Submitted by Eduardo Barros de Almeida Silva (eduardo.philippe@ufpe.br) on 2015-04-14T13:18:30Z No. of bitstreams: 2 Dissertaçao Diego B. de Queiroz.pdf: 1261024 bytes, checksum: 62badf76657df762675be758ddab09c3 (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) / Made available in DSpace on 2015-04-14T13:18:31Z (GMT). No. of bitstreams: 2 Dissertaçao Diego B. de Queiroz.pdf: 1261024 bytes, checksum: 62badf76657df762675be758ddab09c3 (MD5) license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Previous issue date: 2010 / FACEPE / O conceito da “programação fetal” sugere que um individuo pode ser “programado” durante as fases intra-uterina e perinatal para desenvolver doenças na vida adulta. A literatura mostra que o diabetes materno produz importantes alterações metabólicas na prole adulta, predispondo-os ao surgimento de doenças cardiovasculares. Este estudo analisou se o Diabetes mellitus durante a gravidez produz alterações nos parâmetros cardiovasculares em preparações de artéria aorta na prole adulta em diferentes idades e os possíveis mecanismos envolvidos nestas alterações. O diabetes materno foi induzido por estreptozotocina em ratas Wistar. Alterações na homeostasia da glicose, como intolerância a glicose e resistência à insulina foram observados nos ratos adultos com 3, 6 e 12 meses de idade provenientes de mães diabéticas (STZ), como também uma redução do peso corporal. Através da medida direta da PA, a PAM dos ratos com 6 e 12 meses de idade provenientes de ratas diabéticas apresentaram elevadas quando comparado aos seus respectivos controles. Ao analisar a reatividade vascular na artéria aorta dos ratos STZ12M, estes apresentaram modificações significativas no relaxamento à acetilcolina e na contração induzida pela fenilefrina, demonstrando um quadro de disfunção endotelial. Para avaliar o envolvimento dos metabolitos derivados do acido araquidônico neste quadro de disfunção, foram utilizados inibidores da COX-1 e 2 (indometacina) ou da COX-2 (NS-398), onde ambos aumentaram o relaxamento e reduziram a contratilidade, significativamente, nas artérias dos ratos STZ12M. A participação do TXA2 e de outros derivados vasoconstritores da COX-2, foi verificada com o antagonista do receptor TP (SQ29548), o inibidor da síntese do TXA2 (furegrelato), o antagonista dos receptores EP1, EP2 e EP3 (AH 8809) e do receptor FP (AL8810). Em aorta dos ratos STZ12M, os valores percentuais de relaxamento e contração compatível com a observada na presença dos inibidores de COX somente foi alcançada quando pré-incubadas na presença do SQ29548 + AH6809, A presença do AL8810 não induziu qualquer efeito adicional nestes parâmetros. Esses resultados sugerem que o Diabetes mellitus durante a fase intrauterina e perinatal causa modificações metabólicas e cardiovasculares de maneira tempo-dependente em ratos adultos. Além disso, também demonstram que a redução da função endotelial está associada com o aumento da participação de prostanóides vasoconstritores derivados da isoforma induzível da COX (COX-2).

Indiana University-Purdue University Indianapolis (IUPUI) / It has recently been shown that the gamma subtype of the peroxisome proliferator-activated receptor (PPARγ) is a target of ultraviolet B (290-320 nm; UVB) irradiation, and that PPARγ activation is necessary for full UVB-induced cyclooxygenase-2 (COX-2) induction. However, the biological significance of PPARγ activation in cutaneous photobiology is unknown. Acute UVB irradiation results in a characteristic series of events in the epidermis which includes: an initial edema response and subsequent inflammation, COX-2 induction, apoptosis, and a delayed hyperproliferative response. Therefore, the regulatory role of PPARγ activation was examined in this acute photoresponse using a topical application of the potent, irreversible PPARγ antagonist, GW9962. GW9662 was applied to the epidermis of SKH1 hairless albino mice at increasing doses (0.01-1.0mM) prior to UVB irradiation. The photobiological responses were examined through RT-PCR, skin thickness measurements, and immunohistochemistry, at 24 and 72 hours after UVB-irradiation. At the highest dose, GW9622 significantly inhibited UVB-induced inflammation, as measured by COX-2 induction at both 24 and 72 hrs. Inflammation assessed by skin thickness measurements indicated that lower doses mildly increased inflammation at 72 hrs, but suppressed inflammation at the highest dose. In contrast, GW9662 treatment dose dependently augmented UVB-induced apoptosis at 24 hours, while affecting the delayed hyperproliferative response at 72 hours in an inverse dose-response manner. The results from this study suggest that PPARγ is a key regulator of these photobiological responses. Because these responses are well known to be involved in tumor development and progression, this study also suggests a potential role for PPARγ in UVB-induced skin cancers.

