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1.
Brasília; CONITEC; nov. 2020.
No convencional en Portugués | BRISA/RedTESA | ID: biblio-1145537

RESUMEN

INTRODUÇÃO: Esclerose múltipla (EM) é uma doença neurológica crônica, inflamatória, que ocorre em pessoas geneticamente suscetíveis. A doença é caracterizada por infiltração de células imunes, perda de mielina e axônios e formação de placas multifocais no cérebro e medula espinhal. A prevalência média global da EM é de 33 por 100.000 pessoas, com variação entre os diferentes países. As taxas de prevalência no Brasil variaram de 1,36/100.000 a 27,2/100.000 habitantes dependendo da região. A espasticidade, percebida pelos pacientes como rigidez e espasmos musculares, é um sintoma comum na EM e está associado ao comprometimento funcional que pode exacerbar outros sintomas e reduzir a qualidade de vida. A espasticidade ocorre entre 60 a 84% dos pacientes, sendo os sintomas mais comuns associados: rigidez, espasmos e restrições de mobilidade, que ocorrem em cerca de três quartos dos pacientes, avaliados pelos médicos. Outros sintomas comuns incluem fadiga, dor e disfunção da bexiga. O tratamento não farmacológico geralmente inclui evitar fatores desencadeantes e fisioterapia regular. No Sistema Único de Saúde (SUS) está disponível para tratamento da espasticidade, de acordo com o Protocolo Clínico e Diretrizes Terapêuticas de Espasticidade, duas apresentações de toxina botulínica tipo A. A literatura descreve outros tratamentos como baclofeno, tizanidina e gabapentina. PERGUNTA: Tetraidrocanabinol + canabidiol (Mevatyl®) é eficaz e seguro para o tratamento da espasticidade moderada à grave associada à EM em pacientes adultos? EVIDÊNCIAS CLÍNICAS: Após a análise das evidências apresentadas pelo demandante foram incluídos sete ensaios clínicos, uma análise derivada de ensaio clínico e uma revisão sistemática. O demandante apresentou uma meta-análise, no entanto, como alguns estudos permitiram doses superiores a 12 sprays/dia, mesmo que a dose média dos estudos tenha sido menor que a estabelecida em bula, a Secretaria Executiva da Conitec optou por refazer as análises separando estes estudos. Em todas as avaliações, o THC:CBD foi associado a uma melhora média maior da espasticidade quando avaliada pela escala de Ashworth em comparação com o placebo, mão não foi estatisticamente significativo. Quando avaliada pela escala subjetiva foi associado a uma melhora significativa. Adicionalmente, o THC:CBD proporcionou uma redução significativa de ≥ 30% no escore de espasticidade avaliada pela escala NRS, considerada uma diferença clinicamente importante. A evidência foi considerada de baixa qualidade. AVALIAÇÃO ECONÔMICA: Com o preço proposto para incorporação de R$ 1.445,24, o custo mensal de THC:CBD como adjuvante a terapia padrão seria de R$ 1.597,36. Foi estimado um ganho de 0,55 anos de vida ajustados pela qualidade a mais com o tratamento com THC:CBD comparado ao tratamento padrão isolado, e 1,98 meses de controle da doença a mais que a terapia padrão. O custo incremental do tratamento com THC:CBD ao longo de 30 anos foi estimado em R$ 11.724,82 a mais que o custo do tratamento padrão, resultando em uma RCEI de R$21.271,79/QALY. O custo incremental por mês de controle da doença foi de R$ 5.438,76, resultando em uma RCEI de R$2.743,29/mês de espasticidade controlada. Há incertezas no desfecho por QALY pois a na estimativa da utilidade não incluiu população brasileira. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O demandante estimou que entre 823 a 859 pacientes seriam elegíveis e teriam acesso ao medicamento em cinco anos, com impacto orçamentário ao SUS estimado entre R$ 1,3 milhões, chegando a R$ 9,1 milhões no último ano dependendo da difusão de mercado adotada (Caso-base: 10% ao ano e Caso-alternativo: primeiro ano de 25%, com crescimento de 10% ao ano até 65% em 5 anos). Entretanto, foram identificadas algumas discrepâncias na população do modelo apresentado pelo demandante, com a população passando para 918 no primeiro ano a 958 no quinto ano. O impacto orçamentário utilizando a distribuição de mercado do caso-base, no primeiro ano seria de R$ 1,49 milhão, chegando a R$ 7,8 milhões em cinco anos. Já para o cenário do caso alternativo, no primeiro ano o impacto seria de 3,7 milhões e no quinto ano, com 65% dos pacientes recebendo o tratamento, 10,14 milhões. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Para a elaboração desta seção, realizaram-se buscas estruturadas nos campos de pesquisa das bases de dados ClinicalTrials.gov e Cortellis™, a fim de localizar medicamentos potenciais para tratamento sintomático da espasticidade moderada a grave relacionada à esclerose múltipla. Dessa forma, foram detectados dois medicamentos potenciais para a indicação terapêutica em questão, o arbaclofeno e o dronabinol. CONSIDERAÇÕES FINAIS: O THC:CBD proporciona uma diminuição da espasticidade subjetiva quando comparados com placebo, mas não apresentou nenhuma alteração na espasticidade medida objetivamente (escalas de Ashworth e Ashworth modificada). Embora o número total de eventos adversos seja maior que o placebo, o medicamento foi seguro no tratamento da espasticidade em pacientes com EM. As evidências foram consideradas de baixa qualidade. Não há evidências de estudos que avaliem a eficácia de canabinoides em comparação com outros tratamentos ativos. RECOMENDAÇÃO PRELIMINAR DA CONITEC: No dia 06 de agosto de 2020, em sua 89ª reunião de plenário, os membros da Conitec recomendaram preliminarmente a não incorporação da associação tetraidrocanabinol + canabidiol como tratamento adjuvante para melhoria dos sintomas de pacientes adultos com espasticidade moderada a grave devido à esclerose múltipla que não responderam adequadamente a outra terapia. O plenário considerou que o medicamento só apresentou benefício quando avaliado por escala subjetiva e a ausência de eficácia do fitofármaco na redução da espasticidade por escala objetiva comparado ao placebo, além disso os estudos apresentaram médio a alto risco de viés, o que tornou a evidência de baixa qualidade. A matéria foi disponibilizada em consulta pública. CONSULTA PÚBLICA: o Relatório de Recomendação da Conitec foi disponibilizado por meio da Consulta Pública nº 04/2020 entre os dias 15/09/2020 e 05/10/2020. Foram recebidas 306 contribuições, sendo 4 técnico-científicas e 302 contribuições de experiência ou opinião. Os principais temas presentes nas contribuições de experiência e opinião foram referentes a: eficácia; qualidade de vida; melhora da dor e segurança do tratamento. Foram recebidas referências estudos científicos, no entanto não foram consideradas no presente documento por não se enquadrarem na pergunta PICO. A Beaufour Ipsen Ltda - empresa fabricante da tecnologia avaliada reforçou os dados de eficácia do THC:CBD na redução da gravidade da espasticidade relacionada à EM e sintomas associados, como espasmos ou distúrbios do sono. Também abordaram a validade da escala NRS, por se tratar de muitas vezes ser desfecho primário dos estudos clínicos, incluindo ensaios controlados e de vida real e se tratar de um desfecho centrado no paciente com relevância clínica. Com relação a parte econômica, o demandante retrata que realizou vários cenários na avaliação de custo-efetividade: 1) inclusão de probabilidade e de custos relacionados a eventos adversos; 2) utilização do desfecho clínico NRS ≥ 30% (diferença clinicamente importante); 3) sub análise considerando o fornecimento gratuito de Mevatyl® no primeiro mês de tratamento; 5) comparador baclofeno, tizanidina e diazepam. No entanto, de modo geral, os resultados sofreram poucas alterações em relação àquelas apresentadas no documento de submissão. RECOMENDAÇÃO FINAL DA CONITEC: Os membros da Conitec presentes na 92ª reunião ordinária, no dia 03 de novembro de 2020, deliberaram por unanimidade recomendar a não incorporação tetraidrocanabinol (THC) 27 mg/ml + canabidiol (CBD) 25 mg/ml como tratamento adjuvante para melhoria dos sintomas de pacientes adultos com espasticidade moderada a grave devido à esclerose múltipla que não responderam adequadamente a outra terapia. Os membros presentes na reunião consideraram que não houve evidências adicionais para mudar a recomendação preliminar e que ainda há incertezas sobre a eficácia do fitofármaco. Também foi pontuado que existem outros tratamentos para espasticidade, assim há uma necessidade de avaliação ampla dessas tecnologias. Foi assinado o Registro de Deliberação nº 572/2020. DECISÃO: Não incorporar o tetraidrocanabinol 27mg/ml + canabidiol 25mg/ml para o tratamento sintomático da espasticidade moderada a grave relacionada à esclerose múltipla, no âmbito do Sistema Único de Saúde - SUS, conforme Portaria nº 59, publicada no Diário Oficial da União nº 228, seção 1, página 717, em 1º de dezembro de 2020.


