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VEGF Promotes Malaria-Associated Acute Lung Injury in Mice

EPIPHANIO, Sabrina; CAMPOS, Marta G.; PAMPLONA, Ana; CARAPAU, Daniel; PENA, Ana C.; ATAIDE, Ricardo; MONTEIRO, Carla A. A.; FELIX, Nuno; COSTA-SILVA, Artur; MARINHO, Claudio R. F.; DIAS, Sergio; MOTA, Maria M.
Fonte: PUBLIC LIBRARY SCIENCE Publicador: PUBLIC LIBRARY SCIENCE
Tipo: Artigo de Revista Científica
ENG
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56.37%
The spectrum of the clinical presentation and severity of malaria infections is broad, ranging from uncomplicated febrile illness to severe forms of disease such as cerebral malaria (CM), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pregnancy-associated malaria (PAM) or severe anemia (SA). Rodent models that mimic human CM, PAM and SA syndromes have been established. Here, we show that DBA/2 mice infected with P. berghei ANKA constitute a new model for malaria-associated ALI. Up to 60% of the mice showed dyspnea, airway obstruction and hypoxemia and died between days 7 and 12 post-infection. The most common pathological findings were pleural effusion, pulmonary hemorrhage and edema, consistent with increased lung vessel permeability, while the blood-brain barrier was intact. Malaria-associated ALI correlated with high levels of circulating VEGF, produced de novo in the spleen, and its blockage led to protection of mice from this syndrome. In addition, either splenectomization or administration of the anti-inflammatory molecule carbon monoxide led to a significant reduction in the levels of sera VEGF and to protection from ALI. The similarities between the physiopathological lesions described here and the ones occurring in humans...

Defibrotide Interferes With Several Steps of the Coagulation-Inflammation Cycle and Exhibits Therapeutic Potential to Treat Severe Malaria

Francischetti, Ivo M. B.; Oliveira, Carlo J.; Ostera, Graciela R.; Yager, Stephanie B.; Debierre-Grockiego, Francoise; Pereira, Vanessa Carregaro; Jaramillo-Gutierrez, Giovanna; Hume, Jen C. C.; Jiang, Lubin; Moretz, Samuel E.; Lin, Christina K.; Ribeiro,
Fonte: LIPPINCOTT WILLIAMS & WILKINS; PHILADELPHIA Publicador: LIPPINCOTT WILLIAMS & WILKINS; PHILADELPHIA
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
56.42%
Objective-The coagulation-inflammation cycle has been implicated as a critical component in malaria pathogenesis. Defibrotide (DF), a mixture of DNA aptamers, displays anticoagulant, anti-inflammatory, and endothelial cell (EC)-protective activities and has been successfully used to treat comatose children with veno-occlusive disease. DF was investigated here as a drug to treat cerebral malaria. Methods and Results-DF blocks tissue factor expression by ECs incubated with parasitized red blood cells and attenuates prothrombinase activity, platelet aggregation, and complement activation. In contrast, it does not affect nitric oxide bioavailability. We also demonstrated that Plasmodium falciparum glycosylphosphatidylinositol (Pf-GPI) induces tissue factor expression in ECs and cytokine production by dendritic cells. Notably, dendritic cells, known to modulate coagulation and inflammation systemically, were identified as a novel target for DF. Accordingly, DF inhibits Toll-like receptor ligand-dependent dendritic cells activation by a mechanism that is blocked by adenosine receptor antagonist (8-p-sulfophenyltheophylline) but not reproduced by synthetic poly-A, -C, -T, and -G. These results imply that aptameric sequences and adenosine receptor mediate dendritic cells responses to the drug. DF also prevents rosetting formation...

