HAL ENVT (Ecole Nationale Vétérinaire de Toulouse)
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Oligoesters migrating from food can coatings -Filling risk assessment gaps
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Thrombose aortique et thromboembolie chez les bovins: Les causes, les méthodes diagnostiques et la prise en charge des cas de thrombose ou de thromboembolie chez le veau sont discutées au regard des connaissances acquises chez les carnivores domestiques et le cheval
No full textInternational audienceThe main cause of aortic thrombus formation appears to be infection in cattle, heart diseas ein cats, and hypercoagulability in dogs. Sudden onset paralysis seen in cattle is also a commonly described symptom of aortic thromboembolism in cats. Ante-mortem diagnostic methods, notably ultrasound and comparison of lactatemia between affected and unaffected limbs are fairly similar between the different species, but are less commonly performed in cattle. In cattle, often the farmer cannot instigate treatment for the required period of time and the diagnosis is confirmed at autopsy.Chez les bovins, la cause principale de la formation d'un thrombus aortique semble être une infection, alors qu'il s'agit plutôt d'une cardiopathie chez le chat ou d'un état d'hypercoagulabilité chez le chien. La paralysie d'apparition soudaine observée chez les bovins est un signe couramment décrit lors de thromboembolie aortique chez le chat. Les méthodes diagnostiques ante mortem sont assez similaires entre les différentes espèces, notamment l'échographie et la comparaison de la lactatémie entre les membres atteints et sains, mais elles sont moins mises en oeuvre chez les bovins. Chez ces derniers, la durée du traitement nécessaire conduit souvent l'éleveur à l'interrompre. Seule l'autopsie permet alors de confirmer le diagnostic
Automated larval motility assays reveal links between eprinomectin treatment failure and drug resistance in Haemonchus contortus
No full textInternational audienceSmall ruminants are frequently infected with gastrointestinal nematode parasites (GIN) such as the highly pathogenic Haemonchus contortus, which severely impact animal health, welfare and production performance. The increasing prevalence of clinical anthelmintic resistance poses a global threat to effective parasite control and the productivity of livestock farming. This includes resistance to eprinomectin (EPR), the only anthelmintic currently approved for use in dairy production with a zero-withdrawal period. This study aims to link EPR therapeutic failure against H. contortus in dairy sheep farms in southwestern France with drug potency, as determined via the larval motility phenotype in an in vitro test. Six field isolates (four EPR-resistant and two EPR-susceptible isolates) were collected from dairy sheep farms, where EPR efficacy was assessed using the faecal egg count reduction test (FECRT). In addition, two laboratory isolates, known for their EPR-susceptible status, were used. We simultaneously evaluated the effects of ivermectin (IVM), moxidectin (MOX), EPR, and levamisole on larval stage development and motility, comparing putative EPR-resistant isolates with those expected to be EPR-susceptible. The automated motility assay effectively distinguished EPR-susceptible isolates from EPR-resistant isolates, with IC50 values between 0.29 and 0.48 µM for susceptible isolates and between 8.16 and 32.03 µM for resistant isolates, revealing that isolates from farms with EPR treatment failure presented high resistance factors for EPR, ranging from 17 to 101. Our results reveal the sensitivity, reliability, and reproducibility of the motility test in monitoring the response of H. contortus to eprinomectin, and it may be used to detect H. contortus resistance to eprinomectin on farms. This paves the way for improving diagnostics and treatments for helminth infections in dairy sheep farms
Population pharmacokinetic modeling of sulfadimethoxine, sulfadiazine and sulfamethoxazole combined to trimethoprim in pigs
