This thesis consists of three chapters. Chapter 1 explains how the research problems considered in this thesis fit into the investigation of local-global principle in the diophantine geometry, as well as gives a unified sketch of the proofs of the two main results in this thesis. Chapter 2 establishes a similar conclusion to Theorem B of a paper by Poonen and Voloch in another settings. Chapter 3 relates to the object considered in the main result of Chapter 2 to an old conjecture proposed by Skolem and solves some cases of its analog. / text

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Proteome analysis techonologies are commonly employed for discovery-based biomarker identification studies. This thesis aims to help bridge the gap between analytical technology development and clinical application by improving and appling a proteomics workflow for biomarker discovery in congenital urinary tract obstruction (UTO). By accentuating the importance of experimental design, and evaluating the biological relevance of quantitative proteome analyses, the results of this research provide confidence in a number of identified candidate biomarkers of UTO. A sensitive method for quantification of proteome samples was developed using temperature controlled reversed-phase liquid chromatography (TPLC). The TPLC system provides high recovery (> 90 %), as well as high accuracy and precision in estimating the concentration across a number of protein sample types (CV < 10 %). The need for extensive fractionation strategies coupled with LC-MS analysis challenges the throughput of the overall experiment. Development of a dual column LC-MS interface reduced the total analysis time by a factor of 2 over conventional single column LC-MS systems. The system was applied to a quantitative proteome analysis of proximal tubule cells exposed to mechanical stretch, mimicking the conditions they experience during UTO and a urinary exosomal proteome analysis for candidate biomarker identification of this disease. A total of 1636 proteins were identified in the whole cell proteome analysis, of which 317 were found to be significantly altered in abundance. Analysis of the urinary exosomal proteome yielded 318 proteins, of which 189 were found to be altered in abundance due to obstruction. Western blot confirmation of a few select proteins provided backing to the quantitative proteome analysis, while gene ontology and KEGG pathway analysis yielded functional information. The results from the quantitative analyses of the urinary exosomes and proximal tubule cells identified candidates for both diagnosis and prognosis of UTO. In addition, activation of a novel pathway was identified, presenting a potential drug target which could be exploited to improve recovery of children following relief of UTO. This thesis therefore contributes useful technological and methodological advancements towards routine proteome analysis, as well as providing candidate biomarker identification for the leading cause of renal functional loss in children.

Thesis (Ph. D.)--University of Oklahoma. / Bibliography: leaves 116-150.

Orientador: Antônio José Maria Catâneo / Resumo: Objetivo: avaliar se a Mitomicina C (MMC) pode ampliar a taxa de sucesso da Dacriocistorrinostomia (DCR) externa ou endoscópica quando utilizada como tratamento adjuvante ao tratamento cirúrgico. Método: revisão sistemática de ensaios clínicos randomizados referentes a DCR externa ou endonasal, comparando as cirurgias realizadas com e sem MMC. Foram pesquisadas as bases de dados PubMed, Embase e Cochrane Central Register of Controlled Trials, de Janeiro de 1990 até Maio de 2018. A síntese dos resultados seguiu o programa RevMan 5.3 para a realização das meta-análises. Resultados: foram encontrados 937 estudos, dos quais 25 artigos foram considerados para a meta-análise. Subgrupo DCR externa (12 estudos, OR 2,69, IC 95% 1,36 a 5,32; I²= 38%), subgrupo DCR endoscópica (13 estudos, OR 1,70, IC 95% 1,21 a 2,39; I²= 0%). Observou-se que o uso da MMC aumenta a chance de sucesso da DCR nas duas técnicas (OR 2,03, IC 95% 1,44 a 2,88; I²= 16%) Conclusão: A MMC pode melhorar ligeiramente a taxa de sucesso na DCR externa e endoscópica. / Abstract: Objective: to evaluate the success rate of external or endoscopic dacryocystorhinostomy (DCR) with mitomycin C (MMC) as an adjuvant therapy. Method: a systematic review of randomized clinical trials (RCT) was done to analyze if the success