Distinct placental malaria pathology caused by different Plasmodium berghei lines that fail to induce cerebral malaria in the C57BL/6 mouse

Rodrigues-Duarte, Lurdes; de Moraes, Luciana Vieira; Barboza, Renato; Marinho, Claudio Romero Farias; Franke-Fayard, Blandine; Janse, Chris J.; Penha-Goncalves, Carlos
Fonte: BIOMED CENTRAL LTD; LONDON Publicador: BIOMED CENTRAL LTD; LONDON
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
66.42%
Background: Placental malaria (PM) is one major feature of malaria during pregnancy. A murine model of experimental PM using BALB/c mice infected with Plasmodium berghei ANKA was recently established, but there is need for additional PM models with different parasite/host combinations that allow to interrogate the involvement of specific host genetic factors in the placental inflammatory response to Plasmodium infection. Methods: A mid-term infection protocol was used to test PM induction by three P. berghei parasite lines, derived from the K173, NK65 and ANKA strains of P. berghei that fail to induce experimental cerebral malaria (ECM) in the susceptible C57BL/6 mice. Parasitaemia course, pregnancy outcome and placenta pathology induced by the three parasite lines were compared. Results: The three P. berghei lines were able to evoke severe PM pathology and poor pregnancy outcome features. The results indicate that parasite components required to induce PM are distinct from ECM. Nevertheless, infection with parasites of the ANKA Delta pm4 line, which lack expression of plasmepsin 4, displayed milder disease phenotypes associated with a strong innate immune response as compared to infections with NK65 and K173 parasites. Conclusions: Infection of pregnant C57BL/6 females with K173...

Distinct placental malaria pathology caused by different Plasmodium berghei lines that fail to induce cerebral malaria in the C57BL/6 mouse

Rodrigues-Duarte, Lurdes; Moraes, Luciana Vieira de; Barboza, Renato; Marinho, Claudio RF; Franke-Fayard, Blandine; Janse, Chris J; Penha-Gonçalves, Carlos
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN
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66.41%
Abstract Background Placental malaria (PM) is one major feature of malaria during pregnancy. A murine model of experimental PM using BALB/c mice infected with Plasmodium berghei ANKA was recently established, but there is need for additional PM models with different parasite/host combinations that allow to interrogate the involvement of specific host genetic factors in the placental inflammatory response to Plasmodium infection. Methods A mid-term infection protocol was used to test PM induction by three P. berghei parasite lines, derived from the K173, NK65 and ANKA strains of P. berghei that fail to induce experimental cerebral malaria (ECM) in the susceptible C57BL/6 mice. Parasitaemia course, pregnancy outcome and placenta pathology induced by the three parasite lines were compared. Results The three P. berghei lines were able to evoke severe PM pathology and poor pregnancy outcome features. The results indicate that parasite components required to induce PM are distinct from ECM. Nevertheless, infection with parasites of the ANKAΔpm4 line, which lack expression of plasmepsin 4...

Efeito do tratamento da malaria cerebral com celulas da medula ossea em camundongos infectados pelo Plasmodium berghei ANKA; Effect of tratment of cerebral with bone marrow cells in mice infected by Plasmodium berghei ANKA

Helen Cupertino Silva Pinto
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 26/08/2009 PT
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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)...

Análise dos mecanismos protetores desencadeados pela oxigenação hiperbárica na malária cerebral; Analysis of protective mechanisms triggered by hyperbaric oxygenation in cerebral malaria

Yara Carollo Blanco
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 23/02/2012 PT
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66.56%
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.; 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...

Carbon monoxide and brain sequestration of Plasmodium berghei ANKA in experimental cerebral malaria

Pena, Ana Catarina Dias
Fonte: Universidade de Lisboa Publicador: Universidade de Lisboa
Tipo: Dissertação de Mestrado
Publicado em //2009 ENG
Relevância na Pesquisa
56.47%
Tese de mestrado, Biologia (Biologia Celular e Biotecnologia), 2009, Universidade de Lisboa, Faculdade de Ciências; Resumo alargado em português disponível no documento; Malaria is a major infectious disease worldwide, causing ~1 million deaths each year due to severe complications, one of the most lethal being cerebral malaria (CM). Thereby, understanding CM pathogenesis is of vital importance for developing effective therapies against it. The experimental cerebral malaria (ECM) model of C57BL/6 mice infected with P. berghei ANKA (PbA) shares many similarities with human CM. However, whereas in humans a critical event is sequestration of Plasmodium-infected red blood cells (iRBCs) in the brain microvasculature, in rodents is mostly leukocyte sequestration that occurs. Thereby, the pathologic significance of iRBCs brain sequestration during ECM is controversial and remains to be clarified. Recently, it was shown that heme-oxygenase-1 (HO-1) plays a crucial role in protection against ECM, which appears to be mediated by carbon monoxide (CO) production, an end-product of its enzymatic activity. In fact, administration of CO by inhalation rescues all C57BL/6 PbA-infected mice from developing ECM. The present study shows that CO protection comprises the reduction of iRBC brain sequestration in infected mice...