Asunto(s)
Humanos , Dronabinol/uso terapéutico , Cannabidiol/uso terapéutico , Esclerosis Múltiple/etiología , Espasticidad Muscular/tratamiento farmacológico , Evaluación de la Tecnología Biomédica , Sistema Único de Salud , Brasil , Análisis Costo-Beneficio/economía
2.
Brain Nerve ; 72(10): 1079-1083, 2020 Oct.
Artículo en Japonés | MEDLINE | ID: mdl-33051396

RESUMEN

Coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 has become a global pandemic. Neuroimmunological diseases, such as multiple sclerosis, neuromyelitis optica spectrum disorders, and myasthenia gravis, require long-term immunotherapies having the potential to increase the risk of infection. However, there are no evidence-based guidelines for the management of these disease during the pandemic, despite increasing concerns in patients and neurologists. Currently, there is no evidence of an elevated risk of morbidity and aggravation of COVID-19 in patients with these diseases, irrespective of whether they receive treatment. To prevent relapse or aggravation of the underlying diseases due to COVID-19, all patients should perform general preventive measures, such as social distancing, frequent hand washing, and respiratory hygiene. In patients undergoing immunotherapy, current treatment should be continued to prevent exacerbation of symptoms; however, exceptions to this include high-risk patients for COVID-19, such as the elderly, those with comorbidities including cardiac and respiratory diseases, those taking therapy with immunosuppressive agents, and those with deteriorating symptoms of COVID-19.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus , Esclerosis Múltiple , Miastenia Gravis , Neuromielitis Óptica , Pandemias , Neumonía Viral , Infecciones por Coronavirus/complicaciones , Humanos , Esclerosis Múltiple/etiología , Miastenia Gravis/etiología , Neuromielitis Óptica/etiología , Neumonía Viral/complicaciones
3.
Mol Neurobiol ; 57(12): 5263-5275, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32869183

