As alterações neurocognitivas associadas ao HIV-1 (HAND) são frequentes em adultos infectados pelo HIV-1 via transmissão sexual. Existe pouca informação sobre HAND em adultos infectados pelo HIV-1 via transmissão vertical. Este estudo teve como objetivos identificar a prevalência das HAND em adultos infectados por transmissão vertical assim como identificar a prevalência de depressão nessa população. Pacientes e métodos: trata-se de um estudo de delineamento transversal, realizado entre janeiro 2016 e maio de 2017, no Serviço de Extensão ao Atendimento de Pacientes HIV/aids (SEAP) da Divisão de Moléstias Infecciosas e Parasitárias do Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo. O SEAP é um serviço exclusivamente ambulatorial, localizado na cidade de São Paulo. Os critérios de inclusão foram: (i) pacientes com diagnóstico de infecção pelo HIV-1 por transmissão vertical; (ii) idade igual ou superior a 18 anos; (iii) escolaridade mínima de 4 anos; e (iv) consentimento para participar do estudo. Os critérios de exclusão foram: (i) diagnóstico concomitante de doenças neurológicas oportunistas ou condições neurológicas, previamente documentadas; (ii) uso de substâncias psicoativas; (iii) incapacidade física para aplicação dos testes, (iv) recusa da assinatura do Termo de Consentimento Livre e Esclarecido. Foram utilizados como instrumentos de pesquisa: questionário sociodemográfico, escala de ansiedade e depressão hospitalar, escala de atividades de vida diária de Lawton e bateria neuropsicológica formal. Para análise estatística foram calculadas frequência, média e desvio padrão, assim como testes qui-quadrado, anova e análise posthoc. Valores de p < 0.05 foram considerados estatisticamente significativos. Foi utilizado o programa SPSS 21.0. Resultados: foram avaliados 28 participantes: 15 (53.6%) foram do sexo feminino e a idade média e o desvio padrão (DP) foi de 22 (6.7) anos. Foi identificado HAND em 23 (82,1%) pacientes: 12 (42.9%) tiveram alteração neurocognitiva assintomática (ANI), 6 (21,4%) tiveram comprometimento neurocognitivo leve (MND) e 5 (17.9%) tiveram demência associada ao HIV-1 (HAD). A atenção, velocidade de processamento e velocidade motora foram as funções cognitivas mais comprometidas. 3 (10.7%) pacientes apresentaram depressão; 3 (60%) dos 5 pacientes com HAD apresentaram depressão. Conclusões: neste estudo encontramos elevada prevalência de HAND em adultos infectados pelo HIV-1 via transmissão vertical, chamando atenção também a elevada proporção de pacientes com HAD. Por outro lado, identificamos baixa prevalência de depressão na população total do estudo, mas a prevalência de depressão foi elevada dentre os pacientes com HAD / Neurocognitive disorders associated with HIV-1 (HAND) are common in adults sexually infected with HIV-1. There is little information about HAND in adults vertically infected with HIV-1. This study aimed to identify the prevalence of HAND in adults vertically infected with HIV-1 as well as to identify the prevalence of depression in this population. Patients and methods: This is a cross-sectional study, conducted between January 2016 and May 2017, at the Extension Service for HIV/aids Patients (SEAP) of the Division of Infectious and Parasitic Diseases of the Hospital das Clínicas of University of São Paulo Medical School. SEAP is an exclusively outpatient service, located in the city of São Paulo. Inclusion criteria were: (i) patients diagnosed with HIV-1 infected by vertical transmission; (ii) age equal to or more than 18 years; (iii) minimum schooling of 4 years; and (iv) consent to participate in the study. Exclusion criteria were: (i) concomitant diagnosis of opportunistic neurological diseases or neurological conditions, previously documented; (ii) use of psychoactive substances; (iii) physical incapacity to apply the tests, (iv) refusal to sign the Free and Informed Consent Form. The following research assessment tools were used: sociodemographic questionnaire, hospital anxiety and depression scale, Lawton daily life activity scale and formal neuropsychological battery. For statistical analysis, we calculated frequency, mean and standard deviation, as well as chi-square, anova and post-hoc analysis. Values of p < 0.05 were considered statistically significant. The SPSS 21.0 program was used. Results: 28 participants were evaluated: 15 (53.6%) were female and the mean age and standard deviation (SD) were 22 (6.7) years. HAND was identified in 23 (82.1%) patients: 12 (42.9%) had asymptomatic neurocognitive impairment (ANI), 6 (21.4%) had mild neurocognitive impairment and 5 (17.9%) had dementia associated with HIV-1 (HAD). Attention, processing speed and motor speed were the most compromised cognitive functions. 3 (10.7%) patients presented depression; 3 (60%) of the 5 patients with HAD had depression. Conclusions: in this study we found a high prevalence of HAND in adults vertically infected, also calling attention to the high proportion of patients with HAD. On the other hand, we identified a low prevalence of depression in the total study population, but the prevalence of depression was high among patients with HAD

<p> <i>Impulsivity</i>, or the tendency to act prematurely without foresight, has been linked to a diverse range of pathological conditions. Foresight refers to the ability to envision future rewards and events (i.e. prospectively sample) and has been associated with decreased impulsivity. One form of impulsivity is measured by the ability to delay gratification and is often studied in the framework of Delay Discounting (DD). DD provides the means to study impulsivity in a number of pathological conditions. However, whether impulsivity precedes the development of pathological states or results from the pathological state itself is not fully understood. This necessitates an understanding of neurobiological mechanisms contributing to decision making in both non-impulsive as well as impulsive populations of individuals. </p> <p> Animal models allow invasive techniques to be used to dissect the neurocircuitry involved in decision making. Given that the decision-making process is an ongoing process rather than an isolated event, optogenetics provide the temporal and spatial specificity necessary for evaluating brain region specific contributions to decision making in DD. In the present study, optogenetics were used to assess the contribution of the medial Prefrontal Cortex (mPFC), a brain region involved in ‘goal-directed’ behavior, in the planning of future choices (i.e. prospective plans) and subsequent measures of impulsivity in an adjusting amount DD procedure. Optogenetic inhibition of mPFC was conducted in Wistar rats during different epochs of a DD task in order to assess how mPFC affects planning behavior in a population of rat not considered to be highly impulsive. Although no direct effects on planning behavior (e.g. consistency) were observed, inhibiting mPFC after a trial has been initiated and directly before a choice was made (Epoch 2) was observed to increase measures of impulsivity in comparison to days where no optogenetic manipulation occurred in a delay-specific manner. This suggests that mPFC differentially contributes to decision making at different delays. A pattern of associations between choice latency, impulsivity, and consistency began to emerge for inactivation occurring in Epoch 2, suggesting that mPFC contributes to some aspect of planning choices during this epoch. Moreover, these results indicate that mPFC is involved in decision making in Wistar Rats. Understanding the direct role that mPFC plays in promoting choices of delayed rewards provides a neurobiological target for treatment aimed at reducing impulsivity in the clinical population.</p>

