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No. of bitstreams: 2 Dissertação - George Martins Ney da Silva Júnior - 2015.pdf: 2151149 bytes, checksum: 266f50dd135504e70740809576b490bf (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2015-08-04 / Background: this study aimed to contribute to the knowledge of the interrelation of two morbid conditions that affect the autonomy and independence of the elderly: Bipolar disorder (BD) and the dementias. Methods: the medical records were reviewed to meet criteria at the same time for BD and dementia, resulting in a database of 130 cases (n = 130). Their demographics characteristics were described, as well as the frequencies of the diagnoses of dementia subtypes, their correlations with the age of dementia, the age of initiation of BD, its clinical forms and psychopathologic presentation. It was also studied the impact when the DSM4-TR diagnostic criteria was shifted to the Akiskal criteria for BD. Results: in the sample, the predominant dementia age range was senile dementia (senile: 85.71%; presenile: 14.29%) and the most common dementia subtypes were Corticobasal degeneration (CBD: 24.62%) and the Fronto-Temporal Lobar Degeneration (FTLD: 19.23%). The age of initiation of BD starting 35 years old or over amounted to 74.78% (between 10 and 34 years: 25.22%; between 35 and 59 years: 36.52%; and ≥ 60 years: 38.26%), with the following clinical forms of BD present in the sample: BD1: 71.54%, BD2: 20.77%; and Cyclothymia: 7.69%. The psychopathologic clinical presentation of BD prevalent in the sample was Mixed Episodes (38.46%), followed by Mania (33.07%), Hypomania with major depression (20.77%) and Hypomania without major depression (7.7%). When applied diagnostic criteria of Akiskal, the clinical form of BD prevalent in the sample remained the BD1 (46.92%), followed by the BD6 (34.62%) and the BD2 (18.46%). Conclusions: the results showed that the CBD and FTLD were the most common dementia in comorbidity with BD. And that the BD, in such cases, was predominantly late (≥ 35 years) or very late (≥ 60 years) and in its most severe form (BD1), with the most common psychopathologic syndrome of Mixed State or Mania, suggesting that the CBD and FTLD should be actively searched in the follow-up of these cases. DCB and DLFT in comorbidity to BD offer a privileged field of research for the pathophysiology of dementia and TB itself. / Introdução: O presente estudo teve como objetivo contribuir para o conhecimento da inter-relação de duas condições mórbidas que afetam a autonomia e a independência dos idosos: o Transtorno Bipolar (TB) e as demências. Métodos: Foram revistos os prontuários que preenchiam critérios concomitantemente para TB e demência, resultando num banco de dados de 130 casos. Foram descritas as suas caraterísticas sociodemográficas, as frequências dos diagnósticos dos subtipos de demência e suas correlações com: a faixa etária da demência; a faixa etária de início do TB, suas formas clínicas e apresentação psicopatológica. Foi também estudado se a mudança de critérios diagnósticos do DSM4-TR para os de Akiskal impactaria nos resultados. Resultados: Na amostra (n=130), a faixa etária predominante da demência foi a senil (senil: 85,71%; pré-senil:14,29%) e os tipos de demência mais frequentes foram a Degeneração Corticobasal (DCB: 24,62%) e a Degeneração Lobar Fronto-Temporal (DLFT: 19,23%). A faixa etária de início do TB acima dos 35 anos ocorreu em 74,78% (entre 10 e 34 anos: 25,22%; entre 35 e 59 anos: 36,52%; e≥60 anos: 38,26%), com as seguintes formas clínicas de TB presentes na amostra: TB1: 71,54%, TB2: 20,77% e Ciclotimia: 7,69%. A configuração psicopatológica de apresentação clínica do TB predominante na amostra foi a de Episódios Mistos (38,46%), seguida por Mania (33,07%), Hipomania com Depressão Maior (20,77%) e Hipomania sem Depressão Maior (7,7%). Quando aplicados os critérios diagnósticos de Akiskal, a forma clínica de TB predominante na amostra permaneceu o TB1 (46,92%), seguido pelo TB6 (34,62%) e o TB2 (18,46%). Conclusões: Os resultados mostraram que a DCB e a DLFT foram as demências mais frequentes em comorbidade com o TB. E que o TB, nesses casos, foi predominantemente de início tardio (≥35 anos) ou muito tardio (≥60 anos) e em sua forma mais grave (TB1), tendo como síndrome psicopatológica mais frequente o Episódio Misto ou a Mania, sugerindo que a DCB e a DLFT sejam pesquisadas ativamente ao longo de seu seguimento. DCB e DLFT comórbidas ao TB oferecem um campo privilegiado de pesquisas para a fisiopatologia das demências e do próprio TB.

