Nitric oxide, malaria, and anemia: inverse relationship between nitric oxide production and hemoglobin concentration in asymptomatic, malaria-exposed children.

Anstey, Nicholas M.; Granger, Donald L.; Hassanali, M Y; Mwaikambo, Esther D.; Duffy, Patrick E.; Weinberg, J. Brice

doi:10.4269/ajtmh.1999.61.249

Cited by 52 publications

(28 citation statements)

References 28 publications

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“…Since nitric oxide can reduce erythrocyte deformability, 10,11 it could lead to increased red blood cell destruction. 4 This hypothesis is supported by recent findings showing that RNI were negatively correlated with hemoglobin concentrations 12 and were highest in young infants and after 5 years. Thus RNI could possibly contribute to the epidemiological patterns of severe anemia and cerebral malaria.…”

Section: Discussionsupporting

confidence: 77%

Association of helminth infection with decreased reticulocyte counts and hemoglobin concentration in Thai falciparum malaria.

Nacher

Singhasivanon²,

Phumratanaprapin³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

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Abstract. Following a study showing an association between Ascaris and protection from cerebral malaria, we conducted a cross-sectional study comparing admission hemoglobin concentrations in relation to exposure to helminth infection in 2 separate groups of patients: 111 cerebral malaria cases and 180 mild Plasmodium falciparum malaria cases. Hookworm infections were excluded. Mean hemoglobin concentrations were significantly lower in helminthinfected patients compared to those without helminths, both in the cerebral malaria group (10.1 Ϯ 3 [n ϭ 47] versus 11.2 Ϯ 2.4 g/dl [n ϭ 64], P ϭ 0.04) and the mild malaria group (11 Ϯ 2.5 [n ϭ 89] vs 12.2 Ϯ 2.7 g/dl [n ϭ 91], P ϭ 0.004). Median reticulocyte counts, only available in the cerebral malaria group, were lower in helminth-infected patients compared to those without helminths (15,340/23,760 per l, P ϭ 0.03). Adjustments for confounders such as body mass index did not alter these associations. These data are consistent with a mechanism causing anemia linked to differences in the immune response of helminth-infected patients during malaria.

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Section: Discussionsupporting

confidence: 77%

Association of helminth infection with decreased reticulocyte counts and hemoglobin concentration in Thai falciparum malaria.

Nacher

Singhasivanon²,

Phumratanaprapin³

et al. 2001

The American Journal of Tropical Medicine and Hygiene

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“…Further, upregulation of endothelial cell adhesion molecules in response to tumor necrosis factor alpha potentially augments the cytoadherence (22). However, in recent studies, increased NO production has been shown to be beneficial because of its antiparasitic and antidisease effect, although this is controversial, (1). This effect is due to inhibition of the cytoadherence process through downregulation of the expression of ICAM1, VCAM1, and E-selectin, which are involved in cytoadherence and microvascular sequestration of parasitized RBCs (18) and decreased production of tumor necrosis factor by macrophages (9).…”

mentioning

confidence: 99%

Endothelial Nitric Oxide Synthase Gene Polymorphisms and Plasmodium falciparum Infection in Indian Adults

