Publications by authors named "Steven A Ward"

7 Publications

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Lymphocyte Perturbations in Malawian Children with Severe and Uncomplicated Malaria.

Clin Vaccine Immunol 2015 Nov 18;23(2):95-103. Epub 2015 Nov 18.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom Wellcome Trust Sanger Institute, Cambridge, United Kingdom

Lymphocytes are implicated in immunity and pathogenesis of severe malaria. Since lymphocyte subsets vary with age, assessment of their contribution to different etiologies can be difficult. We immunophenotyped peripheral blood from Malawian children presenting with cerebral malaria, severe malarial anemia, and uncomplicated malaria (n = 113) and healthy aparasitemic children (n = 42) in Blantyre, Malawi, and investigated lymphocyte subset counts, activation, and memory status. Children with cerebral malaria were older than those with severe malarial anemia. We found panlymphopenia in children presenting with cerebral malaria (median lymphocyte count, 2,100/μl) and uncomplicated malaria (3,700/μl), which was corrected in convalescence and was absent in severe malarial anemia (5,950/μl). Median percentages of activated CD69(+) NK (73%) and γδ T (60%) cells were higher in cerebral malaria than in other malaria types. Median ratios of memory to naive CD4(+) lymphocytes were higher in cerebral malaria than in uncomplicated malaria and low in severe malarial anemia. The polarized lymphocyte subset profiles of different forms of severe malaria are independent of age. In conclusion, among Malawian children cerebral malaria is characterized by lymphocyte activation and increased memory cells, consistent with immune priming. In contrast, there are reduced memory cells and less activation in severe malaria anemia. Further studies are required to understand whether these immunological profiles indicate predisposition of some children to one or another form of severe malaria.
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http://dx.doi.org/10.1128/CVI.00564-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744922PMC
November 2015

Synthesis and biological activities of 4-N-(anilinyl-n-[oxazolyl])-7-chloroquinolines (n=3' or 4') against Plasmodium falciparum in in vitro models.

Bioorg Med Chem Lett 2011 Aug 15;21(15):4512-5. Epub 2011 Jun 15.

Department of Biology, Acadia University, Wolfville, NS, Canada.

The synthesis (Pd-mediated coupling strategy) and characterization (NMR, IR, elemental analysis, etc.) of a short series of quinoline-oxazole hybrid compounds has been carried out. These materials are found to be moderately active against Plasmodium falciparum in vitro, with activities in the sub-micromolar range, and to display acceptable cytotoxicity to mononuclear leukocytes. Chemical modification strategies, with the intention to increase the biological potency of this new class of anti-malarial agents, are discussed.
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http://dx.doi.org/10.1016/j.bmcl.2011.05.131DOI Listing
August 2011

Rationale design of biotinylated antimalarial endoperoxide carbon centered radical prodrugs for applications in proteomics.

J Med Chem 2010 Jun;53(11):4555-9

Department of Chemistry, University of Liverpool, Oxford Street, Liverpool L697ZD, UK.

The semisynthetic artemisinin derivatives such as artesunate and artemether, along with the fully synthetic endoperoxide antimalarials (e.g., OZ277, Nature 2004, 430, 900-904), are believed to mediate their antimalarial effects by iron-induced formation of carbon-centered radicals capable of alkylating heme and/or protein. Here, we describe the design and synthesis of a series of biotinylated endoperoxide probe molecules for use in proteomic studies. The target molecules include derivatives of the artemisinin and OZ families, and we demonstrate that these conjugates express nanomolar in vitro activity versus cultured strains of Plasmodium falciparum. We also describe the synthesis of chemically cleavable linked conjugates designed to enable mild elution of labeled proteins during target protein identification.
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http://dx.doi.org/10.1021/jm100201jDOI Listing
June 2010

Lymphocyte subsets in healthy Malawians: implications for immunologic assessment of HIV infection in Africa.

J Allergy Clin Immunol 2010 Jan 26;125(1):203-8. Epub 2009 Nov 26.

Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.

Background: CD4(+)T lymphocyte measurements are the most important indicator of mortality in HIV-infected individuals in resource-limited settings. There is currently a lack of comprehensive immunophenotyping data from African populations to guide the immunologic assessment of HIV infection.

Objective: To quantify variation in absolute and relative lymphocyte subsets with age in healthy Malawians.

Methods: Lymphocyte subsets in peripheral blood of 539 healthy HIV-uninfected Malawians stratified by age were enumerated by flow cytometry.

