Individuals with multiple sclerosis (MS), especially those living in Latin America, often require assistance from family caregivers throughout the duration of disease. Previous findings suggest that family caregivers may experience positive and negative effects from providing care to individuals with MS, but few studies have examined the impact of MS caregiving on caregivers from Latin America. The current study examined the relationships between MS impairments (functional, neurological, cognitive, behavioral and emotional), unmet family needs (household, informational, financial, social support, health), and caregiver psychosocial functioning (satisfaction with life, anxiety, burden, and depression) in a sample of 81 MS caregivers from Guadalajara, Mexico. Canonical correlations revealed that behavioral impairments were associated with higher burden and decreased satisfaction with life, and that unmet financial, social support, and informational needs were associated with higher caregiver burden. A structural equation model demonstrated the meditational effect of unmet family needs on the relationship between MS impairments and caregiver mental health. These findings suggest that interventions for MS caregivers in Latin America should focus on reducing caregiver burden by addressing unmet family needs for information, financial, and social support while teaching caregivers ways to manage the patient’s behavioral symptoms.

Title: Evaluation of sensation in hands area in patients with multiple sclerosis Objective: Summarize findings about multiple sclerosis and sensation in the hands area. Find suitable testing methods and use them to evaluate the quality of deep sensation in the hands area in patients with multiple sclerosis. Method: With help of selected tests to evaluate the quality of deep sensation in the fingers and palms area in selected probands with multiple sclerosis. Compare the results depending on the current spasticity and condition of the patient. Results: There were founded, that in people with multiple sclerosis the quality of vibrating and discriminating sensation and stereognosis in the hands area is reduced. The quality of statesthesia, kinesthesia, vibrating and discriminating sensation isn't directly linearly dependent on the current spasticity. The quality of stereognosis is directly linearly dependent on the current spasticity. Keywords: sensation, multiple sclerosis, spasticity

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Introdução: A esclerose múltipla (EM) é uma doença inflamatória autoimune desmielinizante. Diversos estudos evidenciaram a forte associação entre a EM e a expressão do retrovírus endógeno da família W (HERV-W) e do Epstein Barr Vírus (EBV), sem definir seu real papel no desenvolvimento da doença. Objetivo: Investigar a presença de anticorpos anti EBV e a expressão de HERV-W em pacientes com EM e avaliar a correlação entre a atividade clínica e imagiológica da EM com a avaliação quantitativa do HERV-W e EBV. Métodos: Realizamos avaliações clínicas e de ressonância magnética (RM) por 36 meses de 36 pacientes com EM e a comparamos com a análise quantitativa longitudinal do PCR em tempo real do RNA do HERV-W em PBMC e uma análise transversal por ELISA do anti VCA IgG e IgM de EBV. Foram utilizados dois grupos controles sendo o primeiro com 30 indíviduos saudáveis e o segundo com 26 pacientes com outras doenças neurológicas (ODN) para comparação com os títulos de HERV-W e anti- EBV. Resultados: A dosagem do IgG EBV foi estatisticamente maior no grupo EM quando comparado ao grupo controle saudável (p = 0,024) e a expressão de HERV-W foi estatisticamente maior tanto no grupo EM (p = 0,001) como no grupo ODN (p = 0,022) quando comparados com os controles saudáveis nos grupos de pacientes. Nenhuma sorologia IgM do EBV foi positiva. A avaliação longitudinal da expressão relativa do HERV-W não apresentou correlação com nenhum dos parâmetros clínicos ou imagiológicos de avaliação da EM sendo eles: tipo de EM; medicamento em uso; EDSS; taxa anualizada de surtos; novas lesões em T2/FLAIR pela RM; lesões captando gadolíneo pela RM. Conclusão: Existe uma expressão relativa de HERV-W aumentada em pacientes com EM e em ODN quando comparados com controles saudáveis. Os