Human malaria in C57BL/6J mice: An in vivo model for chemotherapy studies.

The present work deals with the development of Plasmodium falciparum stages in mouse model and its potential for the study of efficacy of antimalarial drugs. C57BL/6J mice were infected with multidrug resistant P. falciparum strain then treated with arteether and artesunate. A response was observed to antimalarial drugs in terms of decrease in parasitemia. Mice infected with P. falciparum strain were successfully cured after treatment with either arteether or artesunate. The speed of parasite clearance time and burden of parasitemia differed for each drug and matched the previously reported observations, hence stressing the relevance of the model. These findings thus suggest that P. falciparum. infected human RBC (iRBC) – C57BL/6J mice can provide a valuable in vivo system and should be included in the short list of animals that can be used for the evaluation of P. falciparum responses to drugs.

Mecanismos de patogenia en la malaria por Plasmodium falciparum / Pathogenic mechanisms in Plasmodium falciparum malaria

Se presentan los mecanismos patogénicos más conocidos en la infección por Plasmodium falciparum durante la fase eritrocitaria y extraeritrocitaria. La obstrucción vascular, explicada por los fenómenos de secuestro de glóbulos rojos parasitados y la formación de rosetas, mediados por diversos ligandos y receptores endoteliales, además de los procesos inflamatorios instaurados ante la presencia del parásito, son aspectos centrales en la patogenia de la malaria que permiten explicar. A partir de eventos como la lesión y la destrucción de eritrocitos, hepatocitos y células endoteliales, la pérdida de integridad del endotelio y la activación de promotores de daño celular y de apoptosis, se explican alteraciones como el aumento de la permeabilidad vascular, la hipoxia y el metabolismo anaerobio, que conducen tanto a lesiones localizadas en órganos como cerebro y pulmón, como a un estado de acidosis generalizada y falla multisistémica.

The most recognized pathogenic mechanisms of the infection with Plasmodium falciparum, during both the erythrocytic and exo-erithrocytic stages are presented. Vascular obstruction explained by the sequestration of parasitized red blood cells and erythrocyte rosetting, mediated by different endothelial ligands and receptors, in addition to the inflammatory processes induced by the presence of the parasite, are central aspects in the pathogenesis of malaria that explain the processes of damage, dysfunction and cell death in various organs. Alterations such as increased vascular permeability, hypoxia and anaerobic metabolism leading to localized lesions in organs such as brain and lung, as well as to a generalized acidotic state with multisystem failure can be explained by events such as the injury and destruction of erythrocytes, hepatocytes and endothelial cells, the loss of endothelial integrity, and the activation of cell damage and apoptosis promoters.

Myocardial Infarction Associated with Plasmodium Falciparum Malarial Infection.

Cardiac functions are almost well preserved in malarial infection. We report a rare case with fatal complication of myocardial infarction in patient with delayed diagnosis of Plasmodium falciparum infection. The authors therefore, suggest that every case of fever especially if associated with risk factor for cardiovascular disease should be immediately investigated for malaria so as to prevent this grave complication. This is even more important for people living in malarial endemic areas.

Avaliação da atividade antimalárica de substância obtidas de espécies vegetais nativas ou endêmicas do semi-árido brasileiro e derivados sintéticos / Evaluation of antimalarial activity of a substance obtained from native or endemic plant species of arid and semi-synthetic derivatives

