Nowhere to hide : interrogating different metabolic parameters of Plasmodium falciparum gametocytes in a transmission blocking drug discovery pipeline towards malaria elimination

BACKGROUND : The discovery of malaria transmission-blocking compounds is seen as key to malaria elimination strategies and gametocyte-screening platforms are critical filters to identify active molecules. However, unlike asexual parasite assays measuring parasite proliferation, greater variability in end-point readout exists between different gametocytocidal assays. This is compounded by difficulties in routinely producing viable, functional and stage-specific gametocyte populations. Here, a parallel evaluation of four assay platforms on the same gametocyte populations was performed for the first time. This allowed the direct comparison of the ability of different assay platforms to detect compounds with gametocytocidal activity and revealed caveats in some assay readouts that interrogate different parasite biological functions. METHODS : Gametocytogenesis from Plasmodium falciparum (NF54) was optimized with a robust and standardized protocol. ATP, pLDH, luciferase reporter and PrestoBlue® assays were compared in context of a set of 10 reference compounds. The assays were performed in parallel on the same gametocyte preparation (except for luciferase reporter lines) using the same drug preparations (48 h). The remaining parameters for each assay were all comparable. RESULTS : A highly robust method for generating viable and functional gametocytes was developed and comprehensively validated resulting in an average gametocytaemia of 4 %. Subsequent parallel assays for gametocytocidal activity indicated that different assay platforms were not able to screen compounds with variant chemical scaffolds similarly. Luciferase reporter assays revealed that synchronized stage-specific gametocyte production is essential for drug discovery, as differential susceptibility in various gametocyte developmental populations is evident. CONCLUSIONS : With this study, the key parameters for assays aiming at testing the gametocytocidal activity of potential transmission blocking molecules against Plasmodium gametocytes were accurately dissected. This first and uniquely comparative study emphasizes differential effects seen with the use of different assay platforms interrogating variant biological systems. Whilst this data is informative from a biological perspective and may provide indications of the drug mode of action, it does highlight the care that must be taken when screening broaddiversity chemotypes with a single assay platform against gametocytes for which the biology is not clearly understood.South African Medical Research Council Strategic Health Initiatives Partnerships with the Medicines for Malaria Venture as well as the Council for Scientific and Industrial Research, and the 3R Foundation (project 118–10).http://www.malariajournal.comhb201

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Central Venous Catheters: A Survey of ICU Practices

Aim. This paper describes the current infection control practices for CVC care and compares these to evidence-based practice guidelines. Background. Intensive care patients with central venous catheters (CVCs) are at risk of catheter-related infection, which increases morbidity, mortality and health care costs. Infection control practices, including care of intravenous administration sets and catheter sites, are undertaken by nurses in an attempt to avoid infection. Although practice guidelines are available, infection control practices may vary between practitioners and institutions; however, current practice has not been formally surveyed. Method. A prospective, cross-sectional descriptive survey was carried out. Intensive care units (n = 14) in Australia were surveyed about their infection control policies for CVC care. Results were tabulated and compared with evidence-based practice guidelines. Results. A wide variety of responses was received about duration of administration set use for standard, parenteral nutrition and propofol (lipid-based anaesthetic) infusions; ad hoc administration set connection technique; dressing frequency, materials and solutions; and barrier precautions used during procedures. There was inconsistent adherence to the guidelines. Conclusion. There is variation in the infection control approach to CVC care. Greater adherence to existing Centers for Disease Control Guidelines would assist in the standardization of best practice and facilitate evidence-based care. What is already known about this topic Patients with central venous catheters are at risk of catheter-related infection, which increases morbidity, mortality and health care costs. Many nursing practices attempt to minimize infective risk, although not all are supported by evidence. The Centers for Disease Control provide evidence-based practice guidelines for the prevention of infection and care of central venous catheters. What this paper adds The state of current nursing practice with regards to infection control with central venous catheters. The level of adherence by nurses to the Centers for Disease Control practice guidelines. Recommendations for nursing practice, education and future research

A statistical approach of temperature calculation in electrical machines

International audienceThe thermal behavior of electrical machines is studied. The finite element method is used to calculate the magnetic field and temperature distribution inside the machine. The conductors are randomly distributed inside the slots using the Monte-Carlo method. The random distribution of the maximum temperature of the windings is calculated and its limits of confidence are evaluated

Tree age and soil phosphorus conditions influence N2-fixation rates and soil N dynamics in natural populations of Acacia senegal

