La maladie de Huntington (MH) est une maladie neurodégénérative héréditaire autosomique dominante. Elle est due à l’expansion anormale de polyglutamine dans la partie N-terminal de la protéine huntingtine (HTT). Une des étapes clés de la pathologie est le clivage de la HTT pleine longueur en fragments N-terminaux plus petits, contenant l’expansion de polyglutamine, et qui sont toxiques pour les neurones. En effet, les clivages de la HTT mutée génère des fragments N-terminaux (N-ter) de tailles comprises entre les acides aminés 1-105 et 1-586 observés dans des extraits de cerveaux de patients MH post-mortem et dont l’implication dans la mort neuronal est bien caractérisée. Mes travaux de thèse ont visé à modéliser le clivage de la HTT et à évaluer les conséquences sur la survie neuronale.Au cours de ma thèse, j’ai développé un outil permettant de contrôler le clivage de la HTT dans le temps et à des sites spécifiques. J’ai étudié le clivage de la HTT à deux sites stratégiques : les positions clivées par la caspase-6 et par la bléomycine hydrolase/cathepsine Z. A l’aide de cet outil, j’ai montré que le clivage de la HTT confère une toxicité cellulaire qui dépend du profil du clivage. Plus précisément, J’ai décrit une interaction intramoléculaire au sein des domaines de la HTT. Mes résultats indiquent que cette interaction protège les cellules de la toxicité induite par le clivage de la HTT mutée. En effet, les clivages successifs de la HTT annulent cette interaction, ce qui induit la libération des fragments N-ter mutants et provoque la mort cellulaire à l’issue de leur translocation nucléaire. Pour conclure, au cours de ma thèse, j’ai montré que la protéolyse successive de la HTT induit des processus cytotoxiques différents. / Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in the N-terminus of the protein huntingtin (HTT). A crucial step in HD pathogenesis is the cleavage of full-length HTT into smaller N-terminal (N-ter) fragments that contain the polyQ stretch and that are toxic to neurons. HTT cleavage generates short N-ter fragments whose amino-acid positions range from 1-105 to 1-586. These fragments are observed in HD post mortem brain samples and their participation in neuronal death in HD is well characterized. During my PhD research, I investigated the consequences of full-length mutant HTT proteolysis by developing a time and site-specific controlled system for HTT proteolysis. I have assessed HTT cleavage on two sites caspase-6 and cathepsin Z. My results show that HTT cleavage induces neurotoxicity in vitro as well as in vivo, toxicity which depends on HTT proteolysis pattern. Briefly, we described an intramolecular interaction within the HTT domains which is impaired upon successive proteolysis of HTT. We found that HTT intramolecular interaction buffer mutant N-ter HTT-induced toxicity. Moreover, specific cleavages of the mutant HTT generated toxic N-ter fragments as they translocate into the nucleus. To conclude, my PhD work has shown that additional cleavage of mutant HTT induces cytotoxicity by different mechanisms.

A Senna occidentalis (sinônimo Cassia occidentalis) é uma planta amplamente utilizada pela população para fins medicinais, embora esteja associada a casos de intoxicação humana e animal. Por isso, além de ser considerada um problema de saúde pública, é tida também como uma planta tóxica de interesse pecuário. Sua toxicidade é atribuída à diantrona, uma quinolona, cujo mecanismo de ação tóxico se deve ao desacoplamento da fosforilação oxidativa mitocondrial, promovendo dano mitocondrial especialmente nos órgãos com maior demanda de oxigênio. O objetivo deste trabalho foi estudar, em ratos, os possíveis efeitos tóxicos causados pela exposição à Senna occidentalis durante o período de gestação. Para tanto, 36 fêmeas prenhes foram divididas em 5 grupos, que foram tratados do 6º ao 20º dia de gestação (período de organogênese e de desenvolvimento fetal) com 1%, 2%, 3% e 4% de sementes da planta na ração; o grupo controle recebeu a ração normal do laboratório. A escolha dessas concentrações foi embasada em estudos prévios de toxicidade subaguda em ratos, que mostraram efeito dose-dependente. Durante o período de gestação foram avaliados o peso corpóreo e o consumo de ração e água das fêmeas. Após o nascimento, os filhotes foram analisados quanto ao número de vivos e mortos e para a detecção de possíveis malformações externas. Foi avaliado também o desempenho reprodutivo e o comportamento materno das fêmeas. Com relação à prole, observou-se o seu desenvolvimento físico e de reflexos, bem como atividade geral no campo aberto, comportamento de brincar, labirinto em cruz elevado e labirinto em T. Os resultados do presente estudo mostraram diminuição