A thesis submitted to the Faculty of Health Sciences University of the Witwatersrand. Johannesburg for the degree of Doctor of Philosophy Johannesburg 1997 / a) to develop sensitive tests for the early diagnosis of Crimean-Congo haemorrhagic fever {( '( "II;) infection or humans. based on the detection of viral nucleic add and antibody in serum: [Abbreviated Abstract. Open document to view full version] / MT2017

No description available.

Rift Valley fever (RVF) belongs to the group of viral haemorrhagic fevers (VHFs), most of which are zoonotic diseases causing outbreaks in animals and humans all over Africa. In the absence of haemorrhagic or specific organ manifestations, these diseases are clinically difficult to diagnose. Rapid laboratory confirmation of cases is therefore essential for timely execution of supportive treatment, appropriate case management, infection control, and tracing of contacts. Rift Valley fever virus (RVFV), a mosquito-borne pathogen, is responsible for high mortality rates and abortion in domestic ruminants, resulting in significant socio-economic losses. Furthermore, the virus is potentially infectious by aerosol, can replicate in a wide range of mosquito species and poses a bioweapon threat. The recent spread of the virus outside of the African continent, demonstrates its ability to move northwards to RVF free regions, e.g. to Europe and Northern America. Such fears fuel the international demand for reliable and validated diagnostic tools for rapid diagnosis of RVF. The aim of this study was to develop a rapid and accurate molecular tool for the detection of RVFV. A real-time loop-mediated isothermal amplification assay (LAMP) targeting the L segment of RVFV, was developed and evaluated. The assay proved to be highly specific and able to detect RVFV strains representing the genetic spectrum of the virus. Furthermore, the assay did not amplify the RNA of other genetically and antigenically related phleboviruses. The sensitivity of the assay was compared to that of a previously published TaqMan RTD-PCR protocol and found to be equal. Similarly, the assay demonstrated very high diagnostic sensitivity and specificity in various clinical human and animal specimens, collected during natural outbreaks of the disease in Africa. The detection of specific viral genome targets in positive clinical specimens was achieved in less than 30 minutes. As a highly accurate, rapid and very simple nucleic acid detection format, the RT-LAMP assay has the potential to be used in less well equipped laboratories in Africa. The assay format can be adapted to a portable device that can be utilized during RVF outbreaks in remote areas, and can be a valuable tool for differential diagnosis of VHFs. / Dissertation (MSc)--University of Pretoria, 2010. / Microbiology and Plant Pathology / unrestricted

Les fièvres récurrentes héréditaires (FRH) sont des maladies auto-inflammatoires transmises selon un mode mendélien. Elles se caractérisent par des accès fébriles récurrents spontanément résolutifs accompagnés d'une inflammation systémique et d'une atteinte des séreuses. La complication la plus grave réside dans le risque de survenue d'une amylose inflammatoire, essentiellement rénale. Le diagnostic clinique des FRH est difficile à établir du fait d'une part d'une grande variabilité inter et intra familiale des phénotypes complexes qui peuvent combiner des signes évocateurs de plusieurs FRH, et d'autre part de l'absence, dans la majorité des cas, de critères objectifs de diagnostic. Alors que le diagnostic de certitude repose essentiellement sur l'identification de défauts moléculaires dans des gènes de l'immunité innée (comme NLRP3, NLRP12, ou MEFV), ces mutations ne rendent compte de la pathologie que chez moins de 30% des cas. Le retentissement fonctionnel de ces variations de séquence, qui sont essentiellement des mutations faux-sens, souvent conservatives, n'a été étudié que dans des lignées cellulaires qui n'expriment pas plusieurs acteurs clés de l'inflammasome, un complexe multiprotéique activé chez les patients présentant une FRH. Au cours de cette thèse, nous avons développé un modèle cellulaire pertinent des FRH à partir de cultures primaires de macrophages humains, dans le but d'étudier les conséquences fonctionnelles des mutations identifiées dans les gènes de FRH et de caractériser les réseaux moléculaires auxquels appartiennent les protéines codées par ces gènes. En