In under 6 decades dengue has emerged from South East Asia to become the most widespread arbovirus affecting human populations. Recent dramatic increases in epidemic dengue fever have mainly been attributed to factors such as vector expansion and ongoing ecological, climate and socio-demographic changes. The failure to control the virus in endemic regions and prevent global spread of its mosquito vectors and genetic variants, underlines the urgency to reassess previous research methods, hypotheses and empirical observations. This thesis comprises a set of studies that integrate currently neglected and emerging epidemiological, ecological and evolutionary factors into unified mathematical frameworks, in order to better understand the contemporary population biology of the dengue virus. The observed epidemiological dynamics of dengue are believed to be driven by selective forces emerging from within-host cross-immune reactions during sequential, heterologous infections. However, this hypothesis is mainly supported by modelling approaches that presume all hosts to contribute equally and significantly to the selective effects of cross-immunity both in time and space. In the research presented in this thesis it is shown that the previously proposed effects of cross-immunological reactions are weakened in agent-based modelling approaches, which relax the common deterministic and homogeneous mixing assumptions in host-host and host-pathogen interactions. Crucially, it is shown that within these more detailed models, previously reported universal signatures of dengue's epidemiology and population genetics can be reproduced by demographic and natural stochastic processes alone. While this contrasts with the proposed role of cross-immunity, it presents demographic stochasticity as a parsimonious mechanism that integrates, for the first time, multi-scale features of dengue's population biology. The implications of this research are applicable to many other pathogens, involving challenging new ways of determining the underlying causes of the complex phylodynamics of antigenically diverse pathogens.

「被忽視」的熱帶疾病(NTDs)中的寄生蟲疾病(Parasitic Diseases; PDs)除對非洲人群健康之危害甚鉅外，並進而對非洲地區社經體系造成嚴重衝擊與造成巨大的「失能調整人年」損失。由於不易取得治療PDs傳統基本藥物的問題，許多非洲民眾便以其部落社區的傳統治療師所採用的傳統草藥來進行PDs的治療，雖然這些傳統草藥容易取得，但是成分的內容和藥效品質甚或產生嚴重的致命副作用。雖然TRIPS協定第31條和杜哈宣言的第五和第六段對於製藥能力不足或大部分皆無製藥能力的貧窮國家，可以基於「國家緊急危難或其它緊急狀況」的事由，以強制授權方式取得專利藥或較便宜的學名藥以解決造成國家危難的特定公共健康事件，但是國際大藥廠認為無利可圖，不願意花費資金投注於預防或治療此類疾病藥物的相關研發外，高收入的國家為保護其大藥廠的藥物專利，也往往使用一些經濟制裁手段逼迫上述國家就制定國內專利法以保護其藥物專利。雖然經杜哈宣言修正TRIPS協定第31(f)條有關強制授權對外出口的障礙，但是出口國對於強制授權程序與是否能取得政治上和藥廠業者的支持，仍充滿困難。應用「專利池」可以減少交易成本或法律爭議而可調和「強制授權」與解決「權利耗盡」的爭議，有助於解決非洲開發中國家取得專利藥物的困境。PDs造成非洲開發中國家民眾失能等長期痛苦與健康生活損失，類推適用SARS模式，可依TRIPS協定第31條(b)與杜哈宣言第五段(c)將之視為「造成國家緊急危難或其它緊急狀況」的重大公共健康的事由而可行使強制授權。雖然「生醫專利池BVGH」的「非獨家個別授權與免授權費」的操作模式與傳統電信技術專利池不盡相同，但因藥廠不願投入治療PDs的傳統基本藥物存在的副作用與抗藥性的新藥研發，為鼓勵對治療PDs的藥物進行創新研發， BVGH彈性的授權方式與免繳交授權費，將有利於解決開發中國家未來取得新專利藥的困境。除BVGH外，建議結合全球獎勵基金以「激勵拉拔」的方式獎助願意投入治療PDs新藥研發並將專利自願授權給BVGH的藥廠。鑒於全球暖化與最近中東難民潮大量湧進歐洲，罕見的PDs可預期會大量傳播開來，將嚴重衝擊歐洲等先進國家良好的公共衛生體系，而使得「NTDs尤其是PDs不再只是專屬於貧窮國家的疾病，亦將常現於富有的先進國家」。這些NTDs疾病將提供藥廠進行新藥研發的利基，然而在未來可能產生專利池的反競爭問題，導致支配市場獨占性的隱憂值得關注。 / Parasitic diseases (PDs) not only cause the huge health hazards to African populations, but also they further severely impact on African socio-economic system as resulting in huge economic and health losses as assessed by disability adjusted life-years. Since it is not easy for Africans to access the essential medicine to treat PDs, many of them will seek for the help of local healers in tribal communities to treat PDs. Although these traditional herbs are readily available, the content and quality of drug ingredients may even cause serious fatal side effects. Poor countries with insufficiencies or lacks of the pharmaceutical capacities may still access the patented medicines or cheaper generics to solve the national crisis caused by the specific public health events through compulsory licensing (CL) based on "national emergency or the other emergency situations" according to TRIPS Article 31 and Doha Declaration on the fifth and sixth paragraph due to that the large international pharmaceutical companies consider unprofitable, unwilling to spend money to invest on the research and development (R&D) of new drugs for prevention or treatment purpose. Moreover, the high-income countries also tend to exert some of the economic sanctions to force those poor countries to enact national patent law in order to protect drug patents. Furthermore, the mandatory obstacle of exportation authorized by CL from the amended TRIPS Agreement Article 31 (f) by the Doha Declaration has been improved; nevertheless, it is still fraught with difficulties in utilization of CL for the exporting countries because this should be dependent on whether they may actually get the supports from political and the pharmaceutical industry. Application of patent pools model may benefit to reduce transaction costs or legal dispute thus reconciling and resolving issues related to CL as well as doctrine of patent exhaustion and that it is beneficial to help solve dilemma for African countries to access patented drugs. Because Africans severely suffer from disabled caused by PDs thus leading to long-term pain and health life losses, African countries can grant CL as PDs may be regarded as national crisis like SARS causing "national emergency or the other emergency situations" as authorized from TRIPS Agreement Article 31 (f) and Doha Declaration paragraph 5 (c). Although the practice of individual licensing with royalty-free for BVGH is somewhat different from that of traditional patent pools, this licensing practice mode is beneficial to innovation in new drugs R&D to improve the side effects and drug-resistance of traditional essential medicines and help African countries to access patented new drugs in the future. Finally, it is recommended to cooperate with Award Foundation to encourage incentive for pharmaceutical companies which contribute most to new drugs R&D and voluntary licensing to BVGH. Owing to global warming and recent emergence of huge refugees into Europe rare PDs will be obviously spread out thus causing severe impacts on well-established public health system as leading to emergence of PDs in developed countries like Europe. Altogether, such situations definitely provide a good incentive in new drugs R&D for pharmaceutical companies; however, it guarantees concerns on anti-competitive and monopoly issues derived by biomedical pools in the future.

