La dystrophie myotonique de type 1 (DM1), ou maladie de Steinert, est une maladie qui touche plusieurs tissus, dont le système nerveux central (SNC). L’atteinte neurologique est variable et inclut des troubles de la fonction exécutive, des changements de comportement et une hypersomnolence dans la forme adulte, ainsi qu’une déficience intellectuelle marquée dans la forme congénitale. Dans leur ensemble, les symptômes neurologiques ont un fort impact sur le parcours académique, professionnel et les interactions sociales. Aujourd’hui aucune thérapie n’existe pour cette maladie. La DM1 est due à une expansion anormale d’un triplet CTG non-codant dans le gène DMPK. Les ARN messagers DMPK, porteurs de l’expansion, s’accumulent dans le noyau des cellules (sous forme de foci) et perturbent la localisation et la fonction de protéines de liaison à l’ARN, notamment des familles MBNL et CELF, ce qui entraîne des défauts d’épissage alternatif, d’expression, de polyadenylation et de localisation d’autres ARN cibles. Malgré le progrès récent dans la compréhension des mécanismes de la maladie, les aspects cellulaires et moléculaires de l’atteinte neurologique restent méconnus: nous ne connaissons ni la contribution de chaque type cellulaire du cerveau, ni les voies moléculaires spécifiquement dérégulées dans chaque type cellulaire. L’objectif de ma thèse a été de répondre à ces deux questions importantes en utilisant un modèle de souris transgéniques et des cellules primaires dérivées de celui-ci. Pour mon projet, j’ai utilisé les souris DMSXL générées par mon laboratoire. Ces souris reproduisent des caractéristiques importantes de la DM1, notamment l’accumulation des ARN toxiques et la dérégulation de l’épissage alternatif dans plusieurs tissus. L’impacte fonctionnel des transcrits DMPK toxiques dans le SNC des souris DMSXL se traduit par des problèmes comportementaux et cognitifs et par des défauts de la plasticité synaptique. Afin d’identifier les mécanismes moléculaires associés à ces anomalies, une étude protéomique globale a montré une dérégulation de protéines neuronales et astrocytaires dans le cerveau des souris DMSXL. De plus, l’étude de la distribution des foci d’ARN dans les cerveaux des souris et des patients a montré un contenu plus élevé dans les astrocytes par rapport aux neurones. Ensemble, ces résultats suggèrent une contribution à la fois neuronale et gliale dans la neuropathogenèse de la DM1. L’étude protéomique globale des cerveaux des souris DMSXL, a aussi montré des défauts de protéines synaptiques spécifiques des neurones, que nous avons par la suite validés dans le cerveau des patients. SYN1 est hyperphosphorylée d’une façon CELF-dépendante et RAB3A est surexprimé en réponse à l’inactivation de MBNL1. Les protéines MBNL et CELF régulent l’épissage alternatif d’un groupe de transcrits au cours du développement, et leur dérégulation dans la DM1 entraîne l’expression anormale d’isoformes d’épissage embryonnaires dans le tissu adulte. Dans ce contexte, j’ai étudié si les défauts des protéines RAB3A et SYN1 sont associés à une dérégulation d’épissage, et si les anomalies des protéines synaptiques identifiées dans la DM1 reproduisent des évènements embryonnaires de la régulation de RAB3A et SYN1. Mes résultats indiquent que les défauts de ces protéines dans les cerveaux adultes ne sont pas dus à une altération de l’épissage alternatif des transcrits et ne recréent pas des évènements embryonnaires. La neuropathogenèse de la DM1 va, donc, au delà de la dérégulation de l’épissage et d’autres voies moléculaires restent à explorer dans les cerveaux DM1. Afin d’identifier des sous-populations cellulaires susceptibles à l’accumulation des ARN toxiques, nous avons étudié la distribution des foci dans plusieurs régions cérébrales. (...) / Myotonic dystrophy type 1 (DM1) is a severe disorder that affects many tissues, including the central nervous system (CNS). The degree of brain impairment ranges from executive dysfunction, attention deficits, low processing speed, behavioural changes and hypersomnia in the adult form, to pronounced intellectual disability in the congenital cases. The neurological manifestations have a tremendous impact on the academic, professional, social and emotional aspects of daily life. Today there is no cure for this devastating condition. DM1 is caused by the abnormal expansion of a CTG trinucleotide repeat in the 3’UTR of the DMPK gene. Expanded DMPK transcripts accumulate in RNA aggregates (or foci) in the nucleus of DM1 cells, disrupting the activity of important RNA-binding proteins, like the MBNL and CELF families, and leading to abnormalities in alternative splicing, gene expression, RNA polyadenylation, localisation and translation. In spite of recent progress, fundamental gaps in our understanding of the molecular and cellular mechanisms behind the