Évaluation du risque toxique lié à la prévalence de trihalométhanes dans l'eau utilisée pour la dialyse

L'hémodialyse est une thérapeutique réservée aux sujets insuffisants rénaux en attente d'une greffe. Elle permet de recueillir dans un soluté aqueux les déchets que l'organisme ne peut plus évacuer par voie rénale. L'eau nécessaire à la préparation de ce dialysat représente un volume de 90 à 200 litres par séance et par sujet. Elle est obtenue en faisant subir à l'eau du réseau de distribution un traitement complémentaire. Celui-ci comporte en milieu spécialisé une chloration, un adoucissement par résines cationiques, une filtration sur colonne de charbon actif en grains et une osmose inverse.Les trihalométhanes sont probablement les sous-produits de chloration les plus répandus dans les eaux distribuées. Certains parmi eux sont cancérigènes chez l'animal et mutagènes in vitro. Chez l'homme, leurs effets à faibles doses et à long terme restent discutés. Compte tenu des importants volumes d'eau nécessaires à la pratique de l'hémodialyse, il nous a paru intéressant d'observer l'efflcacité du circuit de pré-traitement sur ces composés et d'évaluer les doses auxquelles sont exposés les patients qui bénéficient de cette thérapeutique.Des prélèvements ont été réalisés aux différentes étapes du pré-traitement, de façon hebdomadaire dans deux installations identiques, à la recherche de trihalométhanes. Ils permettent de constater que du chloroforme à une concentration moyenne de 10,5 llgA est encore présent en bout de chaîne. En tenant compte des volumes d'eau utilisés pour chaque séance, ceci signifie que les patients dialysés sont exposés, selon leur âge, à des doses pouvant atteindre jusqu'à dix fois la valeur préconisée dans l'eau potable par l'OMS. La moitié de ce chloroforme est susceptible de passer dans la circulation sanguine et d'exercer un effet toxique. Cette situation peut être corrigée par le choix d'une ressource en eau à charge organique faible, par un renouvellement fréquent du charbon actif et par l'utilisation de membranes en polyamides dans les modules d'osmose inverse. Ces résultats doivent amener à une réflexion plus générale sur la présenoe de sous-produits de la chloration et de micropolluants dans l'eau utilisée en dialyse. Ils doivent également inciter les cliniciens à rechercher, chez les dialysés les plus exposés, d'éventuels effets délétères liés à ces produits.Hemodialysis is an indispensable therapy for patients with chronic renal failure. Two or three times a week and over several years, their blood is dialyzed in an artificial kidney against a dialysis fluid called dialysate.Each time, 90 to 200 liters of this fluid will flow through the apparatus. Before being mixed with the dialysis concentrate, the water will be treated in order to eliminate harmful substances such as aluminum or endotoxins.Trihalomethanes (THM) are probably the most widespread chlorination byproducts of tap water. Most of them are known as carcinogens for animals and mutagens in vitro. Although their hepatotoxicity and nephrotoxicity are obvious after acute intoxication, their effects at low doses on human health have still not been clearly demonstrated.Considering the great amount of water required by hemodialysis patients, we found interested in determining wether the control of these substances by the hospital water treatment plant was efficient. We decided then to analyze weekly and during two months, the tap water of two hemodialysis departments for THM, before and after various forms of treatment. The treatment in both departments was the same and made up of four important stages: chlorination, softening, charcoal filtering and reverse osmosis.THM determinations were conducted using the headspace technique with a gas chromatograph equipped with a split injector and an [sup]63Ni electron capture detector.Our results show that chloroform and dichlorobromomethane were present in tap water. Their respective mean concentration in both department came to 56 µg/l and 5 µg/l. After chlorination and water softening, these figures had moderately but significantly increased. In the first department, thanks to new granular activated carbon, a large part of THM (especially dichlorobromomethane) had been removed. However after seven weeks, this treatment was no longer efficient and only 7% of the influent chloroform and 50% of the dichlorobromomethane could be removed. In the second department, the charcoal filter had already been working for more than one year at the beginning of our study. No decrease of the chloroform concentration had been observed and dichlorobromomethane had significantly increased. 80 to 90% of influent THM were removed after the double stage of reverse osmosis using polyamide membranes. With new granular activated carbon, the dialysis fluid only contains 1 µg/l of chloroform. But after seven weeks or more, it will reach an average of 10.5 g/l of chloroform and 1 µg/l of dichlorobromomethane. These figures are probably underestimated as our study was performed in winter and THM concentrations are less important during that season.These results mean that during a single session, 0.9 to 2.1 mg of chloroform will reach the artificial kidney. Depending on the weight of the patients, this exposure will be equivalent up to 10 times the value recommended by the World Health Organization (WHO) for drinking water.The last part of our study monitored the chloroform concentration in dialysate coming out the artificial kidney during an hemodialysis period. A significant decrease, reaching up to 45% of the influent amount, was observed. This result suggests that some of the chloroform must have crossed the dialysis membrane.According to all these results, we think that it would be of great interest to explore the metabolism of chloroform on hemodialysis patients and to search for eventual toxic effects. Practical advices to people in charge of water treatment plants in hemodialysis department would be to use raw water with low concentrations of humic materials, in order to restrict THM formation. The charcoal filter should be changed more often (probably after 6 or 7 weeks). Alternatively, ways could be found for rapid regeneration of charcoal for THM removal. Finally and according to previous studies, a polyamide membrane should be systematically used for reverse osmosis.Our study could eventually be completed by searching in the dialysis fluid any other chlorination by-products which are responsible to a large extent for tap water mutagenicity

