RESUMO
Advancing the understanding of the mechanisms involved in the pathogenesis of multiple sclerosis (MS) likely will lead to new and better therapeutics. Although important information about the disease process has been obtained from research on pathologic specimens, peripheral blood lymphocytes and MRI studies, the elucidation of detailed mechanisms has progressed largely through investigations using animal models of MS. In addition, animal models serve as an important tool for the testing of putative interventions. The most commonly studied model of MS is experimental autoimmune encephalomyelitis (EAE). This model can be induced in a variety of species and by various means, but there has been concern that the model may not accurately reflect the disease process, and more importantly, it may give rise to erroneous findings when it is used to test possible therapeutics. Several reasons have been given to explain the shortcomings of this model as a useful testing platform, but one idea provides a framework for improving the value of this model, and thus, it deserves careful consideration. In particular, the idea asserts that EAE studies are inadequately designed to enable appropriate evaluation of putative therapeutics. Here we discuss problem areas within EAE study designs and provide suggestions for their improvement. This paper is principally directed at investigators new to the field of EAE, although experienced investigators may find useful suggestions herein.
Assuntos
Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/fisiopatologia , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Projetos de Pesquisa , Animais , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/terapia , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Preparações Farmacêuticas/administração & dosagem , Distribuição Aleatória , Reprodutibilidade dos Testes , Índice de Gravidade de DoençaRESUMO
Risperidone has shown safety and efficacy for aggressive and destructive behaviors in short-term studies. This longer-duration study includes a broad sample. Forty subjects, aged 8-56 years (mean=22), all with mental retardation and 36 with autism spectrum disorders participated in this 22-week crossover study, with 24 weeks of open maintenance thereafter. Of 40 subjects, 23 (57.5%) responded fully (50% decrease in Aberrant Behavior Checklist-Community Irritability subscale score), while 35 subjects (87.5%) showed a 25% decrease. Gender, mood disorder, and antiseizure medications did not alter response. Increased appetite and weight gain were common. Low dose risperidone was effective for aggressive behavior in persons with MR. More long-term studies are needed, incorporating weight control interventions.
Assuntos
Agressão/psicologia , Antipsicóticos/efeitos adversos , Transtorno Autístico/epidemiologia , Transtorno Autístico/psicologia , Deficiência Intelectual/psicologia , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/epidemiologia , Risperidona/efeitos adversos , Aumento de Peso/efeitos dos fármacos , Adolescente , Adulto , Antipsicóticos/uso terapêutico , Criança , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Deficiência Intelectual/epidemiologia , Masculino , Pessoa de Meia-Idade , Risperidona/uso terapêuticoRESUMO
Research in multiple sclerosis often employs animal models of the disease, especially experimental autoimmune encephalomyelitis (EAE) in rodents. The statistical analysis procedures chosen for these studies are often suboptimal, either because of violations of the assumptions of the procedure or because the analysis selected is inappropriate for the research question. In this paper, we discuss the types of research questions frequently asked in EAE studies and suggest appropriate and useful research designs and statistical methods that will optimize the information contained within the data. We also discuss other troublesome issues such as missing data, atypical disease profiles, and power analysis.
Assuntos
Pesquisa Biomédica , Interpretação Estatística de Dados , Encefalomielite Autoimune Experimental , Animais , Projetos de Pesquisa , Estatística como Assunto/métodosRESUMO
As a consequence of inflammation associated with multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), stress responses are induced in many cells within the CNS, however, those that occur within the primary pathological target, the oligodendrocyte, are not fully established. Recently, we found that phosphorylated eukaryotic initiation factor-2alpha (eIF2alpha), an inhibitor of protein translation associated with the stress response, is expressed in a greater number of oligodendrocytes in EAE animals compared to controls. However, since numerous oligodendrocytes in control animals also expressed phospho-eIF2alpha, a method was developed to detect expression levels within oligodendrocytes that did not rely on the number of oligodendrocytes that were stained. This method utilized a high dilution of the primary antibody so that the staining density was kept below a maximum plateau which could eliminate expression differences. Furthermore, the staining density within oligodendrocytes, as determined by image analysis, was corrected by the background density or that within neurons. In either case, the density of staining was greater in oligodendrocytes from EAE animals versus controls. The expression of heme oxygenase-2 and NADPH cytochrome P450 reductase also were examined, but unlike phospho-eIF2alpha, neither was increased in oligodendrocytes from EAE animals compared to controls. In summary, a protocol involving a high dilution of primary antibody and image analysis revealed that the expression of phospho-eIF2alpha within oligodendrocytes was increased in EAE animals compared to control animals.
Assuntos
Encefalomielite Autoimune Experimental/metabolismo , Processamento de Imagem Assistida por Computador/métodos , Imuno-Histoquímica/métodos , Proteínas do Tecido Nervoso/análise , Oligodendroglia/metabolismo , Coloração e Rotulagem/métodos , Animais , Anticorpos/química , Anticorpos/imunologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/fisiopatologia , Fator de Iniciação 2 em Eucariotos/análise , Fator de Iniciação 2 em Eucariotos/metabolismo , Feminino , Heme Oxigenase (Desciclizante)/análise , Heme Oxigenase (Desciclizante)/metabolismo , Camundongos , Esclerose Múltipla/metabolismo , Esclerose Múltipla/fisiopatologia , NADPH-Ferri-Hemoproteína Redutase/análise , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Proteínas do Tecido Nervoso/metabolismo , FosforilaçãoRESUMO
Before the 1990s, research on the early identification and prevention of severe behavior disorders (SBDs), such as aggression, self-injury, and stereotyped behavior, among young children with intellectual and developmental disabilities (IDD), was mostly done with children 3 years or older. More recent work suggests that signs of SBDs may occur as early as 6 months in some infants. The present study combined a cross-sectional and longitudinal approach to examine SBDs in 180 young children aged 4-48 months recruited through mass screening, then receiving an interdisciplinary evaluation and six-month follow-ups for one year. Twelve potential risk factors related to SBDs were examined. Eight of these risk factors, including age, gender, diagnosis, intellectual and communication levels, visual impairment, parent education, family income, were differentially related to scores for Aggression, SIB, and Stereotyped Behavior subscales on the Behavior Problems Inventory (BPI-01) at initial interdisciplinary evaluation. BPI-01 scores decreased over the year for 57% of the children and increased for 43%. The amount of decrease on each BPI-01 subscale varied with age, gender, and diagnosis.