Desde a abertura dos primeiros cursos de farmácia no Brasil, a estrutura curricular sofreu inúmeras alterações com vistas à adequação do curso com as necessidades locais. Após a homologação das Diretrizes Curriculares Nacionais de Farmácia de 2002, passou a ficar mais urgente a necessidade do desenvolvimento de habilidades e atitudes pelos farmacêuticos, não apenas o acúmulo de conhecimento técnico. Este trabalho teve como objetivo estudar as variáveis envolvidas na organização e estruturação do Integrado de Fisiopatologia e Farmacologia III, uma disciplina central na formação dos farmacêuticos da Universidade de São Paulo, incluindo a investigação dos fatores que influenciam no processo de aprendizagem dos alunos, bem como a aplicação de um método ativo de ensino-aprendizagem neste integrado e, por fim, realizar uma avaliação comparativa entre a opinião dos alunos com relação aos dois métodos. Observou-se resposta positiva estatisticamente significativa dos alunos em favor do método ativo contra o método tradicional em todos os aspectos avaliados, incluindo todos os aspectos relacionados ao plano disciplinar, assim como o impacto no desenvolvimento de competências e auto avaliação dos alunos. Estes resultados sustentam a necessidade de aplicação de métodos nos quais os alunos sejam o centro do processo educacional e tenham responsabilidade sobre sua própria aprendizagem, para assim formar profissionais generalistas, críticos e líderes. / Since the opening of the first pharmacy schools in Brazil, the curriculum has undergone numerous changes in order to keep up with local needs. After the approval of the National Curricular Guidelines for Pharmacy on 2002, it became more urgent for pharmacists to develop skills and attitudes, rather than only to accumulate technical knowledge. This work aimed to study the variables involved in organizing and structuring the Integrated Pathophysiology and Pharmacology III, a central discipline in the curriculum of pharmacy school at the University of São Paulo. Additionally it focused on investigate all factors that influences students\' learning process as well as applying an active learning in this integrated. And, finally, to compare students\' opinions regarding the two methods. We observed a statistically significant positive response of students in favor of the active method against the traditional one in all aspects evaluated, including all aspects of the disciplinary proceedings, impact on skills development and self-assessment of students. These results support the idea of implementation of methods in which students are the center of the educational process and are accountable for their own learning. This way we will be able to assist the development of pharmacists with clinical thinking and leadership skills.

La prééclampsie est une maladie fréquente de la grossesse, caractérisée par l’apparition de novo d’une hypertension et d’une protéinurie à partir de la 20ème semaine d’aménorrhée. Ces symptômes s’aggravent au long de la grossesse, conduisant éventuellement à la mort maternelle en l’absence de prise en charge médicalisée. La thérapeutique définitive l’extraction du placenta, et donc du fœtus, ce qui induit une importante prématurité iatrogène. Les causes restent mal définies, mais il est bien admis que des anomalies au niveau de la mise en place du placenta sont au cœur de sa physiopathologie. Un défaut d’invasion trophoblastique des artères spiralées utérines semble être une constante de la maladie. Des données épidémiologiques démontrent qu’il existe une forte composante génétique dans la prééclampsie, et en 2005, un clonage positionnel dans des familles hollandaises, aboutit à l’identification de STOX1 comme le premier gène lié à cette maladie. STOX1 code un facteur de transcription intervenant dans le contrôle de la prolifération et de l’invasion des trophoblastes. Dans notre laboratoire, l’étude de STOX1 a été initiée par surexpression dans des cellules de choriocarcinome humain (modèle de trophoblastes) suivie d’une analyse transcriptomique. Celle-ci a révélé que les altérations d’expression génique observées suite à la surexpression de STOX1 étaient significativement corrélées à celles trouvées dans des placentas prééclamptiques. La création de souris