HIV associado a desordens neurocognitivas (HAND) continua a ser um grave problema atualmente devido à alta prevalência de suas formas mais brandas. Indivíduos HIV+ possuem o comprimento dos telômeros significativamente mais curtos nas células mononucleares do sangue periférico e células T CD8+, quando comparados aos indivíduos HIV negativos. Diante do exposto, o objetivo deste estudo foi avaliar a associação do comprimento dos telômeros de leucócitos em indivíduos infectados pelo HIV com deficiências cognitivas, pois ainda é um assunto bastante controverso. Métodos: Um total de 73 pacientes infectados pelo HIV-1 de ambos os sexos, com idades entre 20 a 60 anos, participaram deste estudo. Entre 19 indivíduos HIV(+) sem comprometimento cognitivo e 54 indivíduos HIV(+) com distúrbios neurocognitivos: 29 alteração neurocognitiva assintomático (ANI), 15 comprometimento neurocognitivo leve a moderado (MND) e, 10 demência associada ao HIV (HAD); 118 indivíduos HIV negativos formaram o grupo controle. Todos os participantes foram submetidos a uma série de testes neuropsicológicos previamente validados. Determinou-se a carga viral de HIV-1 nas células do líquido cefalorraquidiano (LCR) e em PBMC. Utilizou-se DNA a partir de leucócitos periféricos para calcular o comprimento de telômeros por PCR em tempo real. Resultados: O comprimento dos telômeros não foi associado com gêneros e diminuiu com a idade, independentemente do status de HIV. Indivíduos infectados pelo HIV-1com formas mais leves de deficiência neurocognitiva apresentaram um comprimento dos telômeros reduzida em comparação com pacientes HIV+ sem comprometimento neurocognitivo. Não houve correlação entre a carga viral plasmática e o tamanho dos telômeros. Conclusões: Nossos resultados sugerem que o comprimento dos telômeros pode ser considerado um marcador de senescência celular em indivíduos com alterações neurocognitivas / HIV associated neurocognitive disorders (HAND) remains a serious problem today because of the high prevalence of its milder forms. HIV + individuals have the length substantially shorter telomeres in peripheral blood mononuclear cells and CD8 + T cells compared to HIV negative individuals. Given the above, the objective of this study was to evaluate the association of telomere length of leukocyte (LTL) in HIV-infected individuals with cognitive disabilities because it is still a very controversial subject. Methods: A total of 73 patients infected with HIV-1 of both sexes, aged 20 to 60 years participated in this study. Among 19 HIV patients (+) without cognitive impairment and 54 HIV patients (+) with neurocognitive disorders: 29 asymptomatic neurocognitive disorder (ANI), 15 mild neurocognitive disorder to moderate (MND) and 10 HIVassociated dementia (HAD); 118 HIV-negative individuals formed the control group. All participants underwent a series of previously validated neuropsychological tests. Determined if the viral load of HIV-1 in cerebrospinal fluid cells (CSF) and in PBMC. We used DNA from peripheral leukocytes to calculate the length of telomeres by real time PCR. Results: The telomere length was not associated with genres and decreased with age, irrespective of HIV status. HIV-1-infected individuals with milder forms of neurocognitive impairment had a significantly length of telomeres reduced compared to HIV + patients without neurocognitive impairment. There was no correlation between plasma viral load and the size of telomeres. Conclusions: Our results suggest that telomere length can be considered a marker of cellular senescence in individuals with neurocognitive abnormalities

O mecanismo de controle da secreção de GnRH inclui diversas vias neuronais. Estudos em modelos animais identificaram genes que codificam fatores de transcrição, tais como TTF-1 (thyroid transcription factor 1) e EAP1 (enhanced at puberty), que atuam no controle transcricional de genes codificadores de fatores excitatórios (KiSS1 e GnRH) e inibitórios (preproencefalinas) regulando a secreção de GnRH. Em primatas, a expressão de EAP1 e TTF-1 aumenta, no início da puberdade, nas regiões hipotalâmicas envolvidas na secreção de GnRH. Nos modelos animais, a deleção pós-natal de TTF-1 e o silenciamento do EAP1 provocam atraso puberal e prejuízo na função reprodutiva. TTF-1 também está envolvido na morfogênese diencefálica, por meio da via de sinalização da família Sonic-Hedgehog. Anormalidades na secreção de GnRH resultam em distúrbios puberais, que variam de puberdade precoce central (PPC) a hipogonadismo hipogonadotrófico. Hipotetizamos que anormalidades genéticas no TTF-1 e EAP1 estejam envolvidas na patogênese dos distúrbios puberais centrais. A PPC pode ser idiopática ou devido a causas orgânicas, sendo o hamartoma hipotalâmico, uma malformação congênita não neoplásica, a mais conhecida. Os pacientes com PPC devido a hamartoma hipotalâmico podem cursar com alterações neurológicas e cognitivas. Nossos objetivos foram: estudar as regiões codificadora do TTF-1 e do EAP1 e a região promotora do TTF-1 em pacientes com distúrbios puberais centrais; estabelecer a prevalência, taxa de penetrância e modo de herança da forma familial de PPC e caracterizar as manifestações neurológicas e neurocognitivas de pacientes com PPC devido a hamartoma hipotalâmico. Foram selecionados 133 pacientes com distúrbios puberais centrais - PPC idiopática (n=71), PPC devido a hamartoma hipotalâmico (n=15) e hipogonadismo hipogonadotrópico isolado normósmico (HHIn) (n=47) - e controles (n=53). Os genes TTF-1 e EAP1 foram amplificados e submetidos a sequenciamento automático. Os tratos de poliglutamina e polialanina no EAP1 foram estudados por software de análise de tamanho de fragmento (GeneScan). A avaliação neurológica e neurocognitiva dos pacientes com PPC devido a hamartoma hipotalâmico consistiu de exame neurológico, eletroencefalograma, ressonância magnética de encéfalo e aplicação da escala de inteligência (WISC-III, WAIS-III, WPPSIR). Identificamos 25% de casos familiais de PPC, com modo de herança autossômica dominante e taxa de penetrância de 67,5%. Variantes alélicas no TTF-1 não foram identificadas nos pacientes estudados. No gene EAP1 foram identificadas quatro variantes alélicas sinônimas: p.E87E, p.A163A, p.Y415Y e uma nova variante alélica p.C758C, encontradas em pacientes com PPC e HHIn. A distribuição das frequências alélica e genotípica das variantes alélicas do EAP1 não diferiram entre pacientes com PPC, HHIn e controles (p >0,05). Nas regiões poliglutamina e polialanina 5 distal foi identificada variação similar no número de repetições glutamina e alanina em pacientes e controles. Não houve diferença significativa da frequência alélica em relação ao número de repetições glutamina e alanina entre os grupos PPC e HHIn (p >0,05). A avaliação neurológica dos pacientes com PPC devido a hamartoma hipotalâmico