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1.
Brain ; 145(6): 1962-1977, 2022 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34957478

RESUMO

Focal cortical dysplasia is a highly epileptogenic cortical malformation with few treatment options. Here, we generated human cortical organoids from patients with focal cortical dysplasia type II. Using this human model, we mimicked some focal cortical dysplasia hallmarks, such as impaired cell proliferation, the presence of dysmorphic neurons and balloon cells, and neuronal network hyperexcitability. Furthermore, we observed alterations in the adherens junctions zonula occludens-1 and partitioning defective 3, reduced polarization of the actin cytoskeleton, and fewer synaptic puncta. Focal cortical dysplasia cortical organoids showed downregulation of the small GTPase RHOA, a finding that was confirmed in brain tissue resected from these patients. Functionally, both spontaneous and optogenetically-evoked electrical activity revealed hyperexcitability and enhanced network connectivity in focal cortical dysplasia organoids. Taken together, our findings suggest a ventricular zone instability in tissue cohesion of neuroepithelial cells, leading to a maturational arrest of progenitors or newborn neurons, which may predispose to cellular and functional immaturity and compromise the formation of neural networks in focal cortical dysplasia.


Assuntos
Epilepsia , Malformações do Desenvolvimento Cortical do Grupo I , Malformações do Desenvolvimento Cortical , Encéfalo , Humanos , Recém-Nascido , Neurônios
2.
Epilepsia ; 62(6): 1416-1428, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33949696

RESUMO

OBJECTIVE: Focal cortical dysplasia (FCD) is a major cause of difficult-to-treat epilepsy in children and young adults, and the diagnosis is currently based on microscopic review of surgical brain tissue using the International League Against Epilepsy classification scheme of 2011. We developed an iterative histopathological agreement trial with genetic testing to identify areas of diagnostic challenges in this widely used classification scheme. METHODS: Four web-based digital pathology trials were completed by 20 neuropathologists from 15 countries using a consecutive series of 196 surgical tissue blocks obtained from 22 epilepsy patients at a single center. Five independent genetic laboratories performed screening or validation sequencing of FCD-relevant genes in paired brain and blood samples from the same 22 epilepsy patients. RESULTS: Histopathology agreement based solely on hematoxylin and eosin stainings was low in Round 1, and gradually increased by adding a panel of immunostainings in Round 2 and the Delphi consensus method in Round 3. Interobserver agreement was good in Round 4 (kappa = .65), when the results of genetic tests were disclosed, namely, MTOR, AKT3, and SLC35A2 brain somatic mutations in five cases and germline mutations in DEPDC5 and NPRL3 in two cases. SIGNIFICANCE: The diagnoses of FCD 1 and 3 subtypes remained most challenging and were often difficult to differentiate from a normal homotypic or heterotypic cortical architecture. Immunohistochemistry was helpful, however, to confirm the diagnosis of FCD or no lesion. We observed a genotype-phenotype association for brain somatic mutations in SLC35A2 in two cases with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Our results suggest that the current FCD classification should recognize a panel of immunohistochemical stainings for a better histopathological workup and definition of FCD subtypes. We also propose adding the level of genetic findings to obtain a comprehensive, reliable, and integrative genotype-phenotype diagnosis in the near future.


Assuntos
Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Malformações do Desenvolvimento Cortical/patologia , Adolescente , Adulto , Idade de Início , Diversidade de Anticorpos , Encéfalo/patologia , Criança , Pré-Escolar , Técnica Delphi , Feminino , Genótipo , Humanos , Imuno-Histoquímica , Lactente , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/cirurgia , Pessoa de Meia-Idade , Mutação/genética , Procedimentos Neurocirúrgicos , Variações Dependentes do Observador , Fenótipo , Convulsões/etiologia , Adulto Jovem
3.
Ann Neurol ; 83(3): 623-635, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29461643

RESUMO

OBJECTIVE: Focal cortical dysplasias (FCDs) are an important cause of drug-resistant epilepsy. In this work, we aimed to investigate whether abnormal gene regulation, mediated by microRNA, could be involved in FCD type II. METHODS: We used total RNA from the brain tissue of 16 patients with FCD type II and 28 controls. MicroRNA expression was initially assessed by microarray. Quantitative polymerase chain reaction, in situ hybridization, luciferase reporter assays, and deep sequencing for genes in the mTOR pathway were performed to validate and further explore our initial study. RESULTS: hsa-let-7f (p = 0.039), hsa-miR-31 (p = 0.0078), and hsa-miR34a (p = 0.021) were downregulated in FCD type II, whereas a transcription factor involved in neuronal and glial fate specification, NEUROG2 (p < 0.05), was upregulated. We also found that the RND2 gene, a NEUROG2-target, is upregulated (p < 0.001). In vitro experiments showed that hsa-miR-34a downregulates NEUROG2 by binding to its 5'-untranslated region. Moreover, we observed strong nuclear expression of NEUROG2 in balloon cells and dysmorphic neurons and found that 28.5% of our patients presented brain somatic mutations in genes of the mTOR pathway. INTERPRETATION: Our findings suggest a new molecular mechanism, in which NEUROG2 has a pivotal and central role in the pathogenesis of FCD type II. In this way, we found that the downregulation of hsa-miR-34a leads to upregulation of NEUROG2, and consequently to overexpression of the RND2 gene. These findings indicate that a faulty coupling in neuronal differentiation and migration mechanisms may explain the presence of aberrant cells and complete dyslamination in FCD type II. Ann Neurol 2018;83:623-635.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Epilepsia/metabolismo , Hipoplasia Dérmica Focal/metabolismo , Malformações do Desenvolvimento Cortical/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/genética , Epilepsia/tratamento farmacológico , Epilepsia/genética , Feminino , Hipoplasia Dérmica Focal/genética , Humanos , Lactente , Masculino , Neurônios/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética , Adulto Jovem , Proteínas rho de Ligação ao GTP/metabolismo
4.
J. pediatr. (Rio J.) ; 92(2): 143-148, Mar.-Apr. 2016. tab
Artigo em Inglês | LILACS | ID: lil-779894