rate of external or endoscopic DCR can be improve using MMC as adjuvant therapy. The following databases were searched: PubMed, Embase and Cochrane Central Register of Controlled Trials, ranging from January 1990 to May 2018. The results were obtained using the RevMan software (v5.3) to perform meta-analysis. Results: Nine hundred and thirthy-seven studies were found, of which 25 were considered for meta-analysis. The external DCR group had 12 studies (OR 2,69; 95% CI 1,36-5,32; I2= 38%), while the endoscopic DCR group had 13 studies (OR 1,70; 95% CI 1,12-2,39; I2= 0%). It was observed that the use of MMC can increases the success rate of DCR using both techniques (OR 2,03; 95% CI 1,44-2,88; I2= 16%). Conclusion: The use of MMC as adjuvant treatment in the external or endoscopic DCR can slightly improve the success rate of both techniques. / Mestre

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Realizamos um estudo transversal prospectivo com o objetivo de determinar a prevalência de apnéia obstrutiva do sono em um grupo de pacientes sul-americanos com mucopolissacaridose tipo VI sem tratamento prévio ou atual com terapia de reposição enzimática ou transplante de medula óssea. Os critérios de inclusão foram: ter 4 anos ou mais de idade e confirmação bioquímica da doença (níveis reduzidos da atividade da arilsulfatase B, aumento de glicosaminoglicanos (GAGs) urinários e atividade normal de outra sulfatase). Foram avaliados 28 pacientes através de anamnese, exame físico, ecocardiograma Doppler transtorácico e polissonografia realizada em noite inteira. A amostra estudada tinha 14 (50%) meninos. No momento da avaliação, a média de idade foi de 98,5 meses e a média de idade do diagnóstico de MPS VI foi de 48,4 meses. Em 88% da amostra os sintomas iniciaram com menos de 36 meses e em 27% das famílias houve relato de consangüinidade entre os pais. As manifestações clínicas mais freqüentes durante o sono foram roncos e apnéias observadas. Ao exame físico, 78,6% apresentavam macroglossia e 82,1% deformidade torácica tipo pectus carinatum. Três (10,71%) pacientes já tinham realizado adenotonsilectomia e 6 (21,42%) adenoidectomia isoladamente. Os dados polissonográficos evidenciaram apnéia obstrutiva do sono em 23 (85,1%) pacientes, sendo 4 com transtorno leve, 5 moderado e 14 grave. A média do índice de apnéia hipopnéia (IAH) foi de 19,84 ± 26,25 eventos/hora, da saturação periférica da oxihemoglobina (SpO2) 93,25 ± 5,06%, do nadir da SpO2 80,29 ± 10,01% e do pico do dióxido de carbono final exalado (EtCO2) 44,1 ± 6,01 mmHg. A ocorrência de apnéias centrais foi rara. Quatorze indivíduos da amostra (50%) tiveram evidência de hipertensão pulmonar (HP) documentada através de ecocardiograma. Foi observada associação positiva entre a média e o nadir da SpO2 mais baixos e a presença de HP. No grupo com HP, a média e o nadir da SpO2 foram de 91,2 ± 6,4% e 75,4 ± 10,9% respectivamente, enquanto que nos pacientes sem HP os valores de média e nadir da SpO2 foram 95,3 ± 1,8% e 85,2 ± 6,1% respectivamente (p=0,037 para média; p=0,007 para nadir). A presença de apnéias observadas durante o sono foi a variável mais importante em predizer HP nessa amostra (p=0,016; OR 9,9; IC 1,5 a 63,7). As manifestações clínicas sugestivas de alterações respiratórias durante o sono não apresentaram correlação significativa com o IAH, a média e o nadir de SpO2 e o pico de EtCO2. Também não houve correlação significativa entre a excreção urinária de GAGS e a atividade enzimática com resultado da polissonografia e do ecocardiograma. Concluímos que a prevalência de apnéia obstrutiva do sono nos pacientes com mucopolissacaridose tipo VI é elevada e o nível de dessaturação apresenta correlação positiva com a presença de hipertensão pulmonar. Os sintomas durante o sono não apresentaram associação com o resultado da polissonografia. A presença de apnéias observadas durante o sono foi a variável mais importante para predizer HP. / This prospective cross-sectional study was conducted to determine the prevalence of obstructive sleep apnea in a group of South American patients with mucopolysaccharidosis type VI who had no previous or current treatment with enzyme replacement or bone marrow transplant. Inclusion criteria were: age 4 years or older; and biochemical confirmation of the disease – reduced arylsulfatase B activity, increased glycosaminoglycans (GAGs) in urine, and normal activity of at least one other sulfatase. Twenty-eight patients were examined and data were collected from clinical history, physical examination, transthoracic Doppler echocardiogram and overnight polysomnography. Of the 28 participants, 14 (50%) were boys; mean age at evaluation was 98.5 months, and mean age at MPS diagnosis, 48.4 months. Symptoms started before 38 months of age in 88% of the sample; 27% reported parental consanguinity. The most frequent clinical symptoms during sleep were snoring and witnessed apnea. Physical examination revealed that 78.6% had macroglossia, and 82.1%, pectus carinatum. The most frequent clinical symptoms during sleep were snoring and witnessed apnea. Physical examination revealed that 78.6% had macroglossia, and 82.1%, pectus carinatum. Three (10.71%) patients had already undergone adenotonsillectomy, and 6 (21.42%), isolated adenoidectomy. Polysomnography results showed that 23 (85.1%) patients had obstructive sleep apnea: 4 mild, 5 moderate, and 14 severe. Mean apnea-hypopnea index (AHI) was 19.84 ± 26.25 events/hour, oxygen saturation (SpO2), 93.25 ± 5.06%, SpO2 nadir, 80.29 ± 10.01%, and peak end-tidal carbon dioxide (EtCO2), 44.1 ± 6.01 mmHg. Central apneas were rare. Pulmonary hypertension (PH) was detected by echocardiography in 14 (50%) patients. Lower SpO2 mean and nadir were positively associated with PH. In the group of patients with PH, SpO2 mean and nadir were 91.2 ± 6.4% and 75.4 ± 10.9%, and in the group without PH, 95.3 ± 1.8% and 85.2 ± 6.1% (p=0.037 for mean; p=0.007 for nadir). Witnessed apneas during sleep were the most important variable to predict PH in this sample (p=0.016; OR 9.9; CI, 1.5 to 63.7). Clinical signs suggestive of respiratory abnormalities during sleep were not significantly correlated with AHI, SpO2 mean and nadir, or peak EtCO2. There was no significant correlation between GAGs in urine or enzyme activity and polysomnography or echocardiogram results. The prevalence of obstructive sleep apnea in patients with mucopolysaccharidosis type VI was high, and the level of desaturation was positively correlated with the presence of pulmonary hypertension. Symptoms observed during sleep were not associated with polysomnography results. Witnessed apneas during the sleep were the most important variable to predict PH.

Objetivos: Determinar o percentual de asmáticos com má percepção da dispnéia e sua correlação com a intensidade da broncoconstrição aguda, hiper-responsividade brônquica, uso de medicação de manutenção e controle da asma. Métodos: Ensaio clínico não controlado com pacientes asmáticos do ambulatório de asma do Hospital São Lucas da PUCRS. Foram realizados testes de broncoprovocação com metacolina com protocolo dosimetrado e avaliada a percepção da dispnéia após cada dose administrada, utilizando a escala de Borg. Foram coletados dados demográficos e questionado quanto ao controle da asma, medicação em uso e necessidade de broncodilatador de curta ação. Para análise estatística foram utilizados teste de Chi-Quadrado e Teste t de Student e correlação de Spearman. Resultados: Foram estudados 65 pacientes com asma, dos quais 53 tiveram sua avaliação completa. Trinta e dois pacientes apresentaram percepção da dispnéia (60,5%) quando ocorreu broncoconstrição induzida pela metacolina. Entretanto, 21 pacientes (39,5%) não apresentaram alteração em relação aos sintomas de dispnéia, mesmo com queda de 20% do VEF1. Os grupos dos percebedores e não percebedores não apresentavam diferenças quanto ao VEF1 basal, percentagem de queda do VEF1 e dose de metacolina necessária para broncoprovocação. Não houve correlação significativa entre percepção da dispnéia com idade (p=0,247), sexo (p=0,329), uso de medicação de manutenção (p=0,152), controle da asma (p=0,562), hiper-responsividade brônquica (p=0,082) e gravidade da broncoconstrição aguda (p=0,749). Conclusões: Percentagem significativa dos asmáticos apresenta baixo grau de percepção da broncoconstrição. Os fatores relacionados com a incapacidade de identificação da modificação da função pulmonar não estão bem definidos. Diagnóstico e orientação dos maus percebedores é fundamental para redução de morbidade e mortalidade por asma. / Objective: To assess the percentage of poor perception of dyspnea in asthmatics and its correlation with acute bronchoconstriction severity, airway hyperresponsiveness, medication use and asthma control. Methods: Uncontrolled clinical trial of asthmatics from outpatient department HSL-PUCRS. Methacholine challenge testing was performed with five-breath dosimeter protocol. The perception of airway narrowing after 20% fall in FEV1 was evaluated using the Borg scale. Data concerning demographic information, asthma control, long-term management medication and rescue medication consumption were recorded. Chi-square test and Student´s T test and Spearman’s correlation were applied for the statistical analysis. Results: 65 patients were included and 53 completed the evaluation. 