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Shanks G.D.,Australian Army Malaria Institute | Shanks G.D.,University of Queensland | Shanks G.D.,University of Oxford | White N.J.,Mahidol University | White N.J.,Center for Tropical Medicine
The Lancet Infectious Diseases | Year: 2013

The periodicity of vivax malaria relapses may be explained by the activation of latent hypnozoites acquired from a previous malarial infection. The activation stimulus could be the febrile illness associated with acute malaria or a different febrile infection. We review historical records to examine the association between relapses of Plasmodium vivax and febrile infectious diseases. In data from British soldiers in Palestine, epidemic falciparum malaria triggered a smaller epidemic of P vivax relapses only in those who had been extensively exposed to malaria previously. Relapses did not follow pandemic influenza infection. Evidence from three simultaneous typhoid and malaria epidemics suggest that typhoid fever might activate P vivax hypnozoites. Some data lend support to the notion that vivax malaria relapse followed febrile illness caused by relapsing fever, trench fever, epidemic typhus, and Malta fever (brucellosis). These observations suggest that systemic parasitic and bacterial infections, but not viral infections, can activate P vivax hypnozoites. Specific components of the host's acute febrile inflammatory response, and not fever alone, are probably important factors in the provocation of a relapse of vivax malaria. © 2013 Elsevier Ltd.

Kager L.M.,University of Amsterdam | Weehuizen T.A.,University of Amsterdam | Wiersinga W.J.,University of Amsterdam | Roelofs J.J.T.H.,University of Amsterdam | And 5 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2013

Rationale: α2-Antiplasmin (A2AP) is a major inhibitor of fibrinolysis by virtue of its capacity to inhibit plasmin. Although the fibrinolytic system is strongly affected by infection, the functional role of A2AP in the host response to sepsis is unknown. Objectives: To study the role of A2AP in melioidosis, a common form ofcommunity-acquired sepsis in SoutheastAsia and Northern Australia caused by the gram-negative bacterium Burkholderia pseudomallei. Methods: In a single-center observational study A2AP was measured in patients with culture-proven septic melioidosis. Wild-type and A2AP-deficient (A2AP-/-) mice were intranasally infected with B. pseudomallei to induce severe pneumosepsis (melioidosis). Parameters of inflammation and coagulation were measured, and survival studies were performed. Measurements and Main Results: Patients with melioidosis showed elevated A2AP plasma levels. Likewise, A2AP levels in plasma and lunghomogenates were elevated in mice infected with B. pseudomallei. A2AP-deficient (A2AP-/-) mice had a strongly disturbed host response during experimental melioidosis as reflected by enhanced bacterial growth at the primary site of infection accompanied by increased dissemination to distant organs. In addition, A2AP-/- mice showed more severe lung pathology and injury together with an increased accumulation of neutrophils and higher cytokine levels in lung tissue. A2AP deficiency further was associated with exaggerated systemic inflammation and coagulation, increased distant organ injury, and enhanced lethality. Conclusions: This study is the first to identify A2AP as a protective mediator during gram-negative (pneumo)sepsis by limiting bacterial growth, inflammation, tissue injury, and coagulation. Copyright © 2013 by the American Thoracic Society.

Omodeo-Sale F.,University of Milan | Cortelezzi L.,University of Milan | Vommaro Z.,University of Milan | Scaccabarozzi D.,University of Milan | And 2 more authors.
American Journal of Physiology - Cell Physiology | Year: 2010

Severe Plasmodium falciparum malaria is associated with hypoargininemia, which contributes to impaired systemic and pulmonary nitric oxide (NO) production and endothelial dysfunction. Since intravascular hemolysis is an intrinsic feature of severe malaria, we investigated whether and by which mechanisms free heme [Fe(III)-protoporphyrin IX (FP)] might contribute to the dysregulation of L-arginine (L-Arg) metabolism and bioavailability. Carrier systems "y+" [or cationic amino acid transporter (CAT)] and "y+L" transport L-Arg into red blood cells (RBC), where it is hydrolyzed to ornithine and urea by arginase (isoform I) or converted to NO • and citrulline by endothelial nitric oxide synthase (eNOS). Our results show a significant and dose-dependent impairment of L-Arg transport into RBC pretreated with FP, with a strong inhibition of the system carrier y+L. Despite the impaired L-Arg influx, higher amounts of L-Arg-derived urea are produced by RBC preexposed to FP caused by activation of RBC arginase I. This activation appeared not to be mediated by oxidative modifications of the enzyme. We conclude that L-Arg transport across RBC membrane is impaired and arginase-mediated L-Arg consumption enhanced by free heme. This could contribute to reduced NO production in severe malaria. Copyright © 2010 the American Physiological Society.

