A presença da hipertensão arterial pode comprometer a qualidade da reparação óssea, pois a doença é caracterizada por alterações fisiopatológicas vasculares e do metabolismo mineral. Com o objetivo de avaliar a neoformação e o remodelamento ósseo, este trabalho investigou o processo da reparação óssea em ratos geneticamente hipertensos (SHR) e de seus controles Wistar-Kyoto (WKY). Defeitos bicorticais de 2mm de diâmetro no lado direito e de 5mm no lado esquerdo, foram realizados com trefinas na região do ângulo de mandíbula. Os animais, divididos em grupos de cinco indivíduos cada, foram sacrificados após 2, 3, 5, 10, 15, 30, 60 e 90 dias pós-operatórios; as mandíbulas foram removidas, fixadas em formol a 10%, descalcificadas em ácido fórmico a 20%, incluídas em parafina e as secções histológicas, de 7m de espessura, coradas com hematoxilina e eosina. As imagens foram capturadas com aumento de 40x e a área do defeito mensurada pelo programa de histometria digital Image J versão 1.4. A análise estatística revelou que não houve diferença significante na comparação entre as linhagens WKY e SHR (p = 0,884), independente dos períodos ou lados avaliados; entre períodos, nas linhagens WKY (p = 0,101) e SHR (p = 0,479), independente dos lados avaliados; entre períodos por linhagens no lado direito; e entre linhagens por lados, esquerdo com p = 0,466 e direito com p = 0,689, independente do fator período. Houve diferença estatisticamente significante entre o lado esquerdo e o direito (p < 0,001), independente das linhagens e períodos avaliados; entre os lados por linhagens, WKY e SHR, ambas com p < 0,001; entre períodos por linhagens no lado esquerdo, no qual o grupo WKY de 15 dias apresentou área menor que o grupo WKY de 60 dias e o grupo SHR de 10 dias, e o grupo WKY de 60 dias apresentou área maior que o grupo SHR de 30 dias e SHR de 60 dias. Apesar das alterações encontradas no lado esquerdo, que podem ser atribuídas à remodelação funcional do osso da mandíbula, não houve diferenças significantes na reparação do defeito de 5mm e de 2mm entre ratos espontaneamente hipertensos e de seus controles Wistar-Kyoto. / Arterial hypertension may affect the quality of bone repair because this disease is characterized by physiopathological vascular and bone metabolism changes. With the objective of evaluating the bone neoformation and remodeling, this study investigated the process of bone repair in spontaneously hypertensive rats (SHR) and their match controls Wistar-Kyoto (WKY). Through-in-through defects were done with trephine burs in the mandibular angle area, of 2mm diameter on the right side and 5mm diameter on the left side. The animals were divided into groups of five individuals each one and killed after 2, 3, 5, 10, 15, 30, 60 and 90 postoperative days; the mandibles were removed, fixed in 10% formalin solution, decalcified with 20% formic acid, and embedded in paraffin; the histological sections of 7m thickness were stained with hematoxylin and eosin. The images were captured with 40x magnification and the defect area was measured by the image processing program Image J version 1.4. The statistical analysis showed that there is no significant difference in the comparison of WKY and SHR strains (p = 0,884), independent of periods or sides; among periods, in the WKY strain (p = 0,101) and SHR one (p = 0,479), independent of sides; among periods by strains on the right side; and among strains by sides, left side with p = 0,466 and right side with p = 0,689, independent of periods. There is a significant difference between left and right side (p < 0,001), independent of strains and periods; between sides by strains, WKY and SHR, both with p < 0,001; among periods by strains on the left side, which WKY 15 days group showed an area smaller than WKY 60 days and SHR 10 days groups, and WKY 60 days group showed an area bigger than SHR 30 days and SHR 60 days groups. Despite the changes founded on the left side that could be attributed to the functional remodeling of the mandibular bone, there were no differences in the bone repair of 5mm and 2mm diameter defects between spontaneously hypertensive rats and their match controls Wistar-Kyoto.

The problem of this study was to document the history of radio station WKY, Oklahoma City, and to locate its place within the development of American radio broadcasting. This thesis divides WKY's history into two periods: 1920 through 1925, the years it was operated by Earl Hull, and 1926 through 1989, after it was acquired by E. K. Gaylord. The purpose of this study was to record the history of the oldest radio station operating west of the Mississippi River, its effect on the broadcast industry in general, and its effect on Gaylord Broadcasting Corporation, the parent organization. The study also explored the innovations. in both programming and engineering that caused the station to grow into one of the most popular radio stations in the Southwest, as well as its decline in recent years.