A study on the pathogenesis of human cerebral malaria and cerebral babesiosis

Aikawa,Masamichi; Pongponratn,Emsri; Tegoshi,Tatsuya; Nakamura,Kei-Ichiro; Nagatake,Tsuyoshi; Cochrane,Alan; Ozaki,Luiz S.
Fonte: Instituto Oswaldo Cruz, Ministério da Saúde Publicador: Instituto Oswaldo Cruz, Ministério da Saúde
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/1992 EN
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66.57%
Cerebral complications are important, but poorly understood pathological features of infections caused by some species of Plasmodium and Babesia. Patients dying from P. falciparum were classified as cerebral or non-cerebral cases according to the cerebral malaria coma scale. Light microscopy revealed that cerebral microvessels of cerebral malaria patients were field with a mixture of parazited and unparazited erythrocytes, with 94% of the vessels showing parasitized red blood cell (PRBC) sequestration. Some degree of PRBC sequestration was also found in non-cerebral malaria patients, but the percentage of microvessls with sequestered PRBC was only 13% Electron microscopy demonstrated knobs on the membrane of PRBC that formed focal junctions with the capillary endothelium. A number of host cell molecules such as CD36, thrombospondim (TSP) and intracellular adhesion molecule I (ICAM-1) may function as endothelial cell surfacereports for P. falciparum-infected erythrocytes. Affinity labeling of CD36 and TSP to the PRBC surface showed these molecules specifically bind to the knobs. Babesia bovis infected erythrocytes procedure projections of the erythrocyte membrane that are similar to knobs. When brain tissue from B. bovis-infected cattle was examined...

Plasmodium coatneyi-infected rhesus monkeys: a primate modelfor human cerebral malaria

Aikawa,Masamichi; Brown,Arthur E.; Smith,C. Dahlem; Tegoshi,Tatsuya; Howard,Russell J.; Hasler,Thomas H.; Ito,Yoshihiro; Colins,William E.; Webster,H. Kyle
Fonte: Instituto Oswaldo Cruz, Ministério da Saúde Publicador: Instituto Oswaldo Cruz, Ministério da Saúde
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/1992 EN
Relevância na Pesquisa
66.54%
Although several animal models for human cerebral malaria have been proposed in the past, name have shown pathological findings that are similar to those seen in humans. In order to develop an animal model for human cerebral malaria, we studied the pathology of brains of Plasmodium coatneyi (primate malaria parasite)-infected rhesus monkeys. Our study demonstrated parazitized erythrocyte (PRBC) sequestration and cytoadherence of knobs on PRBC to endothelial cells in cerebral microvessels of these monkeys. This similar to the findings een in human cerebral malaria. Crebral microvessels with sequestred PRBC were shown by immunohistochemistry to possess CD36, TSP and ICAM-1. These proteins were not evident in cerebral microvessels of uninfected control monkeys. Our study indicates, for the first time, that rhesus monkeys infected with P. coatneyi can be used as a primate model to study human cerebral malaria.