no ganho de peso das ratas tratadas com 2%, 3% e 4% da planta na ração, além de diminuição no consumo de ração, prejuízo no desempenho reprodutivo e sinais de intoxicação em ratas do grupo de 4%. Ratas tratadas com 2% de S. occidentalis na ração apresentaram prejuízo no comportamento materno. Ainda, houve adiantamento para o aparecimento de pelos e erupção dos dentes incisivos em filhotes do grupo de 1%, bem como adiantamento para o desenvolvimento do reflexo de geotaxia negativa e para a perda do reflexo de preensão palmar em filhotes dos grupos de 3% e 1% respectivamente. Estes resultados indicam que a exposição à S. occidentalis durante a gestação causou toxicidade materna acompanhada de prejuízo no comportamento materno e alteração no desenvolvimento físico e reflexológico da prole destas ratas. / The Senna occidentalis (synonym Cassia occidentalis) is a plant widely used by people for medicinal purposes, although it is associated with cases of human and animal poisoning. So, besides being considered a public health problem, it is also regarded as a toxic plant of livestock interest. Its toxicity is attributed to diantrone, a quinolone, whose mechanism of action is due to the toxic uncoupling of mitochondrial oxidative phosphorylation, promoting mitochondrial damage especially in organs with higher oxygen demand. The objective of this work was to study, in rats, the possible toxic effects caused by exposure to Senna occidentalis during the gestation period. For this purpose, 36 female rats were divided into 5 groups, which were treated from the 6th to the 20th day of gestation (period of organogenesis and fetal development) with 1%, 2%, 3% and 4% of plant seeds in the diet; the control group received normal chow lab. The choice of these concentrations was based on previous studies of subacute toxicity in rats, which showed dose-dependent effect. During the period of gestation were evaluated: body weight, feed intake and water consumption of females. After birth, pups were analyzed for the number of living and dead, and for the detection of possible external malformations. We also evaluated the reproductive performance and maternal behavior of females. With regard to offspring, it was observed their physical and reflexes development, their general activity in the open field, their play behavior and their behavior in elevated plus maze and T maze. The results of this study showed a decrease in body weight of dams treated with 2%, 3% and 4% of the plant in the diet, in addition to reduced feed intake, impaired reproductive performance and signs of poisoning in dams of group 4%. Dams treated with 2% of S. occidentalis in diet showed impaired maternal behavior. Still, there was an advance for the appearance of hair and for the eruption of incisors in pups from 1%, as well as an advance to the development of negative geotaxis reflex and to the loss of palmar grasp reflex in puppies of 3% and 1% groups respectively. These results indicate that exposure to S. occidentalis during pregnancy caused maternal toxicity accompanied by impairment in maternal behavior and change in reflexology and physical development of the offspring of these rats.

O glioblastoma multiforme (GBM) é um tipo de câncer grave que acomete o sistema nervoso central (SNC), e a sobrevida dos pacientes é de aproximadamente 12 meses. O tratamento com o quimioterápico paclitaxel (PTX) reduz o GBM experimental e humano. No entanto, sua utilização é limitada pelas reações adversas graves que acarreta. A nanoemulsão rica em colesterol (LDE), a qual mimetiza a lipoproteína de baixa densidade, tem sido empregada como um sistema de entrega de fármacos eficiente em alguns casos de tumores. No presente trabalho visou-se avaliar a eficácia do oleato de PTX (OPTX), um derivado mais lipofílico do que o PTX, associado a LDE (LDE-OPTX) em ensaios in vitro e in vivo. Inicialmente, células tumorais da linhagem de glioblastoma murino GL261 foram incubadas com PTX em solução ou com LDE-OPTX, nas concentrações de 1 ou 10 µM. Os resultados obtidos mostraram que o tratamento in vitro com PTX e o LDE-OPTX causa toxicidade in vitro em células GL261 pela redução da proliferação e indução de apoptose, e que ainda reduz a secreção de MCP-1 (proteína quimiotáxica de monócitos). Os ensaios in vivo mostraram a toxicidade intensa do PTX comercial, uma vez que os animais com GBM não sobreviveram ao tratamento com 75mg/Kg, i.p., a cada 3 dias, e foram a óbito a partir do oitavo dia de tratamento. Diferentemente, os animais tratados com a mesma dose de LDE-OPTX sobreviveram ao tratamento, sem sinais de toxicidade, mas os dados obtidos mostraram que este protocolo de tratamento não foi eficaz para redução do volume tumoral. Assim, os animais com