The goal of this research was to determine the procedures used for conducting a search and seizure in a tax-related offence in terms of the Criminal Procedure Act, Act 51 of 1977. Aspects that cause problems for the South African Revenue Service (SARS) investigators are the application for a search warrant and the activities that take place before, during and after the search and seizure. An introduction, definition and explanation are given of certain key concepts such as forensic and criminal investigations, as well as their objectives and purpose. The various search methods are also discussed and explained as are the chain of custody and evidence in general. A large part of this research deals with the legal requirements for a search and seizure in a tax-related offence and encompasses issues such as the procedures for obtaining a search warrant, pre-raid briefing, conducting the search, and the seizing of, marking, storage and disposal of documents. The findings of the research are discussed and recommendations subsequently made regarding the shortcomings identified. The findings that were made related to the process and procedure to obtain a search warrant, the actual execution of a search and seizure and the legislation that authorises searches and seizures in taxrelated offences. Further findings were made in respect of the mandate of SARS criminal investigators to investigate, the admissibility of evidence obtained from a search and seizure and the marking, recording, storage and disposal of seized items. Recommendations were made regarding training, improved communication and skills transfer to address the shortcomings identified. / Police Practice / (M.Tech. (Forensic investigation))

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / In recent years have been identifical numerous pharmacological properties of a selenium compound, diphenyl diselenide [(PhSe)2]. Consequently, it is important the investigation of its toxic effect for a safe application in pharmacological studies. It is known that babies, in particular, have many physiological and biochemical changes related to development, which increase the susceptibility to toxic effects of drugs. Thus, the article 1 investigated the appearance of seizure episodes induced by (PhSe)2 when administered orally at doses of 5 to 500 mg/kg in rat pups (pos natal day 12-14) and the possible glutamatergic (article 2) and GABAergic (article 3) mechanisms involved in this process. Some studies using different experimental models have demonstrated the most different pharmacological and toxicodynamics properties of (PhSe)2. However, little is known about the toxicokinetic disposition of this compound. Therefore, the aim of article 4 was to determine and quantify the plasma levels of (PhSe)2 in adult mice and rats after oral (p.o.) administration of 500 mg/kg (PhSe)2; to verify the involvement of different routes of administration, vehicle and animal species in plasma levels of (PhSe)2 and in the onset of the first seizure episode induced by it. In article 5, it was determined and quantified the levels of (PhSe)2 in plasma, liver and brain of rat pups and these levels were correlated to the latency for the onset of the first seizure episode. To obtain more information about the compound, which were to supplement the data obtained, we carried out in vitro kinetic models. The manuscript 1 investigated the drug-like properties of (PhSe)2 in regards to stability, solubility, absorption and plasma protein binding (PPB) in vitro. In manuscript 2, it was conducted an in vitro study in order to identify possible metabolic pathways responsible for the biotransformation of (PhSe)2 in the body. Results of article 1 showed that administration of (PhSe)2 caused toxicity in rat pups, evidenced by the appearance of seizures. These were dose dependent and were, at least in part, related to oxidative stress. Among the mechanisms involved in the convulsive effect of (PhSe)2 were the interaction with: glutamatergic system by stimulating the inotropic glutamatergic receptors NMDA and by inhibiting the uptake of glutamate (Article 2); GABAergic system by antagonize the GABAA receptor, stimulating GABA transaminase enzyme and increasing GABA uptake (Article 3). The article 4 revealed that the maximum concentration of (PhSe)2 in the plasma of adult rats and mice occurred 30 minutes after p.o administration of the compound and remained detectable up to 8 hours after administration. The use of different routes of administration (intraperitoneal (i.p.), p.o., subcutaneous (s.c.)) or vehicle (canola oil or dimethyl sulfoxide (DMSO)) in rats and mice indicated that the onset of the first seizure episode and plasma levels are dependent on the route of administration (i.p. > p.o. > s.c.), vehicle (DMSO > canola oil) and animal species (mouse > rat). In article 5, it was observed that rat pups showed seizures even presenting lower plasma values of (PhSe)2 as compared to adults. This result demonstrated that rat pups are more sensitive to the toxic effects of (PhSe)2 than adult rats. Levels of (PhSe)2 in the liver and brain of rat pups showed a negative correlation with the latency to the first seizure episode. The