Toxicity, transfer and depuration of anatoxin-a (cyanobacterial neurotoxin) in medaka fish exposed by single-dose gavage

International audienceThe proliferations of cyanobacteria are increasingly prevalent in many rivers and water bodies due especially to eutrophication. This work aims to study in female medaka fish the toxicity, the transfer and the depuration of the anatoxin-a, a neurotoxin produced by benthic cyanobacterial biofilms. This work will provide answers regarding acute toxicity induced by single gavage by anatoxin-a and to the risks of exposure by ingestion of contaminated fish flesh, considering that data on these aspects remain particularly limited.The oral LD50 and NOAEL of a single dose of (±)-anatoxin-a were determined at 11.50 and 6.67 μg.g-1, respectively. Subsequently, the toxico-kinetics of the (±)-anatoxin-a was observed in the guts, the livers and the muscles of female medaka fish for 10 days. Anatoxin-a was quantified by high-resolution qTOF mass spectrometry coupled upstream to a UHPLC chromatographic chain. The toxin could not be detected in the liver after 12 h, and in the gut and muscle after 3 days. Overall, the medaka fish do not appear to accumulate (±)-anatoxin-a and to largely recover after 24 h following a single sub-acute oral liquid exposure at the NOAEL

Subcellular localization of microcystin in the liver and the gonads of medaka fish acutely exposed to microcystin-LR

International audienceAmong the diverse toxic components produced by cyanobacteria, microcystins (MCs) are one of the most toxic and notorious cyanotoxin groups. Besides their potent hepatotoxicity, MCs have been revealed to induce potential reproductive toxicity in various animal studies. However, little is still known regarding the distribution of MCs in the reproductive organ, which could directly affect reproductive cells. In order to respond to this question, an acute study was conducted in adult medaka fish (model animal) gavaged with 10 μg.g −1 body weight of pure MC-LR. The histological and immunohistochemical examinations reveal an intense distribution of MC-LR within hepatocytes along with a severe liver lesion in the toxin-treated female and male fish. Besides being accumulated in the hepatocytes, MC-LR was also found in the connective tissue of the ovary and the testis, as well as in oocytes and degenerative spermatocyte-like structures but not spermatocytes. Both liver and gonad play important roles in the reproductive process of oviparous vertebrates. This observation constitutes the first observation of the presence of MC-LR in reproductive cells (female, oocytes) of a vertebrate model with in vivo study. Our results, which provide intracellular localization of MC-LR in the gonad, advance our understanding of the potential reproductive toxicity of MC-LR in fish

Specificity of the metabolic signatures of fish from cyanobacteria rich lakes

International audienceThe liver metabolomes of fish from cyanobacterial-dominated ponds were investigated. Cyanobacterial metabolites were only be detected in cyanobacterial dominated ponds. The metabolomes of the 2 fish species exhibit similar correlation with cyanobacteria occurrence. Correlations between the levels of some metabolites and phycocyanin or pH were observed. a b s t r a c t With the increasing impact of the global warming, occurrences of cyanobacterial blooms in aquatic ecosystems are becoming a main worldwide ecological concern. Due to their capacity to produce potential toxic metabolites, interactions between the cyanobacteria, their cyanotoxins and the surrounding freshwater organisms have been investigated during the last past years. Non-targeted metabolomic analyses have the powerful capacity to study simultaneously a high number of metabolites and thus to investigate in depth the molecular signatures between various organisms encountering different environmental scenario, and potentially facing cyanobacterial blooms. In this way, the liver metabolomes of two fish species (Perca fluviatilis and Lepomis gibbosus) colonizing various peri-urban lakes of theÎle-de-France region displaying high biomass of cyanobacteria, or not, were investigated. The fish metabolome hydrophilic fraction was analyzed by 1 H NMR analysis coupled with Batman peak treatment for the quantification and the annotation attempt of the metabolites. The results suggest that similar metabolome profiles occur in both fish species, for individuals collected from cyanobacterial blooming lakes compared to organism from non-cyanobacterial dominant environments. Overall, such environmental metabolomic pilot study provides new research perspectives in ecology and ecotoxicology fields, and may notably provide new information concerning the cyanobacteria/fish eco-toxicological interactions

