Thesis (DTech (Biomedical Technology))--Cape Peninsula University of Technology, 2009 / Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), which leads to neuronal demyelination, and eventually to oligodendrocyte and axon loss, with subsequent lesion formation. The wide distribution of lesions in the CNS results in a variety of clinical features, such as cognitive impairment, vertigo, spasticity, ataxia tremors, progressive quadriparesis, pain and depression. Currently no cure exists for CNS disorders, resulting in a decline in quality of life, and an economic burden on society. Metabolic disturbances, especially lipid metabolic abnormalities, have been implicated in the development of MS. Although the disease cannot be cured, disease-modifiers, such as interferon beta, glatiramer acetate and mitoxantrone, as well as fatty acid supplementatlon have been used to delay the progression of the disease. Membrane fatty acids are precursors for mediators of inflammation, the eicosanoids, which are produced soon after stimulation and which regulate a number of inflammatory effects, such as the induction of fever, vasodilation and production of macrophage- and Iymphocyte-derived cytokines. Eicosanoids, in contrast to their fatty acid precursors, have a short half-life and are therefore difficult to measure. The objective in the present study was to determine the role of fatty acids from South African MS patients, by measuring the fatty acid composition of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI) and sphingomyelin (SM) phospholipids in the plasma, red blood cell (RBC) and peripheral blood mononuclear cell (PBMC) membranes and correlate abnormalities with the neurological outcome as measured by the Kurtzke Expanded Disability Status Scale (EDSS) and inflammation assessed by C-reactive protein (CRP). A second objective was to establish whether possible changes in membrane lipids (phospholipids, fatty acids and cholesterol) would have an effect on membrane fluidity, and whether this would correlate with the EDSS and CRP. The plasma, RBC and PBMC membrane lipid composition from 31 white female patients with MS and 30 age- and gender-matched control subjects were assessed. Fatty acids were quanflfied by gas chromatography (GC), phospholipids by colorimetric and cholesterol by enzymatic assays. Membrane fluidity, as measured by the membrane lipid composition, was calculated, using previously established formulae, and includes the following: the saturated nature of the membrane was measured by the phospholipid PC+PS/PE+PS ratio, fluidity and permeability were measured by the cholesterol concentratlon and the cholesterol to total phospholipid ratio and membrane deformability was measured by the phospholipid PE to PS ratio. Membrane fluidity was also measured by the ordered-erystalline-phase to liquidcrystalline- phase lipid composition, which correlates with the phospholipid PE to PC ratio. The membrane saturated (SATS) to polyunsaturated fatty acid (PUFA) ratio was further used as an indication- of the fluidity status of the membranes. CRP was measured in all participants using a Beckman nephelometer. In MS, the n-6 fatty acids, particularly C18:2n-6, C20:4n-6 and C22:4n-6, were significantly decreased in plasma, RBC and/or PBMC membranes. In addition, the relationship between C20:3n-6 and C20:4n-6 showed a metabolic disturbance in both RBC and PBMC membranes from patients with MS, as compared to the control group. C20:4n-6 showed significant inverse correlations with the EDSS and CRP in MS patients, indicating that loss of these fatty acids from membranes correlated with higher disability as well as with increased inflammation. There were significant increases in free fatty acids C18:2n-6 and C20:4n-6 in plasma from MS patients. Saturated fatty acids, SM C14:0 and PI C22:0 were significantly increased in PBMC membranes from MS patients, and SM C14:0, C16:0 and C20:0 showed inverse correlations with the Functional System Scores. In contrast, the longer-ehain SATS, C22:0 and C24:0 showed positive correlations with the Functional System Scores. Red blood cell membrane fluidity as measured by the SATS to PUFA ratio was significantly higher in patients than in controls. In patients with CRP ~ 5.00 Ilglml the ratio showed significant inverse correlation with disease outcome. The saturated nature correlated positively, whilst the .ordered-erystalline-phase to liquid-crystalline-phase lipid ratio correlated inversely with the Functional System Scores. In this study it was consistently shown that C20:4n-6, or its precursor and elongation products, C18:2n-6 and C22:4n-6 respectively, was lower in plasma, RBC and/or PBMC membranes from MS patients. Red blood cells lack the desaturase enzymes and depend on fatty acids sourced from the plasma. Therefore, lower C20:4n-6 in the RBC membranes from MS patients may be due to depleted plasma stores, or an indication of an increased demand of this fatty acid elsewhere. Furthermore, this study has demonstrated that lower RBC C20:4n-6, with an increase in plasma FFA C20:4n6, resulted in worse disease outcome, perhaps due to the pro-inflammatory effect of eicosanoid production. This. study also characterized the specific SATS, that is, longer-ehain SATS that may increase the risk of developing MS, as higher shorter-ehain SATS, C14:0 and C16:0 reflected better disease outcome, demonstrated by the inverse correlation with the EDSS and FSS. Lastly, this study has shown that in the presence of uncontrolled inflammation such as in MS, the altered lipid composition indirectly compromised cell membrane, structure and fluidity, and thereby contributed to the disease progression in MS patients.

