Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by lesions that form within the central nervous system which induce symptoms such as muscle weakness and paralysis. Many aspects of MS, ranging from causation to immunopathology, are currently under investigation as little is known of the factors that contribute to and exacerbate this disease. Presently, evidence suggests MS to be an inflammatory disease mediated by an autoimmune response to an unknown antigen. Results from clinical studies as well as animal models such as experimental autoimmune encephalomyelitis (EAE) suggest MS is initiated and maintained by immune cells such as Th1 lymphocytes. As a result, therapeutics prescribed to MS patients’ focus on modulating the inflammatory response so as to minimize myelin loss and CNS damage. Peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors that show promise as potential targets for MS therapeutics. The PPAR sub-types, PPARα and PPARγ, have been shown to inhibit the propagation of inflammatory pathways and decrease the activity of pro-inflammatory cells in a number of inflammation driven diseases including rheumatoid arthritis and atherosclerosis. The anti-inflammatory role of PPARβ/δ is less well known, although preliminary studies suggest activation of this receptor may potentiate the activity of other transcription factors involved in inhibiting inflammatory pathways. As the PPAR family of transcription factors exhibit similar functions, it is hypothesized that the PPARβ/δ sub-type may have immunomodulatory effects that are comparable and complimentary to PPARα and –γ. This thesis describes a novel model of relapsing-remitting EAE (RR-EAE) that presents a disease course where EAE relapses are followed by periods of recovery that are characterized by the absence of clinical symptoms. Furthermore, a therapeutic intervention study carried out using this model demonstrates that the PPARγ agonist pioglitazone can decrease the severity of a relapse episode when drug treatment begins prior to a predicted relapse event. The inhibition of immune cell infiltration into the CNS and decreased immune cell activity mediated by pioglitazone, suggests that this ligand modulates the immune response. These results indicate that pioglitazone may be an effective treatment for relapsing-remitting MS. To examine the role of PPARβ/δ in RR-EAE and explore its effect on the activity of inflammatory cells, PPARβ/δ knockout mice were used due to the current lack of specific antagonists for this receptor. PPARβ/δ wild-type mice developed RR-EAE when immunized using protocol intended to induce this disease course. PPARβ/δ knockout mice however, developed chronic EAE when immunized in the same manner. Consistent with sustained clinical symptoms, CNS immune cell infiltration and activity was maintained throughout the disease in PPARβ/δ knockout mice. In contrast, the presence of immune cells within the CNS and consequent activity fluctuated according to the relapse and recovery pattern of disease in PPARβ/δ wild-type mice. PPARβ/δ appears to modulate inflammation by potentiating the apoptosis of activated T cells. Therefore, PPARβ/δ agonists may be potential candidates for MS treatment.

Chronic Fatigue Syndrome (CFS) is a contested condition that generates scepticism and occupies a marginalised position within medical and social contexts. The thesis examines the illness experiences, and specifically the experiences of self, for people affected with CFS. Using qualitative inquiry, a substantive theory related to the process of self-renewal and adaptation associated with CFS is explicated. The theory encompasses the trajectory of CFS from onset to chronicity, and in exceptional instances, recovery. Illness narratives were derived from in-depth, semi-structured interviews of 19 adults, including 16 people affected with, and 3 people recovered from, CFS. Data was coded and analysed using a grounded theory approach. Analysis generated two parallel narratives that defined the illness experience of CFS: the narrative of the illness biographies and the narrative of self, specifically the struggling and diminished self seeking renewal. The illness biographies encompassed the stories of symptoms and their explanations, the encounters that ensued and their contentious milieu. The narrative of self was the primary narrative. It articulated the negative consequences to self and personhood associated with CFS, named the Violation of Self, and the consequent efforts of participants to decrease the struggle and violation by use of the Guardian Response and the Reconstructing Response. The Guardian Response provided protection and self-reclamation. The Reconstructing Response fostered self-renewal and meaning. The two narratives were bridged by the threats of CFS. That is, the illness biographies were accompanied by threats of disruption related to chronic illness, and by threats of invalidation that arose from CFS as a contested condition. In turn, these threats provided the catalyst to the violation and responses as described in the narrative of self. Under different conditions the relative strengths of violation, guardianship or reconstruction fluctuated, and it was these fluctuations that presented the participants with the ongoing struggle of CFS.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Oct. 31, 2007). Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Thesis (M.S.)--University of Missouri--Columbia, 2004. / "May 2004." Typescript. Includes bibliographical references (leaves 30-40). Also issued on the Internet.

Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Document formatted into pages; contains xv, 95 p.; also includes graphics (some col.) Includes bibliographical references (p. 85-95). Available online via OhioLINK's ETD Center

Thesis (M.S.)--University of Missouri--Columbia, 2004. / Typescript. Includes bibliographical references (leaves 30-40). Also issued on the Internet.