GBM passaram a ser tratados com doses diárias, i.p., de 15 mg/kg de PTX ou de 75mg/Kg de LDE-OPTX. Os resultados obtidos mostraram a ineficácia e eficácia dos tratamentos com PTX e LDE-OPTX, respectivamente, em reduzir o GBM; no entanto os animais tratados com LDE-OPTX apresentaram redução no peso corporal e no número de linfócitos circulantes. Em conjunto, os dados obtidos mostram a habilidade de preparação LDE-OPTX causar toxicidade in vitro nas células GL261 e sua eficácia terapêutica em dose elevada, em reduzir o GBM em modelo murino. / Glioblastoma multiforme (GBM) is a type of severe cancer that affects the central nervous system, and patient survival is about12 months. The treatment with the chemotherapeutic paclitaxel (PTX) reduces the experimental and human GBM, however, their use is limited by side effects. The lipid nanoemulsion (LDE), that is mimetic to low density protein, has been employed as an efficient drug nanocarrier to treat cancer. Therefore, the present study aimed to assess the effectiveness of the oleate PTX (OPTX), a more lipophilic derivative of PTX, associated to (LDE), in in vitro and in vivo studies. Initially, glioblastoma murine strain GL261 was incubated with commercial PTX solution or LDE-OPTX at concentrations of 1 or 10 µM. Data obtained showed that treatment with PTX or LDE-OPTX caused in vitro toxicity to GL261 cells, by reducing the proliferation and inducing apoptosis. Moreover, both treatments reduced the secretion of monocyte chemotacticprotein-1 (MCP-1). In vivo experiments showed the severe toxicity of commercial PTX, as mice with GBM did not survive to the treatment with 75mg/kg, i.p., each 3 days, and died after 8 days of treatment. Conversely, animals treated with the same schedule of treatment with LDE-OPTX survived until the end of treatment, without any toxicity signal. Nevertheless, the treatment was not effective to reduce the GBM volume. Hence, other sets of animals with GBM were treated with daily i.p. dose of 15mg/kg of PTX or 75mg/kg of LDE-OPTX. Data obtained showed the inefficacy and efficacy of PTX and LDE-OPTX treatments, respectively, to reduce the volume of GBM. Nevertheless, mice treated with LDE-OPTX lost weight and lower number of circulating lymphocytes. Together, our data show the ability of LDE-OPTX treatment cause in vitro toxicity on GL261 cells e the in vivo therapeutic efficacy of higher doses on GBM murine model.

As access and use of antiretroviral therapy continue to increase, the need to improve antiretroviral toxicity monitoring becomes more critical. This is particularly so in underserved settings, where patterns of antiretroviral toxicities possibly alter the need for and frequency of antiretroviral toxicity monitoring. However, barriers such as few skilled healthcare providers and poor infrastructure make antiretroviral toxicity monitoring in underserved settings difficult. The purpose of this dissertation was to investigate how standard clinical guidelines, knowledge-based clinical decision support, and task delegation could be leveraged to overcome barriers to antiretroviral toxicity monitoring in underserved settings. The strategy adopted in this dissertation was guided by the Design Science Research Methodology that emphasizes the generation of scientific knowledge through building novel artifacts. Two qualitative descriptive studies were conducted to characterize the contextual factors associated with antiretroviral toxicity monitoring in underserved settings. Supported by the findings from these studies, a knowledge-based software application prototype that implements clinical practice guidelines for antiretroviral toxicity monitoring was developed. Next, a quantitative validation study was used to evaluate the structure and behavior of the prototype’s knowledge base. Lastly, a quantitative usability study was conducted to assess lay health worker perceptions of the satisfaction and mental effort associated with the use of checklists generated by the prototype. This dissertation research produced empirical evidence about the broad motives and strategies for promoting medication adherence, safety, and effectiveness in underserved settings. It also identified barriers and facilitators of antiretroviral toxicity monitoring within ambulatory HIV care workflows in underserved settings. Additionally, it provided evidence about the extent to which antiretroviral toxicity domain knowledge could be implemented in a knowledge-based application for supporting point-of-care antiretroviral toxicity monitoring. Lastly, the research provided previously unavailable empirical evidence about the perceptions of lay peer health workers on the use of checklists for the documentation of antiretroviral toxicities.