RESUMO

Abstract Objective: To verify the psychometric properties of the Cerebral Palsy: Quality of Life Questionnaire Children – child report (CPQol-Child) questionnaire, after it was translated and culturally adapted into Brazilian Portuguese. Methods: After the translation and cultural adaptation of the tool into Brazilian Portuguese, the questionnaire was answered by 65 children with cerebral palsy, aged 9–12 years. The intraclass correlation coefficient and Cronbach's alpha were used to assess the reliability and internal consistency of the tool and its validity was analyzed through the association between CPQol-Child: self-report tool and Kidscreen-10 using Pearson's correlation coefficient. Results: Internal consistency ranged from 0.6579 to 0.8861, the intraobserver reliability from 0.405 to 0.894, and the interobserver from 0.537 to 0.937. There was a weak correlation between the participation domain and physical health of CPQol-Child: self-report tool and Kidscreen-10. Conclusion: The analysis suggests that the tool has psychometric acceptability for the Brazilian population.


Resumo Objetivo: Verificar as propriedades psicométricas da versão traduzida e adaptada culturalmente para o português do Brasil do instrumento Cerebral Palsy Quality of Life Questionnaire for Children – Child report. Métodos: Após a tradução e a adaptação cultural do instrumento para o português, o questionário foi respondido por 65 crianças com paralisia cerebral, entre nove e 12 anos. Os coeficientes de correlação intraclasse e alfa de Cronbach foram usados para avaliar a confiabilidade e consistência interna do instrumento e a validade do instrumento foi analisada pela relação entre CPQol-Child: self-report toole a Kidscreen-10 por meio do coeficiente de correlação de Pearson. Resultados: A consistência interna variou de 0,6579 a 0,8861, a confiabilidade intraobservador de 0,405 a 0,894 e a interobservador de 0,537 a 0,937. Verificou-se uma fraca correlação entre o domínio participação e saúde física da CPQol-Child e Kidscreen-10. Conclusão: A análise feita sugere que o instrumento usado tem aceitabilidade psicométrica para a população brasileira.


Assuntos
Humanos , Masculino , Feminino , Criança , Qualidade de Vida , Paralisia Cerebral/psicologia , Inquéritos e Questionários , Psicometria , Traduções , Índice de Gravidade de Doença , Brasil , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Características Culturais
5.
J Pediatr (Rio J) ; 92(2): 143-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26699433

RESUMO

OBJECTIVE: To verify the psychometric properties of the Cerebral Palsy: Quality of Life Questionnaire Children - child report (CPQol-Child) questionnaire, after it was translated and culturally adapted into Brazilian Portuguese. METHODS: After the translation and cultural adaptation of the tool into Brazilian Portuguese, the questionnaire was answered by 65 children with cerebral palsy, aged 9-12 years. The intraclass correlation coefficient and Cronbach's alpha were used to assess the reliability and internal consistency of the tool and its validity was analyzed through the association between CPQol-Child: self-report tool and Kidscreen-10 using Pearson's correlation coefficient. RESULTS: Internal consistency ranged from 0.6579 to 0.8861, the intraobserver reliability from 0.405 to 0.894, and the interobserver from 0.537 to 0.937. There was a weak correlation between the participation domain and physical health of CPQol-Child: self-report tool and Kidscreen-10. CONCLUSION: The analysis suggests that the tool has psychometric acceptability for the Brazilian population.


Assuntos
Paralisia Cerebral/psicologia , Qualidade de Vida , Inquéritos e Questionários , Brasil , Criança , Características Culturais , Feminino , Humanos , Masculino , Variações Dependentes do Observador , Psicometria , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Traduções
6.
Rev. Inst. Med. Trop. Säo Paulo ; 41(2): 131-7, mar.-abr. 1999. ilus
Artigo em Inglês | LILACS | ID: lil-236056

RESUMO

Casos de hantavirose foram notificados em diferentes regioes do Estado de Sao Paulo (SP), Brasil, durante o primeiro semestre de 1998. Dois casos fatais de sindrome pulmonar ocorreram em maio de 1998 na Cidade de Guariba, localizada na Regiao Nordeste de SP. Ambos os pacientes trabalhavam no mesmo local, estocando milho em um paiol infestado de roedores. Este pacientes, apos 2 ou 3 dias de doenca febril aguda inespecifica, desenvolveram uma grave pneumonia intersticial, que espalhou-se difusamente por ambos os pulmoes causando insuficiencia respiratoria e obito. A autopsia, ambos os casos apresentavam edema pulmonar intersticial com infiltrado de celulas mononucleares (imunoblastos) sugestivo de etiologia viral...


Assuntos
Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Orthohantavírus/isolamento & purificação , Infecções por Hantavirus/diagnóstico , Síndrome Pulmonar por Hantavirus/diagnóstico , Mudança Climática , Brasil , Conservação dos Recursos Naturais , Infecções por Hantavirus/epidemiologia , Radiografia Torácica , Trabalhadores Rurais , Testes Sorológicos , Síndrome Pulmonar por Hantavirus/epidemiologia , Síndromes da Dor Miofascial/etiologia
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