Submitted by Marlene Santos (marlene.bc.ufg@gmail.com) on 2018-11-29T19:12:14Z No. of bitstreams: 2 Dissertação - Taysa Alexandrino Gonsalves Jubé Ribeiro - 2018.pdf: 2675794 bytes, checksum: 65edb6d962cd57b9ca5d1c95e8914a1f (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Approved for entry into archive by Luciana Ferreira (lucgeral@gmail.com) on 2018-12-03T12:52:01Z (GMT) No. of bitstreams: 2 Dissertação - Taysa Alexandrino Gonsalves Jubé Ribeiro - 2018.pdf: 2675794 bytes, checksum: 65edb6d962cd57b9ca5d1c95e8914a1f (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-12-03T12:52:01Z (GMT). No. of bitstreams: 2 Dissertação - Taysa Alexandrino Gonsalves Jubé Ribeiro - 2018.pdf: 2675794 bytes, checksum: 65edb6d962cd57b9ca5d1c95e8914a1f (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-09-17 / Introduction: The prevalence of multiple sclerosis in Latin America has been estimated in many countries and varies from 0.75 to 30.7 / 100,000 inhabitants. The reasons for varying prevalence rates across the world are unclear, but there are environmental and genetic factors involved in addition to the application of different methodologies. Methodology: The present study consists of the study of the prevalence of multiple sclerosis (MS) in the population of the city of Goiânia, Goiás, in the year 2015, through three sources: the neurologists of the municipality, reference centers in multiple sclerosis of the city of Goiânia and the record of dispensing high-cost medicines from the state pharmacy. Results: 318 patients with multiple sclerosis were found, excluding intersections between sources, resulting in a crude prevalence rate of 22.2 / 100,000 inhabitants. With the application of the capture-recapture method the prevalence found was 26.4 / 100,000 inhabitants. Of the 318 cases of MS found the majority were women (76.7%), whites (77.4%) and the clinical form of relapsing-remiting (90.8%). Conclusion: This is the first study of the prevalence of MS in the state of Goiás, specifically in the city of Goiânia, and these data are fundamental for the planning of better health care for patients with multiple sclerosis, predicting resources, including research methods, drug availability, and treatment and rehabilitation services. The study also concludes that a national epidemiological study, using the same methodology, is fundamental to determine the prevalence and incidence of the disease in Brazil. / No mundo estima-se que existam 2,3 milhões de pessoas com esclerose múltipla (EM). A prevalência da esclerose múltipla na América Latina foi estimada em muitos países e varia de 0,75 a 30,7/100.000 habitantes. Apesar da grande extensão territorial, o Brasil é considerado um país de baixa prevalência de EM (13-38/100.000). As razões para a variação das taxas de prevalência em todo o mundo não são claras, mas existem fatores ambientais e genéticos envolvidos, além da utilização de diversos tipos de metodologias. O presente trabalho realizou o estudo de prevalência da esclerose múltipla na população do município de Goiânia, Goiás, Brasil, no ano de 2015. Métodos: Por meio de um levantamento retrospectivo dos prontuários de pacientes atendidos em três fontes: neurologistas, centros de referência em esclerose múltipla da cidade de Goiânia e o cadastro de dispensação de medicamentos de alto custo da farmácia estadual de Goiás identificou-se o número de pacientes com EM residentes em Goiânia, e a partir destes dados, foi realizado o cálculo das taxas brutas de prevalência, analisado o perfil sócio demográfico e aplicado o método de captura-recaptura no estudo da prevalência. Resultados: Foram encontrados 318 pacientes com esclerose múltipla excluindo as interseções entre as fontes, resultando em uma taxa bruta de prevalência de 22,2/100.000 habitantes. Com a aplicação do método de captura-recaptura a prevalência encontrada foi de 26,4/100.000 habitantes. Dos 318 casos de EM encontrados a maioria eram mulheres (76,7%), brancos (77,4%) e com forma de evolução clínica remitente-recorrente (90,8%). Conclusão: Este foi o primeiro estudo de prevalência da EM no estado de Goiás, especificamente na cidade de Goiânia e estes dados são fundamentais para o planejamento de uma melhor assistência de saúde aos pacientes com esclerose múltipla, com previsão de recursos, incluindo métodos de investigação, disponibilidade de medicamentos e serviços de tratamento e reabilitação, já que a EM é a principal doença autoimune e inflamatória que acomete o sistema nervoso central (SNC). O estudo conclui também que é fundamental um estudo epidemiológico nacional, utilizando a mesma metodologia, para melhor determinar a prevalência e a incidência da doença no Brasil. Palavras-chave: prevalência, esclerose múltipla.

Orientador: Maria da Consolação Gomes Cunha Fernandes Tavares / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Educação Fisica / Made available in DSpace on 2018-08-09T20:01:30Z (GMT). No. of bitstreams: 1 Oliveira_Gersonde_M.pdf: 760082 bytes, checksum: dab5c94436ffceaa7a041492624c8a98 (MD5) Previous issue date: 2007 / Resumo: As práticas do Yoga são caracterizadas pela permanência numa condição de controle e conforto, onde não se estipula um padrão de execução e metas de desempenho motor. A esclerose múltipla é uma doença crônica desmielinizante que resulta de reações inflamatórias desencadeadas por mecanismos complexos de anormalidade imunorregulatória. É freqüente o acometimento do equilíbrio motor, podendo culminar na queda. Existe uma carência de estudos com relação à influência do Yoga no controle do equilíbrio de pessoas com esclerose múltipla. O objetivo desta pesquisa é avaliar a influência de um programa de Yoga no equilíbrio postural de pessoas com esclerose múltipla. Trata-se de uma pesquisa experimental com N=12 (doze), formado por pessoas com esclerose múltipla pertencentes ao Grupo de Esclerose Múltipla de Campinas e que nunca praticaram Yoga ou estão a pelos menos 01 ano sem praticar. O grupo experimental participou das práticas de Yoga uma vez por semana, com duração de 01 hora, durante o período de seis meses e o grupo controle não realizou as práticas. O equilíbrio foi avaliado através da Escala de Equilíbrio de Berg. Foi coletada também a percepção subjetiva do equilíbrio e o histórico de quedas através de questionário; essas avaliações e a avaliação da Escala de Incapacidade Funcional Ampliada (EDSS) foram realizadas no inicio e final do programa, quando foi oportunizado o programa de Yoga ao grupo controle. Constatou-se através da análise estatística dos resultados obtidos através da escala de Berg, que houve uma melhora significativa do equilíbrio postural dos sujeitos do grupo experimental em relação ao grupo controle, especialmente dos sujeitos com maior escore na EDSS. A percepção subjetiva retratou o que foi avaliado na escala de Berg / Abstract: The practice of Yoga is characterized by the remaining in a condition of control and comfort, where a standard and targets of performance are not specified. Multiple sclerosis is a chronic demyelinating disease that results of inflammatory reactions triggered by complex mechanisms of immunoregulatory abnormality. Balance is often involved and may culminate in a fall. There is a shortage of studies about the influence of Yoga in the control of the balance of people with multiple sclerosis. The objective of this research is to evaluate the influence of a program of Yoga in the postural balance of people with multiple sclerosis. This is an experimental research with N=12 (twelve), and with people with multiple sclerosis who belong to the Multiple Sclerosis Group of Campinas and who never practiced Yoga or who are at least 01 year without a practice. The research group practiced Yoga once a week with classes of 01 hour during a period of six months while the control group did not practice Yoga. The balance was evaluated by the Scale of Balance of Berg. The subjective perception of the balance and the data of falls were also evaluated by means of a questionnaire; such assessments and the evaluation of the Functional Disability Extended Scale (EDSS) were conducted at the beginning and at the end of the program when the program of Yoga was offered to the control group. A significant improvement in the postural balance of the subjects of the research group, especially those with higher EDSS score, was found by means of statistical analysis of the results obtained by the Berg Scale, when compared to the control group. The subjective perception represented the same that was evaluated on the Scale of Berg / Mestrado / Atividade Fisica, Adaptação e Saude / Mestre em Educação Física