neurological manifestations still exist: we do not know the contribution of each cell type of the CNS to brain dysfunction, or the molecular pathways specifically deregulated in response to the CTG expansion. The aim of my PhD project has been to gain insight into these two important questions using a relevant transgenic mouse model of DM1 and cell cultures derived thereof. In my studies I used the DMSXL mice, previously generated in my host laboratory. The DMSXL mice express expanded DMPK mRNA with more than 1,000 CTG repeats. They recreate relevant DM1 features, such as RNA foci and missplicing in multiple tissues. The functional impact of expanded DMPK transcripts in the CNS of DMSXL mice translates into behavioural and cognitive abnormalities and defective synaptic plasticity. To identify the molecular mechanisms behind these abnormalities, a global proteomics analysis revealed changes in both neuron-specific and glial-specific proteins in DMSXL brain. We also investigated RNA foci in DMSXL and human DM1 brains and found non-homogenous distribution between cell types, with a higher foci content in astrocytes relative to neurons. Together these results suggest that both neuronal and glial defects contribute to DM1 neuropathogenesis. The global proteomics analysis of DMSXL brains also identified abnormalities in neuronal synaptic proteins that we have validated in human brain samples. SYN1 is hyperphosphorilated in a CELF-dependent manner while RAB3A is upregulated in association with MBNL1 depletion. CELF and MBNL proteins regulate the alternative splicing of a subset of transcripts throughout development, and their deregulation in DM1 leads to abnormal expression of fetal splicing isoforms in adult DM1 brains. In this context, I have studied if RAB3A and SYN1 deregulations observed in adult brains are associated with splicing abnormalities or if they recreated embryonic expression and phosphorylation events. My results indicate that the synaptic proteins abnormalities observed in adult DMSXL brains are not caused by defective alternative splicing and do not recreate embryonic events. Thus, DM1 neuropathogenesis goes beyond missplicing and other molecular pathways must be explored in DM1 brains. To better understand the cellular sub-populations susceptible of accumulating toxic RNA foci we have studied foci distribution in different brain regions. We identified pronounced accumulation of toxic RNAs in Bergman astrocytes of DMSXL mice cerebellum and DM1 patients, associated with neuronal hyperactivity of Purkinje cells. A quantitative proteomics analysis revealed a significant downregulation of GLT1 – a glial glutamate transporter expressed by the Bergmann cell in the cerebellum. I have confirmed the GLT1 downregulation in other brain regions of mouse and human brain. (...)

A detecção de antígenos em amostras de líquido cefalorraquiano (LCR) de pacientes com neurocisticercose (NC) foi realizada empregando-se o teste ELISA com soros policlonais de coelhos imunizados com os antígenos total de Taenia solium (T-Tso), líquido vesicular de Taenia crassiceps (LV-Tcra) e peptídeos <30kDa de LV-Tcra. Os soros policlonais foram fracionados para a obtenção da fração IgG - IgG anti-Tso, IgG antiTcra e IgG anti-Tcra<30kDa. Também foi empregado o anticorpo monoclonal específico para o antígeno de excreção e secreção de Taenia crassiceps (ES-Tcra). A seleção dos clones foi realizada por ELISA empregando-se os antígenos T-Tso e LV-Tcra. Foram analisados diferentes grupos de amostras divididos em: grupo de pacientes com NC (grupo NC), incluindo pacientes em diferentes fases evolutivas da doença, grupo de pacientes \"suspeito\" de NC (grupo \"suspeito\" NC), grupo controle (grupo C) e grupo de outros patologias (grupo OP). No teste ELISA empregando-se as frações IgG anti-Tso, IgG anti-Tcra e IgG anti-Tcra<30kDa, a sensibilidade obtida foi de 70%, 82,5% e 95,8% e a especificidade de 82,5%, 98% e 100%, respectivamente nas amostras do grupo NC e grupo C. Nas amostras do grupo diferentes fases evolutivas da doença, não houve diferença significativa de reatividade entre as amostras com as frações empregadas. Para as 21 amostras do grupo NC - fase ativa da doença, com a fração IgG anti-Tcra e o anticorpo monoclonal anti-ES-Tcra, respectivamente, 13 e 16 amostras foram positivas para a pesquisa de antígenos. As amostras de LCR do grupo C não apresentaram reatividade com os anticorpos empregados nos ensaios. Também foram ensaiadas 68 amostras de LCR de pacientes com \"suspeita\" de NC. De acordo com as características citoprotéicas além da reatividade para a pesquisa de anticorpos anti-T solium, as amostras de LCR apresentaram, neste grupo, padrão de reatividade para a pesquisa de antígenos que variou também de acordo com a presença de anticorpos, além das alterações de proteína e/ou células, que as amostras