Progressive Visceral Leishmaniasis Is Driven by Dominant Parasite-induced STAT6 Activation and STAT6-dependent Host Arginase 1 Expression

The clinicopathological features of the hamster model of visceral leishmaniasis (VL) closely mimic active human disease. Studies in humans and hamsters indicate that the inability to control parasite replication in VL could be related to ineffective classical macrophage activation. Therefore, we hypothesized that the pathogenesis of VL might be driven by a program of alternative macrophage activation. Indeed, the infected hamster spleen showed low NOS2 but high arg1 enzyme activity and protein and mRNA expression (p<0.001) and increased polyamine synthesis (p<0.05). Increased arginase activity was also evident in macrophages isolated from the spleens of infected hamsters (p<0.05), and arg1 expression was induced by L. donovani in primary hamster peritoneal macrophages (p<0.001) and fibroblasts (p<0.01), and in a hamster fibroblast cell line (p<0.05), without synthesis of endogenous IL-4 or IL-13 or exposure to exogenous cytokines. miRNAi-mediated selective knockdown of hamster arginase 1 (arg1) in BHK cells led to increased generation of nitric oxide and reduced parasite burden (p<0.005). Since many of the genes involved in alternative macrophage activation are regulated by Signal Transducer and Activator of Transcription-6 (STAT6), and because the parasite-induced expression of arg1 occurred in the absence of exogenous IL-4, we considered the possibility that L. donovani was directly activating STAT6. Indeed, exposure of hamster fibroblasts or macrophages to L. donovani resulted in dose-dependent STAT6 activation, even without the addition of exogenous cytokines. Knockdown of hamster STAT6 in BHK cells with miRNAi resulted in reduced arg1 mRNA expression and enhanced control of parasite replication (p<0.0001). Collectively these data indicate that L. donovani infection induces macrophage STAT6 activation and STAT6-dependent arg1 expression, which do not require but are amplified by type 2 cytokines, and which contribute to impaired control of infection

Molecular basis of atherosclerotic calcification heterogeneity and heterogeneity of peripheral arteries

Les calcifications artérielles sont fréquemment rencontrées au cours des maladies artérielles périphériques qui comprennent les atteintes athérosclérotiques. Les calcifications artérielles sont un marqueur indépendant de morbidité cardiovasculaire et impactent fortement les réponses thérapeutiques. Leur formation est issue de multiples processus dont certains sont proches de l’ossification. A partir de deux biocollections de patients, nous avons identifié quatre sous-types de calcifications intimales aux niveaux des artères athérosclérotiques carotidiennes, fémorales et infra-poplitées. Nous avons montré que les artères fémorales sont globalement plus calcifiées que les autres territoires, avec une présence beaucoup plus fréquente de métaplasie ostéoïde (structure osseuse), alors que les microcalcifications sont préférentiellement retrouvées au niveau carotidien. Les facteurs de risque cardiovasculaires, n’influencent pas les sous-types de calcifications, qui sont par contre fortement associés aux territoires. L’analyse de l’expression différentielle des gènes et miARNs au sein de la paroi artérielle permet de ségréger les échantillons en fonctions de leur origine anatomique (carotidienne, fémorale ou infra-poplitée). Ces différences d’expression se retrouvent entre les territoires des artères saines comme celles atteintes d’athérosclérose. Dans les artères pathologiques, on retrouve les clusters de gènes associés aux différences de composition de plaques qui s’y développent. De manière intéressante, on retrouve également des gènes différentiellement exprimés entre artères saines, eux aussi associés à ces types de plaques. Ces résultats suggèrent une prédisposition vasculaire pour développer tel ou tel type de plaque, avec pour les artères fémorales une prédisposition particulière pour l’ossification. Cette hypothèse est renforcée les résultats in vitro montrant une susceptibilité de minéralisation plus importante des cellules musculaires lisses (CML) d’artères fémorales saines par rapport à d’autres territoires. De façon particulière, la voie du Tranforming Growth factor (TGF) est surexprimée au niveau des artères fémorales. Nous avons montré que son récepteur TGFβR1 était impliqué dans les différences de minéralisation entre CML fémorales et carotidiennes.Arterial calcifications are frequently encountered in peripheral arterial diseases that include atherosclerotic disease. Arterial calcifications are an independent marker of cardiovascular morbidity and strongly impact therapeutic responses. Their formation is the result of multiple processes, some of which are close to ossification. From two patients’ biocollections, we identified four subtypes of intimal calcifications in carotid, femoral and infra-popliteal atherosclerotic arteries. We have shown that the femoral arteries are globally more calcified than the other territories, with much more frequent presence of osteoid metaplasia (bone structure), whereas the microcalcifications are preferentially found at the carotid level. Cardiovascular risk factors do not influence the subtypes of calcification, but are strongly associated with the territories. The analysis of the differential expression of genes and miRNAs of the arterial wall makes it possible to segregate the samples according to their anatomical origin (carotid, femoral or infra-poplitated). These differences of expression are found between the territories in healthy and atherosclerosis arteries. In pathological arteries, there are clusters of genes associated with differences in plaque composition that develop there. Interestingly, there are also genes differentially expressed between healthy arteries, also associated with plaques. These results suggest a vascular predisposition to develop such or such type of plaque, with for the femoral arteries a special predisposition for ossification. This hypothesis is reinforced by in vitro results showing greater susceptibility to mineralization of smooth muscle cells (SMCs) of healthy femoral arteries compared to other territories. In particular, the Tranforming Growth Factor (TGF) pathway is overexpressed at the level of the femoral arteries. We showed that its TGFβR1 receptor was involved in mineralization differences between femoral and carotid SMCs