An Adjustable Gas-Mixing Device to Increase Feasibility of In Vitro Culture of Plasmodium falciparum Parasites in the Field

A challenge to conducting high-impact and reproducible studies of the mechanisms of P. falciparum drug resistance, invasion, virulence, and immunity is the lack of robust and sustainable in vitro culture in the field. While the technology exists and is routinely utilized in developed countries, various factors–from cost, to supply, to quality–make it hard to implement in malaria endemic countries. Here, we design and rigorously evaluate an adjustable gas-mixing device for the in vitro culture of P. falciparum parasites in the field to circumvent this challenge. The device accurately replicates the gas concentrations needed to culture laboratory isolates, short-term adapted field isolates, cryopreserved previously non-adapted isolates, as well as to adapt ex vivo isolates to in vitro culture in the field. We also show an advantage over existing alternatives both in cost and in supply. Furthermore, the adjustable nature of the device makes it an ideal tool for many applications in which varied gas concentrations could be critical to culture success. This adjustable gas-mixing device will dramatically improve the feasibility of in vitro culture of Plasmodium falciparum parasites in malaria endemic countries given its numerous advantages

Multiplication rate variation in the human malaria parasite Plasmodium falciparum.

It is important to understand intrinsic variation in asexual blood stage multiplication rates of the most virulent human malaria parasite, Plasmodium falciparum. Here, multiplication rates of long-term laboratory adapted parasite clones and new clinical isolates were measured, using a newly standardised assay of growth from low starting density in replicate parallel cultures with erythrocytes from multiple different donors, across multiple cycles. Multiplication rates of long-term established clones were between 7.6 and 10.5 fold per 48 hours, with clone Dd2 having a higher rate than others (clones 3D7, HB3 and D10). Parasite clone-specific growth was then analysed in co-culture assays with all possible heterologous pairwise combinations. This showed that co-culture of different parasites did not affect their replication rates, indicating that there were no suppressive interactions operating between parasites. Multiplication rates of eleven new clinical isolates were measured after a few weeks of culture, and showed a spectrum of replication rates between 2.3 and 6.0 fold per 48 hours, the entire range being lower than for the long-term laboratory adapted clones. Multiplication rate estimates remained stable over time for several isolates tested repeatedly up to three months after culture initiation, indicating considerable persistence of this important trait variation

Widespread distribution of Plasmodium vivax malaria in Mauritania on the interface of the Maghreb and West Africa.