revelou epilepsia gelástica e crises focais com generalização em 3/15 (20%) pacientes. Não houve diferença significativa entre a mediana do maior diâmetro dos hamartomas dos pacientes com PPC com e sem epilepsia (13 e 10 mm, respectivamente). Quanto à forma, 10 hamartomas eram sésseis e 5 pedunculados, sendo que a forma pedunculada foi detectada exclusivamente em pacientes sem epilepsia. A avaliação neurocognitiva em 11 dos 15 pacientes com PPC devido a hamartoma hipotalâmico detectou 2 pacientes com epilepsia com QI significativamente menor que o grupo sem epilepsia (p <0,05). Em conclusão, (i) a considerável prevalência de casos familiais de PPC reforça a influência dos fatores genéticos na puberdade humana; (ii) mutações germinativas no TTF-1 e no EAP1 não estão envolvidas na patogênese dos distúrbios puberais centrais; (iii) a função neurocognitiva reduzida nos pacientes com hamartoma e epilepsia sugere um efeito deletério das crises convulsivas no sistema nervoso central / GnRH secretion control involves multiple neuronal pathways. Animal studies have identified genes which codifies transcription factors, such as TTF-1 (thyroid transcription factor 1) and EAP1 (enhanced at puberty), that act in the transcriptional control of genes that codifies excitatory (KiSS1 and GnRH) and inhibitory factors (preproenkephalines) regulating GnRH secretion. In nonhuman primates, expression of EAP1 and TTF-1 are increased at the hypothalamic regions involved in GnRH secretion, at the beginning of puberty. In animal models, post-natal TTF-1 deletion and silencing of EAP1 lead to pubertal delay and damage of reproductive function. TTF-1 is also involved in diencephalic morphogenesis, through signalization via Sonic-Hedgehog family. Abnormalities in GnRH secretion are responsible for pubertal disorders, varying from central precocious puberty (CPP) to hypogonadotropic hypogonadism. We hypothesized that genetic anomalies at TTF-1 and EAP1 are involved in the pathogenesis of central pubertal disorders. CPP may be idiopathic or due to organic alterations and hypothalamic hamartoma, a non-neoplasic congenital malformation, is the most frequent known organic cause. Patients with CPP due to hypothalamic hamartoma may have neurological and cognitive disfunctions. Our aims were: to evaluated the codifying region of TTF-1 and EAP1 and the promoter region of TTF-1 in patients with central pubertal disorders; to establish the prevalence, penetrance rate and inheritance mode of familial CPP and to characterize neurologic and neurocognitive aspects of patients with CPP due to hypothalamic hamartoma. We selected 133 patients with central pubertal disorders idiopathic CPP (n=71), CPP due to hypothalamic hamartoma (n=15) and normosmic isolated hypogonadropic hypogonadism (nIHH) (n=47) - and controls (n=53). TTF-1 and EAP1 genes were amplified and sequenced. Polyglutamine and polyalanine tracts of EAP1 were studied by a fragment size analyser software (GeneScan). Neurologic and neurocognitive evaluation of CPP patients due to hypothalamic hamartoma consisted of neurologic exam, electroencephalogram, brain magnetic resonance and application of intelligence scale (WISC-III, WAIS-III, WPPSI-R). We identified 25% of familial CPP cases with autosomal dominant mode of inheritance and penetrance rate of 67.5%. No TTF-1 allelic variants were identified in the patients analysed. At EAP1 gene, four synonimous allelic variants were identified: p.E87E, p.A163A, p.Y415Y and a new allelic variant p.C758C, found in CPP and nIHH patients. The allelic and genotypic distribution of theses variants of EAP1 did not differ among patients with CPP and nIHH, and controls (p >0.05). At polyglutamine and 5 distal polyalanine region, similar glutamine and alanine repeats variation was found. No significative difference of allelic frequency distribution regarding the number of glutamines and alanines repeats was found among the studied groups (p >0.05). Neurologic evaluation of CPP patients due to hypothalamic hamartoma revealed epilepsy and focal crisis with generalization in 3/15 (20%) of the patients. No significant difference between the median of the larger diameter of hypothalamic hamartoma of CPP patients with and without epilepsy was found (10 mm and 13 mm, respectively). Regarding the shape, 10 hamartomas were sessile and 5 pedunculated, and the pedunculated shape was found only in non epileptic patients. Neurocognitive evaluation performed in 11 of the 15 patients with CPP due to hypothalamic hamartoma detected 2 patients with epilepsy whose IQ were significantly lower than the IQ found in the group without epilepsy (p <0.05). In conclusion, (i) the considerable prevalence of familial CPP cases reinforce the influence of genetic factors in human puberty; (ii) germinative mutations in TTF-1 and EAP1 are not involved in the pathogenesis of central pubertal disorders; (iii) reduced neurocognitive function in patients with hypothalamic hamartoma and epilepsy suggests a deleterious effect of crisis at the central nervous system

Face au déclin cognitif, à la perte progressive de l'autonomie et aux troubles du comportement accompagnant l'évolution de la maladie d'Alzheimer et des maladies apparentées (MA2), l'implication de l'aidant naturel auprès de son proche atteint s'intensifie et s'accompagne d'un fardeau. Les données de la littérature montrent que les interventions psychosociales évaluées ont un impact modeste et à court terme sur le fardeau de l'aidant. Par ailleurs, les patients âgés atteints de MA2 et leurs aidants sont exposés à un risque important d'iatrogénie médicamenteuse. L'objectif de ce travail de thèse était de concevoir une prise en soin pharmaceutique intégrée à une intervention psychosociale efficiente permettant de réduire le fardeau des aidants de patients âgés atteints de MA2. Afin de garantir l'efficience de l'intervention à concevoir, des études préalables ont été réalisées afin : (1) d'identifier les facteurs prédictifs de fardeau de l'aidant via une étude transversale, une étude longitudinale et à partir des données de la littérature ; (2) d'identifier les besoins prioritaires des aidants via une enquête Delphi incluant le domaine pharmaceutique après réalisation d'une revue systématique de la littérature ; (3) d'identifier les critères d'efficacité des interventions psychosociales et l'étendue du rôle du pharmacien auprès de la dyade patient/aidant à partir des données de la littérature. Ces différents éléments ont permis de concevoir de façon multidisciplinaire et multicentrique, le protocole de l'étude interventionnelle PHARMAID. Il s'agit d'un essai clinique randomisé, contrôlé, à trois bras parallèles, multicentrique dont l'objectif principal est d'évaluer l'impact d'un suivi pharmaceutique personnalisé intégré à une intervention psychociale sur le fardeau des aidants de patients âgés atteints de MA2 à 18 mois. A ce jour, 72 dyades patient/aidant ont été inclues, soit 30% de l'effectif attendu. Si l'intervention psychosociale combinée ou non aux soins pharmaceutiques de l'étude PHARMAID s'avère efficace, sa pérénnité dans les centres participants et son extension au sein des autres centres mémoires, des services de neurologie ou de gériatrie pourront être envisagées. L'étude médico-économique associée permettra d'estimer les