transgéniques exprimant la version humaine de STOX1 sous le contrôle d’un promoteur ubiquitaire a alors été entreprise. Mes travaux de thèse ont principalement consisté à caractériser le phénotype de ces souris. Nous avons décidé de croiser des mâles transgéniques avec des souris sauvages afin de limiter l’expression du transgène à l’unité fœto-placentaire. Ces souris sauvages développent au cours de leur gestation une hypertension sévère, et une protéinurie. Elles constituent donc un nouveau modèle de prééclampsie. De plus, nous avons observé des anomalies que l’on trouve également chez les patientes : une fibrose rénale, une élévation des taux sériques de facteurs pro-angiogéniques (le récepteur soluble du VEGF et l’endogline soluble). Ces souris ont également des marqueurs d’hypertrophie cardiaque, attestant de l’impact sévère de l’hypertension. Pour mieux comprendre comment STOX1 peut induire ce syndrome, nous avons étudié son impact dans le modèle cellulaire surexprimant STOX1 et nous avons pu montré une altération de la gestion du stress oxydatif et de la fonction mitochondriale. En conclusion, nous avons obtenu et caractérisé un modèle de prééclampsie sévère, le seul existant montrant un phénotype hypertensif très marqué et très précoce. Ce modèle est un outil puissant pour découvrir de nouvelles voies impliquées dans la physiopathologie de la prééclampsie, pour rechercher de potentiels marqueurs diagnostiques précoces, tester des approches thérapeutiques innovantes et explorer les mécanismes responsables des conséquences à long terme de la prééclampsie. / Preeclampsia is a common disease of pregnancy characterized by de novo appearance of hypertension and proteinuria from the 20th week of gestation. These symptoms worsen during pregnancy, possibly leading to maternal death in the absence of medical management. The only final treatment is the extraction of placenta and so fetus, which is responsible to a significant iatrogenic prematurity. The causes remain unclear, but it is well accepted that abnormalities in the development of the placenta are at the heart of its pathophysiology. A lack of trophoblastic invasion of the uterine spiral arteries seems to be a constant of the disease. Epidemiological data show that there is a strong genetic component in preeclampsia, and in 2005, a positional cloning in Dutch families led to the identification of STOX1 as the first gene linked to the disease. STOX1 encode a transcription factor involved in the control of proliferation and invasion of trophoblasts. In our laboratory, the study of STOX1 was initiated by its overexpression in human choriocarcinoma cells (trophoblast model) followed by transcriptome analysis. This revealed that the gene expression changes observed after STOX1 overexpression were significantly correlated with those found in preeclamptic placentas. The creation of transgenic mice expressing the human version of STOX1 under the control of a ubiquitous promoter was then initiated. My work during this thesis consisted primarily to characterize the phenotype of these mice. We decided to cross transgenic males with wild-type mice to limit transgene expression in fetal-placental unit. These wild mice develop during gestation severe hypertension and proteinuria. They therefore constitute a new model of preeclampsia. In addition, we observed anomalies that are also found in patients: renal fibrosis, elevated serum levels of pro-angiogenic factors (soluble VEGF receptor and soluble endoglin). These mice also have markers of cardiac hypertrophy, attesting for the severe impact of hypertension. To better understand how STOX1 can induce the syndrome, we studied its impact on the cell model overexpressing STOX1 and we showed a change in the management of oxidative stress and mitochondrial function. In conclusion, we have obtained and characterized a model of severe preeclampsia, the only existing one showing a very strong and very early hypertensive phenotype. This model is a powerful tool for discovering new pathways involved in the pathophysiology of preeclampsia, for searching potential early diagnostic markers, for testing innovative therapeutic approaches and for exploring the mechanisms responsible for the long-term consequences of preeclampsia.