et al. 2009

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To explore the hypothesis that susceptibility to cerebral malaria is influenced by genetic variation in endothelial nitric oxide synthase (eNOS), we genotyped three commonly defined polymorphic loci of eNOS, Glu 298 3Asp, intron 4 variable number of tandem repeat region, and T-7863C, in 244 patients (mean age, 36.2 years) with mild malaria and 194 patients (mean age, 35.6 years) with severe malaria belonging to same ethnic group in Orissa, an eastern Indian state. We found that there was an association of the Glu 298 3Asp substitution (P ‫؍‬ 0.0037; odds ratio, 1.95; 95% confidence interval, 1.2 to 3.0) and a single unique haplotype defined by "C-b-Asp" (P corrected ‫؍‬ 0.0024) for protection against cerebral malaria. Further, the median plasma level of nitrite-nitrate was found to be increased in individuals with the Glu 298 3Asp substitution and was significantly higher in the mild malaria group (P < 0.0001), but the increase was not significant in the severe malaria group (P ‫؍‬ 0.0528). These findings suggest that the Glu 298 3Asp substitution and the "C-b-Asp" haplotype may enhance eNOS expression and NO production, which leads to protection against cerebral malaria. These findings may increase our understanding of the pathogenesis of malaria.Malaria parasites are major human pathogens that annually are associated with 300 million to 500 million clinical cases worldwide and 1 million to 3 million deaths (2). Despite high infection rates, only 1% to 2% of malaria patients develop life-threatening complications, such as cerebral malaria and profound anemia, so natural selection has likely operated, to a large extent, on severity (11). This has prompted the search for factors involved in natural resistance to severe malaria. The severity of malaria depends largely upon the capacity of Plasmodium falciparum-infected erythrocytes (RBCs) to adhere to the endothelia of microvessels (cytoadherence) and to form rosettes with uninfected RBCs (14). This results in a high parasite burden and severe proinflammatory responses in localized areas, leading to endothelial damage and organ dysfunction (7). Further, upregulation of endothelial cell adhesion molecules in response to tumor necrosis factor alpha potentially augments the cytoadherence (22). However, in recent studies, increased NO production has been shown to be beneficial because of its antiparasitic and antidisease effect, although this is controversial, (1). This effect is due to inhibition of the cytoadherence process through downregulation of the expression of ICAM1, VCAM1, and E-selectin, which are involved in cytoadherence and microvascular sequestration of parasitized RBCs (18) and decreased production of tumor necrosis factor by macrophages (9). NO is produced during the enzymatic conversion of L-arginine to L-citrulline by three isoforms of nitric oxide synthase (NOS), namely inducible NOS, endothelial NOS (eNOS), and neuronal NOS (19). The eNOSderived NO mediates vasodilation, inhibits platelet aggregation and endothelial cell activation, and modulates ...

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“…Anemia is an important complication of malaria both in asymptomatic children and in children with acute febrile episodes (4,24,33). The pathogenesis of malarial anemia is not well understood, but inflammatory cytokines, such as tumor necrosis factor alpha (TNF-␣) and IL-10, are believed to be involved (23,30).…”

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confidence: 99%

Anemia and Interleukin-10, Tumor Necrosis Factor Alpha, and Erythropoietin Levels among Children with Acute, UncomplicatedPlasmodium falciparumMalaria

Nussenblatt

Mukasa

Metzger

et al. 2001

Clin Diagn Lab Immunol

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Anemia is an important complication of malaria, and its pathogenesis is not well understood. To gain insight into potential age-related relationships between tumor necrosis factor alpha (TNF-␣), interleukin 10 (IL-10), erythropoietin, and anemia during acute malaria, 273 children of ages 12 to 120 months presenting with acute, uncomplicated malaria in Kampala, Uganda, were monitored at enrollment and 3 and 7 days later. Younger children had higher geometric mean erythropoietin, TNF-␣, and ␣ 1 -acid glycoprotein (AGP) concentrations than older children. Univariate regression analysis revealed that age, log 10 erythropoietin levels, IL-10/TNF-␣ ratio, and AGP levels were each significantly associated with hemoglobin levels at baseline. Hemoglobin concentrations were inversely correlated with the log 10 erythropoietin level at all three visits. For the older age groups, higher levels of TNF-␣ were significantly associated with higher IL-10 levels at all three visits, but this relationship was significant only at baseline for younger children. These data suggest that younger children do not maintain IL-10 production in response to the inflammatory process, and this mechanism may contribute to the more severe anemia found in younger children. Acute malaria is an illness whose incidence and severity are largely age dependent. Further studies are needed to understand the relationships between age-related immune responses to malaria and their role in the pathogenesis of malarial anemia.

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Nitric oxide, malaria, and anemia: inverse relationship between nitric oxide production and hemoglobin concentration in asymptomatic, malaria-exposed children.

Cited by 52 publications

References 28 publications

Association of helminth infection with decreased reticulocyte counts and hemoglobin concentration in Thai falciparum malaria.

Association of helminth infection with decreased reticulocyte counts and hemoglobin concentration in Thai falciparum malaria.

Endothelial Nitric Oxide Synthase Gene Polymorphisms and Plasmodium falciparum Infection in Indian Adults

Anemia and Interleukin-10, Tumor Necrosis Factor Alpha, and Erythropoietin Levels among Children with Acute, UncomplicatedPlasmodium falciparumMalaria

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