coûts engagés par la mise en place d'une telle intervention, tout en prenant en compte les coûts directs de consommation de soins / Alzheimer’s disease and Related Disorders (ADRD) are associated with a caregiver burden that increases with the progression of the disease. Previous psychosocial interventions reported a moderate improvement on caregiver burden. Patients with ADRD and their caregivers are also exposed to higher risk of developing drug-related problems.Our objective was to design an integrated pharmaceutical care at a multidisciplinary psychosocial intervention that reduces the caregiver burden of aged patient with ADRD.To guarantee the effectiveness of the intervention, preliminary studies were conducted to: (1) identify predicting factors that increase the caregiver burden through a cross-sectional study, a longitudinal study and from a literature review ; (2) to identify the prioritized caregivers’ needs through a Delphi survey, including the pharmaceutical field, after conducting a systematic review of the literature; (3) to identify the effectiveness criteria of psychosocial interventions and the extent of the pharmacist's role with the patient / caregiver dyad from a literature review. Our work leaded to design, in a multidisciplinary and multicentric way, the protocol of the PHARMAID study. The PHARMAID study is a 18-month randomized, controlled, with three parallel groups, and multi-center trial. The primary objective is to measure the impact of personalized pharmaceutical collaborative care integrated to a multidisciplinary psychosocial intervention on the caregiver burden of aged patient with ADRD. To date, 72 dyads have been included, representing 30% of the expected sample. If the effectiveness of this collaborative approach is demonstrated, its durability in the participating centers and its extension in the other memory centers, neurology or geriatric wards could be considered. The costs and the cost-effectiveness of different interventions will also be evaluated through detailed analyses of formal and informal resource consumption during the study

HIV associado a desordens neurocognitivas (HAND) continua a ser um grave problema atualmente devido à alta prevalência de suas formas mais brandas. Indivíduos HIV+ possuem o comprimento dos telômeros significativamente mais curtos nas células mononucleares do sangue periférico e células T CD8+, quando comparados aos indivíduos HIV negativos. Diante do exposto, o objetivo deste estudo foi avaliar a associação do comprimento dos telômeros de leucócitos em indivíduos infectados pelo HIV com deficiências cognitivas, pois ainda é um assunto bastante controverso. Métodos: Um total de 73 pacientes infectados pelo HIV-1 de ambos os sexos, com idades entre 20 a 60 anos, participaram deste estudo. Entre 19 indivíduos HIV(+) sem comprometimento cognitivo e 54 indivíduos HIV(+) com distúrbios neurocognitivos: 29 alteração neurocognitiva assintomático (ANI), 15 comprometimento neurocognitivo leve a moderado (MND) e, 10 demência associada ao HIV (HAD); 118 indivíduos HIV negativos formaram o grupo controle. Todos os participantes foram submetidos a uma série de testes neuropsicológicos previamente validados. Determinou-se a carga viral de HIV-1 nas células do líquido cefalorraquidiano (LCR) e em PBMC. Utilizou-se DNA a partir de leucócitos periféricos para calcular o comprimento de telômeros por PCR em tempo real. Resultados: O comprimento dos telômeros não foi associado com gêneros e diminuiu com a idade, independentemente do status de HIV. Indivíduos infectados pelo HIV-1com formas mais leves de deficiência neurocognitiva apresentaram um comprimento dos telômeros reduzida em comparação com pacientes HIV+ sem comprometimento neurocognitivo. Não houve correlação entre a carga viral plasmática e o tamanho dos telômeros. Conclusões: Nossos resultados sugerem que o comprimento dos telômeros pode ser considerado um marcador de senescência celular em indivíduos com alterações neurocognitivas / HIV associated neurocognitive disorders (HAND) remains a serious problem today because of the high prevalence of its milder forms. HIV + individuals have the length substantially shorter telomeres in peripheral blood mononuclear cells and CD8 + T cells compared to HIV negative individuals. Given the above, the objective of this study was to evaluate the association of telomere length of leukocyte (LTL) in HIV-infected individuals with cognitive disabilities because it is still a very controversial subject. Methods: A total of 73 patients infected with HIV-1 of both sexes, aged 20 to 60 years participated in this study. Among 19 HIV patients (+) without cognitive impairment and 54 HIV patients (+) with neurocognitive disorders: 29 asymptomatic neurocognitive disorder (ANI), 15 mild neurocognitive disorder to moderate (MND) and 10 HIVassociated dementia (HAD); 118 HIV-negative individuals formed the control group. All participants underwent a series of previously validated neuropsychological tests. Determined if the viral load of HIV-1 in cerebrospinal fluid cells (CSF) and in PBMC. We used DNA from peripheral leukocytes to calculate the length of telomeres by real time PCR. Results: The telomere length was not associated with genres and decreased with age, irrespective of HIV status. HIV-1-infected individuals with milder forms of neurocognitive impairment had a significantly length of telomeres reduced compared to HIV + patients without neurocognitive impairment. There was no correlation between plasma viral load and the size of telomeres. Conclusions: Our results suggest that telomere length can be considered a marker of cellular senescence in individuals with neurocognitive abnormalities

Neuropsychological impairment following cardiopulmonary bypass (CPB) remains a serious consequence of otherwise successful surgery. The incidence of neuropsychological decline is poorly understood due to varied measurement intervals, and perhaps more importantly the use of unreliable detection and classification methods. The reported incidence varies considerably, ranging anywhere from 30% to 90% of subjects. While the nature of this impairment has not been fully elucidated, recent evidence suggests that microembolism during surgery may be the principal causative agent of postoperative cerebral dysfunction. The work described in this thesis investigates one possible source of microembolism leading to postoperative decline, namely thromboembolism arising from excessive activation of the haemostatic mechanism. Crucial to the accurate detection of significant decline in individual patients, this work also focuses on the development and use of meaningful criteria to be used when describing change in neuropsychological performance measures. The strong haemostatic activation during CPB is controlled by heparin anticoagulation. The clinical performance of the Hepcon heparin-monitoring instrument was compared to the activated clotting time (ACT), which is used in most cardiac centres. An analysis of samples from 42 elective coronary artery bypass grafting (CABG) patients shows that the ACT does not detect the significant decline in heparin concentration seen upon connection to CPB, in comparison to the Hepcon. The Hepcon appears to be in satisfactory agreement with laboratory