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Palomo, Jennifer. "Etude des réponses immunitaires de l'hôte dans la pathogenèse d'infections : modèles murins de mucoviscidose et malaria." Thesis, Orléans, 2013. http://www.theses.fr/2013ORLE2063/document.
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La mucoviscidose est une pathologie pulmonaire causée par un dysfonctionnement du canal CFTR et caractérisée par un mucus visqueux, une susceptibilité accrue aux infections chroniques et une inflammation excessive. Une première partie de ma thèse a eu pour objectif d’étudier les mécanismes inflammatoires impliqués dans le développement de la pathologie. Nous avons plus particulièrement analysé le rôle de l’IL-1β et de l’IL-17 dans la réponse à l’infection par Pseudomonas aeruginosa, dans le modèle murin ΔF508 de mucoviscidose. La seconde partie de ma thèse a porté sur l’étude de la malaria pulmonaire et cérébrale, une complication létale de l’infection à P. falciparum. Nous avons mis en évidence l’importance de trois voies d’activation des lymphocytes T CD8+ cytotoxiques dans le développement de la neuropathologie induite par Plasmodium berghei ANKA chez la souris : la protéine PKC-θ, la sous-unité β2 du récepteur à l’IL-12 et le récepteur des IFN de type I, mais qui ne semblent pas impliquées dans l’inflammation pulmonaire associéeCystic fibrosis is a pulmonary pathology, caused by the CFTR channel dysfunction, and characterized by high mucus viscosity, increased sensitivity to chronic infections and excessive inflammation. The aim of my thesis was first to study the inflammatory mechanisms involved in this lung pathology. Indeed, we analyzed the role of IL-1β and IL-17 in response to Pseudomonas aeruginosa infection, in the ΔF508 mouse model of cystic fibrosis. In the second part of my thesis, I studied pulmonary and cerebral malaria, a lethal complication of P. falciparum infection. We showed the importance of three pathways implicated in cytotoxic CD8+ T lymphocytes activation during the Plasmodium berghei ANKA-induced neuropathology development in mice: PKC-θ protein, β2 subunit of IL-12 receptor and type I IFN receptor, which did not seem essential for the associated lung inflammation
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Crawley, Jane Margaret Stewart. "Seizures in childhood cerebral malaria." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.396249.
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Dennison, Jeremy M. T. J. "Cytoadhesion, cytokines and cerebral malaria." Thesis, University of Liverpool, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337149.
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Almelli, Talleh. "Parasite genetic factors implicated in cerebral malaria." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05P605/document.
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Le paludisme à P. falciparum est l’une des causes majeures de mortalité et de morbidité dans le monde. Ce parasite est responsable de plusieurs manifestations cliniques allant du portage asymptomatique et infections non compliquées aigüe au paludisme grave et compliqué, tel que le neuropaludisme. Nous avons émis l’hypothèse que l’expression différentielle des gènes contribue à la variation phénotypique de parasites, entraînant des interactions spécifiques avec l’hôte, qui à son tour déterminent le type de manifestations cliniques du paludisme. L’objectif principal de cette étude était d’identifier les facteurs génétiques de P. falciparum impliqués dans la pathogenèse du neuropaludisme. Ceci a été réalisé par l’analyse complète du transcriptome d’isolats provenant d’enfants camerounais porteurs asymptomatiques (PA) ou atteints d’accès simple (AS) ou de neuropaludisme (NP). Le transcriptome du clone non sélectionnée (3D7) et la lignée sélectionnée (3D7-Lib) a été également analysé. Les résultats ont montré la surexpression de plusieurs gènes chez des isolats provenant d’enfants atteints de neuropaludisme et chez la lignée 3D7-Lib, par rapport à ceux provenant d’enfants asymptomatiques et 3D7, respectivement. L’analyse de l’ontologie de gène indique que les gènes potentiellement impliqués dans la pathogenèse, la cytoadhérence et l’agrégation des érythrocytes sont surreprésentés parmi les gènes surexprimés chez les isolats de CM et 3D7-Lib. Les résultats les plus marquants étaient la surexpression des gènes var (groups A et B) portant les domaines cassettes DC4, DC5, DC8 et DC13 et les gènes avoisinants rif chez les isolats de NP et la lignée 3D7-Lib, par rapport aux isolats de PA et au clone non sélectionné 3D7, respectivement. Le rôle joué par ces gènes dans la virulence parasitaire est lié à la cytoadhérence, c’est-à-dire la capacité de leurs protéines exprimées à interagir entre les érythrocytes parasités et les récepteurs endothéliaux post capillaires. Parmi ces récepteurs, le CD36 et inter cellular adhesion molecule 1 (ICAM-1) ont été les plus couramment utilisés par les isolats. L’étude sur l’implication de ces deux récepteurs, ainsi que celle des ligands PfEMP-1, dans la pathogenèse du neuropaludisme devrait être approfondie poursuivie. Nous avons analysé le phénotype de cytoadhérence et les profils de transcription des variantes de Pfemp-1 des isolats frais provenant des enfants béninois atteints de NP ou AS à l’aide du test d’adhérence statique aux récepteurs CD36, ICAM-1 et CSPG et au moyen de RT-PCR quantitative pour les groupes A, B, var2, var3, DC8 et DC13. Nos résultats montrent que le niveau de cytoadhérence des parasites associés au neuropaludisme au CD36 est significativement plus important que celui des parasites associés à l’accès simple. En outre, nous n’avons pas trouvé de différence significative entre la cytoadhérence des isolats de deux groupes cliniques à ICAM-1 et au CSPG. En outre, les niveaux d’expression des groupes var A, B, var2, var3 et du DC8 et DC13 sont plus élevés chez les isolats associés au neuropaludisme que chez les isolats associés à l’accès simple. Nos résultats montrent également que, chez les parasites provenant de NP le haut niveau de cytoadhérence des parasites au CD36 est corrélé au niveau de l’expression de groupe B de gènes var. En revanche, les profils d’expression des groupes spécifiques du gène var et le phénotype de cytoadhérence aux récepteurs ICAM-1 et CSPG n’étaient pas corrélés. Nos résultats suggèrent un rôle important du récepteur CD36 et des protéines codées par les variantes de PfEMP-1 codées par le groupe B dans la pathogenèse du neuropaludismePlasmodium falciparum infection is a major cause of mortality and morbidity worldwide. This parasite is involved in several clinical manifestations, ranging from asymptomatic carriage and acute uncomplicated to severe and complicated malaria, including cerebral malaria. We hypothesized that differential gene expression contributes to phenotypic variation of parasites leading to specific interaction with the host which induces several clinical categories of malaria. The principal aim of this study was to identify parasite genetic factors implicated in the pathogenesis of cerebral malaria. We investigated the whole transcriptome of parasites isolated from Cameroonian children with asymptomatic (AM), uncomplicated (UM) and cerebral malaria (CM). We also investigated the transcriptome of 3D7 clone and the selected 3D7-Lib line. Our results revealed the up-regulation of several genes in CM isolates and 3D7-Lib line compared to AM isolates and 3D7 clone respectively. Gene ontology analysis indicates an over-representation of genes implicated in pathogenesis, cytoadherence, and erythrocyte aggregation among up-regulated genes in CM and 3D7-Lib. The most remarkable outcomes were the up-regulation of UPS A and B var genes containing architectural Domains Cassettes DC4, DC5, DC8, and DC13 and their neighboring rif genes in isolates from CM and 3D7-Lib line, compared with isolates from AM and the unselected 3D7 line, respectively. The involvement of these genes in parasite virulence rises from the ability of their encoded proteins to mediate cytoadherence of infected erythrocytes to post-capillary endothelial receptors. Of these receptors, CD36 and Inter Cellular Adhesion Molecule-1 (ICAM-1) were found as the most commonly used by the isolates. The implication of these two receptors, as well as that of PfEMP-1 ligands in the pathogenesis of CM needs to be more elucidated. We examined the adhesive phenotype and the transcription patterns of Pfemp-1 variants of fresh isolates from Beninese children with CM or UM malaria by static binding assay to CD36, ICAM-1 and CSPG and RT-qPCR for groups A, B, var2, var3, DC8, and DC13. Our findings showed that isolates from CM patients bind more to CD36 than those from UM cases. No differences were observed in binding levels to ICAM-1 or CSPG between these two groups. Furthermore, CM isolates transcribed groups A, B, var2, var3, DC8 and DC13 of var genes at higher levels than UM isolates. Interestingly, the high transcription levels of group B in CM parasites correlated with their higher level of binding to CD36. In contrary, the expression profiles of a specific var group and the binding phenotype of isolates to ICAM-1 and to CSPG were not correlated. Our findings support the implication of CD36 along with PfEMP-1 variants encoded by group B in cerebral malaria pathogenesis
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Greene, Jennifer A. "Toll-like Receptor Polymorphisms and Cerebral Malaria." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1270153850.
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Newton, Charles R. J. C. "Intracranial hypertension in Kenyan children with cerebral malaria." Doctoral thesis, University of Cape Town, 1995. http://hdl.handle.net/11427/27054.
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Cerebral malaria is a common encephalopathy in African children, but the cause of death and neurological sequelae are unknown. This dissertation examines the hypothesis that raised intracranial pressure (ICP) is a determinant of poor outcome in Kenyan children with cerebral malaria. The opening cerebrospinal fluid pressure was raised in all 26 children in whom it was measured on admission and 92% of 35 children in whom it was measured after admission. Brain stem signs, particularly an abnormal respiratory pattern, absent pupillary responses and a lack of spontaneous eye movement were associated with a death. In 33 children who died with cerebral malaria, at least 18-42% had clinical features of transtentorial herniation, according to the criteria used. Intracranial pressure monitoring was performed in 18 children with severe CM, of whom 14 had computerised tomography (CT) and in 10 the basal cranial arteries were monitored with transcranial Doppler (TCD) sonography. Three children with severe intracranial hypertension (maximum ICP > 60 mmHg and minimum cerebral perfusion pressure (CPP) < 40 mmHg) had a poor outcome despite aggressive therapy with mannitol. One child with a maximum ICP of 151 mmHg died with the signs of uncal and medullary stages of herniation. In the other 2 children, middle cerebral artery velocity and vascular resistance monitored with TCD sonography changed with ICP and CPP. Both of these children had diffuse brain swelling associated with generalised hypodensity on their acute CT scans. These children survived° with cerebral atrophy on their convalescent scans and severe neurological deficits. In the 8 children with intermediate intracranial hypertension (maximum ICP 20-60 mmHg and CPP < 50 mmHg) mannitol was effective in controlling the intracranial hypertension. TCD was not reliable in detecting changes in ICP or CPP. Two of these children had acute brain swelling, but the tomographic density was normal and the swelling had resolved when the repeat scans were performed 12-24 days later. All the children with intermediate intracranial hypertension survived without major neurological sequelae. In the remaining 7 children who had ICP monitoring, the maximum ICP was <20 mmHg and mannitol was not administered. None of the CT scans showed brain swelling and the children survived without severe sequelae. In a further 9 children with severe malaria (6 with CM) the agonal stages were monitored with TCD. Three children with CM had sonographic features of progressive intracranial hypertension associated with signs of herniation, whilst the other children (including 3 with CM) did not have these sonographic features, although one had evidence of brainstem compromise before dying. Thus raised ICP is a feature of CM in Kenyan children. Severe intracranial hypertension is associated with a poor outcome and could be responsible for at least a third of the children dying from CM. Mannitol reduces the ICP, but does not prevent nor control severe intracranial hypertension.
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Shaw, Tovah. "Defining the immunological basis of cerebral pathology during murine experimental cerebral malaria and understanding the basis of infection induced resistance." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/defining-the-immunological-basis-of-cerebral-pathology-during-murine-experimental-cerebral-malaria-and-understanding-the-basis-of-infection-induced-resistance(cef82ee4-61f7-4f27-afb3-e0ffd1906bd7).html.
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Malaria affects 200 million people annually, resulting in 584,000 - 1,238,000 deaths. The majority of these deaths occur in children, less than 5 years of age, in sub-Saharan Africa and are due to cerebral malaria (CM), a neuropathology induced primarily by the species Plasmodium (P.) falciparum. The pathogenesis of CM remains poorly understood and the mechanisms involved in acquired protection against the syndrome in malaria-endemic regions are undefined. Utilising the well characterised P. berghei ANKA experimental infection model of cerebral malaria (ECM), results presented in this thesis show that the development of ECM is associated with the accumulation and arrest of pathogenic CD8+ T cells within the perivascular spaces of the brain. Accumulation of activated CD8+ T cells, without arrest, was observed in the perivascular spaces of the brains of mice infected with the non-ECM causing P. berghei NK65 strain. These data show that the behaviour of intracerebral CD8+ T cells specifies their pathogenic function during malaria infection. The development of ECM was associated with extensive disruption to the BBB, which developed in the absence of extensive CD8+ T cell-dependent endothelial cell apoptosis. We modified the ECM model, establishing an infection-drug cure strategy, to investigate the immunological basis of parasite exposure-induced resistance to ECM development. Three rounds of infection-drug cure promoted resistance to ECM, which was associated with reduced intracerebral expression of genes involved in defence response, regulation of apoptosis, chemotaxis, CTL activity, antigen processing and presentation and cell adhesion, compared with ECM susceptible mice. Additionally, CD8+ T cell activation was suppressed in exposure-induced resistant mice and was associated with the antibody dependent expansion of a splenic plasmacytoid DC population, with a regulatory phenotype. The infection-induced protection against ECM was critically dependent upon secreted antibody production. A long standing problem in studying the immune response to malaria infection has been the inability to track parasite-specific CD4+ T cell responses. To address this, we generated and validated new transgenic P. berghei parasites expressing the model antigen, ovalbumin (OVA), either in the parasite cytoplasm or on the parasitophorous vacuole membrane (PVM). We found that cellular location and expression level of the antigen influence the induction and magnitude of parasite-specific T-cell responses. These parasites thus provide knowledge on the factors that influence the recognition of parasite antigens by the immune system and represent useful tools to study the development and function of antigen-specific T-cell responses during malaria infection. The results in this thesis improve our understanding of the events that lead to the development of CM, and the host immune responses that develop following parasite exposure to protect against it. The results should contribute towards the rational development of adjunctive therapies and effective vaccines for human CM.