pacientes com EM apresentam valores superiores de anticorpos IgG anti- EBV. Não encontramos nenhuma correlação na avaliação longitudinal entre a atividade clínica e imagiológica de pacientes com EM e a avaliação quantitativa do HERV-W e do anticorpo anti-EBV. / Introduction: Multiple sclerosis (MS) is a demyelinating autoimmune inflammatory disease. Several studies have demonstrated the strong association between MS and the expression of endogenous retrovirus W (HERV-W) and Epstein Barr Virus (EBV), without defining its true role in the development of the disease. Objective: To investigate the presence of anti-EBV antibodies and HERV-W expression in MS patients and to evaluate the correlation between the clinical and imaging activity of MS with the quantitative evaluation of HERV-W and EBV. Method: We performed clinical and magnetic resonance imaging (MRI) evaluations for 36 months of 36 MS patients and compared it with the longitudinal quantitative real-time PCR analysis of HERV-W RNA in PBMC and a cross-sectional analysis by anti-VCA IgG and EBV IgM ELISA. Two control groups were used, the first with 30 healthy subjects and the second with 26 patients with other neurological diseases (OND) for comparison with HERV-W and anti-EBV titers. Results: IgG EBV was statistically higher in the MS group when compared to the healthy control group (p = 0.024). HERV-W expression was statistically higher in the MS group (p = 0.001) and the OND group (p = 0.022) when compared to healthy controls. No IgM EBV serology was positive. The longitudinal evaluation of the relative expression of HERV-W did not present any correlation with the clinical or MRI of the MS group following parameters: type of MS; medication in use; EDSS; annualized rate of relapses; new MRI T2/FLAIR lesions; MRI gadolinium enhancing lesions. Conclusion: There is a relative increased HERV-W expression in patients with MS and in OND when compared with healthy controls. Patients with MS have higher values of anti-EBV IgG antibodies. We found no correlation in the longitudinal evaluation between the clinical and imaging.

Disease progression in Multiple Sclerosis (MS), an autoimmune disease of the CNS, is widely accepted to be due to persistent myelin loss (demyelination) coinciding with lost nerve cells and nerve fibres (neuroaxonal loss). Current treatments are immunomodulatory and do not address the neuroaxonal or demyelinating pathology of the disease. It is hypothesised that a lack of growth factors within the CNS may result in the failure of remyelination. Therefore, biologics such as recombinant therapeutic proteins used for gene therapy offer a promising therapeutic intervention to the progressive stages of the disease. However, due to the short half-lives of these therapeutics and their pleiotropic effects, there is cause for concern over their safety and efficacy. Using LAP technology (the fusion of the therapeutic protein with the latent associated peptide [LAP] of TGFβ), the half-life of the therapeutic protein can be increased and can be targeted to sites of inflammation and disease. This study aimed to investigate the potential neuroprotective, remyelinating and anti-inflammatory effects of latent versions of the growth factors erythropoietin (EPO), insulin-like growth factor 1 (IGF1) and transforming growth factor beta (TGF) respectively. Firstly, using molecular cloning techniques, these growth factors were individually fused and linked to the LAP of TGF via a matrix metalloproteinase (MMP) cleavage site resulting in three latent growth factors. Secondly, these latent growth factors were shown to be expressed, and to be biologically active in vitro when released by MMP cleavage. Finally, syngeneic fibroblasts were engineered to express the latent growth factors. It was found that, in CREAE, the fibroblasts engineered to produce latent TGF significantly reduced the disease clinical score as compared to controls whilst latent EPO produced by transduced fibroblasts failed to exert a statistically significant effect on disease progression. Nonetheless, this study demonstrates the feasibility of the latency platform technology to generate latent therapeutics with the ability to act as an intervention to disease progression in MS.