anti-Xa analysis of heparin concentration, with the mean difference for the Hepcon at -0.46 U/ml, and the limits of agreement +/- 1.12 U/ml. Further analysis shows that that for 95% of cases, the Hepcon will give values that are between 0.53 and 1.27 times the value for anti-Xa. The loss of relationship between ACT and heparin concentration was further investigated by converting ACT values to heparin concentration. The results provide data on the degree of prolongation in ACT times brought about by factors associated with CPB. A methodology is presented by which users can adjust for the loss of relationship between ACT and heparin. This work also demonstrates that under normal usage of the ACT, the user may obtain values up to 3 times appropriate for the plasma heparin concentration. The computer-administered neuropsychological testing tool (the MicroCog) was validated using 40 age-matched control subjects. Using a two-week interval, the summary score correlation coefficients ranged from .49 to .84, with all scores demonstrating significant practice effects. Also presented are retest normative data that may be used to determine significant change in a homogeneous sample using both reliable change and regression models of analysis. The performance of four different models of change analysis was then analysed using data from the clinical group. The regression technique of analysis was shown to be the most useful prediction model as it provides correction for both practice effects and regression toward the mean in each individual. A novel statistical rationale is presented for the choice of criteria in the identification of patients that may be defined as overall impaired when using a battery of test scores. When using one-tailed prediction models for decline, the binomial distribution of scores was shown to be a useful descriptive statistic providing an estimate of change due to chance. When applied to a suitable selection of scores that minimise shared variance, a value +/- 20% of test scores used was demonstrated to be a rational cut-off for an individual to be classified as impaired. Using this methodology, 32.7% of patients were identified as significantly deteriorated in neuropsychological test function immediately prior to discharge from hospital. Patient age was shown to be a significant predictor of neuropsychological decline following CPB. No significant relationship was identified between thrombin generation and neuropsychological change scores, however problems with patient recruitment and retention limited the statistical power of this study. An intriguing relationship with heparin concentration was noted that might warrant further investigation. This work highlights the complex nature of post-bypass neuropsychological dysfunction and the complexities in assessing decline. The regression-based model was shown to be highly useful in the analysis of data from a suitably validated neuropsychological testing tool. The argument that no suitable criterion exists for the identification of patients as overall impaired has been challenged with the development of a rational cut-off based on the likely distribution of change scores across a series. The work presented here confirms the need for standardised testing methods based on sound statistical criteria. This work also highlights the problems associated with current methods for monitoring anticoagulation therapy during bypass surgery. Methodology is presented that allows adjustment of ACT results to account for CPB-induced prolongation of clotting times. Current techniques for heparin monitoring overestimate heparin levels on bypass by up to threefold, which may predispose to subclinical coagulation and increased delivery of protamine.

LES CARTES SENSORIMOTRICES DE LA PAROLE : Corrélats neurocognitifs et couplage fonctionnel des systèmes de perception et de production des voyelles du Français --- La parole est construite sur un jeu de correspondances entre représentations sensorielles et articulatoires, notamment lors de l'acquisition du langage les premières années de vie. Par l'utilisation de l'imagerie par résonance magnétique fonctionelle, l'objectif premier de nos travaux était de déterminer, chez l'adulte, un possible couplage fonctionnel des systèmes de perception et de production des voyelles du Français, considérées comme unités élémentaires de la parole. En parallèle, nos travaux devaient permettre de clarifier les structures cérébrales liées au contrôle moteur orofacial de mouvements simples supralaryngés et, à l'aide de la technique de stimulation magnétique transcrânienne, de déterminer une possible implication causale des régions sensorielles et motrices lors de la perception de la parole. Nos travaux ont permis de souligner l'implication des régions sensorielles et motrices aussi bien lors de la réalisation des gestes orofaciaux que lors de la production et de la perception des voyelles. La mise en évidence d'un effet d'adaptation pour ces régions motrices, auditives et somatosensorielles lors de l'écoute ou de la réalisation répétée d'une même voyelle ou d'un même geste suggère de plus l'existence de boucles sensorimotrices communes, impliquées dans des mécanismes adaptatifs de contrôle en ligne des gestes de parole perçus et produits. Enfin, nous avons pu démontrer le rôle causal et fonctionnel des régions sensorielles et motrices de la voie dorsale lors de la catégorisation de sons de parole. Pris ensemble, nos travaux soulignent la nature distribuée sensorimotrice des représentations cérébrales des unités de parole. Mots clés: perception et production de la parole, voyelles, contrôle moteur orofacial, interactions sensorimotrices, représentations et cartes neurocognitives, IRMf, TMS. / SENSORIMOTOR MAPS OF SPEECH: Neurocognitive correlates and functional coupling of French vowel perception and production systems --- Speech is built on a set of correspondences between sensory and articulatory representations, especially during the acquisition of language in the early years of life. Using functional magnetic resonance imaging, the primary goal of our work was to determine, in adults, a possible functional coupling of French vowel perception and production systems, as elementary speech units. In parallel, our work should help clarify the brain structures related to the orofacial motor control of simple supralaryngeal movements and to determine a possible causal contribution of sensory and motor regions during speech perception. Our work highlights the involvement of sensory and motor areas when performing orofacial gestures and during vowel production and perception. Adaptive effects of these motor, auditory and somatosensory regions during repeated orofacial movements and in vowel perception and production suggest the existence of common adaptive mechanisms involved in the online control of perceived and produced speech gestures. Finally, we demonstrated a causal and functional role of the sensorimotor regions of the dorsal pathway in speech categorization. Taken together, our results emphasize the distributed sensorimotor nature of cerebral representations of speech units. Key words: speech perception and production, vowels, orofacial motor control, sensorimotor interactions, neurocognitive representations and maps, fMRI, TMS.

