Este trabalho faz parte de um projeto maior, o electronic Physician Annotation Device (ePAD). O ePAD permite a criação de uma base de conhecimento médico usando anotações semânticas sobre lesões em imagens radiológicas, usando uma plataforma Web. Essas anotações servirão para identificar, acompanhar e reason sobre lesões tumorais em pesquisas médicas (especialmente sobre câncer). A informação adquirida e persistida pelo sistema permite avaliação automática por computadores; recuperação de imagens hospitalares e outros serviços relacionados a exames médicos. O ePAD é um desenvolvimento conjunto de grupos de pesquisas do ICMC-USP e do Department of Radiology da Stanford University. O principal trabalho, apresentado neste texto, é um novo conjunto de funcionalidades na Web para adicionar a marcação de lesões em imagens radiológicas em três dimensões ao ePAD. Elas permitirão a obtenção de dados mais precisos acerca de medidas tridimensionais de lesões como volume, posição e cálculo de maior diâmetro. O objetivo é facilitar o trabalho dos profissionais de radiologia na análise de diagnósticos e acompanhamento de lesões produzindo um acompanhamento mais acurado da evolução de doenças como o câncer. Anotações podem ser conectadas a lesões e conter informações semânticas, usando termos biomédicos da ontologia RadLex. Essas novas funcionalidades são baseadas em HTML5, com o auxílio de WebGL para visualização e manipulação de objetos 3D. As maiores contribuições deste trabalho são o software para visualização de séries de imagens radiológicas em 3D usando planos ortogonais, os protótipos de vídeo mostrando as três possíveis interfaces para marcação de lesões em 3D, a pesquisa com radiologistas (usando os protótipos de vídeo) para determinar que o cursor esférico era a melhor interface para marcar lesões em 3D e o protótipo dessa interface no ePAD. Este trabalho contou com a ajuda de usuários do Department. of Radiology da Stanford University e do Hospital das Clínicas da Universidade de São Paulo em Ribeirão Preto. / This work is part of a larger project, the electronic Physician Annotation Device (ePAD) project. The ePAD allows the creation of a medical knowledge base using semantic annotation on lesions found on radiological images using the Web platform. The annotation will serve to identify, follow-up and reason about tumor lesions in medical research projects (specially about cancer). The information acquired and persisted by the system allows automatic evaluation by computers; retrieval of hospital images and other services related to medical exams. ePAD is a joint development of the ICMC-USP and the Department of Radiology of the Stanford University research groups. The main work, presented here, is a new set of functionalities on the Web to add recording of lesions on radiological images in three dimensions to ePAD. They will lead to more accurate data about three dimensional lesion measurements, such as volume, position and longest diameter calculations. The objective is to ease the work of radiology professionals doing diagnostic analysis and lesion tracking producing more accurate follow-ups of disease evolution, such as of cancer. Annotation can be attached to lesions and hold semantic information, using biomedical ontology terms from RadLex. These new functionalities are based on HTML5 with the help of WebGL for visualization and manipulation of 3D objects. The main contributions of this work are the software for visualization of radiological image series in 3D using orthogonal planes, the video prototypes showing the three possible interfaces to mark lesions in 3D, the survey with radiologists (using the video prototypes) to determine that the spherical cursor was the best interface to mark lesions in 3D and the prototype of this interface in ePAD. This work received help from users of the Department of Radiology of the Stanford University and the Clinics Hospital of Ribeirão Preto of the University of São Paulo.