The thesis Cooperation of governmental and non-governmental sector in the care of neglected children has theoretical and research nature and is divided into theoretical and practical parts. The first chapter of the theoretical part focuses on the child neglect in the family. In addition to defining the concept are given the educational implications of child neglect in the family, its risk factors and failure of family in relation to child neglect. The second chapter deals with governmental and non-governmental sector entities, intervening in the area of child neglect. Attention is focused on social work in the department of social and legal protection of children, NGOs working with endangered families and children and socio-educational work with children at risk of neglect in selected schools and school facilities. The third chapter deals with the cooperation of governmental and non-governmental entities in the area, factors that affect their cooperation and rehabilitation of the family as an effective intervention in the family of the endangered child. The practical part is aimed at qualitative data analysis of documents concerning activities and cooperation of Department of social and legal protection of children in Prachatice, local NGOs, which have been granted authority to exercise social and legal...

INTRODUÇÃO: A endomiocardiofibrose (EMF) é uma doença típica de países tropicais, na qual ocorre a deposição de uma capa fibrosa na região endomiocárdica com graves consequências clínicas. A patogenia da EMF ainda não foi elucidada, mas uma das principais hipóteses etiológicas sugere que a EMF seja consequência de um processo inflamatório crônico com envolvimento de respostas imunes Th2 pós-infestação helmíntica, mediada por eosinófilos nas fases iniciais da doença. Neste estudo avaliamos o perfil da resposta imune e inflamatória, assim como o perfil de proteínas expressas no endomiocárdio afetado, para compreender melhor os mecanismos envolvidos na patogênese da EMF. MÉTODOS: Foram coletadas amostras de plasma e soro de pacientes com diagnóstico de EMF e de indivíduos saudáveis, para dosagens de 6 citocinas plasmáticas do perfil Th1/Th2, Proteína C Reativa ultrassensível (PCRus), IgE total e IgE específico contra aero-alérgenos prevalentes e alérgenos de helmintos. A análise proteômica do endomiocárdio afetado de quatro pacientes com EMF submetidos à ressecção cirúrgica da fibrose, levou à identificação por espectrometria de massas, de proteínas separadas previamente por gel 1D e 2D. Análises in silico de vias funcionais e redes ligando as proteínas identificadas também foram realizadas. Eosinofilia em sangue periférico, assim como dados clínicos e ecocardiográficos, foram avaliados retrospectivamente. RESULTADOS: Foram selecionados 27 pacientes em estágio avançado da EMF, portadores de disfunção diastólica e/ou valvar. Todas as amostras de plasma analisadas apresentaram níveis detectáveis de pelo menos uma das citocinas avaliadas. As citocinas IL-6, TNF-?, IL-10 e IL-4 foram detectadas em pelo menos 74% das amostras, sendo que os níveis de IL-6, TNF-? e IL-10 se apresentaram significantemente elevados em comparação com os detectados nos indivíduos saudáveis. Foi observada correlação positiva entre os níveis de todas as citocinas avaliadas. Apenas 33% dos pacientes apresentaram algum episódio isolado de eosinofilia periférica ao longo do tempo, sendo que 11% apresentaram hipereosinofilia. Os níveis de IgE total foram semelhantes aos observados na população controle. A análise proteômica permitiu identificar 140 proteínas distintas no tecido endomiocárdico, das quais 18 eram provenientes da matriz extracelular. As análises in silico indicaram IL-6 e TNF-? como dois dos principais indutores da expressão das proteínas identificadas e a principal via canônica envolvida nas proteínas identificadas foi a: \"Resposta de Fase Aguda\". Coincidentemente, os níveis de PCRus encontraram-se significativamente aumentados nos portadores de EMF. CONCLUSÕES: Elevados níveis de citocinas pró e anti-inflamatórias e de PCRus sugerem a presença de perfil inflamatório misto (Th1/Th2) nas fases avançadas da patogênese da EMF. A pouca expressão da eosinofilia descarta sua participação ativa na patogênese da fase avançada da doença, mas não é possível excluir sua participação nas fases iniciais. Nossos dados permitem levantar a hipótese que os níveis elevados de citocinas inflamatórias modulem a expressão de proteínas- incluindo as de fase aguda- no tecido endomiocárdico de pacientes portadores de EMF / INTRODUCTION: Endomyocardial fibrosis (EMF) is a typical disease in tropical countries, characterized by the fibrous deposition in the endomyocardium, with severe clinical manifestations. EMF pathogenesis is still unclear, but one of the major hypothesis suggests that EMF could be a consequence of a chronic inflammatory process with possible involvement of a Th2 immune responses after helminthiasis, mediated by eosinophils, which could contribute to pathogenesis in the early stages of the disease. In this study, we evaluated the inflammatory response profile and the protein expression profile of the affected endomyocardium, to understand the mechanisms involved in this pathogenesis. METHODS: Plasma and serum samples were collected from the 27 patients diagnosed with advanced stage EMFand from healthy controls, to mensured plasma levels of 6 cytokines belonging to the Th1/Th2 cytokine profiles, ultrasensitive C Reactive Protein (CRP), total and allergen-specific serum IgE against prevalent and helminthic allergens. Proteomic analysis of tissue samples obtained from 4 EMF patients submitted to surgical resection of affected endomyocardial tissue allowed the identification of proteins by mass spectrometry, after separation by 1D and 2D electroforesis. In silico analysis of functional pathways and networks connecting the proteins identified in the EMF cardiac tissue was also