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Campino, Susana Gomes. "Genetic analysis of murine malaria /." Umeå : Univ, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-124.
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MacCormick, I. "Malarial retinopathy and neurovascular injury in paediatric cerebral malaria." Thesis, University of Liverpool, 2016. http://livrepository.liverpool.ac.uk/2049100/.
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Background Diseases of the brain are difficult to study because this organ is relatively inaccessible. Only one part of the central nervous system is available to direct, non-invasive observation – the retina. The concept of the retina as a window to the brain has created much interest in the retina as a source of potential markers of brain disease. Paediatric cerebral malaria is a severe neurological complication of infection with the parasite Plasmodium falciparum, which is responsible for death and disability in a significant number of children in sub-Saharan Africa. As with many neurological diseases, the precise mechanisms by which this infection causes damage to the brain remain unclear, and this hampers efforts to develop effective treatments. It may be that studying the retina in paediatric cerebral malaria could both illuminate pathogenesis specific to this disease, and also provide an illustration of how to approach retinal biomarkers in a new, and potentially more effective way. Methods I approached the aim of developing retinal features as markers of brain disease in paediatric cerebral malaria via several objectives. I made use of an existing clinical study to collect new retinal data from ophthalmoscopic examinations and fundus fluorescein angiograms from patients over three successive malaria seasons in Malawi, and added these to historical data obtained previously at the same site. I devised a new method for grading retinal images. I reviewed the biological plausibility of associations between retina and brain in cerebral malaria, and then considered analytical methods to interpret my retinal data effectively. Finally I estimated associations between retinal features, outcomes, and a radiological measure of brain swelling using combinations of regression models. Results My review of retinal and cerebral histopathology, vascular anatomy and physiology indicated that certain retinal and brain regions may be similarly prone to damage from sequestration as a result of interactions between aberrant rheology and microvascular geometry, such as branching patterns and arteriole to venule ratios. My review of evaluations of analogy and surrogacy suggested that biological similarities between retina and brain could be used to justify statistical evaluation of the amount of information the subject and object of the inference share about a common outcome, as used to assess surrogate end points for clinical trials. This kind of approach is able to address questions about whether a particular retinal feature is effectively equivalent to an analogous disease manifestation in the brain. I report analyses on three overlapping groups of subjects, all of whom had retinopathy positive cerebral malaria: children with admission ophthalmoscopy (n=817), children with admission fluorescein angiography (n=260), and children with admission angiography and MRI of the brain (n=134). Several retinal features are associated with death and longer time to recover consciousness in paediatric cerebral malaria. Broadly speaking, these features appear to reflect two processes: neurovascular sequestration (e.g. orange vessel discolouration and death), and neurovascular leakage (e.g. >5 sites of punctate leak and death). Respective adjusted odds ratios and 95% confidence intervals for these particular associations are: 2.88 (1.64-5.05); and 6.90 (1.52-31.3). Other related processes may also be important, such as ischaemia, which can be extensive. Associations between retina and brain are less clear, in part because of selection bias in the samples. Conclusions Neurovascular leak is important in fatal paediatric cerebral malaria, suggesting that fatal brain swelling may occur primarily as a result of vasogenic oedema. Other processes are also likely to be involved, particularly neurovascular sequestration, which is visible on retinal imaging as orange vessels or intravascular filling defects. Sequestration may plausibly cause leak through direct damage to tight junctions and by increasing transmural pressure secondary to venous congestion. Several types of retinal leakage are seen and some of these may represent re-perfusion rather than acute injury. Future work to investigate temporal changes in retinal signs may find clearer associations with radiological and clinical outcomes. The steps taken to evaluate retinal markers in cerebral malaria illustrate a more rigorous approach to retinal biomarkers in general, which can be applied to other neurological diseases.
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Ball, Elisabeth Ann. "Uncovering the role of IFNAR1 in Experimental Cerebral malaria." Doctoral thesis, Universidade Nova de Lisboa. Instituto de Tecnologia Química e Biológica, 2013. http://hdl.handle.net/10362/11964.
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Dissertation presented the Ph.D degree in BiologyCerebral malaria is a severe and fatal form of clinical Plasmodium falciparum infection, resulting in brain injury from a damaging cascade of vascular, inflammatory and immunological host responses. However progression to cerebral malaria can be modified by host genetic factors. This thesis work extensively reveals the role of Interferon type I receptor (IFNAR1) in the development of Experimental cerebral malaria, through the use of the mouse model Ifnar1-/-. We found Ifnar1-/- mice protected from Experimental cerebral malaria upon infection with Plasmodium berghei ANKA-GFP, compared with susceptible wild-type C57BL/6 mice. Ifnar1-/- mice showed diminished blood brain barrier breakage, despite parasite accumulation in the periphery and accumulation of immune cells within the brain tissue during infection.(...)
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Holding, Penny Anne. "Is cerebral malaria a risk factor for special educational needs?" Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286403.
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Moxon, Chris. "Coagulation and the endothelium in Malawian children with cerebral malaria." Thesis, University of Liverpool, 2012. http://livrepository.liverpool.ac.uk/9673/.
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Background: Cerebral malaria is a major cause of mortality and morbidity in African children. Pathology is related to interactions between malaria-infected red blood cells (iRBC) and the endothelium but the aetiology of the neurological compromise remains unclear. Methods: This thesis involved direct and downstream investigation of the endothelium in Malawian children with cerebral malaria and controls in post-mortem samples, plasma and through developing a novel ex vivo method to examine endothelium in subcutaneous tissue. Results: In post-mortem samples of brain in fatal cerebral malaria, there was thrombosis and loss of endothelial protein C receptor (EPCR) associated with iRBC sequestration. iRBC associated loss of EPCR and thrombomodulin was also demonstrated in post- mortem samples of gut and subcutaneous tissue but this was less marked than in the brain and rarely associated with thrombosis. Subcutaneous biopsies taken on admission with cerebral malaria demonstrated reduced EPCR and thrombomodulin ex vivo, showing that loss of these receptors is present at the time of presentation and are not just agonal events. Examination of coagulation in blood demonstrated activation of coagulation, as indicated by raised thrombin-anti-thrombin complexes and reduced protein C and antithrombin levels. However this was compensated as there was normal prothrombin fragment (F1+2)-to-activated protein C ratios and only mildly altered clotting times. Examination of markers of endothelial activation (soluble Intracellular Adhesion 2 Molecule-1 [sICAM-1] and Angiopoetin-2 [Ang-2]) and inflammation (C-reactive protein [CRP]) revealed endothelial activation and inflammation at presentation and during recovery and demonstrated that in cerebral malaria and in uncomplicated malaria there is persistent endothelial activation after parasites are cleared, up to a month after presentation. Complexes of very low density lipoprotein (VLDL) and CRP were also raised in cerebral and uncomplicated malaria. Conclusions: In cerebral malaria in Malawian children there is localised microvascular loss of endothelial anticoagulant receptors at sites of iRBC sequestration. In the brain, where constitutive expression of EPCR and thrombomodulin is low, this is accompanied by thrombosis; outside the brain, where constitutive EPCR and thrombomodulin expression is high, coagulation is compensated. This activation of coagulation and of the endothelium in response to acute infection leaves a residual imprint as detected by markers of endothelial activation and inflammation even in uncomplicated malaria several weeks after parasites are cleared. Since children in sub-Saharan African frequently suffer repeated infections these endothelial alterations may have important consequences both for subsequent infections and for long-term health. These mechanisms highlight potential targets for therapy.
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McCormick, Christopher John. "An investigation of the interactions between Plasmodium falciparum-infected erythrocytes and endothelium." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318757.
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Barks, Lee. "Wheelchair positioning and pulmonary function in children with cerebral palsy." [Tampa, Fla.] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0002107.
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Blanco, Yara Carollo 1980. "Análise dos mecanismos protetores desencadeados pela oxigenação hiperbárica na malária cerebral." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317464.
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Orientador: Fabio Trindade Maranhão CostaTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: A Malária é a principal doença parasitária do mundo, infectando 300-500 milhões de pessoas e levando ao óbito cerca de 1 milhão de indivíduos anualmente. As infecções maláricas geralmente não apresentam complicações, no entanto, infecções por Plasmodium falciparum podem se desenvolver em formas graves da doença, como a malaria cerebral. A malaria cerebral e considerada uma síndrome multifatorial, envolvendo a citoadesão de eritrócitos infectados por P. falciparum (EIPf) através de diferentes receptores como CD36, ICAM-1, VCAM, P-selectina e E-selectina, sendo o ICAM-1 apontado como o principal receptor. Varias evidências sugerem ainda que o desbalanço da resposta imune do hospedeiro, a ativação endotelial e alterações na cascata de coagulação desempenham papel importante na patogênese da MC. Além disso, outros fatores como a presença de heme livre e NOS também tem sido apontados como essenciais para o desenvolvimento da MC... Observação: O resumo, na íntegra, poderá ser visualizado no texto completo da tese digital
Abstract: Malaria still is a major parasitic disease in the world, infecting 300-500 million people and leading to death about 1 million people annually. Usually malaria infections do not lead to complications, however some infections, mainly, by Plasmodium falciparum can evolve into severe forms of disease such as cerebral malaria (CM). CM is considered a multifactorial syndrome involving cytoadhesion of P. falciparum-infected erythrocytes (PfEI) to different host receptors such as CD36, VCAM, P-selectin and E-selectin and ICAM-1 , which is considered the main receptor involved in MC. A large body of evidences suggests that the imbalance of the host immune response, endothelial activation and changes in the coagulation cascade play an important role in the pathogenesis of CM. Moreover, of free heme, and NOS has also been identified as essential for the development of CM...Note: The complete abstract is available with the full electronic document
Doutorado
Parasitologia
Doutor em Parasitologia
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Blanco, Yara Carollo 1980. "Efeitos da oxigenação hiperbarica na infecção experimental por Plasmodium spp." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314692.
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Orientador: Fabio Trindade Maranhão CostaDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: A malária é sem dúvida a doença parasitária mais importante do mundo, infectando 300-500 milhões de pessoas e levando a óbito cerca de 1-2 milhões de indivíduos anualmente. Malária cerebral (MC) é o mais importante tipo de complicação nas infecções maláricas. MC é uma síndrome multifatorial, entretanto sua patogênese ainda não foi totalmente elucidada. Diversos estudos mostram a adesão de eritrócitos infectados (EI) no endotélio microvascular do hospedeiro. No entanto, várias evidências indicam que um desbalanço da resposta imune e da homeostase, acarretando numa elevada expressão de citocinas pró-inflamatórias também desempenham um papel importante na patogênese da MC. O modelo utilizando camundongos C57BL/6 infectados com Plasmodium berghei ANKA (PbA) parece ser o que mais se assemelha a MC humana, já que em ambos casos ocorre um aumento significativo de citocinas próinflamatórias, da destruição neuronal, da hemorragia cerebral e da concentração de lactato. A terapia de oxigenação hiperbárica (HBO) tem sido amplamente utilizada como potencializador de cicatrização e contra microrganismos anaeróbicos. No entanto, nos últimos anos, diversos estudos têm mostrado que o oxigênio pressurizado é capaz de proteger contra a destruição da barreira hemato-encefálica (BHE), inibir a destruição neuronal, reduzir a produção de citocinas pró-inflamatórias e a expressão ICAM-1, receptor leucocitário, e de EI. Neste estudo, avaliamos os efeitos da HBO na prevenção dos sintomas da MC em camundongos infectados com PbA e nos eritrócitos expostos diretamente ao oxigênio hiperbárico. A utilização do oxigênio hiperbárico mostrou-se capaz de reduzir significativamente a taxa de mortalidade associada à malária cerebral experimental, assim como uma redução da queda da temperatura corporal e dos níveis de parasitemia. Além disso, nossos resultados demonstram que a terapia com oxigênio hiperbárico impede a destruição da BHE. Testes In vitro mostraram que a exposição direta de eritrócitos sadios e de eritrócitos infectados (EI), á HBO não é tóxica e nem capaz de alterar a viabilidade e infectividade de EI. Por último, mostramos que o tratamento com HBO realizado após o quarto dia de infecção (quando a parasitemia já é patente), retarda o aparecimento dos sintomas neurológicos da malária cerebral e morte associada
Abstract: Malaria is the world¿s most nefarious infectious disease, affecting 300-500 million people and leads to death of 1-2 million individuals per year. Cerebral malaria (CM) is the most serious complications that might occur during a malarial infection. CM is a multifactorial syndrome; however its pathogenesis is still a matter of debate. Several studies show that in adhesion of infected erythrocytes (IE) to the host microvascular endothelium is involved. Nevertheless, several bodies of evidence indicate that a unbalance in host immune response and homeostasis, leading to the expression at higher levels of proinflammatory cytokines. Infection of C57BL/6 mice with IE of Plasmodium berghei ANKA (PbA) is the largely used model for CM, as a significant augmentation in the expression levels of proinflammatory cytokines and lactate, neuronal damage and cerebral hemorrhage also occurs. Hyperbaric oxygen therapy (HBO) has been widely used against anaerobic microorganism and as an adjunct therapy in surgeries. However, in the last year several studies have shown that HBO is able to prevent brain-blood-barrier (BBB) breakdown, inhibit neural damage and the syntheses of proinflammatory cytokines and the expression of ICAM-1, a the host receptors involved in the adhesion of leukocytes and IE. Herein, we evaluated the HBO effects in preventing CM specific clinical signs in PbA-infected mice and directly against IE of PbA. The data provided by us demonstrated that HBO treatment reduces significantly CM associated mortality and clinical outcomes, such as hypothermia, BBB dysfunction and is able to inhibit parasite burden early on the infection. In vitro analysis showed that directly exposure to HBO, up to six hours, is not harmful to health erythrocytes neither inhibit parasite development and infectivity. Finally, HBO treatment was able to delay significantly the CM neurological signs and death, even thought administrated after parasite establishment
Mestrado
Mestre em Parasitologia
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Tibenderana, James. "The neurological sequelae of cerebral malaria in children and adults in Uganda." Thesis, London School of Hygiene and Tropical Medicine (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416428.
