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Evaluationof ParaSight F Test in Dignosis of Plasmodium Falciparum Infection
Fatima Shujatullah, Haris M. Khan, Abida Malik,Ashraf Malik
JK Science : Journal of Medical Education & Research , 2009,
Abstract: P. falciparum malaria is a severe form of disease which requires urgent diagnosis and treatment to savethe life of patient. Blood smear examination is the commonest method used for diagnosis. The presentstudy was done to evaluate ParaSight F test in patients of P. falciparum infection.The study was performedon 100 patients who where clinically diagnosed as cases of P. falciparum infection. ParaSight F test andLeishman stained blood smear examination was done in all 100 patients (50 patients of cerebral malaria +50 patients of acute malaria).ParaSight F test was positive in 45 patients and blood smear positive in 28patients of cerebral malaria. 35 patients of acute malaria were positive by ParaSight F test while bloodsmear was positive in 15 patients. Sensitivity, specificity, positive and negative predictive values of ParaSightF test are 95.7%, 100%, 100%, 100%, 60% in cerebral malaria and 100% each in acute malaria. ParaSightF test can be used as diagnostic tool in cases of P. falciparum infections, where blood smear is negative.
Comparison of different diagnostic techniques in Plasmodium falciparum cerebral malaria  [PDF]
Fatima Shujatullah, Abida Malik, Haris M. Khan & Ashraf Malik
Journal of Vector Borne Diseases , 2006,
Abstract: Background & objectives: Plasmodium falciparum cerebral malaria remains a major health problemin India. The efficacy of treatment of cerebral malaria lies in its early diagnosis through rapid diagnosticmethods. ParaSights-F test detects HRP-2 antigen secreted by parasitised red blood cells andquantitative buffy coat assay (QBC) is examination of buffy coat for the presence of malarial parasitestained with acridine orange. This study was performed to evaluate the effectiveness of ParaSight-F test and QBC assay as diagnostic methods in the patients of cerebral malaria.Methods: Fifty clinically diagnosed patients of cerebral malaria were included in the study.ParaSight-F test, QBC and conventional blood smear examination was done. Patients who were incoma and there were no obvious features of bacterial or viral etiology were investigated for cerebralmalaria by these diagnostic methods.Results: ParaSight-F test, QBC and peripheral blood smears were examined. Patients were followedupfor signs of clinical recovery. ParaSight-F test was positive in 47 patients, QBC in 46 while bloodsmear examination was positive in 28 cases.Interpretation & conclusion: Sensitivity and specificity of ParaSight-F test were found to be 96.6 and94% while QBC showed 97.8 and 100% respectively. ParaSight-F test and QBC were found to be novelmethods for diagnosis of cerebral malaria especially in the cases where diagnosis can not be made byconventional blood smear examination due to low parasitaemia. These rapid diagnostic methods helpin early therapeutic intervention.
Anti-malarial drugs: how effective are they against Plasmodium falciparum gametocytes?
