ORCID Profile
0000-0002-6685-8208
Current Organisations
Libragem Consulting
,
Union for International Cancer Control
,
American Society for Clinical Pathology
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Publisher: Springer Science and Business Media LLC
Date: 04-10-2006
Publisher: Public Library of Science (PLoS)
Date: 22-11-2005
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-09-2006
Publisher: Elsevier BV
Date: 12-2008
Abstract: This review summarizes progress in preventing and treating severe malaria, which has been accompanied by advances in our understanding of the pathogenesis of severe malaria complications. New drugs such as intravenous artesunate and oral artemisinin combinations, with increased access to insecticide-treated bed nets, are improving outcomes and decreasing malaria deaths. Several groups are beginning to identify characteristics of parasite var genes associated with cerebral malaria. Understanding of the interactions between malaria and other diseases in causing severe anaemia and cerebral malaria has increased substantially, and at the cellular level, the disturbances leading to coma or other complications are becoming clearer.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 04-05-2018
Abstract: In vivo visualization of Plasmodium parasites reveals sublocalization, deformability, and mobility of gametocytes in the bone marrow.
Publisher: Oxford University Press (OUP)
Date: 07-2006
DOI: 10.1086/504689
Abstract: Falciparum malaria is characterized by cytoadherence of host erythrocytes containing mature asexual-stage parasites and the consequent sequestration of these forms in tissue microvasculature. A postmortem study of pediatric malaria provided us with the opportunity to compare the genetic complexity of circulating and sequestered Plasmodium falciparum populations, in patients with fatal cerebral malaria (CM) versus control subjects with incidental P. falciparum parasitemia who died of causes other than malaria. Parasite genotypes identified in peripheral blood collected at the time of admission to the hospital constituted a subset of those detected in the tissues at death. Despite a higher tissue burden of parasitized erythrocytes in patients with CM than in parasitemic control subjects, parasite populations in tissues from patients with CM were less genetically complex, and the genotypes were more homogeneously distributed throughout the body, than in patients with incidental infection. Our findings support the notion that CM is associated with the emergence of a small number of dominant genotypes in an infected in idual.
Publisher: Springer Science and Business Media LLC
Date: 16-03-2023
DOI: 10.1038/S41467-023-36921-2
Abstract: Identifying how small molecules act to kill malaria parasites can lead to new “chemically validated” targets. By pressuring Plasmodium falciparum asexual blood stage parasites with three novel structurally-unrelated antimalarial compounds (MMV665924, MMV019719 and MMV897615), and performing whole-genome sequence analysis on resistant parasite lines, we identify multiple mutations in the P. falciparum acyl-CoA synthetase (ACS) genes Pf ACS10 (PF3D7_0525100, M300I, A268D/V, F427L) and Pf ACS11 (PF3D7_1238800, F387V, D648Y, and E668K). Allelic replacement and thermal proteome profiling validates Pf ACS10 as a target of these compounds. We demonstrate that this protein is essential for parasite growth by conditional knockdown and observe increased compound susceptibility upon reduced expression. Inhibition of Pf ACS10 leads to a reduction in triacylglycerols and a buildup of its lipid precursors, providing key insights into its function. Analysis of the Pf ACS11 gene and its mutations point to a role in mediating resistance via decreased protein stability.
Publisher: Springer Science and Business Media LLC
Date: 2015
Publisher: Elsevier BV
Date: 06-2015
Publisher: Public Library of Science (PLoS)
Date: 04-12-2014
Publisher: American Society for Microbiology
Date: 30-10-2015
Abstract: Cerebral malaria (CM) is a major contributor to malaria deaths, but its pathophysiology is not well understood. While sequestration of parasitized erythrocytes is thought to be critical, the roles of inflammation and coagulation are controversial. In a large series of Malawian children hospitalized with CM, HIV coinfection was more prevalent than in pediatric population estimates (15% versus 2%, P 0.0001, chi-square test), with higher mortality than that seen in HIV-uninfected children (23% versus 17%, P = 0.0178, chi-square test). HIV-infected (HIV + ) children with autopsy-confirmed CM were older than HIV-uninfected children (median age, 99 months versus 32 months, P = 0.0007, Mann-Whitney U test) and appeared to lack severe immunosuppression. Because HIV infection is associated with dysregulated inflammation and platelet activation, we performed immunohistochemistry analysis for monocytes, platelets, and neutrophils in brain tissue from HIV + and HIV-uninfected children with fatal CM. Children with autopsy-confirmed CM had significantly ( times) more accumulations of intravascular monocytes and platelets, but not neutrophils, than did children with nonmalarial causes of coma. The monocyte and platelet accumulations were significantly ( -fold) greater in HIV + children than in HIV-uninfected children with autopsy-confirmed CM. Our findings indicate that HIV is a risk factor for CM and for death from CM, independent of traditional measures of HIV disease severity. Brain histopathology supports the hypotheses that inflammation and coagulation contribute to the pathogenesis of pediatric CM and that immune dysregulation in HIV + children exacerbates the pathological features associated with CM. IMPORTANCE There are nearly 1 million malaria deaths yearly, primarily in sub-Saharan African children. Cerebral malaria (CM), marked by coma and sequestered malaria parasites in brain blood vessels, causes half of these deaths, although the mechanisms causing coma and death are uncertain. Sub-Saharan Africa has a high HIV prevalence, with 3 million HIV-infected (HIV + ) children, but the effects of HIV on CM pathogenesis and mortality are unknown. In a study of pediatric CM in Malawi, HIV prevalence was high and CM-attributed mortality was higher in HIV + than in HIV-uninfected children. Brain pathology in children with fatal CM was notable not only for sequestered malaria parasites but also for intravascular accumulations of monocytes and platelets that were more severe in HIV + children. Our findings raise the possibility that HIV + children at risk for malaria may benefit from targeted malaria prophylaxis and that adjunctive treatments targeting inflammation and/or coagulation may improve CM outcomes.
Location: United States of America
Location: United States of America
No related grants have been discovered for Danny Arnold Milner, Jr.