RESUMEN

Similar to its predecessors, coronavirus disease 2019 (COVID-19) exhibits neurotrophic properties, which lead to progression of neurologic sequelae. Besides direct viral invasion to the central nervous system (CNS), indirect CNS involvement through viral-mediated immune response is plausible. Aberrant immune pathways such as extreme release of cytokines (cytokine storm), autoimmunity mediated by cross-reactivity between CNS components and viral particles, and microglial activation propagate CNS damage in these patients. Here, we review the currently available evidence to discuss the plausible immunologic pathways that may contribute to the development of COVID-19 neurological complications, namely Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis, Guillain-Barre syndrome, seizure, and brainstem involvement.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/complicaciones , Enfermedades del Sistema Nervioso/etiología , Pandemias , Neumonía Viral/complicaciones , Animales , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , Tronco Encefálico/fisiopatología , Tronco Encefálico/virología , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/inmunología , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/inmunología , Efecto Citopatogénico Viral , Brotes de Enfermedades , Síndrome de Guillain-Barré/etiología , Síndrome de Guillain-Barré/inmunología , Humanos , Ratones , Esclerosis Múltiple/etiología , Esclerosis Múltiple/inmunología , Proteínas del Tejido Nervioso/fisiología , Enfermedades del Sistema Nervioso/inmunología , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/inmunología , Neuroglía/patología , Neuroglía/virología , Neuronas/patología , Neuronas/virología , Peptidil-Dipeptidasa A/fisiología , Neumonía Viral/inmunología , Receptores Virales/fisiología , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/fisiopatología , Convulsiones/etiología , Convulsiones/inmunología , Síndrome Respiratorio Agudo Grave/complicaciones , Síndrome Respiratorio Agudo Grave/epidemiología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/inmunología
4.
Sci Rep ; 10(1): 7770, 2020 05 08.
Artículo en Inglés | MEDLINE | ID: mdl-32385326

RESUMEN

A burgeoning number of studies are demonstrating aluminium in human brain tissue. While research has both quantified and imaged aluminium in human brain tissue in neurodegenerative and neurodevelopmental disease there are few similar data for brain tissue from non-neurologically impaired donors. We have used microwave assisted acid digestion and transversely heated graphite furnace atomic absorption spectrometry to measure aluminium in twenty brains from donors without recognisable neurodegenerative disease. The aluminium content of 191 tissue samples was invariably low with over 80% of tissues having an aluminium content below 1.0 µg/g dry weight of tissue. The data for these control tissues were compared with data (measured using identical procedures) for sporadic Alzheimer's disease, familial Alzheimer's disease, autism spectrum disorder and multiple sclerosis. Detailed statistical analyses showed that aluminium was significantly increased in each of these disease groups compared to control tissues. We have confirmed previous conclusions that the aluminium content of brain tissue in Alzheimer's disease, autism spectrum disorder and multiple sclerosis is significantly elevated. Further research is required to understand the role played by high levels of aluminium in the aetiology of human neurodegenerative and neurodevelopmental disease.


Asunto(s)
Aluminio/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Enfermedades Neurodegenerativas/metabolismo , Anciano , Anciano de 80 o más Años , Aluminio/efectos adversos , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Trastorno Autístico/etiología , Trastorno Autístico/metabolismo , Trastorno Autístico/patología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/etiología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Enfermedades Neurodegenerativas/etiología , Enfermedades Neurodegenerativas/patología , Donantes de Tejidos
5.
Am J Med ; 133(7): 783-788, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32259516

RESUMEN

Multiple sclerosis (MS) is a common, severe neurological disease that affects millions of people worldwide. Nevertheless, the actual cause of MS remains unknown. Smoking has been studied with respect to MS development and progression. The objectives of this review were to examine the relationship between smoking and MS and to understand the possible molecular mechanisms underlying the association. PubMed was searched for articles related to the study topic published between 2012 and 2020 using the search terms "multiple sclerosis," "smoking," "risk factors," "cigarettes," and "molecular mechanisms." Studies show a significant relationship between smoking and the risk of MS. Furthermore, smoking has been linked to the progression of MS at the patient and population levels. However, the underlying mechanism remains to be explored in further studies; researchers still disagree on how the relationship between smoking and MS arises in different populations. Evidence from randomized controlled trials, systematic reviews, and epidemiological studies shows that smokers have a higher risk of developing MS and experiencing related adverse symptoms and complications.