apresentavam ou não. Frações de 14 e 18kDa foram identificadas pelo teste imunoblot somente nas amostras de LCR de pacientes com NC utilizando as frações IgG anti-Tso, IgG anti-Tcra e anticorpo monoclonal anti-ES-Tcra. O anticorpo monoclonal anti-ES-Tcra mostrou-se eficiente para a pesquisa de antígenos no teste de competição por ELISA nas amostras de LCR de pacientes com NC e o antígeno ES-Tcra. / Antigen detection in cerebrospinal fluid (CSF) samples of patients with neurocysticercosis (NC) was performed through ELISA test using rabbits polyclonal sera immune with total antigens of Taenia solium (T-Tso) cysticercus, vesicular liquid of Taenia crassiceps (VL-Tcra) and vesicular liquid peptides (VLP-Tcra<30kDa) cysticercus. The polyclonal sera were separated obtaining IgG-lgG anti-Tso, IgG anti-Tcra and IgG anti-Tcra<30kDa fractions. A specific monoclonal antibody was also applied for reaching the excretion and secretion antigen of the T. crassiceps (ES-Tcra) larvae culture. Clones selection was performed through Elisa test applying the T-Tso and VL-Tcra antigens. When IgG anti-Tso, IgG anti-Tcra and IgG anti-Tcra<30kDa fractions were applied in the ELISA test, the accuracy obtained was 70%, 82,5% and 95,8% and the specificity of 82,5%, 98% and 100%, respectively, in samples of both NC and C groups. In the samples of the group in different stages of the disease there was no significant difference on reactivity between the samples when the fractions were applied. For the 21 samples of the NC group - active stage of the disease with IgG anti-Tcra fraction and the anti-ES-Tcra monoclonal antibody respectively, 13 and 16 samples were positive for antigen analyses. The CSF samples of the C group did not present reactivity with the antibodies applied in the tests. Tests for 68 CSF samples of \"suspected\" NC group, were also conducted. According to the cytoproteic characteristics besides the reactivity for the anti-T. solium antibody study, the CSF samples of this group showed standard reactivity for antigen detection ranging also in accordance with the presence of antibodies and of the protein and/or cell alterations that the samples would or not present. Fractions of 14 and 18kDa were identified by immunoblot test only in the CSF samples of patients with NC using the IgG anti-Tso IgG anti-Tcra fractions and the anti-ES-Tcra monoclonal antibody. The anti-ES-Tcra monoclonal antibody has shown to be efficient for analyzing antigens by a comparing method of the ELISA test in CSF samples of patients with NC and the ES-Tcra antigen.

Introdução e objetivos: A dor central pós-acidente vascular cerebral (DCAVC) é causada pela lesão vascular de estruturas somatossensitivas encefálicas e comumente refratária aos tratamentos farmacológicos disponíveis atualmente. A estimulação magnética transcraniana repetitiva (EMTr) do córtex pré-frontal dorsolateral (CPFDL) pode alterar o limiar da dor térmica de indivíduos saudáveis e exercer efeito analgésico na dor aguda pós-operatória e em doentes com síndrome fibromiálgica. No entanto, seu efeito na dor neuropática e na DCAVC, em particular, ainda não foi avaliado. O objetivo do presente estudo, delineado de modo prospectivo, duplamente encoberto e controlado com placebo foi o de se avaliar o efeito analgésico da EMTr do CPFDL em doentes com DCAVC. Casuística e métodos: 21 doentes foram incluídos aleatoriamente em dois grupos, os do grupo ativo (EMTr-A) e os do grupo placebo (EMTr-S) e tratados, respectivamente, com dez sessões diárias de EMTr verdadeira (EMTr-A) ou sham (EMTr-S) do CFPDL esquerdo (10 Hz, 1250 pulsos/dia). A Escala Visual Analógica (EVA), o Questionário de Dor Neuropática e o Questionário de Dor McGill foram utilizados para avaliar-se a DCAVC. A depressão, a ansiedade e a qualidade de vida foram avaliadas, respectivamente, com a Escala de Hamilton para Depressão, Escala de Hamilton para Ansiedade e o Short Form Health Survey com 36 itens. As avaliações foram realizadas antes do início do estudo, durante a fase de estimulação e uma, duas e quatro semanas após a aplicação da última sessão de EMTr-A ou EMTr-S. O desfecho principal foi a alteração da intensidade da dor medida no último dia de estimulação em relação à intensidade do seu valor basal de acordo com a EVA. Foi programada uma análise interina dos resultados ao término da avaliação da metade dos doentes programados de acordo com o protocolo de tratamento. Resultados: Os escores médios basais da EVA foram 6,86 (+/- 1,79) e 6,8 (+/- 2,20) para os doentes dos grupos EMTr-A e EMTr-S, respectivamente; a variação média da EVA após o décimo dia de estimulação foi de - 0,07 (+/- 0,24) para os doentes do grupo EMTr-A e 0,1 (+/- 0,7) para o os do grupo EMTr-S. O tamanho do efeito do tratamento foi 0,02 (d de Cohen= 0,04). O estudo foi encerrado devido à significativa falta de eficácia da EMTr-A. Conclusão: A EMTr do CPFDL esquerdo não proporcionou efeito analgésico em doentes com DCAVC / Introduction and objectives: Central post-stroke pain (CPSP) is caused by an encephalic vascular lesion of the somatosensory pathways and is refractory to current pharmacological treatments. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) can change thermal pain threshold and cause analgesia in healthy subjects and also in acute post operatory pain as well as in fibromyalgia patients. However, its effect on neuropathic pain and particularly in CPSP patients has not been assessed yet. The aim of this prospective, double blind, shamcontrolled study was to evaluate the analgesic effect of left DLPFC rTMS in CPSP patients. Patients and methods: 21 patients were randomly included in two groups: the active (A-rTMS) group and the placebo (S-rTMS) group and were treated, respectively, with 10 daily sessions of real rTMS (A-rTMS) or sham (S-rTMS) of the left DLPFC (10 Hz, 1250 pulses/day). Visual Analogue Scale (VAS), Neuropathic Pain Questionnaire and McGill Pain Questionnaire were used to evaluate the CPSP. The depression, the anxiety and the quality of life were evaluated, respectively, with the Hamilton Scale for Depression, Hamilton Scale for anxiety and the Short Form Health Survey with 36 items. Outcomes were assessed at the baseline, during the stimulation phase and at one, two and four weeks after the last session of ArTMS or S-rTMS. The main outcome was pain intensity change measured with the VAS at the last session of A-rTMS or S-rTMS, compared to the baseline. Interim analysis was scheduled when the first half of the patients have completed the study. Results: The average baseline scores of VAS were 6.86 (+/- 1.79) and 6.8 (+/- 2.20), respectively, for the groups A-rTMS and S-rTMS. The average variation of VAS after the 10th stimulation session was - 0.07 (+/- 0.24) for A-rTMS and 0.1 (+/- 0.7) to the S-rTMS group and the effect size of A-EMTr was 0.02 (Cohen\'s d= 0.04). The study was discontinued due to the significant lack of efficacy of the A-rTMS. Conclusion: Repetitive transcranial magnetic stimulation of the left DLPFC did not provide an analgesic effect in CPSP patients

Trinta e cinco pacientes com malformações arteriovenosas raquimedulares (MAVR) foram tratados por via endovascular. Foram analisados os tipos de MAVR, bem como os aspectos clínicos e angiográficos pré e pós-tratamento endovascular. As MAVR mais freqüentes foram as fístulas arteriovenosas durais (FAD), com 17 pacientes, seguidas das malformações arteriovenosas intramedulares (MAI), fístulas arteriovenosas perimedulares (FAVP) e malformações arteriovenosas metaméricas (MAVM). A avaliação do resultado do tratamento foi dividida em sucesso técnico e clínico, sendo que o primeiro foi subdividido em sucesso técnico do procedimento e do tratamento. O sucesso técnico do procedimento foi caracterizado como oclusão total da MAVR ao final de um procedimento endovascular. O sucesso técnico do tratamento foi caracterizado pela oclusão definitiva da MAVR, independentemente do número de procedimentos. A recidiva foi definida como o reaparecimento da MAVR, identificada na angiografia durante o seguimento dos pacientes, independentemente do quadro clínico apresentado. A recidiva implicava em insucesso do procedimento, mas não necessariamente do tratamento. O sucesso clínico do tratamento foi considerado como a melhora parcial ou total dos sintomas após um período mínimo de acompanhamento de 6 meses. Nas FAD, houve predomínio do sexo masculino e da faixa etária acima dos 36 anos. O tratamento endovascular das FAD mostrou sucesso do procedimento na maioria dos casos, porém com recidiva da lesão em 56,7% dos mesmos. Quando usadas partículas, observou-se recidiva em 73,3% dos procedimentos, porém com sucesso do tratamento em 66,7 dos pacientes. Quando utilizado o adesivo tissular (\"cola\"), houve recidiva em 11,1% dos procedimentos e sucesso do tratamento em 88,9% dos pacientes. A melhora clínica foi obtida em 64,7% dos pacientes. Dos 10 pacientes tratados com MAI, a faixa etária mais freqüente foi dos 19 aos 35 anos de idade e predomínio do sexo masculino. O tratamento endovascular das MAI mostrou sucesso do procedimento em 53,3% e recidiva da lesão em 6,7% dos pacientes. O sucesso do procedimento também foi superior quando usada cola, atingindo 63,6% dos procedimentos e apenas 25,0% com partículas. O sucesso do tratamento foi de 80,0% e a melhora clínica foi observada em 40,0% dos pacientes. Somente 1 paciente com MAVM foi tratado. O tratamento objetivou a embolização parcial da lesão para alívio dos sintomas, resultado que foi obtido com sucesso. Nas FAVP houve predomínio do sexo masculino e a faixa etária mais acometida foi dos 19 aos 35 anos. O tratamento endovascular das FAVP mostrou sucesso do procedimento em 