Journals
2012 EN
Yanina R. Sevastsyanovich · Denisse L. Leyton · Timothy J. Wells
+7 more
Background It is widely believed that laboratory strains of Escherichia coli , including those used for industrial production of proteins, do not secrete proteins to the extracellular milieu. Results Here, we report the development of a generalised module, based on an E. coli autotransporter secretion system, for the production of extracellular recombinant proteins. We demonstrate that a wide variety of structurally diverse proteins can be secreted as soluble proteins when linked to the autotransporter module. Yields were comparable to those achieved with other bacterial secretion systems. Conclusions The advantage of this module is that it relies on a relatively simple and easily manipulated secretion system, exhibits no apparent limitation to the size of the secreted protein and can deliver proteins to the extracellular environment at levels of purity and yields sufficient for many biotechnological applications.
Journals
2012 EN
Rashid Khatib · Jacek Skarbinski · Joseph Njau
+18 more
Background Artemisinin-based combination therapy (ACT) has been promoted as a means to reduce malaria transmission due to their ability to kill both asexual blood stages of malaria parasites, which sustain infections over long periods and the immature derived sexual stages responsible for infecting mosquitoes and onward transmission. Early studies reported a temporal association between ACT introduction and reduced malaria transmission in a number of ecological settings. However, these reports have come from areas with low to moderate malaria transmission, been confounded by the presence of other interventions or environmental changes that may have reduced malaria transmission, and have not included a comparison group without ACT. This report presents results from the first large-scale observational study to assess the impact of case management with ACT on population-level measures of malaria endemicity in an area with intense transmission where the benefits of effective infection clearance might be compromised by frequent and repeated re-infection. Methods A pre-post observational study with a non-randomized comparison group was conducted at two sites in Tanzania. Both sites used sulphadoxine-pyrimethamine (SP) monotherapy as a first-line anti-malarial from mid-2001 through 2002. In 2003, the ACT, artesunate (AS) co-administered with SP (AS + SP), was introduced in all fixed health facilities in the intervention site, including both public and registered non-governmental facilities. Population-level prevalence of Plasmodium falciparum asexual parasitaemia and gametocytaemia were assessed using light microscopy from samples collected during representative household surveys in 2001, 2002, 2004, 2005 and 2006. Findings Among 37,309 observations included in the analysis, annual asexual parasitaemia prevalence in persons of all ages ranged from 11% to 28% and gametocytaemia prevalence ranged from <1% to 2% between the two sites and across the five survey years. A multivariable logistic regression model was fitted to adjust for age, socioeconomic status, bed net use and rainfall. In the presence of consistently high coverage and efficacy of SP monotherapy and AS + SP in the comparison and intervention areas, the introduction of ACT in the intervention site was associated with a modest reduction in the adjusted asexual parasitaemia prevalence of 5 percentage-points or 23% (p < 0.0001) relative to the comparison site. Gametocytaemia prevalence did not differ significantly (p = 0.30). Interpretation The introduction of ACT at fixed health facilities only modestly reduced asexual parasitaemia prevalence. ACT is effective for treatment of uncomplicated malaria and should have substantial public health impact on morbidity and mortality, but is unlikely to reduce malaria transmission substantially in much of sub-Saharan Africa where individuals are rapidly re-infected.
Journals
2012 EN
David M. Pigott · Rifat Atun · Catherine L. Moyes
+2 more
Background The last decade has seen a dramatic increase in international and domestic funding for malaria control, coupled with important declines in malaria incidence and mortality in some regions of the world. As the ongoing climate of financial uncertainty places strains on investment in global health, there is an increasing need to audit the origin, recipients and geographical distribution of funding for malaria control relative to populations at risk of the disease. Methods A comprehensive review of malaria control funding from international donors, bilateral sources and national governments was undertaken to reconstruct total funding by country for each year 2006 to 2010. Regions at risk from Plasmodium falciparum and/or Plasmodium vivax transmission were identified using global risk maps for 2010 and funding was assessed relative to populations at risk. Those nations with unequal funding relative to a regional average were identified and potential explanations highlighted, such as differences in national policies, government inaction or donor neglect. Results US$8.9 billion was disbursed for malaria control and elimination programmes over the study period. Africa had the largest levels of funding per capita-at-risk, with most nations supported primarily by international aid. Countries of the Americas, in contrast, were supported typically through national government funding. Disbursements and government funding in Asia were far lower with a large variation in funding patterns. Nations with relatively high and low levels of funding are discussed. Conclusions Global funding for malaria control is substantially less than required. Inequity in funding is pronounced in some regions particularly when considering the distinct goals of malaria control and malaria elimination. Efforts to sustain and increase international investment in malaria control should be informed by evidence-based assessment of funding equity.