Made available in DSpace on 2015-05-14T13:16:23Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 3324327 bytes, checksum: b85304a7fe276b9b7697e2cdf5a23471 (MD5) Previous issue date: 2013-12-06 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / This study aimed at verifying exposure levels for gasoline and ethanol vapors and their psychophysical, neurocognitive, and physiological consequences in a sample of Brazilian pump attendants. Gas chromatography and microclimate sensing were used to passive and active monitoring of environmental levels of vapors. The psychophysical evaluation comprised the chromatic tests Lanthony D15-d and Cambridge Color Test 2.0, the Contrast Sensitivity Function using vertical sinusoidal gratings and Metropsis at the frequencies 0.2, 0.5, 1.0, 2.0, 5.0, 10.0, and 16.0 cpd, and eye-tracking at 250 Hz. Except by the D15-d test, all vision tests were performed with the dominant eye. The neurocognitive evaluation included the Trial Making Tests (A and B) and the Rey's Complex Figure Test. After applying exclusion criteria, the physiological evaluation was carried out in 16 attendants, who had a blood test to assess hepatic-biliary functions by the following markers: Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Direct Bilirubin (DB), Total Bilirubin (TB), and Gamma-glutamyl transpeptidase (GAMMA GT). The screening phase also included a questionnaire of Psychological and Neurophysiological Symptoms (PNS), a sociodemographic questionnaire, the Ishihara and the Rasquin 'E' tests. Thirty-eight pump attendants (Exposed Group) were selected, all males, with mean age of 32.66 years (SD = 1.30) and average schooling of 9.68 years (SD = 0.34). Thirty-eight volunteers (Control Group) were selected, all males, with mean age of 30.0 years (SD = 1.54), average schooling of 9.84 years (SD = 0.34), without reporting exposure to solvents and considered healthy following the inclusion criteria. The groups did not differ in age (p = .224) or schooling (p = .52), and all participants had normal or corrected-to-normal visual acuity 20/20. The Mann-Whitney test showed significant differences between scores in the Index of Color Confusion of the D15-d (p < .01, with losses in the tritan axis 75%), the Area of ellipses (protan, deutran, and tritan, all at p < .05), the frequencies 5, 10, and 16 cpd (p < .01), the Trail Making A (p < .01) and B (p < .05), the copy and memory of the Rey's complex figure (both at p < .01), and the number of saccades and trajectory time in the visual labyrinth (both at p < .01) as measure by the eye-tracker. The physiological evaluation showed changes in the values of DB (100 % of the pump attendants) and TB (62,5 %). Two attendants had combined changes in hepatic enzymes and biliburin. The Spearman correlation showed a significant association between the time of service and the areas protan (ρ = .46, p < .01) and deutan (ρ = .64, p < .01), the spatial frequency 5 cpd (ρ = .36, p < .05), and the Trail Making A (ρ = .40, p < .05) and B (ρ = .37, p < .05). The weight showed a tendency to attenuate the visual deficits, having a negative correlation with the area deutan (ρ = - .45, p < .01) and a positive one with contrast sensitivity at 0.20 cpd (ρ = .37, p < .05). Correlations were also found between DB and the time to perform the eye-tracker task (ρ = .58, p < .05) and the GGT and complaints of psychoneurovegetative instability (ρ = .57, p < .05). The Kruskal Wallis, and Mann-Whitney as a post-hoc test with Bonferroni's correction, showed that from 8 years of exposure there are consequences to color vision (Protan and Deutan) and for neurocognitive processes related to attention (Trail Making). The questionnaire PNS showed that 52.6% of pump attendants had symptoms of neuropsychological aggressions. Furthermore, there was a convergence between memory and attention complaints, with lower scores in the memory for the Rey's complex figure (ρ = - .34, p < .05). This study brings additional and new evidences for the consequences on color vision and contrast sensitivity, shows a potential occupational etiology in hepatic-biliary changes, presents neurocognitive xviii deficits in Brazilian pump attendants, and concludes that such deficits are correlated with chronic exposure (significant from 8 years of service) with a level of exposure to gasoline and ethanol below the Brazilian tolerance limit, but within an intervention level to gasoline vapor (168 and 153,40 ppm > 150 ppm) according to the Brazilian Standards for Work Health and Safety. / O objetivo deste estudo foi determinar os níveis de exposição aos vapores da gasolina e do etanol e verificar as consequências psicofísicas, neurocognitivas e fisiológicas em uma amostra de frentistas brasileiros. Para avaliar o nível de exposição ambiental foram realizados monitoramentos passivos e ativos de vapor com cromatografia gasosa e sensoriamento microclimático. A avaliação psicofísica foi realizada com os testes cromáticos de Lanthony D15-d e o Cambridge Color Teste 2,0; com a Função de Sensibilidade ao Contraste utilizando grades senoidais verticais e o Metropsis nas frequências 0,2; 0,5; 1,0; 2,0; 5,0; 10,0 e 16,0 cpg e com o rastreamento ocular utilizando um eyetracker 250 Hz. Todos os testes de visão, exceto o D15-d, foram realizados monocularmente com o olho dominante. A avaliação neurocognitiva ocorreu com os testes Trail Making A, B e com a Figura Complexa de Rey. A avaliação fisiológica, após utilização de parâmetros de exclusão, foi realizada pela análise de sangue de 16 frentistas verificando funções hepatotóxicas pelos marcadores Alanina Aminotransferase (ALT), Aspartato Aminotransferase (AST), Bilirrubina Direta (BD), Bilirrubina Total (BT) e Gamaglutamiltraspeptidase (GGT). Utilizou-se ainda o questionário de sintomas Psicológicos