BACKGROUND: Plasmodium vivax is very rarely seen in West Africa, although specific detection methods are not widely applied in the region, and it is now considered to be absent from North Africa. However, this parasite species has recently been reported to account for most malaria cases in Nouakchott, the capital of Mauritania, which is a large country at the interface of sub-Saharan West Africa and the Maghreb region in northwest Africa. METHODS: To determine the distribution of malaria parasite species throughout Mauritania, malaria cases were sampled in 2012 and 2013 from health facilities in 12 different areas. These sampling sites were located in eight major administrative regions of the country, within different parts of the Sahara and Sahel zones. Blood spots from finger-prick samples of malaria cases were processed to identify parasite DNA by species-specific PCR. RESULTS: Out of 472 malaria cases examined, 163 (34.5 %) had P. vivax alone, 296 (62.7 %) Plasmodium falciparum alone, and 13 (2.8 %) had mixed P. falciparum and P. vivax infection. All cases were negative for Plasmodium malariae and Plasmodium ovale. The parasite species distribution showed a broad spectrum, P. vivax being detected at six of the different sites, in five of the country's major administrative regions (Tiris Zemmour, Tagant, Brakna, Assaba, and the capital Nouakchott). Most cases in Nouakchott were due to P. vivax, although proportions vary significantly among different health facilities in the city. In the northern town of Zouérat, all cases were due to P. vivax, whereas almost all cases in the south of the country were due to P. falciparum. All P. vivax cases tested were Duffy blood group positive. CONCLUSIONS: It is important that P. vivax is recognized to be a widespread cause of malaria in Mauritania, occurring in diverse regions. This should be noted by the World Health Organization, as it has significant implications for diagnosis, treatment and control of malaria in the northwestern part of Africa

Inhibitory humoral responses to the Plasmodium falciparum vaccine candidate EBA-175 are independent of the erythrocyte invasion pathway

Plasmodium falciparum utilizes multiple ligand-receptor interactions for invasion. The invasion ligand EBA-175 is being developed as a major blood-stage vaccine candidate. EBA-175 mediates parasite invasion of host erythrocytes in a sialic acid-dependent manner through its binding to the erythrocyte receptor glycophorin A. In this study, we addressed the ability of naturally acquired human antibodies against the EBA-175 RII erythrocyte-binding domain to inhibit parasite invasion of ex vivo isolates, in relationship to the sialic acid dependence of these parasites. We have determined the presence of antibodies to the EBA-175 RII domain by enzyme-linked immunosorbent assay (ELISA) in individuals from areas of Senegal where malaria is endemic with high and low transmission. Using affinity-purified human antibodies to the EBA-175 RII domain from pooled patient plasma, we have measured the invasion pathway as well as the invasion inhibition of clinical isolates from Senegalese patients in ex vivo assays. Our results suggest that naturally acquired anti-EBA-175 RII antibodies significantly inhibit invasion of Senegalese parasites and that these responses can be significantly enhanced through limiting other ligand-receptor interactions. However, the extent of this functional inhibition by EBA-175 antibodies is not associated with the sialic acid dependence of the parasite strain, suggesting that erythrocyte invasion pathway usage by parasite strains is not driven by antibodies targeting the EBA-175/glycophorin A interaction. This work has implications for vaccine design based on the RII domain of EBA-175 in the context of alternative invasion pathways

Identification of disease-causing genes using microarray data mining and gene ontology

Background: One of the best and most accurate methods for identifying disease-causing genes is monitoring gene expression values in different samples using microarray technology. One of the shortcomings of microarray data is that they provide a small quantity of samples with respect to the number of genes. This problem reduces the classification accuracy of the methods, so gene selection is essential to improve the predictive accuracy and to identify potential marker genes for a disease. Among numerous existing methods for gene selection, support vector machine-based recursive feature elimination (SVMRFE) has become one of the leading methods, but its performance can be reduced because of the small sample size, noisy data and the fact that the method does not remove redundant genes. Methods: We propose a novel framework for gene selection which uses the advantageous features of conventional methods and addresses their weaknesses. In fact, we have combined the Fisher method and SVMRFE to utilize the advantages of a filtering method as well as an embedded method. Furthermore, we have added a redundancy reduction stage to address the weakness of the Fisher method and SVMRFE. In addition to gene expression values, the proposed method uses Gene Ontology which is a reliable source of information on genes. The use of Gene Ontology can compensate, in part, for the limitations of microarrays, such as having a small number of samples and erroneous measurement results. Results: The proposed method has been applied to colon, Diffuse Large B-Cell Lymphoma (DLBCL) and prostate cancer datasets. The empirical results show that our method has improved classification performance in terms of accuracy, sensitivity and specificity. In addition, the study of the molecular function of selected genes strengthened the hypothesis that these genes are involved in the process of cancer growth. Conclusions: The proposed method addresses the weakness of conventional methods by adding a redundancy reduction stage and utilizing Gene Ontology information. It predicts marker genes for colon, DLBCL and prostate cancer with a high accuracy. The predictions made in this study can serve as a list of candidates for subsequent wet-lab verification and might help in the search for a cure for cancers

West Africa International Centers of Excellence for Malaria Research: Drug Resistance Patterns to Artemether-Lumefantrine in Senegal, Mali, and The Gambia.