Orientadores: Fernando Cendes, Leonilda Maria Barbosa dos Santos / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-23T03:48:39Z (GMT). No. of bitstreams: 1 Damasceno_Alfredo_D.pdf: 4121143 bytes, checksum: 3ff224aadab1a5ba6aa115d98a6c533e (MD5) Previous issue date: 2013 / Resumo: A esclerose múltipla (EM) é uma doença inflamatória e desmielinizante do sistema nervoso central que afeta cerca de 2,5 milhões de pessoas em todo o mundo e implica em um importante impacto social e econômico para o estado, resultante de incapacidades funcionais sensitivo-motoras e cognitivas. Nas últimas décadas, o estudo e o entendimento da EM se beneficiaram dos avanços das técnicas de neuroimagem. A Ressonância Magnética (RM) tem sido usada para estudar tanto a história natural da doença quanto para monitorar a eficácia de tratamentos, mas a correlação dos achados da RM convencional com os dados clínicos ainda é insatisfatória. Com isso, tem surgido o interesse em outras técnicas de RM, entre elas a avaliação da substância cinzenta cerebral. Entretanto, apesar dos avanços em neuroimunologia e neuroimagem, ainda existem poucos dados que possam predizer a incapacidade em longo prazo. Com isso, nosso objetivo foi identificar fatores clínicos e de RM relacionados a uma pior evolução clínica em pacientes com EM. Inicialmente nós realizamos um levantamento dos dados de 197 pacientes acompanhados no ambulatório de EM do HC-UNICAMP, levando em conta informações clínicas e epidemiológicas e o tempo que cada paciente levou para atingir escores específicos de incapacidade. Nós observamos que o grupo levou 25,8 anos para atingir o EDSS de 6,0, mas que pacientes do sexo masculino, e principalmente aqueles com surtos frequentes nos primeiros anos e com envolvimento do tronco cerebral ou cerebelo apresentaram uma evolução pior. Posteriormente, estabelecemos um subgrupo menor de pacientes a fim de estudar o comportamento longitudinal da patologia cerebral e sua relação com a incapacidade clínica e cognitiva. Foram acompanhados, durante um período de 24 meses, 43 pacientes com EM forma remitente-recorrente e 29 indivíduos controles, submetidos a exame neurológico, neuropsicológico e RM cerebral. O desempenho nos testes clínicos e neuropsicológicos foi pior no grupo dos pacientes, e 44,2% deles foram classificados como tendo disfunção cognitiva. Um pior desempenho cognitivo estava associado à presença de atividade subclínica da doença na RM, com uma alta carga lesional cortical e com a atrofia do corpo caloso. Além disso, uma maior incapacidade clínica também estava relacionada com estas lesões corticais, tanto cerebrais quanto aquelas presentes no córtex cerebelar. Como a presença de atividade subclínica foi um indicador importante de disfunção cognitiva, foi avaliado em um subgrupo de 15 pacientes a produção de citocinas pró-inflamatórias comparando com os dados de RM. Aqueles pacientes com lesões ativas na RM apresentaram uma produção significativamente maior de citocinas pró-inflamatórias, 10 vezes maior de INF-? e 22 vezes maior de TNF-?. O grupo de 43 pacientes foi acompanhado longitudinalmente e no final de 24 meses a atrofia cortical foi de 2,57% e da substância cinzenta subcortical de 3,8%, ambos significativamente maiores que no grupo controle. A presença de atrofia do tálamo no início estava relacionada a um maior risco de disfunção cognitiva após dois anos. Além disso, a presença de uma alta carga