Contribuant à la pathophysiologie des maladies vasculaires comme dans le cas de l’hypertension, le remodelage vasculaire est associé à une altération de la croissance des cellules musculaires lisses vasculaires (CMLV) (prolifération, taille, etc.). Or la prolifération des CMLV est augmentée par les peptides vasoactifs tels que l’angiotensine II (AngII) et l’endothéline-1 (ET-1). Ces peptides étant surexprimés lors de l’hypertension, cette étude fut entreprise pour déterminer leur contribution endogène ainsi que celles du facteur de croissance épidermique (EGF), du facteur de croissance insulinique (IGF-1) et du facteur de croissance dérivé des plaquettes (PDGF) à la prolifération accrue des CMLV et aux mécanismes sous-jacents. Des CMLV A-10 et des CMLV de rats WKY et SHR âgés de 12 semaines ont été utilisées pour cette étude. La prolifération cellulaire fut déterminée par incorporation de [3H]thymidine. La phosphorylation de ERK 1/2 et du récepteur de EGF fut déterminée par immunobuvardage. Les CMLV de SHR, comparées à celles de WKY, ont montré une prolifération accrue qui fut atténuée par le losartan, un antagoniste du récepteur AT1 de l’AngII et par le BQ-123 et le BQ-788, antagonistes des récepteurs ETA et ETB de l’ET-1. La prolifération accrue des CMLV de SHR fut ramenée à celle des WKY par les inhibiteurs des récepteurs au PDGF (AG-1295), au IGF-1 (AG-1024) et au EGF (AG-1478). La phosphorylation du récepteur au EGF, accrue dans les CMLV de rats SHR comparée à celle des WKY, fut atténuée par le losartan, le BQ-123, le BQ-788 et l’AG-1478, mais ne fut pas atténuée par l’AG-1295 et l’AG-1024. De plus, la phosphorylation accrue de ERK 1/2 dans les CMLV de rats SHR fut atténuée par le losartan, le BQ-123, le BQ-788 et les inhibiteurs des récepteurs aux facteurs de croissance. Parallèlement, le rôle de la transactivation de EGF-R dans la prolifération accrue induite par AngII et ET-1 fut aussi examiné dans les CMLV A-10. L’augmentation, induite par AngII et ET-1, de la prolifération et de la phosphorylation de ERK 1/2 dans les CMLV A-10 fut ramenée au niveau contrôle par AG-1478. Ces données suggèrent que les peptides vasoactifs endogènes induisent la prolifération accrue des CMLV par la signalisation des MAP kinases résultant de la transactivation de EGF-R. / Vascular remodelling that contributes to the pathophysiology of vascular diseases, including hypertension, is associated with alteration in vascular smooth muscle cell (VSMC) growth, hypertrophy, etc. We have recently shown that vasoactive peptides such as angiotensin II (AngII) and endothelin-1 (ET-1) increased the proliferation of VSMC. Since the levels of AngII, ET-1 and growth factors are increased in hypertension, the present studies were undertaken to examine if these endogenous vasoactive peptides and growth factors contribute to the enhanced proliferation of VSMC in spontaneously hypertensive rats (SHR) and to further investigate the underlying mechanisms responsible for enhanced proliferation. A10 VSMC and aortic VSMC from 12 week old SHR and age-matched WKY rats were used for these studies. Cell proliferation was determined by [3H]thymidine incorporation and ERK ½ and growth factor receptor phosphorylation was determined by Western blotting. VSMC from SHR exhibited enhanced cell proliferation as compared to WKY as determined by enhanced [3H]thymidine incorporation which was attenuated by AngII AT1 receptor antagonist losartan, as well as by endothelin receptor ETA and ETB antagonists BQ-123 and BQ-788, respectively. The inhibitors of platelet derived growth factor receptor (PDGF-R); AG-1295, epidermal growth factor receptor (EGF-R); AG-1478, and insulin-like growth factor receptor (IGF-R); AG-1024 also attenuated the enhanced proliferation of VSMC from SHR to WKY control levels. In addition, VSMC from SHR exhibited enhanced phosphorylation of EGF-R as compared to WKY, which was attenuated by losartan, BQ-123, BQ-788 and AG-1478, and not by AG-1295 and AG-1024. Furthermore, the enhanced phosphorylation of ERK ½ in VSMC from SHR was also attenuated by losartan, BQ-123 and BQ-788 as well as by growth factor receptor inhibitors, AG-1478, AG-1024 and AG-1295. The implication of growth factor receptor transactivation in AngII and ET-1 induced enhanced cell proliferation was also examined in A10 VSMC. Ang II or ET-1 induced enhanced proliferation of A-10 VSMC and enhanced ERK ½ phosphorylation was also restored to control levels by EGF-R inhibitor. These data suggest that vasoactive peptide-induced growth factor receptor transactivation through MAP kinase signaling may contribute to the enhanced proliferation of VSMC from SHR.