Lipid metabolism in Trypanosoma brucei, the causative agent of African sleeping sickness, differs from its human host, allowing a plethora of novel drug targets to be discovered and validated. Cytidine diphosphate diacylglycerol (CDP-DAG) is a central lipid intermediate produced by the enzyme CDP-DAG synthase (CDS), but nothing was known about CDS in T. brucei. Only one gene encodes CDS in Trypanosoma brucei (Tb927.7.220) and this was shown to encode a functional CDS by overexpression in E. coli and complementation of a yeast CDS null, which was created during this study. Expression and activity of TbCDS was confirmed in T. brucei, and was shown to be essential in both life cycle stages. Disruption of TbCDS altered the lipid profile of T. brucei, confirming a central role for CDP-DAG in phospholipid synthesis. Biochemical and morphological characterisation of mutants in TbCDS expression elucidated at least two separately localised and regulated pools of CDP-DAG and phosphatidylinositol in T. brucei. In bloodstream form these pools are localised to the Golgi and the ER, however in procyclics it is possible that both of these pools are localised to the Golgi, since no phosphatidylinositol synthase protein was detected in the ER of procyclics. Reduction in TbCDS was shown to affect cell cycle regulation and Golgi segregation possibly due to a depletion of phosphorylated phosphatidylinositols (PIPs). These studies also indicate that phosphatidylglycerol may be synthesised by the phosphatidylglycerol-phosphate synthase which may be capable of using phosphatidylserine as a substrate in a headgroup swapping reaction. TbCDS has now been genetically validated as a drug target, and has highlighted novel aspects of lipid biosynthesis in T. brucei. Collectively, these findings highlight the central role played by TbCDS and the new knowledge gained here may lead to the discovery and validation of other novel drug targets against African sleeping sickness.

Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

Abstract Acute rhinosinusitis (ARS) is a common condition often treated with antibiotics, even though the cause is usually viral. Despite the commonness of ARS, there is limited evidence on the development and diagnosis of bacterial cases. So far, we lack prospective studies where the bacterial cause would have been confirmed with a bacterial culture of the paranasal sinus aspirate. The purpose of the study was to investigate the course of ARS with a prospective inception cohort study among young adults with ARS, using sequential and standardized methods. To differentiate viral and bacterial ARS, maxillary sinus aspiration and a bacterial culture were used as a reference standard for bacterial ARS. Fifty conscripts with ARS were recruited between February and April 2012. Eight patients (16%) had a positive culture from the maxillary sinus aspirate at 9–10 days and thus, had bacterial ARS. Viral and bacterial coinfection resulted in extensive paranasal mucosal abnormalities and increased symptoms during the episode. The paranasal mucosal abnormalities developed rapidly and remained relatively constant during the episode in both bacterial and non-bacterial ARS. A change in inflammatory biomarker levels indicated both local and systemic inflammatory responses, which were strongest at the onset of symptoms. Symptoms or their changes were of little use in diagnosing bacterial ARS, but secretion seen in the nasal cavity, posterior pharynx or middle meatus predicted bacterial ARS quite well. These results suggest that bacterial infection may modify symptoms and paranasal abnormalities already at the beginning of an ARS episode, although the spread of paranasal abnormalities may not be an etiological factor in the development of bacterial ARS. ARS involves local and systemic inflammatory responses, which are strongest at the beginning of the episode. Examination of the nose and throat is recommended for diagnosing bacterial ARS. / Tiivistelmä Nenän äkillinen sivuontelotulehdus on tavallinen tauti, jonka hoitoon käytetään paljon antibiootteja, vaikka sen aiheuttaja on useimmiten virus. Bakteerin aiheuttaman tautimuodon kehittymisestä ja diagnostiikasta ei ole julkaistu tutkimuksia, joissa potilaita olisi seurattu taudin alusta lähtien ja bakteerin olemassaolo olisi varmistettu nenän sivuontelosta otetulla bakteerinäytteellä. Tämän väitöskirjatyön tarkoituksena oli selvittää nenän äkillisen sivuontelotulehduksen kulkua käyttämällä toistuvia, standardisoituja menetelmiä. Bakteerin aiheuttama tauti todettiin poskiontelopistolla ja bakteeriviljelyllä. Tutkimukseen osallistui viisikymmentä (50) äkilliseen ylähengitystieinfektioon sairastunutta varusmiestä keväällä 2012. Kahdeksalla (16 %) potilaalla todettiin bakteerin aiheuttama tauti poskiontelopiston avulla 9–10 päivää oireiden alkamisen jälkeen. Viruksen ja bakteerin sekainfektio aiheutti laajemmat sivuonteloiden tulehduslöydökset ja voimakkaammat oireet kuin pelkän viruksen aiheuttama tauti. Sivuonteloiden