No description available.

Thesis (MMedSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: The aetiology of multiple sclerosis (MS) remains largely unknown due to the multifactorial nature of disease susceptibility determined by both environmental and genetic factors. Progress has been made in identifying the genetic component of MS , as well as the possible interactions with the environment. In this study single nucleotide polymorphisms (SNPs) in the FTO (rs9939609, Intron 1 T>A), MTR (rs1805087, 2756 A>G), MTRR (rs1801394, 66 A>G), MTHFR (rs1801133, 677 C>T and rs1801131, 1298 A>C) and COMT (rs4680, 472 G>A) genes involved in the methylation metabolic pathway were studied in the context of MS. The overall objective of this study was to elucidate the mechanism underlying raised homocysteine levels in MS patients. The specific aims were 1) to analytically validate high throughput real-time polymerase chain reaction (RT-PCR) genotyping assays for the 6 selected SNPs against direct sequencing as the gold standard for 2) possible integration into a pathology-supported genetic testing strategy aimed at improved clinical management of MS. The study population included a total of 114 unrelated Caucasian MS patients (98 females and 16 males) and 195 unrelated Caucasian control individuals without a diagnosis of neurological disease (128 females and 67 males). A novel finding of this study was that the risk-associated FTO rs9939609 A-allele was associated with raised homocysteine levels (p=0.003) in patients diagnosed with MS, but not in controls. Furthermore, homocysteine levels correlated significantly with bo dy mass index (BMI) (p=0.046) and total cholesterol levels (p=0.048). Both homocysteine (p=0.011) and BMI (p=0.017) were significantly reduced with increasing intake of folate in the diet, while high saturated/trans fat intake correlated significantly with increased BMI (p<0.001). High physical activity correlated with reduced BMI (p<0.006) in the study population, adjusted for age, gender and disease status. Daily intake of at least five fruit and vegetable portions and the COMT rs4680 (472 G>A) AA genotype had a favourable lowering effect on MS disability as assessed by the expanded disability status scale (EDSS) (p=0.035), while smoking increased MS disability significantly (p<0.001). All SNPs studied were found to be in Hardy-Weinberg equilibrium (HWE), with no significant differences detected between patients and control individuals in genotype distribution or allele frequencies. This study has shown for the first time that the underlying disease process of MS moderates the effect of the FTO rs9939609 polymorphism on homocysteine levels , which is consistent with the role of FTO in demethylation and epigenetic changes. Identification of FTO rs9939609 reinforces the importance of adequate folate intake in the diet that can be assessed accurately with use of the Medical History and Lifestyle Questionnaire applied in this study. Finally, the finding that raised homocysteine levels and BMI are significantly influenced by lifestyle factors such as diet and physical activity in our study cohort , offers a solution to counteract the detrimental effects of genetic risk factors contributing to the development of these established vascular risk factors for MS. Combining this information with FTO rs9939609 and COMT rs4680 genotyping may in future translate into a comprehensive pathology supported genetic testing strategy aimed at improved risk management and quality of life in MS patients. / AFRIKAANSE OPSOMMING: Die etiologie van meervoudige sklerose (MS) is