75,0% dos pacientes e ausência de recidiva. O sucesso do tratamento foi de 85,7%, com melhora clínica em todos os pacientes. O nosso estudo mostrou que as MAVR podem ser tratadas de maneira eficiente e segura através da embolização. O seguimento dos pacientes tratados com cola mostrou menor índice de recidiva do que aqueles tratados com partículas. Após a embolização, houve melhora significativa no padrão da marcha nos pacientes com FAD e MAI / Endovascular treatment was used in 35 patients with spinal cord arteriovenous malformations (SCAVM). SCAVM types, along with clinical and angiographic features of pre-op and post-op endovascular treatments were analyzed. Seventeen patients had dural arteriovenous fístulas (DAVF), being this type the most frequent SCAVM, followed by intramedullary arteriovenous malformations (IAVM), perimedullary arteriovenous fístulas (PAVF) and metameric arteriovenous malformations (MAVM). Evaluation of treatment results was divided into technical and clinical success, being the first subdivided into technical success of the procedure and treatment. The procedural\'s technical success was characterized by total SCAVM occlusion at the end of an endovascular procedure. Technical success of the treatment was characterized by definitive occlusion of the SCAVM, independent of the number of procedures. Recurrence was defined as reappearance of SCAVM, identified on angiograms during patient follow up, independent of the observed clinical situation. Recurrence implied in an unsuccessful procedure but not necessarily in treatment failure. Treatment\'s clinical success was considered partial or total symptom improvement after a minimum 6 month period follow up. Male and age over 36 years was preponderate in DAVF. Endovascular treatment in DAVF had procedural success in most cases, but with lesion recurrence in 56,7% of these patients. When particulate embolic agents were used, recurrence occurred in 73,3% of the procedures but with treatment success in 66,7% of these patients. When liquid tissue adhesive was used, there was 11,1% of recurrence and 88,9% in treatment success in these patients. Clinical improvement occurred in 64,7% of these patients. Male predominance and age between 19 to 35 years was more frequent in the 10 treated patients with IAVM. IAVM endovascular treatment was a procedural success in 53,3% and lesion recurrence in 6,7% of these patients. Procedural success was also superior when liquid tissue adhesive was used, up to 63,6% of these procedures and, only 25,0% with particulate embolic agents. Treatment success occurred in 80,0% and clinical improvement seen in 40,0% of these patients. Only 1 patient with MAVM was treated. Aim in treatment was partial lesion embolization to mitigate symptoms, which was successfully achieved. Male predominance and age between 19 to 35 years occurred in PAVF. PAVF endovascular treatment had procedural success in 75,0% and no recurrences in these patients. Treatment success occurred in 85,7% and clinical improvement in all patients. This study demonstrates that SCAVM can be treated efficiently and safely with endovascular embolization. Patient follow up revealed fewer recurrences in those treated with liquid tissue adhesive than in those with particulate embolic agents. After DAVF and IAVM embolization, patients had significant improvement in their gait

A dor crônica envolve complexos processos de gênese e condução neural e é decorrente da ativação de mecanismos periféricos e centrais de manutenção. Muitos pacientes crônicos são refratários aos diferentes tipos de tratamento propostos, o que gera a suspeita de que de alguma maneira estes não estão sendo totalmente eficazes. O objetivo deste trabalho é avaliar os mecanismos de condução, manutenção e modulação da dor em diferentes condições dolorosas crônicas. Foram avaliadas 92 mulheres, divididas em 5 grupos: Grupo I, 20 pacientes com Dor Miofascial da musculatura mastigatória; Grupo II, 20 pacientes com Fibromialgia; Grupo III, 20 pacientes com Cefaleia Crônica Diária; Grupo IV, 12 pacientes com Neuralgia Trigeminal e Grupo V, 20 pacientes saudáveis assintomáticas. Foram aplicados dois questionários, o IDATE e o OHIP-30, para mensuração do estado ansioso e da qualidade de vida relacionada a condição dolorosa diagnosticada, respectivamente. Todas as pacientes foram submetidas a Testes Quantitativos Sensoriais, como: Limiar de Dor à Pressão, Limiar de Detecção Mecânico, Limiar Doloroso Mecânico, Tolerância à Dor Isquêmica, Sensibilidade Dolorosa ao Frio, Sensação Pós-Estímulo e Controle da Modulação da Dor. Além disso, um Teste Eletrodiagnóstico, que determinou o Limiar de Percepção Atual, através do uso do aparelho Neurometer CPT/C (Neurotron®) foi realizado. Foram avaliadas 3 regiões em cada paciente: trigeminal, cervical e extratrigeminal. Os dados obtidos foram