Evaluation of the expression of matrix metalloproteinase 9 and neutrophil gelatinase associated lipocalin in serum, urine and tumoral tissues of female dogs suffering from mammary gland tumors

In human medicine, it has been shown recently that the level of expression of matrix metalloproteinase-9 (MMP-9) and neutrophil gelatinase-associated lipocalin (NGAL) in serum, urine, and breast tissue were significantly increased in patients with breast cancer and correlated to several prognostic factors. In the first part, the author presents the MMP-9 and NGAL as a synthesis of current knowledge on their ability to serve as biomarkers of breast cancer in women. In the second, the author presents the production of canine MMP9 and NGAL recombinant proteins, the production of polyclonal antibodies, and their use in various techniques (ELISA, western blot, immunohistochemistry) to assess the level of expression of these proteins in the blood, urine and breast tissue of dogs suffering from mammary gland tumors and demonstrate a positive correlation between these proteins and the presence of a tumor disease of the mammary gland

ETUDE DES TRANSFERTS THERMIQUES AU SEIN D'UN LIT DE PARTICULES CONTENANT UN MATERIAU A CHANGEMENT DE PHASE POUR LE STOCKAGE DE CHALEUR

Une solution de stockage d'électricité, le procédé AA-CAES (Advanced Adiabatic Compressed Air Energy Storage), consiste à comprimer de l'air en phase de stockage et à le détendre dans une turbine afin de récupérer une partie de l'énergie électrique utilisée pour la compression. Lors de la compression la température de l'air augmente de plusieurs centaines de degrés. Il est alors nécessaire d'abaisser sa température pour permettre son stockage. Afin d'augmenter le rendement du procédé, la chaleur évacuée lors de cette étape est récupérée dans des unités de stockage d'énergie thermique qui peuvent par exemple être constituées de lits (fixes ou fluidisés) de particules contenant un Matériau à Changement de Phase (MCP). L'étude de ces lits de particules est complexe car elle fait intervenir des phénomènes couplés entre eux ayant lieu à différentes échelles (micro : échelle de la particule, méso : d'une partie du lit et macro : de l'ensemble du lit). Le logiciel PeliGRIFF (http://www.peligriff.com) autour duquel s'axe le travail de cette thèse permet de modéliser des systèmes d'écoulements particulaires à l'échelle micro (toutes les interactions particule-particule et fluide-particule sont directement résolues) et méso (les interactions fluide-particule sont modélisées). Pour être en mesure d'y simuler une unité de stockage via les MCP en vue de son dimensionnement tout en gardant une puissance de calcul nécessaire raisonnable, il est alors nécessaire de modéliser les phénomènes ayant lieu à l'échelle de la particule et influençant de manière significative les transferts thermiques aux échelles supérieures, en particulier la convection naturelle au sein de la phase liquide du MCP et le changement de phase lors du stockage/de la libération de la chaleur. Etablir ces modèles demande l'étude préalable d'une particule isolée. Le travail réalisé a donc consisté à évaluer au travers de simulations l'impact de la convection naturelle au niveau de la particule et de déterminer comment et dans quelle gamme de nombres adimensionnels, il est nécessaire de prendre en compte ce phénomène. Pour cela, des simulations sous OpenFOAM d'une unique particule soumise à un gradient de température sous différents nombres de Rayleigh et de Prandtl permettant le déclenchement de la convection naturelle ont été réalisées. Les résultats obtenus ont permis de déterminer l'effet de la convection sur les échanges et d'établir une corrélation reliant le flux de chaleur moyen (échangé entre l'extérieur et le fluide contenu dans la particule) aux nombres de Prandtl et Rayleigh de la particule . Cette corrélation permet de recalculer l'évolution temporelle de la température moyenne de la particule à partir de la connaissance des nombres de Prandtl et Rayleigh. La température moyenne ainsi recalculée et la température moyenne obtenue par simulation sous OpenFOAM ont ensuite été comparées pour divers couples (Rayleigh, Prandtl) afin de valider cette corrélation

The different molecular forms of urine neutrophil gelatinase-associated lipocalin present in dogs with urinary diseases

Neutrophil gelatinase-associated lipocalin (NGAL) is a useful biomarker for the early prediction of renal diseases. NGAL may exist as monomer, dimer and/or NGAL/MMP-9 complex forms in humans. In this study, the existence of various forms of NGAL in urine (uNGAL) was determined and whether these forms are related to the different urinary diseases found in dogs is further discussed

Elevated monocyte HLA-DR in pediatric secondary hemophagocytic lymphohistiocytosis: a retrospective study

IntroductionHemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition, and its diagnosis may be challenging. In particular, some cases show close similarities to sepsis (fever, organ failure, and high ferritin), but their treatment, while urgent, differ: prompt broad-spectrum antibiotherapy for sepsis and immunosuppressive treatment for HLH. We questioned whether monocyte human leucocyte antigen (mHLA)–DR could be a diagnostic marker for secondary HLH (sHLH).MethodsWe retrospectively reviewed data from patients with a sHLH diagnosis and mHLA-DR quantification. mHLA-DR data from healthy children and children with septic shock, whose HLA-DR expression is reduced, from a previously published study were also included for comparison.ResultsSix patients with sHLH had mHLA-DR quantification. The median level of monocyte mHLA-DR expression in patients with sHLH [79,409 antibodies bound per cell (AB/C), interquartile range (IQR) (75,734–86,453)] was significantly higher than that in healthy children and those with septic shock (29,668 AB/C, IQR (24,335–39,199), and 7,493 AB/C, IQR (3,758–14,659), respectively). Each patient with sHLH had a mHLA-DR higher than our laboratory normal values. Four patients had a second mHLA-DR sampling 2 to 4 days after the initial analysis and treatment initiation with high-dose corticosteroids; for all patients, mHLA-DR decreased to within or close to the normal range. One patient with systemic juvenile idiopathic arthritis had repeated mHLA-DR measurements over a 200-day period during which she underwent four HLH episodes. mHLA-DR increased during relapses and normalized after treatment incrementation.ConclusionIn this small series, mHLA-DR was systematically elevated in patients with sHLH. Elevated mHLA-DR could contribute to sHLH diagnosis and help earlier distinction with septic shock

Intravenous versus subcutaneous tocilizumab in Takayasu arteritis: multicentre retrospective study

ObjectivesIn this large multicentre study, we compared the effectiveness and safety of tocilizumab intravenous versus subcutaneous (SC) in 109 Takayasu arteritis (TAK) patients.MethodsWe conducted a retrospective multicentre study in referral centres from France, Italy, Spain, Armenia, Israel, Japan, Tunisia and Russia regarding biological-targeted therapies in TAK, since January 2017 to September 2019.ResultsA total of 109 TAK patients received at least 3 months tocilizumab therapy and were included in this study. Among them, 91 and 18 patients received intravenous and SC tocilizumab, respectively. A complete response (NIH <2 with less than 7.5 mg/day of prednisone) at 6 months was evidenced in 69% of TAK patients, of whom 57 (70%) and 11 (69%) patients were on intravenous and SC tocilizumab, respectively (p=0.95). The factors associated with complete response to tocilizumab at 6 months in multivariate analysis, only age <30 years (OR 2.85, 95% CI 1.14 to 7.12; p=0.027) and time between TAK diagnosis and tocilizumab initiation (OR 1.18, 95% CI 1.02 to 1.36; p=0.034). During the median follow-up of 30.1 months (0.4; 105.8) and 10.8 (0.1; 46.4) (p<0.0001) in patients who received tocilizumab in intravenous and SC forms, respectively, the risk of relapse was significantly higher in TAK patients on SC tocilizumab (HR=2.55, 95% CI 1.08 to 6.02; p=0.033). The overall cumulative incidence of relapse at 12 months in TAK patients was at 13.7% (95% CI 7.6% to 21.5%), with 10.3% (95% CI 4.8% to 18.4%) for those on intravenous tocilizumab vs 30.9% (95% CI 10.5% to 54.2%) for patients receiving SC tocilizumab. Adverse events occurred in 14 (15%) patients on intravenous route and in 2 (11%) on SC tocilizumab.ConclusionIn this study, we confirm that tocilizumab is effective in TAK, with complete remission being achieving by 70% of disease-modifying antirheumatic drugs-refractory TAK patients at 6 months

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Publisher Copyright: © 2021 The Authors, some rights reserved.Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-alpha and/or IFN-omega are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-alpha and/or IFN-omega (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-beta. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-alpha and/or IFN-omega are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-beta do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.Peer reviewe

Reverse-Transcriptase Inhibitors in the Aicardi–Goutières Syndrome

International audienceTo the Editor:The Aicardi–Goutières syndrome is a genetic encephalopathy that is associated with childhood illness and death. The syndrome is hypothesized to be due to misidentification of self-derived nucleic acids as nonself and the subsequent induction of a type I interferon–mediated response that simulates an antiviral reaction.1 Endogenous retroelements, mobile genetic elements that can be transcribed to RNA and then to DNA by reverse transcription, constitute 40% of the human genome and represent a potential source of immunostimulatory nucleic acid in patients with this syndrome.