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Search Results: 1 - 10 of 6252 matches for " Nicholas PJ Day "
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A review of mixed malaria species infections in anopheline mosquitoes
Mallika Imwong, Supatchara Nakeesathit, Nicholas PJ Day, Nicholas J White
Malaria Journal , 2011, DOI: 10.1186/1475-2875-10-253
Abstract: The biomedical literature was searched for studies of malaria infection and species identification in trapped wild mosquitoes and artificially infected mosquitoes. The study location and year, collection methods, mosquito species, number of specimens, parasite stage examined (oocysts or sporozoites), and the methods of parasite detection and speciation were tabulated. The entomological results in South East Asia were compared with mixed infection rates documented in patients in clinical studies.In total 63 studies were identified. Individual anopheline mosquitoes were examined for different malaria species in 28 of these. There were 14 studies from Africa; four with species evaluations in individual captured mosquitoes (SEICM). One study, from Ghana, identified a single mixed infection. No mixed infections were identified in Central and South America (seven studies, two SEICM). 42 studies were conducted in Asia and Oceania (11 from Thailand; 27 SEICM). The proportion of anophelines infected with Plasmodium falciparum parasites only was 0.51% (95% CI: 0.44 to 0.57%), for P. vivax only was 0.26% (95% CI: 0.21 to 0.30%), and for mixed P. falciparum and P. vivax infections was 0.036% (95% CI: 0.016 to 0.056%). The proportion of mixed infections in mosquitoes was significantly higher than expected by chance (P < 0.001), but was one fifth of that sufficient to explain the high rates of clinical mixed infections by simultaneous inoculation.There are relatively few data on mixed infection rates in mosquitoes from Africa. Mixed species malaria infections may be acquired by simultaneous inoculation of sporozoites from multiply infected anopheline mosquitoes but this is relatively unusual. In South East Asia, where P. vivax infection follows P. falciparum malaria in one third of cases, the available entomological information suggests that the majority of these mixed species malaria infections are acquired from separate inoculations.Where transmission of both vivax and falcipar
A clinicopathological correlation of the expression of the angiopoietin-Tie-2 receptor pathway in the brain of adults with Plasmodium falciparum malaria
Prapansilp Panote,Medana Isabelle,Mai Nguyen Thi,Day Nicholas PJ
Malaria Journal , 2013, DOI: 10.1186/1475-2875-12-50
Abstract: Background Plasma angiopoietin (Ang)-2 is associated with disease severity and mortality in adults and children with falciparum malaria. However the mechanism of action of the angiopoietins in fatal malaria is unclear. This study aimed to determine whether the expression of Ang-1 and Ang-2 and their receptor Tie-2 in cerebral endothelial or parenchymal cells was specific to cerebral malaria (CM), correlated with coma or other severe clinical features, and whether plasma and CSF levels of these markers correlated with the clinical and neuropathological features of severe and fatal malaria in Vietnamese adults. Methods Immunohistochemistry was performed for Ang-1, Ang-2 and Tie-2 on post-mortem brain tissue from fatal malaria cases and controls. Quantitative ELISA for plasma and cerebrospinal fluid levels of Ang-1, Ang-2 and Tie-2 was done to compare fatal cases with surviving patients from the same study. Results Immunohistochemistry revealed significant differences in expression in endothelial and parenchymal cells compared to controls. However there was no significant difference in expression of these markers on endothelial cells, astroglial cells or neurons between CM and non-cerebral malaria cases. Immunostaining of Ang-1, Ang-2 and Tie-2 was also not associated with Plasmodium falciparum-infected erythrocyte sequestration in the brain. However Ang-1 and Ang-2 expression in neurons was significantly correlated with the incidence of microscopic haemorrhages. Plasma levels of Ang-2 and Ang-2/Ang-1 ratio were associated with the number of severe malaria complications and were significant and independent predictors of metabolic acidosis and fatal outcome. Conclusions The independent prognostic significance of Ang-2 and the Ang-2/Ang-1 ratio in severe malaria was confirmed, although immunohistochemistry in fatal cases did not reveal increased expression on brain endothelium in cerebral versus non-cerebral cases. Activation of the Ang-Tie-2 pathway in severe malaria is therefore related to acidosis, number of severity criteria and outcome, but is not a specific event in the brain during cerebral malaria.
