school staff or the children themselves was sometimes associated with frustration and stress. The parent’s partner and the health care providers were important support. Technical aids were perceived as an unburdening support, but could also create more stress. The parents were satisfied with the health care support in general but wanted more understanding in some areas as well as a mandatory follow-up with a psychologist. A need to include siblings in the care and follow-up was also mentioned. Conclusion: The experience of stress among parents of children with type 1 diabetes varied and was affected by demands, control and support. The concern about situations that were beyond their control and prediction created stress as well as the ability to hand over the control to others. The support from partners, health care providers, technical aids and social media was important for perceived strain and stress. Better understanding and preventive interventions are needed to improve the care of parents of children with diabetes.

Varje år drabbas ungefär 900 barn i Sverige av diabetes typ 1. Det är en komplex sjukdom som påverkar hela individen och dennes livsvärld. Diabetes typ 1 är en autoimmun sjukdom som gör att kroppens egna immunsystem attackerar betacellerna i bukspottskörteln. Detta gör att cellerna inte kan producera det livsviktiga hormonet, insulin. Det kan leda till allvarliga följdkomplikationer och i värsta fall döden. Syftet med examensarbetet är att beskriva barns upplevelse av att insjukna i och leva med diabetes typ 1. Metoden är en analys av kvalitativ forskning där vi sammanställer och analyserar data utifrån flera studier. I resultatet presenteras nio kvalitativa artiklar, publicerade mellan år 2009-2017 som på olika sätt belyser vilken innebörd en diabetesdiagnos medför för patienterna. I resultatet urskiljs två huvudkategorier med medföljande subkategorier. I resultatet framkommer det att barn känner sig annorlunda och ensamma. Diabetessjukdomen innebär stora utmaningar för barnen i form av dagliga moment som blodsockerkontroll och insulinadministrering. Barnen har en strävan att vara självständiga och detta sätts på prov i vardagen då barnet förväntas sköta sin diabetessjukdom själv. I diskussionen läggs fokus på vilka utmaningar som barnen ställs inför. Detta diskuteras i relation till föräldrarnas syn för att ge en nyanserad bild av hur de ser på utmaningarna som barnet ställs inför. Slutsatsen är att barn som lever med diabetes typ 1 upplever rädsla, ensamhet och en känsla av att vara annorlunda.

Autoimmunity develops over an extended period of time as the result of an amalgamation of genetic, environmental, and immunologic events. Though the precise etiological factors leading to most autoimmune disease are awaiting consensus, a common thread of the autoimmune paradigm is the inappropriate activation of tissue-specific immune cells by one or more autoantigen, which begins the destruction of the tissue. To prohibit immunopathology and fine-tune the immune responses in healthy individuals, the stimulatory activities of effector/memory T (Teffs) cells must be counteracted by the suppressive mechanisms of regulatory T cells (Tregs). Thus, the potential to modulate the ratio between Teff and Tregs in autoimmune patients has been widely investigated with high hopes to permanently cure certain autoimmune diseases such as type 1 diabetes militus (T1D). Autoantigen therapies, which attempt to induce Tregs to suppress pathogenic effector cells in an autoantigen-specific manner, have shown efficacy in preventing T1D in mice, but have largely failed in clinical trials. One approach to improve the effectiveness of islet autoantigen vaccinations is to combine them with an additional modulator of the T cell response which favors a regulatory phenotype. In the work presented here, we asked whether the addition of anti-interleukin-7 receptor-alpha (anti-IL-7Rα) monoclonal antibodies (mAbs) to islet autoantigen immunizations would modulate the T cell response and prevent T1D in non-obese diabetic (NOD) mice. It was found that anti-IL-7Rα mAbs reduced the absolute numbers of islet antigen-specific T cells when immunized with islet peptide in conjunction with the commonly used vaccine adjuvant alum. Such treatments were also observed to increase nonspecific IL-2, IFN-𝛾, and IL-10 cytokine production, resulting in no improvement of T1D onset prevention. In another approach, we generated a conjugate vaccine by conjugating islet autoantigens to the immunogenic carrier protein, Keyhole Limpet Hemocyanin (KLH). We found that islet antigen-KLH (Ag-KLH) vaccination resulted in significant expansion of the desirable antigen-specific Tregs. Further, Ag-KLH immunization successfully delayed, and in some cases entirely prevented, T1D onset in NOD mice. Indicating that KLH-conjugated vaccine may represent a promising approach for future autoantigen therapies against autoimmunity. Interestingly, administration of anti-IL-7Rα mAbs did not improve these outcomes. To the contrary, we again observed excessive nonspecific cytokine production induced by IL-7Rα blockade that inhibited the beneficial effects of Ag-KLH vaccination. Taken together, we concluded that the addition of anti-IL-7Rα mAbs did not improve the efficacy of autoantigen vaccinations to prevent T1D. Significant work still remains to better characterize and isolate the beneficial effects of anti-IL-7Rα mAbs to treat autoimmunity.