Asunto(s)
Esclerosis Múltiple/etiología , Fumar/efectos adversos , Progresión de la Enfermedad , Salud Global , Humanos , Morbilidad/tendencias , Esclerosis Múltiple/epidemiología , Factores de Riesgo
6.
Int J Nanomedicine ; 15: 17-29, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32021162

RESUMEN

Background: Honokiol has been reported to possess anti-inflammatory and neuroprotective activities. However, the poor aqueous solubility of honokiol limits its clinical application for systemic administration. Purpose: This study aims to develop a novel formulation of nanosome-encapsulated honokiol (NHNK) for intravenous therapy against mouse experimental autoimmune encephalomyelitis (EAE) that mimics human multiple sclerosis. Methods: Nanosomes and NHNK were prepared by using an ultra-high pressure homogenization (UHPH) method. Mice were treated with NHNK or empty nanosomes during the peak phase of EAE symptoms. Symptoms of EAE were monitored and samples of the spinal cord were obtained for histopathological examinations. Results: The stock of NHNK containing honokiol in the nanosome formulation, which showed the structure of single phospholipid bilayer membranes, was well formulated with the particle size of 48.0 ± 0.1 nm and the encapsulation efficiency 58.1 ± 4.2%. Intravenous administration of NHNK ameliorated the severity of EAE accompanied by a significant reduction of demyelination and inflammation in the spinal cord. Furthermore, NHNK decreased the number of IL-6+, Iba-1+TNF +, Iba-1+IL-12 p40+, and CD3+IFN-γ+ cells infiltrating the spinal cord. Conclusion: The UHPH method simplified the preparation of NHNK with uniformly distributed nanosize and high encapsulation efficiency. Intravenous administration of NHNK ameliorated the severity of EAE by suppressing the infiltration of activated microglia and Th1 cells into the spinal cord. Collectively, these results suggest that the formulation of NHNK is a prospective therapeutic approach for inflammatory CNS diseases, such as multiple sclerosis.


Asunto(s)
Compuestos de Bifenilo/administración & dosificación , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Lignanos/administración & dosificación , Nanoestructuras/administración & dosificación , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Sistemas de Liberación de Medicamentos/métodos , Encefalomielitis Autoinmune Experimental/etiología , Femenino , Inyecciones Intravenosas , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/patología , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/etiología , Mielitis/tratamiento farmacológico , Mielitis/etiología , Nanoestructuras/química , Fármacos Neuroprotectores/farmacología , Médula Espinal/patología , Células TH1/efectos de los fármacos , Células TH1/patología
7.
Genes (Basel) ; 11(1)2020 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-31947683

RESUMEN

Genome-wide association studies have identified more than 200 multiple sclerosis (MS)-associated loci across the human genome over the last decade, suggesting complexity in the disease etiology. This complexity poses at least two challenges: the definition of an etiological model including the impact of nongenetic factors, and the clinical translation of genomic data that may be drivers for new druggable targets. We reviewed studies dealing with single genes of interest, to understand how MS-associated single nucleotide polymorphism (SNP) variants affect the expression and the function of those genes. We then surveyed studies on the bioinformatic reworking of genome-wide association studies (GWAS) data, with aggregate analyses of many GWAS loci, each contributing with a small effect to the overall disease predisposition. These investigations uncovered new information, especially when combined with nongenetic factors having possible roles in the disease etiology. In this context, the interactome approach, defined as "modules of genes whose products are known to physically interact with environmental or human factors with plausible relevance for MS pathogenesis", will be reported in detail. For a future perspective, a polygenic risk score, defined as a cumulative risk derived from aggregating the contributions of many DNA variants associated with a complex trait, may be integrated with data on environmental factors affecting the disease risk or protection.


Asunto(s)
Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Genoma Humano , Esclerosis Múltiple , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Estudio de Asociación del Genoma Completo , Humanos , Esclerosis Múltiple/etiología , Esclerosis Múltiple/genética
8.
Int J Neurosci ; 130(3): 279-300, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31588832

RESUMEN

Background: Multiple sclerosis (MS) is a neurodegenerative disease caused by dysfunction of the immune system that affects the central nervous system (CNS). It is characterized by demyelination, chronic inflammation, neuronal and oligodendrocyte loss and reactive astrogliosis. It can result in physical disability and acute neurological and cognitive problems. Despite the gains in knowledge of immunology, cell biology, and genetics in the last five decades, the ultimate etiology or specific elements that trigger MS remain unknown. The objective of this review is to propose a theoretical basis for MS etiopathogenesis.Methods: Search was done by accessing PubMed/Medline, EBSCO, and PsycINFO databases. The search string used was "(multiple sclerosis* OR EAE) AND (pathophysiology* OR etiopathogenesis)". The electronic databases were searched for titles or abstracts containing these terms in all published articles between January 1, 1960, and June 30, 2019. The search was filtered down to 362 articles which were included in this review.Results: A framework to better understand the etiopathogenesis and pathophysiology of MS can be derived from four essential factors; mitochondria dysfunction (MtD) & oxidative stress (OS), vitamin D (VD), sex hormones and thyroid hormones. These factors play a direct role in MS etiopathogenesis and have a modulatory effect on many other factors involved in the disease.Conclusions: For better MS prevention and treatment outcomes, efforts should be geared towards treating thyroid problems, sex hormone alterations, VD deficiency, sleep problems and melatonin alterations. MS patients should be encouraged to engage in activities that boost total antioxidant capacity (TAC) including diet and regular exercise and discouraged from activities that promote OS including smoking and alcohol consumption.