Multiple sclerosis (MS) is a chronic central nervous system disease featuring exacerbations of inflammation and demyelination that cause progressively debilitating clinical effects over time. Current treatments for multiple sclerosis are limited in their ability to impact overall disease progression. Research aimed at generation of novel potential therapeutics for MS is needed. Recently, kallikrein 6 (KLK6), a member of the kallikrein (KLK) family of secreted serine proteases, was found to be elevated in the cerebrospinal fluid and brain of MS patients. The fifteen known tissue-based KLKs cleave proteins through a similar mechanism, but have different binding pocket specificity, diverse localization in human tissues, and multiple biological functions. KLKs have been linked to normal human physiology (e.g. KLK4, enamel formation) and disease (e.g. KLK3, prostate cancer). KLK6 is one of the highest expressed serine proteases in the healthy human brain and is expressed predominately in mature oligodendrocytes in both human and mouse brain. The role of KLK6 in oligodendrocyte maturation, myelination, and disease is not fully understood. To evaluate the role of KLK6 in oligodendrocyte maturation, I used a pluripotent in vitro primary cell system to assess the impact of exogenous KLK6 and modulators of the KLK6 pathway on oligodendrocyte maturation. I demonstrate that signaling through KLK6 decreases the number of mature oligodendrocytes in culture, whereas blockade of KLK6 signaling increases the number of mature oligodendrocytes in culture in the presence of triiodothyronine higher than either agent alone. This work suggests that KLK6 modulation impacts oligodendrocyte maturation. To understand the potential impact of KLK6 pathway inhibition on remyelination, I used the toxin cuprizone to induce demyelination in mice. I found that animals treated with a KLK6 inhibitor had increased myelin staining in the corpus callosum compared to vehicle-treated. This work suggests that KLK6 modulates oligodendrocyte maturation and myelination and may be relevant for improving myelin-related therapeutic outcomes, particularly in multiple sclerosis. / 2019-06-12T00:00:00Z

Made available in DSpace on 2016-04-28T20:40:16Z (GMT). No. of bitstreams: 1 Giuliana Gomes Nogueira.pdf: 569220 bytes, checksum: a6fb400334b18bb296f1efb206f7d21c (MD5) Previous issue date: 2010-04-23 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / This paper intend to open the possibility to discuss the Multiple Sclerosis in the hall of the psychosomatic illnesses taking as references the point of view of D.W. Winnicott about the psychosomatic relationship. Thus, this study will allow the reader to get in touch with several aspects of Multiple Sclerosis as it history, etiology, diagnosis, treatments, prognostics and psychological. This study also focus on the basic concepts of matureness theory, elaborated by Winnicott, reflecting about his patients suffering from psychosomatic illness. Not only are the Winnicott´s patients important to try to understand the perturbations of the psycho-soma in the multiple sclerosis as the revision of Jacqueline du Pré´s biography, which died due the aggravation of the illness. The confrontation of her personal history with the theory elaborated by Winnicott helps to illustrated what have been studied in this paper. After these analyses, it is considered the idea what in the base of all psychosomatic disorder there is a split. So we can infer that split is also one of the important points of the Multiple Sclerosis, that way the geneses of the disease may be related to gaps on the process of psycho-soma integration. Finally, the necessity of more studies on that subject is essentially to help those patients to have a better life quality. At last, the main objective of this research is considered achieved as it opened a new door of possibilities to try to understand of the multiple sclerosis / Esta dissertação busca construir um trajeto que possibilite discutir a Esclerose Múltipla no hall das doenças psicossomáticas tomando como referencial a relação psicossomática, abordada sob a ótica de D. W. Winnicott. Assim, realiza-se um estudo que permite ao leitor conhecer de forma ampla a Esclerose Múltipla detendo-se em seus 4 aspectos históricos; sua etiologia; diagnóstico; tratamentos; prognósticos; aspectos psicológicos. Este estudo se preocupa, ainda, em abordar os conceitos fundamentais da teoria do amadurecimento, elaborada por Winnicott e refletir sobre os pacientes com transtorno psicossomático atendidos por ele. Além dos pacientes de Winnicott, para analisar a esclerose múltipla, recorre-se ao relato da vida da personalidade pública Jacqueline du Pré, que morreu em decorrência de agravamento da doença e à confrontação da sua história tanto com a teoria preconizada por Winnicott quanto com o que foi estudado até então. Após essas análises, considera-se a idéia de que na base de todo transtorno psicossomático está uma cisão. Sugere-se que a cisão é uma forte característica da Esclerose Múltipla. Nota-se que há características semelhantes a outros transtornos psicossomáticos abordados pro Winnicott, considerando os indícios de que a gênese da doença possa ter uma origem em questões relativas à integração da psique-soma. Por fim, é ressaltada a necessidade de estudos mais aprofundados sobre o tema, sendo o principal o objetivo do trabalho atingido, que é a abertura de uma nova porta para a compreensão da esclerose múltipla