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Esamai, Fabian. "Cerebral malaria in children in the highlands of Kenya : aspects of pathogenesis and clinical presentation /." Linköping : Univ, 2002. http://www.bibl.liu.se/liupubl/disp/disp2002/med729s.pdf.
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Campino, Susana. "Genetic analysis of murine malaria." Doctoral thesis, Umeå universitet, Medicinsk biovetenskap, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-124.
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Malaria, an infectious disease caused by Plasmodium parasites, is one of the major world-scale health problems. Despite the efforts aimed at finding an effective way to control the disease, the success has been thwarted by the emergence of parasite drug resistance and mosquito resistance to insecticides. This thesis focuses on the genetic analysis of resistance to murine malaria induced by the lethal Plasmodium berghei ANKA using a wild-derived-inbred strain (WDIS). The aim of this thesis was to exploit the genetic diversity represented among WDIS for identifying loci contributing to resistance/susceptibility to murine malaria. The work included a genome-wide polymorphism survey using microsatellite markers performed on 10 WDIS. Comparisons of these strains to laboratory inbred strains confirmed a higher rate of polymorphism among the WDIS. We conclude that these WDIS represent repositories of unique naturally occurring genetic variability that may prove to be invaluable for the study of complex phenotypes. Next, we used the WDIS to search for novel phenotypes related to malaria pathogenesis. Whereas most laboratory strains were susceptible to experimental cerebral malaria (ECM) after infection with P. berghei ANKA, several WDIS were found to be resistant. To study the genetic inheritance of resistant/susceptibility to P. berghei ANKA infection we analysed backcross and F2 cohorts derived from crossing the WLA wild-derived strain with a laboratory mouse strain (C57BL/6). A novel phenotype represented by the cure of infection, clearance of parasitaemia and establishment of immunological memory was observed in the F2 progeny. The backcross progeny was used to genetically map one locus on chromosome 1 (Berr1) and one locus on chromosome 11 (Berr2) that mediate control of resistance to ECM induced by P. berghei ANKA. Genetic mapping using the F2 progeny showed that a locus on chromosome 1 (Berr1) and a locus on chromosome 9 (Berr3) were contributing to control survival time after infection with lethal Plasmodium. Finally, we identified, a locus on chromosome 4 (Berr4) that appears to control time of death due to hyperparasitaemia. This thesis underlines the value of using WDIS to reveal genetic factors involved in the aetiology of disease phenotypes. The characterisation of the genetic factors represented by the malaria resistance loci identified here are expected to provide a better understanding of the malaria pathology.
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Rutta, Acleus Stanislaus Malinzi Sansanee Chaiyaroj. "Cytokine response and genetic regulation in children and adults with cerebral malaria disease /." Abstract, 1999. http://mulinet3.li.mahidol.ac.th/thesis/2542/42E-AcleusS.pdf.
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Humphries, Duncan Charles. "Investigating the cerebral/pulmonary axis following traumatic brain injury in a preclinical model." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/19511.
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Traumatic Brain Injury (TBI) accounts for 1,000,000 hospital admissions in the European Union every year and is the leading cause of death in individuals under 45 years of age in both Europe and the United States. This thesis examines the consequences to both the brain and lung following TBI using the lateral fluid percussion injury (FPI) in an in-vivo murine model. In the murine FPI model, alongside cerebral inflammation (associated with neuronal damage and the infiltration of inflammatory cells), there is significant neutrophil accumulation within the pulmonary interstitium 6 and 24 hours after TBI. This was associated with pulmonary haemorrhage and increased vascular permeability. In an attempt to reduce pulmonary injury, 17-DMAG, an HSP90 inhibitor, was applied but proved to be nonprotective. Since patients with TBI show increased susceptibility to bacterial infection, microaspiration and ventilator-induced lung injury, a double-hit model was established whereby mice first received the head injury and then received a lung injury. This demonstrated worse lung injury following intra-tracheal administration of hydrochloric acid after TBI. Depleting neutrophils with an anti-LY-6G depleting antibody improved outcome in this model, indicating increased susceptibility to damage was neutrophil dependent. To test whether neutrophil accumulation within the pulmonary interstitium was specifically related to brain injury, lung tissue following other distant organ injury such as renal ischemia-reperfusion injury (IRI) and renal transplantation were assessed. Significant pulmonary interstitial neutrophil accumulation was seen following both models and was associated with significant pulmonary haemorrhage. Inducing HSP70 activity with an HSP90 inhibitor was shown to be protective by reducing the degree of pulmonary haemorrhage in these models. In an attempt to identify the mechanisms behind neutrophil accumulation in TBI, renal IRI and renal transplantation, ICAM-1 (CD54), a marker of the reverse transmigration of neutrophils was investigated. No differences in ICAM-1 expression were seen following TBI, indicating that another mechanism must be responsible. This mechanism is the focus of on going work within the laboratory. Hypoxia is believed to contribute towards the development of secondary brain injury however little is known regarding its direct contribution. Working alongside chemists at the University of Edinburgh, a number of novel fluorescent hypoxia probes were designed and tested, but none proved to be able to detect hypoxia in-vitro. In conclusion, this thesis has demonstrated that following mild TBI, the lungs are “primed” with a massive interstitial neutrophil influx and that a subsequent micro aspiration of acid induces exaggerated lung injury. The mechanism by which this occurs is the focus of on-going investigation. Pulmonary sequestration of neutrophils is also a predominant feature of other distant organ injuries.
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Swann, Olivia Veronica Fowell. "Role of the Swain-Langley and McCoy polymorphisms in complement receptor 1 in cerebral malaria." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/33280.
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Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor 1 (CR1) gene, named Swain-Langley (Sl2) and McCoy (McCb), occur at high frequencies, consistent with selection by malaria. This thesis investigates the association between these two polymorphisms and severe malaria. Previous studies into this area have produced conflicting findings. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, I found that the Sl2 polymorphism was associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism was associated with increased odds of cerebral malaria. I also identified an interaction between Sl2 and α+thalassaemia, with the protective association of Sl2 greatest in children with normal α-globin. Following these epidemiological findings, I explored potential biological hypotheses which might explain them. The first approach examined whether the Sl2 and McCb polymorphisms affected how CR1 forms clusters on erythrocyte membranes, a process which is key in the binding and transfer of immune complexes from erythrocytes to macrophages. Using erythrocytes from Kenyan children, I performed immunofluorescence assays (IFAs) with confocal microscopy to quantify CR1 cluster number and volume. I found no association between the Sl2 and McCb polymorphisms and either the number or volume of CR1 clusters formed. The second approach investigated whether the cerebral malaria-specific associations seen with Sl2 and McCb might be due to expression of CR1 by human brain endothelial cells (HBEC). The immortalised cell line HBEC-5i was investigated for expression of CR1 using IFA, flow cytometry, western blotting, functional C3b degradation assays, mass spectrometry, immunoprecipitation and siRNA knockdown experiments. A pool of α-CR1 monoclonal antibodies recognised an intracellular antigen in permeabilised HBEC-5i cells which was a similar molecular weight to CR1 on western blotting. However, when the α-CR1 monoclonal antibodies were tested individually, only E11 recognised an HBEC-5i antigen. Further investigative approaches did not support the presence of CR1 on HBEC-5i cells, instead suggesting that E11 was not specific for CR1 and was instead recognising a protein in the Golgi apparatus. The final approach was to examine whether the Sl2 and McCb polymorphisms might influence the binding of the complement components mannose binding lectin, C1q and L-ficolin to the LHR-D region of CR1. I aimed to generate recombinant proteins of the LHR-D region which included the polymorphisms. Site-directed mutagenesis of the region was successful and subcloning and expression of the mutant amplicons will be performed at a later date. In summary, I have identified opposing associations between the Sl2 and McCb polymorphisms and cerebral malaria, which do not appear to be due to differences in CR1 clustering or expression of CR1 by human brain endothelial cells. My investigation into whether the polymorphisms might influence complement component binding is ongoing.
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Moussiliou, Azizath. "Paludisme A Plasmodium Falciparum pendant la grossesse et l'enfance : caractérisation moléculaire et immunologique." Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066619.
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Ce travail avait pour objectif, de caractériser le poids des infections au cours de la grossesse et d’étudier la construction de l’immunité anti-PfEMP1 chez le jeune enfant. La première partie, aborde la conséquence des infections et l’efficacité des traitements chez la mère. Cette étude réalisée sur la cohorte de femmes d’une étude prospective au Bénin, a démontré l’impact des infections à bas bruit sur le taux d’hémoglobine maternel et le faible poids de l’enfant. Le TPI-SP, a montré les limites quant à sa capacité à débarrasser les femmes enceintes infectées au moment du traitement de leur parasite. Nos résultats soutiennent davantage la nécessité de trouver des moyens alternatifs de prévention qui offrent une meilleure couverture de la grossesse. La deuxième partie aborde la construction de l’immunité anti-PfEMP1 dans la première année de vie chez l’enfant. Un résultat majeur de cette étude est la démonstration que l’acquisition des anticorps contre les PfEMP1 associés aux complications du paludisme est dépendante des infections patentes de l’enfant. La troisième partie aborde les phénotypes des parasites responsables de diverses formes cliniques du paludisme chez l’enfant Africain âgé de 0 à 5 ans. Cette étude a permis de mettre en évidence un marqueur de mauvais pronostic du paludisme cérébral. Sur un deuxième volet, nous avions montré que les isolats adhérant faiblement à ICAM-1, transcrivent fortement les gènes codant pour les PfEMP1 contenant des motifs DC8. Ces résultats soulèvent la question du rôle de EPCR dans la physiopathologie du neuropaludisme. Le travail développé dans cette thèse a permis de décrire pour la première fois la construction de l’immunité anti-PfEMP1 dans la première année de vie, de mettre à jour les connaissances sur la physiopathologie du paludisme cérébral chez le jeune enfant et de dégager des pistes à explorer prioritairement dans la perspective du développement d'un vaccin contre les formes graves du paludismeThis work aimed to characterize the burden of P. falciparum infections during pregnancy and to study the construction of the anti-PfEMP1 immunity in the early life. The first part discusses the consequence of infection and the effectiveness of treatments in the mother. This study on the cohort of women from a prospective study in Benin, demonstrated the impact of infections with low parasitemia on the maternal hemoglobin and low weight of the child. IPT-SP, has shown the limits of its ability to rid infected pregnant women in the processing of their parasite. Our results further support the need to find alternative means of prevention that provide better coverage of pregnancy. The second part treated the construction of the anti-PfEMP1 immunity in the first year of life in children. A major finding of this study is the demonstration that the acquisition of antibodies against the PfEMP1 associated with complications of malaria depends on patentes infections in children. The third part studies parasites phenotypes responsible of various clinical forms of malaria in African children aged 0-5 years. This study allowed finding a marker of poor prognosis of cerebral malaria. On a second component, we showed that isolates bind to ICAM-1, highly transcribe the genes encoding PfEMP1 containing DC8. These results raise the question of the role of EPCR in the pathophysiology of cerebral malaria. The work developed in this thesis has allowed describing for the first time the construction of the anti-PfEMP1 immunity in the first year of life, to update knowledge on the pathophysiology of cerebral malaria in young children and identify Options to be primarily from the perspective of developing a vaccine against severe forms of malaria
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Mboma, Sebastian Minongwa. "Exploration of community-based rehabilitation for children with neurological impairments following cerebral malaria in Blantyre, Malawi." University of the Western Cape, 2018. http://hdl.handle.net/11394/6901.
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Magister Public Health - MPHBackground: Cerebral malaria (CM) kills up to 25% of its patients and about one third of its survivors develop neurological impairments (NIs). With advancements in diagnostic and management techniques for CM, more children are likely to survive. The increase in the number of CM survivors may increase the prevalence of children with NIs. In Malawi, rehabilitation for children with NIs is mostly institution-based with erratic community-outreach services, resulting in poor long-term outcomes. To date, community-based rehabilitation (CBR), a comprehensive rehabilitation approach that also addresses socio-economic impact of NIs and may supplement institution-based rehabilitation services, has not been well explored and documented. Presented here are experiences and perceptions on CBR programmes for NIs following CM in Blantyre, Malawi.