grootliks onbekend as gevolg van die multifaktoriale aard van siekte vatbaarheid wat bepaal word deur beide genetiese en omgewingsfaktore. Vordering is reeds gemaak in die identifisering van die genetiese component van MS, asook moontlike interaksie met die omgewing. In hierdie studie is enkel nukleotied polimorfismes (SNPs) in die FTO (rs9939609, Intron 1 T > A), MTR (rs1805087, 2756 A> G), MTRR (rs1801394, 66 A> G), MTHFR (rs1801133, 677 C > T en rs1801131, 1298 A> C) en COMT (rs4680, 472 G > A) gene, wat betrokke is in die metilering metaboliese padweg, in die konteks van MS bestudeer. Die oorhoofse doel van hierdie studie was om die onderliggende meganisme betrokke by verhoogde homosisteïen vlakke in MS pasiënte uit te lig. Die spesifieke doelwitte was 1) om die analitiese geldigheid van die hoë deurvoer riëeltyd polymerase kettingreaksie (RT-PCR) genotipering metode soos toegepas vir die 6 geselekteerde SNPs te bevestig teen direkte DNA volgorde bepaling as die goue standaard, vir 2) moontlike integrasie in 'n patologie-gesteunde genetiese toetsing (PSGT) stategie wat gemik is op verbeterde kliniese hantering van MS. Die studiepopulasie bestaan uit 'n totaal van 114 nie-verwante Kaukasiese MS pasiënte (98 vroue en 16 mans) en 195 nie-verwante Kaukasiese kontroles sonder ‘n diagnose van neurologiese siektes (128 vroue en 67 mans). 'n Nuwe bevinding van hierdie studie was dat die risiko-verwante FTO rs9939609 A- alleel geassosieer was met verhoogde homosisteïen vlakke (p = 0,003) in pasiënte gediagnoseer met MS, maar nie in kontroles nie. Homosisteïen vlakke was verder beduidend geassosieer met liggaamsmassa-indeks (BMI) (p=0,046) en totale cholesterol vlakke (p=0.048). Beide homosisteïen (p=0,011) en BMI (p=0,017) het aansienlik verminder met 'n hoër inname van folaat in die dieet, terwyl 'n hoë versadigde/trans vet en koolhidrate inname beduidend gekorreleer het met 'n verhoogde BMI (p <0.001). Hoë fisiese aktiwiteit was gekorreleer met 'n verminderde BMI (p< 0.006) in die gekombineerde groep, aangepas vir die ouderdom, geslag en MS diagnose. Daaglikse inname van ten minste vyf vrugte en groente porsies en die COMT rs4680 (472 G>A) AA genotipe het 'n gunstige uitwerking op vermindering van gestremdheid gehad, soos bepaal deur die uitgebreide gestremdheid status skaal (EDSS) (p=0,035), terwyl rook MS gestremdheid beduidend verhoog het (p <0.001). Alle SNPs bestudeer was in Hardy-Weinberg ewewig (HWE), met geen beduidende verskille waargeneem in genotipe verspreiding of alleelfrekwensies tussen pasiënte en kontroles nie. Hierdie studie het vir die eeste keer aangetoon dat ‘n diagnose van MS die effek van die FTO rs9939609 polimorfisme op homosisteïen vlakke modereer, wat ooreenstem met die rol van FTO in demetilering en epigenetiese veranderinge. Identifikasie van FTO rs9939609 versterk die belangrikheid van genoegsame folaat inname in die dieet wat akkuraat gemeet kon word deur gebruik te maak van die Mediese Geskiedenis en Leefstyl Vraelys soos toegepas in hierdie studie. Ten slotte, die bevinding dat verhoogde homosisteïen vlakke en BMI statisties betekenisvol beïnvloed word deur leefstylfaktore soos dieet en fisiese aktiwiteit in ons studie populasie, verskaf 'n oplossing om die genetiese bydrae tot hierdie gevestigde vaskulêre risikofaktore vir MS teen te werk. Kombinasie van hierdie inligting met FTO rs9939609 en COMT rs4680 genotipering kan moontlik in die toekoms benut word as deel van 'n omvattende patologie- gesteunende genetiese toetsing strategie wat daarop gemik is om die risikobestuur en kwaliteit van lewe te verbeter in MS pasiënte.