performed. Blood peripheral eosinophilia, clinical and echocardiography data were evaluated retrospectively. RESULTS: All EMF patients displayed detectable plasma levels of at least one of the cytokines tested. We found that TNF-?, IL-6, IL-4 and IL-10 were each detected in at least 74% of tested sera, and plasma levels of IL10, IL6 and TNF-? were significantly higher than controls. Plasma levels of such cytokines positively correlated with each other. Only 33% of the patients presented any episode of blood eosinophilia along time, and 11% of these patients presented hypereosinophilia. Total IgE levels were similar to those from healthy subjects. Proteomic analysis allowed the identification of 140 distinct proteins from the resected endomiocardium of the EMF patients, 18 of which belonging to the extracellular matrix. In silico analysis indicated IL-6 and TNF-? as two of the major gene expression inducers of the identified proteins in our analysis, and the Acute Phase Response was identified as the major canonical pathway involved with the identified set of proteins. Similarly, CRP levels were significantly increased in the EMF patients. CONCLUSIONS: Increased levels of an inflammatory/anti-inflammatory circulating cytokines (Th1/Th2), along with increased CRP levels, suggested the presence of a mixed inflammatory profile in EMF advanced stage. The number of EMF patients with blood eosinophilia does not support the active participation of eosinophils in pathogenesis of advanced EMF. However, it is not possible to exclude the participation in the pathogenesis early stages. Our data support the hypothesis that the increased levels of inflammatory cytokines modulate protein expression -including proteins of the acute phase response - in the endomyocardial tissue of EMF patients

INTRODUÇÃO: A endomiocardiofibrose (EMF) é uma doença típica de países tropicais, na qual ocorre a deposição de uma capa fibrosa na região endomiocárdica com graves consequências clínicas. A patogenia da EMF ainda não foi elucidada, mas uma das principais hipóteses etiológicas sugere que a EMF seja consequência de um processo inflamatório crônico com envolvimento de respostas imunes Th2 pós-infestação helmíntica, mediada por eosinófilos nas fases iniciais da doença. Neste estudo avaliamos o perfil da resposta imune e inflamatória, assim como o perfil de proteínas expressas no endomiocárdio afetado, para compreender melhor os mecanismos envolvidos na patogênese da EMF. MÉTODOS: Foram coletadas amostras de plasma e soro de pacientes com diagnóstico de EMF e de indivíduos saudáveis, para dosagens de 6 citocinas plasmáticas do perfil Th1/Th2, Proteína C Reativa ultrassensível (PCRus), IgE total e IgE específico contra aero-alérgenos prevalentes e alérgenos de helmintos. A análise proteômica do endomiocárdio afetado de quatro pacientes com EMF submetidos à ressecção cirúrgica da fibrose, levou à identificação por espectrometria de massas, de proteínas separadas previamente por gel 1D e 2D. Análises in silico de vias funcionais e redes ligando as proteínas identificadas também foram realizadas. Eosinofilia em sangue periférico, assim como dados clínicos e ecocardiográficos, foram avaliados retrospectivamente. RESULTADOS: Foram selecionados 27 pacientes em estágio avançado da EMF, portadores de disfunção diastólica e/ou valvar. Todas as amostras de plasma analisadas apresentaram níveis detectáveis de pelo menos uma das citocinas avaliadas. As citocinas IL-6, TNF-?, IL-10 e IL-4 foram detectadas em pelo menos 74% das amostras, sendo que os níveis de IL-6, TNF-? e IL-10 se apresentaram significantemente elevados em comparação com os detectados nos indivíduos saudáveis. Foi observada correlação positiva entre os níveis de todas as citocinas avaliadas. Apenas 33% dos pacientes apresentaram algum episódio isolado de eosinofilia periférica ao longo do tempo, sendo que 11% apresentaram hipereosinofilia. Os níveis de IgE total foram semelhantes aos observados na população controle. A análise proteômica permitiu identificar 140 proteínas distintas no tecido endomiocárdico, das quais 18 eram provenientes da matriz extracelular. As análises in silico indicaram IL-6 e TNF-? como dois dos principais indutores da expressão das proteínas identificadas e a principal via canônica envolvida nas proteínas identificadas foi a: \"Resposta de Fase Aguda\". Coincidentemente, os níveis de PCRus encontraram-se significativamente aumentados nos portadores de EMF. CONCLUSÕES: Elevados níveis de citocinas pró e anti-inflamatórias e de PCRus sugerem a presença de perfil inflamatório misto (Th1/Th2) nas fases avançadas da patogênese da EMF. A pouca expressão da eosinofilia descarta sua participação ativa na patogênese da fase avançada da doença, mas não é possível excluir sua participação nas fases iniciais. Nossos dados permitem levantar a hipótese que os níveis elevados de citocinas inflamatórias modulem a expressão de proteínas- incluindo as de fase aguda- no tecido endomiocárdico de pacientes portadores de EMF / INTRODUCTION: Endomyocardial fibrosis (EMF) is a typical disease in tropical countries, characterized by the fibrous deposition in the endomyocardium, with severe clinical manifestations. EMF pathogenesis is still unclear, but one of the major hypothesis suggests that EMF could be a consequence of a chronic inflammatory process with possible involvement of a Th2 immune responses after helminthiasis, mediated by eosinophils, which could contribute to pathogenesis in the early stages of the disease. In this study, we evaluated the inflammatory response profile and the protein expression profile of the affected endomyocardium, to understand the mechanisms involved in this pathogenesis. METHODS: Plasma and serum samples were collected from the 27 patients diagnosed with advanced stage EMFand from healthy controls, to mensured plasma levels of 6 cytokines belonging to the Th1/Th2 cytokine profiles, ultrasensitive