manuscript 1 showed that (PhSe)2 has chemical and biological stability. However, the compound has a low solubility in water, a high partition coefficient octanol-water and an extensive plasma protein binding. Manuscript 2 indicated that (PhSe)2 is not biotranformed by Phase I reactions, catalyzed by cytochrome P450. It reacted chemically with reduced glutathione (GSH) and N-acetylcysteine (NAC) to form adducts or reacts with protein SH groups. The presence of GSH or NAC in the incubation medium decreased the binding of (PhSe)2 protein. Finally, it was observed that (PhSe)2 reduced the activity of cytochrome P450. Together, the data presented showed that the intensity of toxic effects caused by (PhSe)2 are directly related to its toxicokinetic. / Nos últimos anos, têm sido identificadas inúmeras propriedades farmacológicas do composto de selênio disseleneto de difenila [(PhSe)2]. Assim, a pesquisa dos efeitos tóxicos deste composto torna-se importante para a segurança na aplicação farmacológica. Sabe-se que os bebês, em particular, apresentam muitas mudanças fisiológicas e bioquímicas relacionadas ao desenvolvimento, que aumentam a suscetibilidade aos efeitos tóxicos de drogas. Desta forma, no artigo 1 investigou-se o aparecimento de convulsões induzida pelo (PhSe)2, quando administrado pela via oral (p.o), nas doses de 5 à 500 mg/kg em ratos bebês (12-14 dias de vida) bem como os possíveis mecanismos glutamatérgicos (Artigo 2) e GABAérgicos (Artigo 3) envolvidos em tal processo. Vários estudos, utilizando diferentes modelos experimentais demonstraram as mais diferentes propriedades farmacológicas e toxicodinâmicas do (PhSe)2 no entanto, pouco se conhece sobre a toxicodinâmica deste composto. Por isso, o objetivo do artigo 4 foi determinar e quantificar os níveis plasmáticos de (PhSe)2 em ratos e camundongos adultos após a administração p.o. de (PhSe)2 na dose de 500 mg/kg; bem como verificar o envolvimento de diferentes vias de administração, veículos e espécie animal nos níveis plasmáticos do composto e no aparecimento de convulsões induzidas pelo mesmo. No artigo 5, determinou-se e quantificou-se os níveis de (PhSe)2 no plasma, fígado e cérebro de ratos bebês e correlacionou-se estes níveis à latência para o aparecimento de convulsões. Devido a necessidade de obter mais informações sobre o composto, que viessem a complementar os dados obtidos, realizou-se modelos cinéticos in vitro. O manuscrito 1 investigou parâmetros relacionados a estabilidade, solubilidade, absorção e ligação às proteínas plasmáticas do (PhSe)2 in vitro. No manuscrito 2 realizou-se um estudo in vitro para identificar as vias metabólicas responsáveis pela biotransformação do (PhSe)2 no organismo. Os resultados do artigo 1 demonstraram que a administração de (PhSe)2 causou toxicidade em ratos bebês, evidenciada pelo aparecimento de convulsões. Estas são dependentes da dose utilizada e estão, pelo menos em parte, relacionadas ao estresse oxidativo. Dentre os mecanismos neuroquímicos envolvidos no efeito convulsivante do (PhSe)2 estão a interação com o sistema glutamatérgico, por estimular os receptores glutamatérgicos ionotrópicos do tipo NMDA e por inibir a captação de glutamato (Artigo 2); e com o sistema GABAérgico, por antagonizar os receptores GABAégicos do tipo GABAA, estimulando a enzima GABA transaminase e estimulando a captação de GABA (Artigo 3). O artigo 4 demonstrou que concentração máxima de (PhSe)2 no plasma de ratos e camundongos adultos ocorreu 30 minutos após a administração pela via oral do composto e permaneceu detectável até 8 horas após sua administração. O uso de diferentes vias de administração (intraperitonial (i.p); p.o; subcutânea (s.c)) e veículo (óleo de canola ou dimetil sulfóxido (DMSO)) em ratos e camundongos indicou que o aparecimento de convulsões e os níveis plasmáticos de (PhSe)2 são dependentes da via de administração (i.p > p.o > s.c), do veículo (DMSO > óleo de canola) e da espécie animal (camundongo > rato). No artigo 5 observou-se ainda que os ratos bebês convulsionaram mesmo apresentando níveis plasmáticos menores de composto que os adultos, o que nos leva a crer que estes são mais sensíveis aos feitos tóxicos do (PhSe)2. Os níveis de (PhSe)2 no fígado e no cérebro de ratos bebês no momento do episódio convulsivo apresentaram uma correlação negativa com a latência para o primeiro episódio convulsivo. O manuscrito 1 revelou que o (PhSe)2 apresenta estabilidade química e biológica. No entanto, o composto apresenta uma baixa solubilidade em água, um alto coeficiente de partição octanol-água e uma extensa ligação às proteínas plasmáticas. O manuscrito 2 indicou que o (PhSe)2 não é biotransformado por reações de fase I catalizadas pelo citocromo P450. O composto reage quimicamente com a glutationa reduzida (GSH) e a N-acetilciateína (NAC), formando adutos ou ainda reage com grupos SH de proteínas. A presença de GSH ou NAC no meio de incubação diminuiu a ligação do (PhSe)2 às proteínas. Por fim, foi observado que o (PhSe)2 reduziu a atividade das enzimas do citocromo P450. Em conjunto, os resultados desta tese demonstraram que a intensidade dos efeitos tóxicos causados pelo (PhSe)2 estão diretamente relacionados a sua toxicocinética.