No full textInternational audienceSulfonamides (S) are old antibiotics combined with trimethoprim (TMP) for synergistic effects against pathogens responsible for a variety of infections in food-producing animals. In growing pigs, the TMP:S ratio is 1:5 based on human TMP/sulfamethoxazole (SMX) dosing which aims to obtain an in vivo ratio concentration of 1:19 considered as optimal against human pathogens. However, different sulfonamides with different pharmacokinetic profiles are used in pigs limiting this direct extrapolation from human. The aim was to conduct a PK study in pigs for three commonly used TMP/S combinations and to analyze data using population pharmacokinetic modeling. We found that a 2-compartment structural model fitted best the four drug PK data. TMP has the highest clearance values (0.48 L/h/kg) compared to SMX (0.21 L/h/kg), SDZ (0.12 L/h/kg) and SDMX (0.015 L/h/kg). SDMX has the longest plasma elimination half-life (14.8 h), followed by SDZ (3.7 h), TMP (2.9 h) and SMX (2.2 h). Monte Carlo simulations (n = 50,000 pigs) showed that only for 8.8%, 46.8%, and 76.5% of pigs for TMP/SMX, TMP/SDZ and TMP/SDMX, respectively, the free plasma concentration ratio fell within the range of 1:10–1:50 at the marketed doses administered. These results should be further linked to pharmacodynamics to optimize the use of these important antimicrobials drugs in veterinary medicine
Brown adipose tissue activity impacts systemic lactate clearance in male mice
No full textInternational audienceNon-shivering thermogenesis in brown adipose tissue (BAT) is linked to metabolic health. Yet, how its activity states impact on systemic metabolism and in particular on lactate, a highly abundant metabolite increasingly recognized as a critical player in energy metabolism, remains unresolved. The goal of this study was to investigate the impact of BAT activity on lactate metabolism at the whole organism level. To activate or inactivate non-shivering thermogenesis in BAT, we housed C57Bl6/J male mice at 4, 21 and 30°C and then conducted lactate tolerance tests. In mice exposed to cold exposure (4°C), systemic lactate clearance was elevated. In contrast, clearance of systemic lactate was poor in mice housed under thermoneutral conditions (30°C) that inactivate BAT thermogenesis, as well as in mice deficient for the mitochondrial uncoupling protein-1. To better understand lactate metabolic fate during the clearance phase, in vivo stable isotope tracing experiments with labelled 13C-lactate and analyses by mass spectrometry were performed. These experiments revealed that lactate contribution to gluconeogenesis was increased under cold exposure while its contribution to the tricarboxylic acid cycle was reduced in BAT under thermoneutrality. Remarkably, we also identified that lactate entered a pyruvate cycling process that was highly active in BAT, and repressed at thermoneutrality. Our study shows that inactivation of non-shivering thermogenesis decreased systemic lactate clearance, concomitantly with changes in metabolic fate of lactate in BAT and in gluconeogenic organs, in male mice
Traits de vie et écologie d'Haemonchus contortus dans un contexte de résistance aux anthelminthiques
No full textMore and more cases of Haemonchus contortus resistance to anthelmintics are being observed worldwide. The Pyrénées-Atlantiques département, with its many dairy ewe farms, is no exception to this phenomenon, with confirmed cases of H. contortus resistance to eprinomectin. Dairy farming has the particularity of rapidly finding itself in a therapeutic impasse when faced with strongyles, due to the limited number of molecules that can be used in lactation. In addition, climate change projections show that the development of H. contortus, a thermophilic species, could be favored in the future. In this context, we addressed several questions on life traits and control of H. contortus, including, i) the evolution over time of its presence in sheep digestive parasite communities, ii) the impact of anthelmintic resistance on H. contortus fitness in order to adapt prevention and control measures against resistant isolates, iii) the use of a new larval motility recording tool for earlier and faster diagnosis of resistance, iv) the evaluation of the benefits and limitations of mixed grazing between cattle and sheep for the control of digestive strongyles. For the first point, we followed sixteen dairy ewe farms in the Basque Country where helminths communities had been studied 25 years ago. Strongyles communities on these farms have evolved over this period, and are now more diverse than they were 25 years ago, with an increase in the prevalence of H. contortus in spring. To assess the cost of eprinomectin resistance, we compared the