No description available.

Multiple Sclerosis (MS) is a neurodegenerative autoimmune disease that affects millions of people worldwide. Although the exact cause of MS is unknown, it is clear that CD4+ T helper cells play a significant role, namely T helper 1 (Th1) and T helper 17 (Th17) cells. The Notch family of proteins plays a role in the development and differentiation of T helper cells. Previous data has shown that inhibition of Notch impairs the ability of T helper cell differentiation. Additionally specific inhibition of certain Notch members inhibits specific T helper cell differentiation, for example the inhibition of Notch 1 inhibits Th1 and iTreg polarization [Samon et al., 2008]. However, the effects of the other Notch family members on CD4+ T cells are not fully studied. We propose that Notch 3 plays an extensive role in the regulation of Th1, Th2, Th17, and iTreg polarizations. In addition, we propose that Notch 3 regulates function of T helper cell function in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Data in this thesis show that Notch 3 plays a significant role in the polarization of Th1, Th17 and iTreg polarization [Karlsson et al., 2011]. We present evidence that the heterozygous and homozygous Notch 3 knockout exhibits a significant decrease in polarization toward Th1, Th17 and iTreg cell fates. Exopolysaccharide (EPS) is a compound that has been previously shown to play a protective role in other inflammatory diseases. EPS has been shown to produce anti-inflammatory macrophages. We propose that a similar anti-inflammatory effect might be possible in EAE. We found that EPS had a significant effect on EAE induction, decreasing the onset and peak disease score. EPS also reduced the concentration of IFN-γ, IL17A, and GM-CSF in the supernatants of the splenocytes after restimulation with MOG. Further experimental data is needed to prove the effects of EPS on EAE and the method by which EPS function. These data indicate that Notch 3 could be crucial in regards to EAE due to the effects on Th1 and Th17 which are instrumental in EAE induction [Raphael et al., 2015].

No description available.

Multiple sclerosis is a complex disease and one for which the aetiology remains largely unanswered. Anti-dsDNA antibodies have been found intrathecally and bordering lesions in multiple sclerosis patients and in view of their known pathogenity in lupus nephritis the aim of this project was to further investigate their role in multiple sclerosis. Using the acute experimental allergic encephalomyelitis (EAE) model in the Lewis rat, the inflammatory phase of disease was profiled using immunohistological and ELISA methods and was related to clinical sign severity. The parameters of interest were central nervous system deposits of IgM, IgG, B cells and C3 and anti-DNA antibodies in sera, cerebrospinal fluid and in situ. In situ evaluation of anti-dsDNA antibodies was also performed in tissue taken from Biozzi (AH) mice (relapsing/remitting EAE model) and from a multiple sclerosis patient. Inflammatory deposits specifically at sites of perivascular cuffing were found to increase with increasing clinical sign severity. At the time clinical signs had plateaued in the Lewis rat, intrathecal anti-dsDNA antibodies were at their highest level and anti-ssDNA antibodies at their lowest. The latter possibly due to their involvement in the `clearing-up¿ process following tissue damage. Using novel DNA probes fluorescence suggestive of the presence of anti-dsDNA iii antibodies was seen in both animal and human tissue. Within human tissue the antibodies appeared to accumulate around active lesions and within vessels, raising the question of these antibodies having differing location dependent functions. EAE models have the potential to investigate these findings further and to evaluate new therapies. / Covance Laboratories Ltd.

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No description available.