The objective of the current work is to develop novel procedures for the analysis of functional data and apply them for investigation of gender disparity in survival of lung cancer patients. In particular, we use the time-dependent Cox proportional hazards model where the clinical information is incorporated via time-independent covariates, and the current age is modeled using its expansion over wavelet basis functions. We developed computer algorithms and applied them to the data set which is derived from Florida Cancer Data depository data set (all personal information which allows to identify patients was eliminated). We also studied the problem of estimation of a continuous matrix-variate function of low rank. We have constructed an estimator of such function using its basis expansion and subsequent solution of an optimization problem with the Schattennorm penalty. We derive an oracle inequality for the constructed estimator, study its properties via simulations and apply the procedure to analysis of Dynamic Contrast medical imaging data.

No description available.

The purpose of this study was to determine the safety and pharmacokinetic profile of firocoxib in healthy neonatal foals. Foals are more sensitive to the side effects of nonsteroidal anti-inflammatory drugs, (NSAIDs), particularly due to immature renal clearance mechanisms and ulcerogenic effects on gastric mucosa. Firocoxib, a novel second generation NSAID, is reported to have reduced side effects due to its COX-2 selectivity. The pharmacokinetic profile of firocoxib in neonates has not been established, making reliable dosing difficult. We hypothesized that firocoxib given per os at the labeled dose to neonatal foals would be absorbed and not be associated with clinically significant adverse events. Seven healthy American Quarter Horse foals of mixed gender were administered 0.1mg/kg firocoxib orally q24h for nine consecutive days, commencing at 36h of age. Blood samples were collected for firocoxib analysis using high pressure liquid chromatography with fluorescence detection at 0 (dose #1 only), 0.25, 0.5, 1, 2, 4, 8, 16 and 24 hours after doses #1, 5 and 9. For all other doses (2, 3, 4, 6, 7 and 8) blood was collected immediately prior to the next dose (24 hour trough). Elimination samples (36, 48, 72, 96, 120 and 144 hours) were collected after dose #9. Safety was assessed via physical examinations, changes in body weight, gastroscopy, complete blood count, serum biochemistry and urinalysis. Firocoxib was rapidly absorbed following oral administration with minimal accumulation after repeat dosing. After the initial dose, an average peak serum concentration (Cmax) of 89.50 ° 53.36 ng/mL (mean ° SD) was achieved (Tmax) in 0.54 ° 0.65 hours. Steady state was obtained after approximately 4 doses and the average maximum concentration (Cavg) in serum was 39.1 ° 8.4 ng/mL. After the final dose, the mean terminal half-life (T½?») was 10.46 ° 4.97 hours. Firocoxib was not detected in plasma 72 hours after the final dose (<2ng/mL). Bioavailability could not be determined as currently, there is no accompanying intravenous dose of firocoxib for this age group to permit the calculation. No significant abnormalities were noted on blood work, urinalysis or gastroscopy. This study demonstrated that firocoxib is absorbed after oral administration in neonatal foals with no observable adverse effects after multiple doses. / Master of Science