In 2006, artemether-lumefantrine (AL) became the first-line treatment of uncomplicated malaria in Senegal, Mali, and the Gambia. To monitor its efficacy, between August 2011 and November 2014, children with uncomplicated Plasmodium falciparum malaria were treated with AL and followed up for 42 days. A total of 463 subjects were enrolled in three sites (246 in Senegal, 97 in Mali, and 120 in Gambia). No early treatment failure was observed and malaria infection cleared in all patients by day 3. Polymerase chain reaction (PCR)-adjusted adequate clinical and parasitological response (ACPR) was 100% in Mali, and the Gambia, and 98.8% in Senegal. However, without PCR adjustment, ACPR was 89.4% overall; 91.5% in Mali, 98.8% in Senegal, and 64.3% in the Gambia (the lower value in the Gambia attributed to poor compliance of the full antimalarial course). However, pfmdr1 mutations were prevalent in Senegal and a decrease in parasite sensitivity to artesunate and lumefantrine (as measured by ex vivo drug assay) was observed at all sites. Recrudescent parasites did not show Kelch 13 (K13) mutations and AL remains highly efficacious in these west African sites

Consensus statement from the 2014 International Microdialysis Forum.

Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.We gratefully acknowledge financial support for participants as follows: P.J.H. - National Institute for Health Research (NIHR) Professorship and the NIHR Biomedical Research Centre, Cambridge; I.J. – Medical Research Council (G1002277 ID 98489); A. H. - Medical Research Council, Royal College of Surgeons of England; K.L.H.C. - NIHR Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme); M.G.B. - Wellcome Trust Dept Health Healthcare Innovation Challenge Fund (HICF-0510-080); L. H. - The Swedish Research Council, VINNOVA and Uppsala Berzelii Technology Centre for Neurodiagnostics; S. M. - Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico; D.K.M. - NIHR Senior Investigator Award to D.K.M., NIHR Cambridge Biomedical Research Centre (Neuroscience Theme), FP7 Program of the European Union; M. O. - Swiss National Science Foundation and the Novartis Foundation for Biomedical Research; J.S. - Fondo de Investigación Sanitaria (Instituto de Salud Carlos III) (PI11/00700) co-financed by the European Regional Development; M.S. – NIHR University College London Hospitals Biomedical Research Centre; N. S. - Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00134-015-3930-

Repeatable patterns in the distribution of freshwater biodiversity indicators across contrasting landscapes

CONTEXT: Freshwater biodiversity is declining at unparalleled rates, but fundamental questions remain over how it is distributed at the spatial scales most relevant for conservation management. OBJECTIVES: Here, we test the hypothesis that freshwater biodiversity is distributed across standing waterbody types in a pattern that is reproducible across disparate biota and contrasting landscapes, such that conservation efforts can be aligned across landscapes and taxa. METHODS: We analysed the richness, composition and distribution of macrophytes, molluscs, beetles and odonates from 199 standing waterbodies (lakes, ponds, ditches and canals) nested within UK landscapes with contrasting dominant land use (agricultural, upland and suburban). RESULTS: We found a common pattern in the distribution of our biodiversity indicators across waterbody types in all landscapes that was largely repeated across biota; lakes consistently had the highest or equal alpha diversity and supported a greater proportion of the sampled species pool in each landscape (mean = 86%) in comparison to ponds (74%). Landscape-specific waterbody types (ditches and canals) also contributed significantly to the regional species pool (69 and 33% respectively). Each waterbody type contributed uniquely to landscape biodiversity and usually species of conservation concern, rather than simply supporting a subset of ubiquitous species found in lakes. CONCLUSIONS: Landscape-wide management strategies that encompass multiple habitats and biota should prove advantageous and generalisable. However, our study landscapes suggest that long-term biodiversity conservation should also recognise lakes as a priority for nature recovery, both to minimise further losses and to maintain the largest reservoir of biodiversity