Made available in DSpace on 2014-10-09T12:24:01Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:07:55Z (GMT). No. of bitstreams: 1 00481.pdf: 828758 bytes, checksum: 1c5f5457d167dcdae526c01f18297ab6 (MD5) / Dissertacao (Mestrado) / IEA/D / Instituto de Biociencias, Universidade de Sao Paulo - IB/USP

Background: Chronic obstructive pulmonary disease (COPD) is a devastating illness that affects 4.3% of the population of British Columbia over the age of 45 years. Asthma is known to coexist in 10-20% of individuals with obstructive lung disease, and adds to the substantial burden of illness posed by COPD alone. Inhaled corticosteroids (ICS) are currently recommended for the management of COPD among individuals with frequent exacerbations; however, the ability of inhaled corticosteroids to reduce death and hospitalizations among individuals with COPD is controversial. Less is known about the effectiveness of ICS among individuals who are afflicted with both COPD and asthma. Methods: We used a retrospective cohort study design and administrative data to estimate the relative effectiveness of ICS in reducing hospitalizations or death among individuals with concomitant asthma and COPD, compared with individuals with COPD alone. We used an extended Cox model to estimate this association, with a time-varying measure of exposure to ICS. Results: We did not find any association between ICS and hazard of death or hospitalization among individuals with COPD alone (HR = 0.99; 95% CI: 0.94 – 1.05), however the hazard was 18% lower (HR = 0.82; 95% CI: 0.69-0.99) among individuals with concomitant disease. Conclusions: Individuals with combined COPD and asthma show significant benefit from the use of ICS and are more responsive to the effects of ICS than individuals with COPD alone. / Medicine, Faculty of / Population and Public Health (SPPH), School of / Graduate

Bronchopulmonary dysplasia (BPD) is diagnosed in approximately 40% of extremely preterm infants, those born before 28 weeks’ gestational age, and affects roughly 10,000 to 15,000 infants annually in the United States alone. Current treatment of BPD aims to not only aid in the survival of the infant but to also minimize further lung damage and promote physiologic growth to enhance lung development and repair. As the pathogenesis of the disease is multifactorial, including pre-, peri-, and postnatal factors, treatment and prevention approaches to BPD are diverse and include both medical treatment and ventilation strategies. Late postnatal steroids (> 7 days of life) have been proven to facilitate extubation and reduce the incidence of BPD in preterm infants. However, there is evidence that the use of steroids may contribute to increased rates of neurological impairment, including increased incidence of cerebral palsy. Given these findings, the American Academy of Pediatrics (AAP) guidelines recommend against the routine use of systemic steroids in the prevention of BPD and instead argues its use should be limited to infants who are considered extremely high-risk. The aim of this study is to determine whether the use of postnatal dexamethasone decreases the risk of developing BPD in a subset of high-risk infants, those with a concomitant diagnosis of necrotizing enterocolitis or late onset sepsis. A sample size of 200 extremely preterm infants with either necrotizing enterocolitis (NEC) and/or sepsis will be enrolled in a multi-center double-blinded randomized controlled trial comparing a low-dose dexamethasone taper and saline placebo. Infants will be evaluated for the development of BPD based on respiratory support and supplemental oxygen requirement at 36 weeks’ post-menstrual age (PMA). Infants will also be evaluated for presence of neurodevelopmental outcomes at 18- to 22-months follow-up. The results of this proposed study will build the evidence base for the safety and efficacy of postnatal steroids in the prevention of BPD in a subset of high risk, extremely preterm infants. This will help to establish a more detailed characterization of infants for which the benefits of steroids outweigh the risks. The results will enable clinicians to make more informed decisions regarding the medical care of extremely preterm infants and more accurately counsel parents on the incidence of subsequent BPD development, as well as long-term morbidities.