A Leucaena leucocephala, popularmente conhecida no nosso país como leucena, é uma planta difundida por todo o mundo e utilizada como forrageira por apresentar vários nutrientes; no entanto, seu uso é limitado, uma vez que possui uma fitotoxina cuja natureza química é de um aminoácido não proteico denominado de mimosina. Em ruminantes, principalmente em bovinos, esta substância causa efeitos tóxicos como alopecia, anorexia, redução no ganho de peso ou perda de peso, salivação excessiva, lesões esofágicas, aumento da tireoide e queda nas concentrações de hormônios tireoidianos. Em monogástricos também tem sido descrita toxicidade evidenciada por alterações como alopecia e diminuição do ganho de peso; porém, os efeitos sobre estes animais ainda não foram bem estudados. Assim, nesta pesquisa objetivou-se inicialmente desenvolver procedimentos químicos para a extração de mimosina das sementes da L.leucocephala e, a partir disto, realizar estudos biológicos, em ratos, para avaliar a toxicidade geral desse aminoácido bem como seus efeitos nos sistemas imune, endócrino e reprodutor. Na extração da mimosina, obteve-se o rendimento de 2,3%. Realizou-se a administração da fitotoxina, por via oral, a ratos Wistar adultos, nas doses de 25, 40 e 60mg/Kg p.v./dia, durante um período de 28 dias. Foram avaliados os seguintes parâmetros: ganho de peso, consumo de ração, bioquímica sérica, histopatologia (fígado, rins, tireoide, timo e baço), peso relativo de órgãos (rins, fígado, timo, baço e testículos), imunidade celular por meio da atividade de macrófagos intraperitoneais, imunidade humoral por meio do título de anticorpos anti-SRBC e \"plaque forming cell\", dosagem de hormônios séricos (testosterona, corticosterona, T3 e T4) e comportamento sexual. Os dados obtidos no presente estudo revelaram que, embora não fossem detectadas alterações clínicas que indicassem toxicidade, e/ou diminuição no consumo de ração e do ganho de peso, nos animais expostos às diferentes doses de mimosina, estes apresentaram lesões consistentes na tireoide. Além disto, observou-se diminuição da testosterona sérica dos ratos que receberam 60mg/Kg de mimosina. Ainda, nas doses de 40 e 60mg/Kg, verificou-se, por meio da avaliação do comportamento sexual, a diminuição no número de montas, bem como o aumento do intervalo entre elas; e nestas maiores doses os ratos também apresentaram aumento da intensidade de fagocitose de macrófagos intraperitoneais. Portanto, os estudos aqui realizados permitem sugerir que a mimosina, nas baixas doses aqui empregadas, não possui efeitos imunotóxicos; porém apresenta potencial bociogênico em ratos e provavelmente atua como desregulador endócrino. / Leucaena leucocephala is a worldwide plant used as forage; however its use in animal production has been limited since it has a phytotoxin denominated mimosine. It is known that this substance cause toxicity as alopecia, anorexia, reduced weight gain or weight loss, excessive salivation, esophageal lesions, thyroid enlargement and low thyroid hormones in ruminants, mainly in bovines. On the other hand, toxic effects of mimosine have not well studied in monogastric, but alopecia and low weight gain already was also reported. Thus, this study aimed to evaluate in rats the general toxicity of this amino acid as well as its effects on immune, endocrine and reproductive systems. In the first step of the study, it was extracted from seeds of L.leucocephala 2.3% of mimosine that was administrated orally to adult Wistar rats at different doses of 25, 40 and 60mg/kg body weight/ day, for 28 days. It was evaluated the following parameters: weight gain, feed intake, serum enzymes, histopathology (liver, kidney, thyroid, thymus and spleen), relative organs weight (kidney, liver, thymus, spleen and testicles), cellular and humoral immunity, serum hormones (testosterone, corticosterone, T3 and T4) and sexual behavior. No clinical sings of toxicity was observed in animals, but histopathology reveled consistent lesions in the thyroids. Additionally, rats that received 60mg/kg of mimosine presented low serum levels of testosterone, and in rats treated with both doses of mimosine, 40 and 60mg/Kg, it was verified increase in phagocytosis intensity of intraperitoneal macrophages, decrease mounts number and increase in mounts interval. Therefore, our study permits to suggest that although low doses of mimosine does not have immunotoxic effects in rats, it has goitrogenic potential and probably acts as an endocrine disrupter.