Christopher L Peatey, Didier Leroy, Donald L Gardiner, Katharine R Trenholme
Malaria Journal , 2012, DOI: 10.1186/1475-2875-11-34
Abstract: Here the use of a simple robust assay to screen a panel of currently used and experimental anti-malarial drugs against mature P. falciparum gametocytes is described.Eight of 44 compounds tested reduced gametocyte viability by at least 50% and three showed IC50 values in nM range.There is a need to identify new compounds with activity against late stage gametocytes and the information provided by this in vitro assay is a valuable first step, which can guide future clinical studies.Gametocytes are the sexual stage of the malaria parasite, which develop in red blood cells and are essential for transmission to the mosquito vector. It has long been recognized that patients treated for malaria should be cleared of gametocytes in order to prevent them transmitting the infection to others [1]. This is particularly challenging in the case of Plasmodium falciparum infections as gametocytes of this species have a much longer lifespan than asexual stages. Late-stage gametocytes (stages IV-V) are more resistant to anti-malarial drugs and metabolic inhibitors [2] than early-stage gametocytes or asexual stage parasites. Primaquine is currently the only licensed anti-malarial drug that is effective against late stage P. falciparum gametocytes but has a number of drawbacks including its propensity to cause acute haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency.With malaria eradication back on the global health agenda there is renewed emphasis on the identification of new and novel agents that can eliminate late-stage gametocytes in the patient's circulation and therefore block transmission of the parasite from its human host to the mosquito vector. However, evaluating the activity of promising anti-malarial drugs against Plasmodium gametocytes is difficult even in vitro. To this end a simple medium-high throughput assay suitable for assessing the potential of new and novel anti-gametocyte drugs has recently been described [3].Here a modification of
Matrix Metalloproteinase-9 and Haemozoin: Wedding Rings for Human Host and Plasmodium falciparum Parasite in Complicated Malaria  [PDF]
Mauro Prato,Giuliana Giribaldi
Journal of Tropical Medicine , 2011, DOI: 10.1155/2011/628435
Abstract: It is generally accepted that the combination of both Plasmodium falciparum parasite and human host factors is involved in the pathogenesis of complicated severe malaria, including cerebral malaria (CM). Among parasite products, the malarial pigment haemozoin (HZ) has been shown to impair the functions of mononuclear and endothelial cells. Different CM models were associated with enhanced levels of matrix metalloproteinases (MMPs), a family of proteolytic enzymes able to disrupt subendothelial basement membrane and tight junctions and shed, activate, or inactivate cytokines, chemokines, and other MMPs through cleavage from their precursors. Among MMPs, a good candidate for targeted therapy might be MMP-9, whose mRNA and protein expression enhancement as well as direct proenzyme activation by HZ have been recently investigated in a series of studies by our group and others. In the present paper the role of HZ and MMP-9 in complicated malaria, as well as their interactions, will be discussed. 1. Introduction Among protozoan parasites of the genus Plasmodium, P. falciparum is the most deadly agent of human malaria, causing a broad spectrum of clinical manifestations ranging from asymptomatic to severe multiorgan disease. Despite recent major efforts by the research community, malaria remains one of the major diseases in poor areas, including Sub-Saharan Africa and South-East Asia. It is associated with several million clinical cases per year and leads annually to over one million deaths [1, 2]. The pathophysiology of severe malaria complications is not well understood. In some cases, including cerebral malaria (CM), renal failure, lung pathology and malaria during pregnancy, it appears associated with cytoadherence and sequestration of P. falciparum-parasitized red blood cells (pRBCs) to vascular endothelium, leading to microcirculatory obstruction, tissue hypoxia, and metabolic disturbances [3–5]. In some cases additional leukocyte extravasation has been reported [6, 7]. As described in the following sections, either pRBCs or parasite products such as haemozoin (HZ, malarial pigment), a lipid-enriched ferriprotoporphyrin IX crystal derived from haemoglobin catabolism by the parasite [8], can modulate the functions of mononuclear and endothelial cells and promote the production of proinflammatory molecules and other soluble factors, including matrix metalloproteinases (MMPs). MMPs are a well-known family of proteolytic enzymes able to disrupt subendothelial basement membranes [9, 10], to destroy tight junctions [11], and to shed, activate, or inactivate
Systems Analysis of Chaperone Networks in the Malarial Parasite Plasmodium falciparum  [PDF]
Soundara Raghavan Pavithra ,Ranjit Kumar ,Utpal Tatu
PLOS Computational Biology , 2007, DOI: 10.1371/journal.pcbi.0030168
Abstract: Molecular chaperones participate in the maintenance of cellular protein homeostasis, cell growth and differentiation, signal transduction, and development. Although a vast body of information is available regarding individual chaperones, few studies have attempted a systems level analysis of chaperone function. In this paper, we have constructed a chaperone interaction network for the malarial parasite, Plasmodium falciparum. P. falciparum is responsible for several million deaths every year, and understanding the biology of the parasite is a top priority. The parasite regularly experiences heat shock as part of its life cycle, and chaperones have often been implicated in parasite survival and growth. To better understand the participation of chaperones in cellular processes, we created a parasite chaperone network by combining experimental interactome data with in silico analysis. We used interolog mapping to predict protein–protein interactions for parasite chaperones based on the interactions of corresponding human chaperones. This data was then combined with information derived from existing high-throughput yeast two-hybrid assays. Analysis of the network reveals the broad range of functions regulated by chaperones. The network predicts involvement of chaperones in chromatin remodeling, protein trafficking, and cytoadherence. Importantly, it allows us to make predictions regarding the functions of hypothetical proteins based on their interactions. It allows us to make specific predictions about Hsp70–Hsp40 interactions in the parasite and assign functions to members of the Hsp90 and Hsp100 families. Analysis of the network provides a rational basis for the anti-malarial activity of geldanamycin, a well-known Hsp90 inhibitor. Finally, analysis of the network provides a theoretical basis for further experiments designed toward understanding the involvement of this important class of molecules in parasite biology.