submetidos à análise estatística (ANOVA, Tukey, t-Student) adotando-se um nível de significância de 5% para todos os testes. Todos os grupos experimentais apresentaram altos níveis de ansiedade e grande comprometimento da sua qualidade de vida, quando comparados ao controle. Os Grupos I, II e III apresentaram valores de Limiar de Dor à Pressão significativamente menores do que o Grupo V. As mulheres do Grupo III apresentaram Limiar de Detecção Mecânico significativamente maior do que o Grupo V. Os Grupos I, II, III e IV apresentaram valores de Limiar de Doloroso Mecânico e Tolerância à Dor Isquêmica estatisticamente menores do que o Grupo V. A capacidade de ativação do mecanismo de modulação endógeno, avaliada pelo teste de Controle de Modulação da Dor, está comprometida nas mulheres com Dor Miofascial e Fibromialgia. Não houve diferença estatisticamente significante no Limiar de Percepção Atual (CPT) entre os Grupos I, II, III e V. Pacientes do Grupo IV apresentaram CPT para a frequência de 5Hz significativamente menor do que as do Grupo V na região trigeminal, indicando uma hiperestesia de origem inflamatória no nervo trigêmeo, caracterizando-se a dor neuropática. Ainda, de acordo com os resultados encontrados, os Grupos I, II e III parecem dividir um mecanismo de dor e etiologia semelhantes, não apresentando danos às estruturas neurais e sim uma alteração no processamento e modulação do impulso nociceptivo, caracterizando-se uma dor disfuncional. Os resultados deste estudo mostraram evidências da presença do processo de sensibilização central e prejuízo no mecanismo de modulação endógeno em pacientes com Dor Miofascial, Fibromialgia e Cefaleia Crônica Diária. / Chronic pain involves complex processes of genesis and neural conduction due to activation of peripheral and central mechanisms of pain maintenance. Many chronic patients are refractory to different types of treatment, which leads to the suspicion that somehow they are not fully effective and probably some mechanism of pain generation and/or maintenance is still unknown. Based on that, the aim of the present study is to evaluate the mechanisms of conduction, maintenance and pain modulation in patients with different types of chronic pain conditions. Ninety two women were evaluated, divided into 5 groups: Group I, 20 patients with Myofascial Pain of the masticatory muscles; Group II, 20 patients with Fibromyalgia; Group III, 20 patients with Chronic Daily Headache; Group IV, 12 patients with Trigeminal Neuralgia and Group V, 20 healthy asymptomatic patients. Two questionnaires were used, the STAI and the OHIP-30, to measure state anxiety and quality of life related to painful condition diagnosed, respectively. All patients underwent Quantitative Sensory Tests such as: Pressure Pain Threshold, Mechanical Detection Threshold, Mechanical Pain Threshold, Ischemic Pain Tolerance, Cold Pain Sensitivity, After- Sensation and Control Pain Modulation. An Electrodiagnostic Test, the Current Perception Threshold, using the apparatus Neurometer CPT/C (Neurotron®) was also performed. Three different regions were evaluated for each patient, for each test: trigeminal, cervical and extratrigeminal. Data were gathered and subjected to statistical analysis (ANOVA, Tukey, t-Student), adopting a significance level of 5% for all tests. All patients had high levels of anxiety and greater impairment of their quality of life, when compared to controls. Groups I, II and III showed significantly lower values of Pressure Pain Threshold than Group V. Group III had a significantly higher Mechanical Detection Threshold than Group V. Groups I, II, III and IV showed statistically lower values for Mechanical Pain Threshold and Ischemic Pain Tolerance than Group V. The ability to activate the mechanism of endogenous modulation, evaluated with the Controled Pain Modulation test, is impaired in women with Fibromyalgia and Myofascial Pain. There was no significant differences in the Current Perception Threshold (CPT) between Groups I, II, III and V. Group IV showed a CPT to 5 Hz frequency significantly lower than Group V for the trigeminal region, indicating an hyperesthesic condition due to inflammation of the trigeminal nerve, characterizing neuropathic pain. According to the results, Groups I, II and III seem to share a common pain mechanism and similar etiology, with no significant damage to neural structures but a change in the processing and modulation of nociceptive stimuli, characterizing a dysfunctional pain. The results of this study showed evidence of the presence of central sensitization process and impaired endogenous modulation system in patients with Myofascial Pain, Fibromyalgia and Chronic Daily Headache.

Hung, Sze Man. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 186-192). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese.