Thesis (M.Sc (Radiography))--Cape Peninsula University of Technology, 2016. / Multiple sclerosis (MS) affects the central nervous system (CNS) and is characterized by multiple demyelinating lesions. It is in this context that a need arises for reliable biomarkers such as Magnetic Resonance Imaging (MRI), which could lead to the early diagnosis and therapeutic intervention when maximum potential impact is possible. This study examines the impact of MRI as a marker and the sequences that give the best images to aid in evaluation of disease progression (which can indirectly be seen as disability) and the early diagnosis of MS which will, in turn, lead to more effective management of the disease. METHOD: Sixteen subjects underwent a neurological examination, the Expanded Disability Status Scale (EDSS), blood tests for iron parameters and a 3Tesla Magnetic Resonance Imaging (MRI) scan. In a study of MS, 11 had MRI data that could be analysed by using tract-based spatial statistics (TBSS). Subjects were divided according to the EDSS score (8 of the subjects had an EDSS score of ≤ 3 while 3 subjects had scores of ≥ 6). Diffusion tensor imaging (DTI), the fused Proton Density and Fluid Attenuation Recovery (FLAIR) was utilised to compute the lesion numbers and standard laboratory procedures were used to measure other biochemical markers (serum iron, % transferrin saturation, ferritin, haemoglobin) in subjects with disability and simultaneously assess the disease process. RESULTS: The FA of white matter tracts (WMTs) as a parameter of myelin integrity was lower in subjects with MS only in those who had high EDSS scores. An association between FA and iron parameters, especially percentage transferrin saturation (% Tf) sat were observed, which suggests that iron availability to the WM may be a requirement for optimal myelin functionality. CONCLUSION: The FA of WMTs as a parameter of myelin integrity was lower only in those MS subjects who had high EDSS scores. Subjects who had EDSS scores < 3 (i.e. who had a “benign” disease outcome) had FA values similar to control values and this finding was not related to their age or disease duration. The association found between FA and iron parameters, especially % Tf sat, suggests that iron availability to the WM may be a requirement for optimal myelin functionality. Results also suggest that serum iron concentration, ferritin and % Tf sat had an effect on myelination. The lack of association between FA and Hb suggests that the iron in this protein is not available for WM function.

Multiple sclerosis (MS) is a chronic neurological disease characterized by the destruction of central nervous system (CNS) myelin. Although the neurotrophin, brain derived neurotrophic factor (BDNF) has a beneficial role in re-myelination and/or myelin repair, these effects are hampered by the over-expression of a transcriptional repressor isoform of methyl CpG binding protein 2 (MeCP2) called MeCP2E1. We hypothesize that following experimental autoimmune encephalomyelitis (EAE) -induced myelin damage, the immune system induction of the pathogenic MeCP2E1 isoform hampers the re-myelination and/or myelin repair process by repressing BDNF expression. Our research identified the temporal gene and protein expression changes of MeCP2E1, MeCP2E2 and BDNF in an EAE mouse model of MS, and correlated them with the changes in the neurological disability scores (NDS). Our results indicated MeCP2E1 mRNA levels are elevated in EAE animals which is responsible for the repressed BDNF production in the spinal cord that prevents re-myelination and/or myelin repair. / February 2016

Temat för vårt kandidatarbete är att skapa spel för dem som har någon typ funktionsvariation, vilket innebär att till viss del att göra spel som är speciellt gjorda för dem som har funktionsvariationer som är skapade så att dem hjälper människorna att kunna spela spelen. Exempelvis med hjälp av ljud som ska kunna leda spelaren till sitt mål eller skapa spelkontroller för dem som har till exempel Multipel Skleros. Detta gör vi genom att skapa ett sätt att kunna låta dem spela spel som dem i vanliga fall inte skulle kunna spela då de inte har full kontroll över sin egen motorik och kan då ha svårt för att använda en traditionell spelkontroll och detta