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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The physiological basis for the resistance to falciparum malaria individuals with sickle cell trait has not been understood. Recent advances in erythrocytic Plasmodium falciparum culture have made possible a direct investigation of the development of the malaria parasite in cells with sickle cell homoglobin. In a high (18%) oxygen atmosphere, there is no apparent sickling of cells, and the growth and multiplication of P. falciparum is identical in normal (AA), hemoglobin S homozygous (SS), and hemoglobin S heterozygous (SA) erythrocytes. Cultures under low (1-5%) oxygen, however, showed clear inhibition of growth. The sickling of SS red cells killed and lysed most or all of the intracellular parasites. Parasites in SA red cells were killed primarily at the large ring stage, probably as a result of a disruption of the parasite metabolism. Incubation in cyanate prior to culture reversed the resistance of SA erythrocytes to plasmodium growth, but had no effect on SS red cell sickling or resistance. Thus, the mechanism of resistance in vivo may be due solely to intraerythrocytic conditions.
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PMID:Erythrocytic mechanism of sickle cell resistance to malaria. 34 52

The kinetics of sickling of malaria-infected red cells from humans with sickle cell trait were studied in vitro in an attempt to obtain direct experimental evidence for a selective advantage of the hemoglobin S heterozygote in a malarious region. The sickling rates of cells infected with Plasmodium falciparum and of non-infected cells were studied both in the total absence of oxygen (by dithionite addition) and at several different concentrations of oxyhemoglobin which might obtain in vivo. In all cases, red cells containing small plasmodium parasite forms (ring forms) sickled approximately eight times as readily as uninfected cells. Cells containing large parasitic forms (trophozoites and schizonts) appeared to sickle less readily than uninfected cells, by light microscopy criteria, but electron micrographs demonstrated the presence of polymerized deoxyhemoglobin S with a high frequency. It is concluded that enhanced sickling of plasmodium-infected AS cells may be one mechanism whereby the hemoglobin S polymorphism is balanced in favor of the heterozygote.
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PMID:Sickling rates of human AS red cells infected in vitro with Plasmodium falciparum malaria. 36 Mar 96

The host cell competence of hemoglobin C (HbC)-containing erythrocytes for Plasmodium falciparum was studied by in vitro culture. HbC homozygous red cells did not support the growth of the intracellular parasite. Heterozygous cells, however, were competent. In addition, HbC increased the resistance of sicle cell hemoglobin (HbS) red cells when present in the double heterozygote, SC, cultured at low oxygen tension. This effect most likely resulted from the ability of HbC to enhance the sickling of HbS-containing red cells. Oxygenated SC cells were indistinguishable from normal and AS cells in host cell competence. Another double heterozygote, SNBalt, showed decreased sickling and decreased resistance to malaria parasite growth. The evolutionary significance of these results is discussed.
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PMID:The role of hemoglobins C, S, and Nbalt in the inhibition of malaria parasite development in vitro. 38 16

Plasmodium falciparum in culture grows optimally at 3% oxygen. Oxygen levels down to 0.5% still support growth, but anaerobic conditions do not. These findings, and the absence of the Krebs cycle in Plasmodium, suggested that in this organism oxygen may not function in electron transport but rather may act through metalloprotein oxygenases. Tetraethylthiuram disulfide (Antabuse, disulfiram) and its reduction product diethyldithiocarbamate inhibit many metalloprotein oxygenases and have a lipid/H2O partition coefficient and high binding constant for metal ions, favoring selective toxicity to the malaria parasite. These compounds exhibited active antimalarial effects in vitro in concentrations down to 0.1 microgram/ml, the lowest level tested. Tetraethylthiuram disulfide at a level as low as 1 microgram/ml inhibited parasite glycolysis with no effect on glycolysis of normal erythrocytes. Erythrocytes pretreated with this drug at 10 microgram/ml did not support growth of the parasite.
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PMID:Tetraethylthiuram disulfide (Antabuse) inhibits the human malaria parasite Plasmodium falciparum. 38 34