This thesis examines one of the premier "big science" projects of the contemporary era - the globalised genetic mapping and sequencing initiative known as the Human Genome Project (HGP), and how Australia has responded to it. The study focuses on the relationship between the HGP, the biomedical model of health, and globalisation. It seeks to examine the ways in which the HGP shapes ways of thinking about health; the influence globalisation has on this process; and the implications of this for smaller nations such as Australia. Adopting a critical perspective grounded in political economy, the study provides a largely structuralist analysis of the emergent health context of the HGP. This perspective, which embraces an insightful nexus drawn from the literature on biomedicine, globalisation and the HGP, offers much utility by which to explore the basis of biomedical dominance, in particular, whether it is biomedicine's links to the capitalist infrastructure, or its inherent efficacy and efficiency, that sustains the biomedical paradigm over "other" or non-biomedical health approaches. Additionally, the perspective allows for an assessment of whether there should be some broadening of the way health is conceptualised and delivered to better account for social, economic, and environmental factors that affect living standards and health outcomes, and also the capacity of globalisation to promote such change. These issues are at the core of the study and provide the theoretical frame to examine the processes by which Australian policy makers have given an increasing level of support to human genomic research over the past decade and also the implications of those discrete policy choices. Overall, the study found that globalisation is renewing and extending the dominance of the biomedical model, which will further marginalise other models of health while potentially consuming greater resources for fewer real health outcomes. While the emerging genomic revolution in health care may lead to some wondrous innovations in the coming decades, it is also highly likely to exacerbate the problems of escalating costs and diminishing returns that characterise health care systems in industrialised countries, and to lead to greater health inequities both within and between societies. The Australian Government has chosen to underwrite human genomic research and development. However, Australia's response to the HGP has involved both convergences and variations from the experiences of more powerful industrial nations. The most significant divergence has been in industry and science policy, where until the mid-1990s, the Australian Government displayed no significant interest in providing dedicated research funding, facilities, or enabling agencies to the emerging field. Driven by the threat of economic marginalisation and cultural irrelevance, however, a transformation occurred. Beginning with the Major National Research Facilities Program of the Department of Industry, Science and Technology, and then the landmark Health and Medical Research Strategic Review, support for human genomic research grew strongly. Comprehensive policy settings have recently been established to promote the innovation, commercialisation, promotion and uptake of the products of medical biotechnology and genomics. As such, local advocates of a broader model of health will be forced to compete on the political and economic stage with yet another powerful new area of biomedicine, and thus struggle to secure resources for perhaps more viable and sustainable approaches to health care in the 21st century.

<p>Upon an inflammation the immune system signals the brain by secreted cytokines to elicit central nervous responses such as fever, loss of appetite and secretion of stress hormones. Since the blood brain barrier, (BBB) protects the brain from unwanted material, molecules like cytokines are not allowed to cross the barrier and enter the brain. However, it is clear that they in some way can signal the brain upon an inflammation. Many suggestions concerning this signaling has been made, one being that cytokines bind to receptors on the endothelial cells of the blood vessels of the brain and trigger the production of prostaglandins that can cross the BBB. This conversion is catalyzed by the enzyme cyclooxygenase-2, (COX-2), which is induced by transcription factors like NF-κB in response to cytokines. One of the central nervous responses to inflammatory stimuli is activation of the HPA-axis whose main purpose is glucocorticoid production. Glucocorticoids inhibit the inflammatory response by suppressing gene transcription of pro-inflammatory genes including those producing prostaglandins through direct interference with transcription factors such as NF-κB or initiation of transcription of anti-inflammatory genes like IκB or IL-10. It has however not been clear if glucocorticoids can target the endothelial cells of the brain in order to provide negative feed-back on the immune-to-brain signaling, and in that way inhibit central nervous inflammatory symptoms. An anatomical prerequisite for such a mechanism would be that the induced prostaglandin production occurs in cells expressing GR. This has however never been demonstrated. Here I show that a majority of the brain endothelial cells expressing the prostaglandin synthesizing enzyme COX-2 in response to immune challenge also express the glucocorticoid receptor, (GR). This indicates that immune-to-brain signaling is a target for negative regulation of inflammatory signaling executed by glucocorticoids and identifies brain endothelial GR as a possible future drug target for treatment of central nervous responses to inflammation such as fever and pain.</p>