Journals
2012 EN
Éric Farfour · Frédéric Charlotte · Catherine Settegrana
+2 more
Background Plasmodium falciparum immature gametocytes accumulate in the bone marrow, but their exact location in this tissue remains unclear. Methods The stage and deposition pattern of gametocytes was analysed on histological sections of a bone marrow sample collected in a patient with subacute P. falciparum malaria. Results A majority (89%) of immature stages II to IV gametocytes and a minority (29%) of mature stage V gametocytes were observed in extravascular spaces. Discussion and conclusion These observations represent a valuable step towards understanding sequestration patterns of P. falciparum gametocytes and may ultimately lead to novel transmission-blocking interventions.
Journals
2012 EN
Francis Schaffner · Isabelle Thiéry · Christian Kaufmann
+4 more
Background Anopheles plumbeus has been recognized as a minor vector for human malaria in Europe since the beginning of the 20 th century. In recent years this tree hole breeding mosquito species appears to have exploited novel breeding sites, including large and organically rich man-made containers, with consequently larger mosquito populations in close vicinity to humans. This lead to investigate whether current populations of An. plumbeus would be able to efficiently transmit Plasmodium falciparum , the parasite responsible for the most deadly form of malaria. Methods Anopheles plumbeus immatures were collected from a liquid manure pit in Switzerland and transferred as adults to the CEPIA (Institut Pasteur, France) where they were fed on P. falciparum gametocytes produced in vitro . Anopheles gambiae mosquitoes served as controls. Development of P. falciparum in both mosquito species was followed by microscopical detection of oocysts on mosquito midguts and by sporozoite detection in the head/thorax by PCR and microscopy. Results A total of 293 wild An. plumbeus females from four independent collections successfully fed through a membrane on blood containing P. falciparum gametocytes. Oocysts were observed in mosquito midguts and P. falciparum DNA was detected in head-thorax samples in all four experiments, demonstrating, on a large mosquito sample, that An. plumbeus is indeed receptive to P. falciparum NF54 and able to produce sporozoites. Importantly, the proportion of sporozoites-infected An. plumbeus was almost similar to that of An. gambiae (31 to 88% An. plumbeus versus 67 to 97% An. gambiae). However, the number of sporozoites produced was significantly lower in infected An. plumbeus . Conclusion The results show that a sample of field-caught An. plumbeus has a moderate to high receptivity towards P. falciparum . Considering the increased mobility of humans between Europe and malaria endemic countries and changes in environment and climate, these data strongly suggest that An. plumbeus could act as a vector for malaria and thus significantly contribute to increasing the malaria transmission risk in Central-Western Europe . In locations showing high vulnerability to the presence of gametocyte carriers, the risk of transmission of malaria by An. plumbeus should be considered.
Journals
2012 EN
Qiuyin Qi · Carlos A. Guerra · Catherine L. Moyes
+4 more
Background Many recent studies have examined the impact of urbanization on Plasmodium falciparum malaria endemicity and found a general trend of reduced transmission in urban areas. However, none has examined the effect of urbanization on Plasmodium vivax malaria, which is the most widely distributed malaria species and can also cause severe clinical syndromes in humans. In this study, a set of 10,003 community-based P . vivax parasite rate ( Pv PR) surveys are used to explore the relationships between Pv PR in urban and rural settings. Methods The Pv PR surveys were overlaid onto a map of global urban extents to derive an urban/rural assignment. The differences in Pv PR values between urban and rural areas were then examined. Groups of Pv PR surveys inside individual city extents (urban) and surrounding areas (rural) were identified to examine the local variations in Pv PR values. Finally, the relationships of Pv PR between urban and rural areas within the ranges of 41 dominant Anopheles vectors were examined. Results Significantly higher Pv PR values in rural areas were found globally. The relationship was consistent at continental scales when focusing on Africa and Asia only, but in the Americas, significantly lower values of Pv PR in rural areas were found, though the numbers of surveys were small. Moreover, except for the countries in the Americas, the same trends were found at national scales in African and Asian countries, with significantly lower values of Pv PR in urban areas. However, the patterns at city scales among 20 specific cities where sufficient data were available were less clear, with seven cities having significantly lower Pv PR values in urban areas and two cities showing significantly lower Pv PR in rural areas. The urban–rural Pv PR differences within the ranges of the dominant Anopheles vectors were generally, in agreement with the regional patterns found. Conclusions Except for the Americas, the patterns of significantly lower P . vivax transmission in urban areas have been found globally, regionally, nationally and by dominant vector species here, following trends observed previously for P . falciparum . To further understand these patterns, more epidemiological, entomological and parasitological analyses of the disease at smaller spatial scales are needed.