tulehduslöydökset kehittyivät nopeasti ja pysyivät sekä bakteerin että viruksen aiheuttamassa taudissa varsin muuttumattomina. Tulehdusmerkkiaineiden muutokset osoittivat sekä paikallisen, että yleisen tulehdusreaktion, jotka olivat voimakkaimmillaan taudin alussa. Oireet tai niissä taudin aikana tapahtuneet muutokset eivät osoittautuneet hyviksi merkeiksi bakteerin aiheuttaman taudin toteamiseksi, mutta eritteen näkyminen nenässä, nielussa tai keskikäytävässä ennakoi hyvin bakteerin aiheuttaman sivuontelotulehduksen toteamista. Bakteeri saattaa vaikuttaa oireisiin ja sivuonteloiden tulehduslöydöksiin jo nenän äkillisen sivuontelotulehduksen alussa, mutta tulehduslöydösten laajuus ei välttämättä liity bakteerin aiheuttaman taudin kehittymiseen. Nenän äkilliseen sivuontelotulehdukseen liittyy paikallinen ja yleinen tulehdusreaktio, jotka ovat voimakkaimmillaan taudin alussa. Potilaan nenän ja nielun tutkiminen on tärkeää bakteerin aiheuttaman nenän sivuontelotulehduksen toteamiseksi.

L'athérosclérose est une maladie inflammatoire chronique déclenchée par l'accumulation de lipides et caractérisée par l'infiltration des cellules immunitaires dans la paroi artérielle. Les études de modèles animaux révèlent des résultats paradoxaux concernant l'effet des cellules B (protecteur ou pro-athérogène). Pour avoir une meilleure compréhension de la physiopathologie de l'athérome humain, nous avons caractérisé les LB résidents et leur production d'immunoglobulines.Treize patients subissant une endartériectomie carotidienne ont été examinés et disséqués pour isoler l'intima et l'adventice. Cette dernière est la couche principale de la domiciliation des cellules B qui constituent des infiltrats diffus ou des agrégats. L'analyse par RT-PCR montre la production locale d'IgA chez tous les patients et d'IgG chez la majorité. L'IgM est plus rarement détectée. De plus, les chaînes légères sont majoritairement d'isotype lambda. L'étude du répertoire des récepteurs d'antigènes montre que l'adventice contient un nombre limité de clones B avec une utilisation récurrente de quelques sous familles de VH. Ces lymphocytes secrètent majoritairement des immunoglobulines hypermutées. Ces anticorps ont été reconstruits et montrent une bonne capacité discriminante en reconnaissant des antigènes tissulaires particuliers. D'autre part, l'analyse des séquences suggère une maturation locale sous la pression des antigènes locaux. Des parties variables d'immunoglobulines différentes (H ou L) codent pour le même CDR3 montrant ainsi une maturation convergente. De plus, l'expression de la cytidine déaminase AID est détectée chez quelques patients, ce qui est compatible avec l'observation d'une commutation de classe dans certains clones B adventitiels. La majorité de cellules B de l'adventice artérielle sont des plasmablastes n'exprimant pas le marqueur CD20 et secrétant des cytokines inflammatoires (IL-6, GM-CSF et TNF-alpha). Les marqueurs clonotypiques CDR3 indiquent que l'adventice et la plaque ont des répertoires différents et qu'une population de cellules B circule entre l'adventice et les ganglions. / Atherosclerosis is a chronic inflammatory disease initiated by lipid accumulation and characterized by immune cells infiltration within arterial walls. Animal models suggest that B cells may have contradictory protective or pro-atherogenic effects. To further understand the pathophysiology of human atheroma, we analyzed Ig production and characterized resident B lymphocytes within vascular lesions.Tissue samples from 13 patients undergoing carotid endarterectomy were examined and dissected to isolate intimal plaques and tunica adventitia. This latter is the main site of B cells homing. These lymphocytes constituted diffuse infiltrates or formed small cell clusters. Functional IgA was present in all adventitias while IgG was detected in the majority. IgM transcripts were less abundant or even absent. Most L chain transcripts were of the lambda type. BCR analysis indicated that individual samples contained each a limited number of B cell clones with a bias for the recurrent utilization of some particular V region sub-families. These lymphocytes produced mainly hypermutated immunoglobulins. Engineered reconstructed antibodies were discriminative as recognizing tissue specific antigens. On the other hand, BCR sequence analysis suggests a local maturation and antigen driven evolution. Both intraclonal diversification and convergence of CDR sequences between different B cell clones were observed. Expression of the cytidine deaminase AID was detected in several arterial wall samples, in keeping with the observation of a local H chain class switch. The majority of resident B lymphocytes are CD20 negative plasmablasts that secrete inflammatory cytokines (IL-6, GM-CSF, and TNF-alpha). CDR3 clonotypic markers revealed that plaque and adventitia repertoires were different and indicated that a population of B cells was circulating between adventitia and draining lymph nodes.