Physiological tests of work performance and measurement of field productivity were made in 194 Sudanese cane cutters in order to study the effect of Schistosoma mansoni infection. The cane cutters were selected from two age ranges (16-24 and 25-45 years) and subdivided into three clinical groups: not infected, infected with, and infected without clinical signs of hepatosplenomegaly. Men infected with Schistosoma haemotobium, malaria (blood film), or with hemoglobin levels less than 10 g/100 ml were excluded. There was a statistically significant (P less than 0.002) higher mean hemoglobin concentration in those not infected but the mean difference was less than 1 g/100 ml. Submaximal responses to exercise on a stationary bicycle ergometer, oxygen intake, ventilation, tidal volume, cardiac frequency and estimated maximal aerobic power output calculated both in absolute terms and relative to lean body mass and leg volume were similar in the six groups of cane cutters. No significant differences were found in physique, body composition or in thermoregulatory function tests. The cane cutters were found to have little natural acclimatization to heat in terms of sweating capacity when compared with a group of fully acclimatized Sudanese soldiers. The mean productivity (mean daily weight of cane cut per man) was significantly correlated with the individual's estimated maximum aerobic capacity determined in the laboratory, but not with the degree of S. mansoni infection. The noninfected group was less "efficient" (mean productivity:oxygen intake) during cutting than the infected groups but a larger proportion of the noninfected were in their first season of cutting. There was a positive correlation between the number of seasons' cutting experience and the individual's age, degree of infection and mean productivity. Cane cutters studied in this investigation were a relatively fit, active population from whom the more seriously ill were excluded. These results do not, therefore necessarily reflect the effects of S. mansoni on physiological work capacity and productivity of more static populations in areas of high endemicity.
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PMID:Physiological performance and work capacity of Sudanese cane cutters with Schistosoma mansoni infection. 93 32

Macrophage activation was examined in resistant C57BL/6 and susceptible A/J mice during the course of blood-stage infection with Plasmodium chabaudi AS. Three parameters of macrophage activation (lipopolysaccharide [LPS]- and malaria antigen-induced tumor necrosis factor [TNF] production in vitro, phorbol myristate acetate [PMA]-induced production of oxygen metabolites in vitro, and Ia antigen expression) were assessed during infection in populations of peritoneal and splenic macrophages recovered from infected mice of the two strains. The peak level of LPS-induced TNF production in vitro by splenic macrophages from both infected C57BL/6 and infected A/J mice occurred on day 7, which was 3 days before the peak of parasitemia. Although the kinetics of TNF production in vitro in response to either LPS, soluble malaria antigen, or intact parasitized erythrocytes varied in some of the other macrophage populations during infection, there was no significant difference in the peak level of production. Peritoneal and splenic macrophages from infected C57BL/6 mice exhibited significantly increased PMA-induced production of H2O2 in vitro on day 7. Peritoneal macrophages from infected A/J mice also exhibited significant PMA-induced H2O2 production on day 7, while production by splenic macrophages from these hosts was not increased in comparison with production by cells from normal animals. Only peritoneal macrophages from infected C57BL/6 mice produced significantly increased levels of O2-, and this occurred on day 7 postinfection. Ia antigen expression by both peritoneal and splenic macrophages from resistant C57BL/6 and susceptible A/J mice was significantly increased during P. chabaudi AS infection. However, the percentage of Ia+ peritoneal macrophages on days 8 and 10 postinfection and Ia+ splenic macrophages on day 3 postinfection was significantly higher in C57BL/6 than in A/J mice. Thus, these results demonstrate that macrophages from P. chabaudi AS-infected A/J mice exhibit defects in oxygen metabolism and Ia antigen expression which may contribute to the susceptibility of these hosts to this intraerythrocytic parasite. The cause-and-effect relationship between these defects and the susceptibility of A/J mice to P. chabaudi AS is unknown.
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PMID:Macrophage activation during Plasmodium chabaudi AS infection in resistant C57BL/6 and susceptible A/J mice. 131 5

The role of reactive oxygen species (ROS) generated by polymorphonuclear leucocytes (PMNs) in the host response against malaria was investigated. Non-activated human PMNs were added to cultures of P. falciparum in microtitre cells. Parasite viability was evaluated by the incorporation of radioactive hypoxanthine. Using PMN/RBC = 1/150 (starting parasitemia was 1%) the incorporation on the second day in culture was only 61% of the control cultures. An effect could be observed already after two hours of incubation (30% reduction at a 1/50 PMN/RBC ratio). A direct contact between the effector and target cells was obligatory for the expression of the damage. Parasites within G6PD-deficient erythrocytes were more sensitive to the PMNs than normal parasitized erythrocytes. This difference could be attributed to the production of reactive oxygen intermediates in the experimental system, since G6PD-deficient erythrocytes are generally more sensitive to oxidant stress. Salicylic acid was used as a scavenger and reporter molecule for hydroxyl radical fluxes. It is converted to the corresponding dihydroxybenzoic acid derivatives, which could be detected by HPLC. Uninfected NRBC or parasitized erythrocytes containing young ring forms could trigger the PMNs to produce much less ROS than the mature forms of the parasites. Other factors associated with PMNs may inactivate the parasites, such as phagocytosis, lysosomal enzymes or degradation toxic products of the PMNs. However our results indicate that increased oxidative stress induced by PMNs interfere with the growth of P. falciparum and could play a role in human evolution of abnormal erythrocytes.
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PMID:Correlation between destruction of malarial parasites by polymorphonuclear leucocytes and oxidative stress. 133 29