In der vorliegenden Arbeit wurden die grundlegenden Mechanismen der Glukokortikoidtherapie bei der MS anhand des Tiermodells der MS, der EAE, untersucht. Hierzu wurde die EAE aktiv mithil-fe von MOG35-55 in C57Bl/6-Mäusen sowie GRdim- und lckGRdim-Mäusen induziert.  Zum einen sollte die Wirkung von Dexamethason auf Bystander- und Effektor-T-Zellen gesondert voneinander betrachtet werden. Hierzu sollte zunächst ein Modell etabliert werden, bei dem die GCs nur auf die Bystander- beziehungsweise nur auf die Effektor-T-Zellen wirkten. Trotz zahlrei-cher Experimente konnte kein Modell etabliert werden, dass den Ansprüchen für die Beantwor-tung der Frage genügte.  Zum anderen wurde in dieser Arbeit gezeigt, dass lckGRdim-Mäuse trotz fehlender Dimerisierungs-fähigkeit des GRs und somit fehlender Apoptose-Induktion in T-Zellen auf die GC-Therapie ebenso gut ansprachen wie Kontrolltiere. Ebenso konnte dies bei reinen GRdim-Tieren beobachtet werden. Zunächst wurde mithilfe von Zellzählungen, FACS-Analysen nach Anfärben der Splenozyten mit AxV und einem Apoptose-Assay ausgeschlossen, dass es in den Tieren mit dem veränderten GR doch zu einer Induktion von Apoptose kam. So konnte bestätigt werden, dass Apoptose nicht es-sentiell für die Therapie der EAE ist. Anhand eines Proliferations-Assays konnte ebenso ausgeschlossen werden, dass GCs unspezifisch die gesamte Funktionalität der Zellen beeinflussen. Im Folgenden wurden weitere mögliche Me-chanismen der Wirkung von GCs in der EAE untersucht.  Anhand von FACS-Analysen und qPCR sowie histologischen Untersuchungen konnte gezeigt wer-den, dass die eingeschränkte Migration der Zellen in das RM nach Dex-Gabe eine wichtige Rolle zu spielen scheint. So sahen wir eine Herunterregulierung von Adhäsionsmolekülen sowie die ver-minderte Expression von einigen Zytokinen. Im Falle der Chemokine, die jedoch nur als Neben-schauplatz in dieser Arbeit betrachtet werden, konnte keine Herunterregulierung von RANTES in GRdim-Tieren beobachtet werden. Andere Publikationen geben jedoch Hinweise darauf, dass auch die Beeinflussung der Chemokine entscheidend am Mechanismus der GC-Therapie beteiligt ist.   Zusammenfassend konnte mit dieser Arbeit gezeigt werden, dass Transaktivierungsprozesse, im Speziellen die Induktion von Apoptose, keinen entscheidenden therapeutischen Effekt von Dex darstellen. Der tatsächliche Mechanismus konnte auch im Rahmen dieser Arbeit nicht geklärt wer-den. Durch die Versuche an GRdim-Tieren gibt es jedoch entscheidende Hinweise darauf, dass vor allem repressive Effekte als Wirkungsmechanismus der Kortisontherapie entscheidend sind. Hierzu zählen zum Beispiel die verminderte Expression von Adhäsionsmoleküle sowie die verminderte Ausschüttung von Zytokinen bzw. Sekretion von Chemokinen. Zusammengenommen also Prozes-se, die die Migration von T-Zellen ins ZNS beeinflussen und steuern.  Dieser Aspekt hat eine große Bedeutung für die Therapie der MS, da gerade die Gene, die durch Transaktivierung induziert werden, zu den unerwünschten Nebenwirkungen der Therapie führen. Da diese keine Bedeutung in der Wirksamkeit der GC-Therapie zu haben scheinen, könnten Medi-kamente entwickelt werden, die selektiv die Gene, die durch Transrepression aktiviert werden, ansteuern. Dies würde ein großes Benefit für MS-Patienten nach sich ziehen, die im Rahmen der notwendigen Therapie ihrer Erkrankung mit teilweise gravierenden Nebenwirkungen zu kämpfen haben.

No description available.