This dissertation is a survey of the homiletical contributions of James W. Cox with particular emphasis upon his writings and methodology. Chapter 1 is an introductory chapter that explains the significance of this study. Heretofore no scholar has written on Cox as the sole subject of research. Chapter 2 is biographical, tracing Cox's background as far back as possible, then moving forward chronologically, leading up to the beginning of his teaching career at The Southern Baptist Theological Seminary. Attention is given to areas such as Cox's conversion experience, call to ministry, education, family, and occasions for pastorates. Chapter 3 is an overview of Cox's written homiletical contributions. The emphasis of this chapter is upon Cox's major homiletical books and articles. Interaction with other homileticians is provided where appropriate. Chapter 4 surveys Cox's hermeneutics for preaching. The focus of this section concerns Cox's convictions about Scripture and the location of meaning in a text. Chapter 5 examines Cox's homiletical method. The chapter surveys Cox's teaching and methodology concerning the preparation and delivery of sermons. Chapter 6 analyzes Cox's sermons. Eight sermons are critiqued according to guidelines Cox himself sets forth in his writings. Chapter 7 is an overview of how Cox is perceived by his colleagues. The author has excerpted critical comments from scholars who have reviewed Cox's published homiletical writings and has provided comments from five of Cox's colleagues who were interviewed for this chapter. Chapter 8 is a summary and conclusion. The significant homiletical contributions are summarized from each section of the dissertation. The dissertation includes six appendices: (1) Time-Line of Significant Events in Cox's Life; (2) Examples of Sermon Preliminaries; (3) Guiding Principles for the Interpretation of the Bible; (4) "A Meditation" (reproduction of weekly article written when Cox was a teenager); (5) Preaching Engagements; and (6) Miscellaneous Anecdotes and Information. / This item is only available to students and faculty of the Southern Baptist Theological Seminary. If you are not associated with SBTS, this dissertation may be purchased from <a href="http://disexpress.umi.com/dxweb">http://disexpress.umi.com/dxweb</a> or downloaded through ProQuest's Dissertation and Theses database if your institution subscribes to that service.

Les modèles de régression dans le cadre des données censurées supposent comme pour tous modèles de régression que l'on ait plus d'observations que de descripteurs et des descripteurs pas trop corrélés entre eux. Ces hypothèses ne sont pas souvent vérifiées dans la pratique et les approches classiques deviennent caduques. C'est le cas par exemple en pharmacogénomique lorsque l'on cherche à prédire la probabilité de survie de patients à partir de profiles, ou signatures transcriptomiques, construits à partir de l'expression de milliers de gènes. L'objectif de cette thèse est d'apporter une solution à ce problème en utilisant les principes de la régression PLS. Le modèle PLS-Cox qui est proposé est issu d'une généralisation de la régression PLS à tous modèles de régression. Il fournit une alternative régularisée aux modèles de survie en grande dimension (p>>n). L'utilisation d'une reparamétrisation de type « Kernel » des algorithmes PLS a permis en outre de développer des solutions à la fois très rapides et particulièrement utiles en très grande dimension, mais aussi adaptées pour l'analyse de structures non-linéaires des données. Une autre solution à ce problème, rapide et simple à mettre en œuvre, a été développée à partir des résidus de la déviance. Une alternative à PLS-NIPALS a été proposée pour la gestion des valeurs manquantes en introduisant le concept d'imputation multiple en régression PLS simple et généralisée. Finalement, on s'est intéressé à la recherche de modèles plus parcimonieux en proposant une approche de type « Thresholding PLS » qui opère implicitement par sélection des variables.

Analysis of functional connectivity of simultaneously recorded multiple spike trains is one of the major issues in the neuroscience. The progress of the statistical methods to the analysis of functional connectivity of multiple spike trains is relatively slow. In this thesis two statistical techniques are presented to the analysis of functional connectivity of multiple spike trains. The first method is known as the modified correlation grid (MCG). This method is based on the calculation of cross-correlation function of all possible pair-wise spike trains. The second technique is known as the Cox method. This method is based on the modulated renewal process (MRP). The original paper on the application of the Cox method (Borisyuk et al., 1985) to neuroscience data was used to analyse only pairs and triplets of spike trains. This method is further developed in this thesis to support simultaneously recorded of any possible set of multiple spike trains. A probabilistic model is developed to test the Cox method. This probabilistic model is based on the MRP. Due to the common probabilistic basis of the probabilistic model and the Cox method, the probabilistic model is a convenient technique to test the Cox method. A new technique based on a pair-wise analysis of Cox method known as the Cox metric is presented to find the groups of coupled spike trains. Another new technique known as motif analysis is introduced which is useful in identifying interconnections among the spike trains. This technique is based on the triplet-wise analysis of the Cox method. All these methods are applied to several sets of spike trains generated by the Enhanced Leaky and Integrate Fire (ELIF) model. The results suggest that these methods are successful for analysing functional connectivity of simultaneously recorded multiple spike trains. These methods are also applied to an experimental data recorded from cat’s visual cortex. The connection matrix derived from the experimental data by the Cox method is further applied to the graph theoretical methods.