Case report: Parsonage-turner syndrome in a melanoma patient treated by BRAF/MEK inhibitors after immune checkpoint inhibitors

IntroductionCombination molecular BRAF/MEK inhibitors targeted therapy has been shown to improve overall survival in patients with BRAF V600 mutated unresectable or metastatic melanoma. Most patients treated with BRAF/MEK inhibitors will experience adverse events but neurological adverse events (nAEs) remain rare.Case reportA 42-year-old woman diagnosed with metastatic melanoma presented with an intense pain in the left shoulder 7 days after the beginning of encorafenib/binimetinib after immune checkpoint inhibitors (ICI) combination. No other triggering factors were identified. Electromyogram performed one month after the pain onset revealed a left brachial plexopathy suggestive of a Parsonage-Turner syndrome. The weakness slowly improved with intensive rehabilitation and targeted therapies were continued.ConclusionWe report the first case of Parsonage-Turner syndrome in a melanoma patient treated with encorafenib/binimetinib following checkpoint inhibitors combination.We cannot rule out the implication of ICI in the development of this syndrome but the rapid onset of the symptoms after the beginning of targeted therapies makes their involvment more likely.Given the increased use of BRAF/MEK inhibitors in managing of stage III and IV melanoma, as well as the development in stage II, clinicians should be aware of this potential side effect

Very Low Phytoplankton Diversity in a Tropical Saline-Alkaline Lake, with Co-dominance of Arthrospira fusiformis (Cyanobacteria) and Picocystis salinarum (Chlorophyta)

International audienceLake Dziani Dzaha (Mayotte Island, Indian Ocean) is a tropical thalassohaline lake which geochemical and biological conditions make it a unique aquatic ecosystem considered as a modern analogue of Precambrian environments. In the present study, we focused on the diversity of phytoplanktonic communities, which produce very high and stable biomass (mean 2014-2015 = 652 ± 179 μg chlorophyll a L −1). As predicted by classical community ecology paradigms, and as observed in similar environments, a single species is expected to dominate the phytoplanktonic communities. To test this hypothesis, we sampled water column in the deepest part of the lake (18 m) during rainy and dry seasons for two consecutive years. Phytoplanktonic communities were characterized using a combination of metagenomic, microscopy-based and flow cytometry approaches, and we used statistical modeling to identify the environmental factors determining the abundance of dominant organisms. As hypothesized, the overall diversity of the phytoplanktonic communities was very low (15 OTUs), but we observed a co-dominance of two, and not only one, OTUs, viz., Arthrospira fusiformis (Cyanobacteria) and Picocystis salinarum (Chlorophyta). We observed a decrease in the abundance of these co-dominant taxa along the depth profile and identified the adverse environmental factors driving this decline. The functional traits measured on isolated strains of these two taxa (i.e., size, pigment composition, and concentration) are then compared and discussed to explain their capacity to cope with the extreme environmental conditions encountered in the aphotic, anoxic, and sulfidic layers of the water column of Lake Dziani Dzaha

Global Metabolomic Characterizations of Microcystis spp. Highlights Clonal Diversity in Natural Bloom-Forming Populations and Expands Metabolite Structural Diversity

