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Fluid Resuscitation in Malaria: The Need for New Randomised Clinical Trials
Nick Day
PLOS ONE , 2006, DOI: 10.1371/journal.pctr.0010024
Genetic diversity of Plasmodium vivax in Kolkata, India
Jung-Ryong Kim, Mallika Imwong, Amitabha Nandy, Kesinee Chotivanich, Apichart Nontprasert, Naowarat Tonomsing, Ardhendu Maji, Manjulika Addy, Nick PJ Day, Nicholas J White, Sasithon Pukrittayakamee
Malaria Journal , 2006, DOI: 10.1186/1475-2875-5-71
Abstract: Blood from 151 patients with P. vivax infection diagnosed in Kolkata between April 2003 and September 2004 was genotyped at three polymorphic loci: the P. vivax circumsporozoite protein (pvcs), the merozoite surface protein 1 (pvmsp1) and the merozoite surface protein 3-alpha (pvmsp3-alpha).Analysis of these three genetic markers revealed that P. vivax populations in Kolkata are highly diverse. A large number of distinguishable alleles were found from three genetic markers: 11 for pvcs, 35 for pvmsp1 and 37 for pvmsp3-alpha. These were, in general, randomly distributed amongst the isolates. Among the 151 isolates, 142 unique genotypes were detected the commonest genotype at a frequency of less than 2% (3/151). The overall rate of mixed genotype infections was 10.6%.These results indicate that the P. vivax parasite population is highly diverse in Kolkata, despite the low level of transmission. The genotyping protocols used in this study may be useful for differentiating re-infection from relapse and recrudescence in studies assessing of malarial drug efficacy in vivax malaria.Malaria remains one of the most important communicable diseases in the world. Despite enormous control efforts over many decades malaria is still a significant health problem. It is estimated that around 300–500 million cases occur each year with one to three million deaths. The problem is compounded by multiple drug resistance in Plasmodium falciparum and chloroquine resistance in Plasmodium vivax [1]. The global burden of malaria due to P. vivax is 70–80 million cases annually. Vivax malaria is usually a non-lethal infection but its prolonged and recurrent infection can have major deleterious effects on personal well-being, growth and on the economic performance at the individual, family, community and national levels [2]. The recent emergence of chloroquine-resistant strains is of great concern [3-5].P. vivax causes about 60–65% of all malaria infections in India [6,7,42]. The frequency of re
Overdiagnosis and breast cancer screening
Nick E Day
Breast Cancer Research , 2005, DOI: 10.1186/bcr1321
Abstract: Screening for cancer is based on the supposition that earlier diagnosis will lead to improved prognosis. Experience of screening for several types of cancer (breast, cervix uteri or large bowel) has shown that on average this will be true, in the sense that groups targeted for screening for these cancers show reduced cancer-specific mortality. However, what is true on average may conceal major differences between individuals. For most cancer types there is a wide divergence of behaviour between individual cancers. Some, usually the most malignant, will be fast growing and less amenable to the benefits of earlier detection, particularly in the context of periodic testing in a mass screening programme; others, often the more benign, will be slow growing and probably successfully treatable whenever diagnosed. Among these slower-growing tumours will be a proportion that were never destined to surface as clinically apparent cancers in the lifetime of the individual. The effect of this heterogeneity has been seen particularly clearly in the early randomised trials of screening for lung cancer, in which despite an increase in the number of early (stage 1) cancers diagnosed on the screened arm of the trial, no reduction in lung cancer mortality rates was seen among those randomised to screening. That is, the cancers preferentially detected at screening were not those that prove fatal. Furthermore, many more early cancers were diagnosed through screening than appeared on the control arm even after extended follow-up. In these trials, screening yielded no benefit but generated considerable harm.Lesions that are detected at screening but which would not have surfaced clinically in the lifetime of the individual constitute overdiagnosis, the major form of harm associated with screening programmes. The individuals concerned undergo unnecessary further investigations and treatment, with all the consequent side effects, and the health care system has to bear the unnecessary costs.
Mammographic screening and mammographic patterns
Nick Day, Ruth Warren
Breast Cancer Research , 2000, DOI: 10.1186/bcr64
Abstract: The main interest in mammography has focused on its value as a method of screening. However, the population-screening trials conducted over the past 35 years have generated extensive longitudinal data on the relation of mammographic features both to tumour behaviour and the future risk of breast cancer in the normal population. In this review we briefly examine the effectiveness of mammographic screening, then discuss more generally the contribution that mammography can make to understanding the natural history and epidemiology of breast cancer.Mammography as a method of screening for the early detection of breast cancer has undergone many randomised trials. The results of seven of the eight trials that have been published display a considerable consistency. For women over 50 years of age at entry to a trial, the reduction in breast cancer mortality in those invited to screening is approx. 25%, and in women who are screened the reduction is approx.33% [1]. For women under the age of 50 (the lower age limit varies across the trials between 35 and 40 years), the reduction in breast cancer mortality is considerably less, approx. 15% in all women invited to screening [2]. The one discrepant trial is the Canadian National Breast Screening. Two aspects of this trial give cause for concern. Firstly, an independent review of the quality of the mammography concluded that, at least in the early stages, the quality was unacceptably poor [3]. No one has ever suggested that poor mammography is effective. Secondly, there was a substantial and unexplained excess of advanced cancers at randomisation among women randomised to mammography, giving rise to concern that the randomisation process might have been poorly controlled [4,5].In view of the importance of breast screening to public health, and the soundness of the evidence demonstrating benefit, it was unfortunate that The Lancet chose to publish an incompetent attempt at an overview [6]. The shortcomings of that paper are well
Authors' Reply: Response to Ian Clark
Arjen Dondorp ,Nick White,Nick Day
PLOS Medicine , 2006, DOI: 10.1371/journal.pmed.0030069
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.
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
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
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