Ir-LBP, an Ixodes ricinus Tick Salivary LTB4-Binding Lipocalin, Interferes with Host Neutrophil Function

BACKGROUND: During their blood meal, ticks secrete a wide variety of proteins that can interfere with their host's defense mechanisms. Among these proteins, lipocalins play a major role in the modulation of the inflammatory response. METHODOLOGY/PRINCIPAL FINDINGS: We previously identified 14 new lipocalin genes in the tick Ixodes ricinus. One of them codes for a protein that specifically binds leukotriene B4 with a very high affinity (Kd: +/-1 nM), similar to that of the neutrophil transmembrane receptor BLT1. By in silico approaches, we modeled the 3D structure of the protein and the binding of LTB4 into the ligand pocket. This protein, called Ir-LBP, inhibits neutrophil chemotaxis in vitro and delays LTB4-induced apoptosis. Ir-LBP also inhibits the host inflammatory response in vivo by decreasing the number and activation of neutrophils located at the tick bite site. Thus, Ir-LBP participates in the tick's ability to interfere with proper neutrophil function in inflammation. CONCLUSIONS/SIGNIFICANCE: These elements suggest that Ir-LBP is a "scavenger" of LTB4, which, in combination with other factors, such as histamine-binding proteins or proteins inhibiting the classical or alternative complement pathways, permits the tick to properly manage its blood meal. Moreover, with regard to its properties, Ir-LBP could possibly be used as a therapeutic tool for illnesses associated with an increased LTB4 production.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Comprendre le phénotype des macrophages résidents de l’îlot pancréatique : potentiels gardiens de l’équilibre antioxydant des cellules β

Β cells are the main compounds of the pancreatic islet, to maintain normoglycemia through insulin secretion. Inside islets, there are immune cells, mainly macrophages who display an activated and inflammatory phenotype at steady state. The molecular mechanisms underlying this activation are not well described. My PhD project aims at studying the phenotype and function of these islet macrophages at steady state and during diet-induced obesity. By combining single cell RNA sequencing and flow cytometry in mouse models, we confirmed the inflammatory phenotype at steady state of islet macrophages. Islet macrophages express at homeostasis, pro-inflammatory cytokines such as Il1b, Tnf or Ccl4, and have a membranous expression of MHC-II and CD11c, surface markers associated with activated macrophage phenotype. Using clustering method, we defined a continuum of 3 associated subpopulations of islet resident macrophages including profiles differentially characterized by i) inflammatory secretory and ii) an antioxidant profile. The antioxidant macrophage subpopulation was marked by genes encoding for the glutathione pathway, involved in the detoxification of reactive oxygen species (ROS). Based on this pioneer observation, we propose that the glutathione pathway in macrophages may modulate its inflammatory status. To confirm our hypothesis, using pharmacological agents, we antagonized glutathione pathway, and observed a significant decrease of proinflammatory factors. Our analyses show that the glutathione pathway contributes to the activated phenotype of islet macrophages. The glutathione production is limited by cystine availability. We developed an inhibitory model of glutathione production by blocking the cystine transporter xCT, highly expressed in islet macrophages. Using this mouse model, we performed bone marrow transplantation experiments to limit cystine importation restricted to immune cells. We showed an increase of oxidative stress associated with an increase of ROS production by macrophages in reconstituted xCT KO mice. Analysis of β cells showed an increase of ROS and an increase of insulin secretion. The β cells redox status seems to be associated to alteration of iron metabolism, an ion essential for endocrine function. Our data propose for the first time that interaction between macrophages and β cells may be key in the maintenance of islet homeostasis by modulating the cellular stress in β cells. In a diet-induced obesity model, we observed an increase of islet macrophage counts closely related with the increased of islet size. Our analyses also revealed a minor regulation of macrophages inflammatory state but it highlighted the rewiring of cellular metabolism, suggesting the contribution of islet macrophages in the maintenance of endocrine function through glutamine exchange. My PhD work highlighted the implication of redox pathways on islet macrophage phenotype, and potential new functions of islet macrophages in the modulation of β cell oxidative state.Les cellules β sont les principales composantes de l’îlot pancréatique, où elles jouent un rôle majeur par la sécrétion d’insuline afin de réguler la glycémie. Les îlots pancréatiques contiennent d’autres types cellulaires, parmi lesquels des cellules immunitaires résidentes, composées majoritairement de macrophages. Ces macrophages ont un phénotype activé, plutôt inflammatoire à l’homéostasie. Les mécanismes moléculaires d’une telle activation n’étant pas connus, mon projet de thèse a pour but de définir le phénotype et le rôle des macrophages des îlots à l’homéostasie et lors d’un régime obésogène. Dans un modèle murin, en combinant des techniques de cytométrie et de séquençage, nous avons confirmé le phénotype pro-inflammatoire des macrophages de l’îlot pancréatique avec une forte expression génique de cytokines et chimiokines telles qu’Il1b ou Ccl4, ainsi qu’une expression membranaire de CD11c et CMH-II à l’homéostasie. De plus, nous avons identifié 3 sous-populations de macrophages résidents de l‘îlot pancréatique, parmi lesquelles deux sous-populations liées et associées d’une part à un profil de sécrétion de facteurs inflammatoires, et d’autre part, à un profil métabolique antioxydant. Ces macrophages antioxydants sont caractérisés par l’expression de nombreux gènes de la voie du glutathion impliquée dans la dégradation des espèces réactives de l’oxygène (ROS). Ainsi, nous proposons que le niveau élevé de glutathion dans les macrophages de l’îlot conditionne leur activité inflammatoire. Afin de tester notre hypothèse, nous avons modulé la production et l’utilisation du glutathion dans les macrophages par des composés pharmacologiques, et nous avons observé que l’inhibition de la voie glutathion induit une diminution significative de l’expression génique des facteurs inflammatoires. Ainsi, la voie du glutathion semble importante pour maintenir le phénotype pro-inflammatoire des macrophages de l’îlot pancréatique. Le glutathion étant produit à partir de cystine, nous avons développé un modèle d’inhibition de la production du glutathion en ciblant le transporteur de cystine xCT, qui semble spécifique aux macrophages dans l’îlot. Ainsi, nous mettons en évidence dans des modèles de reconstitution xCT KO spécifique des cellules immunitaires, une augmentation du stress oxydatif des macrophages, associé à une augmentation des ROS qui s’accompagne d’une augmentation du stress oxydatif aussi chez les cellules β et d’une altération de leur fonction. L’état oxydant des cellules β semble être associé à une modulation du métabolisme du fer, ion essentiel à leur fonction. Nous mettons ainsi en évidence une forte interaction entre les macrophages et les cellules β et proposons que les macrophages de l’îlot participent au maintien des capacités antioxydants des cellules β. Lors de l’obésité, induite par un régime riche en graisses, nous avons mis en évidence que la densité des macrophages et leur phénotype inflammatoire ne semble pas être modulés. En revanche, ils pourraient participer à garantir une bonne fonction endocrine par l’apport de glutamine. Ainsi, mes travaux ont permis de mettre en évidence l’implication des voies antioxydants dans le phénotype des macrophages de l’îlot ainsi qu’une implication potentielle des macrophages de l’îlot pancréatique dans la régulation de l’équilibre oxydant et de la fonction des cellules β