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Master of Science / Department of Psychology / Kimberly Kirkpatrick / Several studies have examined timing and impulsive choice behavior in spontaneously hypertensive rats (SHR) as a possible pre-clinical model for Attention Deficit Hyperactivity Disorder (ADHD). However, the strain has not been specifically selected for the traits of ADHD and as a result their appropriateness as a model has been questioned. This study investigated whether SHR would exhibit timing deficits, poor reward processing and impulsive behavior in comparison to the Wistar Kyoto (WKY) control strain in a discrete-trial choice task. In addition, as a first approach to find another potential animal model of ADHD, we evaluated a strain that has shown high levels of impulsivity, the Lewis (LEW) rats and compared them with the Wistar (WIS) rats. In the first phase of the experiment, rats could chose a lever associated with a Smaller-sooner (SS) reward of 1 pellet delivered after 10 s and a Larger-later (LL) reward of 2 pellets delivered after 30 s. Subsequently, the rats were exposed to different phases, where the reward on the LL choice was increased to 3 and 4 pellets and where the delay to the SS choice was increased to 15 and 20 s. The SHR and WKY strains did not differ in their timing or choice behavior. In comparison to WIS, LEW showed timing deficits in both manipulations and deficits in choice behavior in the delay manipulation, indicating deficits in time processing. Individual differences among the rat within a strain accounted a significant proportion of the total variance and contributed more variance than the strain of the rat. These results indicate that the SHR and LEW strains are not sufficiently homogeneous with respect to impulsive choice behavior to be considered as viable models for impulse control disorders such as ADHD.

Le trouble déficit de l’attention avec ou sans hyperactivité (TDAH) est une maladie neurodéveloppementale de l’enfant et de l’adulte caractérisée par un déficit attentionnel, une impulsivité et une hyperactivité. La physiopathologie de cette maladie demeure non élucidée, néanmoins des stratégies thérapeutiques médicamenteuses s’avèrent efficaces. En France, le médicament utilisé dans le traitement du TDAH est le méthylphénydate (MPH) qui est un psychostimulant, et deux autres molécules paraissent prometteuses : le dymésilate de lisdexamfétamine (LDX - psychostimulant) et la guanfacine (GFC - non psychostimulant). Les cibles moléculaires de ces médicaments sont bien connues mais l’impact de ces traitement en aigu et chronique sur le fonctionnement cérébral est pour l’instant peu documenté. L’objectif de cette thèse a été d’étudier (i) la physiopathologie du TDAH et (ii) les effets de ces traitements du TDAH en aigu et en chronique sur un versant préclinique et à l’aide de l’imagerie microTEP couplée au 2-deoxy-2-(18F)fluoro-d-glucose (18FDG). Dans la première étude, des modèles animaux du TDAH ont été utilisés : des rats SHR/NCrl présentanttroubles de l’attention, hyperactivité et impulsivité et des rats WKY/NCrl présentant uniquement des troubles de l’attention. Une imagerie microTEP au 18FDG sur animal éveillé a été réalisée sur ces animaux adultes afin d’obtenir leurs profils d’activité cérébrale. Notre hypothèse était que les rats SHR/NCrl et WKY/NCrl présenteraient des modifications de capture de 18FDG similaires qui seraient impliquées dans le trouble attentionnel commun aux deux souches, alors que les rats SHR/NCrl présenteraient aussi des modifications non retrouvés chez les WKY/NCrl qui joueraient un rôle dans la genèse de l’hyperactivité-impulsivité. Cettehypothèse a été confirmée par nos résultats montrant des dysfonctions fronto-striatales limbiques et du réseau du mode par défaut chez les rats SHR/NCrl et WKY/NCrl, ainsi que des dysfonctions fronto-striatales associatives spécifiques aux rats SHR/NCrl.Dans la seconde étude, un traitement journalier au MPH, au LDX ou à la GFC a été mis en place chez des rats témoins de l’adolescence à l’âge adulte (mimant un traitement de l’enfance à la fin de l’adolescence chez l’homme). Les effets de ces traitements sur l’activité cérébrale ont été évalués après la première et la dernière injection par imagerie microTEP au 18FDG sur animal éveillé. Nos résultats montrent que chaque médicament a un effet important sur les régions limbiques, et que le LDX présente une action supplémentaire sur des régions associatives et sur les régions du réseau du mode par défaut. A notre connaissance, ce sont les premières données de neuroimagerie en préclinique qui mettent en avant l’implication des régions limbiques liées à la motivation et du réseau du mode par défaut dans la physiopathologie du