A malária é uma das mais importantes infecções parasitárias de seres humanos devido à alta morbidade e mortalidade atribuídas a esta doença, que constitui uma ameaça para mais de dois bilhões de pessoas vivendo nas áreas de alta incidência. O Plasmodium falciparum, um dos agentes causadores da malária, apresenta alta capacidade de adaptação por mutação e pode ser resistente a vários tipos de drogas antimaláricas já disponíveis, como a cloroquina, o que torna importante a busca de novos antimaláricos. A região do semi-árido brasileiro abrange cerca de 11,5% do território nacional, e possui o bioma menos estudado em relação à flora e fauna, e um dos que tem sofrido maior degradação pelo uso desordenado e predatório nos últimos 400 anos. Tendo em vista o potencial farmacológico dos produtos naturais, o objetivo desse trabalho foi avaliar a atividade antimalárica de substâncias puras extraídas de espécies vegetais nativas ou endêmicas do semi-árido brasileiro e derivados sintéticos. A partir de uma biblioteca de 160 substâncias triadas para atividade antimalárica, foram selecionadas duas classes de compostos para avaliações in vitro e in vivo: o ácido betulínico e derivados, bem como o lapachol e derivados. Foi selecionada ainda uma terceira classe de moléculas, as fisalinas, utilizando o método do Similarity Ensemble Approach (SEA), que previu a ação antimalárica dessas substâncias. Dentre os derivados do ácido betulínico testados, o acetato do ácido betulínico apresentou a maior potência farmacológica in vitro quando comparado com os outros derivados, e foi ativo in vivo. A atividade antimalárica das fisalinas foi confirmada em ensaios in vitro. Ao serem analisadas in vivo, as fisalinas F e D apresentaram resultados opostos (exacerbação e proteção contra a infecção, respectivamente), possivelmente devido à atividade imunossupressora da fisalina F e ausente na fisalina D. A análise do lapachol e seus derivados iniciou-se através de estudos in silico por Quantitative Structure-Activity Relationship (QSAR), que indicaram ser o isolacet o derivado com maior atividade, o que foi confirmado por ensaios in vitro. A atividade antimalárica do isolacet foi confirmada in vivo, sendo ainda realizados estudos de Docking desta molécula com a falcipaína 2 de P. falciparum, que indicaram ser esta cisteíno-protease um possível alvo do isolacet. Nossos resultados indicam o potencial antimalárico de compostos isolados a partir de plantas do semi-árido e demonstram a importância da associação de várias abordagens para entendimento dos mecanismos de ação de moléculas com atividade farmacológica.

Sintomas neurológicos agudos e residuais na malária / Acute and residual neurological symptoms in malaria

A malária é a principal e a mais grave doença parasitária no mundo. A infecção pelo Plasmodium falciparum é capaz de afetar diretamente o sistema nervoso central, causando déficits cognitivos e comportamentais que caracterizam a malária cerebral (MC). A MC é uma complicação decorrente da malária grave sendo responsável pela maioria dos casos de incapacidade e óbito. A ocorrência de seqüelas cognitivas e comportamentais após tratamento da MC tem sido descrita, principalmente em crianças. Adultos e crianças apresentam diferenças nas manifestações clínicas resultantes da MC. Geralmente, as crianças cursam com um espectro maior de alterações e apresentam déficits em vários domínios cognitivos após o tratamento da doença. Apesar da sua relevância clínica, os mecanismos patogênicos envolvidos no desenvolvimento das seqüelas resultantes da MC permanecem pouco elucidados. O entendimento desses mecanismos é fundamental para elaboração de intervenções terapêuticas adequadas que atuem na prevenção desses transtornos.

Malaria is the main and most serious parasitic disease in the world. Plasmodium falciparum infection can affect directly the central nervoussystem leading to cognitive and behavioral impairment which characterize cerebral malaria (CM). CM is a complication of severe malaria beingresponsible for almost all disability and death. The occurrence of cognitive and behavioral impairment after treatment has been reported, especially in children. Adults and children have differences in clinical manifestations related to CM. In general, children tend to present a greater spectrum of symptoms and impairment in almost all domains of cognition after infection treatment. Despite of its clinical relevance, pathogenic mechanisms involved in the development of CM sequelae remain poorly understood. A better understanding of these mechanisms is essential for the elaboration of appropriate therapeutic interventions which may contribute to the prevention of CM sequelae.

Transcriptional Activity of Plasmodium Subtilisin-like Protease 2 (Pf-Sub2) 5'Untranslated Regions and Its Interaction with Hepatocyte Growth Factor

The onset, severity, and ultimate outcome of malaria infection are influenced by parasite-expressed virulence factors and individual host responses to these determinants. In both humans and mice, liver injury is involved after parasite entry, which persists until the erythrocyte stage after infection with the fatal strain Plasmodium falciparum (Pf). Hepatocyte growth factor (HGF) has strong anti-apoptotic effects in various kinds of cells, and also has diverse metabolic functions. In this work, Pf-subtilisin-like protease 2 (Pf-Sub2) 5'untranslated region (UTR) was analyzed and its transcriptional activity was estimated by luciferase expression. Fourteen TATA boxes were observed but only one Oct-1 and c-Myb were done. In addition, host HGF interaction with Pf-Sub2 was evaluated by co-transfection of HGF- and Pf-Sub2-cloned vector. Interestingly, -1,422/+12 UTR exhibited the strongest luciferase activity but -329 to +12 UTR did not exhibit luciferase activity. Moreover, as compared with the control of unexpressed HGF, the HGF protein suppressed luciferase expression driven by the 5'untranslated region of the Pf-Sub2 promoter. Taken together, it is suggested that HGF controls and interacts with the promoter region of the Pf-Sub2 gene.