fitness of four eprinomectin-resistant and two eprinomectin-susceptible isolates in experimental infestations. This comparison did not reveal any cost of resistance in H. contortus under our experimental conditions. Similarly, a comparison of the fitness of a resistant isolate under two conditions, exposed or not to eprinomectin, revealed a decrease in the development of larval stages in faeces, but no loss of fitness for stages present in the host. Under these conditions, reversion of resistance is unlikely, so measures to prevent the introduction of resistant H. contortus into a farm must be reinforced. The need for an early, easy-to-use resistance diagnostic tool in the field is obvious. Our work has shown that measuring larval motility is an interesting tool for diagnosing resistance to eprinomectin, but it still requires further development and validation before it can be used under field conditions. Finally, mixed grazing is presented as one of the levers available to limit infections by digestive strongyles. Our work has identified an initial limitation to this strategy. In fact, the Dicrocoelium dendriticum parasite, which is transmitted between sheep and cattle, has shown a decline in sensitivity to the only molecule available for treatment in France. In the current context, improved diagnostic techniques are essential to better understand the evolution of parasite communities and the factors influencing them, as well as to improve resistance detection and prevention of its spread between herds. This will facilitate the analyses of risk factors for the appearance of resistance, so as to prevent it more effectively. The challenge now is to improve our knowledge of the ecology of resistant strongyles, so that we can combat them more effectively and preserve the sustainability of grazing sheep farms.De plus en plus de cas de résistance d’Haemonchus contortus aux anthelminthiques sont observés dans le monde. Le département des Pyrénées-Atlantiques, qui compte de nombreux élevages de brebis laitières, n’échappe pas à ce phénomène avec des cas avérés de résistance d’H. contortus à l’éprinomectine. L’élevage laitier a la particularité de se trouver rapidement en situation d’impasse thérapeutique face aux strongles à cause du nombre limité de molécules utilisables en lactation. De plus, les projections réalisées dans le cadre du changement climatique montrent que le développement d’H. contortus, espèce thermophile, pourrait être favorisé dans le futur. Dans ce contexte, nous avons abordé plusieurs questions sur les traits de vie et la lutte contre H. contortus, notamment, i) l’évolution dans le temps de sa présence dans les communautés de parasites digestifs des ovins, ii) l’impact de la résistance aux anthelminthiques sur le fitness des H. contortus afin d’adapter les mesures de prévention et de lutte contre les isolats résistants, iii) l’utilisation d’un nouvel outil d’enregistrement de la motilité larvaire pour un diagnostic plus précoce et plus rapide de la résistance, iv), l’évaluation de l’intérêt et des limites de l’utilisation du pâturage mixte entre les bovins et les ovins pour la lutte contre les strongles digestifs. Pour le premier point, nous avons suivi seize élevages de brebis laitières du Pays Basque pour lesquels l’helminthofaune avait été étudiée il y a 25 ans. Dans ces élevages, les communautés de strongles ont évolué durant cette période et elles sont aujourd’hui plus diversifiées qu’il y a 25 ans mais avec une augmentation de la prévalence d’H. contortus au printemps. Pour évaluer le coût de la résistance à l’éprinomectine, nous avons comparé le fitness de quatre isolats résistants et de deux isolats sensibles à l’éprinomectine lors d’infestations expérimentales. Cette comparaison n’a pas permis de mettre en évidence de coût de la résistance d’H. contortus dans nos conditions expérimentales. De même, la comparaison de fitness d’un isolat résistant dans deux conditions, exposé ou non à l’éprinomectine, a mis en évidence une baisse de développement des stades larvaires en développement dans les matières fécales mais une absence de perte de fitness pour les stades présents chez l’hôte. Dans ces conditions, il est peu probable qu’il y ait réversion de la résistance ; les mesures de prévention de l’introduction d’H. contortus résistant dans un élevage doivent donc être renforcées. La nécessité d’un outil de diagnostic de la