Nas questões ambientais legais, muitas vezes a referência à toxicidade de uma substância é vaga. No entanto, essa informação é essencial para a determinação da extensão do dano. Para fazer a previsão desses valores para o benzeno e hidrocarbonetos policíclicos aromáticos (PAHs), componentes do petróleo, foi feito um estudo QSAR (Quantitative Structure Activity Relationship) por meio de cálculos de mecânica quântica e quimiometria. O objetivo foi construir modelos para prever os valores de coeficiente de partição n-octanol/água, Kow (n-octanol/water partition coefficient) além do estudo das toxicidades dos PAHs. Para este estudo, as geometrias de todas as moléculas foram otimizadas utilizando os métodos semiempíricos AM1, PM3, PM6 e PM7. Desses resultados ainda foram extraídos os descritores teóricos que foram utilizados para descrever os valores de log Kow. Entre todos aqueles calculados, os descritores: energia total, energia eletrônica, área, volume e massa molar foram escolhidos como os parâmetros para o estudo PLS (Partial Least Squares). Além disso, as toxicidades dos PAHs foram calculadas por meio do programa T.E.S.T (Toxicity Estimation Software Tool) disponibilizado gratuitamente pelo EPA (Environmental Protection Agency) e estimados por meio de modelo PLS e gráficos de correlação. Observou-se com esse estudo que todos os métodos apresentaram resultados bastante satisfatórios, uma vez que valores próximos de 1 foram obtidos tanto para o coeficiente de correlação interno, Q2, quanto para o externo, R2. / In the environmental legal issues, often the reference to toxicity of a substance is vague. However, this information is essential for determining the extent of damage. To forecast these values for benzene and polycyclic aromatic hydrocarbons (PAHs), petroleum components, one study QSAR (Quantitative Structure Activity Relationship) was done by calculation of quantum mechanics and chemometrics. The goal was to build models to predict the values of the partition coefficient n-octanol / water, Kow (n-octanol / water partition coefficient) beyond the study of the toxicity of PAHs. For this study, the geometries of all molecules were optimized using the semi-empirical methods AM1, PM3, PM6 and PM7. These theoretical results also descriptors that were used to describe the Log Kow values were extracted. Among those calculated descriptors: total energy, electronic energy, area, volume and molar mass were chosen as the parameters for the study PLS (Partial Least Squares). Furthermore, the toxicities of PAHs were calculated using the TEST (Toxicity Estimation Software Tool) program available free of charge by the EPA (Environmental Protection Agency) and estimated by PLS model and correlation charts. It was observed in this study that all the methods have shown promising results, since values near one were obtained for the standard and cross-validated correlation coefficients R2 and Q2.

Polyglutamine (polyQ) diseases are a group of progressive neurodegenerative disorders, which are caused by the expansion of an existing glutamine-coding CAG repeat in the coding region of disease genes. The cell nucleus is a major site of polyQ toxicity, and gene transcription is compromised in polyQ-induced neurodegeneration. Understanding the nuclear translocation of mutant polyQ proteins is therefore crucial to unfold the complex pathogenic mechanisms that underlie the neuronal toxicity of polyQ disease. The polyQ domain is the only common sequence found among different mutant disease proteins. Nuclear transport signals have been identified in some, but not all, polyQ disease proteins. The detection of those mutant polyQ proteins that carry no classical nuclear transport signal, but not their normal counterparts, in the cell nucleus suggests the existence of uncharacterized nuclear transport signals in mutant polyQ proteins. Thus, the objective of the present study is to elucidate the nuclear transport pathway(s) adopted by an expanded polyQ domain and determine its correlation with polyQ toxicity. / Through a series of genetic and biochemical studies in cell culture, mouse and transgenic Drosophila models, exportin-1 was found to modulate the nucleocytoplasmic localization of mutant polyQ protein and its toxicity. Further, mutant polyQ protein was also demonstrated to be a novel transport substrate of exportin-1. By promoting the nuclear export of mutant polyQ protein, exportin-1 suppressed polyQ toxicity by reducing the interference of mutant polyQ protein on gene transcription. It was found that the protein level of exportin-1 diminished in the normal ageing process, which would result in an exaggeration of nuclear mutant polyQ toxicity. Thus, the age-dependent decline of exportin-1 level, at least in part, accounts for the progressive degeneration observed in polyQ patients. Results obtained from this project first demonstrated that expanded polyQ domain is a nuclear export signal, and further provided mechanistic explanation of how protein nuclear transport receptors modulate polyQ toxicity. / Chan, Wing Man. / Source: Dissertation Abstracts International, Volume: 71-01, Section: B, page: 0113. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 189-203). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese.