Possible Role of Heme Oxygenase-1 and Prostaglandins in the Pathogenesis of Cerebral Malaria: Heme Oxygenase-1 Induction by Prostaglandin D2 and Metabolite by a Human Astrocyte Cell Line

Astrocytes are the most abundant cells in the central nervous system that play roles in maintaining the blood-brain-barrier and in neural injury, including cerebral malaria, a severe complication of Plasmodium falciparum infection. Prostaglandin (PG) D2 is abundantly produced in the brain and regulates the sleep response. Moreover, PGD2 is a potential factor derived from P. falciparum within erythrocytes. Heme oxygenase-1 (HO-1) is catalyzing enzyme in heme breakdown process to release iron, carbon monoxide, and biliverdin/bilirubin, and may influence iron supply to the P. falciparum parasites. Here, we showed that treatment of a human astrocyte cell line, CCF-STTG1, with PGD2 significantly increased the expression levels of HO-1 mRNA by RT-PCR. Western blot analysis showed that PGD2 treatment increased the level of HO-1 protein, in a dose- and time-dependent manner. Thus, PGD2 may be involved in the pathogenesis of cerebral malaria by inducing HO-1 expression in malaria patients.

Imunopatogênese da malária cerebral / Immunopathogenesis of cerebral malaria

A malária cerebral é a mais grave manifestação ocasionada pela infecção pelo Plasmodium falciparum, sendo responsável por elevadas taxas de mortalidade no continente africano. Apresenta mecanismos imunopatogênicos complexos, ainda não totalmente elucidados. Devido às dificuldades em acompanhar casos humanos e a limitada possibilidade de examinar os processos patológicos, alguns modelos experimentais de MC foram desenvolvidos. O modelo experimental utilizando roedores é bem aceito no meio científico e a grande diversidade de linhagens de camundongos associada à infecção por diferentes espécies de Plasmodium tem contribuído para elucidar aspectos envolvidos na patogênese da doença. O entendimento dos mecanismos imunopatogênicos é um pré-requisito necessário para a elaboração de novas terapias para o tratamento seguro e efetivo desta manifestação.

The cerebral malaria is the most serious manifestation caused for the infection by Plasmodium falciparum, being responsible for high rates of mortality in the African continent. It presents a complex immunopathogenics mechanisms, still not total elucidated. Due to the difficulties in following human cases and the limited possibility to examine pathological processes, some experimental models of CM had been developed. The experimental model using rodents is well accepted in the scientific way and the great diversity of strains of mice associated to the infection by different species of Plasmodium has contributed to elucidate some aspects involved in pathogenesis of the illness. A better understanding of the immunopathogenics mechanisms is a prerequisite necessary for the elaboration of new therapies for a safe and effective treatment of this manifestation.

Observation on Plasmodium infection in students residing in the University Hostels, Quetta, Balochistan, Pakistan

A survey of malaria parasites was conducted in the residential Hostels of Balochistan University during the years 2001-2003, Blood smears from 1000 students were takes. Giemsa's stain was used. The overall incidence was 25.00% Ring stages and gametocytes were observed. Plasmodium falciparum and P. vivax both were present. The hygienic conditions and epidemiological factors were also discussed

Systematic review and meta-analysis of the interaction between Plasmodium falciparum and Plasmodium vivax in humans.

