Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 2008. / Vita. Includes bibliographical references (leaves 173-208).

Thesis (Ph.D. in Biochemistry) -- University of Colorado Denver, 2008. / Typescript. Includes bibliographical references (leaves 128-144). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

abstract: Healthy mitochondria are essential for cell survival. Described herein is the synthesis of a family of novel aminoquinone antioxidants designed to alleviate oxidative stress and prevent the impairment of cellular function. In addition, a library of bleomycin disaccharide analogues has also been synthesized to better probe the tumor targeting properties of bleomycin. The first study involves the synthesis of a benzoquinone natural product and analogues that closely resemble the redox core of the natural product geldanamycin. The synthesized 5-amino-3-tridecyl-1,4-benzoquinone antioxidants were tested for their ability to protect Friedreich's ataxia (FRDA) lymphocytes from induced oxidative stress. Some of the analogues synthesized conferred cytoprotection in a dose-dependent manner in FRDA lymphocytes at micromolar concentrations. The biological assays suggest that the modification of the 2-hydroxyl and N-(3-carboxypropyl) groups in the natural product can improve its antioxidant activity and significantly enhance its ability to protect mitochondrial function under conditions of oxidative stress. The second project focused on the synthesis of a library of bleomycin disaccharide-dye conjugates and monitored their cellular uptake by fluorescence microscopy. The studies reveal that the position of the carbamoyl group plays an important role in modulating the cellular uptake of the disaccharide. It also led to the discovery of novel disaccharides with improved tumor selectivity. / Dissertation/Thesis / Ph.D. Chemistry 2013

Orientador: Satoshi Kitamura / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-22T11:47:36Z (GMT). No. of bitstreams: 1 Luchesi_KarenFontes_D.pdf: 2231982 bytes, checksum: 2f5ef1dbfa543808275311de510df643 (MD5) Previous issue date: 2013 / Resumo: A Doença de Parkinson (DP) é uma das doenças neurodegenerativas mundialmente mais prevalentes. Dentre as doenças do neurônio motor, a Esclerose Lateral Amiotrófica (ELA) é a mais frequente. A qualidade de vida e o prolongamento da expectativa de vida dos sujeitos com doenças neurodegenerativas, como ELA e DP, são foco da intervenção fonoaudiológica, visto que uma das maiores causas de morte são as pneumonias aspirativas. Esta pesquisa teve por objetivo analisar e descrever aspectos relacionados à disfagia e à sua progressão em sujeitos diagnosticados com ELA e DP. Ao todo, participaram 49 sujeitos com ELA e 24 sujeitos com DP. Todos foram avaliados e acompanhados no ambulatório de Otorrinolaringologia/Disfagia do Hospital de Clínicas da Universidade Estadual de Campinas. Foram incluídos no estudo, apenas os sujeitos que estavam em acompanhamento periódico no ambulatório de neurologia do referido hospital e em tratamento medicamentoso. Foram excluídos os sujeitos sem queixa de deglutição ou que apresentassem outras doenças que pudessem causar alteração na deglutição. Todos foram submetidos à entrevista estruturada, videoendoscopia da deglutição, avaliação clínica da deglutição e intervenção fonoaudiológica, além de terem a funcionalidade de ingestão oral classificada pela Functional Oral Intake Scale. Foi realizada uma análise descritiva dos dados com apresentação de frequência das variáveis categóricas e medidas de tendência central e dispersão das variáveis numéricas. Na análise exploratória foram utilizados: Regressão de Cox, teste Exato de Fisher, teste de Kruskal-Wallis, Qui-quadrado, teste de Mann-Whitney e análise de sobrevivência de Kaplan-Meier. As análises foram realizadas por meio do software SPSS versão 13.0 para Windows, tendo sido adotado o nível de significância para os testes estatísticos de 0,05. Na ELA, foi identificado como fator associado à disfagia moderada ou grave, a odinofagia (p=0,01). Foram identificados como fatores que influenciaram na progressão da disfagia na ELA a idade de início da doença (p=0,02) e o início bulbar (p=0,04). A idade de início avançada (p=0,03) e o menor tempo de doença até a primeira avaliação (p=0,004) foram identificados como fatores que levaram à necessidade de indicação de uma via alternativa de alimentação em menor tempo na ELA. Não foram identificados fatores que influenciassem a progressão da disfagia na DP. Observou-se melhora e estabilização da função de deglutição na maioria dos sujeitos com DP estudados. Conclui-se que a idade de início e o início bulbar da ELA são fatores associados à piora rápida da disfagia. Não houve fatores associados à progressão da disfagia na PD e a funcionalidade na deglutição destes pacientes foi caracterizada por melhora e manutenção / Abstract: Parkinson's disease (PD) is one of the most prevalent neurodegenerative diseases worldwide. Among the motor neuron diseases, the Amyotrophic Lateral Sclerosis (ALS) is the most common. The quality of life and longer life expectancy for these individuals with neurodegenerative diseases are the purpose of speech-language therapy, as the leading cause of death are aspirative pneumonias. The objective of this study was to analyze and describe aspects related to dysphagia and its progression in patients diagnosed with ALS and PD. Altogether, 49 patients with ALS and 24 patients with PD participated in the study. All patients were evaluated and followed by at the Otolaryngology/Dysphagia services of the Clinical Hospital of the University of Campinas. The study included only patients who have been regularly monitored at the neurology service and undergoing drug treatment. Patients who had other conditions that could cause changes in swallowing or with no complaints concerning swallowing were excluded. All patients underwent a structured interview, Fiberoptic Endoscopic Evaluation of Swallowing, clinical evaluation of swallowing and swallowing management. Furthermore, they had the swallowing functionality classified by the Functional Oral Intake Scale. We performed a descriptive analysis with presenting the frequency of categorical variables, central measures tendency and dispersion of numerical variables. In exploratory data analysis were applied Cox Regression, Kruskal-Wallis, Chi-square, Mann-Whitney and survival analysis of Kaplan-Meier. The analyses were performed using SPSS version 13.0 for Windows and the significance level for statistical tests was 5%. Odynophagia was identified as an associated factor with moderate or severe dysphagia in ALS. The onset age of ALS (p = 0.02) and the bulbar onset ALS (p = 0.04) were identified as factors that influence the progression of dysphagia in ALS. Advanced onset age (p = 0.03) and shorter disease duration (p = 0.004) were identified as factors that lead to sooner need for non-oral feeding. We did not identify any associated factors with the progression of dysphagia in PD. We noticed an improvement and stabilization of the swallowing function in most patients with PD. We conclude that the onset age and bulbar onset of ALS are factors associated with rapid worsened dysphagia / Doutorado / Epidemiologia / Doutora em Saúde Coletiva