The nematode Caenorhabditis elegans is an alternative model used in biomedical research for the investigation of descriptive and mechanistic toxicity assessment of chemicals. There are considerable differences in published data, especially in terms of reproducibility and validation of toxicity endpoints, and the techniques used in the investigation of these endpoints. This thesis describes the evaluation of toxicological endpoints following the exposure of C. elegans to chemicals which include; zinc oxide nanoparticles (ZnONP), Diethylstilbestrol (DES) and derivatized target-specific anthelmintics. The results suggest that ZnONP prepared in anionic and cationic dispersants (AZNP and CZNP respectively) were the most toxic against the nematode resulting in the ‘bag of worms' (BOW) phenotype which can be exploited as a marker for reproductive toxicity. Also, worms treated with ZnONP prepared in 0.1% FBS (FZNP), molecular grade water (WZNP) or E. coli OP50 supernatant (SZNP) presented three-fold embryo elongation showing fully differentiated tissues encapsulated within the eggshell and still within the hermaphrodite gravid adult. The phenotype has been named accelerated embryonic development (AED) and could be used as a developmental toxicity endpoint. The results suggest that the AED endpoint is the most sensitive while lethality endpoint appears to be the least sensitive despite its extensive use in the literature. Also, microRNA microarray expression appears to be the most sensitive molecular endpoint while behavioural endpoints such as speed should be interpreted with caution, especially when performed manually. Importantly, good C. elegans culture practice (GCeCP) is required for reproducible chemical toxicity assessment and different endpoints may be required for different types of toxicity assessment. Additionally, the thesis describes a second but related study which explores a potential for enhanced anthelmintic targeting. Novel fluorophore-based asparagine-containing oligopeptide substrate probes were used to target the helminth protease, legumain. These probes were selectively cleaved by legumain in C. elegans, Haemonchus contortus and Teladorsagia circumcincta. The protease-specific probes could potentially be exploited to achieve protease-mediated prodrug activation and drug delivery.

本研究的目的是評估長期服用氯胺酮對青少年認知功能和精神健康狀況的影響。 自2009年12月至2011年12月，共300名受試者入組。受試者分為3組：氯胺酮組，氯胺酮及多種藥物組和健康對照組，每組有100名受試者入組。精神狀況評估包括問卷篩查和麵談。所有受試者均完成一套詳細的認知測試。該測試涵蓋一般智慧、語詞記憶、視覺記憶、執行功能、動作速度和語言。 / 氯胺酮組受試者主要濫用氯胺酮，而氯胺酮及多種藥物組受試者除氯胺酮外主要濫用可卡因和冰毒。兩組氯胺酮濫用者最常見的共患精神障礙是抑鬱障礙。在單因素分析中,兩組氯胺酮濫用者在幾乎所有的測試中得分低於健康對照。多因素分析控制混雜因素如年齡、性別、教育程度和Beck 抑鬱量表總分後，兩組氯胺酮濫用組與健康對照組在語詞記憶和視覺記憶仍存在顯著差異。本研究進一步將氯胺酮組及氯胺酮多種藥物組分別分為現用藥者和戒斷者。在氯胺酮組中現用藥者在詞記憶、視覺記憶、動作速度和部分執行功能測試上得分低於戒斷者和健康對照，並且現用者Beck 抑鬱量表總分高於戒斷者和健康對照，而戒斷者和健康對照在認知測試和Beck 抑鬱量表總分沒有顯著差別。但在氯胺酮及多種藥物組，現用藥者和戒斷者均在記憶測試中得分低於及Beck 抑鬱量表總分高於健康對照。另外, 女性氯胺酮濫用組視覺記憶得分低於男性，但女性在語詞記憶得分普遍高於男性。 / 本研究認為氯胺酮或氯胺酮合用多種藥物均能導致記憶和執行功能的損害。這種損害主要與近期濫用氯胺酮有關，並且氯胺酮組現用藥者語詞記憶損害較氯胺酮合用多種藥物現用藥者嚴重。單純氯胺酮導致的記憶和執行功能損害在戒斷1月後明顯好轉但氯胺酮合用多種藥物者戒斷一月後未能見到記憶功能好轉。超過半數的氯胺酮濫用者共患抑鬱障礙。本研究的結果為治療氯胺酮濫用有用資訊，亦有助於戒毒者鞏固其戒斷行為。但氯胺酮所致認知損害的可逆性還需要前瞻性或縱向研究進一步證實，並且這種可逆性損害的機制還不明確。未來的研究還需要進一步明確氯胺酮對人體的損害作用是否具有性別差異性。 / The objective of this study was to evaluate the long-term effect of ketamine use on both the cognition and psychological well-being of youths in Hong Kong. / Three hundred participants were recruited for the study, which lasted from December 2009 to December 2011. Participants were divided into three groups of 100 each: primarily ketamine (Primarily K) users, poly-drug ketamine (Poly K) users and healthy controls (HCs). Psychiatric assessments included screening with self-rating questionnaires and face-to-face interviews. All participants completed a detailed cognitive battery covering general intelligence, verbal memory, visual memory, executive function, motor speed and language. / The participants in the Primarily K group predominantly used ketamine, whereas those in the Poly K group used ketamine in addition to secondary drugs, of which cocaine and methamphetamine were the most frequent. Depressive disorder was the most common psychiatric disorder in both ketamine groups. Univariate analysis also showed the two ketamine groups to score poorly on most of the cognitive tests relative to the HC group. After adjusting for age, sex, education and Beck Depression Inventory (BDI) score, verbal