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Maude, Richard James. "Retinopathy and central nervous system microcirculatory abnormalities in adult cerebral malaria and their prediction of outcome." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/22807.
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Introduction Malaria retinopathy is a set of visible changes in the retina which are specific to falciparum malaria. Studies to date have been mostly limited to comatose African children. Retinal changes in adults with severe malaria and severely unwell patients without malaria have been less well studied and the specificity, pathogenesis, diagnostic and prognostic value of malarial retinopathy in adults are not known. Methods A series of observational studies of retinopathy in Bangladesh, India and Malaysia were done from 2008-2012. The aims were to describe the spectrum of retinal changes in falciparum and knowlesi malaria in adults, determine their specificity for severe falciparum malaria, quantify the impact of malaria retinopathy on visual function, understand its pathogenesis and assess the potential contribution of retinopathy to confirming diagnosis of malarial coma, predicting prognosis and understanding pathogenesis of cerebral malaria. Results 495 patients were enrolled and underwent retinal photography (305 with P. falciparum malaria (112 cerebral, 68 noncerebral severe, 125 uncomplicated), 44 P. knowlesi, 43 sepsis, 41 encephalopathy and 62 healthy). Retinal whitening and white-centred haemorrhages were common and specific to severe falciparum malaria. Retinopathy was most common and severe in cerebral (88%) and fatal (91%) falciparum malaria. Moderate-severe retinopathy was 95% specific for cerebral malaria in comatose patients, and its severity correlated with depth of coma. Vessel whitening was not seen and papilloedema was rare. In noncerebral severe falciparum malaria, retinopathy predicted increased likelihood of later development of coma and death. Retinal findings in Bangladeshi children were similar to those in adults. Optic nerve sheath diameter was mildly increased and brain swelling minimal on MRI. Severity of retinopathy correlated with plasma lactate, serum bicarbonate, sequestered parasite load and red cell stiffness suggesting a central role for microvascular obstruction in the pathogenesis. Severity of retinal whitening correlated with decreased visual acuity. Conclusions Retinal changes seen in severe P. falciparum malaria in Asian adults is similar, but not identical, to that seen in African children. They have potential to help with diagnosis and prognosis of Asian adults with severe falciparum malaria. Microvascular obstruction is prominent in the pathogenesis of retinopathy and coma in adults whereas raised intracranial pressure is not.
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Steinbeis, Fridolin [Verfasser]. "Protective potential and immunological evaluation of synthetic Plasmodium GPI glycoconjugate vaccines against experimental cerebral malaria / Fridolin Steinbeis." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2017. http://d-nb.info/1133492908/34.
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Alkaitis, Matthew S. "Biochemical determinants of nitric oxide synthesis in severe malaria." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:dde50b9c-fea1-432a-8c5f-35e97e641061.
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Inhibition of nitric oxide (NO) signalling may contribute to the pathogenesis of severe malaria. This thesis examines the impact of Plasmodium infection on three key determinants of nitric oxide synthase (NOS) biochemistry: substrate availability, substrate/inhibitor homeostasis and cofactor availability. Arginine, the NOS substrate, is depleted in human patients with severe Plasmodium falciparum malaria and mice infected with P. berghei ANKA. Using heavy isotope tracer infusions to quantify arginine metabolism in infected mice, we found no evidence of increased catabolism by the enzyme arginase, widely assumed to be responsible for arginine depletion. Genetic knock-out of parasite arginase had no effect on arginine depletion in mice. Instead, our findings link arginine depletion to decreased rates of arginine and citrulline appearance in the plasma of infected mice. Asymmetric dimethylarginine (ADMA) competes with arginine for binding to the NOS catalytic site. We observed elevation of the ADMA/arginine ratio in Gambian children with severe malaria, favouring NOS inhibition. In mice infected with P. berghei ANKA, we found evidence of degradation of dimethylarginine dimethylaminohydrolase 1 (DDAH1), the enzyme primarily responsible for ADMA metabolism. We also observed reduced DDAH activity and accumulation of intracellular ADMA in hepatic tissue of infected mice, suggesting that DDAH dysfunction could contribute to disruption of ADMA/arginine homeostasis. Tetrahydrobiopterin (BH4) is an essential NOS cofactor. In P. berghei ANKA-infected mice, BH4 concentrations were decreased in plasma, erythrocytes and brain tissue, which could inhibit NO synthesis and promote NOS-dependent superoxide production. To reverse deficiencies of NOS substrate and cofactor availability, we infused P. berghei ANKA-infected mice with citrulline, an arginine precursor, and sepiapterin, a BH4 precursor. Restoration of systemic arginine and BH4 availability in infected mice improved whole blood nitrite concentrations, a biomarker of NO synthesis, but did not prevent onset of disease symptoms. These studies have identified biochemical disturbances that may contribute to severe malaria pathogenesis by inhibiting NO synthesis.
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Pinto, Helen Cupertino Silva. "Efeito do tratamento da malaria cerebral com celulas da medula ossea em camundongos infectados pelo Plasmodium berghei ANKA." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317842.
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Orientador: Ana Maria Aparecida GuaraldoDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: A malária cerebral humana é a manifestação mais grave do Plasmodium falciparum que ocorre em 1% das infecções, sendo responsável por mais de dois milhões de mortes anuais entre crianças abaixo de cinco anos. O modelo experimental mais aceito da malária cerebral é o camundongo C57BL/6 infectado pelo Plasmodium berghei ANKA (PbA). A administração da fração mononuclear da medula óssea, contendo principalmente células tronco mesenquimais e hematopoiéticas, constitui uma estratégia promissora no tratamento de danos neurais causados por acidente vascular cerebral. Neste estudo, foi avaliado o efeito de células da medula óssea de camundongos transgênicos C57BL/6 GFP HET transplantadas em C57BL/6JUnib infectados com 106 hemácias parasitadas pelo PbA. Resumidamente, células perfundidas da medula do fêmur e tíbia de C57BL/6 GFP HET foram purificadas por gradiente de Ficoll (Histopaque) a 1000 x g por 15 minutos. Após duas lavagens em meio RPMI, as células foram ressuspensas em NaCl 0,15 M. No segundo dia após a infecção (dai) pelo PbA, foram injetadas 3,0 x 106 a 4,6 x 107 células de medula óssea (CMO) no plexo oftálmico dos camundongos devidamente anestesiados com ketamina/xylasina (protocolo 1078-1 CEEA/Unicamp). Alguns camundongos receberam apenas a injeção de células totais da medula óssea (CTMO), sem a purificação pelo gradiente de Ficoll. Foi avaliada a integridade da barreira hemato-encefálica, mediante a injeção de azul de Evans 1% no plexo oftálmico em camundongos transplantados e não transplantados com células mononucleares da medula óssea (CMoMO) no 2º dai. Após 3 e 4 dias do transplante, não houve proteção da barreira hemato-encefálica. Para constatação da presença das células de medula óssea no cérebro, outro grupo de camundongos infectados pelo PbA recebeu no 2º dai, 4,6 x 107 CMoMO provenientes de camundongos GFP. Após a manifestação de sinais clínicos da MC os camundongos foram sacrificados para remoção do cérebro e preparo de cortes em criostato. Foi possível observar, sob microscópio de fluorescência, a presença de células da medula no bulbo olfatório de camundongos com MC+. Também foram avaliadas a sobrevivência, a parasitemia e a ação coadjuvante do tratamento com cloroquina (0,8 mg/dia/animal). Todos os 38 animais do grupo controle morreram até o 7º dia de infecção pelo PbA (13,16% no 5º dia, 68,42% no 6º dia e 18,42 % no 7º dai). A injeção de células da medula óssea não interferiu na parasitemia dos animais. Apesar dos animais que superaram a fase aguda da malária cerebral morrerem em decorrência de hiperparasitismo e anemia, o tratamento com células da medula óssea (fração mononuclear ou células totais) mostrou-se capaz de ampliar a sobrevivência em 10 a 21 dias, resultados considerados promissores. As células da medula óssea promoveram a melhora clínica do quadro neurológico da malária cerebral.
Abstract: The cerebral malaria (CM) is the most serious complication of Plasmodium falciparum occurring in 1% of infections, and is responsible for more than two million of annual deaths among children under five years old. The experimental model for brain malaria currently used is the C57BL/6 mice infected by Plasmodium berghei ANKA (PbA). Administration of mononuclear population from bone marrow containing mainly mesenchymal stem cells and haematopoietic stem cells, is a promising strategy to treat neural damages caused by stroke. In this study was evaluated the effect of bone marrow mononuclear cells of transgenic mice C57BL/6 GFP HET transplanted into C57BL/6JUnib, infected by 106 parasitized erythrocyte PbA. Briefly, bone marrow mononuclear cells flushed from femur and tibia of C57BL/6 GFP HET were purified through Ficoll (Histopaque) gradient at 1000xg during 15 minutes. After two washes with RPMI medium, the cells were resuspended in NaCl 0,15M. On the second day after infection (DAI) by PbA, were injected into mice orbital plexus 3x10 6 to 4.6x107 cells of after anaesthesia with Ketamine/Xylazine (protocol nº 1078-1 CEEA/UNICAMP). Some mice received only injection of total bone marrow cells without purification on Ficoll gradient. The injection of bone marrow mononuclear cells on the second day of infection by PbA was unable in recovering the brain blood barrier after three or four days. In order to confirm the presence of bone marrow cells in the brain, another group of infected C57BL/6JUnib received on the second day after infection 4.6 x 107 bone marrow mononuclear cells from GFP mice. They were sacrificed between 6th and 8th day after onset of clinical signs of the CM. After removal and preparation of the brain for criostate cuts, was possible to observe, under fluorescence microscope, the presence of GFP bone marrow cells in the olfactory bulb on CM+ mice. It was evaluated survival, parasitemia and action of the adjuvant treatment of chloroquine (0.8 mg/day/animal) as well. All the 38 animals from control group died until 7th DAI. (13.16% at 5th DAI,68.42% at 6th DAI and 18.42% at 7th DAI). The transplantation of bone marrow cells did not affect the parasitemia. The bone marrow cells therapy infected mice by PbA was able to revert the clinical signs of cerebral malaria, increasing the survival up to 21 days.
Mestrado
Parasitologia
Mestre em Parasitologia
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TORRES, Marjorie Lujan Marques. "Efeito protetor da ração enriquecida com açaí (Euterpe oleracea) no quadro de malária cerebral experimental." Universidade Federal do Pará, 2018. http://repositorio.ufpa.br/jspui/handle/2011/10060.
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CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico
FAPESPA - Fundação Amazônia de Amparo a Estudos e Pesquisas
A malária cerebral (MC) é uma das complicações mais severas atribuídas à infecção pelo protozoário Plasmodium falciparum, ganhando destaque nas taxas de mortalidade infantil em áreas endêmicas. Esta enfermidade apresenta uma patogênese complexa e ainda pouco elucidada, estando associada a alterações cognitivas, comportamentais e motoras. Visando ampliar os conhecimentos a respeito desta patologia e procurando os benefícios atribuídos ao consumo diário de antioxidantes, o principal objetivo deste trabalho é avaliar o possível efeito protetor do fruto da Euterpe oleracea (açaí) durante a evolução do quadro de malária cerebral experimental (MCE) induzida em modelo murino por meio da inoculação da cepa ANKA de Plasmodium berghei (PbA). Para tal, utilizaram-se camungondos da linhagem albino suíço, os quais foram inoculados intraperitonealmente (i.p.) com 10⁶ de eritrócitos parasitados. Os animais (fêmeas e machos entre 4 a 6 semanas) foram divididos em quatro grupos, dentre os quais os grupos Açaí e PbA+Açaí foram mantidos com uma dieta exclusiva com ração enriquecida com açaí, e aos grupos Controle e PbA foram proporcionadas somente ração padrão durante os 22 dias de experimento. Para caracterização do quadro de MCE foram avaliados diversos parâmetros como o surgimento dos sinais clínicos, curva de sobrevivência, parasitemia (%), ganho de massa corpórea e permeabilidade vascular. Para avaliação das alterações comportamentais e locomotoras dos animais foi utilizado o protocolo SHIRPA. Observamos prolongamento de sobrevida dos animais infectados e tratados com dieta enriquecida com açaí, além de diminuição das alterações neurológicas decorrentes da exposição do parênquima cerebral. Este trabalho nos permitiu validar o desenvovimento do quadro de malária cerebral experimental (MCE) em modelo murino e avaliar o efeito neuroprotetor do açaí (Euterpe oleracea) no decorrer da doença.
Cerebral malaria (CM) is one of the most severe complications attributed to protozoal infection by Plasmodium falciparum, gaining prominence in infant mortality rates in endemic areas. It´s a complex pathogenesis and still little elucidated, being associated with cognitive, behavioral and motor changes. Aiming to broaden the knowledge about this pathology and looking for the benefits attributed to the daily consumption of antioxidants, the objective of this work is to evaluate the possible protective effect of Euterpe oleracea fruit (açaí) during evolution of experimental cerebral malaria (ECM) induced in murine model by means of inoculation of Plasmodium berghei (PbA), ANKA stain. For this, we used the Swiss line, which were inoculated intraperitoneally (i.p.) with 10⁶ of parasited erythrocytes. The animals (females and males between 4 and 6 weeks) were divided into four groups, among which Açaí and PbA+Açaí groups were maintained on a ration-exclusive diet enriched with açaí and the Control and PbA groups were given only standard ration during 22 days of experiment. To characterize the ECM framework, several parameters were evaluated such as the appearence of clinical signs, survival curve, parasitemia, body mass gain and vascular permeability. The SHIRPA protocol was used to evaluate the behavioral and locomotor changes in animals. We observed an extension of survival of the infected animals and treated with a diet enriched with acai berry, and decreased the neurological changes arising from the exposure of the cerebral parenchyma. This work allowed us to validate the development of the experimental brain malaria framework in murine model and evaluate the neuroprotective effect of Acai (Euterpe oleracea) in the course of the disease.