TDAH. Nos résultats renforcent l’hypothèse selon laquelle les médicaments du TDAH agiraient sur les troubles primaires du TDAH et non en compensant un déficit d’attention par une augmentation de la motivation. Ces résultats suggèrent aussi que (i) la GFC est un non psychostimulant qui présente deseffets similaires au médicament de référence le MPH, et que (ii) le LDX montre un profil d’action intéressant car touchant à la fois les régions limbiques, associatives et le réseau du mode par défaut que nous trouvons toutes perturbées chez les rats SHR/NCrl. / Attention Deficit Hyperactivity Disorders (ADHD) is a neurodevelopment disorder affecting childs and adults presenting attention deficits, hyperactivity and impulsivity. Despite numerous neuroimaging studies on ADHD patients, the specific dysfunctions underlying the symptoms of ADHD remain unknown. To date, ADHD patients can be treated using psychostimulant drugs such as methylphenidate (MPH) and other promising compounds are currently in development (dymesilate-lisdexamfétamine (LDX) and guanfacine (GFC), that are psychostimulant and non psychostimulant medications, respectively). Even if the molecular targets of these medications are well defined, how these compounds will impact the brain activity to reverse ADHD symptoms is less known. The objectives of this work were to study (i) the pathophysiology of ADHD and (i) the effects of an acute or repeated administration of MPH, LDX or GFC using animal models and microPET imaging with 2-deoxy-2-(18F)fluoro-d-glucose (18FDG). First, we used an animal model of ADHD, namely the SHR/NCrl and WKY/NCrl rats that both exhibit attention deficits, with impulsivity-hyperactivity only displayed by SHR/NCrl rats. MicroPET imaging using 18FDG on awake rats was performed to obtain brain metabolic profiles of these animals. Our hypothesis was that SHR/NCrl and WKY/NCrl would shared brain dysfunctions in several regions of interest involved in the attention deficits, while SHR/NCrl rats would also displayed specific abnormalities related to hyperactivity-impulsivity. Our results confirmed these hypothesis as both SHR/NCrl and WKY/NCrl showed metabolic alterations in fronto-striatal limbic regions and in areas of the default mode network. In addition, SHR/NCrl specifically exhibited functional modifications in fronto-striatal associative areas.Second, daily injections with MPH, LDX or GFC were performed on control rats from adolescence to adulthood (corresponding to a treatment from childhood to the end of adolescence in humans). The effects of such treatments were evaluated after the first and the last injections on freely moving rats using microPET imaging with 18FDG. Our results showed that each medication affects the activity of limbic brain regions. In addition, LDX has an interesting profile showing effects also on associative fronto-striatal areas and on thedefault mode network. To our knowledge, these are the first preclinical neuroimaging results highlighting the crucial role of limbic brain regions related to motivation and the default mode network in the pathophysiology of attention deficits in ADHD. These data also reinforce the hypothesis that ADHD medications act on the brain areas primarily involved in the pathophysiology of ADHD. Interestingly, we showed that GFC and MPH shared the same effects on the limbic brain regions suggesting that this non psychostimulant medication is of a great interest for the treatment of ADHD. While MPH and GFC act primarily on limbic circuits, LDX also altered the activity of the default mode network and associative fronto-striatal areas. This support the hypothesis that LDX could be an interesting education for treating ADHD acting on all the systems identified as dysfunctional in the animal models of ADHD.

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There are gaps in the fundamental understanding of the expression of nitric oxide synthases (NOS) in the microvasculature. We examined co-localization of NOS1 (nNOS), NOS2 (iNOS) and NOS3 (eNOS) in the spinotrapezius muscle of young adult male Wistar-Kyoto (WKY) and Spontaneously Hypertensive (SHR) rats according to fiber type using immunohistochemistry and brightfield microscopy. Data regarding fiber distribution, population and morphology data were collected. Alkaline phosphatase staining was used to determine capillary density and average number of capillaries around a fiber. Gel electrophoresis and Western blot techniques were used to compare myosin heavy chain (MHC) protein expression with fiber type population data and to determine NOS1-3 protein expression in whole muscle homogenate. This study should provide a more accurate understanding of differences in NOS expression between these two strains of rats.