IL4 gene polymorphism and previous malaria experiences manipulate anti-Plasmodium falciparum antibody isotype profiles in complicated and uncomplicated malaria
Piyatida Tangteerawatana, Hedvig Perlmann, Masashi Hayano, Thareerat Kalambaheti, Marita Troye-Blomberg, Srisin Khusmith
Malaria Journal , 2009, DOI: 10.1186/1475-2875-8-286
Abstract: Anti-P.falciparum IgG subclasses and IgE antibodies in plasma of complicated and uncomplicated malaria patients with or without previous malaria experiences were analysed using ELISA. IL4-590 polymorphisms were genotyped using RFLP-PCR. Statistical analyses of the IgG subclass levels were done by Oneway ANOVA. Genotype differences were tested by Chi-squared test.The IL4-590T allele was significantly associated with anti-P. falciparum IgG3 antibody levels in patients with complicated (P = 0.031), but not with uncomplicated malaria (P = 0.622). Complicated malaria patients with previous malaria experiences carrying IL4-590TT genotype had significantly lower levels of anti-P. falciparum IgG3 (P = 0.0156), while uncomplicated malaria patients with previous malaria experiences carrying the same genotype had significantly higher levels (P = 0.0206) compared to their IL4-590 counterparts. The different anti-P. falciparum IgG1 and IgG3 levels among IL4 genotypes were observed. Complicated malaria patients with previous malaria experiences tended to have lower IgG3 levels in individuals carrying TT when compared to CT genotypes (P = 0.075). In contrast, complicated malaria patients without previous malaria experiences carrying CC genotype had significantly higher anti-P. falciparum IgG1 than those carrying either CT or TT genotypes (P = 0.004, P = 0.002, respectively).The results suggest that IL4-590C or T alleles participated differently in the regulation of anti-malarial antibody isotype profiles in primary and secondary malaria infection and, therefore, could play an important role in alteration of malaria severity.Anti-Plasmodium falciparum specific antibodies play a critical role in immune protection against asexual blood stages of the parasite, in which anti-P. falciparum IgG antibodies involved in reducing severity of the disease [1]. In particular, the cytophilic IgG1 and IgG3 subclasses are considered to protect against P. falciparum, whereas IgG2 and IgM are not, a
Ex vivo susceptibility of Plasmodium falciparum isolates from Dakar, Senegal, to seven standard anti-malarial drugs
Bécaye Fall, Silmane Diawara, Kowry Sow, Eric Baret, Bakary Diatta, Khadidiatou B Fall, Pape S Mbaye, Fatou Fall, Yaya Diémé, Christophe Rogier, Boubacar Wade, Raymond Bercion, Bruno Pradines
Malaria Journal , 2011, DOI: 10.1186/1475-2875-10-310
Abstract: The ex vivo susceptibility of 93 P. falciparum isolates from Dakar was successfully determined using the Plasmodium lactate dehydrogenase (pLDH) ELISA for the following drugs: chloroquine (CQ), quinine (QN), mefloquine (MQ), monodesethylamodiaquine (MDAQ), lumefantrine (LMF), dihydroartemisinin (DHA) and doxycycline (DOX).After transformation of the isolate IC50 in ratio of IC50 according to the susceptibility of the 3D7 reference strain (isolate IC50/3D7 IC50), the prevalence of the in vitro resistant isolates with reduced susceptibility was 50% for MQ, 22% for CQ, 12% for DOX, 6% for both QN and MDAQ and 1% for the drugs LMF and DHA. The highest significant positive correlations were shown between responses to CQ and MDAQ (r = 0.569; P < 0.0001), LMF and QN (r = 0.511; P < 0.0001), LMF and DHA (r = 0.428; P = 0.0001), LMF and MQ (r = 0.413; P = 0.0002), QN and DHA (r = 0.402; P = 0.0003) and QN and MQ (r = 0.421; P = 0.0001).The introduction of ACT in 2002 has not induced a decrease in P. falciparum susceptibility to the drugs DHA, MDAQ and LMF, which are common ACT components. However, the prevalence of P. falciparum isolates with reduced susceptibility has increased for both MQ and