Asunto(s)
Esclerosis Múltiple , Animales , Humanos , Esclerosis Múltiple/etiología , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/fisiopatología
9.
Immunol Lett ; 217: 15-24, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31689443

RESUMEN

The aetiology of multiple sclerosis (MS) is as yet poorly understood. Multiple mechanisms in different disease stages are responsible for immunopathology in MS. HLA Class II DR2b (DRB1*1501 ß, DRA1*0101 α) is the strongest genetic risk factor for MS. Remnants of ancient retroviruses in the human genome, termed human endogenous retroviruses (HERV), and Epstein-Barr virus (EBV) infection are also associated with MS. In silico analyses of human endogenous retroviral envelope (HERV env) proteins and three myelin proteins that are principal targets of an autoimmune response in MS showed sequence similarities between potential TH epitopes within pairs of viral and myelin peptides predicted to bind HLA DR2b. This led to the proposal that such molecular mimicry may potentially trigger MS. HLA DR2b binding characteristics of previously identified peptides from the three myelin proteins and HERV env proteins as well as additional in silico predicted peptides from other encephalitogenic brain proteins and EBV proteins were studied to further investigate molecular mimicry. Peptides containing potential TH epitopes from the myelin oligodendrocyte glycoprotein and HERV env previously predicted to bind HLA DR2b as well as other pertinent potential HLA DR2b-restricted TH epitopes were confirmed to bind HLA DR2b molecules. Molecular modelling of HLA DR2b in complex with high affinity peptides derived from MOG and HERV env proteins showed that their binding could occur in a similar manner to a HLA DR2b-binding peptide containing a known TH epitope. A structurally related pair of peptides predicted to bind HLA DR2b from the EBV protein EBNA1 and ß synuclein, a brain protein implicated in MS, were also shown to similarly bind HLA DR2b. The findings justify investigating CD4+ T cell responses to the identified peptides.


Asunto(s)
Retrovirus Endógenos/química , Productos del Gen env/química , Cadenas beta de HLA-DR/química , Herpesvirus Humano 4/química , Esclerosis Múltiple/genética , Proteína Básica de Mielina/química , Glicoproteína Mielina-Oligodendrócito/química , Sinucleína beta/química , Secuencia de Aminoácidos/genética , Retrovirus Endógenos/genética , Epítopos/química , Productos del Gen env/genética , Cadenas beta de HLA-DR/genética , Herpesvirus Humano 4/genética , Humanos , Modelos Moleculares , Imitación Molecular , Esclerosis Múltiple/etiología , Esclerosis Múltiple/inmunología , Proteína Básica de Mielina/genética , Proteína Proteolipídica de la Mielina/genética , Proteína Proteolipídica de la Mielina/metabolismo , Glicoproteína Mielina-Oligodendrócito/genética , Unión Proteica , Factores de Riesgo , Linfocitos T/química , Linfocitos T/inmunología , Sinucleína beta/genética , Sinucleína beta/metabolismo
10.
J Neuroimmunol ; 338: 577107, 2020 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-31726376

RESUMEN

The role of damage-associated molecular patterns in multiple sclerosis (MS) is under investigation. Here, we studied the contribution of circulating high mobility group box protein 1 (HMGB1) and mitochondrial DNA (mtDNA) to neuroinflammation in progressive MS. We measured plasmatic mtDNA, HMGB1 and pro-inflammatory cytokines in 38 secondary progressive (SP) patients, 35 primary progressive (PP) patients and 42 controls. Free mtDNA was higher in SP than PP. Pro-inflammatory cytokines were increased in progressive patients. In PP, tumor necrosis factor-α correlated with MS Severity Score. Thus, in progressive patients, plasmatic mtDNA and pro-inflammatory cytokines likely contribute to the systemic inflammatory status.


Asunto(s)
Citocinas/sangre , ADN Mitocondrial/sangre , Esclerosis Múltiple/etiología , Adolescente , Adulto , Anciano , Femenino , Proteína HMGB1/sangre , Humanos , Interleucina-8/sangre , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Factor de Necrosis Tumoral alfa/sangre , Adulto Joven
11.
PLoS One ; 14(12): e0226615, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31846493

RESUMEN

BACKGROUND: Entropy is a thermodynamic variable statistically correlated with the disorder of a system. The hypothesis that entropy can be used to identify potentially unhealthy conditions was first suggested by Schrödinger, one of the founding fathers of quantum mechanics. Shannon later defined entropy as the quantity of information stored in a system. Shannon's entropy has the advantage of being adaptable across a variety of disciplines, including genetic studies on complex immunogenetic systems such as the human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptor (KIR) systems. METHODS: In our study, entropy associated to the HLA and KIR systems was compared between a cohort of 619 Sardinian healthy controls and a group of 270 patients affected by multiple sclerosis (MS), the latter stratified into 81 patients with primary progressive multiple sclerosis (PPMS) and 189 patients with relapsing remitting multiple sclerosis (RRMS). RESULTS: The entropy associated to HLA four-loci haplotypes (A, B, C, DR) and combinations of two inhibitory KIR genes was significantly higher in patients affected by RRMS than in healthy controls. No significant differences were observed for patients with PPMS. By calculating the total HLA and KIR entropy ratio in each subject, it was possible to determine the individual risk of developing MS, particularly RRMS. CONCLUSIONS: In addition to the standard statistical methods used to evaluate immunogenetic parameters associated to immune-mediated disease, the analysis of entropy measures the global disorder status deriving from these parameters. This innovative approach may represent a useful complementary tool to the risk assessment of immune-mediated disorders. Improved risk assessment is particularly important for family members of patients with MS. However, further investigation is warranted to confirm our findings and to evaluate the validity of the entropy-based method in other types of immune-mediated disorders.