The clinical manifestations, including variations, of the Stevens-Johnson syndrome (SJS) are reviewed. Lesions of the skin, eye, and mucous membranes are described and discussed. The potential complications and therapeutic approaches are outlined. Finally, the review discusses the controversy over the use of systemic corticosteroids in this syndrome.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18171号 / 医博第3891号 / 新制||医||1003(附属図書館) / 31029 / 京都大学大学院医学研究科医学専攻 / (主査)教授 三森 経世, 教授 生田 宏一, 教授 河本 宏 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

The two options for treatment of the inflammatory bowel disease Crohn’s Disease are surgery and pharmacotherapy. Pharmacotherapy with the goal of inducing and maintaining remission is the preferred treatment route, but the current medications are not entirely effective in achieving these goals. Approximately half of Crohn’s Disease patients will be required to have surgical bowel resection within 20 years of diagnosis, and many patients are at higher risk of adverse events such as cancer, either directly as a result of Crohn’s Disease or due to side-effects of the drugs used to treat the condition. Medical management of the disease is very complicated and there is a relative lack of uniformity in treatment. Different drugs used either in monotherapy, sequential therapy, or combination therapy produce differing levels of efficacy and different outcomes. This analysis provides an overview of the four major classes of drugs used in the treatment of Crohn’s Disease and a discussion of the overall efficacy of the different methods of treatment. While more studies need to be conducted into the differing outcomes of monotherapy, sequential therapy, and combination therapy, it appears as though any treatment involving the use of biologics such as tumor necrosis factor alpha (TNF-alpha) inhibitors results in improved outcomes relative to treatment styles that lack the use of biologics.

Stress can be defined as a condition in which the dynamic equilibrium of the body is disturbed and several studies have demonstrated the action of some corticosteroids modulating stress situations, such as reproduction. However, the role of corticosteroids in fish reproduction can be either positive or deleterious, depending on many variables. In the Astyanax genus, the same stress stimulus can successfully induce the reproduction in Astyanax altiparanae, but not in other species of the same genus. Therefore, the aim of this study was to analyze cortisol and progestogens plasma levels and receptor gene expression in the ovaries of A. altiparanae, a teleost species that successfully reproduce using crowding and water level drawdown as stimulus. Three experimental groups were considered: Stress (high stocking density and water level drawdown); human chorionic gonadotropin (hCG, a positive control); and Saline (a control group). Females were sampled at three different moments of the artificial reproduction experiment, initial, intermediary and at spawning. Indices of spawning performance as, fertilization rate, Gonadosomatic Index (GSI), as well as histological analysis of the ovaries were carried out. 17α-hydroxiprogesterone (17 OHP) and cortisol (CORT) levels were measured in plasma by ELISA. Additionally, the ovarian gene expression of CORT and 17 OHP receptors (CR and PR) were carried out by Real-time quantitative PCR. Females from Stress and hCG groups released a larger volume of eggs when compared with females from the Saline (Control) group. Females from Stress group presented a decrease in GSI and ovaries mass at spawning, and many post ovulatory follicles (POFs) were present in the ovaries after spawning. At the intermediary sampling, plasma levels of CORT increased in females from the Stress group, but not in the hCG and Saline groups. 