and visual memory remained impaired in both ketamine groups in comparison with the HC group. Ketamine use in the past month was independently related to memory impairment in the Primarily K group. In subgroup analyses of Primarily K users, verbal and visual memory, motor speed, and some of the executive function indexes were significantly impaired in current users but not in ex-users. These findings suggest that the cognitive influence of ketamine is reversible. Moreover, the current ketamine users had a higher BDI score than the ex-users or HCs. However, the ex- and current poly-drug ketamine users exhibited a similar degree of memory impairment compared with the HCs. The female Primarily K users showed more visual memory impairment than their male counterparts, although females generally performed better than males in verbal memory. / In conclusion, the use of ketamine alone and in conjunction with other psychotropic drugs is associated with deficits in memory and executive function. The observed memory impairment was related primarily to recent ketamine use, with current Primarily K users presenting with a more severe memory deficit than current Poly K users. However, the Primarily K group realised improvement in cognitive impairment after abstaining from ketamine, whereas the Poly K group did not. In addition to cognitive functioning difficulties, more than half of the ketamine users suffered from depressive disorder. Moreover, the findings suggest that women may be more sensitive than men to visual memory impairment following chronic ketamine use. The findings of this study will be helpful in treating ketamine abuse, and reinforce the efficacy of abstinence from drugs. Further longitudinal research is needed to determine the reversibility of ketamine’s effects and the mechanism by which that reversibility takes place. Further study is also needed to clarify the drug’s sex-specific effects. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Liang, Huajun. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 102-119). / Abstract also in Chinese. / DECLARATION OF ORIGINALITY --- p.I / ACKNOWLEDGEMENTS --- p.II / PUBLICATIONS AND PRESENTATIONS --- p.1 / LIST OF ABBREVIATIONS --- p.XI / LIST OF TABLES AND FIGURES --- p.XIII / ABSTRACT --- p.XV / 摘要 --- p.XVIII / CONTENTS --- p.XX / Chapter CHAPTER 1 --- BACKGROUND --- p.1 / Chapter 1.1 --- Introduction to ketamine and ketamine misuse --- p.1 / Chapter 1.2 --- Effects profile of ketamine in the brain --- p.4 / Chapter 1.2.1 --- Glutamate system dysfunction underlying ketamine actions --- p.4 / Chapter 1.2.2 --- Different effect patterns between acute and repeated administration --- p.7 / Chapter 1.2.3 --- Acute and chronic effects of ketamine on human cognitive functions --- p.9 / Chapter 1.2.4 --- Sex differences in addiction --- p.11 / Chapter 1.3 --- Introduction to cognition and intelligence and their assessments --- p.13 / Chapter 1.3.1 --- Memory and memory assessments --- p.13 / Chapter 1.3.2 --- Executive function and assessments of executive function --- p.16 / Chapter 1.3.3 --- Intelligence and intelligence tests --- p.19 / Chapter 1.4 --- Study hypotheses --- p.31 / Chapter CHAPTER 2 --- METHODS --- p.29 / Chapter 2.1 --- Study design --- p.29 / Chapter 2.2 --- Study subjects --- p.31 / Chapter 2.2.1 --- Subject recruitment sites --- p.31 / Chapter 2.2.2 --- Inclusion criteria --- p.32 / Chapter 2.3 --- Data collection --- p.33 / Chapter 2.3.1 --- Demographic information --- p.33 / Chapter 2.3.2 --- Drug use pattern and severity --- p.34 / Chapter 2.3.3 --- Psychiatric comorbidities --- p.34 / Chapter 2.3.4 --- Cognitive function evaluation --- p.40 / Chapter 2.4 --- Statistical methods --- p.44 / Chapter CHAPTER 3 --- RESULTS --- p.45 / Chapter 3.1 --- Demographics and basic information --- p.45 / Chapter 3.2 --- Drug use patterns --- p.47 / Chapter 3.3 --- Comorbid psychiatric problems --- p.51 / Chapter 3.4 --- Cognitive functions --- p.59 / Chapter 3.4.1 --- Cognitive functions among primarily ketamine, poly-drug ketamine and control groups --- p.59 / Chapter 3.4.2 --- Cognitive functions in current and ex-primarily ketamine users --- p.60 / Chapter 3.4.3 --- Cognitive functions in current and ex-poly-drug ketamine users --- p.70 / Chapter 3.4.4 --- Cognitive functions in current primarily ketamine and current poly-drug ketamine users --- p.79 / Chapter 