Herpes Zoster é uma doença causada pela reativação do vírus Varicela Zoster nos gânglios sensoriais, caracterizada pelo desenvolvimento de lesões na pele e dor. Não há modelos animais disponíveis para estudo da patofisiologia da doença. No entanto, um modelo murino que utiliza o HSV-1 tem sido usado para tal fim, visto que os animais desenvolvem lesões zosteriformes e desenvolvem hipersensibilidade na pata infectada. Não há dados na literatura acerca da resposta imune que se desenvolve nos gânglios da raiz dorsal destes animais. Logo, o objetivo deste trabalho foi o de avaliar células e mediadores inflamatórios presentes nos gânglios da raiz dorsal e sua relação com a hiperalgesia durante a infecção cutânea por HSV-1. Durante a fase aguda da infecção, os camundongos desenvolveram hiperalgesia nas patas ipsilaterais a partir do 3 dia pós-infecção, que perdurou até o 7 dia pós-infecção. A maior carga viral foi detectada nos gânglios L4, L5 e L6, os quais compõem o nervo ciático, que inerva a área infectada. O tratamento dos animais infectados com dexametasona ou fucoidina resultou na redução do comportamento de hiperalgesia, a partir do 5 dia pós-infecção, que corresponde ao período em que a migração de leucócitos passa a aumentar nos gânglios da raiz dorsal. Macrófagos, neutrófilos e linfócitos T CD4 foram detectados nos gânglios durante a infecção aguda. No entanto, linfócitos T CD8 estavam ausentes. A expressão do mRNA de TNF- e COX-2 estava aumentada nos gânglios, e o tratamento de animais infectados com drogas inibidoras de ambos resultou na redução da hiperalgesia. Os receptores do tipo Toll-like e da IL-1 não participam da geração da hipersensibilidade herpética. Após 50 dias da infecção, constatou-se que alguns animais apresentavam comportamento de hiperalgesia irreversível, semelhante à neuralgia pós-herpética humana (NPH). Não houve diferença significativa na incidência da NPH em animais de linhagens ou sexos diferentes. Ainda, o tratamento com drogas anticonvulsivantes e antidepressivas, mas não com morfina e anti-inflamatórios, resultou na redução transiente da hiperalgesia. Neste período, não há participação da inflamação na manutenção da hiperalgesia. A expressão de TNF- e COX-2 retorna aos níveis basais, e não são mais detectados neutrófilos e macrófagos. No entanto, a migração de linfócitos T CD4+ e CD8+ aos gânglios aumenta de maneira tempo-dependente. Durante a NPH, detectou-se uma intensa ativação das células satélites gliais, que contribuem para a manutenção da hiperalgesia pós-herpética. Nossos resultados demonstram que a manutenção hiperalgesia herpética é resultado da intensa resposta inflamatória que ocorre nos gânglios da raiz dorsal infectados, com aumento da produção de TNF- e COX-2, importantes mediadores para a hipersensibilidade. No entanto, durante a neuralgia pós-herpética, não há participação de células ou mediadores inflamatórios, mas de células da glia, as quais são importantes na manutenção da hiperalgesia. / Herpes Zoster is a disease caused by reactivation of varicella zoster virus in sensory ganglia, characterized by dermal rash and pain. There are no animal models available to study the pathophysiology of the disease. A murine model of HSV-1 infection on the hind paw skin has been used to study HZ, since mice develop HZ-like skin lesions and pain-related responses. There are no data available about the immune response in dorsal root ganglion (DRG) of these mice. Thus, the aim of this study was to evaluate cells and inflammatory mediators present in DRGs and its relationship with hiperalgesia during HSV-1 cutaneous infection. During the acute phase of infection, mice developed hyperalgesia in ipsilateral paws from 3 days post-infection, which persisted until 7 days post-infection. The highest viral load was detected in ganglia L4, L5 and L6. Treatment of infected mice with fucoidin or dexamethasone resulted in the reduction of hyperalgesic behavior, from the 5th post-infection day, which corresponds to the period in which leukocyte migration increase in the dorsal root ganglia. Macrophages, neutrophils and CD4 + T lymphocytes were detected in the ganglia during acute infection. However, CD8 + T lymphocytes were absent. The mRNA expression of TNF- and COX-2 was increased in dorsal root ganglia, and the treatment of infected mice with drugs that inhibits both mediators resulted in reduced hyperalgesia. The Toll-like receptors and IL-1 does not participate in the generation of herpetic hypersensitivity. After 50 days of infection, it was found that some animals presented irreversible hyperalgesic behavior, like human post-herpetic neuralgia (PHN). There was no significant difference in the incidence of PHN in animals of different genders or strains. Furthermore, treatment with anticonvulsant and antidepressant drugs, but not morphine and anti-inflammatory, resulted in transient reduction of hyperalgesia. In this period, there is no participation of inflammation in the hyperalgesia maintenance of. The expression of TNF- and COX-2 returns to baseline levels, and neutrophils and macrophages are no longer detected. However, the migration of CD4 + and CD8 + to ganglia increases in a time-dependent manner. During NPH, an intense activation of glial cells satellites was detected, that contributes to the maintenance of post-herpetic hyperalgesia. Our results demonstrate that herpetic hyperalgesia maintenance is a result of an intense inflammatory response that occurs in the infected dorsal root ganglia, with increased production of TNF- and COX-2. However, during post-herpetic neuralgia, there is involvement of glial cells, which are important in hyperalgesia maintenance.