Results: B and T-lymphocyte and T-lymphocyte subset absolute concentrations peaked in early childhood then decreased to adult levels, whereas lymphocyte subset proportions demonstrated much less variation with age. Adult lymphocyte subsets were similar to those in developed countries. In contrast, high B-lymphocyte and CD8(+)T-lymphocyte levels among children under 2 years, relative to those in developed countries, resulted in low CD4(+)T-lymphocyte percentages that varied little between 0 and 5 years (35% to 39%). The CD4(+)T-lymphocyte percentages in 35% of healthy children under 1 year and 18% of children age 1 to 3 years were below the World Health Organization threshold defining immunodeficiency in HIV-infected children in resource-limited settings. Thirteen percent of healthy children under 18 months old had a CD4:CD8T-lymphocyte ratio <1.0, which is commonly associated with HIV infection. All immunologic parameters except absolute natural killer lymphocyte concentration varied significantly with age, and percentage and overall absolute CD4(+)T-lymphocyte counts were higher in females than males.

Conclusion: Although lymphocyte subsets in Malawian adults are similar to those from developed countries, CD4(+)T-lymphocyte percentages in young children are comparatively low. These findings need to be considered when assessing the severity of HIV-related immunodeficiency in African children under 3 years.
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http://dx.doi.org/10.1016/j.jaci.2009.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2887487PMC
January 2010

An efficient route into synthetically challenging bridged achiral 1,2,4,5-tetraoxanes with antimalarial activity.

Bioorg Med Chem Lett 2008 Mar 18;18(5):1720-4. Epub 2008 Jan 18.

Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK.

Here we present an efficient route into synthetically challenging bridged 1,2,4,5-tetraoxanes. The key to the success of this route is the use of H(2)O(2) and catalytic I(2) to form the gem-dihydroperoxide followed by a Ag(2)O mediated alkylation using 1,3-diiodopropane. Using this methodology a range of bridged tetraoxanes which display good in vitro antimalarial activity were synthesized.
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http://dx.doi.org/10.1016/j.bmcl.2008.01.053DOI Listing
March 2008

Study on the biochemical basis of mefloquine resistant Plasmodium falciparum.

Exp Parasitol 2007 Oct 10;117(2):141-8. Epub 2007 Apr 10.

Pharmacology and Toxicology Unit, Graduate Program in Biomedical Sciences, Faculty of Allied Health Sciences, Thammasat University (Rangsit Campus), Klong Luang District, Patumthani 12121, Thailand.

Increase in drug detoxification and alteration of drug uptake and efflux of Plasmodium falciparum were investigated for their possible association with mefloquine (MQ) resistance in five different clones of P. falciparum from Thailand (T994b(3), K1CB(2), PR70CB(1), PR71CB(2) and TM(4)CB8-2.2.3). Fifty percent inhibitory concentration (IC(50)) values from these five clones varied between 30- and 50-fold. Regarding the detoxification mechanism, the ability of P. falciparum clones to biotransform MQ was shown in vitro by parasite microsomal protein prepared from parasite infected red blood cells protein (30mug), NADPH (1nM) and phosphate buffer pH 7.4, carried out at 37 degrees C with agitation. Radiolabelled unmetabolized MQ and possible metabolite(s) generated from the reaction was extracted into ethylacetate and separated by radiometric-HPLC after 1 h. All clones were capable of converting MQ into carboxymefloquine (CMQ), which is the main metabolite in human plasma. In addition, another unidentified metabolite eluted at 4.2 min on the chromatograph could be detected from the incubation reaction. This metabolite has never been detected in human liver microsomes before. There was no significant difference in the percentages of CMQ formed in the resistant (T994(b3), PR(70)CB(1), PR(71)CB(2)) and sensitive (TM(4)CB8-2.2.3, K1CB(2)) clones. Another possible mechanism, i.e., alteration in the accumulation of MQ in the parasites was investigated in vitro using [(14)C]MQ as a tracer. The time courses of [(14)C]MQ uptake and efflux were generally characterized by two phases. A trend of increased efflux of [(14)C]MQ was observed in the resistant compared with sensitive clones.
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http://dx.doi.org/10.1016/j.exppara.2007.04.002DOI Listing
October 2007

Clinical status and implications of antimalarial drug resistance.

Microbes Infect 2002 Feb;4(2):157-64

Department of Pharmacology and Therapeutics, University of Liverpool, L69 3GE, Liverpool, UK.

Africa carries the greatest burden of disease caused by Plasmodium falciparum, and we can expect this burden to rise in the near future, mainly because of drug resistance. Although effective drugs are available (such as artemether-lumefantrine, mefloquine, atovaquone-proguanil and halofantrine) they are uniformly too expensive for routine use. Affordable options include chloroquine plus sulfadoxine-pyrimethamine (SP), amodiaquine (alone or in combination with SP) and chlorproguanil-dapsone. Artemisinin combination therapy may offer considerable advantages over alternative therapies, but its introduction faces considerable logistic difficulty.
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http://dx.doi.org/10.1016/s1286-4579(01)01523-4DOI Listing
February 2002