Made available in DSpace on 2014-12-17T14:13:34Z (GMT). No. of bitstreams: 1 AnaMCS.pdf: 1887892 bytes, checksum: 05f9c6bffc3d95915a924712e4e7b5c7 (MD5) Previous issue date: 2007-12-19 / The purpose of this paper was to study patients with congenital and acquired hemiparesis, their clinical aspects, the presence or not of epileptic seizures, and electroencephalographic (EEG) and Magnetic Resonance Imaging (MRI) findings. We analyzed the interrelation between etiology, the presence and seriousness of epileptic seizures (ES) and the possible causes of refractoriness. This is a prospective study using the clinical diagnosis of a child neurologist, who attested to the presence of unilateral motor lesions. We compared the electroencephalographic findings in patients with or without epileptic seizures, and investigated if among the former, these seizures were controlled or not, their likely etiology and risks of refractoriness. EEG background activity on the lesion and contralateral side was analyzed, in addition to the presence of concomitant epileptiform activity. Encephalon MRIs of all the patients were studied to correlate etiology and the control or not of epileptic seizures. The disorganization of bilateral EEG activity correlated with the difficult-to-control epileptic seizures. Suitably organized background activity contralateral to the lesion is a good prognosis in relation to epileptic seizures. Focal epileptogenic activity does not necessarily predispose to epileptic manifestation. The MRI is more important in determining etiology than in prognosing epileptic seizures. This study used a multidisciplinary approach involving child neurologists, a physical therapist and a neuroradiologist. This meets the criteria of multidisciplinarity of the Postgraduate Program in Health Sciences / O objetivo do nosso trabalho foi estudar pacientes com hemiparesia, cong?nitas e adquiridas, seus aspectos cl?nicos e epidemiol?gicos, a presen?a ou n?o de crises epil?pticas e os achados eletrencefalogr?ficos e de neuroimagem por Resson?ncia Nuclear Magn?tica. Tentando relacionar a etiologia ? presen?a e gravidade de crises epil?pticas e as poss?veis causas de refratariedade. Trata-se de um estudo prospectivo a partir do diagn?stico cl?nico por um neurologista infantil que atestou a presen?a de les?o motora unilateral. Compararam-se os achados eletrencefalogr?ficos em pacientes sem ou com crises epil?pticas, e dentre esses ?ltimos, se h? ou n?o controle das crises, sua prov?vel etiologia e riscos de refratariedade. Analisou-se a atividade de base do EEG do lado da les?o e contra lateral a esta, al?m da presen?a de atividade epileptiforme concomitante. Estudaram-se as RNM do enc?falo realizadas em todos os pacientes, tentando relacionar a etiologia e controle ou n?o de crises epil?pticas. A desorganiza??o da atividade de base bilateral no EEG correlacionou-se com crises epil?pticas de dif?cil controle. A atividade de base adequadamente organizada contra lateral a les?o ? de bom prognostico em rela??o ?s crises epil?pticas. A atividade epileptog?nica focal n?o necessariamente predisp?e a manifesta??o epil?ptica. A RNM ? mais importante na determina??o da etiologia do que no progn?stico das crises epil?pticas. A realiza??o deste estudo foi concretizada pela abordagem multidisciplinar, envolvendo neurologistas infantis, fisioterapeuta e neurorradiologista. Este aspecto preenche os requisitos de multidisciplinaridade do programa de p?s-gradua??o em Ci?ncias da Sa?de

Made available in DSpace on 2014-12-17T14:13:50Z (GMT). No. of bitstreams: 1 AuriniceSIM_DISSERT.pdf: 523192 bytes, checksum: d28bf5a5e1dd30cfeab1db694982f134 (MD5) Previous issue date: 2010-10-07 / The epilepsy is one of the neurological disorders more common in the pediatric period, and which interferes significantly in the psycho and social life of children and teenagers. The objective of this study was analyzing the practice of sedentary practices, physicals, traditional infant fun and games of children and teenagers with and without epilepsy. The study was prospective, transversal descriptive, done with 60 children and teenagers with epilepsy (Epileptic Group - EG) patients from Pediatric Neurology Clinic of the Centre Integrated Health Lineu Ara?jo and 60 children and teenagers without epilepsy (Control Group - CG) students from municipal public school, both of the two groups paired with the same age (age group 7 to 14 years) of both the genders (female = 25/41,6% and male = 35/58,3%) of the Teresina city Piau?. It was done two pattern questionnaires, one applied to children and teenagers of the EG and CG to identify the sedentary activities, physical and traditional infant games and other to the parents/responsible of the EG about the clinical and demographic information. The results permitted the elaboration of two manuscripts: a) the first one titled The Practice of Sedentary and Physical Activities of Children and Teenagers with Epilepsy which showed significant difference in the sedentary activities of playing with car toy (p=0,021) to the EG and reading to the CG (p=0,001); in the