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Claessens, Antoine. "How Plasmodium falciparum malaria parasites bind to human brain endothelial cells." Thesis, University of Edinburgh, 2011. http://hdl.handle.net/1842/4897.
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Cerebral malaria is characterised by an accumulation of infected erythrocytes in the microvasculature of the brain. Plasmodium falciparum infected erythrocytes have been shown to bind to a Human Brain Endothelial Cell line (HBEC-5i) in vitro. This provides a model for the investigation of interactions between P. falcuparum and human brain endothelium. Currently neither the parasite adhesion ligands on infected erythrocytes, nor the host endothelial cell receptors necessary for this interaction have been identified. In this work, the identity of the host receptor on brain endothelial cells was addressed by binding assays of selected and unselected parasites on a wide range of malaria-associated host molecules. The identity of the parasite ligand was investigated by microarray analysis of parasites after selection for cytoadherence to HBEC-5i. The hypothesis being tested was that the gene encoding the parasite cytoadherence ligand would show significant upregulation in selected compared to unselected paarasites. The P. falciparum laboratory strains 3D7, HB3 and IT/FCR3 were selected for binding to HBEC-5i using a panning assay. Compared to unselected parasites, HBEC-5i selected parasites showed a distinct phenotype with reduced platelet-mediated clumping. There was no significant increase in binding of parasites to any of the known endothelial cytoadherence receptors for P. falciparum after selection on HBEC-5i. Binding inhibition assays with various antibodies and soluble receptors did not greatly block the adhesion of parasites to HBEC-5i except for heparin. Altogether, the receptor(s) mediating the interation with HBEC-5i remains unknown. In order to carry out transcriptional analysis of selected and unselected paarasites form all three parasite strains, it was necessary to update the existing microarray chip which is based on the 3D7 genome. This is because each parasite train has a unique repertoire of variant surface antigens (VSAs) including var, rif and stevor genes. Therefore, to fully analysis HB3 and IT genomes. Unique oligonnucleotide probes were then designed for each new sequence and the 3D7-based microarray chip was updated. Transcriptional analysis was then carried out on selected and unselected parasites of all strains. Microarray data clearly indicated that the most highly upregulated genes after selection were group A or group A-like var genes (HB3var3, 3D7_PFDOO2Oc, ITvar7 and ITvar19), showing 11 to over 100 fold upregulation in selected parasites. The rif gene adjacent to the upregulated var gene was also highly expressed. To a lesser extent some exported proteins like RESA-1, PfEMP3 or PHIST family members also showed increased transcription in HBEC-selected parasites (2-3 fold upregulation). Reverse transcriptase-PCR confirmed the upregulation of group A var genes in selected parasites, suggessted that the group A PfEMP1 variants are major candidate ligands for parasite binding to HBEC-5i. These findings are consistent with previous work showing an association between Group A var genes and cerebral malaria.
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McGown, Anne Dora. "Assessment of cerebral oxygenation using near infra-red spectroscopy in obstructive sleep apnoea and chronic obstructive pulmonary disease." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445942/.
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This thesis describes a set of studies of the use of near infrared spectroscopy to measure cerebral oxygenation in obstructive sleep apnea (OSA) and chronic hypoxia. Cerebral oxygenation depends on cerebral blood flow and arterial oxygen saturation. The hypothesis underlying these studies was whether measurement of cerebral oxygenation using near infra-red spectroscopy (MRS) gives additional valid information compared to measuring arterial oxygen saturation alone. We also hypothesized that this technique could be used to assess overnight cerebral oxygenation in sleep studies. Our first validation study in 13 subjects with significant OS A showed that the fall in cerebral tissue saturation (measured as tissue oxygenation index, TO I) during sleep apnoea is related to arterial saturation (Sa02) (p=0.012), apnoea duration (p=0.001) and sleep stage (p<0.001) in a multiple regression in 1036 apnoeas. We also demonstrated changes in cerebral blood volume (range 0.41 - 0.09 ml/lOOg) and cytochrome oxidase oxidation state (range 0.48 - 0.13uM) occurring during apnoeas in 8 of these subjects. In a second validation study in 8 subjects we demonstrated correlations between changes in TOI and both arterial saturation (p=0.001), apnoea duration (p=0.001) and cerebral blood flow velocity (p=0.012) measured using carotid Doppler. We derived area under the curve (AUC) measures and dip rates for TOI and Sa02 during overnight studies and compared them to conventional polysomnographic measures, showing significant correlations of pretreatment apnoea hypopnoea index (AHI) with dip rates for both TOI and Sa02. AUC TOI correlations with pretreatment AHI were weak. Mean AUC for TOI was 339.4 (161-675) and mean AUC for Sa02 was 308.5 (89-944). Mean 4% Sa02 dip rate was 32.6 (1.5-90.6) and mean 4% TOI dip rate was 24 (0.1-95.7). Pilot studies were also carried out on 11 subjects with chronic obstructive pulmonary disease (COPD) during oxygen challenge. Calculated cerebral blood volume measurements varied from 1.51 ml/lOOg to 3.65 ml/lOOg. Changes in TOI in response to supplementary oxygen in patients with COPD and chronic hypoxia are related to both cerebral blood volume (p=0.001) and arterial saturation (p=0.001). The most important new findings in these studies are that cerebral blood flow changes appear to exacerbate rather than compensate for arterial hypoxia during sleep apnoea, and so it is plausible that TOI measurement (which picks up both Sa02 and cerebral blood flow velocity (CBFV) changes) may be more closely related to changes in neuropsychological function than pulse oximetry. The changes in cerebral oxygenation are profound enough to affect intracerebral redox state measured as cytochrome oxidase oxidation. Pilot work in COPD patients suggests that changes in cerebral blood volume affecting cerebral oxygenation occur during supplementary oxygen administration. NIRS provides a non-invasive method of measuring cerebral oxygenation suitable for use in sleep studies, and during oxygen administration.
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Janßen, Marthe [Verfasser], and Iris [Akademischer Betreuer] Bruchhaus. "Influence of IL-12 cytokine family members on T cell differentiation in experimental cerebral malaria / Marthe Janßen. Betreuer: Iris Bruchhaus." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2012. http://d-nb.info/1027573231/34.
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Mohd, Nasir Mohd Hamzah. "Activation of endothelial cells and its potential involvement in blood-brain barrier damage in cerebral malaria : an in vitro study." Thesis, Keele University, 2015. http://eprints.keele.ac.uk/3252/.
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One of the severe complications of a Plasmodium falciparum infection is cerebral malaria (CM). CM is characterised by the accumulation of mature infected red blood cells (RBC) in the brain microvasculature. One of the consistent detrimental effects of sequestration is the breakdown of the blood-brain barrier (BBB), often with a fatal outcome in children in endemic areas. This study investigates the mechanisms underlying BBB breakdown secondary to sequestration, using immortalised human brain microvascular endothelial cells (tHBEC) as an in-vitro model of BBB and ITG-strain Plasmodium falciparum. First, the tHBEC monolayer was co-cultured with Plasmodium falciparum infected red blood cell (PRBC) or uninfected red blood cells (uRBC) control for 20 hours and the supernatant was recovered for subsequent analysis. The co-culture supernatants showed upregulation of inflammatory mediators (MCP-1 and IL-8) and a member of metalloproteases (ADAMTS-1, ADAMTS-4, MMP-2 and MMP-9) in the PRBC-tHBEC co-culture supernatants. The PRBC-tHBEC co-culture supernatants induced loss of endothelial cell monolayer integrity, represented by real time reduction in the transendothelial electrical resistance, measured using Electrical Cell-Substrate Impedance Sensing (ECIS™). The same supernatants also increased the permeability of tHBEC monolayer to the fluorescently labelled 40 kDa dextran showing leakage across the tHBEC monolayer. Interestingly, the loss of barrier function of tHBEC monolayer is partially inhibited by the addition of protease inhibitors GM6001 and rhTIMP-3. Prolonged exposure to PRBC-tHBEC co-culture supernatants reduced the level of vinculin. This study demonstrates that the interactions between PRBC and tHBEC induces activation of tHBEC and the release of proteases that contribute to BBB breakdown in CM, and could be a potential drug target for adjunct therapy in CM.
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Prapansilp, Panote. "Molecular pathological investigation of the pathophysiology of fatal malaria." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:e966a2f2-a37d-4586-b09e-2bb616e5dce2.
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Malaria remains one of the world's major health problems, especially in developing countries. A better understanding of the pathology and pathophysiology of severe malaria is key to develop new treatments. Different approaches have been used in malaria research including the in vitro co-culture models with endothelial cells and both murine and simian animal models. However these are open to controversy due to disagreement on their representativeness of human disease. Using human post-mortem tissue in malaria research is another important approach but is practically challenging, limiting the availability of post mortem samples from malaria patients. The work in this thesis had two main themes. First I examined the role of the endothelial signalling Angiopoetin-Tie-2 receptor pathway in malaria. Ang-2 has been shown to be a significant biomarker of severe and fatal malaria. I examined the tissue specific expression of proteins from this pathway in post-mortem brain tissues from fatal malaria cases, but found no difference between cerebral malaria and non-cerebral malaria cases. Ang-2 correlated with the severity of malaria in these patients. An attempt to examine the interaction of hypoxia and the Ang-Tie-2 pathway in vitro using a co-culture model of human brain endothelial cells was unsuccessful due to contamination of the cell line. The second part of the thesis aimed to utilise molecular pathology techniques including miRNA and whole-genome microarrays. I have shown for the first time that these can be successfully applied to human post-mortem tissue in malaria. First I used archival tissues to examine the microRNA signature in the kidney of patients with malaria associated renal failure. Second I optimised a protocol to preserve post mortem tissue for molecular pathology, from an autopsy study in Mozambique. Using the subsequent total mRNA transcriptomic data and bioinformatics analysis this work has expanded our knowledge of differential gene expression and the families of genes which are dysregulated in the brain in response to malaria infection.
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Fry, Andrew E. "Genome mapping of malaria resistance genes : the host ligands of PfEMP1." Thesis, University of Oxford, 2009. http://ora.ox.ac.uk/objects/uuid:df1ffe4b-ba67-4fc6-9024-b278b887d4f9.
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Erythrocytes infected by mature forms of the Plasmodium falciparum parasite adhere to other components of the vascular space, a behavior considered critical to the pathogenesis of severe malaria. Adhesion is mediated by the P. falciparum erythrocyte membrane protein 1 (PfEMP1), a highly variant antigen expressed by the parasite and subject to switching during the course of an infection. The host ligands of PfEMP1 include CD36, ICAM-1 and the ABO antigens. By employing a series of population- and family-based association studies from multiple African populations, we examined whether variation in the genes underlying these molecules affects susceptibility to severe malaria. Our results suggest that a common frameshift mutation in the ABO glycosyltransferase, responsible for blood group O, is associated with protection from severe malarial phenotypes (P=2x10⁻⁷), particularly severe malarial anaemia. However, we found no significant disease associations with variation in either the ICAM1 or CD36 genes. We focused on two particular functional polymorphisms, the missense ICAM-1Kilifi and the CD36 nonsense mutation T1264G. We genotyped both markers in around 10,000 individuals, but neither demonstrated an association with severe malarial phenotypes. Malaria has been a profound selection pressure shaping human genetic diversity. The last decade has seen the development of several haplotype-based methods to detect signatures of recent positive evolutionary selection. These techniques are potentially invaluable tools in our hunt for genetic variants that protect from life threatening malaria. We used simulations and empirical data from the International HapMap Project to demonstrate the validity of searching for long regions of haplotype homozygosity, as an approach to finding alleles undergoing selective sweeps. We analysed genetic data from a range of populations, particularly those utilized by HapMap, to investigate whether our candidate genes were associated with signals of recent positive selection. We characterized the distribution of a selection event associated with the CD36 1264G allele, focused in Central-West Africa, and demonstrated a novel signal of low population differentiation at the ABO gene, suggestive of longstanding balancing selection. Our work confirms that variation in the host ligands of PfEMP1 modulates severe malaria susceptibility, and highlights the value of using signals of selection, along with functional experiments and genetic association studies, to dissect the biology of severe malaria.
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Issitt, Richard William. "Quantification of lipid and leucocyte filtration and the effects on cerebral and renal injury markers and pulmonary function during cardiopulmonary bypass." Thesis, University of Southampton, 2017. https://eprints.soton.ac.uk/422268/.