<p>The telomeres are specialized structures at the end of the chromosomes composed of the repeated DNA sequence (TTAGGG)n and specific proteins bound to the DNA. The telomeres protect the chromosomes from degradation and end to end fusions. Due to the end-replication problem, the telomeric DNA shortens every cell division, forcing the cells into senescence at a critical telomere length. This process can be counteracted by activating a specialized enzyme, telomerase, which adds telomeric repeats to the chromosome ends leading to an extended or infinite cellular life span. Telomerase activity is absent in most somatic tissues but is found in germ cells, stem cells, activated lymphocytes and the vast majority of tumor cells and permanent cell lines. Hence, telomerase has been suggested as a target for cancer treatment as malignant cells almost exclusively express the enzyme and in that context telomere length measurements will be of great importance.</p><p>Telomere length is traditionally measured with a Southern blot based technique. A new method for telomere analysis of cells in suspension, called flow-FISH, was developed based on fluorescence in situ hybridization using a telomeric peptide nucleic acid (PNA) probe,</p><p>DNA staining with propidium iodide and quantification by flow cytometry. Flow-FISH had high reproducibility and the telomere length measurements showed good correlation with Southern blotting results. The flow-FISH technique also allows studies of cells in specific phases of the cell cycle and the replication timing of telomeric, centromeric and other repetitive sequences were analyzed in a number of cells. Like previous studies, centromeres were shown to replicate late in S phase while the telomere repeats were found to replicate early in S phase or concomitant with the bulk DNA, which is opposite to the patterns described in yeast.</p><p>In benign immunopurified lymphocytes from tonsils, high telomerase activity was found in germinal center (GC) B cells. This population also had high hTERT mRNA levels and displayed a telomere elongation as shown by flow-FISH and Southern blotting. Combined immunophenotyping and flow-FISH on unpurified tonsil cells confirmed the results.</p><p>Chronic lymphocytic leukemia (CLL), the most common leukemia in adults, can be divided into pre-GC CLL, characterized by unmutated immunoglobulin VH genes and worse prognosis, and post-GC CLL, with mutated VH genes and better prognosis. In 61 cases of CLL, telomere length was measured with Southern blotting and VH gene mutation status was analyzed. A new association was found between VH mutation status and telomere length, where cases with longer telomeres and mutated VH genes (post-GC CLL) had better prognosis</p><p>than CLL with short telomeres and unmutated VH genes (pre-GC CLL). A larger study of 112 CLL cases was performed using flow-FISH. The same correlation between telomere length and VH mutation status was found but gender seemed to be of importance as telomere length was a significant prognostic factor for the male CLL patients but not in the female group. Age of the patients and spread of disease seemed to affect the prognostic value of VH gene mutation status.</p>

The telomeres are specialized structures at the end of the chromosomes composed of the repeated DNA sequence (TTAGGG)n and specific proteins bound to the DNA. The telomeres protect the chromosomes from degradation and end to end fusions. Due to the end-replication problem, the telomeric DNA shortens every cell division, forcing the cells into senescence at a critical telomere length. This process can be counteracted by activating a specialized enzyme, telomerase, which adds telomeric repeats to the chromosome ends leading to an extended or infinite cellular life span. Telomerase activity is absent in most somatic tissues but is found in germ cells, stem cells, activated lymphocytes and the vast majority of tumor cells and permanent cell lines. Hence, telomerase has been suggested as a target for cancer treatment as malignant cells almost exclusively express the enzyme and in that context telomere length measurements will be of great importance. Telomere length is traditionally measured with a Southern blot based technique. A new method for telomere analysis of cells in suspension, called flow-FISH, was developed based on fluorescence in situ hybridization using a telomeric peptide nucleic acid (PNA) probe, DNA staining with propidium iodide and quantification by flow cytometry. Flow-FISH had high reproducibility and the telomere length measurements showed good correlation with Southern blotting results. The flow-FISH technique also allows studies of cells in specific phases of the cell cycle and the replication timing of telomeric, centromeric and other repetitive sequences were analyzed in a number of cells. Like previous studies, centromeres were shown to replicate late in S phase while the telomere repeats were found to replicate early in S phase or concomitant with the bulk DNA, which is opposite to the patterns described in yeast. In benign immunopurified lymphocytes from tonsils, high telomerase activity was found in germinal center (GC) B cells. This population also had high hTERT mRNA levels and displayed a telomere elongation as shown by flow-FISH and Southern blotting. Combined immunophenotyping and flow-FISH on unpurified tonsil cells confirmed the results. Chronic lymphocytic leukemia (CLL), the most common leukemia in adults, can be divided into pre-GC CLL, characterized by unmutated immunoglobulin VH genes and worse prognosis, and post-GC CLL, with mutated VH genes and better prognosis. In 61 cases of CLL, telomere length was measured with Southern blotting and VH gene mutation status was analyzed. A new association was found between VH mutation status and telomere length, where cases with longer telomeres and mutated VH genes (post-GC CLL) had better prognosis than CLL with short telomeres and unmutated VH genes (pre-GC CLL). A larger study of 112 CLL cases was performed using flow-FISH. The same correlation between telomere length and VH mutation status was found but gender seemed to be of importance as telomere length was a significant prognostic factor for the male CLL patients but not in the female group. Age of the patients and spread of disease seemed to affect the prognostic value of VH gene mutation status.