L’hypodynamie-hypokinésie est une situation correspondant à une diminution de l’activité motrice (hypokinésie) couplée à une diminution des charges corporelles (hypodynamie). Chez l’homme, cette situation est retrouvée lors d’une immobilisation, d’un alitement prolongé, d'un séjour en microgravité, ou lors du vieillissement (syndrome d’immobilité). L’hypodynamie-hypokinésie entraine une sévère altération de la performance motrice, notamment de l’équilibre, de la posture et de la locomotion. Cette altération est due à une dégradation du système musculaire (atrophie, changements phénotypiques), mais également à une modification des propriétés fonctionnelles du cortex sensorimoteur (réorganisation corticale, changements d’excitabilité corticale, modifications morphologiques). Si l’altération du système musculaire est bien décrite dans la littérature, les mécanismes impliqués dans la plasticité corticale restent mal connus. Une meilleure compréhension des systèmes mis en jeu dans l’hypodynamie-hypokinésie permettrait de développer des stratégies de prévention et/ou de récupération chez les patients soumis à cette situation. Dans cette optique, un modèle animal est communément utilisé au laboratoire. Il s'agit du modèle d'élévation du train postérieur pendant 14 jours chez le rat. Ainsi, les charges corporelles, s’exerçant habituellement sur les membres postérieurs, sont prévenues et l’activité musculaire limitée. Ce modèle animal reproduit la plupart des effets de l'hypodynamie-hypokinésie décrits chez l'homme.L’objectif de cette étude a été d’explorer les mécanismes de la réorganisation corticale induite par l’hypodynamie-hypokinésie. Notre intérêt s’est plus particulièrement porté sur l’insulin-like growth factor 1 (IGF-1), une protéine ubiquitaire possédant de nombreux rôles au niveau cérébral. En effet, en se fixant à son récepteur, l’IGF-1, parmi une multitude de phénomènes, stimule l’angiogenèse, la neurogenèse, et participe à la plasticité synaptique. De plus, il est reconnu comme étant un acteur central des effets bénéfiques de l’exercice physique au niveau cérébral.Aussi, dans un premier temps, nous avons déterminé les effets de cette hypoactivité sur l’IGF-1 et les voies de signalisation associées dans plusieurs structures impliquées dans la régulation de la performance motrice (cortex sensorimoteur, striatum, cervelet). Nos résultats montrent une sévère diminution des taux d’IGF-1 et de l’activation de la voie PI3K-AKT, et ce spécifiquement dans le cortex sensorimoteur.Dans un second temps, nous avons voulu déterminer si en maintenant le taux d’IGF-1 pendant toute la durée de l’hypodynamie-hypokinésie, il était possible de prévenir la réorganisation corticale et ses conséquences délétères sur le comportement moteur. Pour cela, dans une première partie, notre étude a porté sur le cortex somesthésique et la sensibilité tactile. Nos résultats montrent que l’IGF-1 prévient partiellement la réorganisation corticale et l’altération de la sensibilité tactile induites par l’hypoactivité. Dans une seconde partie, nous nous sommes intéressés à l’analyse du cortex moteur et de la performance motrice. Il apparait qu’un maintien des taux d’IGF-1 prévient une partie de l’altération du système moteur retrouvée en situation d’hypodynamie hypokinésie. Ainsi, l’ensemble de ces données suggère que la diminution des taux d’IGF-1 observée en condition d’hypoactivité joue un rôle clé dans la réorganisation corticale. De plus, notre étude montre qu’une prévention, même partielle, de cette réorganisation corticale peut induire une amélioration fonctionnelle de la performance motrice. / Hypodynamia-hypokinesia is a condition in which the motor activity (hypodynamia) as well as the weight exerted on the lower limbs (hypokinesia) are reduced. In humans, this condition is induced in immobilization, bed-rest, spaceflight or ageing (immobility syndrome) and is characterized by a chronic reduction in neuromuscular activity. This hypoactivity results in a profound alteration of motor task performances, in particular posture, gait and locomotion. These impairments are due to alterations in the muscular system (atrophy, phenotypic changes), but also to plastic changes in neural functions (cortical reorganization, alterations in cortical excitability, morphologic modifications). While degradation of the muscular system is described in the literature, the mechanisms involved in cortical plasticity are still unclear. A better understanding of the systems involved in hypodynamia-hypokinesia would allow the development of preventive and / or recovery strategies for patients affected by this hypoactivity. In this regard, hindlimb unloading is a disuse rodent model in which the elevation of the hindlimbs, during 14 days, prevents the weight to be normally exerted on the hindlimbs and reduces the normal muscular activity, finally causing hypoactivity. Studies performed on this model have shown that hindlimb unloading and human hypoactivity have similar effects. Today, our interest is turned towards insulin-like growth factor 1 (IGF-1), a ubiquitous protein involved in many cerebral functions. Indeed, IGF-1 is known to improve, inter alia, angiogenesis, neurogenesis and to be involved in synaptic plasticity in the whole brain. Moreover, several publications suggest that IGF-1 might mediate the beneficial effects of exercise on the brain.The aim of this study is to characterize the role of IGF-1 in cortical reorganization induced by hindlimb unloading as well as its functional consequences on motor performance. In the first part of the study, we have determined the effects of hindlimb unloading on IGF-1 level and the impact of its downstream main molecular pathways in motor control (sensorimotor cortex, striatum, cerebellum). Our results indicate that hindlimb unloading induces a decrease in IGF-1 level specifically in the sensorimotor cortex. This alteration is associated to a decrease in activation of the PI3K-AKT pathway. The second part of this study is dedicated to the effects of a restoration of IGF-1 levels, during the whole unloading period, on cortical reorganization and behavioral alterations focusing on sensory cortex and tactile sensory discrimination as well as motor cortex and motor performances. Our results show that treatment with IGF-1 partially prevents cortical reorganization and degradation of tactile sensory discrimination. Additionally, it appears that restoration IGF-1 levels prevent some of the effects of hindlimb unloading on the motor system.Taken together, ours results suggest that the decrease in the level of IGF-1 in the sensorimotor cortex during hindlimb unloading plays a key role in the cortical reorganization induced by hypoactivity. Moreover, our study shows that the prevention of this cortical reorganization, even when partial, can induce functional improvement in motor performance.