OBJECTIVES: This study aimed to quantify the interaction between Plasmodium falciparum and R vivax and the sources of heterogeneity between studies. METHODS: We systematically reviewed three databases: Medline (1966-2001), Embase (1980-2001) and CAB-health (1976-2001). Random effects meta-analysis was applied to the data of 62 selected populations. Meta-regression was used to assess the following potential sources of heterogeneity: age-group, presence of fever, continent, temporal and spatial span of studies, and endemicity level. RESULTS: The summary odds ratio (OR) between P. falciparum and P. vivax was 0.6 (95% CI: 0.49-0.79). The minimum and maximum observed ORs were 0.01 and 10.9, respectively, and the heterogeneity test was highly significant (tau2 = 0.92, p < 0.0001)--the ORs varied over a very wide range. The ORs in longer studies and in those from areas with higher prevalence yielded smaller, more strongly negative association. This is consistent with the idea that any difference in the species' temporal patterns should decrease the OR, and more so over longer periods of time. INTERPRETATION & CONCLUSION: Although such odds ratios between Plasmodium species may be partly due to missed mixed infections when reading blood slides, the negative association between the OR and prevalence supports the existence of biological interactions such as suppression or cross-immunity between species.

Study of P. falciparum-infected erythrocytes and induced anisotropies under optical and fluid forces.

BACKGROUND & OBJECTIVES: The effect of P. falciparum on erythrocytes has been studied for a long time at the population level but actual studies at the single cell level remain largely unexplored. The aim of this study was to address the host-parasite relationship at the single cell level under two different kinds of forces, an optical force and a fluid force. The questions addressed were about the basic host-parasite interactions, but our findings have larger implications in diverse fields of parasite biology. METHODS: Erythrocytes were monitored under optical forces (using optical tweezers) and fluid forces (using microfluidic chambers) and dynamical images were captured in real-time video clips. These videos were then split into their respective frames so as to yield temporal information and various parameters pertaining to membrane structure, ionic imbalance and interaction with different forces were studied. RESULTS: The results of this study mainly bring to fore the inherent differences between infected and normal cell populations at the single cell level under various external forces. We probed three different criteria folding times, rotation speeds and rolling frequency to show inherent difference in various cell populations and also the dependence of the above to the cycle of the parasite. INTERPRETATION & CONCLUSION: This study portrays the importance of single cell observations pertaining to the host-parasite relationship. It shows the effect the malarial parasite has on erythrocytes and how the intrinsic property of the infected and its neighbouring uninfected cells change as compared to normal erythrocytes. There are thus implications in the fields of cytoadherence, parasite invasions and host immune evasion.

Malaria in Iran: past and present situation

Malaria had being widely prevalent for a long time in Iran. Before starting any anti-malarial campaign in Iran about 60% of population was living in malaria endemic areas. In hyper-endemic areas, approximately 30 to 40% of the total mortality was due to malaria. The malariometric data, reported during 1921-1949 in the malaria surveys in some endemic areas, showed high endemicities of the disease in most parts of the country. The first malaria-training course for preliminary operations of anti-malaria campaign was started in Iran in 1945. Afterwards, in the courses conducted, mostly by the Institute of Malariology many technical personnel were trained. In 1947, for the first time DDT was used in mosquito control in a pilot study in malaria hyper-endemic villages near Tehran. It caused great reduction in malaria transmission. Anti-malarial campaign including drug prophylaxis and treatment, anti-mosquito spraying with DDT and some anti-larval control measures, carried out during 1948-1956, considerably decreased malaria infection rate in most endemic areas. In 1957, malaria eradication programme [MEP] started in Iran and up to 1980 almost interrupted malaria transmission in the north parts of the country. However, in the south parts although the infection rate considerably decreased, but due to some technical and operational problems, malaria transmission was not interrupted. Therefore, in 1980 the MEP shifted to malaria control programme [MCP] which has been continuing up to present time. From 25 species of Anopheles found in Iran, 8 species of A. stephensi, A. fluviatilis, A. culicifacies, A. pulcherimus, A. d_thali, A. superpictus, A. sacharovi and A. maculipennis are considered to be malaria vectors. The prevalent species of Plasmodia in Iran are P. falciparum and P. vivax. P. malariae is rare. The main problems, in the malaria endemic areas of the southeast parts of Iran are resistance of the main vectors to some insecticides as well as high resistance of P. falciparum to chloroquine. The total reported malaria cases in Iran from 96340 with 45% P. falciparum in 1991, gradually, decreased to 18966 with 12% P. falciparum in 2005. About 30 to 50% of malaria patients have been among foreign immigrants