physical activities the school physical education (p=0,001) and riding a bike (p=0,014) to the CG; b) the second one The Practice of Infant Games and Fun the children and teenagers with and without Epilepsy in this one the playing with marble presented significant difference (p=0,016) to the CG, despite the girls of the two groups don t do this activity. Observing the distribution of frequencies, it was verified that in the play catch-up and hide-and-seek and burn the EG plays more than the CG both in female and male gender. The girls of the EG play less skip, 60 while the boys of the two groups don t play. Elastic jump the girls of the two groups play in a same frequency and the boys don t participate of this fun. The seizures were found to occur during: soccer (23,3%); hide-and-seek (6,6%) and running (3,3%). In the sedentary activities, seizures were reported to occur: resting and watching TV (18,3%), sleeping (36,0%); sitting (13,3%) and lying down (11,7%). Our results showed that the epileptic group and the controls group engage in the same activities, although the epileptic group participates less than the controls. Although the EG had presented a bigger percentage of generalized attacks, they don t occur during the practice of formal physical activities. The research was developed by a multidisciplinary team, and this contributed a lot to the realization of this study / A epilepsia ? uma das desordens neurol?gicas mais comuns na faixa pedi?trica e que interfere significativamente na vida psico-social de crian?as e adolescentes. O objetivo deste estudo foi analisar a pr?tica de atividades sedent?rias, f?sicas, brincadeiras e jogos infantis de crian?as e adolescentes com e sem epilepsia. O estudo foi prospectivo, transversal descritivo, realizado com 60 crian?as e adolescentes com epilepsia (Grupo Epilepsia - GE) pacientes do Ambulat?rio de Neuropediatria do Centro Integrado de Sa?de Lineu Ara?jo e 60 crian?as e adolescentes sem epilepsia (Grupo Controle - GC), escolares de uma escola p?blica municipal, sendo os dois grupos pareados com a mesma idade (faixa et?ria 7 a 14 anos) de ambos os g?neros (feminino = 25/41,6% e masculino = 35/58,3%) da cidade de Teresina Piau?. Utilizou-se dois question?rios padr?o, um aplicado as crian?as e adolescentes dos GE e GC para identificar as atividades sedent?rias, f?sicas e jogos tradicionais infantis, e outro aos pais/respons?veis do GE sobre as informa??es cl?nicas e demogr?ficas. Os resultados permitiram a elabora??o de dois manuscritos: a) o primeiro intitulado - A Pr?tica de Atividades Sedent?rias e F?sicas de Crian?as e Adolescentes com Epilepsia - que mostrou diferen?a significante nas atividades sedent?rias de brincar de carrinho (p=0,021) para o GE e leitura para o GC (p=0,001); nas atividades f?sicas a educa??o f?sica escolar (p=0,001) e andar de bicicleta (p=0,014) para o GC; b) o segundo A Pr?tica de Jogos e Brincadeiras Infantis de crian?as e adolescentes com e sem Epilepsia neste, o brincar com bola de gude apresentou diferen?a significante (p=0,016) para o GC, apesar das meninas dos dois grupos n?o brincarem dessa atividade. Observando as distribui??es de freq??ncias, verificou-se que nas brincadeiras de pega-pega, esconde-esconde e queimada o GE brinca mais que o GC tanto no g?nero feminino como no masculino. Pular corda, as meninas do GE brincam menos, enquanto os meninos dos dois grupos n?o brincam. Pular el?stico, as meninas dos dois grupos brincam numa mesma freq??ncia e os meninos n?o participam desta brincadeira. Quanto ?s crises epil?pticas, elas aconteceram durante as brincadeiras livres como: jogando bola (23,3%); esconde-esconde (6,6%); correndo (3,3%). Nas atividades sedent?rias: assistindo TV (18,3%); dormindo (36,0%); sentado (13,3%); deitado (11,7%) e em mais de uma atividade: jogando bola/assistindo TV (6,6%); dormindo/assistindo TV (3,3%) e correndo/dormindo (2/3,3%). De um modo geral, conclui-se que as crian?as e adolescentes dos dois grupos praticam os mesmos tipos de atividades, sendo que o GE pratica numa freq??ncia menor. Embora o GE tenha apresentado um maior percentual de crises generalizadas, elas n?o ocorreram durante a pr?tica de atividades f?sicas formais. Esta pesquisa foi desenvolvida por uma equipe multidisciplinar, o que muito contribuiu para a realiza??o deste estudo

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Glutaric acidemia type I (GA-I) is an inborn error of metabolism (EIM) biochemically characterized by the main accumulation of glutaric acid (GA) and 3- hydroxyglutaric acid (3-OH-GA), and pathologically by a characteristic striatal degeneration. Due the absence of effective therapeutic strategies for this acidemia, several studies have investigated new therapies, since that one in three children subject to current treatments show striatal degeneration. In this context, the present work aimed in the first part, to investigate the effects of acute treatment with creatine (Cr), an endogenous compound guanidine which has shown neuroprotective effects in a variety of experimental models of neurodegenerative diseases and also in organic