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      Pathogenesis of cerebral malaria—inflammation and cytoadherence

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          Abstract

          Despite decades of research on cerebral malaria (CM) there is still a paucity of knowledge about what actual causes CM and why certain people develop it. Although sequestration of P. falciparum infected red blood cells has been linked to pathology, it is still not clear if this is directly or solely responsible for this clinical syndrome. Recent data have suggested that a combination of parasite variant types, mainly defined by the variant surface antigen, P. falciparum erythrocyte membrane protein 1 (PfEMP1), its receptors, coagulation and host endothelial cell activation (or inflammation) are equally important. This makes CM a multi-factorial disease and a challenge to unravel its causes to decrease its detrimental impact.

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          Most cited references106

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          Malaria biology and disease pathogenesis: insights for new treatments.

          Plasmodium falciparum malaria, an infectious disease caused by a parasitic protozoan, claims the lives of nearly a million children each year in Africa alone and is a top public health concern. Evidence is accumulating that resistance to artemisinin derivatives, the frontline therapy for the asexual blood stage of the infection, is developing in southeast Asia. Renewed initiatives to eliminate malaria will benefit from an expanded repertoire of antimalarials, including new drugs that kill circulating P. falciparum gametocytes, thereby preventing transmission. Our current understanding of the biology of asexual blood-stage parasites and gametocytes and the ability to culture them in vitro lends optimism that high-throughput screenings of large chemical libraries will produce a new generation of antimalarial drugs. There is also a need for new therapies to reduce the high mortality of severe malaria. An understanding of the pathophysiology of severe disease may identify rational targets for drugs that improve survival.
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            Antigenic variation in Plasmodium falciparum.

            The persistence of the human malaria parasite Plasmodium falciparum during blood stage proliferation in its host depends on the successive expression of variant molecules at the surface of infected erythrocytes. This variation is mediated by the differential control of a family of surface molecules termed PfEMP1 encoded by approximately 60 var genes. Each individual parasite expresses a single var gene at a time, maintaining all other members of the family in a transcriptionally silent state. PfEMP1/var enables parasitized erythrocytes to adhere within the microvasculature, resulting in severe disease. This review highlights key regulatory mechanisms thought to be critical for monoallelic expression of var genes. Antigenic variation is orchestrated by epigenetic factors including monoallelic var transcription at separate spatial domains at the nuclear periphery, differential histone marks on otherwise identical var genes, and var silencing mediated by telomeric heterochromatin. In addition, controversies surrounding var genetic elements in antigenic variation are discussed.
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              Pathogenesis, clinical features, and neurological outcome of cerebral malaria.

              Cerebral malaria is the most severe neurological complication of Plasmodium falciparum malaria. Even though this type of malaria is most common in children living in sub-Saharan Africa, it should be considered in anybody with impaired consciousness that has recently travelled in a malaria-endemic area. Cerebral malaria has few specific features, but there are differences in clinical presentation between African children and non-immune adults. Subsequent neurological impairments are also most common and severe in children. Sequestration of infected erythrocytes within cerebral blood vessels seems to be an essential component of the pathogenesis. However, other factors such as convulsions, acidosis, or hypoglycaemia can impair consciousness. In this review, we describe the clinical features and epidemiology of cerebral malaria. We highlight recent insights provided by ex-vivo work on sequestration and examination of pathological specimens. We also summarise recent studies of persisting neurocognitive impairments in children who survive cerebral malaria and suggest areas for further research.
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                Author and article information

                Contributors
                Journal
                Front Cell Infect Microbiol
                Front Cell Infect Microbiol
                Front. Cell. Infect. Microbiol.
                Frontiers in Cellular and Infection Microbiology
                Frontiers Media S.A.
                2235-2988
                26 June 2014
                29 July 2014
                2014
                : 4
                : 100
                Affiliations
                [1] 1Department of Parasitology, Liverpool School of Tropical Medicine Liverpool, UK
                [2] 2Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW), University of Malawi College of Medicine Blantyre, Malawi
                Author notes

                Edited by: Samuel C. Wassmer, New York University School of Medicine, USA

                Reviewed by: Yi Xu, Texas A&M Health Science Center, USA; Diana Silvia Hansen, The Walter and Eliza Hall Institute of Medical Research, Australia; Ana Rodriguez, New York University, USA

                *Correspondence: Janet Storm, Department of Parasitology, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK e-mail: jstorm@ 123456liverpool.ac.uk

                This article was submitted to the journal Frontiers in Cellular and Infection Microbiology.

                Article
                10.3389/fcimb.2014.00100
                4114466
                25120958
                7c45e0b4-d013-47b5-967f-33d96392a1ef
                Copyright © 2014 Storm and Craig.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 May 2014
                : 07 July 2014
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 130, Pages: 8, Words: 8206
                Categories
                Microbiology
                Mini Review Article

                Infectious disease & Microbiology
                cerebral malaria,endothelium dysfunction,inflammation,histopathology,pfemp1

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