Vascular dysfunction as a target for adjuvant therapy in cerebral malaria

Carvalho,Leonardo José de Moura; Moreira,Aline da Silva; Daniel-Ribeiro,Cláudio Tadeu; Martins,Yuri Chaves
Fonte: Instituto Oswaldo Cruz, Ministério da Saúde Publicador: Instituto Oswaldo Cruz, Ministério da Saúde
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/08/2014 EN
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66.38%
Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum malaria that continues to be a major global health problem. Brain vascular dysfunction is a main factor underlying the pathogenesis of CM and can be a target for the development of adjuvant therapies for the disease. Vascular occlusion by parasitised red blood cells and vasoconstriction/vascular dysfunction results in impaired cerebral blood flow, ischaemia, hypoxia, acidosis and death. In this review, we discuss the mechanisms of vascular dysfunction in CM and the roles of low nitric oxide bioavailability, high levels of endothelin-1 and dysfunction of the angiopoietin-Tie2 axis. We also discuss the usefulness and relevance of the murine experimental model of CM by Plasmodium berghei ANKA to identify mechanisms of disease and to screen potential therapeutic interventions.

Modulation of cerebral malaria by curcumin as an adjunctive therapy

Jain,Kunal; Sood,Sumeet; Gowthamarajan,K.
Fonte: Brazilian Society of Infectious Diseases Publicador: Brazilian Society of Infectious Diseases
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/10/2013 EN
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66.44%
Cerebral malaria is the most severe and rapidly fatal neurological complication of Plasmodium falciparum infection and responsible for more than two million deaths annually. The current therapy is inadequate in terms of reducing mortality or post-treatment symptoms such as neurological and cognitive deficits. The pathophysiology of cerebral malaria is quite complex and offers a variety of targets which remain to be exploited for better therapeutic outcome. The present review discusses on the pathophysiology of cerebral malaria with particular emphasis on scope and promises of curcumin as an adjunctive therapy to improve survival and overcome neurological deficits.

Human Cerebral Malaria and Plasmodium falciparum Genotypes in Malawi

Milner, Danny Arnold; Vareta, Jimmy; Valim, Clarissa; Montgomery, Jacqui; Daniels, Rachel Fath; Cooke, Sarah Volkman; Neafsey, Daniel Edward; Park, Daniel John; Schaffner, Stephen; Mahesh, Nira C; Barnes, Kayla G; Rosen, David M; Lukens, Amanda Kathleen;
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN_US
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66.58%
Background: Cerebral malaria, a severe form of Plasmodium falciparum infection, is an important cause of mortality in sub-Saharan African children. A Taqman 24 Single Nucleotide Polymorphisms (SNP) molecular barcode assay was developed for use in laboratory parasites which estimates genotype number and identifies the predominant genotype. Methods The 24 SNP assay was used to determine predominant genotypes in blood and tissues from autopsy and clinical patients with cerebral malaria. Results: Single genotypes were shared between the peripheral blood, the brain, and other tissues of cerebral malaria patients, while malaria-infected patients who died of non-malarial causes had mixed genetic signatures in tissues examined. Children with retinopathy-positive cerebral malaria had significantly less complex infections than those without retinopathy (OR = 3.7, 95% CI [1.51-9.10]).The complexity of infections significantly decreased over the malaria season in retinopathy-positive patients compared to retinopathy-negative patients. Conclusions: Cerebral malaria patients harbour a single or small set of predominant parasites; patients with incidental parasitaemia sustain infections involving diverse genotypes. Limited diversity in the peripheral blood of cerebral malaria patients and correlation with tissues supports peripheral blood samples as appropriate for genome-wide association studies of parasite determinants of pathogenicity.; Organismic and Evolutionary Biology

A histological method for quantifying Plasmodium falciparum in the brain in fatal paediatric cerebral malaria