de lesões corticais no início do estudo estava relacionada a um risco 5,14 vezes maior de incapacidade clínica após 24 meses. Pode-se concluir que a substância cinzenta, cortical e subcortical, está difusamente afetada nos pacientes com EM, e que este dano progride consideravelmente em um período de dois anos, com importante impacto clínico e cognitivo / Abstract: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that affects about 2.5 million people worldwide. MS entails a significant economic impact due to both motor and cognitive functional impairments. In recent decades, the study and understanding of MS have benefited from advances in neuroimaging techniques. Magnetic resonance imaging (MRI) has been used to study both the natural history and to monitor the effectiveness of treatments, but the correlation of conventional MRI findings with clinical data is not yet fully satisfactory. Thus, there has been great interest in other MRI techniques, including the assessment of grey matter. Nevertheless, despite advances in neuroimmunology and neuroimaging, there are few data that can predict the long-term disability in MS patients. Therefore, our goal was to identify clinical and MRI factors related to a worse clinical outcome in patients with MS. Initially, we surveyed the data of 197 patients followed in the outpatient clinic of the MS center at UNICAMP University Hospital, gathering clinical and epidemiologic information and the time to achieve specific scores on EDSS disability scale. The median time from onset to the assignment of a disability score of 6 was 25.8 years, but male patients, especially those with frequent relapses in the first years of disease, and with involvement of the brainstem or cerebellum showed a worse outcome. Subsequently, we established a smaller subgroup of patients in order to study the longitudinal behavior of brain pathology as seen by MRI and its relationship to clinical and cognitive disability. We followed for a period of 24 months, 43 patients with relapsing-remitting MS and 29 healthy subjects, who underwent neurological examination, neuropsychological testing and brain MRI. At baseline, performance on clinical and neuropsychological tests was worse in the patients group, and 44.2% were classified as having cognitive dysfunction. Worse performance on neuropsychological battery was associated with the presence of subclinical MRI activity, with a high burden of cortical lesions and atrophy of the corpus callosum. In addition, worse clinical disability was also associated with these cortical lesions, both those in the brain as those present in the cerebellar cortex. As the presence of MRI subclinical disease activity was an important indicator of cognitive impairment, coupled with the fact that there are no strong biological markers so far, we assessed the production of proinflammatory cytokines in a subgroup of 15 patients and compared with MRI data. We found that patients with subclinical active MRI lesions had significantly higher production of proinflammatory cytokines, 10-fold greater in IFN-? and 22-fold in TNF-?. The group of 43 patients was followed longitudinally and after 24 months grey-matter atrophy was 2.57% in the cortex and 3.8% in subcortical structures, both rates significantly higher than in the control group. The presence of thalamus atrophy at the baseline was associated with an increased risk of cognitive dysfunction after 2 years. Furthermore, the presence of a high load of cortical lesions at baseline was related to a 5.14 fold increased risk of clinical disability after 24 months. It can be concluded that both cortical and subcortical grey matter are diffusely affected in MS patients, and that this damage progresses considerably over a period of two years, with important clinical and cognitive impact / Doutorado / Neurologia / Doutor em Ciências Médicas