Upon an inflammation the immune system signals the brain by secreted cytokines to elicit central nervous responses such as fever, loss of appetite and secretion of stress hormones. Since the blood brain barrier, (BBB) protects the brain from unwanted material, molecules like cytokines are not allowed to cross the barrier and enter the brain. However, it is clear that they in some way can signal the brain upon an inflammation. Many suggestions concerning this signaling has been made, one being that cytokines bind to receptors on the endothelial cells of the blood vessels of the brain and trigger the production of prostaglandins that can cross the BBB. This conversion is catalyzed by the enzyme cyclooxygenase-2, (COX-2), which is induced by transcription factors like NF-κB in response to cytokines. One of the central nervous responses to inflammatory stimuli is activation of the HPA-axis whose main purpose is glucocorticoid production. Glucocorticoids inhibit the inflammatory response by suppressing gene transcription of pro-inflammatory genes including those producing prostaglandins through direct interference with transcription factors such as NF-κB or initiation of transcription of anti-inflammatory genes like IκB or IL-10. It has however not been clear if glucocorticoids can target the endothelial cells of the brain in order to provide negative feed-back on the immune-to-brain signaling, and in that way inhibit central nervous inflammatory symptoms. An anatomical prerequisite for such a mechanism would be that the induced prostaglandin production occurs in cells expressing GR. This has however never been demonstrated. Here I show that a majority of the brain endothelial cells expressing the prostaglandin synthesizing enzyme COX-2 in response to immune challenge also express the glucocorticoid receptor, (GR). This indicates that immune-to-brain signaling is a target for negative regulation of inflammatory signaling executed by glucocorticoids and identifies brain endothelial GR as a possible future drug target for treatment of central nervous responses to inflammation such as fever and pain.

Parkinson's Disease can be treated by a micro-electrode guided neurosurgery called a Pallidotomy or Deep Brain Stimulus. A new software program, called Onetrack, is being developed and incorporates a three dimensional virtual model of the brain, a advanced digital signal processor and a knowledge based system (KBS). This thesis discusses the design and development of this KBS. The purpose of the KBS is to assist the surgical team in identifying the different anatomical structures and neuronal cell types of the brain. Therefore, improving the efficiency of the procedure.

This thesis explores the ontological content of the integration of complementary and alternative medicine (CAM) in biomedical education, through a critical exploration of “CAM" policy related documents from the World Bank, the World Health Organization and Health Canada, as a means of contextualizing "CAM" in biomedical education. It also interrogates curriculum documents from a project that seeks to standardize “CAM” in biomedical education. This thesis suggests that there are ontological parallels to the colonial era conversion of indigenous medicine evoked in the contemporary 'integration' of CAM in biomedical education.

