Other
-
Scientific MembershipsAcademy of Medical Sciences
Fellow of the Royal College of Physicians
Publications (228) View all
-
Article: Antidogmatic approaches to artemisinin resistance: reappraisal as treatment failure with artemisinin combination therapy.
[show abstract] [hide abstract]
ABSTRACT: The definition of artemisinin resistance is becoming one of a prolonged parasite clearance phenotype, although this variable is a complex function of both host and parasite characteristics. We discuss some of the limitations of this definition of artemisinin resistance, particularly because of its potential global impact. This opinion article reviews the mechanisms underlying parasite clearance after artemisinin treatment and how these might relate to in vitro methods to assay for resistance. It revisits criteria for defining artemisinin resistance that are not currently being applied and suggests the term 'treatment failure of artemisinin combination therapy' (TFACT) as a more accurate description of most cases of 'artemisinin resistance'.Trends in Parasitology 04/2013; · 5.14 Impact Factor -
Article: Expression in yeast links field polymorphisms in PfATP6 to in vitro artemisinin resistance and identifies new inhibitor classes.
[show abstract] [hide abstract]
ABSTRACT: Background. The mechanism of action of artemisinins against malaria is unclear, despite their widespread use in combination therapies and the emergence of resistance.Results. Here, we report expression of PfATP6 (a SERCA pump) in yeast and demonstrate its inhibition by artemisinins. Mutations in PfATP6 identified in field isolates (such as S769N) and in laboratory clones (such as L263E) decrease susceptibility to artemisinins, whereas they increase susceptibility to unrelated inhibitors such as cyclopiazonic acid. As predicted from the yeast model, Plasmodium falciparum with the L263E mutation is also more susceptible to cyclopiazonic acid. An inability to knockout parasite SERCA pumps provides genetic evidence that they are essential in asexual stages of development. Thaperoxides are a new class of potent antimalarial designed to act by inhibiting PfATP6. Results in yeast confirm this inhibition.Conclusions. The identification of inhibitors effective against mutated PfATP6 suggests ways in which artemisinin resistance may be overcome.The Journal of Infectious Diseases 04/2013; · 6.41 Impact Factor -
Article: Neopterin Is a Cerebrospinal Fluid Marker for Treatment Outcome Evaluation in Patients Affected by Trypanosoma brucei gambiense Sleeping Sickness.
[show abstract] [hide abstract]
ABSTRACT: BACKGROUND: Post-therapeutic follow-up is essential to confirm cure and to detect early treatment failures in patients affected by sleeping sickness (HAT). Current methods, based on finding of parasites in blood and cerebrospinal fluid (CSF) and counting of white blood cells (WBC) in CSF, are imperfect. New markers for treatment outcome evaluation are needed. We hypothesized that alternative CSF markers, able to diagnose the meningo-encephalitic stage of the disease, could also be useful for the evaluation of treatment outcome. METHODOLOGYPRINCIPAL FINDINGS: Cerebrospinal fluid from patients affected by HAT and followed for two years after treatment was investigated. The population comprised stage 2 (S2) patients either cured or experiencing treatment failure during the follow-up. IgM, neopterin, B2MG, MMP-9, ICAM-1, VCAM-1, CXCL10 and CXCL13 were first screened on a small number of HAT patients (n = 97). Neopterin and CXCL13 showed the highest accuracy in discriminating between S2 cured and S2 relapsed patients (AUC 99% and 94%, respectively). When verified on a larger cohort (n = 242), neopterin resulted to be the most efficient predictor of outcome. High levels of this molecule before treatment were already associated with an increased risk of treatment failure. At six months after treatment, neopterin discriminated between cured and relapsed S2 patients with 87% specificity and 92% sensitivity, showing a higher accuracy than white blood cell numbers. CONCLUSIONSSIGNIFICANCE: In the present study, neopterin was highlighted as a useful marker for the evaluation of the post-therapeutic outcome in patients suffering from sleeping sickness. Detectable levels of this marker in the CSF have the potential to shorten the follow-up for HAT patients to six months after the end of the treatment.PLoS Neglected Tropical Diseases 02/2013; 7(2):e2088. · 4.69 Impact Factor -
Article: The Plasmodium berghei Ca(2+)/H(+) Exchanger, PbCAX, Is Essential for Tolerance to Environmental Ca(2+) during Sexual Development.
[show abstract] [hide abstract]
ABSTRACT: Ca contributes to a myriad of important cellular processes in all organisms, including the apicomplexans, and . Due to its varied and essential roles, free Ca is tightly regulated by complex mechanisms. These mechanisms are therefore of interest as putative drug targets. One pathway in Ca homeostatic control in apicomplexans uses a Ca/H exchanger (a member of the cation exchanger family, CAX). The CAX (PfCAX) has recently been characterised in asexual blood stage parasites. To determine the physiological importance of apicomplexan CAXs, tagging and knock-out strategies were undertaken in the genetically tractable and parasites. In addition, a yeast heterologous expression system was used to study the function of apicomplexan CAXs. Tagging of and CAXs (TgCAX and PbCAX) under control of their endogenous promoters could not demonstrate measureable expression of either CAX in tachyzoites and asexual blood stages, respectively. These results were consistent with the ability of parasites to tolerate knock-outs of the genes for TgCAX and PbCAX at these developmental stages. In contrast, PbCAX expression was detectable during sexual stages of development in female gametocytes/gametes, zygotes and ookinetes, where it was dispersed in membranous networks within the cytosol (with minimal mitochondrial localisation). Furthermore, genetically disrupted parasites failed to develop further from "round" form zygotes, suggesting that PbCAX is essential for ookinete development and differentiation. This impeded phenotype could be rescued by removal of extracellular Ca. Therefore, PbCAX provides a mechanism for free living parasites to multiply within the ionic microenvironment of the mosquito midgut. Ca homeostasis mediated by PbCAX is critical and suggests plasmodial CAXs may be targeted in approaches designed to block parasite transmission.PLoS Pathogens 02/2013; 9(2):e1003191. · 9.13 Impact Factor -
Article: New biomarkers for stage determination in Trypanosoma brucei rhodesiense sleeping sickness patients.
[show abstract] [hide abstract]
ABSTRACT: Accurate stage determination is crucial in the choice of treatment for patients suffering from sleeping sickness, also known as human African trypanosomiasis (HAT). Current staging methods, based on the counting of white blood cells (WBC) and the detection of parasites in the cerebrospinal fluid (CSF) have limited accuracy. We hypothesized that immune mediators reliable for staging T. b. gambiense HAT could also be used to stratify T. b. rhodesiense patients, the less common form of HAT.A population comprising 85 T. b. rhodesiense patients, 14 stage 1 (S1) and 71 stage 2 (S2) enrolled in Malawi and Uganda, was investigated. The CSF levels of IgM, MMP-9, CXCL13, CXCL10, ICAM-1, VCAM-1, neopterin and B2MG were measured and their staging performances evaluated using receiver operating characteristic (ROC) analyses.IgM, MMP-9 and CXCL13 were the most accurate markers for stage determination (partial AUC 88%, 86% and 85%, respectively). The combination in panels of three molecules comprising CXCL13-CXCL10-MMP-9 or CXCL13-CXCL10-IgM significantly increased their staging ability to partial AUC 94% (p value < 0.01).The present study highlighted new potential markers for stage determination of T. b. rhodesiense patients. Further investigations are needed to better evaluate these molecules, alone or in panels, as alternatives to WBC to make reliable choice of treatment.Clinical and translational medicine. 01/2013; 2(1):1.