Erythropoietin and its receptors in the brainstem of adults with fatal falciparum malaria
Isabelle M Medana, Nicholas PJ Day, Tran Hien, Nicholas J White, Gareth DH Turner
Malaria Journal , 2009, DOI: 10.1186/1475-2875-8-261
Abstract: High sensitivity immunohistochemistry was used to assess the frequency, distribution and concordance of Epo and components of its homodimeric and heteromeric receptors, Epo receptor and CD131, within the brainstem of adults who died of severe malaria. The following relationships with Epo and its receptor components were also defined: (i) sequestration and indicators of hypoxia; (ii) vascular damage in the form of plasma protein leakage and haemorrhage; (iii) clinical complications and neuropathological features of severe malaria disease. Brainstems of patients dying in the UK from unrelated non-infectious causes were examined for comparison.The incidence of endogenous Epo in parenchymal brain cells did not greatly differ between severe malaria and non-neurological UK controls at the time of death. However, EpoR and CD131 labelling of neurons was greater in severe malaria compared with non-neurological controls (P = .009). EpoR labelling of vessels was positively correlated with admission peripheral parasite count (P = .01) and cerebral sequestration (P < .0001). There was a strong negative correlation between arterial oxygen saturation and EpoR labelling of glia (P = .001). There were no significant correlations with indicators of vascular damage, neuronal chromatolysis, axonal swelling or vital organ failure.Cells within the brainstem of severe malaria patients showed protein expression of Epo and its receptor components. However, the incidence of endogeneous expression did not reflect protection from vascular or neuronal injury, and/or clinical manifestations, such as coma. These findings do not provide support for Epo as an adjuvant neuroprotective agent in adults with severe malaria.The ability of the brain to adapt to a range of insults may be critical in determining whether patients are protected from neurological complications and death during severe malaria infection. Boosting endogenous protective mechanisms is a potential treatment strategy of current inte
Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies
Wirichada Pongtavornpinyo, Shunmay Yeung, Ian M Hastings, Arjen M Dondorp, Nicholas PJ Day, Nicholas J White
Malaria Journal , 2008, DOI: 10.1186/1475-2875-7-229
Abstract: A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment.The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with mismatched half-lives, together with reducing malaria transmission through vector control measures.This paper has demonstrated the use of a comprehensive mathematical model to describe malaria transmission and the spread of drug resistance. The model is strongly linked to the empirical evidence obtained from extensive data available from various sources. This model can be a useful tool to inform the design of treatment policies, particularly at a time when ACT has been endorsed by WHO as first-line treatment for falciparum malaria worldwide.For the past half-century, the malaria parasites of humans
Overestimating resistance in field testing of malaria parasites: simple methods for estimating high EC50 values using a Bayesian approach
Kasia Stepniewska, Kesinee Chotivanich, Alan Brockman, Nicholas PJ Day, Nicholas J White
Malaria Journal , 2007, DOI: 10.1186/1475-2875-6-4
Abstract: The development of resistance to antimalarial drugs poses one of the greatest threats to malaria control and is the main cause of recent increases in malaria morbidity and mortality. The precise quantitation of resistance is therefore of prime importance. Initially the only way of assessing resistance to antimalarials was by inference from clinical treatment failures. Occasionally these were supported by measurement of antimalarial drug concentrations in the patients' blood. Once methods of culturing Plasmodium falciparum became established, in vitro methods for measuring the effect of the antimalarial drug directly on malaria parasite were developed [1]. This allowed resistance (i.e. reduced susceptibility) to be differentiated from poor adherence or unusual pharmacokinetics as the cause of treatment failure.In in vitro susceptibility tests, blood samples from malaria patients are obtained and the infecting malaria parasites are cultured ex-vivo in the presence of stepwise increases in the concentrations of antimalarial drugs. Some methods call for adaptation of parasites to culture first, while others put blood directly from patients into the test system. Field testing, where blood is taken and malaria parasites are cultured directly in 96-well plastic plates pre-dosed with antimalarial at different concentrations, is now widely used. These freshly obtained parasites are usually not cryo-preserved and so there is only the one opportunity to assess the parasite drug susceptibility.The three most commonly used methods of in vitro susceptibility testing of malaria parasites are (i) the micro test which assesses inhibition of parasite growth to the schizont stage microscopically, (ii) the radioisotope test which measures uptake of 3H-hypoxanthine, and (iii) ELISA based methods which measure the production of lactate dehydrogenase or histidine rich protein by the parasite [2,3]. Results of in vitro tests are expressed as the percentage parasite growth/viability plotted