parallèle, nous avons cherché à identifier de nouveaux gènes impliqués dans les FRH. / Hereditary recurrent fevers (HRF) define a group of auto-inflammatory diseases transmitted in a Mendelian fashion. They are characterized by recurrent episodes of fever spontaneously resolved, accompanied by systemic inflammation, usually revealed by sterile arthritis, peritonitis, and/or pleurisy. The most serious complication in HRFs is the risk of inflammatory amyloidosis, mainly renal. The clinical diagnosis of HRF is challenging due on the one hand to the inter- and intra- family variability and to complex phenotypes, which combine signs suggestive of different HRFs, and on the other hand, to the absence of objective diagnostic criteria in the majority of cases. While definitive diagnosis is mainly based on the identification of molecular defects in genes of innate immunity (as NLRP3, NLRP12 or MEFV), mutations in these genes account for the pathology in a limited number of patients (30% of cases in our experience). The functional impact of these sequence variations, which are mainly conserved missense mutations, has been studied mainly in heterologous cell lines that do not express several key players of the inflammasome, a multiprotein complex active in patients with HRF. In this thesis, we developed a physiologically relevant cell model of HRF using primary human macrophages in order to assess the functional consequences of the disease-causing mutations and to characterize the molecular networks to which the involved proteins belong. In parallel, we sought to identify novel genes involved in HRF.

A presente análise das três séries históricas, compondo um total de 42 casos de hepatopatias fulminantes da região Amazônica, teve por objetivos o estudo de aspectos morfológicos e imuno-histoquímicos no diagnóstico diferencial entre febre amarela (FA), hepatite de Lábrea (HL) e de outras entidades. Visou, ainda, aprimorar o conhecimento de aspectos da morfogênese da morte hepatocelular, de eventual fibrose, relacionando-as aos padrões de regeneração e de lesões vasculares, conforme recentemente descrito na gênese de hepatopatias crônicas. Dentre o extenso painel de critérios histológicos aqui estudados, os padrões de morte hepatocelular e sua distribuição, incluindo corpos apoptóticos medio-zonais, assim como a balonização foram os achados mais característicos da FA, enquanto as células em mórula foram o principal achado na HL. Dezenove casos bem caracterizados (10 FA e 9 HL) foram então submetidos a estudos imuno-histoquímicos para a detecção dos antígenos da FA, AgHBs e antígeno do vírus da hepatite D (VHD), sendo então demonstrado que, em ambas as doenças, mas principalmente na HL, flebite, principalmente de ramos da veia porta, foi evidente e deve ter tido participação na patogênese do dano hepático, com extensa extinção parenquimatosa hepática e aproximação de espaços porta. O padrão de regeneração também foi marcante: nos casos de FA, um elevado índice de proliferação celular foi observado enquanto que, na HL, multinucleações e transformação pseudoacinar, associadas a depósitos portais de colágeno do tipo I e de fibras elásticas, foram encontrados. Concluindo, a pesquisa imuno-histoquímica de antígenos virais permitiu a caracterização etiológica dos casos destas importantes séries históricas de hepatopatias fulminantes da Amazônia, mesmo em amostras arquivadas em parafina por até sete décadas. Permitiu, ainda, o relato original de cinco casos de possível superposição de infecção pelos vírus da FA, VHB e/ou VHD. Dentre os aspectos histopatológicos, o quadro dominante na FA fulminante incluiu apoptose medio-zonal associada com flebite portal e um alto índice de proliferação celular, em pacientes sem evidência de dano hepático prévio. Por outro lado, a HL fulminante mostrou extensa necrose lítica de hepatócitos, associada à flebite portal e de veia hepática e à presença de células em mórula, em pacientes com evidências morfológicas de doença hepática crônica. / This study aimed at assessing morphological and immunohistochemical aspects useful for the differential diagnosis of yellow fever (YF), Labrea hepatitis (LH) and other entities by revisiting 42 fulminant hepatic failure cases, from three historical series from Amazon Basin. Additional studies were performed aiming at further understanding the morphogenesis of hepatocelular death, in relation to regeneration and fibrosis patterns and to