CD46 is a ubiquitously expressed transmembrane molecule and has an important role in the innate and adaptive immune system. CD46 was originally identified as a complement receptor that protects cells from autologous attack. However, CD46’s immunological profile is ever expanding and more recently it was identified as a T cell costimulatory molecule. Notably, in the presence of IL-2, CD46 can induce a Tr1-like phenotype that is characterized by the secretion of large amounts of the potent anti-inflammatory cytokine, IL-10. Defects in CD46- induced IL-10 secretion have been identified in multiple sclerosis, asthma and rheumatoid arthritis. Despite CD46’s promiscuous nature in immune responses there is little known about its underlying processing and signalling pathways. Herein, I report that CD46 expression and processing are important for regulating T cell anti-inflammatory responses and activation. Cyt1 but not Cyt2 promotes an increased ratio IL-10+ cells compared to cells that secrete both Il-10 and IFNγ. Upon CD46 costimulation, proteolytic cleavage of CD46 occurs at the surface and intracellularly with the subsequent release of a functional intracellular domain (ICD). As a result of alternative splicing, there are two main cytoplasmic isoforms of CD46, both of which release ICDs, Cyt1 and Cyt2. It is shown that the smaller Cyt1 ICD fragment facilitates T cell activation, whereas, Cyt2 promotes T cell activation when expressed in an uncleaved form. As the expression and cleavage of CD46 is important for regulating T cell function, I went on to identify factors that can regulate CD46 cleavage. Herein, it is demonstrated that T cell activation by the T cell receptor (TCR) acts as a major regulator of CD46 cleavage and expression, emphasizing the inherent role of CD46 in T cell activation. TCR stimulation also modulates CD46 glycosylation, which may effect CD46 expression and T cell phenotype. Importantly, I have identified a dysregulated expression of CD46 in a preliminary cohort of RRMS patients. It will be interesting to examine if aberrant CD46 glycosylation or cleavage accounts for its altered expression levels and impaired IL-10 secretion in RRMS patients.

Multipel Skleros (MS) är en kronisk autoimmun och neurodegenerativ sjukdom som drabbar det centrala nervsystemet och det är en av de vanligaste orsakerna till funktionsnedsättning hos medelålders och unga vuxna. Ett vanligt symptom är spasticitet som drabbar runt 60% av alla MS-sjuka. Tillståndet leder till stelhet, smärta, spasmer och nedsatt rörlighet. Spasticitet är svårbehandlat och existerande behandlingar ger ofta otillräcklig effekt eftersom den dos som krävs för symptomlindring kan ge svårtolererade biverkningar. Detta litteraturarbete hade som syfte att undersöka hur effektivt det nya cannabisbaserade läkemedlet Sativex är mot spasticitet. Fem olika randomiserade och placebo-kontrollerade studier från databasen Pubmed valdes ut och granskades. Gemensamt för dem var att patientskattade skalor användes som primära effektmått och att studiepopulationen var likartad. I den första studien undersöktes Sativex effekt på flera olika MS-symptom, men det var endast för spasticitet som en signifikant skillnad erhölls (p=0,001). De två följande studierna var snarlika varandra, men det var bara i en av dem som ITT-analysen för det primära effektmåttet visade att Sativex var signifikant överlägset placebo som behandling mot spasticitet (p=0,048 respektive p=0,219). Till den fjärde studien valdes de patienter ut som i en inledningsfas bedömts svara på behandling med Sativex. Resultatet i den studien visade på starkare signifikant skillnad jämfört med de andra studierna (p=0,0002). Den sista studien var en utsättningsstudie och resultaten från den visade att risken för behandlingssvikt var tre gånger högre för de som erhållit placebo jämfört med Sativex (p=0,013). Sett till gruppnivå var resultaten från några av studierna relativt blygsamma, vilket kan bero på att alla patienter inte svarade på behandlingen. De som svarar på behandlingen gör dock oftast det inom fyra veckor så för enskilda patienter kan läkemedlet vara till nytta och väl värt ett behandlingsförsök.