skapar vi med hjälp av Furuboda folkhögskola. Vi gör detta för att dem som har någon form av funktionsvarianter ska kunna använda spelet för att dels träna upp sina muskler om det är Multipel skleros eller om dem har nedsatt syn, att kunna använda spelet för att träna på hur de ska hitta i nya miljöer utan risken att skada sig Till detta använde vi oss utav Game Maker för att skapa ett spel tillsammans med en Makey Makey som vi använde för att skapa nya spelkontroller av nästan vad vi ville och därmed ge oss möjligheten att skapa spelkontroller som vem som helst kan använda, även med en funktionsvariation. Det vi kan ta från detta är att med hjälp av Makey Makey som spelkontroll så kan personer med funktionsvariationer spela vårt spel utan att behöva använda en traditionell spelkontroll som kan vara svårare att använda. På grund av detta så kan personer med funktionsvariationer lättare få tillgång till vårt spel och därmed träna upp sin motorik eller förmåga att hitta i nya områden. / The theme for our bachelor thesis project is to create a video game for those that have some sort of disability and this means in part making a video game especially for those that have a disability. Which are made in such a way to help these people to play video games with, for example, the help of sounds that will lead the player to their goal or create a video game controller for those that have Multiple sclerosis with focus on two of the many symptoms people with the disability might experience, lack in motor skills/control or reduced vision. We create a way for these people to play games that they usually wouldn't be able to play. Which is due to the fact that they might not have complete control over their motor skills, or muscles, and because they could have trouble using a traditional video game controller. We do this with the help of Furuboda folk-school.We did this so that those with some sort of disability could use to train up their motor skills of they have Multiple sclerosis or if it's reduced vision to be able to use the game to practice how to find their way around new areas without risk of harming themselves. We created the game using Game Maker in combination with a Makey Makey that we could use to create our own video game controllers out of almost anything and in turn gives us the opportunity to create controllers that most people can use, even if they have some form of disability. Therefore, our game is accessible to people with disabilities as well, and they consequently would be able to exercise their motor skills or ability to navigate through new areas. What we can take from this is that with the help of Makey Makey as a game controller, people with disabilities lay our games without the need of a traditional controller that can be harder for them to use. Because of this people with disabilities can have an easier access to our game and easier way to train up their motor skills or ability to find their way in new areas.

Objectives: The purpose of the current study was to evaluate whether a 12-week neuropsychological rehabilitation program has a positive effect on the improvement of cognitive functions and what methods can be used to measure this effect. Furthermore, this study intended to verify the effect of the chosen training plan on the resulting state of cognitive functions, in particular with regard to the frequency and duration of the plan. Methodology: Forty-three patients diagnosed with MS were randomized into an experimental condition or the control group. The experimental condition included 26 patients (22 women and 4 men), whole the control group consisted of 17 patients (12 women and 5 men). All of these patients had a cognitive defect that was assessed at the beginning of the study and monitored using the neuropsychological tests after the participation in the training program. Participants in the experimental group received their rehabilitation of cognitive functions using a PC training program, which they completed in their home environments (30 minutes/4 times per week, for 8 consecutive weeks). Overall, there were 32 training sessions on predetermined days with a specific detailed training plan. The control group received no training. The neuropsychological tests used at the beginning and the...