Si l’alternative est de nos jours et dans nos sociétés occidentales un concept de plus en plus en vogue, son caractère lui, en demeure pas moins ambigu. En effet, et alors même que nombre de pratiques dites alternatives émergent de part et d’autre de la société, en faire allusion dans certains domaines équivaut à s’affliger soi-même d’une étiquette sur laquelle serait inscrite « New-Age » en caractère gras. Pourtant, son caractère loin d’évoquer cette seule dimension, semble par ailleurs être conséquente d un déséquilibre de plus en plus prégnant au sein même des prérogatives de l’État. Ce mémoire tente donc de rendre compte de ce phénomène tout en investiguant les répercussions de cette asymétrie sur l’intégration de pratiques médicales alternatives au Québec. Ceci dans l’intention non seulement d’explorer davantage la nature de la relation entre médecine alternative et biomédecine, mais aussi afin de poser un nouveau regard sur son expansion. Un regard, lequel permettrait potentiellement de poser les jalons nécessaires à un espace de conciliation entre les médecines, lequel découlerait alors d’un nouvel équilibre au cœur des prérogatives mêmes de l’État. / If the alternative is to our days and in our western societies a concept more and more in vogue, its character remains ambiguous. In effect, and even that number of practices called “alternatives” emerge on both sides of the society, in referring to in some areas is equivalent to plague itself-even a label on which would be marked “New-Age” in bold. Yet, its character far from referring to this single dimension, seems also be consistent to a more and more significant unbalance within the prerogatives of the State. This dissertation therefore attempts to account for this phenomenon while inquiry into the repercussions of this asymmetry on the integration of alternative medical practices in Quebec. This with the intention not only to further explore the nature of the relationship between alternative medicine and biomedicine, but also in order to install a new look on its expansion. A look, which would potentially lay the groundwork necessary to a space of conciliation between the medicines and which would lead to a new balance in the heart of the prerogatives of the State.

Tendo em vista a compreensão dos significados atribuídos às infeções oportunistas pelos pacientes HIV+ entre os moçambicanos da etnia Tsonga do distrito de Xai-Xai e a consequente busca de atendimento nas redes tradicionais de cura, na pesquisa adotamos uma metodologia qualitativa com caráter etnográfico. Embora Xai-Xai seja a capital de Gaza, importante província de Moçambique, ali, os Tsonga ainda estão muito inseridos nas redes tradicionais de cura. Por outro lado, a rede do Sistema Nacional da Saude se faz também presente e não muito precária, relativamente ao resto do país. Essa peculiaridade nos levou a indagação central do trabalho: no que concerne aos pacientes HIV+ será que os serviços de saúde do distrito da cidade de Xai-Xai dispõem de estruturas de acolhimento tão adequadas aos pressupostos ontológicos da cultura local quanto as redes tradicionais de cura? A nossa hipótese é a de que o desajuste de um acolhimento inadequado aos pacientes Tsonga impele-os a intensificar a busca de cuidados alternativos à medicina convencional nas redes tradicionais. A metodologia que escolhemos permitiu-nos compreender as vivências dos pacientes não somente a partir das questões apresentadas verbalmente, mas também podemos acompanhar as suas práticas cotidianas relacionadas a busca de cura. A pesquisa fez nos perceber que a ausência do diálogo entre a biomedicina e as redes tradicionais de cura influência em grande medida o elevado número de óbitos e a não retenção dos pacientes em Tratamento antiretroviral- Tarv mesmo com as constantes reinvenções de políticas de assistência aos pacientes HIV+. A situação colonial dessa relação se consubstância na negação ou subalternização do conhecimento local mesmo por atores nativos que atuam no sistema nacional de saúde. / In order to understand the meanings attributed to opportunistic infections by HIV+ patients among the Tsonga Mozambicans in the Xai-Xai district and the consequent search for care in the traditional healing networks, a qualitative methodology with an ethnographic character was used in the research. Although Xai-Xai is the capital of Gaza, a major province in Mozambique, the Tsonga are still very much embedded in traditional healing networks. On the other hand, the network of the National Health System is also present and not very precarious, relative to the rest of the country. This peculiarity has led us to the central inquiry of the work: as far as HIV + patients are concerned, the health services of the Xai-Xai city district have reception facilities that are as appropriate to the ontological presumptions of the local culture as the traditional cure? Our hypothesis is that the mismatch of inadequate care for Tsonga patients prompts them to intensify the search for alternative care to conventional medicine in traditional networks. The methodology we chose allowed us to understand the patients' experiences not only from the questions presented verbally, but we can also follow their daily practices related to the search for cure. The research made us realize that the absence of dialogue between biomedicine and traditional healing networks greatly influences the high number of deaths and non-retention of patients in antiretroviral treatment-TARV even with the constant reinvention of HIV+ patient care policies. The colonial situation of this relationship is consubstantiated in the negation or subalternization of local knowledge even by native actors who work in the national health system.