e Neurofisiológicos (PNF) além de um questionário sóciodemográfico e os testes de Ishihara e o ―E‖ de Rasquin na triagem. Essa etapa selecionou 38 frentistas do sexo masculino (Grupo Exposto), com idade média de 32,66 anos (DP = 1,30), grau de escolaridade média igual a 9,68 anos de estudo (DP = 0,34) e 38 voluntários (Grupo Controle) também do sexo masculino, sem histórico de exposição a solventes, considerados saudáveis pelos parâmetros de exclusão, com idade média de 31,00 anos (DP = 1,54) e grau de escolaridade médio de 9,84 anos de estudo (DP = 0,34). Não existiu diferença significativa entre a idade (p = 0,224) e o grau de escolaridade (p = 0,52) dos grupos que apresentaram ainda acuidade visual de 20/20 ou corrigida. Pelo teste de Mann-Whitney foram encontradas diferenças significativas entre os escores para: o Índice de Confusão de Cores do teste D15-d (p < 0,01, prevalecendo perdas no eixo tritan 75%), as Áreas das elipses (protan, deutan e tritan, ambos p < 0,05), as frequências 5 cpg, 10 cpg e 16 cpg (ambos p < 0,01), o teste Trail Making A (p < 0,01) e B (p < 0,05), a cópia e a memória da Figura complexa de Rey (ambas p < 0,01) e o número de sacadas e tempo de percurso do labirinto no eyetracker (ambos p < 0,01). A avaliação biológica demonstrou principalmente alterações nos valores da BD (100 % dos frentistas) e BT (62,5 %). Dois frentistas tiveram alterações combinadas de enzimas hepáticas e bilirrubinas. A correlação de Spearman demonstrou a influência do tempo de serviço no acréscimo das áreas protan (ρ = 0,46; p < 0,01) e deutan (ρ = 0,64; p < 0,01), além de correlações com a frequência de 5 cpg (ρ = 0,36; p < 0,05) e com os testes Trail Making A (ρ = 0,40; p < 0,05) e B (ρ = 0,37; p < 0,05). O peso apresentou a tendência de atenuar os déficits nos testes de visão, correlacionando negativamente com a área deutan (ρ = - 0,45; p < 0,01) e positivamente com a sensibilidade ao contraste na frequência 0,20 cpg (ρ = 0,37; p < 0,05). Existiram ainda correlações entre a BD e o tempo para realizar a prova no eyetracker (ρ = 0,58; p < 0,05) e entre o GGT e as queixas de instabilidade psiconeurovegetativa (ρ = 0,57; p < 0,05). Os testes Kruskal Wallis, e Mann- Whitney como post hoc com correção Bonferroni, demonstraram que a partir de 8 anos de exposição existem consequências para a visão de cores (Protan e Deutan) e para processos neurocognitivos relacionados a atenção (Trail Making A). O questionário PNF apontou que 52,60 % dos frentistas possuem sintomas de agressões neuropsicológicas. Além disso, existiram convergências entre as queixas de falta de memória e concentração, com menores pontuações da memória na Figura Complexa de Rey (ρ = - 0,34; p < 0,05). Este estudo confirma e avança nas descobertas de consequências na visão de cores e sensibilidade ao contraste, aponta uma possível etiologia ocupacional nas alterações hepatotóxicas, apresenta as deficiências neurocognitivas nos frentistas brasileiros e conclui que essas deficiências e as da visão de cores estão correlacionadas a uma exposição crônica (significativa aos 8 anos de serviço) com um nível de exposição a gasolina e ao álcool etílico abaixo do Limite de Tolerância brasileiro, mas a um nível de intervenção para o vapor de gasolina (168,00 e 153,40 ppm > 150 ppm) conforme as Normas de Saúde e Segurança do Trabalho brasileiras.

O mecanismo de controle da secreção de GnRH inclui diversas vias neuronais. Estudos em modelos animais identificaram genes que codificam fatores de transcrição, tais como TTF-1 (thyroid transcription factor 1) e EAP1 (enhanced at puberty), que atuam no controle transcricional de genes codificadores de fatores excitatórios (KiSS1 e GnRH) e inibitórios (preproencefalinas) regulando a secreção de GnRH. Em primatas, a expressão de EAP1 e TTF-1 aumenta, no início da puberdade, nas regiões hipotalâmicas envolvidas na secreção de GnRH. Nos modelos animais, a deleção pós-natal de TTF-1 e o silenciamento do EAP1 provocam atraso puberal e prejuízo na função reprodutiva. TTF-1 também está envolvido na morfogênese diencefálica, por meio da via de sinalização da família Sonic-Hedgehog. Anormalidades na secreção de GnRH resultam em distúrbios puberais, que variam de puberdade precoce central (PPC) a hipogonadismo hipogonadotrófico. Hipotetizamos que anormalidades genéticas no TTF-1 e EAP1 estejam envolvidas na patogênese dos distúrbios puberais centrais. A PPC pode ser idiopática ou devido a causas orgânicas, sendo o hamartoma hipotalâmico, uma malformação congênita não neoplásica, a mais conhecida. Os pacientes com PPC devido a hamartoma hipotalâmico podem cursar com alterações neurológicas e cognitivas. Nossos objetivos foram: estudar as regiões codificadora do TTF-1 e do EAP1 e a região promotora do TTF-1 em pacientes com distúrbios puberais centrais; estabelecer a prevalência, taxa de penetrância e modo de herança da forma familial de PPC e caracterizar as manifestações neurológicas e neurocognitivas de pacientes com PPC devido a hamartoma hipotalâmico. Foram selecionados 133 pacientes com distúrbios puberais centrais - PPC idiopática (n=71), PPC devido a hamartoma hipotalâmico (n=15) e hipogonadismo hipogonadotrópico isolado normósmico (HHIn) (n=47) - e controles (n=53). Os genes TTF-1 e EAP1 foram amplificados e submetidos a sequenciamento automático. Os tratos de poliglutamina e polialanina no EAP1 foram estudados por software de análise de tamanho de fragmento (GeneScan). A avaliação neurológica e neurocognitiva dos pacientes com PPC devido a hamartoma hipotalâmico consistiu de exame neurológico, eletroencefalograma, ressonância magnética de encéfalo e aplicação da escala de inteligência (WISC-III, WAIS-III, WPPSIR). Identificamos 25% de casos familiais de PPC, com modo de herança autossômica dominante e taxa de penetrância de 67,5%. Variantes