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A esclerose múltipla (EM), doença neurodegenerativa do sistema nervoso central (SNC) com característica auto-imune e inflamatória, com eventos iniciais, bem como a evolução da EM. É uma doença heterogênea (três principais formas clínicas) e multifatoriais. A imunidade inata demonstrou recentemente ser um fator importante na EM e as variantes genéticas dos componentes do inflamassoma têm sido associadas a doenças autoimunes e neurodegenerativas, com isso hipotetizamos que o inflamassoma e suas citocinas IL-1Beta e IL-18, podem representar importantes contribuintes na patogênese da EM e eventualmente explicar, pelo menos em parte, a heterogeneidade observada em pacientes com EM. Fizemos uma análise multivariada que foi realizada com base na forma clínica (recorrente remitente/RR, primária progressivo /PP ou secundário progressiva /SP, índice de gravidade (EDSS) e índice de progressão (IP). Os monócitos do sangue periférico (PBMC) dos pacientes foram examinados para ativação do inflamassoma (Produção de IL-1Beta e IL-18, clivagem de caspase-1). Com os objetivos de avaliar a contribuição do inflamassoma na EM, em termos de (a) efeito genético sobre o desenvolvimento, gravidade e / ou prognóstico, e (b) ativação complexa de células de sangue periférico como uma forma de avaliar a inflamação sistêmica. Para isso, utilizamos variantes genéticas funcionais em componentes do inflamassoma, que foram analisadas em uma coorte de pacientes com EM, pelo uso de ensaios específicos de alelos e qPCR. A analise multivariada resultou em associação com a variante -511C / T IL1B ganho de função, sendo essa mais frequente em formas progressivas (especialmente SP) do que em RR. A variante de ganho de função NLRP3 Q705K resultou mais frequente em pacientes com EDSS > 3 do que em pacientes com EDSS < 3 e, consequentemente, esse SNP está associado a um IP mais elevado. A análise de PBMC mostrou que as células de indivíduos EM, são mais propensas a responder a um estímulo NLRP3 clássico (isto é, LPS) do que as dos doadores saudáveis. Em conjunto, esses achados indicaram que os pacientes com EM apresentam uma desregulação no inflamassoma NLRP3, podendo ser avaliada no sangue periférico facilitando um prognóstico, e que esse perfil pode ser secundário a um mecanismo genético pró-inflamassoma / The multiple sclerosis (MS), neurodegenerative disease of the central nervous system (CNS) with autoimmune and inflammatory characteristics, with initial events, as well as the evolution of MS, are heterogeneous (three main clinical forms) and multifactorial. Innate immunity has recently been shown to be an important factor in MS and the genetic variants of the components of inflammassoma have been associated with autoimmune and neurodegenerative diseases, thereby hypothesizing that the inflammassoma and its IL-1Beta and IL-18 cytokines may represent important contributors in the pathogenesis of MS and possibly explain, at least in part, the heterogeneity observed in MS patients. We performed a multivariate analysis that was performed based on clinical form (recurrent recurrent / RR, progressive primary / PP or progressive secondary / SP, EDSS and progression index.) Peripheral blood mononuclear cells (PBMC) of patients were examined for inflammatory activation (IL-1Beta and IL-18 production, caspase-1 cleavage). With the objectives of evaluating the contribution of inflammassoma in MS in terms of (a) genetic effect on development, severity and / or prognosis, and (b) complex activation of peripheral blood cells as a way of assessing systemic inflammation. For this, we used functional genetic variants in components of the inflammassoma, which were analyzed in a cohort of MS patients, through the use of specific allele and qPCR assays. For this, we used functional genetic variants in components of the inflammassoma, which were analyzed in a cohort of MS patients, through the use of specific allele and qPCR assays. Multivariate analysis resulted in association with the -511C / T IL1B function gain, which is more frequent in progressive forms (especially SP) than in RR. The gain variant of NLRP3 Q705K function was more frequent in patients with EDSS > 3 than in patients with EDSS < 3 and, consequently, this SNP is associated with a higher PI. PBMC analysis showed that cells from MS individuals are more likely to respond to a classical NLRP3 (ie LPS) stimulus than healthy donors. Taken together, these findings indicated that patients with MS have a dysregulation in the NLRP3 inflammassoma and can be evaluated in the peripheral blood facilitating a prognosis and that this profile may be secondary to a pro-inflammatory genetic mechanism