résistance, précoce et facile à utiliser sur le terrain, s’impose. Nos travaux ont montré que la mesure de la motilité larvaire est un outil intéressant pour le diagnostic de la résistance à l’éprinomectine mais il nécessite encore des travaux de mise au point et de validation pour être utilisé en conditions de terrain. Enfin, le pâturage mixte est présenté comme un des leviers disponibles pour limiter les infestations par les strongles digestifs, Nos travaux ont permis d’identifier une première limite à cette stratégie. En effet, le parasite Dicrocœlium dendriticum, qui se transmet entre ovins et bovins, a montré une baisse de sensibilité à la seule molécule disponible en France pour le traitement. Dans le contexte actuel, l’amélioration des techniques de diagnostic est indispensable pour mieux appréhender les évolutions des communautés parasitaires et les facteurs les influençant mais aussi pour améliorer la détection de la résistance et la prévention de sa diffusion entre les cheptels. Cela permettra également d’analyser les facteurs de risque d’apparition de la résistance pour mieux la prévenir. L’enjeu maintenant est d’améliorer nos connaissances de l’écologie des strongles résistants pour lutter de manière plus pertinente et de préserver la durabilité des élevages ovins au pâturage
A Human Colon-based Microphysiological System with Mechanical Microenvironment Control for 3D Imaging
No full textInternational audienceIn vitro artificial colonic micro-devices that better replicate complex in vivo systems are essential tools for advancing our understanding of human gut (patho)physiology. Micro-physiological systems (MPS) offer controlled environments, enabling precise manipulation of tissue topography, rigidity and nutrient flow. We present the EnView system configured as a human colon-based MPS that faithfully replicates the 3D topography and matrix stiffness of the human colonic environment using an interpenetrating network of polyacrylamide and collagen I hydrogels, and enabling the culture of human colonic epithelium for weeks. The EnView system integrates a microfluidic chamber with active control of apical/luminal and basal/stromal compartments, allowing for in situ imaging and monitoring. Human colonic epithelial Caco-2 cells cultured up to 21 days in this system follow the crypt topography and formed a polarized epithelial monolayer. This innovative MPS recapitulates in vitro a human colon epithelium with its 3D matrix topology and stiffness control, integrates a microfluidic chamber allowing active control of the apical/luminal and basal/stromal compartments by accurate injection, as well as in situ imaging. Teaser Human gut-on-chip reproducing tissue mechanical properties with active microfluidic control for 3D tissue characterization
Maternal stress triggers early-life eczema through fetal mast cell programming
No full textInternational audiencePrenatal stress (PS) is a repeated exposure to aversive situations during pregnancy, including high emotional strain, which is suspected to affect homeostatic systems in infants. Paediatric eczema develops quickly after birth at flexural sites subjected to continuous mechanical constraints1,2. Although epidemiological studies have suggested an association between PS and a higher risk of eczema in children3, 4, 5-6, no causative biological link has yet been identified. Here we show that eczema at birth originates from molecular dysregulations of neuroimmune circuits in utero, triggered by fluctuations in the maternal hypothalamic-pituitary-adrenal axis. We found that offspring of stressed pregnant dams have dysregulated mast cells and skin-projecting neurons and quickly develop eczema in response to harmless mechanical friction. We demonstrated that PS transiently modulates amniotic fluid corticosterone concentrations, which directly alters the activation program of skin mast cells expressing the glucocorticoid receptor Nr3c1 and the adjacent sensory neurons conveying mechanosensation. Therapeutic normalization of maternal corticosterone concentrations or genetic depletion of Mcpt5+ mast cells during stressed gestation prevents fetal immune dysregulation and protects against eczema development after birth. Our findings support a new model in which early-onset paediatric eczema originates from dysregulations in the fetal immune system, caused by fluctuations in maternal glucocorticoids induced by stress