C Reactive Protein (CRP), total and allergen-specific serum IgE against prevalent and helminthic allergens. Proteomic analysis of tissue samples obtained from 4 EMF patients submitted to surgical resection of affected endomyocardial tissue allowed the identification of proteins by mass spectrometry, after separation by 1D and 2D electroforesis. In silico analysis of functional pathways and networks connecting the proteins identified in the EMF cardiac tissue was also performed. Blood peripheral eosinophilia, clinical and echocardiography data were evaluated retrospectively. RESULTS: All EMF patients displayed detectable plasma levels of at least one of the cytokines tested. We found that TNF-?, IL-6, IL-4 and IL-10 were each detected in at least 74% of tested sera, and plasma levels of IL10, IL6 and TNF-? were significantly higher than controls. Plasma levels of such cytokines positively correlated with each other. Only 33% of the patients presented any episode of blood eosinophilia along time, and 11% of these patients presented hypereosinophilia. Total IgE levels were similar to those from healthy subjects. Proteomic analysis allowed the identification of 140 distinct proteins from the resected endomiocardium of the EMF patients, 18 of which belonging to the extracellular matrix. In silico analysis indicated IL-6 and TNF-? as two of the major gene expression inducers of the identified proteins in our analysis, and the Acute Phase Response was identified as the major canonical pathway involved with the identified set of proteins. Similarly, CRP levels were significantly increased in the EMF patients. CONCLUSIONS: Increased levels of an inflammatory/anti-inflammatory circulating cytokines (Th1/Th2), along with increased CRP levels, suggested the presence of a mixed inflammatory profile in EMF advanced stage. The number of EMF patients with blood eosinophilia does not support the active participation of eosinophils in pathogenesis of advanced EMF. However, it is not possible to exclude the participation in the pathogenesis early stages. Our data support the hypothesis that the increased levels of inflammatory cytokines modulate protein expression -including proteins of the acute phase response - in the endomyocardial tissue of EMF patients

La recherche dans le domaine des maladies sans traitement existant obéit à plusieurs impératifs définis par le législateur européen dans le règlement (CE) n° 141/2000 du 16 décembre 1999 concernant les médicaments orphelins. Les patients atteints de maladies rares et négligées ont le droit à « la même qualité de traitement que les autres » ce qui suppose de prendre les mesures d'incitation nécessaires pour « promouvoir la recherche, le développement et la commercialisation de traitements adéquats ». C'est un « domaine prioritaire ». Après avoir désigné les médicaments concernés, l'Union européenne veut « éviter la dispersion de ressources limitées » notamment par la promotion d'une « coopération transnationale ». Dans une démarche téléologique, cette recherche décrit les effets de la législation européenne sans ignorer la réception de ce droit par les États membres. Des fondements théoriques à même d'assurer une meilleure performativité du droit et des propositions concrètes en vue de conformer le droit positif à l'intention du législateur et aux attentes des parties prenantes sont proposés. En se focalisant sur le seul levier de la propriété intellectuelle, ce droit spécial et incitatif ne semble pas en mesure d'apporter aux patients la plupart des traitements attendus. La régulation de la concurrence et la compétence nationale sur le prix des médicaments perpétuent un seuil de rentabilité éloignant de nombreuses recherches de la phase du développement. L'accès aux médicaments orphelins demeure très restreint. Un changement de paradigme dans la construction de ce droit apparaît nécessaire afin qu'un modèle économique favorable se mette en place. Il convient que le profit des pharmaciens de l'industrie ne dépende plus de la conquête de parts de marché, mais de l'intérêt de leurs inventions pour les besoins de santé non satisfaits. / Research in the field of diseases without an existing treatment is governed by several requirements defined by the European legislator in Regulation (CE) No 141/2000 of 16 December 1999 on orphan medicinal products. Patients with rare and neglected diseases have the right to "the same quality of treatment as other patients" which means taking the necessary incentives to stimulate research, development and bringing to the market of appropriate medications". It is a "priority area". After designating the drugs concerned, the European Union wants to "avoid the dispersion of limited resources", in particular by promoting "cross national co-operation". In a teleological approach, this research analyses the positive law endeavouring to implement the objectives of Orphan Drug Law. It describes the effects of European legislation without ignoring the receipt of this law by the Member States. Theoretical foundations that can ensure a better performativity of the law, as well as concrete proposals to conform the positive law to the intention of the legislator and to the stakeholders' wills are proposed. By focusing solely on the leverage of intellectual property rights, this special and incentive law does not seem to be able to provide patients with many of the expected treatments. Competition regulation and setting of the price which is a national competency perpetuate a high profitability threshold, often withholding research projects from reaching the development phase. Access to orphan drugs remains very limited. A paradigm shift in the construction of this law appears necessary in order for a favorable economic model to emerge. The profit of the industry's pharmacists should no longer depend on the conquest of market shares, but on the value of their inventions for unmet health needs.