Immune tolerance to self antigens prevents the onset of autoimmune diseases such as Multiple Sclerosis (MS). There are three branches of tolerance which allow the auto-aggressive potential of T lymphocytes to be limited; these are death, anergy-adaptation and regulation. The main body of this work attempts to clarify a role for adaptation in maintaining the sensitivity of the autoreactive T cell repertoire below a ‘threshold for harm’ in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). The well defined myelin basic protein (MBP) Ac1-9 epitope altered peptide ligand (APL) system has been used to develop a model allowing the examination of mechanisms underlying the adaptation of cells. Previous data showed immunisation with the 4Lys (wild-type) epitope mediated disease whereas a superagonist APL with a tyrosine substitution at position 4 (4Tyr) did not, despite showing potency in vitro. This was shown to be a result of both activation induced cell death and adaptation. Here an in vitro model was developed using MBP-reactive TCR transgenic cells to make predictions about the mechanisms underlying adaptation. These data lead to the conclusion that T cells can adapt (become less sensitive) either before or after encounter with the wild-type peptide, leading to a reversal of their pathogenic potential. The MBP APL system and MBP reactive transgenic cells were also used to assess the contribution of epitope spreading in a relapsing-remitting (RR) model of EAE induced with proteolipid protein. The cells were tracked and changes in phenotype and behaviour were monitored. The data show that disease induced with one antigen can be manipulated with cells relevant to a different antigen and that bystander suppression may be an effective weapon in controlling the progression to RR-EAE.

Introdução: A esclerose múltipla (EM) é uma doença inflamatória autoimune desmielinizante. Diversos estudos evidenciaram a forte associação entre a EM e a expressão do retrovírus endógeno da família W (HERV-W) e do Epstein Barr Vírus (EBV), sem definir seu real papel no desenvolvimento da doença. Objetivo: Investigar a presença de anticorpos anti EBV e a expressão de HERV-W em pacientes com EM e avaliar a correlação entre a atividade clínica e imagiológica da EM com a avaliação quantitativa do HERV-W e EBV. Métodos: Realizamos avaliações clínicas e de ressonância magnética (RM) por 36 meses de 36 pacientes com EM e a comparamos com a análise quantitativa longitudinal do PCR em tempo real do RNA do HERV-W em PBMC e uma análise transversal por ELISA do anti VCA IgG e IgM de EBV. Foram utilizados dois grupos controles sendo o primeiro com 30 indíviduos saudáveis e o segundo com 26 pacientes com outras doenças neurológicas (ODN) para comparação com os títulos de HERV-W e anti- EBV. Resultados: A dosagem do IgG EBV foi estatisticamente maior no grupo EM quando comparado ao grupo controle saudável (p = 0,024) e a expressão de HERV-W foi estatisticamente maior tanto no grupo EM (p = 0,001) como no grupo ODN (p = 0,022) quando comparados com os controles saudáveis nos grupos de pacientes. Nenhuma sorologia IgM do EBV foi positiva. A avaliação longitudinal da expressão relativa do HERV-W não apresentou correlação com nenhum dos parâmetros clínicos ou imagiológicos de avaliação da EM sendo eles: tipo de EM; medicamento em uso; EDSS; taxa anualizada de surtos; novas lesões em T2/FLAIR pela RM; lesões captando gadolíneo pela RM. Conclusão: Existe uma expressão relativa de HERV-W aumentada em pacientes com EM e em ODN quando comparados com controles saudáveis. Os pacientes com EM apresentam valores superiores de anticorpos IgG anti- EBV. Não encontramos nenhuma correlação na avaliação longitudinal entre a atividade clínica e imagiológica de pacientes com EM e a avaliação quantitativa do HERV-W e do anticorpo anti-EBV. / Introduction: Multiple sclerosis (MS) is a demyelinating autoimmune inflammatory disease. Several studies have demonstrated the strong association between MS and the expression of endogenous retrovirus W (HERV-W) and Epstein Barr Virus (EBV), without defining its true role in the development of the disease. Objective: To investigate the presence of anti-EBV antibodies and HERV-W expression in MS patients and to evaluate the correlation between the clinical and