vascular lesions, as recently described in chronic hepatic diseases. Among the extensive panel of histological criteria studied, liver cell death pattern and distribution, including midzonal apoptotic bodies, as well as hepatocelular ballooning degeneration were YF most characteristic findings, while morula cells were the major hint for LH. Five cases were herein suggested as coinfected with YF, HBV and/or HDV, a finding not previously reported. Nineteen well characterized cases (10 YF and 9 LH) were further submitted to immunohistochemical studies for YF antigen, HBsAg and Delta virus Ag. In both diseases, but mainly in LH, phlebitis, mainly of portal vein branches, was evident and closely related to the degree of hepatocellular damage, with severe hepatic parenchymal extinction and portal tract approximation. Regeneration pattern was also remarkable: in YF cases, a high hepatocellular proliferative index was detected whereas in LH, multinucleation and pseudo-acinar transformation, associated with portal type I collagen and elastic fiber deposition were found. In conclusion, immunohistochemical viral antigen detection yielded further etiological characterization of these important historical cases of fulminant hepatic failure from Amazon Basin, even in paraffin samples stored for up to seven decades. YF morphology depicted midzonal apoptosis, portal phlebitis and a high hepatocellular proliferative index, in patients without evidence of previous hepatic injury. On the other hand, fulminant LH showed extensive lytic hepatocellular necrosis, portal and hepatic vein phlebitis and the presence morula cells, in patients with morphological evidences of chronic liver disease.

A presente análise das três séries históricas, compondo um total de 42 casos de hepatopatias fulminantes da região Amazônica, teve por objetivos o estudo de aspectos morfológicos e imuno-histoquímicos no diagnóstico diferencial entre febre amarela (FA), hepatite de Lábrea (HL) e de outras entidades. Visou, ainda, aprimorar o conhecimento de aspectos da morfogênese da morte hepatocelular, de eventual fibrose, relacionando-as aos padrões de regeneração e de lesões vasculares, conforme recentemente descrito na gênese de hepatopatias crônicas. Dentre o extenso painel de critérios histológicos aqui estudados, os padrões de morte hepatocelular e sua distribuição, incluindo corpos apoptóticos medio-zonais, assim como a balonização foram os achados mais característicos da FA, enquanto as células em mórula foram o principal achado na HL. Dezenove casos bem caracterizados (10 FA e 9 HL) foram então submetidos a estudos imuno-histoquímicos para a detecção dos antígenos da FA, AgHBs e antígeno do vírus da hepatite D (VHD), sendo então demonstrado que, em ambas as doenças, mas principalmente na HL, flebite, principalmente de ramos da veia porta, foi evidente e deve ter tido participação na patogênese do dano hepático, com extensa extinção parenquimatosa hepática e aproximação de espaços porta. O padrão de regeneração também foi marcante: nos casos de FA, um elevado índice de proliferação celular foi observado enquanto que, na HL, multinucleações e transformação pseudoacinar, associadas a depósitos portais de colágeno do tipo I e de fibras elásticas, foram encontrados. Concluindo, a pesquisa imuno-histoquímica de antígenos virais permitiu a caracterização etiológica dos casos destas importantes séries históricas de hepatopatias fulminantes da Amazônia, mesmo em amostras arquivadas em parafina por até sete décadas. Permitiu, ainda, o relato original de cinco casos de possível superposição de infecção pelos vírus da FA, VHB e/ou VHD. Dentre os aspectos histopatológicos, o quadro dominante na FA fulminante incluiu apoptose medio-zonal associada com flebite portal e um alto índice de proliferação celular, em pacientes sem evidência de dano hepático prévio. Por outro lado, a HL fulminante mostrou extensa necrose lítica de hepatócitos, associada à flebite portal e de veia hepática e à presença de células em mórula, em pacientes com evidências morfológicas de doença hepática crônica. / This study aimed at assessing morphological and immunohistochemical aspects useful for the differential diagnosis of yellow fever (YF), Labrea hepatitis (LH) and other entities by revisiting 42 fulminant hepatic failure cases, from three historical series from Amazon Basin. Additional studies were performed aiming at further understanding the morphogenesis