Data_Sheet_1_Understanding acceptability of digital health technologies among francophone-speaking communities across the world: a meta-ethnographic study.XLSX

IntroductionIncreasingly, people are turning toward digital health technologies to support their care management, communication with health professionals, and performing activities of daily living. Digital health technologies may be well implemented in clinical practices in several jurisdictions, but the influence of sociocultural factors may sometimes be neglected. To increase use and sustainability of these innovative solutions in health care, we need to understand acceptability among diverse groups of the population such as linguistically diverse populations. Francophone-speaking populations in Canada, for example, are known to endure challenges with income, health and difficulties associated with living in rural areas which impede on their likelihood to use digital health technologies. As part of the University of Ottawa International Francophonie Research Chair on Digital Health Technologies, this study aimed to understand the conditions that make digital health technologies acceptable among francophone-speaking communities.MethodsUsing a meta-ethnography methodology, this study synthesizes international qualitative research on social acceptability of digital health technology among francophone-speaking communities. We focused on four types of digital health technologies: telemedicine, mobile technologies, wearable technologies, and robotic technologies. Using Noblit and Hare's 7 phase approach to conducting a meta-ethnography, we were able to get a comprehensive synthesis and understanding of the research landscape on the issue. Studies published between 2010 and 2020 were included and synthesized using NVivo, excel and a mind mapping technique.ResultsOur coding revealed that factors of social acceptability for digital health technologies could be grouped into the following categories: care organization, self-care support, communication with care team, relational and technical risks, organizational factors, social and ethical values. Our paper discusses the themes evoked in each category and their relevance for the included digital health technologies.DiscussionIn discussing the results, we present commonalities and differences in the social acceptability factors of the different digital health technologies. In addition, we demonstrate the importance of considering sociocultural diversity in the study of social acceptability for digital health technologies.ImplicationsThe results of this study have implications for practitioners who are the instigators of digital health technology implementation with healthcare service users. By understanding factors of social acceptability among francophone-speaking communities, practitioners will be better suited to propose and support the implementation of technologies in ways that are suitable for these individuals. For policymakers, this knowledge could be used for developing policy actions based on consideration for diversity.</p