Journals
2012 EN
Catherine Mullié · Alexia Jonet · Camille Desgrouas
+2 more
Background A better anti-malarial efficiency and lower neurotoxicity have been reported for mefloquine (MQ) (+)- enantiomer. However, the importance of stereoselectivity remains poorly understood as the anti-malarial activity of pure enantiomer MQ analogues has never been described. Building on these observations, a series of enantiopure 4-aminoalcohol quinoline derivatives has previously been synthesized to optimize the efficiency and reduce possible adverse effects. Their in vitro activity on Plasmodium falciparum W2 and 3D7 strains is reported here along with their inhibition of β-haematin formation and peroxidative degradation of haemin, two possible mechanisms of action of anti-malarial drugs. Results The ( S )-enantiomers of this series of 4-aminoalcohol quinoline derivatives were found to be at least as effective as both chloroquine (CQ) and MQ. The derivative with a 5-carbon side-chain length was the more efficient on both P. falciparum strains. ( R )-enantiomers displayed an activity decreased by 2 to 15-fold as compared to their ( S ) counterparts. The inhibition of β-haematin formation was significantly stronger with all tested compounds than with MQ, irrespective of the stereochemistry. Similarly, the inhibition of haemin peroxidation was significantly higher for both ( S ) and ( R )-enantiomers of derivatives with a side-chain length of five or six carbons than for MQ and CQ. Conclusions The prominence of stereochemistry in the anti-malarial activity of 4-aminoalcohol quinoline derivatives is confirmed. The inhibition of β-haematin formation and haemin peroxidation can be put forward as presumed mechanisms of action but do not account for the stereoselectivity of action witnessed in vitro .
Journals
2012 EN
Devojit Kumar Sarma · Anil Prakash · Samantha M. O’Loughlin
+9 more
Background Anopheles baimaii is a primary vector of human malaria in the forest settings of Southeast Asia including the north-eastern region of India. Here, the genetic population structure and the basic population genetic parameters of An. baimaii in north-east India were estimated using DNA sequences of the mitochondrial cytochrome oxidase sub unit II (COII) gene. Methods Anopheles baimaii were collected from 26 geo-referenced locations across the seven north-east Indian states and the COII gene was sequenced from 176 individuals across these sites. Fifty-seven COII sequences of An. baimaii from six locations in Bangladesh, Myanmar and Thailand from a previous study were added to this dataset. Altogether, 233 sequences were grouped into eight population groups, to facilitate analyses of genetic diversity, population structure and population history. Results A star-shaped median joining haplotype network, unimodal mismatch distribution and significantly negative neutrality tests indicated population expansion in An. baimaii with the start of expansion estimated to be ~0.243 million years before present (MYBP) in north-east India. The populations of An. baimaii from north-east India had the highest haplotype and nucleotide diversity with all other populations having a subset of this diversity, likely as the result of range expansion from north-east India. The north-east Indian populations were genetically distinct from those in Bangladesh, Myanmar and Thailand, indicating that mountains, such as the Arakan mountain range between north-east India and Myanmar, are a significant barrier to gene flow. Within north-east India, there was no genetic differentiation among populations with the exception of the Central 2 population in the Barail hills area that was significantly differentiated from other populations. Conclusions The high genetic distinctiveness of the Central 2 population in the Barail hills area of the north-east India should be confirmed and its epidemiological significance further investigated. The lack of genetic population structure in the other north-east Indian populations likely reflects large population sizes of An. baimaii that, historically, were able to disperse through continuous forest habitats in the north-east India. Additional markers and analytical approaches are required to determine if recent deforestation is now preventing ongoing gene flow. Until such information is acquired, An. baimaii in north-east India should be treated as a single unit for the implementation of vector control measures.
Journals
2012 EN
Mariana De Niz · Chi Eziefula · Catherine MaitekiSebuguzi
+5 more
Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against malaria and its distribution and prevalence are geographically correlated with malaria endemicity. This enzymopathy has been identified as the cause of haemolysis following administration of the antimalarial drug primaquine. Screening for G6PD deficiency prior to administration of primaquine together with artemisinin combination therapy for treatment or massdrug administration is being considered for malaria elimination. Current conventional methods for G6PD screening have limitations for field use.
Journals
2012 EN
Maxine Whittaker · Catherine Parsons Smith
Background Imported malaria is no longer a challenge only for malaria free countries, but for countries implementing in malaria elimination strategies and seeking to address cross-border transmission. Mobility is frequently mentioned as a risk factor and a barrier to elimination by malaria researchers and policy makers. However, only a small body of research has engaged in a detailed analysis of the links between mobility and malaria transmission, and attempts to incorporate these findings into policy are rarer still. This paper presents the findings of a literature review on malaria and human mobility supported by the Asia Pacific Malaria Elimination Network (APMEN). It attempts to shift the agenda from identifying human mobility as a risk factor, to finding strategies to work collaboratively with mobile populations towards the goal of malaria elimination.