Asunto(s)
Entropía , Enfermedades del Sistema Inmune/etiología , Modelos Teóricos , Esclerosis Múltiple/diagnóstico , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Antígenos HLA/química , Antígenos HLA/genética , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/etiología , Esclerosis Múltiple Crónica Progresiva/diagnóstico , Esclerosis Múltiple Crónica Progresiva/etiología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/etiología , Proyectos Piloto , Receptores KIR/química , Receptores KIR/genética , Medición de Riesgo
12.
Front Immunol ; 10: 2725, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31849944

RESUMEN

Objective: To investigate whether low-density granulocytes (LDGs) are an immunophenotypic feature of patients with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD). Methods: Blood samples were collected from 20 patients with NMOSD and 17 patients with MS, as well as from 15 patients with Systemic Lupus Erythematosus (SLE) and 23 Healthy Donors (HD). We isolated peripheral blood mononuclear cells (PBMCs) with density gradient separation and stained the cells with antibodies against CD14, CD15, CD16, and CD45, and analyzed the cells by flow cytometry or imaging flow cytometry. We defined LDGs as CD14-CD15high and calculated their share in total PBMC leukocytes (CD45+) as well as the share of CD16hi LDGs. Clinical data on disease course, medication, and antibody status were obtained. Results: LDGs were significantly more common in MS and NMOSD than in HDs, comparable to SLE samples (median values HD 0.2%, MS 0.9%, NMOSD 2.1%, SLE 4.3%). 0/23 of the HDs, but 17/20 NMOSD and 11/17 MS samples as well as 13/15 SLE samples had at least 0.7 % LDGs. NMOSD patients without continuous immunosuppressive treatment had significantly more LDGs compared to their treated counterparts. LDG nuclear morphology ranged from segmented to rounded, suggesting a heterogeneity within the group. Conclusion: LDGs are a feature of the immunophenotype in some patients with MS and NMOSD.


Asunto(s)
Biomarcadores , Granulocitos/metabolismo , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/metabolismo , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/metabolismo , Adulto , Autoinmunidad , Estudios de Casos y Controles , Susceptibilidad a Enfermedades , Femenino , Humanos , Inmunofenotipificación , Recuento de Leucocitos , Leucocitos Mononucleares/metabolismo , Lupus Eritematoso Sistémico , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/etiología , Neuromielitis Óptica/etiología
13.
Neurocirugía (Soc. Luso-Esp. Neurocir.) ; 30(6): 288-293, nov.-dic. 2019. graf, tab
Artículo en Español | IBECS | ID: ibc-186958

RESUMEN

Introducción: La espasticidad representa un problema médico cuya incidencia está aumentando debido a enfermedades como parálisis cerebral, ictus, esclerosis múltiple, traumatismos o encefalopatías, afectando tanto a adultos como a niños. Los tratamientos incluyen rehabilitación, farmacoterapia y cirugía, entre las cuales destacamos las bombas de baclofeno intratecal. Material y métodos: Seleccionamos a los pacientes portadores de bomba de baclofeno intratecal implantada en el Hospital Clínico de Santiago de Compostela entre 2005-2018 y analizamos retrospectivamente los resultados mediante escalas de valoración de espasticidad, como la de Ashworth, así como las complicaciones observadas. Resultados: Se implantaron bombas de baclofeno a 17 pacientes, obteniendo una mejoría de 2 puntos en la escala de Ashworth en el 88,2% y de 1 punto en la escala de Penn en el 94%. Se observaron complicaciones en 3 pacientes. Conclusiones: El tratamiento con baclofeno intratecal es una técnica sencilla con resultados muy positivos para mejorar la calidad de vida de pacientes con espasticidad


Introduction: Spasticity represents a medical problem whose incidence is increasing during the last years due to pathologies such as cerebral palsy, stroke, multiple sclerosis, trauma or encephalopathy, affecting both adults and children. The treatments include rehabilitation, pharmacotherapy and surgery, among which we highlight intrathecal baclofen infusion devices. Material and methods: Intrathecal baclofen devices implanted patients in Clinical Hospital of Santiago de Compostela from 2005 to 2018 were selected for retrospective analysis using assessment of spasticity scales, such as Ashworth scale. Complications are described. Results: Surgery was performed in 17 patients for baclofen pump implant, achieving an improvement of 2 points on the Ashworth Scale in 88,2% of the patients and of 1 point on the Penn Scale in 94%. Complications were seen in 3 patients. Conclusions: Intrathecal baclofen is a simple technique with good results for improving the quality of life of patients with spasticity


Asunto(s)
Humanos , Masculino , Femenino , Adulto , Baclofeno/administración & dosificación , Espasticidad Muscular/tratamiento farmacológico , Estudios Retrospectivos , Espasticidad Muscular/complicaciones , Esclerosis Múltiple/etiología , Neurofisiología
14.
Rev Neurol (Paris) ; 175(10): 625-630, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31676154

RESUMEN

Organic solvents exposure has for a long time been suspected as a risk factor for developing multiple sclerosis. The evidence, containing case reports, case-control studies and cohort studies has been contradictory. An early meta-analysis, however, pointed to a doubled risk for MS. Recent major case-control studies confirm this, but also have elucidated the risk pattern, being dependent on another risk factor, i.e. smoking.