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 77-90).

Orientador: Alexandre Leite Rodrigues de Oliveira / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-09T22:49:48Z (GMT). No. of bitstreams: 1 Marques_KarinadeBrito_D.pdf: 8050913 bytes, checksum: f9c7d621391d6f3f99413a9c27749530 (MD5) Previous issue date: 2007 / Resumo: Durante o curso da encefalomielite autoimmune experimental ocorre uma grave redução das funções motoras e sensitivas. Esses eventos têm sido classicamente atribuídos ao processo desmielinizante da doença. Em ratos, os sinais clínicos da doença desaparecem 5 dias após completa tetraplegia, indicando que o processo desmielinizante não é a única causa da rápida evolução da doença. Assim sendo, investigamos as alterações sinaptológicas e o processo inflamatório induzidos pela encefalomielite autoimune experimental (EAE) em motoneurônios medulares e sua relação com o surto e remissão da doença. Para esse estudo, foram utilizados ratos Lewis, fêmeas de 7 semanas. Os animais foram induzidos à EAE por meio de dose única de proteína básica de mielina emulsificada com adjuvante completo de Freund e sacrificados no 13º dia após indução (surto grau 3) e no 26º dia (remissão da doença). Também, para investigar a possibilidade de que o tratamento com acetato de glatirâmer, uma droga imunomoduladora baseada na estrutura de aminoácidos da proteína básica de mielina, interfira no processo de plasticidade sináptica, os animais foram induzidos à EAE, tratados com AG diariamente e sacrificados após 2 semanas. Os grupos experimentais foram divididos em: estudo da aposição sináptica durante surto e remissão da doença e tratamento dos animais induzidos à EAE com AG. Assim, os espécimes foram processados para análise através de imunohistoquímica e microscopia eletrônica de transmissão. Nossos resultados indicaram que os componentes gliais (astrócitos e microglia), estimulados pela inflamação, desempenham papel ativo no processo de retração sináptica em motoneurônios alfa. Apresentamos evidências de que a eliminação de terminais sinápticos contribui para a perda da função motora observada no curso da doença e que o imunomodulador AG não só possui efeito antiinflamatório, mas também influencia diretamente na plasticidade de elementos neurais no microambiente medular. Reforçam, também, que um processo agudo de inflamação pode colaborar diretamente para a recuperação e sobrevivência neuronal, uma vez que as células inflamatórias produzem citocinas e fatores neurotróficos no microambiente medular / Abstract: During the course of experimental autoimmune encephalomyelitis, a massive loss of motor and sensitive function occurs, which has been classically attributed to the demyelination process. In rats, the clinical signs disappear within 5 days following complete tetraplegia, indicating that demyelination might not be the only cause for the rapid evolution of the disease. The immunomodulador glatiramer acetate (GA) has been shown significantly reduce the seriousness of the symptoms during the exacerbation of the disease. However, little is known about its effects on the spinal motoneurons and on their afferents. The present work investigated the occurrence of experimental autoimmune encephalomyelitis-induced changes of the synaptic covering of spinal motoneurons during exacerbation and after remission and investigated whether GA has a direct influence on synapse plasticity and on the deafferentiation of motoneurons during the course of EAE in rats. Lewis rats were subjected to EAE associated with GA or placebo treatment. The animals were sacrificed after fifteen days of treatment. For the both cases the spinal cords was processed for immunohistochemical analysis (IH) and electron transmission microscopy. The terminals were typed with transmission electron microscopy as C-, F- and Stype. Immunohistochemical analysis of synaptophysin, glial fibrillary acidic protein and the microglia/macrophage marker F4/80 were also used in order to draw a correlation between the synaptic changes and the glial reaction. The ultrastructural analysis showed that, during exacerbation, there was a strong retraction of both F- and S-type terminals. In this sense, both the covering as well as the length of the remaining terminals suffered great reductions. However, the retracted terminals rapidly returned to apposition, although the mean length remained shorter. A certain level of sprouting may have occurred as, after remission, the number of F-terminals was greater than in the control group. The immunohistochemical analysis showed that the peak of synaptic loss was coincident with an increased macro- and microglial reaction. Interestingly, although the GA treatment preserved synaptophysin labelling, it did not significantly reduce the glial reaction, indicating that inflammatory activity was still present. Our results suggest that the major changes occurring in the spinal cord network during the time course of the disease may contribute significantly to the origin of the clinical signs as well as help to explain their rapid recovery and that the immunomodulator GA has a direct influence on the stability of nerve terminals in the spinal cord, which in turn may contribute to its neuroprotective effects during the course of multiple sclerosis / Doutorado / Anatomia / Doutor em Biologia Celular e Estrutural