Cyanobacteria are photosynthetic prokaryotes capable of synthesizing a large variety of secondary metabolites that exhibit significant bioactivity or toxicity. Microcystis constitutes one of the most common cyanobacterial genera, forming the intensive blooms that nowadays arise in freshwater ecosystems worldwide. Species in this genus can produce numerous cyanotoxins (i.e., toxic cyanobacterial metabolites), which can be harmful to human health and aquatic organisms. To better understand variations in cyanotoxin production between clones of Microcystis species, we investigated the diversity of 24 strains isolated from the same blooms or from different populations in various geographical areas. Strains were compared by genotyping with 16S-ITS fragment sequencing and metabolite chemotyping using LC ESI-qTOF mass spectrometry. While genotyping can help to discriminate among different species, the global metabolome analysis revealed clearly discriminating molecular profiles among strains. These profiles could be clustered primarily according to their global metabolite content, then according to their genotype, and finally according to their sampling location. A global molecular network of all metabolites produced by Microcystis species highlights the production of a wide set of chemically diverse metabolites, including a few microcystins, many aeruginosins, microginins, cyanopeptolins, and anabaenopeptins, together with a large set of unknown molecules. These components, which constitute the molecular biodiversity of Microcystis species, still need to be investigated in terms of their structure and potential bioactivites (e.g., toxicity)

Pharmacokinetic/pharmacodynamic modelling approaches in paediatric infectious diseases and immunology.

Pharmacokinetic/pharmacodynamic (PKPD) modelling is used to describe and quantify dose-concentration-effect relationships. Within paediatric studies in infectious diseases and immunology these methods are often applied to developing guidance on appropriate dosing. In this paper, an introduction to the field of PKPD modelling is given, followed by a review of the PKPD studies that have been undertaken in paediatric infectious diseases and immunology. The main focus is on identifying the methodological approaches used to define the PKPD relationship in these studies. The major findings were that most studies of infectious diseases have developed a PK model and then used simulations to define a dose recommendation based on a pre-defined PD target, which may have been defined in adults or in vitro. For immunological studies much of the modelling has focused on either PK or PD, and since multiple drugs are usually used, delineating the relative contributions of each is challenging. The use of dynamical modelling of in vitro antibacterial studies, and paediatric HIV mechanistic PD models linked with the PK of all drugs, are emerging methods that should enhance PKPD-based recommendations in the future

Think and Act: Reflective Tool for professionals working with families (TART). Summary version

The IO3 aims to help organise and articulate reflection by the professional who works with families in situations of vulnerability or that are at risk and encourages professionals to continue questioning themselves about the processes of accompanying families with a broad, systemic, and ecological perspective. - The content of TART (IO3) is focused on a series of specific challenges of attention and intervention with today’s families in Europe. These challenges are listed in the previous IO by describing situations (IO1) and mentioning the main challenges that were identified by the professionals, parents, and young people (IO2). - The tool can be used both by the direct care professionals themselves to address their own practice, as well as by professionals who are dedicated to supervising teams, or by professionals who guide the professional practices of university students

Think and Act: Reflective Tool for professionals working with families (TART)

This tool, Think and Act: Reflective Tool for Professionals working with Families (TART) (hereinafter TART) has been created within the framework of the Erasmus + Grow in Family Today project (hereinafter GIFT) (2018-FR01-KA202-0488115) with the participation of 4 European countries (France, Spain, Italy and Romania) represented by 4 entities and/or professional services that attend families in vulnerable situations (Caminante-FR, Consell Comarcal del Vallès Occidental-ESP, Casa di Ramia-IT and Holtis-RO) and the universities of 4 European countries (Pau et Pays de l’Adour University-UPPA-FR; Barcelona University and Lleida University-ESP; Padova University and Verona University-IT; Iasi University-RO). Within the framework of the GIFT project, two previous intellectual outputs have been created that are antecedents to and complement this current output. The first of them "Growing in family today: the challenge of diversity" addresses the issue of the family and the exercise of parenthood in the family today from the perspective of diversity, and identifies the main challenges in terms of intervention, defined by the components of the aforementioned partnership. The second output, entitled “Representations of growing in family today” focuses on the view held by families, fathers, mothers, sons and daughters, as well as professionals, of what it means to grow in a family today. Both intellectual outputs are antecedents of this third intellectual output and contribute valuable elements to nurture the reflective processes that are proposed here..