of hepatocelular death, in relation to regeneration and fibrosis patterns and to vascular lesions, as recently described in chronic hepatic diseases. Among the extensive panel of histological criteria studied, liver cell death pattern and distribution, including midzonal apoptotic bodies, as well as hepatocelular ballooning degeneration were YF most characteristic findings, while morula cells were the major hint for LH. Five cases were herein suggested as coinfected with YF, HBV and/or HDV, a finding not previously reported. Nineteen well characterized cases (10 YF and 9 LH) were further submitted to immunohistochemical studies for YF antigen, HBsAg and Delta virus Ag. In both diseases, but mainly in LH, phlebitis, mainly of portal vein branches, was evident and closely related to the degree of hepatocellular damage, with severe hepatic parenchymal extinction and portal tract approximation. Regeneration pattern was also remarkable: in YF cases, a high hepatocellular proliferative index was detected whereas in LH, multinucleation and pseudo-acinar transformation, associated with portal type I collagen and elastic fiber deposition were found. In conclusion, immunohistochemical viral antigen detection yielded further etiological characterization of these important historical cases of fulminant hepatic failure from Amazon Basin, even in paraffin samples stored for up to seven decades. YF morphology depicted midzonal apoptosis, portal phlebitis and a high hepatocellular proliferative index, in patients without evidence of previous hepatic injury. On the other hand, fulminant LH showed extensive lytic hepatocellular necrosis, portal and hepatic vein phlebitis and the presence morula cells, in patients with morphological evidences of chronic liver disease.

No description available.

Os ambientes terrestres têm sido gradativamente alterados pelo ser humano, mas a partir da Revolução Industrial, o homem começou a atuar de maneira mais intensa sobre o meio, fazendo com que as modificações ambientais tomassem proporções alarmantes, tanto em velocidade quanto em dimensão. As mudanças, como as climáticas, hídricas e biológicas, entre outras, ocorridas durante o século XX foram as maiores já registradas. As alterações ambientais associadas ao quadro demográfico do mundo contemporâneo, às condições socioeconômicas e à revolução técnico-científico-informacional que interligou o mundo, acabaram resultando em um cenário nunca vivenciado pela humanidade e ao mesmo tempo preocupante, tanto para saúde ambiental da Terra como para a humana. Se por um lado essa situação, baseada principalmente no avanço tecnológico, resultou numa verdadeira revolução nas taxas de mortalidade e na esperança de vida, por outro lado criou um ambiente que vem facilitando a emergência e reemergência de doenças, que pode comprometer o próprio futuro. Esse estudo tem por objetivo principal dar subsídios para o acesso a um conhecimento integrado, em escala global, tanto das alterações ambientais das áreas tropicais úmidas e do quadro socioeconômico dos países localizados nessa faixa tropical, quanto do surgimento e/ou expansão de quatro doenças infecciosas de caráter hemorrágico - dengue hemorrágica, febre amarela, marburg e ebola - no período de 1981 a 2005. No campo teórico-metodológico, a Geografia, mediante as suas características científicas de transitar pelos campos das ciências naturais e humanas, devido ao seu objeto de estudo, ofereceu a sustentação científica necessária para a realização, enquanto o avanço tecnológico das comunicações e da informática, associado ao processo de globalização pelo qual o mundo passa, proporcionou uma realidade de trabalho totalmente nova, permitindo a execução operacional do estudo. Foram realizados levantamentos bibliográficos e estudos sobre aquecimento global, mundo tropical, devastação das florestas tropicais úmidas, condições socioeconômicas dos países localizados nesta porção do globo e expansão das doenças citadas nos últimos 25 anos. O conjunto dos dados foi transformado em uma tabela síntese e em material cartográfico que retrata a situação atual desses países, destacando o nível das condições sócio ambientais e o risco saúde em que se encontram. / The terrestrial environments have been gradually altered by human being but from the Industrial Revolution on, this process has been even more intensive, resulting in environmental modifications of fast, huge and alarming proportions. The