Milner, Danny A; Valim, Clarissa; Carr, Richard A; Chandak, Pankaj B; Fosiko, Nedson G; Whitten, Richard; Playforth, Krupa B; Seydel, Karl B; Kamiza, Steve; Molyneux, Malcolm E; Taylor, Terrie E
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
66.61%
Background: The sequestration of Plasmodium falciparum-infected erythrocytes in brain microvasculature through cytoadherence to endothelium, is the hallmark of the definitive diagnosis of cerebral malaria and plays a critical role in malaria pathogenesis. The complex pathophysiology, which leads each patient to the final outcome of cerebral malaria, is multifaceted and thus, metrics to delineate specific patterns within cerebral malaria are needed to further parse patients. Methods: A method was developed for quantification utilizing counts of capillary contents (early-stage parasites, late-stage parasites and fibrin) from histological preparations of brain tissue after death, and compared it to the standard approach, in which the percentage of parasitized vessels in cross-section is determined. Results: Within the initial cohort of 50 patients, two different observers agreed closely on the percentage of vessels parasitized, pigmented parasites and pigment globules (ICC = 0.795-0.970). Correlations between observers for correct diagnostic classification were high (Kendall’s tau-b = 0.8779, Kappa = 0.8413). When these methods were applied prospectively to a second set of 50 autopsy samples, they revealed a heterogeneous distribution of sequestered parasites in the brain with pigmented parasites and pigment globules present in the cerebellum > cortex > brainstem. There was no difference in the distribution of early stages of parasites or in the percentage of vessels parasitized across the same sites. The second cohort of cases was also used to test a previously published classification and regression tree (CART) analysis; the quantitative data alone were able to accurately classify and distinguish cerebral malaria from non-cerebral malaria. Classification errors occurred within a subclassification of cerebral malaria (CM1 vs CM2). A repeat CART analysis for the second cohort generated slightly different classification rules with more accurate subclassification...

The Role of Animal Models for Research on Severe Malaria

Craig, Alister G.; Grau, Georges E.; Janse, Chris; Kazura, James W.; Milner, Danny Arnold; Barnwell, John W.; Turner, Gareth; Langhorne, Jean
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
56.39%
In light of the recent controversies over the role of animal models for research into the development of new treatments for severe malaria, particularly cerebral disease, a group of scientists came together to discuss the relative merits of a range of animal models and their overlap with the complex clinical syndromes of human disease. While it was not possible to fully resolve differences over the utility of the Plasmodium berghei ANKA model of experimental cerebral malaria, the meeting did bring the two research communities closer together to identify further work to provide information needed to validate the model and revitalise the development of other animal models displaying features of human pathology. The driving force behind this was the desire to ensure better translation of experimental findings into effective treatments for severe malaria.

The systemic pathology of cerebral malaria in African children

Milner, Danny A.; Whitten, Richard O.; Kamiza, Steve; Carr, Richard; Liomba, George; Dzamalala, Charles; Seydel, Karl B.; Molyneux, Malcolm E.; Taylor, Terrie E.
Fonte: Frontiers Media S.A. Publicador: Frontiers Media S.A.
Tipo: Artigo de Revista Científica
EN_US
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66.49%
Pediatric cerebral malaria carries a high mortality rate in sub-Saharan Africa. We present our systematic analysis of the descriptive and quantitative histopathology of all organs sampled from a series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi on pediatric cerebral malaria patients and control patients (without coma, or without malaria infection) who were clinically well characterized prior to death. We found brain swelling in all cerebral malaria patients and the majority of controls. The histopathology in patients with sequestration of parasites in the brain demonstrated two patterns: (a) the “classic” appearance (i.e., ring hemorrhages, dense sequestration, and extra-erythrocytic pigment) which was associated with evidence of systemic activation of coagulation and (b) the “sequestration only” appearance associated with shorter duration of illness and higher total burden of parasites in all organs including the spleen. Sequestration of parasites was most intense in the gastrointestinal tract in all parasitemic patients (those with cerebral malarial and those without).

Severity of Retinopathy Parallels the Degree of Parasite Sequestration in the Eyes and Brains of Malawian Children With Fatal Cerebral Malaria

Barrera, Valentina; Hiscott, Paul Stephenson; Craig, Alister Gordon; White, Valerie Ann; Milner, Danny Arnold; Beare, Nicholas Alexander Venton; MacCormick, Ian James Callum; Kamiza, Steve; Taylor, Terrie Ellen; Molyneux, Malcolm Edward; Harding, Simon Pe
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
66.36%
Background. Malarial retinopathy (MR) has diagnostic and prognostic value in children with Plasmodium falciparum cerebral malaria (CM). A clinicopathological correlation between observed retinal changes during life and the degree of sequestration of parasitized red blood cells was investigated in ocular and cerebral vessels at autopsy. Methods. In 18 Malawian children who died from clinically defined CM, we studied the intensity of sequestration and the maturity of sequestered parasites in the retina, in nonretinal ocular tissues, and in the brain. Results. Five children with clinically defined CM during life had other causes of death identified at autopsy, no MR, and scanty intracerebral sequestration. Thirteen children had MR and died from CM. MR severity correlated with percentage of microvessels parasitized in the retina, brain, and nonretinal tissues with some neuroectodermal components (all P < .01). In moderate/severe MR cases (n = 8), vascular congestion was more intense (ρ = 0.841; P < .001), sequestered parasites were more mature, and the quantity of extraerythrocytic hemozoin was higher, compared with mild MR cases (n = 5). Conclusions. These data provide a histopathological basis for the known correlation between degrees of retinopathy and cerebral dysfunction in CM. In addition to being a valuable tool for clinical diagnosis...