17 OHP levels did not change during the experiment. PR gene was more expressed in females from hCG group throughout the experiment, but CR gene expression did not change. We suggest a possible role of CORT as an inducing agent in ovulation and/or spawning of A. altiparanae. CR and PR did not seem to be the candidates for triggering ovulation, so the relationship between the derivative of progesterone (17,20DHP) should be deeper studied, as well as the role of CORT and different progestagens in A. altiparanae reproduction / O estresse pode ser definido como uma condição na qual o equilíbrio dinâmico do corpo é perturbado e muitos estudos têm demonstrado a ação de alguns corticosteroides modulando situações de stress, tal como a reprodução. No entanto, o papel dos corticosteroides na reprodução de peixes pode ser positivo ou deletério, dependendo de muitas variáveis. No gênero Astyanax, o mesmo estímulo de estresse pode induzir com sucesso a reprodução em A. altiparanae, mas não em outras espécies do mesmo gênero. Portanto, o objetivo deste estudo foi analisar os níveis de cortisol e progestágenos no plasma e a expressão dos receptores destes esteroides nos ovários de A. altiparanae, espécie de teleósteo que consegue se reproduzir com sucesso usando o aumento da densidade e variação no nível da água como um estímulo. Três grupos experimentais foram considerados: Estresse (alta densidade de estocagem e intenso fluxo de água); Gonadotropina Coriônica Humana (hCG, um controle positivo); e Salina (grupo controle). As fêmeas foram amostradas em três diferentes momentos do experimento de reprodução artificial, inicial, intermediário e na desova. Índices de desempenho de desova como, taxa de fertilização, Índice Gonadossomático (IGS), bem como a análise histológica dos ovários foram considerados. Os níveis de 17α-hydroxiprogesterone (17 OHP) e cortisol (CORT) foram medidos em amostras de plasma por ELISA. Além disso, a expressão de genes de receptores de CORT (CR) e 17 OHP (PR) foram analisadas nos ovários por qPCR. Fêmeas dos grupos Estresse e hCG desovaram um volume maior de ovos quando comparadas às fêmeas do grupo Salina (controle). As fêmeas do grupo Estresse apresentaram também uma redução nos valores do IGS e na massa dos ovários no momento da desova, e muitos folículos pós - ovulatórios estavam presentes nos ovários após a desova. Na amostragem do período intermediário, os níveis plasmáticos de CORT aumentaram nas fêmeas do grupo de Estresse, mas não nos grupos de hCG e Salina. A concentração de 17OHP não se alterou durante o experimento ou entre os grupos. O PR foi mais expresso em fêmeas do grupo hCG ao longo do experimento, e a expressão do CR não se alterou. Sugerimos um possível papel de CORT como um agente indutor na ovulação e / ou de desova de A. altiparanae. No entanto, CR e PR não parecem ser os candidatos para desencadear a ovulação, de modo que a relação entre receptores derivados PR (17,20DHP) devem ser mais profundamente estudados, bem como a efetiva ação de CORT e diferentes progestágenos na reprodução de A. altiparanae

Foram estudados os efeitos da metilprednisolona na traquéia de coelhas albinas adultas da raça Nova Zelândia. O objetivo deste estudo foi investigar os efeitos potenciais desta substância nas propriedades biomecânicas da traquéia de coelhas por meio de ensaio de tração axial. Os animais foram divididos em dois grupos. Dez coelhas do grupo controle receberam por via subcutânea 2 mg/Kg/dia de metilprednisolona diluída em solução salina. As dez coelhas do grupo controle receberam também de modo subcutâneo volumes proporcionais de solução salina. Após 21 dias, os animais foram sacrificados e suas traquéias submetidas a ensaio de tração e estudo histopatológico. Os animais do grupo experimental apresentaram peso significantemente inferior ao do grupo controle no final do tratamento (C = 3996 ± 314 g x E = 3555 ± 373 g). Os grupos não diferiram do ponto de vista estatístico quanto as seguintes variáveis: carga no limite de proporcionalidade (C = 8,94 ± 1,68 N x E = 8,93 ± 1,52 N); carga máxima (C = 9,12 ± 2,2 N x E = 9,57 ± 1,90 N); alongamento no limite de proporcionalidade (C = (683 ± 2,08) x '10 POT.-3' m x E = (6,05 ± 1,50) x '10 POT.-3' m); alongamento máximo (C = (7,44 ± 2,60) x '10 POT.-3' m x E = (6,85 ± 1,55) x '10 POT.-3' m); energia absorvida na fase elástica (C = (28,70 ± 14,43) x '10 POT.