Acacia senegal, an important leguminous tree in arid and semi-arid environments, has shown promise as a multipurpose species, including gum production and soil fertility improvement, linked with N2-fixation capabilities. Of particular interest are ontogenetic and edaphic effects on A. senegal performance in natural populations. Our research objectives were to investigate the effect of tree age and site phosphorus conditions on (1) tree N2-fixation and (2) soil N and C dynamics in natural stands of A. senegal var. senegal, Baringo District, in the Rift Valley, Kenya. Sites consisted of A. senegal saplings (9 months) and mature A. senegal trees (7 years) along an edaphic gradient of soil P availability. A single-tree neighborhood approach was employed using a two by two factorial design: site conditions [high and low soil P contents] and tree age class [juvenile and mature]. Soil (N and C pools and fluxes) and plant metrics were quantified. A soil transfer experiment was also employed to confirm age and site effects on soil N mineralization. On the high soil P site, A. senegal had significantly lower foliar (15N levels than neighboring non-leguminous species (Balanites aegyptiaca), while foliar ?15N values in A. senegal on the low P site exhibited no significant difference with our reference plant, B. aegyptiaca. Across P sites, B. aegyptiaca had similar foliar ?15N values. These results indicate that the rate of N2-fixation of A. senegal trees, as determined with foliar 15N natural abundance methodology, increased with increasing soil P availability in these natural populations. However, N2-fixation rates declined with age. Although soil texture and soil CO2 efflux did not differ between sites or across ages, soils under mature A. senegal at the high P site exhibited significantly greater total N content and total C content in comparison to soils at the low P site and under juvenile plants. Furthermore, under mature A. senegal trees, soil N mineralization rates were significantly greater as compared to under saplings. Soil transplants confirmed that soil microbial activity may be stimulated under mature trees as N mineralization rates were 2 3 fold greater compared to under A. senegal saplings. Our findings suggest that tree age and soil P availability are important factors in the nitrogen budget of natural populations of A. senegal, determining N2-fixation rates, and potentially influencing soil total N and C pools and soil mineral N. This study provides information regarding the adaptation of A. senegal under differing edaphic conditions thus increasing accuracy of management support for A. senegal populations as productive agroforests

Onchocerciasis control programme in West Africa : a 20-year monitoring of fish assemblages

Maladie largement répandue en Afrique intertropicale l'onchocercose est un fléau qui provoque, à son stade ultime, une cécité irréversible. La maladie est transmise par un petit Diptère, #Simulium damnosum$, qui présente une phase larvaire et nymphale aquatique. Ce sont les gîtes larvaires de ce vecteur, biefs à courant rapide des rivières, que le Programme de lutte contre l'onchocercose en Afrique de l'Ouest (OCP : Onchocerciasis Control Programme in West Africa) traite lors de ses campagnes de lutte. Comme toute lutte insecticide, OCP représentait une menace importante pour l'environnement. C'est pourquoi le programme s'est doté d'un réseau de surveillance des écosystèmes aquatiques, couvrant l'ensemble de la zone exposée aux épandages d'insecticides. Ce sont les résultats de vingt années de surveillance de l'ichtyofaune, régulièrement exposée aux traitements larvicides, qui sont présentés ici. Les différentes variables étudiées dans cette étude, ne permettent pas de mettre en évidence un effet décelable des pesticides sur la structure et la richesse spécifique des peuplements. De même, la composition trophique ou la santé des poissons ne semblent pas affectées. Cependant, nous observons parfois certaines tendances, à moyen terme, qui semblent être essentiellement sous l'influence des conditions climatiques, probablement hydrologiques. Ainsi, nous observons une diminution régulière des prises par unité d'effort (PUE) du début de la surveillance jusque vers 1995. Durant cette période, les rivières ont été, selon les stations, traitées jusque 1990 ou 1993. Mais, alors que les traitements étaient terminés, la diminution des captures s'est poursuivie. Nous pouvons donc estimer que d'autres facteurs en sont la cause. Si nous considérons les crues moyennes annuelles et régionales, nous observons une diminution régulière depuis le début des années 1970... (D'après résumé d'auteur

Accuracy of cytology in distinguishing adrenocortical tumors from pheochromocytoma in companion animals

Background: The distinction between adrenocortical tumors and pheochromocytoma can be challenging using clinical findings, diagnostic imaging and laboratory tests. Cytology might be a simple, minimally invasive method to reach a correct diagnosis. Objectives: The purpose of this study was to assess the accuracy of cytology in differentiating cortical from medullary tumors of the adrenal glands in dogs and cats. Methods: Cytologic key features of adrenocortical tumors and pheochromocytoma were defined by one reference author. Cytologic specimens from primary adrenal tumors were submitted to 4 cytopathologists who were asked to classify the tumors based on the previously defined key features without knowledge of previous classification. Results: Twenty specimens from histologically confirmed adrenal tumors (Group 1) and 4 specimens from adrenal tumors causing adrenal-dependent Cushing's syndrome (Group 2) were evaluated by the 4 cytopathologists. Accuracy in differentiating cortical from medullary origin ranged from 90% to 100%, with a Kappa coefficient of agreement between cytopathologists of 0.95. Conclusions: The origin of an adrenal tumor can be easily determined by cytology alone in many cases. However, cytology was not reliable in distinguishing benign from malignant neoplasia. Additional studies are needed to assess possible risks and complications associated with fine-needle biopsy of adrenal tumors in dogs and cats