Computer Games as a New Media Phenomenon Jan Rylich 1 1 [ T H E S I S ] Jan Rylich Abstract: This thesis is focused on the development of computer games and video games, evolution of gaming and game technologies and their impact on our society. In addition to an important historical context and practical and theoretical analysis of game genres and potential of games, key chapters of this thesis are devoted to the importance of games and their impact on various aspects of our lives, from economic and demographic factors to influence on our culture and contemporary art. This thesis also aims to introduce computer games and video games in the context of "neglected media" and the theory of "remediation".

INTRODUÇÃO: A hanseníase é uma doença infecciosa crônica granulomatosa, cujo agente etiológico é uma bactéria de vida intracelular obrigatória, o Mycobacterium leprae, que tem no homem seu principal reservatório. A doença possui distribuição universal, predominando atualmente, em latitudes tropicais e tem sido enquadrada entre as enfermidades negligenciadas, atingindo desproporcionalmente populações pobres e marginalizadas. O bacilo é altamente contagioso, de baixa patogenicidade e acomete primordialmente pele e nervos, com grande potencial incapacitante. A doença grassou no Velho Mundo durante a Idade Média e praticamente desapareceu da Europa ainda no início do século XX, antes que qualquer recurso terapêutico eficaz estivesse disponível. Introduzida com os primeiros colonizadores europeus, a hanseníase é doença endêmica no Brasil e um problema de saúde pública. A hanseníase é hiperendêmica em muitos municípios, notadamente nos estados das regiões Norte e Centro-Oeste, que abrangem biomas de cerrado, pântano e floresta amazônica, em vastas áreas de baixa densidade demográfica; estas áreas vêm sofrendo enorme pressão antrópica relacionada ao incremento de atividades agropecuárias e extrativistas, gerando preocupações em relação ao impacto ambiental sobre a saúde humana, decorrente de transformações na dinâmica territorial. OBJETIVO: O propósito desta pesquisa foi conhecer o efeito ecológico de fatores sociodemográficos na delimitação de espaços endêmicos de hanseníase e gerar hipóteses sobre a relação entre a constituição do território e a exposição ambiental ao agente biológico da doença. MATERIAL E MÉTODOS: Supondo que a variação dos fatores de risco para contrair hanseníase pudesse ser maior entre grupos populacionais do que entre indivíduos, foi empreendido um estudo epidemiológico de delineamento ecológico do tipo grupo múltiplo, envolvendo 203 municípios dos estados do Mato Grosso e Mato Grosso do Sul, que estão localizados na região Centro-Oeste do Brasil. Foram constituídas variáveis sociodemográficas de exposição e a variável de efeito foi representada pela taxa de detecção média anual de hanseníase entre os anos de 2000 e 2006. Foram aproveitados dados secundários provenientes do Instituto Brasileiro de Geografia e Estatística e do Ministério da Saúde. Para compor um modelo multivariado, 14 variáveis foram analisadas por regressão linear simples e selecionadas sete variáveis com probabilidade de p < 0,2 para o coeficiente de inclinação da reta de regressão. As variáveis independentes selecionadas foram passo a passo testadas, simultaneamente e analisada a associação da variável dependente, visando o ajuste de um modelo singular da variabilidade da taxa de detecção de hanseníase. RESULTADOS: As variáveis que restaram no modelo após o processo de ajuste foram: Proporção da população moradora em domicílios com seis ou mais pessoas; Proporção da população não natural do estado; e, Cobertura populacional da estratégia de Atenção Saúde da Família. Estas variáveis juntas explicam 24,1% da variação nas taxas de detecção de hanseníase. CONCLUSÕES: Fatores sociodemográficos representam um importante domínio na epidemiologia da doença. A associação positiva do desfecho com a cobertura da estratégia de Atenção Saúde da Família indica que deve haver melhora no acesso ao diagnóstico mediante a implantação de modelos de Atenção Primária à Saúde baseados em racionalidades preventivas. Doentes poderiam ter sua contagiosidade interrompida mais precocemente, uma vez melhorada a capacidade diagnóstica dos serviços de saúde. Como recomendação para melhorar o acesso ao diagnóstico nas áreas endêmicas, a adoção da estratégia de Atenção Saúde da Família deve ser encorajada. Aglomeração domiciliar como variável ecológica foi interpretada como sendo um indicador socioeconômico indireto, mais do que propriamente relacionada às condições de contato. A qualidade da moradia, talvez seja mais importante para controle da endemia, tanto quanto possa vir acompanhada de melhorias gerais no padrão de vida. Reservatórios do M. leprae constituídos por indivíduos que eliminam bacilos cronicamente são os que perpetuam a endemia, embora possam, em tese, serem suplementados por fontes secundárias representadas por portadores transitórios. Fatores ligados à formação da fronteira agrícola e à urbanização brasileira podem ter fomentado a endemia de hanseníase, ao predisporem a renovação de susceptíveis pelas migrações, que modificam a composição populacional quanto à experiência de contato com o bacilo. Migrações poderiam romper os focos de hanseníase que estivessem saturados de indivíduos resistentes ao redistribuir espacialmente a população susceptível, levar infectantes para áreas indenes ou instalar as premissas biológicas e territoriais para tornar o contágio recorrente na população, mesmo que o contingente demográfico proveniente de imigrações não seja predominantemente mais vulnerável à doença. Tecnicização rural e constrições na esfera do trabalho têm movimentado populações que procuram refúgio nas periferias das cidades, caracterizadas por escassa infraestrutura urbana e rápido crescimento demográfico, supostamente continentes de grupos humanos dotados de diferentes perfis de resistência ao M. leprae. O circuito inferior da