Clinical and molecular aspects of severe malaria

O ciclo eritrocítico do Plasmodium falciparum apresenta uma particularidade em relação às outras espécies de Plasmodium que infectam o homem. Trofozoítas maduros e esquizontes são seqüestrados da circulação periférica devido à adesão de eritrócitos infectados às células endoteliais. Modificações na superfície dos eritrócitos infectados, denominadas "knobs", permitem adesão ao endotélio e a outros eritrócitos. A adesão fornece uma melhor maturação na atmosfera venosa microaerofílica e permite que o parasita escape do clareamento pelo baço, que reconhece a perda de deformabilidade do eritrócito infectado. A adesão ao endotélio ou citoaderência, tem importante função na patogenicidade da doença, causando obstrução de pequenos vasos e contribuindo para danos em muitos órgãos. Citoaderência designa também a adesão de eritrócitos infectados a eritrócitos não infectados, fenômeno amplamente conhecido como "rosetting". Aspectos clínicos da malária grave bem como receptores do hospedeiro e ligantes do parasita envolvidos em citoaderência e "rosetting", são revisados aqui. A proteína de membrana do eritrócito 1 de P. falciparum (PfEMP1) parece ser o principal ligante adesivo dos eritrócitos infectados e será discutida em maiores detalhes. Uma melhor compreensão da função dos receptores do hospedeiro e dos ligantes do parasita no desenvolvimento de diferentes síndromes clínicas é urgentemente necessária para identificar alvos para vacinação visando diminuir as taxas de mortalidade desta doença.

Haematozoan parasites in Kashmiri refugees

An attempt has been made on blood survey of refugees of Kashmir settled in Muzafferabad, Azad Kashmir during July-September, 1997. A total of 300 sample specimens were collected. Among these blood films, the results showed that 7% persons suffered from malaria parasite. The prevalence of plasmodium vivax was 6.33% and that of P. falciparum was 0.67%. Infection in female was 61.9% and in male 38.1% Age wise prevalence of the disease was highest [8.4%] for age group 11-20 years and lowest [6.12%] in age group 31-40 years. Seasonal variation was also noted with the highest [9%] infection of malaria in August and lowest [5%] in September

Malaria transmission

No Brasil, a malária está restrita à regiäo amazônica, onde ocorre mais de 95 por cento dos casos registrados no país. Somente as fêmeas de mosquitos do gênero Anopheles säo capazes de transmitir os parasitos da malária humana. Treze espécies de anofelinos do Brasil foram encontradas naturalmente infectadas com Plasmodium, mas somente poucas estäo envolvidas na transmissäo. Anopheles darlingi é o principal vetor de malária nas ecorregiões de savana e floresta plana enquanto que o A. aquasalis é responsável pela transmissäo desta infecçäo na área costeira. Todavia, A. deaneorum, A. oswaldoi e A. marajoara tem sido incriminados como vetores locais de malária. Controlar a transmissäo de malária na regisäo Amazônica é uma tarefa muito difícil por causa de suas características ecológicas, ambientais, sociais e econômicas. Nos últimos 10 anos, os assentamentos desordenados (invasões) têm sido uma das principais causas de disseminaçäo de malária humana nos grandes centros urbanos, como é o caso da cidade de Manaus e Belém.

Infecciones tropicales en viajeros a Latinoamérica: parte II / Tropical diseases in travelers to Latin America: part II

Las infecciones permanecen como una de las más importantes causas de morbilidad entre los viajeros. Los países de América Latina son uno de los puntos de destino más importantes. Las dos enfermedades de mayor frecuencia son malaria y diarrea del viajero; sin embargo, Latinoamérica es aún un importante lugar de transmisión de fiebre amarilla, dengue, leishmaniasis, hepatitis por virus A, hepatitis por virus B y enfermedades de transmisión sexual. Alrededor del 7 por ciento de los casos de malaria en el viajero en todo el mundo, se adquirieron en Sudamérica y 40 a 60 por ciento de ellos son causados por Plasmodium falciparum. Se deben suministrar a los viajeros recomendaciones adecuadas de vacunación, quimioprofilaxis y medidas de protección individual, orientadas a sus lugares de destino. Un problema interesante de discutir es la enfermedad en el viajero que retorna a casa