Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some clinical manifestations of severe malaria resemble those of sepsis and there may be mediators of the host response that are common to both sepsis and malaria. Phospholipase A2 (PLA2), a proinflammatory enzyme whose expression is induced by tumor necrosis factor (TNF), has been implicated in the pathogenesis of complications of the sepsis syndrome. We examined levels of circulating PLA2 in Plasmodium falciparum malaria and studied the association of PLA2 with disease severity. Plasma PLA2 and TNF were measured in 75 Malawian children with P. falciparum malaria. The mean (SD) plasma PLA2 activity in children with acute malaria was 53,804 (37,256) units/ml as compared with 424 (349) units/ml in 34 healthy controls (P < 0.00001). The mean PLA2 activity in 45 convalescent patients was 2,546 (7,372) units/ml (P < 0.00001). In 48 patients with pretreatment PLA2 activity less than 60,000 units/ml, mortality was 8.3%, while in 27 patients with pretreatment PLA2 levels greater than 60,000 units/ml, mortality was 33.3% (P = 0.008). There were significant correlations between PLA2 and TNF (r = 0.471, P < 0.01), density of parasitemia (r = 0.443, P < 0.0001) and a decrease in hematocrit (r = 0.352, P < 0.005). These data show that P. falciparum malaria is associated with a markedly increased circulating PLA2, especially in patients with severe disease, as manifested by high parasite burden, anemia, coma, and death.
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PMID:Increased serum phospholipase A2 activity in Malawian children with falciparum malaria. 821 74

Volunteers immunized with gamma-irradiated Plasmodium falciparum sporozoites serve as the gold standard for protective immunity against mosquito-borne malaria transmission and provide a relevant model for studying protective immune effector mechanisms. During a 7-12 month period, we immunized four volunteers via the bites of irradiated, infected mosquitoes. Following these exposures to attenuated sporozoites, all four volunteers developed antibodies to sporozoites as measured by an immunofluorescence assay and by an enzyme-linked immunosorbent assay using the circumsporozoite (CS) protein repeat-based molecule R32LR as capture antigen. Three volunteers also developed antibodies against the nonrepeating (flanking) regions of the CS protein; the level of these antibodies paralleled the serum activity to inhibit sporozoite invasion of hepatoma cells in vitro. These three volunteers were protected against malaria transmitted by the bites of five infected mosquitoes. Two of these protected volunteers received additional immunizing doses of irradiated sporozoites and were subsequently protected against challenge with a heterologous P. falciparum clone. No detectable fluctuations were observed in circulating levels of tumor necrosis factor, interferon-gamma, or interleukin-6 during the course of this study. Analysis of the humoral and cellular immune responses of these protected volunteers is expected to yield important clues to additional targets of immunity against the pre-erythrocytic stages of malaria parasites.
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PMID:Humoral immune responses in volunteers immunized with irradiated Plasmodium falciparum sporozoites. 835 78

In this study, we have identified a dominant glycolipid toxin of Plasmodium falciparum. It is a glycosylphosphatidylinositol (GPI). The parasite GPI moiety, free or associated with protein, induces tumor necrosis factor and interleukin 1 production by macrophages and regulates glucose metabolism in adipocytes. Deacylation with specific phospholipases abolishes cytokine induction, as do inhibitors of protein kinase C. When administered to mice in vivo the parasite GPI induces cytokine release, a transient pyrexia, and hypoglycemia. When administered with sensitizing agents it can elicit a profound and lethal cachexia. Thus, the GPI of Plasmodium is a potent glycolipid toxin that may be responsible for a novel pathogenic process, exerting pleiotropic effects on a variety of host cells by substituting for the endogenous GPI-based second messenger/signal transduction pathways. Antibody to the GPI inhibits these toxic activities, suggesting a rational basis for the development of an antiglycolipid vaccine against malaria.
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PMID:Signal transduction in host cells by a glycosylphosphatidylinositol toxin of malaria parasites. 841 96

Cerebral malaria (CM) is the most common cause of death in severe malaria; more than two million children die of CM annually. Although the mechanisms of this neurologic complication remain poorly understood, studies in an experimental model of CM suggest that a natural body protein seems to be a major cause of this deadliest complication of malaria, a finding that could point towards new methods of treatment. We have explored the pathogenesis of CM with particular attention to the possible relationship between susceptibility or resistance to CM and cytokine expression and secretion patterns. We found that CM is associated with an increased expression of tumor necrosis factor (TNF) and interferon (IFN)-gamma and a reduced expression of interleukin-4 (IL-4) and transforming growth factor (TGF)-beta. The data obtained are consistent with a predominantly Th1 response in mice developing the cerebral complications of malaria. The overexpression of TNF in brain was also correlated with the augmented expression of adhesion molecules involved in the sequestration of leukocytes in brain vessels, a distinctive feature of CM. These observations were seen in relation to the immune status of man, in which, akin to the mouse model, a predominant Th1 response and upregulation of adhesion molecules in brain endothelium appear to be associated with susceptibility to the neurological complications of CM.
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PMID:Role of cytokines and adhesion molecules in malaria immunopathology. 845 80

When pentoxifylline was present during stimulation of human mononuclear leukocytes with Plasmodium falciparum exogenous antigens, an increase in interleukin-6 production was observed simultaneously with a reduction of tumor necrosis factor secretion. Similar results were obtained in murine macrophages stimulated with P. vinckei antigens. This indicates the independence of interleukin-6 and tumor necrosis factor secretion in response to malaria antigens.
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PMID:Production of interleukin-6 by human and murine mononuclear leukocytes stimulated with Plasmodium antigens is enhanced by pentoxifylline, and tumor necrosis factor secretion is reduced. 850 Sep 16