Inhaled Nitric Oxide as an Adjunctive Treatment for Cerebral Malaria in Children: A Phase II Randomized Open-Label Clinical Trial

Mwanga-Amumpaire, Juliet; Carroll, Ryan W.; Baudin, Elisabeth; Kemigisha, Elisabeth; Nampijja, Dorah; Mworozi, Kenneth; Santorino, Data; Nyehangane, Dan; Nathan, Daniel I.; De Beaudrap, Pierre; Etard, Jean-François; Feelisch, Martin; Fernandez, Bernadett
Fonte: Oxford University Press Publicador: Oxford University Press
Tipo: Artigo de Revista Científica
EN_US
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66.33%
Background. Children with cerebral malaria (CM) have high rates of mortality and neurologic sequelae. Nitric oxide (NO) metabolite levels in plasma and urine are reduced in CM. Methods. This randomized trial assessed the efficacy of inhaled NO versus nitrogen (N2) as an adjunctive treatment for CM patients receiving intravenous artesunate. We hypothesized that patients treated with NO would have a greater increase of the malaria biomarker, plasma angiopoietin-1 (Ang-1) after 48 hours of treatment. Results. Ninety-two children with CM were randomized to receive either inhaled 80 part per million NO or N2 for 48 or more hours. Plasma Ang-1 levels increased in both treatment groups, but there was no difference between the groups at 48 hours (P = not significant [NS]). Plasma Ang-2 and cytokine levels (tumor necrosis factor-α, interferon-γ, interleukin [IL]-1β, IL-6, IL-10, and monocyte chemoattractant protein-1) decreased between inclusion and 48 hours in both treatment groups, but there was no difference between the groups (P = NS). Nitric oxide metabolite levels—blood methemoglobin and plasma nitrate—increased in patients treated with NO (both P < .05). Seven patients in the N2 group and 4 patients in the NO group died. Five patients in the N2 group and 6 in the NO group had neurological sequelae at hospital discharge. Conclusions. Breathing NO as an adjunctive treatment for CM for a minimum of 48 hours was safe...

NOS2 Variants Reveal a Dual Genetic Control of Nitric Oxide Levels, Susceptibility to Plasmodium Infection, and Cerebral Malaria

Trovoada, M. d. J.; Martins, M.; Ben Mansour, R.; Sambo, M. d. R.; Fernandes, A. B.; Antunes Goncalves, L.; Borja, A.; Moya, R.; Almeida, P.; Costa, J.; Marques, I.; Macedo, M. P.; Coutinho, A.; Narum, D. L.; Penha-Goncalves, C.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em //2013 ENG
Relevância na Pesquisa
56.44%
Nitric oxide (NO) is a proposed component of malaria pathogenesis, and the inducible nitric oxide synthase gene (NOS2) has been associated to malaria susceptibility. We analyzed the role of NOS2 polymorphisms on NO bioavailability and on susceptibility to infection, Plasmodium carrier status and clinical malaria. Two distinct West African sample collections were studied: a population-based collection of 1,168 apparently healthy individuals from the Príncipe Island and a hospital-based cohort of 269 Angolan children. We found that two NOS2 promoter single-nucleotide polymorphism (SNP) alleles associated to low NO plasma levels in noninfected individuals were also associated to reduced risk of pre-erythrocytic infection as measured anti-CSP antibody levels (6.25E-04 < P < 7.57E-04). In contrast, three SNP alleles within the NOS2 cistronic region conferring increased NO plasma levels in asymptomatic carriers were strongly associated to risk of parasite carriage (8.00E-05 < P < 7.90E-04). Notwithstanding, three SNP alleles in this region protected from cerebral malaria (7.90E-4 < P < 4.33E-02). Cohesively, the results revealed a dual regimen in the genetic control of NO bioavailability afforded by NOS2 depending on the infection status. NOS2 promoter variants operate in noninfected individuals to decrease both NO bioavailability and susceptibility to pre-erythrocytic infection. Conversely...