economia, uma resposta social à escassez de meios de vida e um traço da territorialização brasileira, tem oferecido os predicados espaciais para a persistência da endemia de hanseníase nos bolsões de pobreza urbana, ao gerar uma multiplicidade de contatos em proximidade e alimentar suas relações sociais de uma massa de recém-chegados do campo e da cidade, sua principal e mais abundante variável. Se a geografia estuda as condições de vida sobre a terra, estes resultados sugerem que a topografia médica, para além da descrição dos aspectos demográficos e socioeconômicos dos lugares de surgimento de doenças, pode contribuir em muito ao conhecimento em saúde, ao considerar analisar tais fatores enquanto potenciais condicionantes de endemias / BACKGROUND: Leprosy is a chronic granulomatous infectious disease whose causative agent is an obligate intracellular bacterium of life, Mycobacterium leprae, which has its main reservoir in man. The disease has a worldwide distribution, currently prevailing in tropical latitudes and has been framed between neglected diseases, disproportionately affecting poor and marginalized populations. The bacillus is highly contagious, and low pathogenic primarily affects the skin and nerves, with great potential crippling. The disease raged in the Old World during the Middle Ages and still practically disappeared from Europe in the early twentieth century, before any effective therapeutic resource was available. Introduced with the first European settlers, leprosy is endemic in Brazil and a public health problem. Leprosy is hyperendemic in many cities, especially in the states of North and Midwest, covering biomes savannah, swamp and rainforest, in vast areas of low population density; these areas have suffered huge human pressure related to increased activity agricultural and extractive, generating concerns about the environmental impact on human health, due to dynamic changes in territorial. OBJECTIVE: The purpose of this research was to understand the ecological effect of sociodemographic factors in the delimitation of leprosy-endemic areas and generating concerns about the relationship between the constitution of the territory and environmental exposure to the biological agent of the disease. MATERIAL AND METHODS: Assuming that the variation of the risk factors for contracting leprosy could be higher among population groups than between individuals, an epidemiological study was undertaken to design ecological type group multiple, involving 203 municipalities in the states of Mato Grosso and Mato Grosso do Sul, which are located in the Midwest region of Brazil. Sociodemographic variables were recorded for exposure and effect was variable represented by annual average detection rate of leprosy between 2000 and 2006. We utilized secondary data from the Brazilian Institute of Geography and Statistics and the Ministry of Health to compose a multivariate model, 14 variables were analyzed by linear regression and seven variables selected with probability p<0.2 for the slope coefficient of regression line. The independent variables were tested step by step, and simultaneously analyzed the association of the dependent variable in order to fit a model of the variability of the detection rate of leprosy. The variables that remained in the model after adjustment process were: \"Proportion of population living in households with six or more people,\" \"Proportion of population unnatural state,\" and \"Coverage of Population Health Care Strategy Family \". These variables together explain 24.1% of the variation in detection rates of leprosy. CONCLUSIONS: Sociodemographic factors represent an important area in the epidemiology of the disease. The positive association with the outcome of the strategic coverage of Family Health Care indicates that there must be improved access to diagnosis by implementing models of primary care-based preventive rationales. Patients could have their contagiousness interrupted earlier, once improved the diagnostic capacity of health services. As a recommendation to improve access to diagnosis in endemic areas, the adoption of the strategy of the Family Health Care should be encouraged. Household crowding as ecological variable was interpreted as an indirect socioeconomic indicator, rather than strictly related to contact conditions. The quality of housing, perhaps most important for disease control, as far as can be accompanied by general improvements in living standards. Reservoirs of M. leprae consist of individuals who are chronically eliminate bacilli that perpetuate endemic, although, in theory, be supplemented by secondary sources represented by transient carriers. Factors related to the formation of the agricultural frontier and the Brazilian urbanization may have fostered endemic leprosy, predispose to the renewal of the likely migration, which modify the composition of the population as to the experience of contact with the bacillus. Migration could break outbreaks of leprosy that were saturated with individuals resistant to spatially redistribute the population likely lead to infective areas unaffected or install the territorial and biological assumptions to make the recurring infection in the population, even though the population from immigration quota is not predominantly more vulnerable to disease. Technicisation rural and constrictions in the sphere of labor are busy people seeking refuge on the outskirts of cities, characterized by poor urban infrastructure and rapid population growth, supposedly continents groups of humans with different resistance profiles to M. leprae. The lower circuit of the economy, a social response to the scarcity of livelihood and a dash of Brazilian territorialization, has offered the spatial predicates for the persistence of endemic leprosy in pockets of urban poverty, to generate a plurality of contacts in proximity and feed their social relationships from a mass of newcomers from the countryside and the city, its main and most abundant variable. If geography studies the conditions of life on earth, these results suggest that medical topography, beyond the description of the demographic and socioeconomic aspects of the places outbreaks of diseases, can contribute greatly to health knowledge, to consider examining such factors as potential determinants of diseases