DOX. Taken together, these data suggest that intensive surveillance of the P. falciparum in vitro susceptibility to anti-malarial drugs in Senegal is required.During the past 20 years, many strains of Plasmodium falciparum have become resistant to chloroquine and other anti-malarial drugs [1]. The emergence and spread of drug-resistant parasites has generated an urgent need for the development of novel anti-malarial drugs. One strategy for reducing malaria prevalence is the use of drugs in combination. Drug combinations protect each component drug from the development of resistance and reduce the overall transmission of malaria [2]. Since 2001, more than 60 countries have officially adopted artemisinin-based combination therapy (ACT) for the treatment of falciparum malaria; moreover,
Atorvastatin as a potential anti-malarial drug: in vitro synergy in combinational therapy with quinine against Plasmodium falciparum
Véronique Parquet, Maud Henry, Nathalie Wurtz, Jerome Dormoi, Sébastien Briolant, Marine Gil, Eric Baret, Rémy Amalvict, Christophe Rogier, Bruno Pradines
Malaria Journal , 2010, DOI: 10.1186/1475-2875-9-139
Abstract: The susceptibilities to combination of AVA with QN were assessed against 21 parasite strains using the in vitro isotopic microtest. Genotypes and gene copy number were assessed for pfcrt, pfmdr1, pfmdr2, pfmrp genes. In addition, the number of DNNND, DDNHNDNHNN repeats in pfnhe-1 ms4760 and the ms4760 profile were determined for each strains of P. falciparum.AVA demonstrated synergistic effects in combination with QN against 21 P. falciparum strains. The QN IC50 was reduced by 5% (0% to 15%; 95%CI: 1%-8%), 10% (3% to 23%; 95%CI: 7%-14%) and 22% (14% to 40%; 95%CI: 19%-25%) in presence of AVA at concentrations of 0.1, 0.5 and 1.0 μM, respectively. These reductions were all significant (p < 0.009). The reduction in the QN IC50 in presence of AVA was not significantly correlated with the QN IC50 (r = 0.22, P = 0.3288) or the AVA IC50 (r = 0.03, P = 0.8946). The synergistic effect of AVA in combination with QN was not significantly associated with polymorphisms in the pfcrt, pfmdr1, pfmrp, and pfnhe-1 genes that could be involved in QN resistance. The synergistic effect of AVA on QN responses was not significantly associated with pfmdr1 copy number (P = 0.0428).The synergistic effect of AVA in combination with QN was found to be unrelated to mutations occurring in transport protein genes involved in QN drug resistance. The different mechanisms of drug uptake and/or mode of action for AVA compared to the other anti-malarial drugs, as well as the AVA-mediated synergy of the anti-malarial effect of QN, suggests that AVA will be a good candidate for combinatorial malaria treatment. All of these observations support calls for both an in vivo evaluation with pharmacokinetic component and clinical trials of AVA as an anti-malarial therapy.During the past 20 years, many strains of Plasmodium falciparum have become resistant to chloroquine and other anti-malarial drugs [1]. This has prompted a search for an effective alternative anti-malarial drug with minimal side effects. The
In vitro activity of pyronaridine against Plasmodium falciparum and comparative evaluation of anti-malarial drug susceptibility assays
Florian Kurth, Peter Pongratz, Sabine Bélard, Benjamin Mordmüller, Peter G Kremsner, Michael Ramharter
Malaria Journal , 2009, DOI: 10.1186/1475-2875-8-79