Co-Designing an Integrated Care Network with People Living with Parkinson’s Disease: A Heterogeneous Social Network of People, Resources and Technologies

As part of the iCARE-PD project, a multinational and multidisciplinary research endeavour to address complex care in Parkinson’s disease, a Canadian case study focused on gaining a better understanding of people living with Parkinson’s disease (PwP) experiences with health and medical services, particularly their vision for a sustainable, tailored and integrated care delivery network. The multifaceted nature of the condition means that PwP must continuously adapt and adjust to every aspect of their lives, and progressively rely on support from care partners (CP) and various health care professionals (HCP). To envision the integrated care delivery network from the perspective of PwP, the study consisted of designing scenarios for an integrated care delivery network with patients, their CP and their HCP, as well as identifying key requirements for designing an integrated care delivery network. The results demonstrate that numerous networks interact, representing specific inscriptions, actors and mediators who meet at specific crossing points. This resulted in the creation of a roadmap and toolkit that takes into consideration the unique challenges faced by PwP, and the necessity for an integrated care delivery network that can be personalized and malleable so as to adapt to evolving and changing needs over time

Effect of dog-related parameters on the flexion test outcome: A large cohort retrospective study on physiological and orthopedic pathological-related factors.

OBJECTIVES This retrospective study evaluates the dog-related factors of variation influencing the outcome of the flexion test (FT), when performed to localize pain to a joint area, on a large group of canine orthopedic patients. MATERIALS AND METHODS The selection criteria for this retrospective study were dogs undergoing a FT in a referral orthopedic clinic between 2009 and 2020 with a complete medical record. The canine FT, described in a previously published protocol, was performed on dogs presented with an orthopedic problem. In summary, a dog's joint, identified as suspected of an orthopedic problem according to the clinical examination, was flexed for 1 min before walking 15 m on a hard and even surface. The FT was considered positive if the lameness increased after the application of the FT and negative when it remained unchanged. Statistical analysis was performed to determine which of the following criteria could influence the outcome of the flexion test: age, gender, neutered status, weight category, tested joint and initial lameness score. RESULTS Over 1,161 patients' files were collected and analyzed for this research. The FT showed 82.8% (95%IC: 80.5-84.9) of true positives and 17.2% of false negatives. None of the patient's intrinsic characteristics influenced the outcome of the test (age, gender, neutered status, and weight category). The orthopedic parameters, such as the initial lameness score and the tested joint, showed to have a statistically significant influence on the outcome of the test. CLINICAL RELEVANCE The FT is an easy-to-perform technique presenting reliable results on most joints. This test presents an interest when performed in addition to a complete orthopedic examination to localize pain to a joint area. Only the orthopedic pathological-related parameters such as the lameness score and the tested joint seem to influence the outcome of the FT. The FT is not influenced by the physiological-related characteristic of the patient (age, weight category, sex, and neutered status)

Excrétion du cytomégalovirus (CMV) dans les crèches françaises : une étude nationale sur l'épidémiologie, les facteurs de risque, les pratiques des centres et la sensibilisation des parents au CMV

Abstract Background Congenital cytomegalovirus (CMV) remains an important healthcare burden, resulting from primary or secondary infection in pregnant women. Exposure to young children’s saliva is a major risk factor, as prevalence of CMV shedding can reach 34%. Methods This cross-sectional, multicenter, nationwide study was conducted in randomly selected day care centers (DCCs), and complemented with a survey among parents and DCCs. All children aged &gt;3 months were eligible. The study measured the CMV shedding prevalence in children’s saliva and described CMV genotypes epidemiology. The risk factors for CMV shedding and high viral load were evaluated using multivariable models. Results A total of 93 DCCs participated. Among the 1770 enrolled children with evaluable samples, the CMV shedding prevalence was 40% (713/1770, 95% confidence interval, 34.6–46.1), independently associated with children aged between 12 and 18 months, history of CMV infection in ≥1 parents, a mid-level income. Prevalence increased with DCC staff workload and attending children number. Viral load was ≥5 log-copies CMV/mL in 48% (342/713). Risk factors for higher viral load included children aged between 12 and 18 months, and still being breastfed. The most frequent genotype combinations were gB1-gN4c-gH2 (6.9%), gB1-gN2-gH2 (6.3%), gB4a-gN3a-gH1 (6.3%), and gB1-gN3b-gH2 (5,7%). CMV awareness was low in parents: their serological status was unknown by 72% of mothers and 82% of fathers. Only 41% knew something about CMV. Conclusions CMV shedding was independently associated with risk factors related to the children, family and DCC. Some of these risk factors may influence prevention strategies, including through an improved information provided to parents. Clinical Trials Registration NCT01704222

Etude de la modulation du système myéloperoxydase/H2O2/Cl- par les carbazoles

info:eu-repo/semantics/nonPublishe