Effect of colony morphology variation of Burkholderia pseudomallei on intracellular survival and resistance to antimicrobial environments in human macrophages in vitro
Sarunporn Tandhavanant, Aunchalee Thanwisai, Direk Limmathurotsakul, Sunee Korbsrisate, Nicholas PJ Day, Sharon J Peacock, Narisara Chantratita
BMC Microbiology , 2010, DOI: 10.1186/1471-2180-10-303
Abstract: Morphotype was associated with survival in the presence of H2O2 and antimicrobial peptide LL-37, but not with susceptibility to acid, acidified sodium nitrite, or resistance to lysozyme, lactoferrin, human neutrophil peptide-1 or human beta defensin-2. Incubation under anaerobic conditions was a strong driver for switching of type III to an alternative morphotype. Differences were noted in the survival and replication of the three types following uptake by human macrophages, but marked strain-to strain-variability was observed. Uptake of type III alone was associated with colony morphology switching.Morphotype is associated with phenotypes that alter the ability of B. pseudomallei to survive in adverse environmental conditions.Burkholderia pseudomallei is an environmental Gram-negative bacterium that causes a severe and often fatal disease called melioidosis. This is an important cause of sepsis in south-east Asia and northern Australia, a geographic distribution that mirrors the presence of B. pseudomallei in the environment [1]. Melioidosis may develop following bacterial inoculation or inhalation and occurs most often in people with regular contact with contaminated soil and water [1]. Clinical manifestations of melioidosis are highly variable and range from fulminant septicemia to mild localized infection. The overall mortality rate is 40% in northeast Thailand (rising to 90% in patients with severe sepsis) and 20% in northern Australia [1,2].A major feature of melioidosis is that bacterial eradication is difficult to achieve. Fever clearance time is often prolonged (median 8 days), antimicrobial therapy is required for 12-20 weeks, and relapse occurs in around 10% of patients despite an appropriate course of antimicrobial therapy [3,4]. The basis for persistence in the infected human host is unknown, although several observations made to date may be relevant to the clinical behaviour of this organism [2,5]. B. pseudomallei can resist the action of bactericidal
Protein-based signatures of functional evolution in Plasmodium falciparum
Kate B Gardner, Ipsita Sinha, Leyla Y Bustamante, Nicholas PJ Day, Nicholas J White, Charles J Woodrow
BMC Evolutionary Biology , 2011, DOI: 10.1186/1471-2148-11-257
Abstract: Evolutionary comparisons were undertaken using a set of forty P. falciparum metabolic enzyme genes, both within the hominid malaria clade (P. reichenowi) and across the genus (P. chabaudi). All genes contained coding elements highly conserved across the genus, but there were also a large number of regions of weakly or non-aligning coding sequence. These displayed remarkable levels of non-synonymous fixed differences within the hominid malaria clade indicating near complete release from purifying selection (dN/dS ratio at residues non-aligning across genus: 0.64, dN/dS ratio at residues identical across genus: 0.03). Regions of low conservation also possessed high levels of hydrophilicity, a marker of non-globularity. The propensity for such regions to act as potent sources of non-synonymous genetic drift within extant P. falciparum isolates was confirmed at chromosomal regions containing genes known to mediate drug resistance in field isolates, where 150 of 153 amino acid variants were located in poorly conserved regions. In contrast, all 22 amino acid variants associated with drug resistance were restricted to highly conserved regions. Additional mutations associated with laboratory-selected drug resistance, such as those in PfATPase4 selected by spiroindolone, were similarly restricted while mutations in another calcium ATPase (PfSERCA, a gene proposed to mediate artemisinin resistance) that reach significant frequencies in field isolates were located exclusively in poorly conserved regions consistent with genetic drift.Coding sequences of malaria parasites contain prospectively definable domains subject to neutral or nearly neutral evolution on a scale that appears unrivalled in biology. This distinct evolutionary landscape has potential to confound analytical methods developed for other genera. Against this tide of genetic drift, polymorphisms mediating functional change stand out to such an extent that evolutionary context provides a useful signal for identifyi
Computational analysis of binding between malarial dihydrofolate reductases and anti-folates
Kiattawee Choowongkomon, Sasikrit Theppabutr, Napat Songtawee, Nicholas PJ Day, Nicholas J White, Charles J Woodrow, Mallika Imwong
Malaria Journal , 2010, DOI: 10.1186/1475-2875-9-65