Asunto(s)
Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/etiología , Exposición Profesional/efectos adversos , Solventes/toxicidad , Estudios de Casos y Controles , Estudios de Cohortes , Humanos , Exposición Profesional/estadística & datos numéricos , Factores de Riesgo , Fumar/efectos adversos , Fumar/epidemiología
15.
Neurology ; 93(24): e2203-e2215, 2019 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-31690681

RESUMEN

OBJECTIVE: To determine risk factors for multiple sclerosis (MS) in immigrants and to compare MS risk in immigrants and long-term residents in Ontario, Canada. METHODS: We applied a validated algorithm to linked, population-based immigration and health claims data to identify incident cases of MS in immigrants and long-term residents between 1994 and 2016. We conducted 2 multivariable Cox proportional hazards regression analyses: 1 analysis limited to the immigrant cohort assessing potential risk factors for developing MS, and 1 analysis comparing MS risk between immigrants and matched long-term residents (1:3 match). RESULTS: We identified 2,304,302 immigrants for the immigrant-only analysis, of whom 1,526 (0.066%) developed MS. Risk was greatest in those <15 years old at landing (referent <15 years; 16-30 years: hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.63-0.85; 31-45 years: HR 0.55, 95% CI 0.47-0.64). Immigrants from the Middle East (HR 1.22, 95% CI 1.06-1.40) were at greater MS risk than immigrants from Western nations; all other regions had lower risk (p < 0.0001). The matched analysis included 2,207,751 immigrants and 6,362,169 long-term residents. Immigrants were less likely to develop MS than long-term residents (p < 0.0001), although this lower risk was attenuated with longer residence in Canada. CONCLUSIONS: MS incidence in immigrants to Ontario, Canada, varied widely by region of origin, with greatest risk seen in those from the Middle East. Longer residence in Canada was associated with increased risk, even with migration in adulthood, suggesting that environmental exposures into adulthood contribute to MS risk.


Asunto(s)
Emigrantes e Inmigrantes , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/etiología , Adolescente , Adulto , Estudios de Cohortes , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Ontario/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Adulto Joven
16.
Semin Immunopathol ; 41(6): 711-726, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31732775

RESUMEN

Multiple sclerosis (MS) is a frequent autoimmune demyelinating disease of the central nervous system (CNS). There are three clinical forms described: relapsing-remitting multiple sclerosis (RRMS), the most common initial presentation (85%) among which, if not treated, about half will transform, into the secondary progressive multiple sclerosis (SPMS) and the primary progressive MS (PPMS) (15%) that is directly progressive without superimposed clinical relapses. Inflammation is present in all subsets of MS. The relapsing/remitting form could represent itself a particular interest for the study of inflammation resolution even though it remains incomplete in MS. Successful resolution of acute inflammation is a highly regulated process and dependent on mechanisms engaged early in the inflammatory response that are scarcely studied in MS. Moreover, recent classes of disease-modifying treatment (DMTs) that are effective against RRMS act by re-establishing the inflammatory imbalance, taking advantage of the pre-existing endogenous suppressor. In this review, we will discuss the active role of regulatory immune cells in inflammation resolution as well as the role of tissue and non-hematopoietic cells as contributors to inflammation resolution. Finally, we will explore how DMTs, more specifically induction therapies, impact the resolution of inflammation during MS.


Asunto(s)
Susceptibilidad a Enfermedades , Inflamación/etiología , Inflamación/metabolismo , Esclerosis Múltiple/etiología , Esclerosis Múltiple/metabolismo , Animales , Biomarcadores , Manejo de la Enfermedad , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Inmunomodulación , Inflamación/patología , Inflamación/terapia , Esclerosis Múltiple/patología , Esclerosis Múltiple/terapia
17.
Rev Neurol (Paris) ; 175(10): 644-649, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31629544

RESUMEN

Intranasal administration delivers molecules directly to the brain bypassing the blood-brain barrier. Three distinct routes of access have been identified; olfactory, trigeminal and via the paranasal sub-mucosa of the posterior sinuses. Consequently, environmental toxins may access the CNS directly to induce inflammatory and degenerative disease. They may also activate bacterial species of the nasal mucosal microbiome to release both immune-deviating cell wall antigens and transportable neurotoxins with local direct access to the CNS. Evidence is reviewed that toxins of the nasal bacterial microbiota may be directly implicated in the inflammatory and degenerative pathogenesis of multiple sclerosis.


Asunto(s)
Toxinas Bacterianas/aislamiento & purificación , Encéfalo/efectos de los fármacos , Microbiota/fisiología , Esclerosis Múltiple/etiología , Nariz/microbiología , Administración Intranasal , Animales , Toxinas Bacterianas/efectos adversos , Toxinas Bacterianas/toxicidad , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/microbiología , Humanos , Esclerosis Múltiple/microbiología , Factores de Riesgo
18.
J Neuropathol Exp Neurol ; 78(12): 1130-1146, 2019 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-31665376

RESUMEN

Astrocytes are increasingly recognized as active contributors to the disease process in multiple sclerosis (MS), rather than being merely reactive. We investigated the expression of a selected microRNA (miRNA) panel that could contribute both to the injury and to the recovery phases of the disease. Individual astrocytes were laser microdissected from brain sections. We then compared the miRNAs' expressions in MS and control brain samples at different lesional stages in white versus grey matter regions. In active MS lesions, we found upregulation of ischemia-related miRNAs in white but not grey matter, often with reversion to the normal state in inactive lesions. In contrast to our previous findings on MS macrophages, expression of 2 classical inflammatory-related miRNAs, miRNA-155 and miRNA-146a, was reduced in astrocytes from active and chronic active MS lesions in white and grey matter, suggesting a lesser direct pathogenetic role for these miRNAs in astrocytes. miRNAs within the categories regulating aquaporin4 (-100, -145, -320) and glutamate transport/apoptosis/neuroprotection (-124a, -181a, and -29a) showed some contrasting responses. The regional and lesion-stage differences of expression of these miRNAs indicate the remarkable ability of astrocytes to show a wide range of selective responses in the face of differing insults and phases of resolution.