-3' J x E = (27,75 ± 11,06) x '10 POT.-3' J); rigidez (C = (1,08 ± 0,41) x '10 POT.-3' N/m x E = (1,2 ± 0,37) x '10 POT.-3' N/m). Concluiu-se ao término deste estudo que não houve alterações morfológicas e biomecânicas das traquéias estudadas, no entanto, os animais do grupo experimental sofreram significante emagrecimento ao final do tratamento, quando comparado ao grupo experimental / The effects of methilprednisolona in the adult’s trachea albinos female rabbits were studied. The goal of this study was examine the potential effects of this armorial traction. The animals were divided in two groups. Ten female rabbits of control group received by way of subcutaneous 2mg/kg/day of salt bed diluted solution. These ten female rabbits of the control group also received by way of subcutaneous proportional volumes of salt bed solution. After 21 days, the animals were sacrificed and their trachea were subjected to traction tests and anatomical pathological studies. Animals of the experimental group presented inferior weight significant from the control group in the end of the treatment (C = 8,94 ± 314g X E = 3555 ± 373g). The groups didn’t differ from the statistic point of view as regards of the following variables: limit load of proportionality (C = 8,94 ± 1,68 N X E = 8,93 ± 1,52 N); maxim load (C = 9,12 ± 2,2 N X E = 9,57 ± 1,90 N); stretch out on the limit of proportionality (C = (683 ± 2,08) x '10 POT.-3' m X E = (6,05 ± 1,50) x '10 POT.-3' m); maxim stretch out (C = (7,44 ± 2,60) x '10 POT.-3' J X E = (6,85 ± 1,55) x '10 POT.-3' J); absorbed energy in the elastic phase (C = 28,70 ± 14,43) x '10 POT.-3' m J X E = (27,75 ± 11,06) x '10 POT.-3' J); rigidity (C = 1,08 ± 0,41) x '10 POT.-3' N/m X E = (1,2 + 0,37) x '10 POT.-3' N/m). It was concluded in the end of the treatment that there weren’t any morphological and biomechanical alterations of the trachea studied, although, the animals of the experimental group suffered a significant slimming in the end of the treatment when compared with the experimental group

ix, 120 p. : ill. (some col.) A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number. / Gene duplication underlies the evolution of many protein functions and is a known stimulus for molecular innovation. Many models exist to explain the maintenance of duplicate genes in the genome and the dynamics that drive the evolution of novel protein functions; few if any of these models, however, incorporate knowledge of how protein structures and functions actually evolve. A growing body of work on the historical mechanisms of molecular evolution and the ways in which proteins evolve in the lab has provided profound insights into the ways in which proteins respond to mutation, selection, and drift. Evolutionary models of duplicate gene evolution could greatly benefit from the knowledge gained from these mechanistic studies of protein evolution. My dissertation seeks to address this gap in knowledge by reconstructing the process by which novel steroid signaling pathways evolved after gene duplication. I focus specifically on a class of hormones called corticosteroids--critical regulators of the stress response, metabolism, and immunity--and the mineralocorticoid and glucocorticoid receptors that mediate the steroid response. Both the enzymes that synthesize corticosteroids and the hormone receptors are the result of ancient gene duplication events, and I make use of methods in phylogenetics, molecular biology, and structural biology to reconstruct the mechanisms and dynamics by which they evolved. This dissertation comprises three separate but complementary studies that illuminate the origins of corticosteroid signaling. In the first project, I show how lineage-specific steroid signaling arose in elasmobranchs as a novel hormone exploited the structural promiscuity of preexistent receptors. Next, I describe how degenerative and stabilizing mutations defined the divergence of the glucocorticoid receptor after gene duplication. And finally, I use phylogenetic and functional analyses to reconstruct the origins