acidemias, on the GA-induced behavioral and neurochemical changes in vivo. Our results demonstrated that acute administration of Cr prevented the GA-induced behavioral and electrographic seizures, the carbonyl protein content increased and the Na+,K+-ATPase enzyme activity reduction in rats. Moreover, the Cr also protected the GA-induced sinaptossomal L-[3H]glutamate uptake reduction in vitro. As was observed in this first part, that the GA in a low concentration (10 nM) was able to reduce the L-[3H]glutamate uptake in striatal sinaptossomas of rats, and since that responsible mechanisms for striatal degeneration observed in patients are still poorly understood, we decided to evaluate in a second step, a primary action mechanism for the neurotoxic effects this low concentration of GA, which possibly may be present at the beginning of GA-I. We find that the GA reduced the L-[3H]glutamate uptake and increased the reactive species (ER) formation in sinaptossomas the striatum of rats in all times tested. Furthermore, we observed for the first time that the GA reduced the efficacy (VMax), but not the affinity (KD) of L-[3H]glutamate uptake in striatal sinaptossomas, suggesting a non-competitive inhibition. The addition of both the L-trans-pyrrolidine-2,4-dicarboxylate (PDC), a glutamate transporters inhibitor, with the GA did not alter the inhibitory effect on the of L-[3H]glutamate uptake induced by organic acid, indicating the involvement of glutamate transporters in the GA-induced uptake reduction. Since the glutamate transporters activity can be inhibited by oxidation, we show that although the antioxidant trolox protects against GA-induced ER formation increase, it did not protect against GA-induced glutamate uptake reduction in the synaptosomes of cerebral structure studied, suggesting that ER formation may be a late event in the neurotoxicity observed in GA-I. Moreover, we can not exclude the possibility that the GA may also directly stimulate the glutamate receptors, since the GA-induced ER formation was reduced by the non-NMDA glutamate receptor antagonist, the CNQX, but not by MK-801, suggesting that these receptors contributed, at least partly, to the GA-induced oxidative stress. Also determined GA, in this low concentration, did not show oxidant activity per se. Therefore, from results in this study it was observed the protective effect of Cr administration in the deleterious actions caused by the GA. Furthermore, we show for the first time that a GA low concentration cause primary excitotoxicity, and oxidative stress in brain structure predominantly affected in this disease. Therefore, we believe that this work may help explain the genesis of GA-I, as well as the development of effective adjuvant therapeutic strategies in the treatment this acidemia. / A acidemia glutárica tipo I (GA-I) é um erro inato do metabolismo (EIM) caracterizada bioquimicamente pelo acúmulo principal de ácido glutárico (GA) e ácido 3-hidroxiglutárico (3-OH-GA), e patologicamente por uma característica degeneração estriatal. Devido à escassez de medidas terapêuticas efetivas para essa acidemia, vários estudos têm investigado novas terapias, já que uma em cada três crianças submetidas aos atuais tratamentos sofre degeneração estriatal. Nesse contexto, o presente trabalho teve por objetivo em sua primeira parte, investigar os efeitos do tratamento agudo com creatina (Cr), um composto guanidínico endógeno que tem mostrado efeitos neuroprotetores em uma variedade de modelos experimentais de doenças neurodegenerativas e também em acidemias orgânicas, sobre as alterações comportamentais e neuroquímicas induzidas pelo GA in vivo. Nossos resultados demonstraram que a administração aguda de Cr preveniu as convulsões comportamentais e eletrográficas, o aumento do conteúdo de proteína carbonil e a redução da atividade da enzima Na+,K+-ATPase induzidos pelo GA em ratos. Além disso, a Cr também protegeu da redução da captação de L-[3H]glutamato sinaptossomal induzida pelo GA in vitro. Como foi observado nesta primeira parte, que o GA em uma baixa concentração (10 nM) foi capaz de reduzir a captação de L-[3H]glutamato em sinaptossomas estriatais de ratos, e desde que os mecanismos responsáveis pela degeneração estriatal observada nos pacientes glutaricoacidêmicos ainda não estão bem esclarecidos, decidimos avaliar em uma segunda etapa, um provável mecanismo de ação primário para os efeitos neurotóxicos desta baixa concentração de GA, que possivelmente pode estar presente no início da GA-I. Verificamos que o GA reduziu a captação de L-[3H]glutamato e aumentou a formação de espécies reativas (ER) em sinaptossomas de estriado de ratos em todos os tempos testados. Além disso, observamos pela primeira vez que o GA reduziu a eficácia (VMax), mas não a afinidade (KD) da captação de L-[3H]glutamato em sinaptossomas estriatais, sugerindo uma inibição do tipo não competitiva. A adição simultânea do L-trans-pirrolidina-2,4-dicarboxilato (PDC), um inibidor dos transportadores de glutamato, com o GA não alterou o efeito inibitório sobre a captação de L-[3H]glutamato induzido pelo ácido