3.4.5 --- Cognitive functions in female and male primarily ketamine users --- p.80 / Chapter CHAPTER 4 --- DISCUSSION --- p.86 / Chapter 4.1 --- Demographics and drug use patterns --- p.86 / Chapter 4.2 --- Effects of ketamine on psychological health --- p.87 / Chapter 4.3 --- Effects of ketamine on cognitive functions --- p.88 / Chapter 4.3.1 --- Effects of primarily ketamine use on memory --- p.90 / Chapter 4.3.2 --- Effects of primarily ketamine use on executive functions --- p.92 / Chapter 4.3.3 --- Effects of poly-drug ketamine use on cognitive functions --- p.96 / Chapter 4.3.4 --- Sex-specific effects of ketamine use on cognitive functions --- p.98 / Chapter CHAPTER 5 --- LIMITATIONS AND CONCLUSIONS --- p.98 / Chapter 5.1 --- Limitations --- p.98 / Chapter 5.2 --- Conclusions --- p.99 / REFERENCES --- p.102

Submitted by Bruno Galvão de Campos null (bruno12323@hotmail.com) on 2017-02-02T21:45:41Z No. of bitstreams: 1 Dissertacao Bruno Campos-revisada-pos-defesa.pdf: 1612994 bytes, checksum: 8486d4d50565a54b53b33f19060e0263 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-02-06T17:38:53Z (GMT) No. of bitstreams: 1 campos_bg_me_svic.pdf: 1612994 bytes, checksum: 8486d4d50565a54b53b33f19060e0263 (MD5) / Made available in DSpace on 2017-02-06T17:38:53Z (GMT). No. of bitstreams: 1 campos_bg_me_svic.pdf: 1612994 bytes, checksum: 8486d4d50565a54b53b33f19060e0263 (MD5) Previous issue date: 2017-01-06 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A Baía de Guanabara concentra aproximadamente 70% das indústrias do Estado do Rio de Janeiro. Os resíduos produzidos por essas fontes, somados à carga de esgoto doméstico, transformaram a região em umas das áreas mais poluídas da costa Brasileira. O presente estudo realizou a avaliação do risco ecológico dos metais em sedimentos da Baía de Guanabara, por meio de um método escalonado utilizando múltiplas linhas de evidência: caracterização do sedimento quanto à sedimentologia e concentração de metais, comparação das concentrações ambientais com guias de qualidade de sedimento, ensaios de toxicidade crônica utilizando os organismos Anomalocardia brasiliana e Nitocra sp., ensaios de toxicidade aguda utilizando os organismos Tiburonella viscana, Kalliapseudes schubartii, e Anomalocardia brasiliana. Para comprovar existência de relação causa e efeito entre os metais e a toxicidade, foram empregadas a técnica do TIE, análises multivariadas (PCA) e matrizes qualitativas. Os sedimentos mostraram níveis altos a moderados de metais (Zn, Pb, Cu, Cr) associados com a toxicidade. O TIE revelou que, além dos metais, amônia e compostos orgânicos são contaminantes presentes na região que tem a capacidade de causar toxicidade. Desse modo constatou-se que os metais constituem uma importante classe de contaminantes para a Baía de Guanabara, os quais, além de estarem presentes em altas concentrações, interagem com outros contaminantes e são também (co)responsáveis por efeitos biológicos negativos. / The Guanabara Bay (GB) comprises approximately 70% of the industries of Rio de Janeiro State. The wastes produced by these sources, combined with the domestic sewage loads, have transformed the region into one of the most polluted areas of the Brazilian coast. The present study evaluated the ecological risk of metals in sediments from the GB by the use of a tiered approach. The chosen method combines the following lines of evidence: geochemistry, comparison of environmental concentrations of metals with sediment quality guidelines, chronic sediment toxicity tests with Anomalocardia brasiliana and Nitocra sp.; and acute sediment toxicity tests with Tiburonella viscana, Kalliapseudes schubartii, and Anomalocardia brasiliana. To verify the existence of cause and effect relationships between metals and toxicity, the Toxicity Identification Evaluation (TIE) technique, multivariate analysis (PCA) and qualitative matrices were used. Sediments showed high to moderate levels of metals (Zn, Pb, Cu, Cr) associated with toxicity. In addition, the TIE has revealed that metals, ammonia and organic compounds contribute to cause sediment toxicity. We concluded that metals are an important class of contaminants for the GB, together with other chemicals, as they are present in high concentrations, interact with other substances and are (co)responsible for the negative biological effects. / FAPESP: 2015/13143-0