imaging activity of MS with the quantitative evaluation of HERV-W and EBV. Method: We performed clinical and magnetic resonance imaging (MRI) evaluations for 36 months of 36 MS patients and compared it with the longitudinal quantitative real-time PCR analysis of HERV-W RNA in PBMC and a cross-sectional analysis by anti-VCA IgG and EBV IgM ELISA. Two control groups were used, the first with 30 healthy subjects and the second with 26 patients with other neurological diseases (OND) for comparison with HERV-W and anti-EBV titers. Results: IgG EBV was statistically higher in the MS group when compared to the healthy control group (p = 0.024). HERV-W expression was statistically higher in the MS group (p = 0.001) and the OND group (p = 0.022) when compared to healthy controls. No IgM EBV serology was positive. The longitudinal evaluation of the relative expression of HERV-W did not present any correlation with the clinical or MRI of the MS group following parameters: type of MS; medication in use; EDSS; annualized rate of relapses; new MRI T2/FLAIR lesions; MRI gadolinium enhancing lesions. Conclusion: There is a relative increased HERV-W expression in patients with MS and in OND when compared with healthy controls. Patients with MS have higher values of anti-EBV IgG antibodies. We found no correlation in the longitudinal evaluation between the clinical and imaging.

Axonal degeneration is the major cause of disability in progressive multiple sclerosis (MS). It has been shown that in MS and relevant disease models, demyelinated axons harbor an increased number of mitochondria, which is reflected in bigger stationary sites of mitochondria, increased mitochondrial activity and increased transport speed of mitochondria. This axonal response of mitochondria to demyelination (ARMD) is protective, as there is an increase in energy demand due to the redistribution of sodium channels along the axon following demyelination. However, it remains to be determined how this ARMD is mounted and how mitochondrial dynamics are involved. By using in vivo and in vitro systems we are determined to elucidate the transport and fusion dynamics of the ARMD and where these additional mitochondria come from. Using a cerebellar slice culture system with lysolecithin induced demyelination, we show that the increase in mitochondrial occupancy of the axon already occurs at 24 hours after demyelination and plateaus around 3 to 4 days after demyelination. At 24 hours, there was a steep increase in the mitochondrial numbers inside the axon, which is then followed by an increase in mitochondrial size over the following days. All parameters decrease again over the following days, but remain elevated compared to baseline even 12 days after demyelination. To determine the source of these additional mitochondria and to assess the fusion dynamics within the axon, we used a lentivirus expressing a mitochondrial targeted photoconvertible dye (mEOS2) to label mitochondria in Purkinje cells. The mitochondria that are labelled green in the Purkinje cell axons are then photoconverted to red by illuminating the initial part of the axon with a 405-nm laser and imaged over the following 20 minutes to determine the transport and fusion dynamics. This showed an increased number of mitochondria moving from the cell body into the axon, as well as an increase in retrograde transport of mitochondria in the demyelinated compared to the myelinated axons. Furthermore the size of newly transported mitochondria and their speed was increased in the anterograde direction. Furthermore, the fusion rate of newly transported mitochondria with stationary converted mitochondria was increased in the demyelinated axons compared to myelinated control. These changes can also be observed in unmyelinated axons, as well as axons of cerebellar slices of the dysmyelinating shiverer mutant with or without lysolecithin treatment. The manipulation of mitochondrial dynamics after demyelination with the fission inhibitor mdivi-1 and the ATPase inhibitor oligomycin both showed an increasing or decreasing effect on the mitochondrial parameters after demyelination respectively. The effect on the axonal health after demyelination was detrimental with both of these treatments. Increasing mitochondrial biogenesis with pioglitazone increased axonal mitochondrial parameters, as well as ameliorated axonal damage after demyelination with lysolecithin. As the neuronal cell bodies in MS harbour mitochondrial DNA deletions, which affects their physiology, including energy production efficiency, another aim of this thesis was to model this deficiency in vitro. As it was not possible to model these mitochondrial defects in vitro within the experiments of this thesis, the characterization of a mitochondrial mutant in vivo model was done as a contribution to a greater set of experiments performed by other members of the Mahad lab.