orgânico, indicando a participação dos transportadores de glutamato na redução da captação desse neurotransmissor induzida pelo GA. Desde que a atividade dos transportadores de glutamato pode ser inibida por oxidação, evidenciamos que embora o antioxidante trolox proteja do aumento da formação de ER induzidas pelo GA, ele não protege da redução da captação de L-[3H]glutamato induzida por este ácido orgânico em sinaptossomas de estriado. Estes achados sugerem que a formação de ER pode ser um evento tardio na neurotoxicidade observada na GA-I. Além disso, não podemos excluir a possibilidade de que o GA também possa estimular diretamente os receptores de glutamato, desde que a formação de ER induzidas pelo GA foi atenuada pelo antagonista de receptor de glutamato não-NMDA, o CNQX, mas não pelo MK-801 e o GA, nessa baixa concentração, não apresentou atividade oxidante per se. Portanto, os resultados apresentados no presente estudo demonstram que a administração previa de creatina protege das ações deletérias ocasionadas pelo GA. Além disso, evidenciamos, pela primeira vez, que uma baixa concentração de GA causa ações excitotóxicas primárias, bem como, estresse oxidativo na estrutura cerebral predominantemente afetada nesta doença. Assim, acreditamos que este trabalho possa auxiliar na elucidação da gênese da GA-I, bem como no desenvolvimento de estratégias terapêuticas adjuvantes eficazes no tratamento desta acidemia.

Le stress est continuellement associé à la genèse, la fréquence et la sévérité des convulsions en épilepsie. De nombreux modèles animaux suggèrent qu’une relation entre le stress et les convulsions soit mise en place en début de vie, voire dès la période prénatale. Or, il existe peu de preuves de cette hypothèse chez l’humain. Ainsi, l’objectif général de cette thèse était d’examiner le lien entre le stress en début de vie, dès la conception, et les convulsions chez les humains. Pour ce faire, cette thèse avait comme intérêt principal les convulsions fébriles (CF). Il s’agit de convulsions pédiatriques communes et somme toute bénignes, bien qu’elles soient associées à de légères particularités neurologiques et cognitives. En ce sens, les CF représentent un syndrome de choix pour notre étude, considérant leur incidence fréquente en très bas âge et l’absence de conséquences majeures à long terme. Ainsi, elles permettent l’étude de la relation entre le stress en début de vie et les convulsions par l’entremise d’un relativement grand bassin populationnel, en réduisant l’impact de potentiels facteurs confondants. Dans ce contexte, notre objectif général a été étudié par l’entremise de cinq objectifs secondaires. D’abord, le premier objectif secondaire de cette thèse était de faire le point sur la littérature expliquant le lien entre les convulsions, le stress, ainsi que l’impact que pourrait avoir le stress sur le pronostic cognitif des syndromes convulsifs (article 1). Le second était d’examiner la relation entre les symptômes maternels auto-rapportés de stress, d’anxiété spécifique à la grossesse ou de dépression durant la grossesse et la période postpartum et les CF. Par le biais d’un devis longitudinal, les résultats de cette thèse suggèrent qu’une plus forte anxiété spécifique à la grossesse ainsi qu’une plus grande présence de symptômes dépressifs en période postnatale sont associées à une diminution du seuil convulsif des CF, caractérisée par un plus jeune âge lors du premier épisode convulsif (article 2). Étudié à travers ce même devis longitudinal, le troisième objectif secondaire de cette thèse était d’évaluer le lien entre des changements biologiques associés à l’exposition au stress prénatal et les CF. Or, nos résultats mettent plutôt en lumière des différences sur le plan du système sérotoninergique placentaire, sous-tendant une exposition ou une propension au stress. D’une part, ces changements seraient associés à une hausse de l’incidence des CF et, d’autre part, à une baisse du seuil convulsif (article 3). Par ailleurs, le quatrième sous-objectif couvert par cette thèse était d’étudier la réponse biologique de stress chez des enfants avec antécédents de CF afin de voir si elle se distingue de celle d’enfants sans antécédents convulsifs. Notre étude appariée suggère une plus forte sensibilité au stress chez les enfants avec antécédents de CF « simple » (article 4). Ainsi, ces résultats ne démontrent pas de changements systématiques à l’ensemble des enfants sur le plan de la réactivité au stress. Toutefois, des changements chez les enfants avec CF simples pourraient sous-tendre des anomalies prémorbides. Accessoirement, durant l’étude du quatrième sous-objectif, nous n’avons pas été en mesure d’identifier des anomalies cognitives dans les mois suivants un épisode de CF, ni d’associer le pronostic cognitif au profil de réactivité au stress. Dans ce contexte, le cinquième et dernier objectif secondaire visait à investiguer le pronostic électrophysiologique des CF et à en étudier l’association avec la réactivité au stress. Les résultats suggèrent la présence de particularités électrophysiologiques chez les enfants avec