Abstract: In vitro response of field isolates of P. falciparum to pyronaridine, chloroquine, artesunate and quinine was assessed using the traditional WHO microtest. In addition, the histidine-rich protein 2 (HRP-2) assay was performed and evaluated for its future implementation for follow-up of drug susceptibility testing.Pyronaridine exhibited a high in vitro activity against P. falciparum, with a geometric mean cut-off concentration of 9.3 nmol/l. Fifty percent effective concentrations were 1.9 nmol/l and 2.0 nmol/l in the WHO microtest and HRP-2 assay, respectively. Results matched closely in vivo findings from a recent clinical trial on pyronaridine-artesunate treatment. One isolate showed diminished sensitivity to artesunate. For chloroquine and quinine resistance levels were comparable to prior studies from Lambaréné. Results from the novel HRP-2 assay corresponded well to those obtained by the WHO microtest.Pyronaridine is highly active in chloroquine-resistant parasites and seems a promising partner drug for artemisinin-based combination therapy in Africa.Malaria continues to be a major cause of morbidity and mortality in sub-Saharan Africa, particularly in young children. Early detection and effective chemotherapy remain the cornerstones in its control [1]. The rapid development and spread of anti-malarial drug resistance has made surveillance of drug sensitivity a high priority issue. In addition to assessing the activity of common anti-malarials against Plasmodium falciparum in routine surveys, the evaluation of new compounds against field isolates is of major importance for drug development.In Lambaréné, Gabon, routine anti-malarial drug susceptibility monitoring has been performed since 1992 [2-5]. So far the WHO microtest – one of the longest used and best validated assays for the assessment of in vitro drug sensitivity under field conditions – has been used for this purpose [6]. Meanwhile, novel methods in drug susceptibility testing have been developed, such
Modulating effects of plasma containing anti-malarial antibodies on in vitro anti-malarial drug susceptibility in Plasmodium falciparum
Preeyaporn Monatrakul, Mathirut Mungthin, Arjen M Dondorp, Srivicha Krudsood, Rachanee Udomsangpetch, Polrat Wilairatana, Nicholas J White, Kesinee Chotivanich
Malaria Journal , 2010, DOI: 10.1186/1475-2875-9-326
Abstract: Titres of antibodies against blood stage antigens (mainly the ring-infected erythrocyte surface antigen [RESA]) were measured in plasma samples obtained from Thai patients with acute falciparum malaria. 'Immune' plasma was selected and its effects on in vitro parasite growth and multiplication of the Thai P. falciparum laboratory strain TM267 were assessed by light microscopy. The in vitro susceptibility to quinine and artesunate was then determined in the presence and absence of 'immune' plasma using the 3H-hypoxanthine uptake inhibition method. Drug susceptibility was expressed as the concentrations causing 50% and 90% inhibition (IC50 and IC90), of 3H-hypoxanthine uptake.Incubation with 'immune' plasma reduced parasite maturation and decreased parasite multiplication in a dose dependent manner. 3H-hypoxanthine incorporation after incubation with 'immune' plasma was decreased significantly compared to controls (median [range]; 181.5 [0 to 3,269] cpm versus 1,222.5 [388 to 5,932] cpm) (p= 0.001). As a result 'immune' plasma reduced apparent susceptibility to quinine substantially; median (range) IC50 6.4 (0.5 to 23.8) ng/ml versus 221.5 (174.4 to 250.4) ng/ml (p = 0.02), and also had a borderline effect on artesunate susceptibility; IC50 0.2 (0.02 to 0.3) ng/ml versus 0.8 (0.2 to 2.3) ng/ml (p = 0.08). Effects were greatest at low concentrations, changing the shape of the concentration-effect relationship. IC90 values were not significantly affected; median (range) IC90 448.0 (65 to > 500) ng/ml versus 368.8 (261 to 501) ng/ml for quinine (p > 0.05) and 17.0 (0.1 to 29.5) ng/ml versus 7.6 (2.3 to 19.5) ng/ml for artesunate (p = 0.4).'Immune' plasma containing anti-malarial antibodies inhibits parasite development and multiplication and increases apparent in vitro anti-malarial drug susceptibility of P. falciparum. The IC90 was much less affected than the IC50 measurement.Falciparum malaria remains the most important parasite infection in the tropical world. Develop
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