Les parasomnies forment un ensemble de troubles du sommeil caractérisés par la survenue de comportements ou de phénomènes psychiques indésirables au cours du sommeil. Les parasomnies du sommeil lent profond (SLP) regroupent le somnambulisme, les terreurs nocturnes et les éveils confusionnels et surviennent au décours d’éveils brutaux en SLP. Elles s’associent souvent chez un même individu et pourraient représenter des variantes cliniques d’une même pathologie.Longtemps considérées comme des troubles bénins du sommeil, les données actuelles soulignent les conséquences des parasomnies, avec des mises en danger et un retentissement fonctionnel diurne. Nos trois premiers travaux ont permis une meilleure caractérisation du phénotype et des conséquences des parasomnies, en particulier sur le plan de la somnolence et des phénomènes douloureux chroniques. Près de la moitié des adultes parasomniaques rapportaient une plainte de somnolence diurne excessive associée à une propension marquée au sommeil sur les premières heures de la journée. Nous retrouvions une fréquence élevée de douleurs chroniques, de céphalées et de migraine. Par ailleurs nous avons décrit un phénomène fréquent d’hypo/analgésie au cours des accès parasomniaques.Le diagnostic des parasomnies du SLP repose uniquement sur des éléments cliniques, sans critères polysomnographiques objectifs. Si des travaux récents suggèrent que les parasomnies sont associées à des altérations discrètes de la microstructure du SLP, les performances diagnostiques de ces paramètres n’ont pas fait l’objet d’études spécifiques. Nous avons développé une nouvelle méthode d’analyse polysomnographique qui offre de bonnes performances de classification chez des adultes parasomniaques et des sujets témoins.Malgré cinq décennies d’études cliniques et expérimentales, la physiopathologie de ces parasomnies reste mal connue. Un modèle permet de conceptualiser les mécanismes de la maladie. Chez un patient prédisposé génétiquement, certaines conditions responsables d’une instabilité du SLP favorisent la survenue d’un éveil dissocié précipité par un stimulus éveillant. Nos travaux en cours et futurs porteront sur l’étude de ces mécanismes au moyen de techniques innovantes de génétique, d’électrophysiologie et d’imagerie fonctionnelle. / Parasomnias are sleep disorders characterized by undesirable behavioral or experiential phenomena occurring during sleep. Disorders such as sleepwalking (somnambulism), sleep terrors and confusional arousal are classified under the term “Non Rapid Eye Movement (NREM) Sleep-related parasomnias” as they frequently occur during sudden arousals from slow wave sleep. They often coexist within the same individual and are considered as different phenotypes for a similar underlying pathophysiology.The widespread belief that NREM parasomnias are benign disorders is actually challenged as they can result in various adverse consequences such as violent and injurious behaviors and daytime functional impairment. Our first three studies investigated the clinical phenotype and the consequences of NREM parasomnias, especially subjective and objective daytime sleepiness and chronic pain. We found that almost an half of sleepwalkers had complaint of sleepiness with an increased objective sleep propensity in the morning. We also reported a high frequency of chronic pain, headaches and migraine in patients and described a frequent analgesia phenomenon during injurious parasomniac episodes.The diagnosis of NREM parasomnias is usually made from clinical history, without polysomnographic-based diagnostic criteria. If recent works suggested that NREM parasomnia were associated with subtle changes on the NREM microstructure, the diagnostic performances of these parameters have been poorly studied with appropriate design. We developed a new polysomnographic scoring method that offers a good classification rate of NREM parasomnia patients and controls.Despite almost five decades of clinical and laboratory investigations, the pathophysiology of NREM parasomnias remains poorly understood. One model is currently used to conceptualize the mechanisms of the disease. A predisposed patient is primed by conditions that impair slow wave sleep stability resulting in dissociated arousal precipitated by arousing stimuli. Our further works will investigate the pathophysiology of NREM parasomnia using innovative genetic, electrophysiological and functional imagery approaches.