O objetivo deste trabalho foi comparar o desempenho do modelo de riscos proporcionais de Cox convencional, modelo de Cox modificado quando os riscos não são proporcionais e o modelo de análise de sobrevida baseado na teoria de processos de contagem. Para tanto utilizou-se uma coorte de 648 pacientes portadores de câncer de pênis, atendidos no Departamento de Cirurgia Pélvica do Hospital A. C. Camargo, no período de 1953 a 1985. Dessa coorte foram selecionadas três amostras com o objetivo de validar internamente os resultados da análise de sobrevida do banco de dados original. Os resultados do modelo de riscos proporcionais de Cox, no banco de dados original, foram confirmados por uma das amostras desse conjunto de dados. Apenas o estadiamento N foi confirmado como fator prognóstico também nas outras duas amostras. O modelo de riscos proporcionais de Cox e o modelo de análise de sobrevida baseado na teoria de processos de contagem apresentaram resultados semelhantes, na definição dos fatores prognósticos dessa coorte de pacientes com câncer de pênis. O modelo utilizando processos de contagem é mais sofisticado, do ponto de vista matemático. Porém o modelo de Cox está disponível em grande número de pacotes estatísticos e a interpretação de seus coeficientes se faz com maior facilidade. Por isso, talvez, continue a ser a técnica estatística mais utilizada quando o objetivo do estudo é definir fatores prognósticos e grupos de risco. Os fatores prognósticos para a sobrevida de pacientes com câncer de pênis foram os estadiamentos T e N e o grau de diferenciação do tumor. Esses resultados foram ajustados pelo ano de início de tratamento no Hospital A.C. Camargo. Os pacientes com prognóstico favorável foram os que apresentaram tumor pequeno, sem presença de linfonodos clinicamente positivos, e tumor bem diferenciado. / The aim of this study was to compare the performance of the Cox proportional hazards model, the Cox model with time-dependent covariates and the survival model using the counting process theory. These methods were applied in a cohort of 648 patients with penile cancer treated at the Department of Pelvic Surgery, Hospital A.C. Camargo (São Paulo-Brazil), between 1953 and 1985. Three samples were selected from the total database in order to check the internal validity. The prognostic factors selected using the Cox proportional hazards model were the same in one sample. The only prognostic factor selected in all samples was the N stage. The T and N stages, and the grade of differentiation were independent prognostic factors of survival using both the Cox proportional hazards model and the survival,model using the counting process theory. The statistical significance was the same and even the values of estimation of the coefficients were very close. The survival model using the counting process is more sophisticated from the mathematical point of view, but the Cox model is more available in statistical software, and, probably because of this, is more applied in survival analysis than the model using the counting processo Patients with small tumors, clinically negatives nodes and well differentiated tumors showed a favorable prognosis. These results were adjusted by year of the beginning in the study.