No description available.

Yes / ... Sustaining a sport-related concussion (SRC) has been associated with negative consequences to emotion and cognition in recent years,4,5 and head impacts are no different.1 Moreover, there is a consistent link reported with neurodegenerative diseases such as motor-neuron disease, Parkinson’s disease, and dementia. Although this is well-known within the scientific community, and becoming so in the general population, we still place children at risk. Promoting attitude change toward SRC and head impacts in sport is difficult enough with adults as many are accustomed to the way their contact sports are played and spectated. However, a redeeming feature for many researchers is that the evidence is there, and the rhetoric is being discussed in the mainstream media across the world.

The Transmissible Spongiform Encephalopathies (TSEs) or “prion” diseases are a group of fatal neurodegenerative diseases the aetiology of which is not fully understood. These diseases are characterised by a number of pathological changes in the central nervous system (CNS) including; vacuolation of the neuropil, gliosis and deposition of PrPSc; the abnormal form of the host glycoprotein PrP. Although the major pathology in these diseases is associated with the CNS the immune system is central to the pathogenesis of many natural and experimental TSEs including natural scrapie in sheep, chronic wasting disease in free ranging and captive deer and variant CJD (vCJD) in humans. Unlike many infectious diseases where deficiencies in immune function are opportunistic for the invading pathogen a competent immune system is required for efficient TSE infection via peripheral routes. As infection of the lymphoid tissues in many TSEs can occur many months before the detection of infectivity in the CNS, the determination of those cells in the lymphoid system has been the focus of much research and a number of studies now point towards the importance of the follicular dendritic cell (FDC), a long-lived radio resistant cell, in TSE pathogenesis. The involvement of FDCs in peripheral TSE pathogenesis relates to the inability of ionising radiation to influence pathogenesis, the association of PrP protein with FDCs in both uninfected and infected lymphoid tissues, and the demonstration that TSE pathogenesis is severely impaired in mice devoid of these cells. The aims of this thesis were to further understand the role of FDCs in the pathogenesis of a range of mouse-adapted experimental TSE strains and to determine if peripherally acquired TSE infections are influenced by host age or by stimulation of the immune system. Using chimaeric mouse models where a mismatch in the expression of PrP protein between FDCs and lymphoid/myeloid cells was produced, further evidence for a critical role for in the pathogenesis of the ME7 TSE strain was produced. Although these findings produced strong evidence that FDCs were important for the ME7 strain the possibility that different TSE strains may target different cell types in the peripheral lymphoid system was explored using a range of mice with specific immunological defects. Infection of these mice with several experimental TSE strains showed that the presence of mature FDCs was also important for the pathogenesis of the strains tested. Clinical cases of vCJD have been confined almost exclusively to young adults, although the reasons behind this apparent age-related susceptibility are not fully understood. The capacity of the immune system to mediate immune responses to pathogens declines with age as a result of impaired lymphocyte and FDC function. As FDCs are critically involved in the pathogenesis of many TSEs, including vCJD, it was hypothesised that an aging immune system may impair disease pathogenesis. Peripheral infection of senescent mice failed to produce clinical disease during lifespan, although evidence of disease transmission, was detected in a proportion of aged mice. These findings demonstrate that this inefficient disease transmission, as a consequence of age, may lead to considerable levels of sub-clinical disease within the population. Finally the influence of immune system stimulation, by the generation of a humoral immune response, on peripheral TSE pathogenesis was investigated. These findings demonstrated that immunisation can influence pathogenesis, but only during the early stages of infection prior to spread to the CNS. These data imply that modulation of the immune system does not alter TSE pathogenesis once disease has been initiated in the CNS. Finally, these studies have found some preliminary evidence that TSE infection may induce FDC activation suggesting that TSE infection may influence the immune response. Together, these data show that a functional immune system and specifically, the presence of mature FDCs, are central to the pathogenesis of peripherally acquired TSE infections.