INTRODUÇÃO: A hanseníase é uma doença infecciosa crônica granulomatosa, cujo agente etiológico é uma bactéria de vida intracelular obrigatória, o Mycobacterium leprae, que tem no homem seu principal reservatório. A doença possui distribuição universal, predominando atualmente, em latitudes tropicais e tem sido enquadrada entre as enfermidades negligenciadas, atingindo desproporcionalmente populações pobres e marginalizadas. O bacilo é altamente contagioso, de baixa patogenicidade e acomete primordialmente pele e nervos, com grande potencial incapacitante. A doença grassou no Velho Mundo durante a Idade Média e praticamente desapareceu da Europa ainda no início do século XX, antes que qualquer recurso terapêutico eficaz estivesse disponível. Introduzida com os primeiros colonizadores europeus, a hanseníase é doença endêmica no Brasil e um problema de saúde pública. A hanseníase é hiperendêmica em muitos municípios, notadamente nos estados das regiões Norte e Centro-Oeste, que abrangem biomas de cerrado, pântano e floresta amazônica, em vastas áreas de baixa densidade demográfica; estas áreas vêm sofrendo enorme pressão antrópica relacionada ao incremento de atividades agropecuárias e extrativistas, gerando preocupações em relação ao impacto ambiental sobre a saúde humana, decorrente de transformações na dinâmica territorial. OBJETIVO: O propósito desta pesquisa foi conhecer o efeito ecológico de fatores sociodemográficos na delimitação de espaços endêmicos de hanseníase e gerar hipóteses sobre a relação entre a constituição do território e a exposição ambiental ao agente biológico da doença. MATERIAL E MÉTODOS: Supondo que a variação dos fatores de risco para contrair hanseníase pudesse ser maior entre grupos populacionais do que entre indivíduos, foi empreendido um estudo epidemiológico de delineamento ecológico do tipo grupo múltiplo, envolvendo 203 municípios dos estados do Mato Grosso e Mato Grosso do Sul, que estão localizados na região Centro-Oeste do Brasil. Foram constituídas variáveis sociodemográficas de exposição e a variável de efeito foi representada pela taxa de detecção média anual de hanseníase entre os anos de 2000 e 2006. Foram aproveitados dados secundários provenientes do Instituto Brasileiro de Geografia e Estatística e do Ministério da Saúde. Para compor um modelo multivariado, 14 variáveis foram analisadas por regressão linear simples e selecionadas sete variáveis com probabilidade de p < 0,2 para o coeficiente de inclinação da reta de regressão. As variáveis independentes selecionadas foram passo a passo testadas, simultaneamente e analisada a associação da variável dependente, visando o ajuste de um modelo singular da variabilidade da taxa de detecção de hanseníase. RESULTADOS: As variáveis que restaram no modelo após o processo de ajuste foram: Proporção da população moradora em domicílios com seis ou mais pessoas; Proporção da população não natural do estado; e, Cobertura populacional da estratégia de Atenção Saúde da Família. Estas variáveis juntas explicam 24,1% da variação nas taxas de detecção de hanseníase. CONCLUSÕES: Fatores sociodemográficos representam um importante domínio na epidemiologia da doença. A associação positiva do desfecho com a cobertura da estratégia de Atenção Saúde da Família indica que deve haver melhora no acesso ao diagnóstico mediante a implantação de modelos de Atenção Primária à Saúde baseados em racionalidades preventivas. Doentes poderiam ter sua contagiosidade interrompida mais precocemente, uma vez melhorada a capacidade diagnóstica dos serviços de saúde. Como recomendação para melhorar o acesso ao diagnóstico nas áreas endêmicas, a adoção da estratégia de Atenção Saúde da Família deve ser encorajada. Aglomeração domiciliar como variável ecológica foi interpretada como sendo um indicador socioeconômico indireto, mais do que propriamente relacionada às condições de contato. A qualidade da moradia, talvez seja mais importante para controle da endemia, tanto quanto possa vir acompanhada de melhorias gerais no padrão de vida. Reservatórios do M. leprae constituídos por indivíduos que eliminam bacilos cronicamente são os que perpetuam a endemia, embora possam, em tese, serem suplementados por fontes secundárias representadas por portadores transitórios. Fatores ligados à formação da fronteira agrícola e à urbanização brasileira podem ter fomentado a endemia de hanseníase, ao predisporem a renovação de susceptíveis pelas migrações, que modificam a composição populacional quanto à experiência de contato com o bacilo. Migrações poderiam romper os focos de hanseníase que estivessem saturados de indivíduos resistentes ao redistribuir espacialmente a população susceptível, levar infectantes para áreas indenes ou instalar as premissas biológicas e territoriais para tornar o contágio recorrente na população, mesmo que o contingente demográfico proveniente de imigrações não seja predominantemente mais vulnerável à doença. Tecnicização rural e constrições na esfera do trabalho têm movimentado populações que procuram refúgio nas periferias das cidades, caracterizadas por escassa infraestrutura urbana e rápido crescimento demográfico, supostamente continentes de grupos humanos dotados de diferentes perfis de resistência ao M. leprae. O circuito inferior da economia, uma resposta social à escassez de meios de vida e um traço da territorialização brasileira, tem oferecido os predicados espaciais para a persistência da endemia de hanseníase nos bolsões de pobreza urbana, ao gerar uma multiplicidade de contatos em proximidade e alimentar suas relações sociais de uma massa de recém-chegados do campo e da