changes, such as the climatic, hydric and biological ones, among others, that took place in the 20th century, were the largest registered. The environmental alterations, associated to the current demographic panorama, to the socioeconomic conditions and to the technical-scientific-informational revolution - that have linked the whole world - resulted in a scenario never before experienced by humanity and, at the same time, very preoccupying for the Earth environmental health as well as for the humans. If on one hand that situation, based mainly on the technological progress, has resulted in lower mortality rates and higher life expectancy at birth, on the other hand it has also created an environment that made the emergence and re-emergence of diseases much easier to occur, so that future may be at risk. This study intend to bring up subsidies that allow for access to global integrated knowledge, not only about the environmental changes in the countries located in humid tropical areas and their socioeconomic conditions, but also about the influence of these alterations on the appearance and/or expansion of four infectious hemorrhagic diseases - hemorrhagic dengue, yellow fever, marburg and ebola - in the period from 1981 to 2005. In the theoreticalmethodological field, Geography - in face of its scientific characteristics of acting on the fields of both natural and human sciences, due to its object of studying - offered the necessary scientific support for the study accomplishment, while the technological progress in Communications and Computer Sciences, associated to the current world process of globalization, provided a new view of working, which allowed the operational execution of this study. The study was also based on bibliographical researches in world warming, tropical world, deforestation of tropical rain forests, socioeconomic conditions of the countries where the forests are placed and in the expansion of the mentioned diseases over the past 25 years. The set of data were synthesized in a table and in cartographic material that show the socio environmental conditions and the health risk of these countries.

Os ambientes terrestres têm sido gradativamente alterados pelo ser humano, mas a partir da Revolução Industrial, o homem começou a atuar de maneira mais intensa sobre o meio, fazendo com que as modificações ambientais tomassem proporções alarmantes, tanto em velocidade quanto em dimensão. As mudanças, como as climáticas, hídricas e biológicas, entre outras, ocorridas durante o século XX foram as maiores já registradas. As alterações ambientais associadas ao quadro demográfico do mundo contemporâneo, às condições socioeconômicas e à revolução técnico-científico-informacional que interligou o mundo, acabaram resultando em um cenário nunca vivenciado pela humanidade e ao mesmo tempo preocupante, tanto para saúde ambiental da Terra como para a humana. Se por um lado essa situação, baseada principalmente no avanço tecnológico, resultou numa verdadeira revolução nas taxas de mortalidade e na esperança de vida, por outro lado criou um ambiente que vem facilitando a emergência e reemergência de doenças, que pode comprometer o próprio futuro. Esse estudo tem por objetivo principal dar subsídios para o acesso a um conhecimento integrado, em escala global, tanto das alterações ambientais das áreas tropicais úmidas e do quadro socioeconômico dos países localizados nessa faixa tropical, quanto do surgimento e/ou expansão de quatro doenças infecciosas de caráter hemorrágico - dengue hemorrágica, febre amarela, marburg e ebola - no período de 1981 a 2005. No campo teórico-metodológico, a Geografia, mediante as suas características científicas de transitar pelos campos das ciências naturais e humanas, devido ao seu objeto de estudo, ofereceu a sustentação científica necessária para a realização, enquanto o avanço tecnológico das comunicações e da informática, associado ao processo de globalização pelo qual o mundo passa, proporcionou uma realidade de trabalho totalmente nova, permitindo a execução operacional do estudo. Foram realizados levantamentos bibliográficos e estudos sobre aquecimento global, mundo tropical, devastação das florestas tropicais úmidas, condições socioeconômicas dos países localizados nesta porção do globo e expansão das doenças citadas nos últimos 25 anos. O conjunto dos dados foi transformado em uma tabela síntese e em material cartográfico que retrata