Ce travail a consisté premièrement en une étude en cross over comparant l’effet d’une sieste versus une période de repos sur une mesure électrophysiologique de récupération motrice post-exercice chez des patients fatigués atteints de sclérose en plaques (SEP) (n=12) et des témoins sains (n=12). Cette mesure correspondait à l'amplitude des potentiels moteurs évoqués par la stimulation magnétique corticale et enregistrés au niveau de la main effectuant l'exercice. Cette étude a montré que la fonction restauratrice du sommeil sur la récupération de la dépression des potentiels évoqués moteurs post-exercice était altérée chez les patients atteints de SEP et fatigués comparativement à la population témoin. Deuxièmement, une étude comparative de la puissance spectrale de la bande de fréquence delta et sigma dans les différents stades de sommeil puis de la pente des ondes lentes du sommeil lent profond a été effectuée à partir de données polysomnographiques dans une série de patients atteints de SEP et fatigués (n=15) comparés à des sujets sains (n=15). L’hypothèse posée était que la perte de l’effet restaurateur du sommeil sur les performances motrices dans la SEP pouvait être le reflet d’un dysfonctionnement de la synchronisation de certains réseaux neuronaux. Nos résultats ne montrent pas d’altération de la pente des ondes lentes chez les patients atteints de SEP comparativement aux sujets sains, ce qui invalide notre hypothèse. Cependant, une diminution de la puissance spectrale dans les bandes de fréquences sigma et delta a été retrouvée chez les patients atteints de SEP comparativement à la population témoin. Ce résultat pourrait être expliqué par des différences concernant les microéveils corticaux, les mouvements périodiques de jambes éveillants ou le sex-ratio entre les deux groupes. L'implication d'une altération des connexions thalamo-corticales par atteinte myélinique dans la perte de la fonction restauratrice du sommeil reste tout de même une hypothèse à explorer dans le cadre de la SEP. / This work consisted first in a crossover study comparing the effect of a nap versus a rest on an electrophysiological measure of post-exercise motor recovery in fatigued patients with multiple sclerosis (MS) (n = 12) and healthy controls (n = 12). This measure corresponded to the amplitude of motor potentials evoked by magnetic stimulation of the cortex, recorded at the hand performing the exercise. This study showed that the restorative function of sleep on the recovery of post-exercise motor evoked potential depression was impaired in fatigued MS patients compared to controls. Second, a comparative study of the spectral power density in the sigma and delta bands at different stages of sleep and of the slope of slow wave during deep sleep was conducted from polysomnographic data in a series of fatigued MS patients (n = 15) compared to healthy subjects (n = 15). The assumption was that the loss of the restorative effect of sleep on motor performance in MS could be due to a dysfunction of synchronization in some neural networks. Our results show no impairment of slow waves slope in patients with MS compared to healthy subjects, which invalidates our hypothesis. However, a decrease in the spectral power density in the sigma and delta bands was found in patients with MS as compared to controls. This result could be explained by differences in micro-arousals, periodic movements of legs or sex-ratio between the two groups. The involvement of an alteration in thalamocortical connections due to myelin damage in the loss of the restorative function of sleep still remains a hypothesis to be explored as part of MS.

Objectives: Adherence to multiple sclerosis (MS) treatment is essential to optimize the likelihood of full treatment effect. This prospective, observational, single-center cohort study investigated adherence to fingolimod over the 2 years following treatment initiation. Two facets of adherence - implementation and persistence - were examined and compared between new and experienced users of disease-modifying treatments (DMTs). Materials and methods: Implementation rates were based on the proportion of days covered and calculated as percentages per half-yearly visits and over 2 years, captured through refill data, pill count, and self-report. Nonadherence was defined as taking less than 85.8% of prescribed pills. Implementation rates were classified as nonadherent (< 85.8%), suboptimally adherent (>= 85.8% but. 96.2%), and optimally adherent (>= 96.2%), including perfectly adherent (100%). Persistence, ie, time until discontinuation, was analyzed by Kaplan-Meier analysis. Reasons for discontinuation were recorded. Results: The cohort included 98 patients with relapsing MS, all of whom received a dedicated education session about their medication. Of these 80% were women, 31.6% had fingolimod as first DMT, and 68.4% had switched from other DMTs. The mean implementation rate over 2 years was 98.6% (IQR(1-3) 98.51%-98.7%) and did not change significantly over time; 89% of measurements were in the optimally adherent category, 45.6% in the perfectly adherent category. There was one single occurrence of nonadherence. New users of DMTs were 1.29 times more likely to be adherent than experienced users (OR 1.29, 95% CI 1.11-1.51; P < 0.001), but not more persistent. Nineteen of 98 patients discontinued fingolimod. Conclusion: The very high implementation rates displayed in this sample of MS patients suggest that facilitation by health care professionals in preserving adherence behavior may be sufficient for the majority of patients. Targeted interventions should focus on patients who are nonadherent or who stop treatment without intention to reinitiate.