cidade, sua principal e mais abundante variável. Se a geografia estuda as condições de vida sobre a terra, estes resultados sugerem que a topografia médica, para além da descrição dos aspectos demográficos e socioeconômicos dos lugares de surgimento de doenças, pode contribuir em muito ao conhecimento em saúde, ao considerar analisar tais fatores enquanto potenciais condicionantes de endemias / BACKGROUND: Leprosy is a chronic granulomatous infectious disease whose causative agent is an obligate intracellular bacterium of life, Mycobacterium leprae, which has its main reservoir in man. The disease has a worldwide distribution, currently prevailing in tropical latitudes and has been framed between neglected diseases, disproportionately affecting poor and marginalized populations. The bacillus is highly contagious, and low pathogenic primarily affects the skin and nerves, with great potential crippling. The disease raged in the Old World during the Middle Ages and still practically disappeared from Europe in the early twentieth century, before any effective therapeutic resource was available. Introduced with the first European settlers, leprosy is endemic in Brazil and a public health problem. Leprosy is hyperendemic in many cities, especially in the states of North and Midwest, covering biomes savannah, swamp and rainforest, in vast areas of low population density; these areas have suffered huge human pressure related to increased activity agricultural and extractive, generating concerns about the environmental impact on human health, due to dynamic changes in territorial. OBJECTIVE: The purpose of this research was to understand the ecological effect of sociodemographic factors in the delimitation of leprosy-endemic areas and generating concerns about the relationship between the constitution of the territory and environmental exposure to the biological agent of the disease. MATERIAL AND METHODS: Assuming that the variation of the risk factors for contracting leprosy could be higher among population groups than between individuals, an epidemiological study was undertaken to design ecological type group multiple, involving 203 municipalities in the states of Mato Grosso and Mato Grosso do Sul, which are located in the Midwest region of Brazil. Sociodemographic variables were recorded for exposure and effect was variable represented by annual average detection rate of leprosy between 2000 and 2006. We utilized secondary data from the Brazilian Institute of Geography and Statistics and the Ministry of Health to compose a multivariate model, 14 variables were analyzed by linear regression and seven variables selected with probability p<0.2 for the slope coefficient of regression line. The independent variables were tested step by step, and simultaneously analyzed the association of the dependent variable in order to fit a model of the variability of the detection rate of leprosy. The variables that remained in the model after adjustment process were: \"Proportion of population living in households with six or more people,\" \"Proportion of population unnatural state,\" and \"Coverage of Population Health Care Strategy Family \". These variables together explain 24.1% of the variation in detection rates of leprosy. CONCLUSIONS: Sociodemographic factors represent an important area in the epidemiology of the disease. The positive association with the outcome of the strategic coverage of Family Health Care indicates that there must be improved access to diagnosis by implementing models of primary care-based preventive rationales. Patients could have their contagiousness interrupted earlier, once improved the diagnostic capacity of health services. As a recommendation to improve access to diagnosis in endemic areas, the adoption of the strategy of the Family Health Care should be encouraged. Household crowding as ecological variable was interpreted as an indirect socioeconomic indicator, rather than strictly related to contact conditions. The quality of housing, perhaps most important for disease control, as far as can be accompanied by general improvements in living standards. Reservoirs of M. leprae consist of individuals who are chronically eliminate bacilli that perpetuate endemic, although, in theory, be supplemented by secondary sources represented by transient carriers. Factors related to the formation of the agricultural frontier and the Brazilian urbanization may have fostered endemic leprosy, predispose to the renewal of the likely migration, which modify the composition of the population as to the experience of contact with the bacillus. Migration could break outbreaks of leprosy that were saturated with individuals resistant to spatially redistribute the population likely lead to infective areas unaffected or install the territorial and biological assumptions to make the recurring infection in the population, even though the population from immigration quota is not predominantly more vulnerable to disease. Technicisation rural and constrictions in the sphere of labor are busy people seeking refuge on the outskirts of cities, characterized by poor urban infrastructure and rapid population growth, supposedly continents groups of humans with different resistance profiles to M. leprae. The lower circuit of the economy, a social response to the scarcity of livelihood and a dash of Brazilian territorialization, has offered the spatial predicates for the persistence of endemic leprosy in pockets of urban poverty, to generate a plurality of contacts in proximity and feed their social relationships from a mass of newcomers from the countryside and the city, its main and most abundant variable. If geography studies the conditions of life on earth, these results suggest that medical topography, beyond the description of the demographic and socioeconomic aspects of the places outbreaks of diseases, can contribute greatly to health knowledge, to consider examining such factors as potential determinants of diseases