Recentes evidências sugerem que a dor lombar crônica está associada a alterações plásticas no cérebro, que podem ser modificadas por estratégias de neuromodulação. Neste ensaio clínico investigamos a eficácia analgésica de 12 sessões não consecutivas de estimulação transcraniana por corrente contínua (ETCC), estimulação elétrica periférica (EEP), ETCC+EEP e estimulação simulada (sham) em 92 pacientes com dor lombar crônica inespecífica. A intensidade, aspecto sensorial e afetivo da dor, incapacidade e percepção global de recuperação foram avaliadas antes do tratamento e quatro semanas, três e seis meses pós-randomização. Efeitos adversos, satisfação do paciente com o tratamento e fatores de confusão como ansiedade e depressão também foram avaliados. Os resultados demonstraram efeitos analgésicos clinicamente importantes da ETCC+EEP (MD = -2,6 IC95% = -4,4 a -0,9) e EEP isolada (MD = -2,2 IC95% = -3,9 a -0,4) comparada ao grupo sham, mas não da ETCC isolada (MD = -1,7 IC95% = -3,4 a -0,0). Além da manutenção do efeito analgésico por até três meses a ETCC+EEP obteve maior proporção de respondedores em diferentes pontos de corte. Os resultados sugerem que tanto a ETCC+EEP quanto EEP isolada são eficazes em curto prazo para o alívio da dor lombar crônica inespecífica. No entanto o efeito analgésico mais duradouro aliado a maior proporção de respondedores indicam um possível efeito aditivo e sinérgico da ETCC+EEP no alívio da dor em pacientes com dor lombar crônica não específica. Os nossos resultados não apoiam o uso da ETCC no regime de tratamento utilizado / Recent evidence suggests that chronic low back pain is associated with plastic changes in the brain that can be modified by neuromodulation strategies. In this clinical trial we have investigated the analgesic efficacy of 12 non-consecutive sessions of transcranial direct current stimulation (tDCS), peripheral electrical stimulation (PES), tDCS+PES and sham stimulation in 92 patients with chronic nonspecific low back pain. Intensity, the sensory and affective aspect of pain, disability, and overall perception of recovery were assessed before treatment and four weeks, three and six months post-randomization. Adverse effects, patient satisfaction with treatment and confounding factors such as anxiety and depression were also evaluated. The results showed clinically significant analgesic effects of tDCS+PES (Mean Reduction (MR) = -2.6; CI95% = -4.4 to - 0.9) and PES alone (MD = -2.2, CI95% = -3.9 to -0.4) compared to sham group, but not tDCS alone (MD = -1.7, CI95% = -3.4 to -0.0). In addition to maintaining the analgesic effect for up to three months, tDCS+PES treatment had a higher proportion of responders in different cutoff points. The results suggest that both tDCS+PES and PES alone are effective in relieving chronic nonspecific low back pain in the short term. However the most lasting analgesic effect, combined with a higher proportion of responders, indicates a possible additive and synergistic effect of tDCS+PES in relieving low back pain. Our findings do not support the use of tDCS alone in this condition

INTRODUÇÃO: A dosagem bioquímica do lactato no líquor (LCR) é um procedimento rotineiro e necessário na investigação diagnóstica e no acompanhamento evolutivo de várias doenças neurológicas, como, por exemplo, as doenças mitocondriais (DM). Pacientes com DM e comprometimento do sistema nervoso central frequentemente apresentam aumento do lactato no LCR. O lactato no LCR também pode ser detectado através da espectroscopia de prótons através da ressonância magnética (ERM), uma técnica não invasiva que pode ser empregada juntamente com as imagens estruturais obtidas através da ressonância magnética (RM). Nosso objetivo neste estudo é avaliar a existência ou não de correlação entre a dosagem bioquímica do lactato no LCR e no sangue e a sua quantificação através da ERM em pacientes em investigação de encefalopatia mitocondrial. Não é de nosso conhecimento a existência de estudos semelhantes in vivo na literatura médica. MÉTODOS: 22 pacientes (idades entre 9 meses e 20 anos) em investigação diagnóstica por suspeita clínica de encefalopatia relacionada a DM participara deste estudo prospectivo realizado entre novembro de 2005 a novembro de 2006. Foram comparados os valores do lactato nas dosagens séricas e liquóricas. Todos os pacientes realizaram RM e ERM e, quando presente, analisou-se o pico do lactato (PL). Os dados da quantificação do lactato obtidos nestas três modalidades foram comparados. RESULTADOS: A análise de correlação demonstrou evidências de associação entre as variáveis PL à ERM e lactato liquórico (p=0,001); não foi evidenciada correlação entre os valores do PL à ERM e as medidas sanguíneas dessa substância (p=0,736) e entre as dosagens bioquímicas liquórica e sanguínea (p=0,937). CONCLUSÕES: Este estudo demonstrou a existência de correlação entre a dosagem bioquímica do lactato no LCR e o PL obtido através de ERM. A ERM do LCR é uma técnica factível e recomendamos que a mesma seja empregada rotineiramente em pacientes com suspeita ou em seguimento de DM com comprometimento do sistema nervoso central. / INTRODUCTION: The cerebrospinal fluid (CSF) lactate biochemical dosage is a routine and a requisite procedure to evaluate and to monitor many neurological diseases, such