A esclerose múltipla (EM), doença neurodegenerativa do sistema nervoso central (SNC) com característica auto-imune e inflamatória, com eventos iniciais, bem como a evolução da EM. É uma doença heterogênea (três principais formas clínicas) e multifatoriais. A imunidade inata demonstrou recentemente ser um fator importante na EM e as variantes genéticas dos componentes do inflamassoma têm sido associadas a doenças autoimunes e neurodegenerativas, com isso hipotetizamos que o inflamassoma e suas citocinas IL-1Beta e IL-18, podem representar importantes contribuintes na patogênese da EM e eventualmente explicar, pelo menos em parte, a heterogeneidade observada em pacientes com EM. Fizemos uma análise multivariada que foi realizada com base na forma clínica (recorrente remitente/RR, primária progressivo /PP ou secundário progressiva /SP, índice de gravidade (EDSS) e índice de progressão (IP). Os monócitos do sangue periférico (PBMC) dos pacientes foram examinados para ativação do inflamassoma (Produção de IL-1Beta e IL-18, clivagem de caspase-1). Com os objetivos de avaliar a contribuição do inflamassoma na EM, em termos de (a) efeito genético sobre o desenvolvimento, gravidade e / ou prognóstico, e (b) ativação complexa de células de sangue periférico como uma forma de avaliar a inflamação sistêmica. Para isso, utilizamos variantes genéticas funcionais em componentes do inflamassoma, que foram analisadas em uma coorte de pacientes com EM, pelo uso de ensaios específicos de alelos e qPCR. A analise multivariada resultou em associação com a variante -511C / T IL1B ganho de função, sendo essa mais frequente em formas progressivas (especialmente SP) do que em RR. A variante de ganho de função NLRP3 Q705K resultou mais frequente em pacientes com EDSS > 3 do que em pacientes com EDSS < 3 e, consequentemente, esse SNP está associado a um IP mais elevado. A análise de PBMC mostrou que as células de indivíduos EM, são mais propensas a responder a um estímulo NLRP3 clássico (isto é, LPS) do que as dos doadores saudáveis. Em conjunto, esses achados indicaram que os pacientes com EM apresentam uma desregulação no inflamassoma NLRP3, podendo ser avaliada no sangue periférico facilitando um prognóstico, e que esse perfil pode ser secundário a um mecanismo genético pró-inflamassoma / The multiple sclerosis (MS), neurodegenerative disease of the central nervous system (CNS) with autoimmune and inflammatory characteristics, with initial events, as well as the evolution of MS, are heterogeneous (three main clinical forms) and multifactorial. Innate immunity has recently been shown to be an important factor in MS and the genetic variants of the components of inflammassoma have been associated with autoimmune and neurodegenerative diseases, thereby hypothesizing that the inflammassoma and its IL-1Beta and IL-18 cytokines may represent important contributors in the pathogenesis of MS and possibly explain, at least in part, the heterogeneity observed in MS patients. We performed a multivariate analysis that was performed based on clinical form (recurrent recurrent / RR, progressive primary / PP or progressive secondary / SP, EDSS and progression index.) Peripheral blood mononuclear cells (PBMC) of patients were examined for inflammatory activation (IL-1Beta and IL-18 production, caspase-1 cleavage). With the objectives of evaluating the contribution of inflammassoma in MS in terms of (a) genetic effect on development, severity and / or prognosis, and (b) complex activation of peripheral blood cells as a way of assessing systemic inflammation. For this, we used functional genetic variants in components of the inflammassoma, which were analyzed in a cohort of MS patients, through the use of specific allele and qPCR assays. For this, we used functional genetic variants in components of the inflammassoma, which were analyzed in a cohort of MS patients, through the use of specific allele and qPCR assays. Multivariate analysis resulted in association with the -511C / T IL1B function gain, which is more frequent in progressive forms (especially SP) than in RR. The gain variant of NLRP3 Q705K function was more frequent in patients with EDSS > 3 than in patients with EDSS < 3 and, consequently, this SNP is associated with a higher PI. PBMC analysis showed that cells from MS individuals are more likely to respond to a classical NLRP3 (ie LPS) stimulus than healthy donors. Taken together, these findings indicated that patients with MS have a dysregulation in the NLRP3 inflammassoma and can be evaluated in the peripheral blood facilitating a prognosis and that this profile may be secondary to a pro-inflammatory genetic mechanism

No description available.