a situação atual desses países, destacando o nível das condições sócio ambientais e o risco saúde em que se encontram. / The terrestrial environments have been gradually altered by human being but from the Industrial Revolution on, this process has been even more intensive, resulting in environmental modifications of fast, huge and alarming proportions. The changes, such as the climatic, hydric and biological ones, among others, that took place in the 20th century, were the largest registered. The environmental alterations, associated to the current demographic panorama, to the socioeconomic conditions and to the technical-scientific-informational revolution - that have linked the whole world - resulted in a scenario never before experienced by humanity and, at the same time, very preoccupying for the Earth environmental health as well as for the humans. If on one hand that situation, based mainly on the technological progress, has resulted in lower mortality rates and higher life expectancy at birth, on the other hand it has also created an environment that made the emergence and re-emergence of diseases much easier to occur, so that future may be at risk. This study intend to bring up subsidies that allow for access to global integrated knowledge, not only about the environmental changes in the countries located in humid tropical areas and their socioeconomic conditions, but also about the influence of these alterations on the appearance and/or expansion of four infectious hemorrhagic diseases - hemorrhagic dengue, yellow fever, marburg and ebola - in the period from 1981 to 2005. In the theoreticalmethodological field, Geography - in face of its scientific characteristics of acting on the fields of both natural and human sciences, due to its object of studying - offered the necessary scientific support for the study accomplishment, while the technological progress in Communications and Computer Sciences, associated to the current world process of globalization, provided a new view of working, which allowed the operational execution of this study. The study was also based on bibliographical researches in world warming, tropical world, deforestation of tropical rain forests, socioeconomic conditions of the countries where the forests are placed and in the expansion of the mentioned diseases over the past 25 years. The set of data were synthesized in a table and in cartographic material that show the socio environmental conditions and the health risk of these countries.

At present time of modern worldwide tourism using air transport, the risk of spreading an infectious disease in the Czech Republic cannot be underestimated. Air transport has become quite common way of travelling for Czech citizens so the travel time has shortened significantly. From this viewpoint Czech residents are at potential hazard of highly infectious diseases (HID). This Diploma thesis deals with biological agents which are divided into four risk groups on the basis of patogenes, a hazard to the staff and possible treatment and prophylaxis. Each of the groups requires different level of protection against the infection and its spread. The groups are graded from 1 to 4, i.e. BSL-1, BSL-2, BSL{--}3 and BSL{--}4. Biosafety level 4 (BSL-4) poses a high individual risk of life-threatening diseases where no prevention and treatment are available. This group includes various viral hemorrhanic fevers (VHF) accompanied by heavy tissue bleeding which can be caused by philoviruses, arenaviruses, buniaviruses and flaviviruses. These virus families include viruses like Ebola, Marburg, Lassa, Junin (Argentine VHF), Machupo (Bolivian VHF), Sabia (Brazilian VHF), Guanarito (Venezuelan VHF), Rift Halley fever, Hanta virus, Variola virus, Severe Acute Respiratory Syndrome (SARS) and others. Even the hazard of BSL-3 biological agents with, in history well-known, Bacillus anthracis should not be ignored. The hazard of highly infectious diseases (HID) related to tourism consists in the incubation period. Tourists are infected during their stay abroad and on their way back to the Czech Republic the disease is highly developed. The HID transmission to other people confined in the space of the plane is then very simple. The attention is also paid to the pandemic (H1N1) 2009 influenza virus which showed the possible ways of infection identification and population protection in the Czech Republic together with all subsequent effects.