as mitochondrial disease (MD). Patients with MD and central nervous system (CNS) involvement, usually show an increase of CSF lactate. Another choice to study the lactate instead of CSF biochemical dosage is the CSF magnetic resonance proton spectroscopy (SRM), a noninvasive technique, which can be employed as an adjunct tool with structural magnetic resonance imaging (MRI). Our objective is to study the correlation between the CSF and blood lactate dosages and the SRM lactate quantification in patients under investigation for the MD encephalopathy. To our knowledge there is no report of similar studies in vivo in the literature. METHODS: 22 patients (aging 9 months to 20 years old) under investigation for MD encephalopathy were elected for this prospective study between November 2005 and December 2006. The lactate levels were analyzed by biochemical dosages in the CSF and blood serum. Brain MRI was performed for all patients and the lactate peak (LP) obtained from SRM was analyzed. All lactate level data obtained from the three different sources were compared. RESULTS: The statistical analysis demonstrated a correlation between the LP at SRM and the CSF lactate dosage (p=0.0001); no correlation was observed between the LP and the blood lactate (p=0.736) as well the blood lactate and CSF lactate (p=0.937). CONCLUSION: Our study showed correlation between the lactate level in the CSF biochemical dosage and the LP found on SRM. The CSF SRM is tangible technique and we recommend it to be applied in the daily clinical practice to evaluate suspicious and diagnosed CNS compromised ME patients.

No description available.

Brain stroke is considered as one of the three diseases that threaten human health all over the world. Hypertension and cerebral arteriosclerosis are thought to be the most dangerous risk factors of brain stroke, and they frequently occur together, leading to ischemia of brain tissue. Unfortunately, it is not clear whether the pathological changes resulting from hypertension are related to those resulting from cerebral arteriosclerosis. There have been no ideal animal models mimicking the pathological changes in such a combined condition. In this thesis, an animal model of hypertension combined with cerebral arteriosclerosis in rats was established by occlusion of both the left and right common carotid arteries in spontaneous hypertension rats. Pien Tze Huang (PTH), a reputed traditional Chinese medicinal complex, contains Radix notoginseng, snake bile, calculus bovis, and musk and some other components that are known to protect vessels and cells from injuries. Since different tissue injuries share many common cellular mechanisms, the protection by PTH to in nerves and the circulation systems may also be benefical to cerebrovascular conditions as well. In present experiments, PTH was used to treat hypertension rats that also developed chronic brain ischemia as a result of the bilateral carotid occlusion, and its protective role for neurons and blood vessels was investiaged. / From the data above, more severe damage could be caused by hypertension combined with chronic ischemia. The model of SHR with bilaterally occluded common carotid artery can be used to study pathological changes resulted from hypertension combined with chronic ischemia. PTH was able to protect neurons in stroke. / In the initial part of the work, patients from clinics in two cities in South and North China were compared and analysed; they had been suffering from brain ischemic stroke. About two thirds of the stroke patients were found to have hypertension before the onset of stroke. Their prognosis was significantly worse than those stroke patients without hypertension. In the hypertensive rats with occluded arteries, mean of functional magnetic resonance imaging (fMRI) examination showed that brain blood flow was very weak or even transiently became undetectable at the beginning of the acute stage of brain ischemia, but was restored one hour after the occlusion surgery. In addition, pathological changes in brains of hypertensive rats with induced brain ischemia (carotid occlusion) were examined by Nissl staining, TUNEL staining, cell death ELISA and anti-oxidation enzymes. At day 15 after ischemia, a large number of pyramid cells in the hippocampus of SHR were lost and a great deal of apoptotic cells were found in the CA1 of the hippocampus, while activities of some enzyme including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) were increased. At day 30 and 60, some degenerative changes appeared to have subsided and the cells appeared morphologically normal. The activities of the above enzymes were also decreased at day 60. In WKY control rats with normal blood pressure, neurons in the CA1 were found less damaged after the bilateral carotid occlusion. It was found that apoptotic and dead cells were significantly reduced in rats with hypertension combined with chronic brain ischemia if they had been pre-treated with PTH. Moreover, brain stroke damage was less severe in this pretreated rats. / Zhang, Lihong. / "March 2010." / Adviser: WH Kwong. / Source: Dissertation Abstracts International, Volume: 72-01, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 116-134). / 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. / Abstract also in Chinese.