Asunto(s)
Astrocitos/metabolismo , Astrocitos/patología , Encéfalo/patología , MicroARNs/metabolismo , Esclerosis Múltiple/metabolismo , Esclerosis Múltiple/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/metabolismo , Isquemia Encefálica/complicaciones , Isquemia Encefálica/metabolismo , Encefalitis/complicaciones , Encefalitis/metabolismo , Femenino , Sustancia Gris/patología , Humanos , Masculino , Esclerosis Múltiple/etiología , Sustancia Blanca/patología
19.
Int J Mol Sci ; 20(20)2019 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-31600882

RESUMEN

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that involves the autoreactive T-cell attack on axonal myelin sheath. Lesions or plaques formed as a result of repeated damage and repair mechanisms lead to impaired relay of electrical impulses along the nerve, manifesting as clinical symptoms of MS. Evidence from studies in experimental autoimmune encephalomyelitis (EAE) models of MS strongly suggests that mitochondrial dysfunction presents at the onset of disease and throughout the disease course. The aim of this study was to determine if mitochondrial dysfunction occurs before clinical symptoms arise, and whether this is confined to the CNS. EAE was induced in C57B/L6 mice, and citrate synthase and mitochondrial respiratory chain (MRC) complex I-IV activities were assayed at presymptomatic (3 or 10 days post first immunisation (3 or 10 DPI)) and asymptomatic (17 days post first immunisation (17 DPI) time-points in central nervous system (CNS; spinal cord) and peripheral (liver and jaw muscle) tissues. Samples from animals immunised with myelin oligodendrocyte glycoprotein (MOG) as EAE models were compared with control animals immunised with adjuvant (ADJ) only. Significant changes in MOG compared to control ADJ animals in MRC complex I activity occurred only at presymptomatic stages, with an increase in the spinal cord at 10 DPI (87.9%), an increase at 3 DPI (25.6%) and decrease at 10 DPI (22.3%) in the jaw muscle, and an increase in the liver at 10 DPI (71.5%). MRC complex II/III activity changes occurred at presymptomatic and the asymptomatic stages of the disease, with a decrease occurring in the spinal cord at 3 DPI (87.6%) and an increase at 17 DPI (36.7%), increase in the jaw muscle at 10 DPI (25.4%), and an increase at 3 DPI (75.2%) and decrease at 17 DPI (95.7%) in the liver. Citrate synthase activity was also significantly decreased at 10 DPI (27.3%) in the liver. No significant changes were observed in complex IV across all three tissues assayed. Our findings reveal evidence that mitochondrial dysfunction is present at the asymptomatic stages in the EAE model of MS, and that the changes in MRC enzyme activities are tissue-specific and are not confined to the CNS.


Asunto(s)
Encefalomielitis Autoinmune Experimental/metabolismo , Mitocondrias/metabolismo , Esclerosis Múltiple/metabolismo , Animales , Biomarcadores , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Encefalomielitis Autoinmune Experimental/diagnóstico , Encefalomielitis Autoinmune Experimental/etiología , Femenino , Ratones , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/etiología , Músculo Esquelético/metabolismo , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Índice de Severidad de la Enfermedad
20.
Int J Mol Sci ; 20(19)2019 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-31574937

RESUMEN

The transcription factor NURR1 is a constitutively active orphan receptor belonging to the steroid hormone receptor class NR4A. Although a genetic association between NURR1 and autoimmune inflammatory diseases has never emerged from genome-wide association studies (GWAS), alterations in the expression of NURR1 have been observed in various autoimmune diseases. Specifically, its role in autoimmune inflammatory diseases is mainly related to its capability to counteract inflammation. In fact, NURR1 exerts anti-inflammatory functions inhibiting the transcription of the molecules involved in proinflammatory pathways, not only in the peripheral blood compartment, but also in the cerebral parenchyma acting in microglial cells and astrocytes. In parallel, NURR1 has been also linked to dopamine-associated brain disorders, such as Parkinson's disease (PD) and schizophrenia, since it is involved in the development and in the maintenance of midbrain dopaminergic neurons (mDA). Considering its role in neuro- and systemic inflammatory processes, here we review the evidences supporting its contribution to multiple sclerosis (MS), a chronic inflammatory autoimmune disease affecting the central nervous system (CNS). To date, the specific role of NURR1 in MS is still debated and few authors have studied this topic. Here, we plan to clarify this issue analyzing the reported association between NURR1 and MS in human and murine model studies.


Asunto(s)
Susceptibilidad a Enfermedades , Esclerosis Múltiple/etiología , Esclerosis Múltiple/metabolismo , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Animales , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental , Regulación de la Expresión Génica , Humanos , Ratones , Transducción de Señal , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
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