antécédents de CF « complexes », lesquelles pourraient être associées aux altérations cognitives vues chez cette population à long terme (article 5). Par-dessus tout, notons que ces particularités diffèrent en fonction du sous-type de CF complexes. Toutefois, les résultats obtenus dans le cadre de notre devis expérimental n’ont pas été en mesure d’identifier un rôle du stress sur ces atypies (addenda). Ensemble, ces résultats suggèrent l’existence d’un lien entre le stress en début de vie, dès la période prénatale, et les CF. Ils appuient l’importance d’investiguer le stress prénatal, postnatal et actuel en contexte de syndromes convulsifs en général, dont les CF. En raison de l’impact considérable du stress sur la qualité de vie des personnes vivant avec un syndrome convulsif, une meilleure caractérisation de la relation entre le stress précoce et les convulsions pourrait à long terme mener au développement d’interventions précoces et non invasives. Par ailleurs, même si ces résultats n’ont pas été en mesure d’identifier une relation entre la réactivité au stress et le pronostic cognitif ou électrophysiologique des CF, l’étude de ce lien est néanmoins suggérée par les études animales et devrait faire l’objet d’études futures. / Stress is a phenomenon frequently associated with epileptogenesis and increased seizure frequency and severity. Animal studies suggest the relationship between stress and seizures may begin early in life, maybe even prenatally. Evidence showing a link between early programming through stress and seizure disorders has yet to be found in humans. Hence, the general objective of this thesis was to examine the relationship between early-life stress, including the prenatal period, and seizures in humans. For this purpose, the prime focus of this research was on febrile seizures (FS). FS are common and benign pediatric seizures, associated only with mild neurological and cognitive peculiarities. Due to their frequent incidence in early childhood and lack of severe consequences, they allow for the investigation of the relationship between early-life stress and seizures through a relatively large sample, while reducing the impact of potential confounding variables.In this context, our general objective was investigated through five sub-objectives. First, we aimed toreview the current knowledge on the link between seizures and stress, as well as the impact stress could have on the cognitive prognosis of seizure disorders (1starticle).The second sub-objective was to study the relationship between self-reported maternal emotion distress during both the pregnancy and postpartum period, on FS. Through a longitudinal cohort, this research supports increased prenatal pregnancy-specific anxiety and postpartum depressive symptoms are associated with a lowered FS threshold, as shown through a younger age at first FS occurrence (2ndarticle). Moreover, the third sub-objective, which was studied through the same longitudinal research, was to evaluate how biological changes associated with prenatal exposure to stress may be linked to FS. This study showed changes in the placental serotoninergic system are found in children with FS history. More precisely, these changes are associated with increased FS incidence, and lowered FS threshold (3rdarticle). On the other hand, the fourth sub-objective of this thesis was to study the biological stress response of children with past FS, compared to that of children without personal history of seizures. Our case-control study suggested only children with “simple” FS showed increased sensibility to stress (4tharticle). Hence, these results do not show systematic changes in the ivbiological stress reaction of all children with FS. Still, they do show changes in some children, which could be premorbid to the first FS episode.Incidentally, while studying the fourth sub-objective, we were unable to show changes in the developmental skills of children with FS, nor did we show an interaction with stress reactivity. Hence, the fifth and final subjective of this thesis was to investigate the electrophysiological prognosis of children with past FS, and its association with stress reactivity. Our results show differences in the electrophysiological profile of children with “complex” FS only, which could be linked to cognitive alterations in the long-term (5tharticle). Moreover, we showed these abnormalities differ depending on the type of complex FS. Still, we were unable to identify an additive or interactive link with stress reactivity (addendum). Taken together, these results highlight the existence of a link between stress, starting in the prenatal period, and FS. Hence, they highlight the importance of investigating prenatal, postnatal and current stress in the context of seizure disorders at large, including FS. Given the significant impact of stress on the quality of life of people living with epilepsy, increased knowledge on the link between early stress and seizures could lead to the development of early and non-invasive treatments targeting stress in the future. Moreover, although these results do not show stress to be associated with altered cognitive or electrophysiological prognosis in the context of FS, this link is nevertheless supported by animal research and should be the subject of future studies