Intercellular adhesion molecule-1 and E-selectin levels were increased in the plasma of 60 falciparum malaria patients and were not related to levels of tumor necrosis factor alpha, interleukin 10, or interleukin 1 alpha. Soluble E-selectin was correlated to disease; its level in plasma was related to levels of both tumor necrosis factor soluble receptors and biological markers of disease severity and returned to baseline after parasite clearance faster than that of soluble intercellular adhesion molecule-1.
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PMID:Soluble intercellular adhesion molecule-1 and E-selectin levels in plasma of falciparum malaria patients and their lack of correlation with levels of tumor necrosis factor alpha, interleukin 1 alpha (IL-1 alpha), and IL-10. 855 30

We have recently shown that some squirrel monkeys (Saimiri sciureus) develop cerebral malaria when experimentally infected with asexual blood stage forms of different Plasmodium falciparum isolates. Since cerebral malaria is neither an inconsistent nor predictable event, several clones of endothelial cells isolated from the squirrel monkey brain microvasculature have been developed. Infected red blood cell (IRBC) adherence involved the knobs and direct membrane interactions through pseudopodes and microvilli on the Saimiri brain endothelial cell (SBEC) surface, similar to that observed with both brain microvascular endothelial cells from a patient who died of cerebral malaria and the rhesus monkey/P. coatneyi cerebral malaria model. The involvement of pseudopodes and microvilli increase the endothelial cell surface for the attachment of IRBCs; however, they are already present before the SBECs are exposed to IRBCs. With some SBEC phenotypes, embedding of IRBCs into the cytoplasma membrane of the endothelial cell was observed, resulting in an extremely close apposition of both SBEC and IRBC membranes during the adherence process. Once IRBCs are adherent, particularly for the embedding type, heterocellular communication-like structures between the cells become apparent. The upregulation of CD36 and intercellular adhesion molecule-1 by soluble recombinant (sr)-tumor necrosis factor-alpha or sr-interferon-gamma did not modify the IRBC interactions with SBECs at the ultrastructural level. The study shows further that the observed differences of IRBC adherence are due to unidentified phenotypic differences of SBECs rather than to a parasite isolate or particular endothelial cell receptor-associated phenomenon. Exploring P. falciparum IRBC cytoadherence in the squirrel monkey using a homologous physiologic target cell model in vitro should be useful for the evaluation of vaccine strategies and drugs to prevent human cerebral malaria.
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PMID:Ultrastructural aspects of Plasmodium falciparum-infected erythrocyte adherence to endothelial cells of Saimiri brain microvasculature. 861 43

Plasma concentrations of big endothelin-1 were determined by ELISA in 18 patients with complicated Plasmodium falciparum malaria in Bangkok. Before therapy, elevated levels were recorded (21 +/- 12 vs. 2.9 +/- 1.1 pmol/L in age- and sex-matched healthy subjects; P < .001). Even 7 days after therapy, elevated concentrations were seen (25 +/- 14 pmol/L). Plasma endothelin levels were correlated with levels of tumor necrosis factor-alpha (r = .632, P < .01), and a negative correlation with platelet counts was seen (r = .783, P < .005). No relation between plasma endothelin concentrations and parasitemia, fever, or other indices of severe infection (hypotension, renal, hepatic or pulmonary impairment, cerebral malaria) existed. During and after complicated malaria, increased levels of plasma endothelin could contribute to malarial pathology or reflect endothelial damage or both.
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PMID:Big endothelin in patients with complicated Plasmodium falciparum malaria. 862 87

We compared the tumor necrosis factor (TNF-alpha), interferon gamma (IFN-gamma) and granulocyte-macrophage colony stimulating factor (GM-CSF) serum levels in 87 patients with malaria from the Brazilian Amazon. They included asymptomatic infected individuals and symptomatic patients with mild disease or severe malaria with or without cerebral involvement. As controls we examined individuals living in endemic areas without past history of malaria. The TNF-alpha serum levels were increased in patients with malaria and progressively decreased in those with severe disease 7 days after specific treatment. We found correlation between parasitaemia, TNF-alpha levels and severity of the disease. The correlation between high TNF-alpha levels and severe malaria was independent of cerebral involvement. The increase in both IFN-gamma and GM-CSF levels among malarious patients was not related to the degree of severity or mortality. IFN-gamma concentration, however, was associated with high parasitaemia at admission.
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PMID:Tumor necrosis factor alpha interferon gamma and macrophage stimulating factor in relation to the Severity of Plasmodium falciparum malaria in the Brazilian Amazon. 865 Jul 40

It is increasingly evident that sepsis triggers a complex host reaction that is responsible for a variety of pathophysiologic changes during the inflammatory process. Pentoxifylline (PTX) is a methylxanthine with selective anti-inflammatory activity. Because of the current concept of an exaggerated immune response during severe inflammatory response syndrome (SIRS), this drug has received interest as a potential beneficial modulator of SIRS. Animal studies suggest that randomized clinical trials should be carefully planned with regard to dose-response relationship, disease severity, etiologic pathogens, and mechanisms that result in SIRS. The efficacy of PTX has been promising in human malaria. It is probably also effective in other hyper-tumor necrosis factor (TNF) states. The effective dosage is unclear to date, and its use is restricted by intolerance. Potential adverse effects may be related to the selective depression of TNF expression and to the depression of granulocyte phagocytic activity and the neutrophil/endothelium interaction. However, it is unlikely that any single agent will prove to be the magic bullet in the therapy of sepsis and SIRS. Multiple agents, perhaps tailored to individual circumstances, will most probably be needed, raising dramatic economic and ethical challenges.
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PMID:Pentoxifylline in severe inflammatory response syndrome. 869 53


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