Submitted by PPG Medicina e Ci?ncias da Sa?de (medicina-pg@pucrs.br) on 2018-07-10T18:25:20Z No. of bitstreams: 1 ANA_CAROLINE_ZIMMER_GELATTI.pdf: 1750167 bytes, checksum: 02c99a9c64d394787d90c14d2caa6312 (MD5) / Approved for entry into archive by Sheila Dias (sheila.dias@pucrs.br) on 2018-07-13T17:58:48Z (GMT) No. of bitstreams: 1 ANA_CAROLINE_ZIMMER_GELATTI.pdf: 1750167 bytes, checksum: 02c99a9c64d394787d90c14d2caa6312 (MD5) / Made available in DSpace on 2018-07-13T19:08:26Z (GMT). No. of bitstreams: 1 ANA_CAROLINE_ZIMMER_GELATTI.pdf: 1750167 bytes, checksum: 02c99a9c64d394787d90c14d2caa6312 (MD5) Previous issue date: 2017-08-31 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Background: Cancer is one of the three leading causes of death in Brazil, and one of the most prevalent diseases in our country. Febrile neutropenia is a febrile syndrome associated with a reduction in neutrophil count and a frequent complication of systemic cancer treatment. Febrile neutropenia may affect up to 40% of cancer patients. Considering the large number of patients stricken by febrile neutropenia, and the risk that inadequate management imposes on patients' lives, standardization of care and the early identification of a high-risk population is key to improving clinical outcomes. Guidelines for treatment of febrile neutropenia universally recommend immediate start of antibiotic therapy (<60 minutes). Objective and Methods: The goal of this retrospective study was to evaluate the epidemiological profile and clinical outcomes of patients treated with chemotherapy or radiotherapy who met criteria for febrile neutropenia and required a visit to the emergency department of a tertiary hospital. Results: A total of 212 patients with cancer presented with fever and required an emergency room evaluation between September 2014 and August 2016. Of these, 68 met criteria for febrile neutropenia. Hematologic neoplasms were associated with an increased risk of neutropenia [OR = 3,41 (95%, CI: 1,52-7,65) p = 0,003] when compared to solid tumors. Seven (10.3%) patients with neutropenia were treated on an outpatient setting and 61 (89,7%) were admitted. The median time to onset of the antibiotic was 140 minutes. Of the patients admitted to the hospital, 47 (77,0%) were discharged from hospital and 14 (23,0%) died. The median of the Multinational Association for Supportive Care in Cancer (MASCC) score was statistically higher in the group that was discharged when compared to the group that died (23,5 versus 14,5 points), with an OR=0,69 [(95%, CI: 0,51-0,94) p = 0,017]. Conclusion: This analysis corroborates previously published data supporting that febrile neutropenia is a potential morbidity and mortality factor in cancer patients. Strategies that aim to qualify the care of patients at higher risk in the emergency room is essential to reduce mortality rates. / Introdu??o: O c?ncer ? uma das tr?s principais causas de morte no Brasil, destacando-se como uma das doen?as mais prevalentes em nosso meio. A neutropenia febril ? uma s?ndrome febril associada a redu??o na contagem do n?mero de neutr?filos, sendo uma complica??o frequente do tratamento oncol?gico sist?mico, com taxas de preval?ncia que podem atingir at? 40%. Tendo em vista o grande n?mero de pacientes oncol?gicos acometidos pela neutropenia febril, e o risco que o seu manejo inadequado imp?e ? vida dos doentes, a padroniza??o da assist?ncia e a identifica??o precoce de uma popula??o de alto risco ? fundamental para melhorarmos os desfechos cl?nicos. As diretrizes de tratamento da neutropenia febril universalmente recomendam o in?cio imediato de antibioticoterapia (<60 minutos). Objetivo e M?todos: O objetivo do presente estudo ? avaliar, de forma retrospectiva, o perfil epidemiol?gico e os poss?veis desfechos cl?nicos de pacientes com neutropenia febril tratados com quimioterapia ou radioterapia que procuraram a emerg?ncia de um hospital terci?rio. Resultados: Um total de 212 pacientes oncol?gicos foram avaliados por febre entre Setembro de 2014 e Agosto de 2016. Destes, 68 apresentavam neutropenia febril. Neoplasias hematol?gicas foram associadas a um maior risco de neutropenia [OR = 3,41 (IC 95%: 1,52-7,65) p = 0,003], quando comparados com tumores s?lidos. Sete (10,3%) pacientes com neutropenia foram tratados a n?vel ambulatorial e 61 (89,7%) a n?vel de interna??o hospitalar. A mediana de tempo para in?cio do antibi?tico foi de 140 minutos. Dos pacientes tratados a n?vel de interna??o, 47 (77,0%) receberam alta hospitalar e 14 (23,0%) evolu?ram para ?bito. A mediana do escore ?Multinational Association for Suportive Care in Cancer? (MASCC) foi estatisticamente superior no grupo que recebeu alta hospitalar quando comparado com o grupo que evolui para ?bito (23,5 versus 14,5 pontos), com OR=0,69 (IC 95% 0,51 - 0,94) e p=0,017. Conclus?o: Esta an?lise corrobora dados previamente publicados, refor?ando que a neutropenia febril ? potencial fator de morbimortalidade em pacientes oncol?gicos. Estrat?gias que possam qualificar o atendimento de pacientes de maior risco nos setores de emerg?ncia ? fundamental para reduzir as taxas de mortalidade.

Submitted by Jorge Silva (jorgelmsilva@ufrrj.br) on 2017-05-03T19:19:19Z No. of bitstreams: 1 2015 - Marina Jorge de Lemos.pdf: 6290720 bytes, checksum: 466915088ab49af16fcd11435ccc2913 (MD5) / Made available in DSpace on 2017-05-03T19:19:19Z (GMT). No. of bitstreams: 1 2015 - Marina Jorge de Lemos.pdf: 6290720 bytes, checksum: 466915088ab49af16fcd11435ccc2913 (MD5) Previous issue date: 2015-12-08 / CAPES / An experiment was conducted in order to evaluate the intestinal morphology, performance, egg quality and analysis of the financial feasibility of including various additives in feed during the whole production period of Japanese quails. 360 quails were distributed in a completely randomized design in a time split plot scheme (9 to 23 weeks of age and 24 to 39 weeks old) with five treatments and eight repetitions of nine birds each. The used treatments were: control, antibiotic, prebiotic, probiotic and synbiotic. The intestinal morphology was evaluated by the height and width and width/height ratio of the villus, crypt depth and villus/crypt ratio; performance, by the feed intake, egg production, egg weight average, feed conversion (kg / kg and kg / dozen), egg mass and viability; egg quality, by the Haugh unit, yolk index, percentage of egg components, shell thickness measured by the micrometer and the scanning electron microscope (SEM); financial analysis was computed by the internal rate of return, net present value and cost benefit. The inclusion of additives in the feed increased the height and width of the villi, decreased crypt depth and increased villous / crypt ratio compared to the control. The inclusion of the additives reduced the feed intake in the two periods of production of the quails in comparison with the control. Throughout the production period, consumption was lower after inclusion of antibiotic and synbiotic in the feed. Egg production, egg weight average, egg mass and feed conversion (kg / kg and kg / dozen) were improved in the quails fed with additives in the two periods of production. The supply of additives within 24 to 39 weeks of age increased the Haugh unit of the eggs compared to the control. The inclusion of additives in the feed increased the yolk and shell percentage, and improved shell and membrane thickness measured by the micrometer compared to the control in both periods of production. The shell thickness (SEM) and the shell palisade layer were improved after inclusion of antibiotic and synbiotic in the feed within 24 to 39 weeks of age. The financial analysis showed best values in the treatments that used antibiotics and synbiotic. The inclusion of antibiotics, probiotic, prebiotic and synbiotic in the feed improves performance and egg quality throughout the production phase of Japanese quails, and these improvements increase effects when the birds receive the additives in the first productive period. The inclusion of antibiotics and synbiotic is more effective than the inclusion of the other additives in reducing food intake throughout the production period and improving shell thickness during the second production period. Intestinal integrity of Japanese quails improved after the inclusion of the tested additives. The financial analysis proved to be more viable to include antibiotic or synbiotic in the feed of Japanese quails in comparison to the other studied additives. / Foi conduzido um experimento com o objetivo de avaliar a morfologia intestinal, o desempenho, a qualidade dos ovos e an?lise da viabilidade financeira da inclus?o de diferentes aditivos na ra??o durante todo o per?odo produtivo de codornas japonesas. Foram utilizadas 360 codornas distribu?das em um delineamento inteiramente casualizado em esquema de parcela subdividida no tempo (de 9 at? 23 semanas de idade e de 24 at? 39 semanas de idade) com cinco tratamentos e oito repeti??es de nove aves cada. Os tratamentos utilizados foram: controle, antibi?tico, prebi?tico, probi?tico e simbi?tico. A morfologia intestinal foi avaliada atrav?s da altura e largura e propor??o largura/altura das vilosidades, profundidade de cripta e rela??o vilo: cripta; o desempenho pelo consumo de ra??o, produ??o de ovos, peso m?dio dos ovos, convers?o alimentar (kg/kg e kg/d?zia), massa dos ovos e viabilidade; a qualidade de ovos pela unidade Haugh, ?ndice de gema, percentagem dos componentes do ovo, espessura de casca medida pelo micr?metro e pelo microsc?pio eletr?nico de varredura (MEV); a an?lise financeira foi computada pela taxa interna de retorno, valor presente l?quido e benef?cio custo. A inclus?o dos aditivos na ra??o aumentou a altura e largura das vilosidades, diminuiu a profundidade de cripta e aumentou a rela??o vilo:cripta em compara??o com o controle. A inclus?o dos aditivos reduziu o consumo de ra??o nos dois per?odos de produ??o das codornas em compara??o com o controle. Durante todo o per?odo produtivo, o consumo foi menor ap?s inclus?o de antibi?tico e simbi?tico na ra??o. A produ??o de ovos, o peso m?dio dos ovos, a massa de ovos e a convers?o alimentar (kg/kg e kg/d?zia) foram melhores nas codornas alimentadas com os aditivos nos dois per?odos de produ??o. O fornecimento dos aditivos no per?odo de 24 at? 39 semanas de idade aumentou a unidade Haugh dos ovos em rela??o ao controle. A inclus?o dos aditivos na ra??o aumentou a porcentagem de gema e de casca, e melhorou a espessura da casca avaliada pelo micr?metro e das membranas da casca em compara??o com o controle nos dois per?odos de produ??o. A espessura da casca (MEV) e da camada pali?ada da casca foi melhor ap?s inclus?o de antibi?tico e simbi?tico na ra??o no per?odo de 24 at? 39 semanas de idade. A an?lise financeira mostrou os melhores valores nos tratamentos que utilizaram antibi?tico e simbi?tico. A inclus?o de antibi?tico, probi?tico, prebi?tico e simbi?tico na ra??o melhora o desempenho e a qualidade dos ovos durante toda a fase produtiva de codornas japonesas, sendo esse efeito potencializado quando as aves recebem os aditivos no primeiro per?odo produtivo. A inclus?o de antibi?tico e simbi?tico ? mais eficaz que a inclus?o dos outros aditivos na redu??o do consumo de ra??o em todo per?odo produtivo e em melhorar a espessura da casca durante o segundo per?odo produtivo. A integridade intestinal das codornas japonesas melhora ap?s a inclus?o dos aditivos testados. A an?lise financeira demonstrou ser mais vi?vel a inclus?o de antibi?tico ou de simbi?tico na ra??o das codornas japonesas em compara??o com os outros aditivos estudados.

Submitted by PPG Biologia Celular e Molecular (bcm@pucrs.br) on 2018-03-05T13:21:28Z No. of bitstreams: 1 BRUNO_LOPES_ABBADI_TES.pdf: 4934736 bytes, checksum: 58e4c3c86d9fb96bb1476ae3c18bfdf0 (MD5) / Approved for entry into archive by Caroline Xavier (caroline.xavier@pucrs.br) on 2018-03-06T16:15:19Z (GMT) No. of bitstreams: 1 BRUNO_LOPES_ABBADI_TES.pdf: 4934736 bytes, checksum: 58e4c3c86d9fb96bb1476ae3c18bfdf0 (MD5) / Made available in DSpace on 2018-03-06T16:21:42Z (GMT). No. of bitstreams: 1 BRUNO_LOPES_ABBADI_TES.pdf: 4934736 bytes, checksum: 58e4c3c86d9fb96bb1476ae3c18bfdf0 (MD5) Previous issue date: 2018-01-19 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Epidemiologic data regarding tuberculosis (TB) show that there is still a high burden of this disease worldwide. In addition, the emergence of drug-resistant strains imposes a new threat in preventing TB spread. Therefore, it is pivotal to continuously find new candidates for drug development. In the Chapter 2 of this thesis, the compound IQG-607 is presented, which is a metal complex that has been reported as a promising anti-TB molecule against isoniazid (INH)-resistant strains of M. tuberculosis. Previous studies suggested that the compound inhibits both the wild-type NADH-dependent trans-2-enoyl-[ACP] reductase (InhA) enzyme and some of its structural mutants in the absence of NAD+ or NADH and without requiring KatG enzyme. IQG-607 has also shown a favorable toxicological profile in vivo, with a considerable lesser toxicity compared to INH. However, there is still a gap regarding the activity of IQG-607 against strains carrying mutations in the katG gene, which are the most common genetic alterations in clinical isolates resistant to INH. Therefore, this study focused in elucidating the mechanism of resistance (MOR) of the Mycobacterium tuberculosis, the main causative agent of TB, to compound IQG-607. First the minimum inhibitory concentration (MIC) of IQG-607 was established against eight multi-drug resistant (MDR) clinical isolates, which were resistant to our compound. Then spontaneous mutants were selected using high concentrations of compound in 7H10 agar medium, and their whole genomes were sequenced; the results revealed alterations in the katG gene. A laboratory strain carrying the mutant katG(S315T) gene was developed to assess the effect of this single mutation in the compound activity both by MIC determination and by a macrophage infection model. Results showed that this mutation was indeed sufficient to confer resistance to IQG-607. Finally, the resistance observed for a strain expressing a mutant InhA(S94A) protein suggested that IQG-607 has this enzyme as its molecular target. In the Chapter 3, two new compounds, called Labio-16 and Labio-17, are presented, which were previously selected to interact and inhibit the InhA enzyme and that had already shown to be active against M. tuberculosis H37Rv strain. A set of experiments were conducted to elucidate their mechanism of action (MOA) and to understand the MOR of the M. tuberculosis against them, similar to those carried for studying IQG-607. So far, results suggested that the InhA is not the molecular target of these compounds. Other experiments are undergoing in our laboratory to evaluate in a murine model of TB infection their potential as anti-TB drug candidates. / Os dados epidemiol?gicos relacionados ? tuberculose (TB) indicam que ainda existe uma carga elevada desta doen?a no mundo todo. Al?m disso, o surgimento de cepas resistentes aos f?rmacos imp?e uma nova amea?a na preven??o da propaga??o da TB. Portanto, ? fundamental buscar continuamente novos candidatos para o desenvolvimento de medicamentos. No Cap?tulo 2 desta tese ? apresentado o composto IQG-607, que ? um complexo met?lico que tem sido reportado como uma mol?cula anti-TB promissora contra cepas de M. tuberculosis resistentes ? isoniazida (INH). Estudos pr?vios sugeriram que o composto inibe a enzima selvagem trans-2-enoil-[ACP] redutase dependente de NADH (InhA) e algumas das suas mutantes estruturais, na aus?ncia de NAD+ ou NADH e sem necessitar da enzima KatG. O IQG-607 tamb?m mostrou um perfil toxicol?gico favor?vel in vivo, com uma menor toxicidade em compara??o ? INH. No entanto, ainda existe uma lacuna em rela??o ? atividade do IQG-607 contra cepas que carregam muta??es no gene katG, as quais s?o as altera??es gen?ticas mais comuns em isolados cl?nicos resistentes ? INH. Sendo assim, este estudo focou em elucidar o mecanismo de resist?ncia (MOR) do Mycobacterium tuberculosis, o principal agente causador da TB, ao composto IQG-607. Primeiramente, a concentra??o inibit?ria m?nima (MIC) do IQG-607 foi estabelecida contra oito isolados cl?nicos multirresistentes a f?rmacos (MDR), os quais foram resistentes ao nosso composto. Ent?o, mutantes espont?neos foram selecionados, usando-se altas concentra??es do composto em meio ?gar 7H10, e seus genomas completos foram sequenciados; os resultados revelaram altera??es no gene katG. Uma cepa laboratorial, carregando o gene katG(S315T) mutante, foi desenvolvida para acessar o efeito desta ?nica muta??o na atividade do composto, atrav?s da determina??o de MIC e por meio de um modelo de infec??o de macr?fagos. Os resultados mostraram que essa muta??o de fato foi suficiente para conferir resist?ncia ao IQG-607. Finalmente, a resist?ncia observada para a cepa que expressa a prote?na InhA(S94A) mutante sugeriu que o IQG-607 tem esta enzima como seu alvo molecular. No Cap?tulo 3, dois novos compostos, denominados Labio-16 e Labio-17, s?o apresentados, os quais foram previamente selecionados para interagir e inibir a enzima InhA, e que j? tinham mostrado ser ativos contra a cepa H37Rv de M. tuberculosis. Um conjunto de experimentos foi conduzido para elucidar os seus mecanismos de a??o (MOA) e para compreender o MOR do M. tuberculosis contra eles, similar ?quele usado para estudar o IQG-607. At? o momento, os resultados sugerem que a InhA n?o ? o alvo molecular desses compostos. Outros experimentos est?o em andamento em nosso laborat?rio, para avaliar em um modelo murino da infec??o da TB os seus potenciais como candidatos a f?rmacos anti-TB.