Made available in DSpace on 2014-06-11T19:27:23Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-06-05Bitstream added on 2014-06-13T20:35:49Z : No. of bitstreams: 1 cardoso_pa_me_jabo.pdf: 283666 bytes, checksum: 9d4635249701354d18b4a667c65f5861 (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O objetivo deste estudo foi investigar a ocorrência de cepas de Escherichia coli produtoras de Shiga toxina (STEC) em queijos mussarela produzidos artesanalmente. Foram analisadas 59 amostras de queijo, produzidas no Vale do Jequitinhonha (Nordeste de Minas Gerais, Brasil). Isolando-se 147 cepas de E. coli e através da técnica de PCR, foram investigadas a presença dos genes da Shiga toxina (stx 1 e stx 2) e da intimina (eae). Dezesseis cepas bacterianas (10,8%) apresentaram o gene stx ( todas portavam o gene stx 1) e 13 delas também se mostraram eae positivas. Os isolados de E. coli foram também examinados para a detecção dos genes codificadores de adesinas (pap, sfa e afa). Não foram identificados nenhum desses genes.Todas as cepas STEC isoladas foram pesquisadas para resistência a 12 agentes antimicrobianos. As resistências predominantes detectadas foram de 37,5% para estreptomicina, 37,5% para a tetraciclina, 31,2% para a ampicilina e 31,2% para a amicacina. A resistência a múltiplas drogas foi encontrada em 5 cepas (31,2%). A presença dos genes codificadores dos fatores de virulência indica que o queijo mussarela produzido artesanalmente pode representar um risco à saúde dos consumidores. / The aim of the present study was to investigate the occurrence of Escherichia coli strains presenting the Shiga toxin gene (probably STEC strains) in mussarela cheese produced by artesanal method in the Jequitinhonha Valey (Northeast of Minas Gerais State, Brazil). Fifty-nine cheese samples were analyzed and a hundred forty seven strains of E. coli were isolated. Using the PCR method the strains were screened for the Shiga toxin (stx 1 and stx 2) and the intimin (eae) genes. Sixteen isolates (10,8%) carried the stx gene (all of them showed the stx 1 gene ) and thirteen also presented the eae gene. Using the same method the strains were screened for the presence of pap, afa, and sfa genes, adhesin genes caracteristics of the E. coli extraintestinal pathogenic strains (ExPEC). None of them showed these adhesin genes and could not be classified as an ExPEC strains. The susceptibility of the probably STEC strains to twelve antimicrobial drugs were evaluated. The most important resistance was detected to the streptomycin (37,5%), tetracycline (37,5%), ampicillin (31,2%) and amikacin (31,2%). The multidrug resistance was detected in 5 isolates (31,2%). The presence of coding genes for virulence factors in the E. coli isolates recovered from mussarela cheese produced by artesanal method could represent a risk for the human health.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-01-07T13:29:52Z No. of bitstreams: 1 maluegidiodasilveira.pdf: 1270797 bytes, checksum: c6aeb32eed6132e545ad6c185c1b11ea (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T16:45:14Z (GMT) No. of bitstreams: 1 maluegidiodasilveira.pdf: 1270797 bytes, checksum: c6aeb32eed6132e545ad6c185c1b11ea (MD5) / Made available in DSpace on 2016-01-25T16:45:14Z (GMT). No. of bitstreams: 1 maluegidiodasilveira.pdf: 1270797 bytes, checksum: c6aeb32eed6132e545ad6c185c1b11ea (MD5) Previous issue date: 2015-02-24 / Entende-se por engajamento escolar o nível de envolvimento do aluno em atividades escolares, sendo composto em quatro dimensões: comportamental, cognitiva, emocional e agente. Na realidade brasileira, existem poucos instrumentos específicos e com evidências de validade para medir o engajamento escolar. O presente estudo teve como objetivos adaptar e obter evidências de validade da escala EAE-4DE para o contexto brasileiro, bem como relacionar os tipos de engajamento com o desempenho acadêmico e a compreensão de leitura. Participaram da pesquisa 258 estudantes do 6º ano do ensino fundamental, de escolas públicas e privadas. A adaptação da escala EAE-4DE foi satisfatória com base na análise de juízes, em que o índice Kappa de concordância foi de 0,956, e, também foram obtidas evidências de validade com base na análise fatorial. As medidas de engajamento escolar consideradas em conjunto não apresentaram relação significativa com a compreensão de leitura, porém apresentaram uma relação próxima à moderada com a média escolar. / The term school engagement is understood as the level of student’s involvement in school activities, consisting in four dimensions: behavioral, cognitive, emotional and agent. In Brazilian reality, there are few specific tools and evidence of validity to measure school engagement. This study aimed to adapt and bring evidence of validity of EAE - 4DE scale for the Brazilian context as well as relate the types of engagement with the academic performance and reading comprehension. 258 students from the 6th grade of private and public elementary schools took part in the study. The adaptation of EAE - 4DE scale was satisfactory based on the judges’ analysis, in which Kappa index of concordance was 0,956, also obtained evidence of validity based on factor analysis. The school engagement measures taken together showed no significant relationship with reading comprehension, despite they showed a close to moderate relationship with the school average.