Multipel skleros är en kronisk, inflammatorisk autoimmun störning i det centrala nervsystemet och är en av världens mest förekommande neurologiska sjukdomar. Omvårdnadsteoretikern Katie Eriksson beskriver människan som en helhet av kropp, själ och ande, hon framhäver även att livet innebär ett lidande. Syftet var att beskriva individers upplevelser av att leva med multipel skleros. Denna litteraturstudie inkluderade sökningar i flera databaser för att finna vetenskapliga artiklar. Utifrån 13 resultatartiklar som berörde individers upplevelser av att leva med multipel skleros, genererades ett huvudtema Att känna sig motarbetad av kroppen och två teman Kroppsliga upplevelser och Själsliga och andliga upplevelser med subteman. Livet med sjukdomen innebar fler själsliga och andliga upplevelser än kroppsliga upplevelser. De olika temana identifierades med hjälp av Erikssons teori om att människan är en helhet. En betydande slutsats för studien var att livet med sjukdomen innebar en begränsning i vardagen. Litteraturstudien kan bidra till ytterligare kunskap och förståelse hos berörda personer, vilket kan leda till att individer med sjukdomen upplever minskat själsligt lidande. / Multiple Sclerosis is a chronic, inflammatory disruption in the central nervous system and also one of the world’s most common neurological diseases. The nursing theorist Katie Eriksson describes the human being as a whole unit of body, soul and spirit. She also explains that suffering is a part of life. The aim of the study was to describe the experiences of individuals living with Multiple Sclerosis. This literature study included searches in several databases with the intention to find scientific results articles. 13 results articles which referred to experiences of individuals with Multiple Sclerosis, generated one main theme To feel discouraged by one’s body and two themes Physical experiences and Mental and spiritual experiences with subthemes. Living with the disease meant that the mental and spiritual experiences were more numerous than the physical experiences. The different themes were identified using Eriksson’s theory of the human being, as a whole unit. A conclusion of great importance was that living with the disease meant a limitation in everyday life. The literature study can contribute to further knowledge and understanding in people whom are involved in the disease. In turn, this can lead to decreased life suffering in people with Multiple Sclerosis.

Multiple sclerosis is a neurodegenerative disorder affecting the central nervous system (CNS). Currently, the disease is incurable and immunomodulating drugs are the only option to control the disease. CD49d is an adhesion receptor expressed on most immune cells. Antibodies that bind to CD49d and block immune cells from trafficking toward the CNS are being pursued as one class of therapeutics. In this work, by combining recombinant antibody and phage display technologies we isolated 10 anti-CD49d single domain antibodies from a synthetic antibody light chain variable domain (VL) phage display library. Isolated VLs (~ 12 kDa) were expressed in Escherichia coli, purified and analysed for biophysical characteristics. The majority were expressed in good yields and were non-aggregating. All 10 VLs bound recombinant CD49d by ELISA, and 7 bound to CD49d-expressing cells in flow cytometry experiments. To empower the VLs for better therapeutic efficacy (thru increasing avidity and half-life), three of the lead VLs were re-engineered as fusions to fragment crystallisable (Fc) of human immunoglobulin gamma (IgG). The engineered hFc-VL fragments (~ 70 – 90 kDa) retained their specificity for CD49d by flow cytometry. With (i) being less immunogenic due to their human nature, (ii) their efficient access to cryptic epitopes (iii) having half-lives comparable to IgGs’ and (iv) being more cost effective compared to IgGs, these novel antibody fragments (monovalent VLs and bivalent hFc-VLs) provide a promising therapeutic platform against multiple sclerosis.