Objective: Project ECHO (Extension for Community Healthcare Outcomes), a telementoring program, utilizes lectures, case-based learning, and an “all teach–all learn” approach to increase primary care provider (PCP) knowledge/confidence in managing chronic health conditions. The American Academy of Pediatrics (AAP) Epilepsy and Comorbidities ECHO incorporated quality improvement (QI) methodology to create meaningful practice change, while increasing PCP knowledge/self-efficacy in epilepsy management using the ECHO model. Methods: Monthly ECHO sessions (May 2018 to December 2018) included lectures, case presentations/discussion, and QI review. Pediatric practices were recruited through the AAP. Practices engaged in ECHO sessions and improvement activities including monthly Plan-Do-Study-Act cycles, team huddles, chart reviews, and QI coaching calls to facilitate practice change. They were provided resource toolkits with documentation templates, safety handouts, and medication side effects sheets. QI measures were selected from the American Academy of Neurology Measurement Set for Epilepsy. The AAP Quality Improvement Data Aggregator was used for data entry, run chart development, and tracking outcomes. Participants completed retrospective surveys to assess changes in knowledge and self-efficacy. Results: Seven practices participated across five states. Average session attendance was 14 health professionals (range = 13-17). A total of 479 chart reviews demonstrated improvement in six of seven measures: health care transition (45.3%, P =.005), safety education (41.6%, P =.036), mental/behavioral health screening (32.2% P =.027), tertiary center referral (26.7%, not significant [n.s.]), antiseizure therapy side effects (23%, n.s.), and documenting seizure frequency (7.1%, n.s.); counseling for women of childbearing age decreased by 7.8%. Significance: This project demonstrated that integrating QI into an ECHO model results in practice change and increases PCP knowledge/confidence/self-efficacy in managing epilepsy.

No description available.

Bakgrund: Epilepsi är klassat som en folksjukdom, ca 50 miljoner människor i världen har diagnosen. Epilepsi innebär att personen har ett kroniskt anlag för att få oprovocerade epileptiska anfall.  Syfte: Syftet var att undersöka vuxna personers upplevelser av vardagslivet med epilepsi. Metod: En litteraturöversikt med kvalitativ metod och induktiv ansats. Artikelsökningen gjordes i CINAHL och Medline samt kompletterandes med en frisökning. Artiklarna är skrivna mellan 2012 och 2022. Analys av elva artiklar skedde med hjälp av Fribergs granskningsmall.  Resultat: Personerna upplevde rädsla för anfall, stigmatisering och utanförskap. Epilepsianfall orsakade frustration då de hindrade personernas vardagsliv.  Vårdmöten var en del i vardagslivet, upplevelserna av dessa var individuella. Personerna behövde omvärdera drömmar och mål som en följd av epilepsin. Detta upplevdes ansträngande och när omvärderingen skett fortlöpte livet i en ny riktning. Personerna använde sig av olika strategier för att hantera sitt vardagsliv. De använde direkta problemlösande metoder, fysisk aktivitet, psykisk bearbetning, informatik och stöd från omgivningen.  Slutsatser: Alla upplevde vardagen med diagnosen olika. Det finns behov av vidare, mer specifika studier. Utveckling av information för vårdpersonal, samhället och individer är vitalt för att skapa möjligheter för en god och fungerande vardag. / Background: Epilepsy is classified as an endemic disease. Around 50 million humans have the diagnosis around the world. Epilepsy is a chronic predisposition for unprovoked epileptic seizures.  Aim: Describe adult people's everyday life with epilepsy. Method: A qualitative study with an inductive approach. The article search was made in CINAHL and Medline, with a complementing free search. The articles are written between 2012-2022. Twelve articles were analysed with the Friberg’s review template.   Result: The individuals experienced fears of seizures, stigmatization, and exclusion. Epileptic seizures caused frustration as they hindered people's everyday lives, this was managed with the help of information and relatives. Healthcare meetings were part of everyday life, the experiences varied. The persons needed to reassess dreams and goals because of their epilepsy. This was a taxing process and afterwards life continued in a new direction. The people used different strategies to manage their everyday life. They adopted direct problem-solving methods, physical activity, mental processing, informatics, and support from society. Conclusion: All subjects experienced everyday life with the diagnosis differently. There is a need for more specific studies. Development of information for healthcare professionals, society and individuals is vital to create opportunities for a good and functioning everyday life.

No description available.