NOS2 Variants Reveal a Dual Genetic Control of Nitric Oxide Levels, Susceptibility to Plasmodium Infection, and Cerebral Malaria

Trovoada, M. d. J.; Martins, M.; Ben Mansour, R.; Sambo, M. d. R.; Fernandes, A. B.; Antunes Goncalves, L.; Borja, A.; Moya, R.; Almeida, P.; Costa, J.; Marques, I.; Macedo, M. P.; Coutinho, A.; Narum, D. L.; Penha-Goncalves, C.
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica
Publicado em /03/2014 ENG
Relevância na Pesquisa
56.49%
Nitric oxide (NO) is a proposed component of malaria pathogenesis, and the inducible nitric oxide synthase gene (NOS2) has been associated to malaria susceptibility. We analyzed the role of NOS2 polymorphisms on NO bioavailability and on susceptibility to infection, Plasmodium carrier status and clinical malaria. Two distinct West African sample collections were studied: a population-based collection of 1,168 apparently healthy individuals from the Príncipe Island and a hospital-based cohort of 269 Angolan children. We found that two NOS2 promoter single-nucleotide polymorphism (SNP) alleles associated to low NO plasma levels in noninfected individuals were also associated to reduced risk of pre-erythrocytic infection as measured anti-CSP antibody levels (6.25E-04 < P < 7.57E-04). In contrast, three SNP alleles within the NOS2 cistronic region conferring increased NO plasma levels in asymptomatic carriers were strongly associated to risk of parasite carriage (8.00E-05 < P < 7.90E-04). Notwithstanding, three SNP alleles in this region protected from cerebral malaria (7.90E-4 < P < 4.33E-02). Cohesively, the results revealed a dual regimen in the genetic control of NO bioavailability afforded by NOS2 depending on the infection status. NOS2 promoter variants operate in noninfected individuals to decrease both NO bioavailability and susceptibility to pre-erythrocytic infection. Conversely...

Evidence of IL-17, IP-10, and IL-10 involvement in multiple-organ dysfunction and IL-17 pathway in acute renal failure associated to Plasmodium falciparum malaria

Herbert, Fabien; Tchitchek, Nicolas; Bansal, Devendra; Jacques, Julien; Pathak, Sulabha; Bécavin, Christophe; Fesel, Constantin; Dalko, Esther; Cazenave, Pierre-André; Preda, Cristian; Ravindran, Balachandran; Sharma, Shobhona; Das, Bidyut; Pied, Sylvia
Fonte: BioMed Central Publicador: BioMed Central
Tipo: Artigo de Revista Científica
Publicado em 24/11/2015 ENG
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Plasmodium falciparum malaria in India is characterized by high rates of severe disease, with multiple organ dysfunction (MOD)-mainly associated with acute renal failure (ARF)-and increased mortality. The objective of this study is to identify cytokine signatures differentiating severe malaria patients with MOD, cerebral malaria (CM), and cerebral malaria with MOD (CM-MOD) in India. We have previously shown that two cytokines clusters differentiated CM from mild malaria in Maharashtra. Hence, we also aimed to determine if these cytokines could discriminate malaria subphenotypes in Odisha.; Indo-French Centre for the Promotion of Advanced Research (IFCPAR project No 3703), International Associated Laboratory Systems Immunology and Genetics of Infectious Diseases (LIA SIGID, CNRS, Lille University and the Department of Biotechnology (DBT), Ministry of Science and Technology of India and the ANR LAbEx Parafrap).