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Background: Despite the extremely low mortality and morbidity rates of coronary artery bypass graft (CABG) surgery involving cardiopulmonary bypass (CPB), there are a number of pathological injuries believed to be due to the CPB circuit. Lipid Microemboli (LME) are produced when fats are released from bone marrow during a sternotomy, which then mix with blood in the pericardium during surgery. This blood is passed into the CPB circuit and reintroduced into the systemic circulation and is thought to promote an increased inflammatory response and ischaemia-inducing blockages. There are at present no adequate methods of dealing with this problem. Methods: A randomised controlled trial was undertaken to determine if a new Oxygenator, the RemoweLL, which contains a lipid and leucocyte filter, can effectively remove LME from the patient’s circulation compared with current gold standard CPB technologies and examine the effects on markers of cerebral, renal injury; neuron specific enolase, Cystatin C and pulmonary function. The Null hypothesis was that there would be no difference in peak neuron specific enolase concentrations. Results: The data presented in this Thesis provide the first biochemical evidence for a direct effect of LME upon neuron specific enolase release, which correlates in a linear fashion with increasing numbers of LME. The filtration of LME does not appear to significantly reduce systemic levels of activated leucocytes, which is reflected in similar pulmonary functions of those patients with and without LME filtration. However, there is evidence of a weak association towards renal protection with LME, with peak Cystatin C clearance lower than non-filtered patients. This met statistical trial stopping criteria. Conclusions: The RemoweLL CPB system removes significant numbers of LME compared to current CPB technology. Significant differences in the release of neuron specific enolase in the immediate postoperative period have been demonstrated. Furthermore, there is weak evidence towards improved clearance of Cystatin C. Further work is now planned to determine if LME filtration translates into longer-term neurocognitive and renal protection. The statistical differences between groups were so great from neuron specific enolase that the Ethics Committee advised early termination of the trial.
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Carpinter, Bárbara Albuquerque. "Indução de imunidade com extrato proteico de Plasmodium berghei NK65 contra o desenvolvimento de malária cerebral por Plasmodium berghei ANKA em modelo murino." Universidade Federal de Juiz de Fora (UFJF), 2018. https://repositorio.ufjf.br/jspui/handle/ufjf/7782.
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Devido à ampla distribuição da malária entre os continentes e ao elevado número de casos clínicos e óbitos registrados anualmente, o desenvolvimento de uma vacina antimalárica segura e eficaz contra a doença ainda é de extrema importância. Dentre os vários modelos propostos até o momento, aquelas compostas por parasitos vivos ou por extrato proteico têm sido as mais promissoras no desenvolvimento de imunidade antimalárica. Entretanto, ainda não claro se imunizações com cepas com baixo potencial de virulência seriam capazes de prevenir ou amenizar os sintomas associados à malária grave. Assim, o presente estudo teve como objetivo investigar se camundongos imunizados com extrato proteico de Plasmodium berghei NK65, cepa de baixa virulência e não indutora de malária cerebral nesse modelo, são protegidos contra o desenvolvimento de malária cerebral induzida pela cepa ANKA de Plasmodium berghei (PbA). Para isto, foram realizados dois ciclos de imunização utilizando extrato proteico de Plasmodium berghei associado ao adjuvante CPG-ODN, com intervalo de 21 dias, em camundongos fêmeas C57BL/6, com idade entre 6 e 8 semanas. Após 30 dias da última imunização foi realizado o desafio experimental utilizando a cepa ANKA de P. berghei e iniciado o acompanhamento diário dos animais para avaliação do seu quadro clínico e da carga parasitária. Diante da presença de sinais neurológicos (escore clínico < 5), os animais foram pesados e eutanasiados para realização da coleta de sangue, baço e cérebro, enquanto animais sem esses sinais continuaram por ser acompanhados diariamente e, então, sacrificados a partir do 13º dia. A partir das amostras coletadas, foram determinados os níveis de anticorpos sorológicos, a frequência da população celular esplênica (células T CD4+ e CD8+, e linfócitos B), níveis de citocinas teciduais e análise histopatológica do tecido nervoso. Observouse que 46% dos animais imunizados com extrato de PbN e 69% dos animais imunizados com extrato de PbA foram protegidos do desenvolvimento de malária cerebral e tiveram sua taxa de sobrevivência prolongada, entretanto, estes animais desenvolveram hiperparasitemia sanguínea, com níveis de até 38% de parasitos circulantes. Estes animais não apresentaram sinais clínicos neurológicos, o que foi confirmado macroscopicamente pela ausência de hemorragia e reduzida inflamação no cérebro em relação aos animais que evoluíram para malária cerebral. Histopatologicamente, os animais com hiperparasitemia apresentaram poucos leucócitos aderidos ao endotélio vascular e ausência de vasos obstruídos. Em relação aos níveis de citocinas (IL-10, TNF-α, IFN-) e número de linfócitos esplênicos (T CD4+ e CD8+, e linfócitos B), estes estiveram significativamente reduzidos nos animais que desenvolveram hiperparasitemia em relação aos que desenvolveram malária cerebral. Interessantemente, os animais imunizados foram capazes de reconhecer tanto antígenos homólogos quanto heterólogos ao utilizado durante o processo de imunização, porém, esses anticorpos pareceram não influenciar o padrão clínico apresentado pelos animais. Portanto, nosso estudo demonstra que imunizações com parasitos de baixa virulência podem induzir imunidade capaz de proteger contra cepas altamente virulentas, mas os fatores que medeiam essa proteção ainda precisam ser melhor investigados.
The broad distribution of malaria around of the globe and the large number of clinical cases/deaths attributed to this disease turns the discovery of a safe and effective malaria vaccine an essential tool to halt the spread of the disease. Vaccines focused on the use of live parasites and crude parasites antigens have shown good results on the induction of antimalarial immunity, although it is still not clear if immunizations with low virulent strains are capable to prevent the development of symptoms of cerebral malaria. This research aim to investigate if immunizations with crude antigen of Plasmodium berghei NK65 (PbN), a low virulence strain noninductive of cerebral malaria in C57BL/6 mice, are able to protect the animals against the development of cerebral malaria after challenge with Plasmodium berghei ANKA (PbA). Mice were immunized twice with crude antigen associated to CPG-ODN adjuvant. Thirty days after the second immunization animals were challenged with 105 red blood cells infected with P. berghei ANKA. Animals were daily monitored to evaluate the clinical score and parasitaemia levels. If the presence of neurological signs (score < 5) were detected, animals were euthanized and blood samples, spleen and brain were collected; animals without neurological commitment were followed daily until the 14 day post-infection. Antibodies and cytokines levels, splenic cellular population (T CD4+, T CD8+ and B lymphocytes) and histopathological analysis were performed. The results showed that 46% of the animals immunized with crude antigen of PbN and 69% of the animals immunized with crude antigen of PbA were protected from the development of cerebral malaria and had their survival rate prolonged, however, these animals developed hyperparasitaemia, with levels up to 38% of circulating parasites. These animals did not present neurological signs which were confirmed macroscopically by the absence of hemorrhage and reduce brain inflammation in relation to the animals that evolved to cerebral malaria. Histopathologically, the animals with hyperparasitaemia presented few adhered leukocytes in the vascular endothelium and absence of obstructed vessels. In relation to cytokine levels and number of splenic lymphocytes, these were significantly reduced in animals that developed hyperparasitism in comparison with those who developed cerebral malaria. Interestingly, the immunized animals were able to recognize both homologous and heterologous antigens used during the immunization process, however, these antibodies did not appear to influence at the clinical condition presented by the animals. Therefore, our study demonstrates that immunizations with low virulence parasites may induce immunity capable of protecting against highly virulent strains, but the factors that mediate this protection still need to be better investigated.
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Mandala, Wilson Lewis. "Immunological mechanisms that determine why some African children develop severe malarial anaemia while others develop cerebral malaria in response to infection with Plasmodium falciparum." Thesis, University of Liverpool, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485895.
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Introduction and Objectives: In Sub-Sahara Africa, malaria is an infectious disease caused mainly by Plasmodium falciparum. Most cases occur in children under five years of age. About 98 percent of the children suffer only from uncomplicated malaria (UCM) but a minority develop life-threatening severe malaria. Severe malaria encompasses three clinical syndromes; cerebral malaria (CM), severe malarial. anaemia (SMA) and severe respiratorY distress (SRD). The underlying reasons for this disparity are ·still unknown. The objective of this study was to investigate the immunological mechanisms that determine why some children develop CM while others develop SMA when infected with P. falciparum. Materials and Methods: Leucocyte and lymphocyte subsets were determined in Malawian children aged between 6 months and 5 years presenting with UCM, SMA and CM and in healthy controls. Activation and memory status of different cells were also determined. Sera Th1 and Th2 cytokines and percentages of cytokine-producing cells were measured for all groups. Results: CM patients were characterised by transient pan-lymphopenia, neutrophilia and thrombocytopenia while SMA patients were characterised by lymphocytosis. Interestingly, the percentage of T regulatory cells was lower in acute SMA patients compared to acute CM patients. Lymphocytes from CM patients were more activated and had a higher proportion with a memory phenotype compared with those from SMA patients, but monocytes in both groups showed a lack of activation markers. The sera of CM patients contained higher concentrations of both Th1 and Th2 cytokines. Surprisingly, CM patients had lower percentages of TNF-u, IFN-y and IL-2producing CD4+, CD8+ and yo T cells and NK cells compared to controls, whereas SMA patients had higher percentages of cytokine-producing lymphocyte subsets compared to controls. Both CM and SMA patients had low percentages of TNF-u and IL-6 producing monocytes compared to controls, but recovery of function was quicker in CM patients. Conclusion: Children with CM and SMA have cytokine profiles and lymphocyte activation and memory phenotypes which are consistent with the hypothesis that CM is a result of immunopathological response while SMA is a result of a na'ive response to the malaria infection. However, the panlymphopenia and apparently low proportion of cytokine-producing lymphocytes and monocytes in the CM group do not fit this hypothesis and require further investigation.
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Schmidt, Kim Ellen [Verfasser]. "Analysis of parasite-specific T cells and cellular interactions in the spleen during Plasmodium berghei induced experimental cerebral malaria / Kim Ellen Schmidt. Mathematisch-Naturwissenschaftliche Fakultät." Bonn : Universitäts- und Landesbibliothek Bonn, 2011. http://d-nb.info/1018326677/34.
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Fernandes, Priyanka Noel [Verfasser], and Ann-Kristin [Akademischer Betreuer] Mueller. "Differences in antigen presentation between sporozoite and parasitised-erythrocyte infections uncovers divergent mechanisms in the development of experimental cerebral malaria / Priyanka Noel Fernandes ; Betreuer: Ann-Kristin Mueller." Heidelberg : Universitätsbibliothek Heidelberg, 2016. http://d-nb.info/1180617630/34.
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Fernandes, Priyanka Noel Verfasser], and Ann-Kristin [Akademischer Betreuer] [Müller. "Differences in antigen presentation between sporozoite and parasitised-erythrocyte infections uncovers divergent mechanisms in the development of experimental cerebral malaria / Priyanka Noel Fernandes ; Betreuer: Ann-Kristin Mueller." Heidelberg : Universitätsbibliothek Heidelberg, 2016. http://d-nb.info/1180617630/34.
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Fernandes, Priyanka [Verfasser], and Ann-Kristin [Akademischer Betreuer] Müller. "Differences in antigen presentation between sporozoite and parasitised-erythrocyte infections uncovers divergent mechanisms in the development of experimental cerebral malaria / Priyanka Noel Fernandes ; Betreuer: Ann-Kristin Mueller." Heidelberg : Universitätsbibliothek Heidelberg, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:16-heidok-219812.
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Daniels, Rachel Fath. "Genomic Tools Reveal Changing Plasmodium falciparum Populations." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10931.
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A new era of malaria eradication programs relies on increased knowledge of the parasite through sequencing of the Plasmodium genome. Programs call for re-orientation at specific epidemiological markers as regions move from control towards pre- and total elimination. However, relatively little is known about the effects of intervention strategies on the parasite population or if the epidemiological cues correspond to effects on the parasite population. We hypothesized that genomic tools could be used to track population changes in Plasmodium falciparum to detect significant shifts as eradication programs apply interventions. Making use of new whole-genome sequencing data as well as GWAS and other studies, we used SNPs as biological markers for regions associated with drug resistance as well as a set of neutral SNPs to identify individual parasites. By utilizing tools developed as proxy for full genomic sequencing of the human pathogen Plasmodium falciparum, we characterized and tracked parasite populations to test for changes over time and between populations. When applied to markers under selection - those associated with reduced antimalarial drug sensitivity - we were able to track migration of resistance-associated mutations in the population and identify new mutations with potential implications for resistance. Using a population genetic analysis toolbox to study changes in neutral allele frequencies in samples from the field, we found significant population changes over time that included restricted effective population size, reduced complexity of infections, and evidence for both clonal and epidemic propagation of parasites.
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Keita, Alassane Ndeye Sokhna. "Etude d'un modèle de neuropaludisme chez le rat et évaluation des effets pharmacologiques d'un candidat-médicament." Thesis, Toulouse 3, 2016. http://www.theses.fr/2016TOU30379.