This investigation was concerned with measuring aspects of cardiac function in conscious control, diabetic, hypertensive control, and hypertensive diabetic rats. Preliminary studies were conducted to determine catheter suitability and acute responses to atropine and angiotensin II in conscious animals. The catheter-manometer was tested using a square wave impact and was shown to accurately reproduce a left ventricular pressure pulse. Intravenous atropine caused both heart rate and left ventricular +dP/dt to rise. Intravenously administered angiotensin II caused systolic blood pressure to increase dramatically. In this case heart rate fell and +dP/dt was elevated. Hypertension was induced with deoxycorticosterone acetate (DOCA) and saline drinking water. Rats were first made diabetic with streptozotocin (60 mg/kg; i.v.). One week following this, subcutaneous DOCA (25 mg/kg) was administered twice weekly and all animals received saline drinking water. Following 2 and 5 weeks of DOCA treatment rats were catheterized and resting cardiovascular function was measured. DOCA treatment caused increased systolic and diastolic blood pressures to occur in control and diabetic rats at 2 and 5 weeks. Bradycardia was also observed in DOCA-diabetic and DOCA-control rats at 2 and 5 weeks of treatment. Two and 5 week hypertensive diabetic and control rats exhibited elevated -dP/dt and +dP/dt. The rate of contraction was shown to be proportional to the magnitude of systolic blood pressure in all treatment groups. It is concluded that diabetic rats and control rats did not differ in their response to hypertension after 5 weeks of DOCA treatment. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

This thesis assessed the suitability of unilateral, electrolytic lesions as a model of spinal cord damage and repair in the adult rat. This type of lesion resulted acutely in localized damage in the upper motor neuron at the L2-L3 level of the spinal cord. Minimal acute damage to ascending sensory pathways was indicated by preserved somatosensory evoked potentials elicited by stimulation of the tibial nerve. Immediately after lesion generation one of several substrates was injected into the lesion cavity. These substrates were saline buffer, liquid collagen solution, foetal spinal cord cells from 14 day old rat embryos, and a mixture of collagen and E 14 foetal spinal cord cells. The 4 groups were compared for functional recovery over 3 months using the inclined plane test and a Tarlov movement scale. After sacrifice, the tibialis anterior muscles were dissected and weighed to assess atrophy due to lower motor neuron injury. After removing and embedding the spinal cords in paraffin, transverse and longitudinal sections were taken for cytoarchitectural investigation. Cresyl violet was used to indicate Nissl substance, Luxol fast blue stained for myelin and anti - glial fibrillary acidic protein (GFAP) antibody revealed the expression of GFAP in the cord sections. Chronic electrolytic lesions were characterized by the highly variable degree of cavitation, demyelination and macrophage infiltration that was present. There was no significant performance deficit on the inclined plane test in any of the lesioned groups when compared to unoperated animals. The tibialis muscles from all groups were of normal weight, indicating that the lower motor neurons were not significantly damaged by the lesions used. There was, however, a marked decrease in the number of GFAP reactive astrocytes in the lesioned animals when compared to unlesioned controls (P < 0.01, Wilcoxon test). Moreover, this reduction of GFAP - like immunoreactivity was not prevented by implants of foetal neurons, collagen or foetal neurons suspended in collagen. Possible explanations for the reduced GFAP - like immunoreactivity seen in all electrolytically lesioned cords are discussed. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate