Tese (doutorado) - Universidade Federal de Santa Catarina, Centro de Ciencias da Saude / Made available in DSpace on 2012-10-17T03:31:37Z (GMT). No. of bitstreams: 0Bitstream added on 2016-01-08T22:58:06Z : No. of bitstreams: 1 149256.pdf: 21008391 bytes, checksum: bfec588b9661266b87487f277012a0e5 (MD5) / A pesquisa propõe valorizar a importância de condutas profissionais que favoreçam a prática da bioética nas ações educativas. Sugere-se a incorporação de aspectos bioéticos e estratégias educativas adequadas e coerentes aos sistemas educativos em saúde, às características da população destinatária e suas necessidades, desde que a perspectiva bioética destas estratégias evidenciem respeito pela pessoa, sua dignidade e sua autonomia.

Shape-based approaches have many potential areas for development in the future for application to in silico pharmacology. Further exploration of the role of molecular shape may lead to better understanding of the substrate specificity of enzymes and the possibility to reduce toxic effects that may be caused by ligands binding to undesired target proteins. Methods exploiting molecular shape for activity and toxicity prediction might have a great influence on the drug discovery process. There are different approaches that might be used for this purpose, e.g. shape fingerprints and shape multipoles. Both methods describe the shape of molecules, discarding any chemical information, using numerical values. Focusing only on shape can lead to identifying novel core structures of molecules, with improved properties. Molecular fingerprints are binary bit strings that encode the structure or shape of compounds; shape is measured indirectly by alignment to a database of standard molecular shapes – the reference shapes. The Shape Database should represent a wide range of possible molecular shapes to produce accurate results. Therefore, this was the main focus of the investigation. The shape multipoles method is a fast computational method to describe the shape of molecules by using only numbers and therefore it requires low storage needs and comparison is performed by simple mathematical operations. To describe the shape, it uses only 13 values (3 quadrupole components and 10 octupole components). The performances of both methods in grouping compounds based on shared biological activity were evaluated using several test sets with slightly better results in case of shape fingerprints. However, the shape multipole approach showed potential in finding differences in shape between enantiomers. Among the possible applications of the shape fingerprints method are solubility prediction (on comparable level as well-established methods) and virtual screening.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico, Programa de Pós-Graduação em Engenharia Elétrica, Florianópolis, 2009 / Made available in DSpace on 2012-10-24T20:34:03Z (GMT). No. of bitstreams: 1 270061.pdf: 2289916 bytes, checksum: 13fdaeb43bbfd9ad34d40a453e2fb642 (MD5) / O registro de dados dos pacientes internados em estabelecimentos de saúde envolve rotinas que objetivam descrever seu estado atual de saúde. Apesar da crescente informatização, algumas destas tarefas, como a prescrição médica e verificação dos sinais vitais, ainda são executadas manualmente, o que aumenta o tempo de atendimento e ocorrência de erros. Assim, a proposta deste trabalho é desenvolver um protótipo de sistema para visualização e prescrição de medicamentos, bem como possibilitar a visualização e transcrição das informações referentes a verificação de sinais vitais diretamente no Prontuário Eletrônico de Paciente, reduzindo um dos principais fatores de risco encontrados no meio hospitalar: a má interpretação das informações contidas nestes documentos. Este sistema foi baseado em dispositivos móveis do tipo PDA (Personal Digital Assistent) com acesso à web e utiliza como meio de comunicação a wireless, possibilitando desta forma, o acompanhamento do paciente em seu leito pela equipe enfermagem e médica. Para avaliar o protótipo desenvolvido, foram utilizados questionários aplicados aos profissionais atuantes no Hospital da Universidade Federal de Santa Catarina, com a finalidade de verificar aspectos subjetivos de usabilidade (Satisfação) e observação do tempo gasto nas atividades diárias de verificação dos sinais vitais no processo tradicional. Os resultados mostraram que o grau de satisfação médio entre os participantes foi de 78,85 pontos, em escala de 0-100. Quanto ao tempo gasto nas atividades de verificação dos sinais vitais, o sistema apresentou ganho de 97,6%, em média, o que se atribui à redução das etapas a serem realizadas, quando comparado ao processo tradicional.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico, Programa de Pós-Graduação em Engenharia Elétrica, Florianópolis, 2010 / Made available in DSpace on 2012-10-25T04:15:14Z (GMT). No. of bitstreams: 1 276574.pdf: 5124276 bytes, checksum: f7ea0236e674e6ef7c5d5cf6ce00ef19 (MD5) / Nos últimos anos, as mudanças no perfil epidemiológico da população, e o novo paradigma do sistema de saúde com foco no atendimento remoto e personalizado no paciente, têm contribuído para um significativo incremento do parque tecnológico e mudanças no perfil da tecnologia médico-hospitalar. Este novo cenário do sistema de saúde implica em novos desafios para a engenharia clínica, na busca por soluções que contribuam para a criação de um ambiente interconectado e ubíquo. Isto integrando os diversos ambientes assistenciais de saúde em um único sistema que ofereça mobilidade para a prestação dos serviços de cuidados à saúde focados no paciente. Diante destes desafios, o presente projeto estudou três diferentes ambientes assistenciais de saúde, sob a óptica da engenharia clínica e das atividades de gerenciamento da tecnologia médico-hospitalar, nestes novos cenários de alta mobilidade da tecnologia. A partir disto, foi desenvolvida uma proposta de plataforma de auxílio ao gerenciamento do parque tecnológico, para supervisão e controle da tecnologia baseada na identificação por rádio freqüência (RFID). Esta proposta foi avaliada, por meio de um protótipo implementado na unidade de terapia intensiva de um hospital e em simulações de ambientes, cujos resultados indicaram, neste novo contexto do sistema de saúde, um significativo potencial no auxílio à engenharia clínica para o gerenciamento do parque tecnológico de forma eficiente. / In the past years, the changes in the population's epidemiologic profile, and the new health system paradigm focused on remote and personalized assistance for the patient, has contributed with a significant increase in equipment inventory, and much wider deployment. This new health system paradigm implies new challenges for clinical engineering in the search for new solutions that contribute with the creation of an interconnected and ubiquitous environment, integrating the several healthcare environments in one system that offers mobility to the provision of healthcare services focused on the patient. Considering these challenges, the present project has studied three different healthcare environments from the point of view of clinical engineering and the activities of healthcare technology management in these new high technology mobility sceneries. Based upon the above, a proposal of a support platform was developed for the management of the health system's technology, for the supervision and control of technology based on radio frequency identification (RFID). This proposal has been evaluated through a prototype implemented in the intensive care unit of a hospital and in environment simulations, which results indicated, in this new health system context, a significant potential in the support to clinical engineering for the efficient management of the health systems technology.

Dissertação (mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico. Programa de Pós-Graduação em Ciência da Computação. / Made available in DSpace on 2012-10-22T16:26:11Z (GMT). No. of bitstreams: 1 233630.pdf: 3084918 bytes, checksum: ecf789d1899b2e3f4fe9d06bfa28d160 (MD5) / Dados tridimensionais referentes a pacientes são utilizados em diversos setores médico-hospitalares, fornecendo embasamento à diagnósticos e orientação durante procedimentos cirúrgicos. No entanto, apesar de bastante úteis estes dados são bastante inflexíveis, não permitindo que o usuário interaja com estes ou os manipule. O emprego de técnicas de computação gráfica e realidade virtual para a representação destes dados sanaria estas dificuldades, gerando representações indivíduais e adaptadas para cada paciente e permitindo a realização de planejamentos cirúrgicos e cirurgias auxiliadas por computador, dentre outras possibilidades. A representação destes dados e as formas de manipulação devem conter um conjunto de elementos e obedecer alguns requisitos para que se obtenha realismo nas aplicações, caso contrário, o emprego destas técnicas não traria grandes vantagens. Analisando os elementos e requisitos a serem obedecidos, é construído um grafo de dependências que mostra as técnicas e estruturas computacionais necessárias para a obtenção de ambientes virtuais imersivos realistas. Tal grafo demonstra as estruturas de dados para representação de sólidos como peça chave para este tipo de aplicativos. Para suprir as necessidades destes, é apresentada uma estrutura de dado capaz de representar uma vasta classe de topologias espaciais, além de permitir rápido acesso a elementos e suas vizinhanças, bem como métodos para a construção de tal estrutura. É apresentada, também, uma aplicação para mensuração de artérias utilizando a estrutura e os métodos previamente mencionados e os resultados por obtidos por estes.

Tese (doutorado) - Universidade Federal de Santa Catarina, Centro Tecnológico. Programa de Pós-Graduação em Engenharia de Produção / Made available in DSpace on 2012-10-23T08:43:23Z (GMT). No. of bitstreams: 1 241054.pdf: 5221121 bytes, checksum: 47fc54981ae7596b9ac9d2be2f8b936d (MD5) / Esse estudo teve como objetivo identificar o processo de raciocínio clínico na elaboração de hipóteses diagnósticas, contextualizado a um tema protótipo em Clínica Médica (CM), tendo como pressuposto que a estratégia hipotético-dedutiva é a base do raciocínio clínico e a esquema-indutiva e o reconhecimento de um padrão são estratégias auxiliares ou combinadas. O delineamento foi transversal, com base epistemológica qualitativa, com amostra não-probabilística do tipo intencional. Foi realizado no Hospital Universitário, da UFSC, em Florianópolis - SC, com 30 médicos-professores de um Departamento de Ensino em CM, que exercem ou exerceram atividade clínica por mais de 5 anos. A construção de protótipos em CM pelos participantes permitiu selecionar um caso clínico real, que foi o estímulo para a aplicação da técnica "think aloud" ou "pensando em voz alta". O texto obtido do processo de raciocínio clínico com a verbalização dos participantes foi gravado, transcrito e analisado com a aplicação da técnica de análise temática, do método de análise de conteúdo; para o perfil profissional foi aplicado um questionário estruturado. A estratégia de raciocínio mais freqüente foi a hipotético-dedutiva (HD) (47% (72/153)), com a mesma freqüência para a esquema-indutiva (E-I) (15,6% (24/153)) e o reconhecimento de um padrão (RP) (15,6%(24/153)), seguida pela mista E-I (E-I + HD) e mista RP (RP + HD) (respectivamente, 11,7% (18/153) e 9,8% (15/153), ao estabelecerem 153 hipóteses dentro de 31 tipos distintos. Concomitantemente, foram criados 356 eixos semânticos inseridos em 135 tipos, e os dados processados com 515 interpretações e 290 combinações. O perfil geral da amostra mostrou expressivo tempo de exercício na atividade clínica (27,3 anos) e na docência (24,4 anos), com uma média de especialização latu sensu de 2,3/participante, e mais da metade (53% (16/30) com strictu sensu. Os médicos-professores têm conhecimento formal e tácito diferenciado, com organização e conteúdo, utilizando múltiplas e combinadas estratégias no processo de raciocínio clínico, no qual a estratégia HD é a base. The objective of this study is to identify the clinical reasoning process in the elaboration of the diagnoses hypothesis, inserted in a prototype subject in Medical Clinic (MC), having as presupposition that the hypothetic deductive strategy, is the base of the clinical reasoning, and the inductive-scheme and the pattern recognition are auxiliaries or combined strategies. The outline was cross-sectional, with epistemological qualitative basis, using non-probabilistic sample of intentional type. This research was done in the Hospital from Santa Catarina Federal University, in Florianopolis, Santa Catarina State, with thirty teachers from the Medical Clinic (MC) Teaching Department, which perform or performed the clinical activity for more than five years. The prototype definition in MC by the participants, allow selecting a real clinical case, which was stimulated to apply a think aloud technique. The text gathered from the clinical reasoning process with the participant's verbal stimulation was taped, transcribed and analysed with the application of the thematic analysis technique, this analysis used the content analysis method, for the professional profile was applied a structured questionnaire. The more frequent reasoning strategy was hypothetic-deductive (HD) (47% (72/153)), the inductive-scheme (IE) (15.6% (24/153)) and the recognition of a standard (RS) (15.6% (24/153)) have the same frequency, followed by the mixed IE (IE + HD) and the mixed RS (RS + HD), (respectively, 11.7% (18/153) and 9.8% (15/153)), which established 153 hypothesis into 31 different types. At the same time, was created 356 semantic axis into 135 types, and these dates were processed with 515 interpretations and 290 combinations. The sample general profile showed an expressive time of the clinical activity experience (27.3 years) and in the medical teaching (24.4 years), with a latu sensu specialization average of the 2.3 years/ participant, and more than a half (53%) with strictu sensu. The doctors-teachers as formal and tacit knowledge, with the organization and content, using multiple and combined strategies in the clinical reasoning process, in which the HD strategy is the basis.

Hydrogen sulfide (H2S) is the simplest endogenously produced thiol and has an indispensable role in cardiovascular homeostasis. It has been shown that exogenous H2S supplementation protected the heart against myocardial ischaemia/reperfusion injury through a mechanism which is yet to be defined. In this thesis, it was hypothesised that controlled application of thiol/H2S donors at reperfusion would mitigate acute myocardial infarction. We sought to characterise the cardioprotection and molecular targets of three H2S donors (mesna, GYY4137 (a slow-releasing, non-mitochondrial targeted H2S donor) and AP39 (a mitochondria-targeting H2S donor)). This characterisation was conducted using a broad range of experimental models and techniques including anaesthetised rat model of ischaemia/reperfusion injury, Western blotting and mitochondrial studies using isolated cardiomyocyte mitochondria, namely subsarcolemmal and interfibrillar mitochondria. Mesna did not limit infarct size when it was given pre-ischaemia or at reperfusion. GYY4137 and AP39 significantly limited infarct size when given specifically at the time of reperfusion through different mechanisms. Cardioprotection established by GYY4137 was mediated mainly by triggering of PI3K/Akt/GSK-3β signalling at reperfusion with partial dependency on eNOS activity. Selective mitochondrial delivery of H2S at reperfusion using AP39 had no effect on Akt, eNOS, GSK-3β and ERK1/2. In isolated mitochondria, AP39 inhibited Ca2+-sensitive opening of PTP in subsarcolemmal and interfibrillar mitochondria through attenuation of mitochondrial reactive oxygen species generation. The studies presented in this thesis provided novel mechanistic insights into cardioprotection by H2S. These studies suggest that targeted delivery of H2S represents a novel and effective adjunctive therapy to ameliorate the injurious effects of reperfusion which contribute to acute myocardial infarction.

The research in this thesis describes investigations of (i) mixed polymer HPMC and PEO hydrophilic matrices and their performance in low and high ionic environments and (ii) understanding the internal behaviour of HPMC and PEO mixed systems. It was postulated that using a blend of these polymers might provide advantages over the use of single polymers. A series of ‘realistic’ 30% w/w polymer matrix formulations, containing different weight ratios of HPMC and PEO and a soluble model drug (caffeine), were tested in ionically challenging media, up to 1M sodium chloride (NaCl). Dissolution testing showed how HPMC dominated formulations exhibited accelerated release in high ionic strength media (0.8M NaCl or higher), whereas PEO dominated formulations did not. Power law analyses suggested the release mechanism of matrices in 0.6M NaCl and below were anomalous non-Fickian transport, but case II transport was observed in HPMC dominated matrices at 0.8M NaCl and above. A polymer ratio of 4:6 HPMC:PEO allowed an extended release tablet to be formulated that was resistant to 1M NaCl. In 0.6M NaCl or below, increasing the proportion of HPMC in a mixed HPMC:PEO tablets, increased the duration of extended release. Confocal laser scanning microscopy was used to investigate the structure of the HPMC:PEO matrix hydrated gel layer. The results provided evidence that HPMC and PEO particles swell independently in the gel layer. They remained substantially unmixed during gel layer formation, and each appeared to contribute independently to gel layer structure. Magnetic resonance imaging showed how PEO matrices hydrated more rapidly than HPMC matrices, but PEO matrices completely dissolved after 9 hours. In the case of 4:6 HPMC:PEO and HPMC matrices, a hydrated gel remained. This reflected the behaviour of these matrices in the dissolution tests. Unfortunately, MRI could only be applied in zero salt media, as the dielectric properties of NaCl interfered with the results, and other techniques were required to examine matrix behaviour in high salt media. Texture analysis showed that at low NaCl concentrations, the HPMC gel layer exhibited higher gel strength than PEO, and that by substituting HPMC for PEO increased gel layer strength was obtained. The later stages of gel layer morphology were also investigated by digital optical macroscopy. Images showed greater gel longevity of HPMC and mixed matrices, with evidence for a higher gel strength and less erosion than PEO matrices. Swelling of single polymer particles showed how increasing NaCl concentration significantly inhibited HPMC particle swelling but only had a limited effect on PEO particle swelling. The ability of PEO particles to swell in high salt media may explain the resistance of PEO matrices to high NaCl dissolution media. The miscibility of HPMC and PEO in dilute solution was studied by rheology and phase contrast microscopy. Measurements of storage modulus (G’) at 1% w/v showed how most polymer mixtures showed negative deviations from ideal mixing at all oscillatory frequencies studied (0.1Hz, 1Hz, and 10Hz). This is evidence that these polymers are immiscible in solution. Phase contrast microscopy provided direct optical evidence of phase separation in blended HPMC:PEO solutions (4% w/v). The tendency of these polymers to be immiscible, suggests that they may also be phase separated in the more concentrated environment of the gel layer. Gel layer morphology in binary polymer tablets was investigated directly by confocal microscopy (up to 15 min) and by attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) up to 3 hours. The confocal microscopy images showed that HPMC and PEO appeared to swell independently during early gel layer. Each polymer appeared to contribute independently to gel layer structure. ATR-FTIR imaging allowed chemical mapping of the three components (water, PEO and HPMC) in the gel layer, providing evidence that each polymer formed individual domains. PEO appears to be more extensively swollen than HPMC and may form the outer part of the gel layer, protecting HPMC from the effect of high ionic media. The work in this thesis suggests that mixed polymer HPMC:PEO matrices may have certain advantages over the use of matrices containing only single polymer. PEO confers resistance to highly ionic media, while HPMC provides a longer drug release than PEO alone. Each polymer appears to contribute separately to the gel layer, but the ability of PEO to swell in highly ionic environments, may allow formation of a diffusion barrier that protects the incorporated HPMC from ionic media, and allows it to contribute to gel layer structure.

Polyphosphate biosynthesis and the stringent response play an important role in the virulence of pathogenic bacteria. Our objective is to validate these pathways as an antimicrobial target and to identify inhibitors of the key enzymes polyphosphate kinase (PPK), (p)ppGpp synthetase I (RelA) and (p)ppGpp synthetase/hydrolase II (SpoT). The role of polyphosphate and (p)ppGpp metabolism in Francisella virulence has been explored with deletion mutants. These exhibited defects for intracellular growth in macrophages and were attenuated in mice, indicating a key role for the FtPPK, FtRelA and FtSpoT in the virulence of Francisella. The development of three in vitro activity assays will enable the discovery of PPK inhibitors. Ion-pairing HPLC analysis has been used to measure substrate kinetics, providing evidence that FtPPK belongs to the PPK2 superfamily with little preference between substrates (KM: ADP - 369 μM; GDP - 624 μM) as displayed by other PPK2 enzymes. 31P NMR spectroscopy has been used to monitor the overall time course of the PPK reaction. To facilitate high-throughput screening, a coupled luminescence based activity assay has been developed in a 96-well plate format. These assays can also be applied to the discovery of inhibitors for FtRelA and FtSpoT. Understanding the structural basis of inhibitor action requires a crystal structure of the target enzyme. For FtPPK, a crystallisation screen has identified conditions for obtaining suitable crystals and data has been collected to 2.1 Å resolution. Future studies will use the high throughput assay to identify PPK inhibitors; NMR and HPLC assays to characterise the mode of action and crystal structures of PPK:inhibitor complexes will identify the precise molecular interactions.

The discovery of drugs that can effectively treat disease and alleviate pain is one of the core challenges facing modern medicine. The tools and techniques of machine learning have perhaps the greatest potential to provide a fast and effcient route toward the fabrication of novel and effective drugs. In particular, modern structured kernel methods have been successfully applied to range of problem domains and have been recently adapted for graph structures making them directly applicable to pharmaceutical drug discovery. Specifically graph structures have a natural fit with molecular data, in that a graph consists of a set of nodes that represent atoms that are connected by bonds. In this thesis we use graph kernels that utilize three different graph representations: molecular, topological pharmacophore and reduced graphs. We introduce a set of novel graph kernels which are based on a measure of the number of finite walks within a graph. To calculate this measure we employ a dynamic programming framework which allows us to extend graph kernels so they can deal with non-tottering, softmatching and allows the inclusion of gaps. In addition we review several graph colouring methods and subsequently incorporate colour into our graph kernels models. These kernels are designed for molecule classification in general, although we show how they can be adapted to other areas in drug discovery. We conduct three sets of experiments and discuss how our augmented graph kernels are designed and adapted for these areas. First, we classify molecules based on their activity in comparison to a biological target. Second, we explore the related problem of lead hopping. Here one set of chemicals is used to predict another that is structurally dissimilar. We discuss the problems that arise due to the fact that some patterns are filtered from the dataset. By analyzing lead hopping we are able to go beyond the typical cross-validation approach and construct a dataset that more accurately reflect real-world tasks. Lastly, we explore methods of integrating information from multiple targets. We test our models as a multi-response problem and later introduce a new approach that employs Kernel Canonical Correlation Analysis (KCCA) to predict the best molecules for an unseen target. Overall, we show that graph kernels achieve good results in classification, lead hopping and multiple target experiments.