alélicas no TTF-1 não foram identificadas nos pacientes estudados. No gene EAP1 foram identificadas quatro variantes alélicas sinônimas: p.E87E, p.A163A, p.Y415Y e uma nova variante alélica p.C758C, encontradas em pacientes com PPC e HHIn. A distribuição das frequências alélica e genotípica das variantes alélicas do EAP1 não diferiram entre pacientes com PPC, HHIn e controles (p >0,05). Nas regiões poliglutamina e polialanina 5 distal foi identificada variação similar no número de repetições glutamina e alanina em pacientes e controles. Não houve diferença significativa da frequência alélica em relação ao número de repetições glutamina e alanina entre os grupos PPC e HHIn (p >0,05). A avaliação neurológica dos pacientes com PPC devido a hamartoma hipotalâmico revelou epilepsia gelástica e crises focais com generalização em 3/15 (20%) pacientes. Não houve diferença significativa entre a mediana do maior diâmetro dos hamartomas dos pacientes com PPC com e sem epilepsia (13 e 10 mm, respectivamente). Quanto à forma, 10 hamartomas eram sésseis e 5 pedunculados, sendo que a forma pedunculada foi detectada exclusivamente em pacientes sem epilepsia. A avaliação neurocognitiva em 11 dos 15 pacientes com PPC devido a hamartoma hipotalâmico detectou 2 pacientes com epilepsia com QI significativamente menor que o grupo sem epilepsia (p <0,05). Em conclusão, (i) a considerável prevalência de casos familiais de PPC reforça a influência dos fatores genéticos na puberdade humana; (ii) mutações germinativas no TTF-1 e no EAP1 não estão envolvidas na patogênese dos distúrbios puberais centrais; (iii) a função neurocognitiva reduzida nos pacientes com hamartoma e epilepsia sugere um efeito deletério das crises convulsivas no sistema nervoso central / GnRH secretion control involves multiple neuronal pathways. Animal studies have identified genes which codifies transcription factors, such as TTF-1 (thyroid transcription factor 1) and EAP1 (enhanced at puberty), that act in the transcriptional control of genes that codifies excitatory (KiSS1 and GnRH) and inhibitory factors (preproenkephalines) regulating GnRH secretion. In nonhuman primates, expression of EAP1 and TTF-1 are increased at the hypothalamic regions involved in GnRH secretion, at the beginning of puberty. In animal models, post-natal TTF-1 deletion and silencing of EAP1 lead to pubertal delay and damage of reproductive function. TTF-1 is also involved in diencephalic morphogenesis, through signalization via Sonic-Hedgehog family. Abnormalities in GnRH secretion are responsible for pubertal disorders, varying from central precocious puberty (CPP) to hypogonadotropic hypogonadism. We hypothesized that genetic anomalies at TTF-1 and EAP1 are involved in the pathogenesis of central pubertal disorders. CPP may be idiopathic or due to organic alterations and hypothalamic hamartoma, a non-neoplasic congenital malformation, is the most frequent known organic cause. Patients with CPP due to hypothalamic hamartoma may have neurological and cognitive disfunctions. Our aims were: to evaluated the codifying region of TTF-1 and EAP1 and the promoter region of TTF-1 in patients with central pubertal disorders; to establish the prevalence, penetrance rate and inheritance mode of familial CPP and to characterize neurologic and neurocognitive aspects of patients with CPP due to hypothalamic hamartoma. We selected 133 patients with central pubertal disorders idiopathic CPP (n=71), CPP due to hypothalamic hamartoma (n=15) and normosmic isolated hypogonadropic hypogonadism (nIHH) (n=47) - and controls (n=53). TTF-1 and EAP1 genes were amplified and sequenced. Polyglutamine and polyalanine tracts of EAP1 were studied by a fragment size analyser software (GeneScan). Neurologic and neurocognitive evaluation of CPP patients due to hypothalamic hamartoma consisted of neurologic exam, electroencephalogram, brain magnetic resonance and application of intelligence scale (WISC-III, WAIS-III, WPPSI-R). We identified 25% of familial CPP cases with autosomal dominant mode of inheritance and penetrance rate of 67.5%. No TTF-1 allelic variants were identified in the patients analysed. At EAP1 gene, four synonimous allelic variants were identified: p.E87E, p.A163A, p.Y415Y and a new allelic variant p.C758C, found in CPP and nIHH patients. The allelic and genotypic distribution of theses variants of EAP1 did not differ among patients with CPP and nIHH, and controls (p >0.05). At polyglutamine and 5 distal polyalanine region, similar glutamine and alanine repeats variation was found. No significative difference of allelic frequency distribution regarding the number of glutamines and alanines repeats was found among the studied groups (p >0.05). Neurologic evaluation of CPP patients due to hypothalamic hamartoma revealed epilepsy and focal crisis with generalization in 3/15 (20%) of the patients. No significant difference between the median of the larger diameter of hypothalamic hamartoma of CPP patients with and without epilepsy was found (10 mm and 13 mm, respectively). Regarding the shape, 10 hamartomas were sessile and 5 pedunculated, and the pedunculated shape was found only in non epileptic patients. Neurocognitive evaluation performed in 11 of the 15 patients with CPP due to hypothalamic hamartoma detected 2 patients with epilepsy whose IQ were significantly lower than the IQ found in the group without epilepsy (p <0.05). In conclusion, (i) the considerable prevalence of familial CPP cases reinforce the influence of genetic factors in human puberty; (ii) germinative mutations in TTF-1 and EAP1 are not involved in the pathogenesis of central pubertal disorders; (iii) reduced neurocognitive function in patients with hypothalamic hamartoma and epilepsy suggests a deleterious effect of crisis at the central nervous system