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Le neuropaludisme (NP) est la forme la plus mortelle du paludisme. C'est une complication neurologique observée uniquement dans les cas d'infection par Plasmodium falciparum, principalement chez les enfants de moins de 5 ans vivant en Afrique Sub-saharienne, et les adultes non-immuns, notamment les femmes enceintes et les touristes visitant les zones d'endémie. Les signes cliniques sont à présent bien décrits (prostration, convulsions répétées, difficultés respiratoires, coma,...), mais les mécanismes physiopathologiques conduisant au NP sont encore mal définis. Leur élucidation est rendue difficile par la localisation cérébrale de la pathologie du vivant des patients et la faible disponibilité des données nécropsiques. Bien que l'accès aux tissus humains soit limité en nombre, les résultats d'autopsie ont permis d'établir que le NP résulte d'une séquestration des globules parasités au niveau de l'endothélium intra-vasculaire, associée à une forte réaction immunitaire. La stratégie de prise en charge du NP combine un traitement étiologique à base de dérivés d'artémisinine, ou de quinine et un traitement adjuvant symptomatique destiné à pallier à la défaillance multiorganique qui est à l'origine de l'issue fatale souvent observée. Le modèle de NP expérimental actuellement le plus utilisé est le modèle souris infecté par P. berghei ANKA. La pertinence de ce modèle est toutefois remise en cause en raison notamment des différences histo-pathologiques observées par rapport à la forme humaine. En effet, les souris manifestant les symptômes du NP ne présentent que très rarement le phénomène de séquestration, caractéristique majeure du NP chez l'Homme. Par ailleurs, comparativement à la réponse immunitaire de la souris, le modèle rat s'est également révélé plus proche de la réaction de l'Homme, dans le cas d'une autre parasitose, la schistosomose. L'objectif de la première partie du projet thèse a donc été la mise en place et l'évaluation d'un modèle alternatif de NP chez le rat. Ainsi un modèle de NP chez le rat Sprague Dawley infecté par la souche murine P. berghei K173 a été caractérisé sur les plans clinique, biologique (paramètres hématologiques et biochimiques),histopathologique et du profil cytokinique (cytokines cérébrales et sériques). La forte similarité des symptômes et des lésions associées au NP du rat Sprague Dawley infecté par P. berghei K173 par rapport au NP humain permet de valider la pertinence de ce modèle pour l'étude de la physiopathologie du NP. L'objectif de la deuxième partie de mon projet de thèse a été d'évaluer les effets pharmacologiques d'un candidat-médicament, l'isoflurane, pour le traitement adjuvant du NP. Ce composé présente l'avantage d'être déjà utilisé chez l'Homme à d'autres fins thérapeutiques et dispose donc d'une autorisation de mise sur le marché. Les résultats obtenus montrent une efficacité nette de l'isoflurane avec une rémission totale des signes de paralysie pour 47.8% des rats traités ainsi qu'un gain de survie des rats NP traités de 2 à 10 jours par rapport aux rats NP non traités. Ce gain de survie des animaux traités pourrait permettre un allongement de la fenêtre du temps de traitement étiologique, améliorant ainsi sensiblement le pronostic du NP. L'isoflurane, dont le mécanisme d'action semble être la réversion de la séquestration des globules parasités, limite les complications neurologiques souvent responsables de séquelles liées au NP. Des études ultérieures permettront d'optimiser ce nouveau protocole de traitement adjuvant du NPCerebral malaria (CM) is the most deadly form of malaria. It is a neurological complication observed only in cases of infection with Plasmodium falciparum that affects mainly children under five years living in Sub-Saharan Africa and non-immune adults including pregnant women and tourists visiting endemic areas. Although clinical signs are well described (prostration, respiratory distress convulsions, coma), the pathophysiological mechanisms leading to CM are still unclear. Their elucidation in vivo is made difficult by the cerebral location and the low availability of autopsy data. Instead of limited access to human tissues, autopsy results have shown that CM results from a strong immune response linked to sequestration of infected red blood cells in the intravascular endothelium. Cerebral malaria management combines an etiological treatment with artemisinin derivatives or quinine and adjunct treatment of the multi-visceral failures, responsible of fatal outcome. P. berghei ANKA-infected mouse is widely used as experimental murine model of CM. However the relevance of this model is still questioned because of the histopathologic differences from the human form. Indeed, CM mice rarely exhibit the red blood cell sequestration that is a major feature of human CM. Furthermore, compared to mouse, the rat displays a closer immune response to human in Schistosoma infection. This PhD research project first aimed to implement and assess an alternative rat model of CM. The clinical, biological, histo-pathological features as well as the cytokine profiling of an experimental model of CM were characterized in Sprague Dawley rats infected with P. berghei strain K173. The strong similarity of the symptoms and lesions observed in this model with those reported in human CM confirms its high relevance. The second objective of this thesis project was to assess the pharmacological effects of a drug-candidate in adjunct treatment of CM. Results demonstrated a strong efficacy of the molecule tested with 47.8% of the treated CM rats showing total remission. Moreover we observed a 2- to 10-day survival gain in the treated CM rats group compared to the non-treated CM rat group. Preliminary data suggest that this drug-candidate may reverse the endothelial sequestration of parasitized red blood cells and so limit the neurological sequels related to CM. It is anticipated that the gain in survival associated with this drug-candidate use will extend the window of the etiological treatment time, thus significantly improving the global prognosis of CM. Further studies are needed to optimize this adjunct CM treatment protocol
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Ikefuti, Priscilla Venâncio. "Associação entre variáveis meteorológicas, índice climático, fatores socioeconômicos e mortalidade por doenças do aparelho circulatório (acidente vascular cerebral e embolia pulmonar) no município de São Paulo - SP." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/8/8135/tde-13022017-114517/.
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Com a transição epidemiológica no Brasil, as doenças crônicas passaram a ser responsáveis pelo maior número de óbitos entre homens e mulheres. Entre os componentes que definem o estado de saúde humana, alguns do contexto geográfico, como clima local e fatores socioeconômicos, parecem influenciar na mortalidade por doenças do aparelho circulatório, tais como no acidente cerebral vascular (AVC) e na embolia pulmonar (EP). O objetivo principal deste trabalho foi verificar a influência do contexto geográfico (variáveis meteorológicas, índice climático e fatores socioeconômicos) na mortalidade por doenças do aparelho circulatório (AVC e EP) no município de São Paulo, no período de 2002 a 2011. Para analisar a associação da mortalidade com as variáveis meteorológicas foi utilizado um modelo linear generalizado empregando-se o método de Poisson e os modelos de lags distribuídos. Espacialmente a associação da mortalidade com as variáveis socioeconômicas foram testadas utilizando-se os modelos de regressão espacial OLS e GWR. Como resultado encontramos que tanto o frio quanto o calor são fatores de risco para todos os tipos de AVC e EP, com risco maior dependendo do tipo em homens e mulheres. Espacialmente os valores mais elevados do risco relativo (RR) da mortalidade por AVC estavam concentrados nas regiões periféricas do municipio de São Paulo, o que coincidiu com as áreas de menor renda per capita e vegetação e maior porcentagem de população preta. Já com relação à distribuição espacial dos altos valores de RR por EP esses estavam presentes principalmente na região central do município. Concluindo, a nossa pesquisa gerou grande quantidade de resultados que mostram que tanto as variáveis ambientais como socioeconômicas têm influência na mortalidade por algumas doenças do aparelho circulatório. Tendo em vista que o atendimento de urgência para os casos de AVC e EP pode evitar óbitos e sequelas graves, a melhor compreensão da importância do contexto geográfico pode permitir o desenvolvimento de sistemas de alertas junto aos serviços de atendimento de urgência e o direcionamento de campanhas para a prevenção dos fatores de risco evitáveis.With the epidemiological transition in Brazil, chronic diseases are now responsible for more deaths among men and women. Among the components that define the state of human health, some geographical context, as local climate and socioeconomic factors appear to influence the mortality from circulatory diseases, such as in stroke and pulmonary embolism (PE). The main objective of this study was to investigate the influence of the geographical context (meteorological variables, climate index and socioeconomic factors) in mortality from cardiovascular diseases (stroke and PE) in São Paulo, between 2002 to 2011. In order to analyze the association of mortality with the meteorological variables we used a generalized linear model using the Poisson distribution and distributed lag non linear models. Spatially the association of mortality with socioeconomic variables were tested using the spatial regression models OLS and GWR. As a result we found that both the cold and the heat are risk factors for all types of stroke and PE with a higher risk depending on the type of men and women. Spatially the highest values of relative risk (RR) for stroke mortality were concentrated in the outskirts of the city of São Paulo, which coincided with areas of lower per capita income and vegetation and higher percentage of black population. In relation to spatial distribution of high values of RR PE by these were present mainly in the inner area. In conclusion, our research has generated a lot of results that show that both environmental and socioeconomic variables influence on mortality from some diseases of the circulatory system. In view of the urgent care for stroke and PE cases can avoid serious sequelae and deaths, a better understanding of the importance of geographic context may allow the development of warning systems at the urgent care services and targeting campaigns for the prevention of avoidable risk factors.
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Dormoi, Jérôme. "Statines et paludisme." Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM5025.
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Seulement 1 à 3% des cas de paludisme dégénèrent en NP. Cependant, les séquelles à long termes touchent 3 à 10% des adultes et 25% des enfants et ces personnes présentent des déficits cognitifs notamment au niveau de l'apprentissage. Au niveau de l'armée française, ce sont 15 000 militaires qui sont exposés chaque année dans les zones impaludées, avec au moins 350 accès palustres mais surtout 1 à 2 morts chaque année.Dans le but de lutter contre P. falciparum mais aussi diminuer les séquelles dans le cas du NP deux molécules ont été étudiées. D'une part, l'atorvastatine (AVA) et d'autre part le bleu de méthylène (BM). Les données, précédemment publiées, ont montré l'efficacité de l'AVA non seulement comme antibactérien, antiviral ou antiparasitique mais aussi comme modulateur de l'immunité et adjuvant potentiel pour les antipaludiques actuels. Le BM est un antipaludique qui jusqu'ici présentait une voie de synthèse avec métaux lourds. C'est une nouvelle voie de synthèse sans métaux lourds et une efficacité démontrée qui nous ont incités à étudier cette molécule.Pour estimer l'efficacité de l'AVA et du BM en association avec les antipaludiques actuels nous avons successivement testé ces molécules dans un modèle in vitro (micro test isotopique simplifié) contre P. falciparum, puis dans un modèle murin de neuropaludisme en utilisant des souris C57BL/6N infectées avec Plasmodium berghei. Un gain d'efficacité a été observé en associant l'AVA ou le BM avec les antipaludiques contre P. falciparum mais aussi une protection par rapport au NP chez les souris traitées par les associations. Le BM protégeant aussi bien contre le paludisme simple que le NPOnly 1 to 3% of malaria infections turn into CM. Meanwhile, long term neurological sequelae range from 3 to 10 % in adults and 25% of child survivors present long term cognitive impairments. In a military framework, there are 15 000 soldiers localized in endemic malaria areas, with at less 350 infection cases giving clinical malaria syndrome but mainly 2 deaths each year.In the aim to fight against P. falciparum but also to decrease sequelae related to CM, two molecules were studied. In one hand, atorvastatin (AVA) and in the other hand methylene blue (MB). AVA is a synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (3HMG-CoA) reductase used in the treatment of hypercholesterolemia. Previous data, reported in numerous articles support the efficacy of AVA not only as antimicrobial, antiviral or antiparasitic agent but also as immune system modulator and potential adjuvant in vitro for common antimalarial drugs. BM is an antimalarial drug which until now had a synthesis pathway with heavy metals. It is a new synthesis pathway without heavy metals and an efficacy demonstrated which encouraged us to study this molecule.To evaluate AVA and BM efficacies in combination with common antimalarial drugs, we successively tested these molecules in an in vitro model (simplified isotopic microtest) against P. falciparum, then in experimental cerebral malaria using C57BL/6N mice infected with Plasmodium berghei. An increased efficacy was observed when AVA or MB is associated with common antimalarial drugs against P. falciparum but also a protection against CM in mice treated by drugs combinations. MB protects against malaria but also CM
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Rodriguez, Adriana Alejandra Marin. "Avaliação do álcool perílico como potencial antimalárico em Plasmodium falciparum e Plasmodium berghei." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-22022016-162207/.
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A malária mata mais de um milhão de pessoas por ano, sendo uma das doenças infecciosas mais relevantes e um grande problema de saúde pública. Além disso, o surgimento de cepas resistentes aos quimioterápicos utilizados faz necessário o estudo de novos alvos para tratamentos contra esta doença. No nosso laboratório foi demonstrada a biossíntese de isoprenóides, em P. falciparum pela via MEP. Sabe-se que substâncias inibidoras da biossíntese de isoprenóides, dentre essas os terpenos, apresentam atividade antimalárica. Levando em consideração o anterior, nós avaliamos o potencial antimalárico do álcool perilico (POH) em P. falciparum e P. berghei. Nossos resultados demonstraram que o POH teve efeito inibitório contra o crescimento do P. falciparum in vitro, nas cepas 3D7 e K1 com uma IC50 de 4,8 ± 0,5 μM, e 10,41±2,33 μM, respectivamente. Além disso, o POH não teve efeito tóxico na linhagem celular Vero. Ainda, Comprovamos que o POH inibiu a farnesilação de proteinas entre 20 e 37 KDa de P. falciparum. Por outro lado, os experimentos in vivo não mostraram eficácia do tratamento do POH contra PbGFP em camundongos Balb/c. Em contraste, foi demostrada a eficácia do POH na de malária cerebral experimental (MCE), , indicando uma redução na taxa de incidência da MCE no grupo tratado com POH, comparado o não tratado ( P<0,05). Além disso, o POH reduziu a inflamação no cérebro dos animais tratados, uma vez que teve uma redução significativa na adesão de leucócitos aos vasos cerebrais (P<0.001), como também, o numero de hemorragias foi menor comparados com os animais não tratados. (P<0.0001). Portanto, os resultados obtidos nesta pesquisa abrem novas alternativas no estudo do mecanismo de ação do POH como um terpeno com grande potencial para tratar MC.Malaria kills over one million people a year worldwide, and is one of the most important infectious diseases and a major public health problem. Furthermore, the emergence of resistant strains to chemotherapeutic agents used, make it necessary to study new targets for treatments against this disease. In our laboratory we have demonstrated the isoprenoids biosynthesis in P. falciparum, by the MEP pathway. It is known that the substances that inhibit isoprenoid biosynthesis, among these terpenes, have antimalarial activity in vitro and in vivo. Considering this, we evaluate the antimalarial potential of PA (POH) in P. falciparum and P. berghei. Our results showed that the POH had inhibitory effect against the growth of strains 3D7 and K1 of P. falciparum in vitro, with an IC50 of 4.8 μM ± 0.5, and 10.41 ± 2.33 μM, respectively. Furthermore, the POH had no toxic effect on cell line Vero. Moreover, the POH proved that inhibited proteins farnesylation from 20 to 37 kDa of P.falciparum. On the other hand, in vivo experiments did not show efficacy on treatment against POH PbGFP in BALB/c mice. In contrast, the effectiveness of POH in the experimental cerebral malaria (MCE) was demonstrated, indicating a reduction in the incidence rate of MCE in the group treated with POH, compared with of untreated animals (P <0.05). In addition, the POH reduced inflammation in the brain of treated animals, since it had a significant reduction in leukocyte adhesion to cerebral vessels (P <0.001), as also the number of bleeding was lower compared to untreated animals (P<0.0001). Therefore, the results obtained in this work provide new alternatives to study the POH\'s mechanism of action as a terpene with great potential to treat MC.