Abstract: DHFR models for PmDHFR and PoDHFR were constructed using the solved PfDHFR-TS and PvDHFR structures respectively as templates. The modelled structures were docked with three DHFR inhibitors as ligands and more detailed interactions were explored via simulation of molecular dynamics.Highly accurate models were obtained containing sets of residues that mediate ligand binding which are highly comparable to those mediating binding in known crystal structures. Within this set, there were differences in the relative contribution of individual residues to inhibitor binding. Modelling of PmDHFR mutant sequences revealed that PmDHFR I170M was associated with a significant reduction in binding energy to all DHFR inhibitors studied, while the other predicted resistance mutations had lesser or no effects on ligand binding.Binding of DHFR inhibitors to the active sites of all four Plasmodium enzymes is broadly similar, being determined by an analogous set of seven residues. PmDHFR mutations found in field isolates influenced inhibitor interactions to a varying extent. In the case of the isolated I170M mutation, the loss of interaction with pyrimethamine suggests that DHFR-inhibitor interactions in P. malariae are different to those seen for DHFRs from P. falciparum and P. vivax.Resistance to anti-malarials is a major cause of morbidity and mortality in tropical countries. Resistance has complicated the treatment of malaria and threatened the control and elimination of the disease. The antifols, a group of drugs that competitively inhibit the folate pathway enzyme dihydrofolate reductase DHFR, and thereby disrupt parasite nucleotide metabolism (Figure 1), were developed in the years following the Second World War. First proguanil (chloroguanide) and then pyrimethamine were deployed extensively, as individual and mass treatments, and as chemoprophylaxis in mass treatment. Resistance developed in both Asia and Africa within a few years of introduction. Combinations with sulphonamid
Coma in fatal adult human malaria is not caused by cerebral oedema
Isabelle M Medana, Nicholas PJ Day, Navakanit Sachanonta, Nguyen TH Mai, Arjen M Dondorp, Emsri Pongponratn, Tran T Hien, Nicholas J White, Gareth DH Turner
Malaria Journal , 2011, DOI: 10.1186/1475-2875-10-267
Abstract: The brains of 20 adult Vietnamese patients who died of severe malaria were examined for evidence of disrupted vascular integrity. Immunohistochemistry and image analysis was performed on brainstem sections for activation of the vascular endothelial growth factor (VEGF) receptor 2 and expression of the aquaporin 4 (AQP4) water channel protein. Fibrinogen immunostaining was assessed as evidence of blood-brain barrier leakage and perivascular oedema formation. Correlations were performed with clinical, biochemical and neuropathological parameters of severe malaria infection.The presence of oedema, plasma protein leakage and evidence of VEGF signalling were heterogeneous in fatal falciparum malaria and did not correlate with pre-mortem coma. Differences in vascular integrity were observed between brain regions with the greatest prevalence of disruption in the brainstem, compared to the cortex or midbrain. There was a statistically non-significant trend towards higher AQP4 staining in the brainstem of cases that presented with coma (P = .02).Histological evidence of cerebral oedema or immunohistochemical evidence of localised loss of vascular integrity did not correlate with the occurrence of pre-mortem coma in adults with fatal falciparum malaria. Enhanced expression of AQP4 water channels in the brainstem may, therefore, reflect a mix of both neuropathological or attempted neuroprotective responses to oedema formation.Cerebral malaria (CM) is a diffuse but potentially reversible encephalopathy, caused by infection with the protozoan parasite Plasmodium falciparum. CM presents clinically with decreased consciousness, seizures and coma. The treated mortality rate is high (15-30%), and there may be long-term neurological and developmental sequelae in survivors, particularly young children. However, no major neurological deficit is detectable in the majority of survivors, suggesting that the processes leading to coma may be rapidly and potentially completely reversible [1,
Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance
Nicholas J White, Wirichada Pongtavornpinyo, Richard J Maude, Sompob Saralamba, Ricardo Aguas, Kasia Stepniewska, Sue J Lee, Arjen M Dondorp, Lisa J White, Nicholas PJ Day
Malaria Journal , 2009, DOI: 10.1186/1475-2875-8-253
Abstract: The probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed.Recrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission.Current dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens (often children or pregnant women). Patients with hyperparasitaemia who receive outpatient treatments provide the greatest risk of selecting de-novo resistant parasites. This emphasizes the importance of ensuring that only quality-assured anti-malarial combinations are used, that treatment doses are optimized on the basis of pharmacodynamic and pharmacokinetic assessments in the target populations, and that patients with heavy parasite burdens are identified and receive sufficient treatment to prevent recrudescence.Resistance to anti-malarial drugs poses a major threat to mal
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