White N.J.,Mahidol University | White N.J.,Center for Tropical Medicine | Pukrittayakamee S.,Mahidol University | Hien T.T.,University of Oxford | And 4 more authors.
The Lancet | Year: 2014

Although global morbidity and mortality have decreased substantially, malaria, a parasite infection of red blood cells, still kills roughly 2000 people per day, most of whom are children in Africa. Two factors largely account for these decreases; increased deployment of insecticide-treated bednets and increased availability of highly effective artemisinin combination treatments. In large trials, parenteral artesunate (an artemisinin derivative) reduced severe malaria mortality by 22·5% in Africa and 34·7% in Asia compared with quinine, whereas adjunctive interventions have been uniformly unsuccessful. Rapid tests have been an important addition to microscopy for malaria diagnosis. Chemopreventive strategies have been increasingly deployed in Africa, notably intermittent sulfadoxine-pyrimethamine treatment in pregnancy, and monthly amodiaquine-sulfadoxine-pyrimethamine during the rainy season months in children aged between 3 months and 5 years across the sub-Sahel. Enthusiasm for malaria elimination has resurfaced. This ambitious but laudable goal faces many challenges, including the worldwide economic downturn, difficulties in elimination of vivax malaria, development of pyrethroid resistance in some anopheline mosquitoes, and the emergence of artemisinin resistance in Plasmodium falciparum in southeast Asia. We review the epidemiology, clinical features, pathology, prevention, and treatment of malaria.

McGready R.,Shoklo Malaria Research Unit SMRU | McGready R.,Mahidol University | White N.J.,Mahidol University | White N.J.,Center for Tropical Medicine | And 2 more authors.
BJOG: An International Journal of Obstetrics and Gynaecology | Year: 2011

Background: Pregnant women are at increased risk from malaria. Resistance to all classes of antimalarials has affected the treatment and prevention of malaria in pregnancy. Objectives To review the therapeutic efficacy of antimalarials used for treatment and intermittent preventive treatment (IPT) in pregnancy. Search strategy We searched MEDLINE and the Cochrane Library between January 1998 and December 2009 for publications using the medical subject headings: efficacy, antimalarials, malaria, pregnancy, pharmacokinetics, treatment, IPT and placenta positive. In May 2010 we searched the register of clinical trials (http://clinicaltrials.gov/) and of WHO (http://apps.who.int/ trialsearch/) using 'malaria', and 'pregnancy' and 'treatment'. Selection criteria We identified 233 abstracts, reviewed 83 full text articles and included 60 studies. Data collection and analysis Two authors entered extracted data to an excel spreadsheet. Main results Parasitological failure rates, placenta positivity rates (assessed by microscopy) or both were reported in 44% (21/48), 46% (22/48) and 10% (5/48) of articles, respectively. Most pharmacokinetic studies (9/12) suggested dose optimisation. In 23 treatment studies 17 different antimalarial drugs were delivered in 53 study arms; 43.4% (23/53) reported a failure rate of < 5%; 83.3% of sulphadoxine-pyrimethamine (SP) arms and 9% of artemisinin combination therapy (ACT) arms had failure rates ≥ 10%. Placenta-positive rates (mostly reported in the context of IPT in pregnancy) were > 10% in 68% (23/34) of SP trial arms and > 15% in all seven chloroquine arms. The ACT provided lower parasitological failure and gametocyte carriage rates. Author's conclusions Drugs used in pregnancy should aim for 95% efficacy but many currently deployed regimens are associated with much lower cure rates. © RCOG 2010 BJOG An International Journal of Obstetrics and Gynaecology.

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