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Cola?o, Eliete Moreira. "Avalia??o eletromiogr?fica de m?sculos inspirat?rios em hemipar?ticos." Universidade Federal do Rio Grande do Norte, 2009. http://repositorio.ufrn.br:8080/jspui/handle/123456789/16677.
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Made available in DSpace on 2014-12-17T15:16:06Z (GMT). No. of bitstreams: 1
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Previous issue date: 2009-07-22The objective was measured by surface electromyography (EMGs), the activity of inspiratory muscles during incremental test in subjects with hemiparesis and show its correlation with the Functional Independence Measure (FIM). Were included in the study 32 individuals hemiparetics and 14 healthy as control group. We performed an evaluation of lung function and anthropometric data. The EMGs were performed during the incremental test with Threshold ? (15, 30, 45 and 60% of MIP) and during maximal inspiratory pressure (MIP). The electromyographic findings were calculated by the signal amplitude (RMS). All data were initially analyzed by Kolmogorov-Smirnov, the anthropometric characteristics of both groups were tested with the Levene and then intra-subject analysis (hemiparetic hemithorax and healthy hemithorax) and inter-group analysis (experimental group and control group) by paired and non-paired Student t tests and Pearson correlation. In intra-subject comparison was observed less activation (p <0.01) of the sternocleidomastoid muscle, scalene and diaphragm paretic side in both sexes - for the Threshold ? incremental test (15, 30, 45 and 60% of the MIP) and during maximal inspiratory pressure (MIP). In inter-group comparison, there was reduced activity in the diaphragm and the scalene, in hemiparetics males and females, respectivelly, during the same test. Our results demonstrate the existence of reduced electromyographic activity of inspiratory muscles in hemiparetics, including changes between different genders and suggests the need of further studies to assess the effects of specific training of inspiratory muscles.
O objetivo do estudo foi avaliar atrav?s da eletromiografia de superf?cie a ativa??o dos m?sculos inspirat?rios durante o teste incremental em indiv?duos com sequela decorrente de acidente vascular encef?lico (hemiparesia) e correlacionar com a Medida de independ?ncia Funcional (MIF). Foram inclu?dos no estudo 32 indiv?duos hemipar?ticos e 14 saud?veis como grupo controle. Foi realizada uma avalia??o da fun??o pulmonar e dos dados antropometricos. A EMGs realizou-se durante o teste incremental com Threshold? (15, 30, 45 e 60% da PImax) e durante press?o inspirat?ria m?xima (PImax). Os achados eletromiogr?ficos foram calculados por meio da da amplitude do sinal (RMS). Todos os dados foram inicialmente analisados pelo teste de Kolmogorov-Smirnov, as caracter?sticas antropom?tricas dos dois grupos foram submetidas ao teste de Levene e em seguida realizadas an?lises intra-sujeitos (hemit?rax hemipar?tico e o contralateral) e an?lises inter-grupos (grupo experimental e grupo controle), utilizando os testes t de Student pareado e n?o pareado e correla??o de Pearson. Na compara??o intrasujeitos observou-se menor ativa??o (p<0,01) dos m?sculos esternocleidomastoid?o, escaleno e diafragma do lado par?tico em ambos os sexos durante o teste incremental com Threshold? (15, 30, 45 e 60% da PImax) e durante press?o inspirat?ria m?xima. Na compara??o inter-grupos, houve menor atividade do diafragma em hemipar?ticos e do escaleno em hemipar?ticas durante mesmo teste. Nossos resultados demonstram a exist?ncia de redu??o da atividade eletromiogr?fica dos m?sculos inspirat?rios em hemipar?ticos, apresentando inclusive altera??es distintas entre os sexos e sugere a necessidade de novos estudos que avaliem os efeitos do treinamento espec?ficos dos m?sculos inspirat?rios.
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Camara, Aissata. "Plantes médicinales guinéennes : validation de l'effet antipaludique et impact sur la modulation de l'immunité." Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30028.
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Le paludisme demeure la première préoccupation médicale de bien des pays africains dont la Guinée où la quasi-totalité de la population est exposée au risque d'infection avec une prévalence estimée à 15% chez les enfants de moins de 5 ans. En dehors de la médecine conventionnelle, la pharmacopée et la médecine traditionnelle guinéennes constituent des recours fréquents dans la gestion du paludisme par les familles. A cet égard, des enquêtes ethnobotaniques ont permis de recenser et de collecter de nombreuses plantes médicinales parmi lesquelles Terminalia albida, Desmodium velutinum et Rourea minor. Dans le cadre d'une validation des usages traditionnels, ces plantes ont été évaluées in vitro avec la souche chloroquino-résistante PfK1 et in vivo dans deux modèles murins à Plasmodium chabaudi chabaudi pour le paludisme simple, et à Plasmodium berghei ANKA pour le neuropaludisme. Les résultats obtenus ont permis de mettre en évidence le potentiel antipaludique de T.albida. En outre, la comparaison de deux extraits de T. albida issus de deux régions différentes de Guinée, a permis de mettre en évidence des efficacités in vitro et in vivo différentes selon la provenance de la plante. Afin de comprendre les mécanismes d'action de T. albida dans le modèle de neuropaludisme, les capacités anti-inflammatoires et anti-oxydantes de la plante ont été étudiées in vivo et in vitro dans des conditions inflammatoires. In vivo, l'administration de l'extrait de T.albida a permis de limiter le recrutement des lymphocytes T et l'expression des marqueurs pro-inflammatoires dans le cerveau des souris traitées. Ces propriétés ont été confirmées in vitro dans un modèle inflammatoire non palustre. In vitro, T.albida a également démontré une remarquable activité dose-dépendante de neutralisation des espèces réactives de l'oxygène. Ainsi, les propriétés anti-inflammatoires et anti-oxydantes de T.albida participent à la résolution du neuropaludisme dans le modèle d'infection à P. berghei ANKA. Des investigations phytochimiques ont permis d'identifier trente-huit composés dans l'écorce de la tige de T. albida. Parmi elles, plusieurs molécules déjà identifiées peuvent être responsables des différentes activités biologiques observées, notamment les tanins et les triterpénoïdes. Enfin, des investigations botaniques ont permis de fournir des éléments caractéristiques permettant de déterminer la provenance de T. albida et de mettre en évidence l'influence de l'écosystème sur la production des métabolites secondaires dans les espèces de Terminalia récoltées à différents endroits. Ces résultats confirment l'effet antipaludique de T. albida et valident son usage traditionnel. Cependant, des études complémentaires sont nécessaires pour identifier plus précisément les molécules actives. Les activités anti-inflammatoires et anti-oxydantes de T. albida démontrées dans ce travail présentent également un intérêt pour la prise en charge de nombreuses pathologies, autres que le paludismeMalaria remains the primary medical concern in many African countries, including Guinea, where almost the entire population is at risk of infection with an estimated prevalence of 15% among children under 5 years of age. Apart from conventional medicine, Guinean pharmacopoeia and traditional medicine are frequent uses in the management of malaria by families. In this respect, previous ethnobotanical surveys have identified and collected many medicinal plants in Guinea, including Terminalia albida, Desmodium velutinum and Rourea minor. As part of a validation of traditional uses, these plants were evaluated in vitro with the chloroquine resistant strain PfK1 and in vivo in two murine models: Plasmodium chabaudi chabaudi for uncomplicated malaria, and Plasmodium berghei ANKA for cerebral malaria. The results obtained highlighted the antimalarial effect of T. albida. In addition, the comparison of two extracts of T. albida from two different regions of Guinea revealed different in vitro and in vivo efficacy depending on the origin of the plant. In order to understand the mechanisms of action of T. albida in the cerebral malaria model, the plant's anti-inflammatory and antioxidant capacities were studied in vivo and in vitro under inflammatory conditions. In vivo, the administration of T. albida extract limited T cell recruitment and expression of pro-inflammatory markers in the brains of treated mice. These properties were confirmed in vitro in a non-malarial inflammatory model. In vitro, T. albida also demonstrated a remarkable dose-dependent activity by neutralizing reactive oxygen species. Thus, the anti-inflammatory and antioxidant properties of T. albida contribute to the resolution of cerebral malaria in the P. berghei ANKA infection model. Phytochemical investigations have identified thirty-eight compounds in the bark of the stem of T. albida. Among them, several molecules already identified may be responsible for the different biological activities observed, including tannins and triterpenoids. Finally, botanical investigations provided characteristic elements to determine the origin of T. albida and to highlight the influence of the ecosystem on the production of secondary metabolites in Terminalia species collected at different locations. These results confirm the antimalarial effect of T. albida and validate its traditional use. However, further studies are needed to identify more precisely the active molecules. The anti-inflammatory and antioxidant activities of T. albida demonstrated in this work are also of interest for the management of many diseases, other than malaria
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Cabibel, Vincent. "Mécanismes physiopathologiques de l’altération de la commande motrice dans la bronchopneumopathie chronique obstructive." Thesis, Montpellier, 2020. http://www.theses.fr/2020MONT4004.
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La bronchopneumopathie chronique obstructive (BPCO) est une pathologie respiratoire chronique présentant de nombreuses comorbidités. La faiblesse musculaire, caractérisée par une diminution de la force musculaire (de 30% en moyenne par rapport aux sujets sains) en dehors de tout état de fatigue, est une complication majeure de la pathologie impactant très largement la vie des patients. La production de force dépend de deux processus physiologiques : la capacité du système nerveux à activer le muscle et la capacité du muscle à réaliser une contraction. Ces deux processus sont défaillants dans la BPCO. Cependant, si les altérations du muscle du patient atteint de BPCO sont bien documentées, les mécanismes impliqués dans la production d’une commande motrice non-optimale sont quant à eux mal compris. Le but de ce travail de thèse était donc d’identifier les mécanismes responsables de l’altération de la commande motrice chez les patients atteints de BPCO. Nos travaux ont confirmé l’existence d’une commande motrice réduite, par rapport à des sujets sains. L’utilisation de neuromodulation chez les patients n’a pas permis d’augmenter l’excitabilité corticale et la commande motrice, donc d’évaluer s’il existait des réseaux neuronaux latents chez les BPCO. Nous avons démontré qu’il existait une altération de la connectivité entre les hémisphères cérébraux des patients par rapport à des sujets sains et que l’activation des aires motrices ipsilatérales des patients n’était pas altérée lors de la production de force. Enfin, nous avons montré que les traitements psychoactifs, prescrits pour traiter le syndrome anxio-dépressif, étaient fortement prévalents dans la BPCO. Nous avons montré qu’ils induisent une réduction de l’excitabilité et une augmentation de l’inhibition au niveau cortical, ainsi qu’une altération de la commande motrice. Cependant, l’absence de répercussions sur la force volontaire suggère la présence d’un mécanisme compensatoireChronic obstructive pulmonary disease (COPD) is a respiratory pathology associated with several repercussions. The muscle weakness, characterized by a reduction of the muscle strength (30% on average, compared to healthy individuals) without any fatigue, is a major repercussion of the disease. Strength production relies on two physiological processes: the nervous system ability to activate the muscles and the capacity of the muscles to perform a contraction. Both these processes are impaired in COPD. However, while the muscles alterations are well documented, the mechanisms involved in the production of a non-optimal motor command are not fully understood. The aim of this thesis was therefore to identify the mechanisms involved in the motor command alteration in COPD patients. Our work confirmed the existence of a reduced motor command in COPD, compared to healthy subjects. The application of neuromodulation in patients failed to increase cortical excitability and motor command, and consequently to determine whether latent motor networks exists in COPD. We then demonstrated that the connectivity was altered between the brain hemispheres in COPD and that the ipsilateral motor areas activation was preserved in patients during force generation. Finally, we observed that psychoactive medications, prescribed to manage anxiety and depression, we highly prevalent in COPD. The consumption of these medications was associated with reduced excitability and increased inhibition at the cortical level and with an altered motor command. However, the absence of repercussion on strength suggests the existence of a compensatory mechanism