Erythrocyte antioxidants catalase, superoxide dismutase, reduced glutathione and glutathione peroxidase were studied in cells harbouring different growth stages of Plasmodium falciparum. Catalase and superoxide dismutase showed significant decrease during parasite maturation indicating hampered metabolism of hydrogen peroxide and superoxide anions. Glutathione peroxidase also exhibited a downward trend during the growth of P. falciparum, while there was a moderate accumulation of reduced glutathione. These findings suggest decreased utilization of the reduction potential in detoxification of reactive oxygen species. The fall in all three antioxidant enzymes studied was highly significant (P less than 0.001) in erythrocytes with mature stages of the parasite (trophozoites, schizonts). The increased vulnerability of erythrocytes to damage, which parallels the growth phases of the parasite emphasizes the need for early treatment of P. falciparum malaria to minimise red cell destruction and the resulting anaemia.
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PMID:Plasmodium falciparum induced perturbations of the erythrocyte antioxidant system. 139 36

Malaria parasites have been shown to be more susceptible to oxidative stress than their host erythrocytes. In the present work, a chloroquine resistant malaria parasite, Plasmodium falciparum (FCR-3) was found to be susceptible in vitro to a pyridoxal based iron chelator--(1-[N-ethoxycarbonylmethylpyridoxlidenium]-2-[2'-pyridyl ] hydrazine bromide--(code named L2-9). 2h exposure to 20 microM L2-9 was sufficient to irreversibly inhibit parasite growth. Desferrioxamine blocked the drug effect, indicating the requirement for iron. Oxygen however, was not essential. Spectrophotometric analysis showed that under anoxic conditions, L2-9-Fe(II) chelate undergoes an intramolecular redox reaction which presumably involves a one electron transfer and is expected to result in the formation of free radical. Spin trapping coupled to electron spin resonance (ESR) studies of L2-9-iron chelate showed that L2-9-Fe(II) produced free radicals both in the presence and absence of cells, while L2-9-Fe(III) produced free radicals only in the presence of actively metabolising cells.
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PMID:Growth inhibition of Plasmodium falciparum involving carbon centered iron-chelate radical (L., X-)-Fe(III) based on pyridoxal-betaine. A novel type of antimalarials active against chloroquine-resistant parasites. 166 64

A free radical is any species capable of independent existence that contains one or more unpaired electrons. Free radical reactions have been implicated in the pathology of more than 50 human diseases. Radicals and other reactive oxygen species are formed constantly in the human body, both by deliberate synthesis (e.g. by activated phagocytes) and by chemical side-reactions. They are removed by enzymic and nonenzymic antioxidant defence systems. Oxidative stress, occurring when antioxidant defences are inadequate, can damage lipids, proteins, carbohydrates and DNA. A few clinical conditions are caused by oxidative stress, but more often the stress results from the disease. Sometimes it then makes a significant contribution to the disease pathology, and sometimes it does not. Several antioxidants are available for therapeutic use. They include molecules naturally present in the body [superoxide dismutase (SOD), alpha-tocopherol, glutathione and its precursors, ascorbic acid, adenosine, lactoferrin and carotenoids] as well as synthetic antioxidants [such as thiols, ebselen (PZ51), xanthine oxidase inhibitors, inhibitors of phagocyte function, iron ion chelators and probucol]. The therapeutic efficacy of SOD, alpha-tocopherol and ascorbic acid in the treatment of human disease is generally unimpressive to date although dietary deficiencies of the last two molecules should certainly be avoided. Xanthine oxidase inhibitors may be of limited relevance as antioxidants for human use. Exciting preliminary results with probucol (antiatherosclerosis), ebselen (anti-inflammatory), and iron ion chelators (in thalassaemia, leukaemia, malaria, stroke, traumatic brain injury and haemorrhagic shock) need to be confirmed by controlled clinical trials. Clinical testing of N-acetylcysteine in HIV-1-positive subjects may also be merited. A few drugs already in clinical use may have some antioxidant properties, but this ability is not widespread and drug-derived radicals may occasionally cause significant damage.
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PMID:Drug antioxidant effects. A basis for drug selection? 172 62


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