of corticosteroid synthesis with the duplication of enzymes in the steroid synthesis pathway. Together, I provide a comprehensive reconstruction of the evolution of corticosteroid signaling. This work also highlights specific evolutionary mechanisms--molecular exploitation, structural and functional promiscuity, degenerative mutations, and stabilizing mutations--that could drive the evolution of novel protein functions after gene duplication. This dissertation includes both previously published and unpublished co-authored materials. / Committee in charge: Patrick Phillips, Chairperson, Biology; Joseph Thornton, Advisor, Biology; William Cresko, Member, Biology; John Postlethwait, Member, Biology; Kenneth Prehoda, Outside Member, Chemistry

Foram estudados os efeitos da metilprednisolona na traquéia de coelhas albinas adultas da raça Nova Zelândia. O objetivo deste estudo foi investigar os efeitos potenciais desta substância nas propriedades biomecânicas da traquéia de coelhas por meio de ensaio de tração axial. Os animais foram divididos em dois grupos. Dez coelhas do grupo controle receberam por via subcutânea 2 mg/Kg/dia de metilprednisolona diluída em solução salina. As dez coelhas do grupo controle receberam também de modo subcutâneo volumes proporcionais de solução salina. Após 21 dias, os animais foram sacrificados e suas traquéias submetidas a ensaio de tração e estudo histopatológico. Os animais do grupo experimental apresentaram peso significantemente inferior ao do grupo controle no final do tratamento (C = 3996 ± 314 g x E = 3555 ± 373 g). Os grupos não diferiram do ponto de vista estatístico quanto as seguintes variáveis: carga no limite de proporcionalidade (C = 8,94 ± 1,68 N x E = 8,93 ± 1,52 N); carga máxima (C = 9,12 ± 2,2 N x E = 9,57 ± 1,90 N); alongamento no limite de proporcionalidade (C = (683 ± 2,08) x '10 POT.-3' m x E = (6,05 ± 1,50) x '10 POT.-3' m); alongamento máximo (C = (7,44 ± 2,60) x '10 POT.-3' m x E = (6,85 ± 1,55) x '10 POT.-3' m); energia absorvida na fase elástica (C = (28,70 ± 14,43) x '10 POT.-3' J x E = (27,75 ± 11,06) x '10 POT.-3' J); rigidez (C = (1,08 ± 0,41) x '10 POT.-3' N/m x E = (1,2 ± 0,37) x '10 POT.-3' N/m). Concluiu-se ao término deste estudo que não houve alterações morfológicas e biomecânicas das traquéias estudadas, no entanto, os animais do grupo experimental sofreram significante emagrecimento ao final do tratamento, quando comparado ao grupo experimental / The effects of methilprednisolona in the adult’s trachea albinos female rabbits were studied. The goal of this study was examine the potential effects of this armorial traction. The animals were divided in two groups. Ten female rabbits of control group received by way of subcutaneous 2mg/kg/day of salt bed diluted solution. These ten female rabbits of the control group also received by way of subcutaneous proportional volumes of salt bed solution. After 21 days, the animals were sacrificed and their trachea were subjected to traction tests and anatomical pathological studies. Animals of the experimental group presented inferior weight significant from the control group in the end of the treatment (C = 8,94 ± 314g X E = 3555 ± 373g). The groups didn’t differ from the statistic point of view as regards of the following variables: limit load of proportionality (C = 8,94 ± 1,68 N X E = 8,93 ± 1,52 N); maxim load (C = 9,12 ± 2,2 N X E = 9,57 ± 1,90 N); stretch out on the limit of proportionality (C = (683 ± 2,08) x '10 POT.-3' m X E = (6,05 ± 1,50) x '10 POT.-3' m); maxim stretch out (C = (7,44 ± 2,60) x '10 POT.-3' J X E = (6,85 ± 1,55) x '10 POT.-3' J); absorbed energy in the elastic phase (C = 28,70 ± 14,43) x '10 POT.-3' m J X E = (27,75 ± 11,06) x '10 POT.-3' J); rigidity (C = 1,08 ± 0,41) x '10 POT.-3' N/m X E = (1,2 + 0,37) x '10 POT.-3' N/m). It was concluded in the end of the treatment that there weren’t any morphological and biomechanical alterations of the trachea studied, although, the animals of the experimental group suffered a significant slimming in the end of the treatment when compared with the experimental group