32 patients presented dyspnea (60,5%) when methacholine induced bronchoconstriction occurred but 21 patients (39,5%) did not show any difference related to dyspnea symptoms, even with 20% fall in FEV1. There were no differences between the two groups in terms of the baseline FEV1, % of fall FEV1, and methacoline dose that promoted a positive test. There was no significant association between airway obstruction and age (p= 0.247), sex (p=0.329), long term management medication use (p=0.152), asthma control (p=0.562), airway hyperresponsiveness (p=0.082), and acute bronchoconstriction severity (p=0.749). Conclusion: Significant percentage of astmatics presents poor perception of bronchoconstriction. The identification and orientation of this group of patients is essential to make plans of interventions and eventually reduce asthma morbidity and mortality.

Made available in DSpace on 2014-06-11T19:31:08Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-27Bitstream added on 2014-06-13T18:41:44Z : No. of bitstreams: 1 uribediaz_ap_dr_jabo.pdf: 327728 bytes, checksum: 95978c4b4ea30b83afc2bcabbfd833d4 (MD5) / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / Trabalhos recentes relatam a eficácia do azul de metileno na prevenção dos danos impostos por espécies reativas de oxigênio aos tecidos de vários órgãos, em vários modelos de isquemia/reperfusão. Este estudo foi concebido com o fito de avaliar o efeito do azul de metileno sobre as respostas clínico-laboratoriais, na obstrução experimental do jejuno em equinos, associada à exposição de lipopolissacarídeo. Dois grupos de animais foram submetidos à indução da endotoxemia e à obstrução experimental do jejuno em período anterior. Posteriormente administrou-se em um deles, infusão de azul de metileno (3 mg/kg I.V), 15 minutos antes da obstrução experimental, e no outro, a mesma infusão 15 minutos antes da desobstrução do jejuno. Foi realizada avaliação clínica, hematológica e bioquímico-sérica, e perfil bioquímico e citológico do líquido peritoneal a partir de aferições em oito tempos durante 12 horas, também foram caracterizadas as lesões intestinais. Após 3 horas de isquemia, verificou-se hemorragia, edema, infiltração de neutrófilos e desprendimento da mucosa. Essas lesões manifestaram-se predominantemente após a reperfusão, e de forma concomitante com o aumento dos componentes celulares e moleculares da inflamação, tanto no sangue quanto no líquido peritoneal. Contudo, todos os achados foram discretamente menos evidentes nos animais que receberam o azul de metileno antes da fase de reperfusão. Não é possível afirmar efeito benéfico do azul de metileno sobre a resposta dos equinos na obstrução experimental do jejuno. / Intestinal ischemia is one of the most serious intra-abdominal alterations and reflects extremely elevated morbility and mortality. Reoxygenation on the ischemic tissue produces deleterious inflammatory events with consequences even more severe than the ischemia itself. Methylene blue, due to this action as an inhibitor of free-radical formation. The objective of this test was to study the effects of methylene blue on the clinical and laboratory response before and after the experimental obstruction of the jejunum, associated to the exposition of lypopolysacharide. Two groups of animals were submitted to endotoxemia and experimental obstruction of the jejunum. After, in one group was administered, intravenously, a solution of methylene blue (3 mg/kg), immediately before the experimental obstruction, in the other group, the solution was administered immediately before interrupt the obstructive process in the intestinal segment. The horses were submitted to the evaluation of clinical signs and laboratory response during the 12 hours of study. Based on the clinical and laboratory findings we concluded that, the administration of methylene blue was not able to avoid the clinical and laboratory responses in the experimental model proposed for this study.