Impact of Femoral Ossification on Local and Systemic Cardiovascular Patients' Condition

International audienceBackground: Vascular calcifications are associated with a high cardiovascular morbi-mortality in the coronary territory. In parallel, femoral arteries are more calcified and develop osteoid metaplasia (OM). This study was conducted to assess the predictive value of OM and local inflammation on the occurrence of mid- and long-term adverse cardiovascular events.Method: Between 2008 and 2015, 86 atheromatous samples were harvested during femoral endarterectomy on 81 patients and processed for histomorphological analyses of calcifications and inflammation (monocytes and B cells). Histological findings were compared with the long-term follow-up of patients, including major adverse cardiac event (MACE), major adverse limb event (MALE), and mortality. Frequencies were presented as percentage, and continuous data, as mean and standard deviation. A P-value < 0.05 was considered statistically significant.Results: Median follow-up was 42.4 months (26.9-58.8). Twenty-eight percent of patients underwent a MACE; a MALE occurred in 18 (21%) limbs. Survival rate was 87.2% at 36 months. OM was found in 41 samples (51%), without any significant impact on the occurrence of MACE, MALE, or mortality. Preoperative white blood cell formulae revealed a higher rate of neutrophils associated with MACE (P = 0.04) and MALE (P = 0.0008), correlated with higher B cells counts in plaque samples.Conclusions: OM is part of femoral calcifications in almost 50% of the cases but does not seem to be an independent predictive variable for MACE or MALE. However, a higher rate of B cell infiltration of the plaque and preoperative neutrophil blood count may be predictive of adverse events during follow-up

Specific features to differentiate Giant cell arteritis aortitis from aortic atheroma using FDG-PET/CT

International audienceAortic wall 18 F-fluorodeoxyglucose (FDG)-uptake does not allow differentiation of aortitis from atheroma, which is problematic in clinical practice for diagnosing large vessel vasculitis giantcell arteritis (GCA) in elderly patients. The purpose of this study was to compare the FDG uptake characteristics of GCA aortitis and aortic atheroma using positron emission tomography/FDG computed tomography (FDG-PET/CT). This study compared FDG aortic uptake between patients with GCA aortitis and patients with aortic atheroma; previously defined by contrast enhanced CT. Visual grading according to standardized FDG-PET/CT interpretation criteria and semi-quantitative analyses (maximum standardized uptake value (SUV max), delta SUV (∆SUV), target to background ratios (TBR)) of FDG aortic uptake were conducted. The aorta was divided into 5 segments for analysis. 29 GCA aortitis and 66 aortic atheroma patients were included. A grade 3 FDG uptake of the aortic wall was identified for 23 (79.3%) GCA aortitis patients and none in the atheroma patient group (p < 0.0001); grade 2 FDG uptake was as common in both populations. Of the 29 aortitis patients, FDG uptake of all 5 aortic segments was positive for 21 of them (72.4%, p < 0.0001). FDG uptake of the supra-aortic trunk was identified for 24 aortitis (82.8%) and no atheromatous cases (p < 0.0001). All semi-quantitative analyses of FDG aortic wall uptake (SUV max , ∆SUV and TBRs) were significantly higher in the aortitis group. ∆SUV was the feature with the largest differential between aortitis and aortic atheroma. In this study, GCA aortitis could be distinguished from an aortic atheroma by the presence of an aortic wall FDG uptake grade 3, an FDG uptake of the 5 aortic segments, and FDG uptake of the peripheral arteries

Traduction et republication de : « Traitement à domicile des patients atteints de maladie veineuse thromboembolique associée au cancer »

International audiencePatients hospitalised with acute venous thromboembolism (VTE), and notably patients with pulmonary embolism, often remain in hospital for extended periods due to the perceived risk of complications. However, several studies have shown that home treatment of selected patients is feasible and safe, with a low incidence of adverse events. This may offer clear benefits for patients’ quality of life, hospital planning and cost to the health service. Nonetheless, there is a need for a VTE risk-stratification tool specifically addressing prognosis in patients with cancer. This may aid in the selection of low-risk patients with cancer and VTE who are suitable for outpatient treatment. Although several prognostic scores have been proposed, we suggest using a pragmatic clinical decision-making tool such as the Hestia criteria for selecting patients for home care in everyday clinical practice. Once patients have been discharged, it is mandatory to monitor patients regularly (we suggest after 3 days, 10 days, 1 month and 3 months, or more frequently if needed) with the involvement of a multidisciplinary team, so that appropriate and timely remedial action can be taken in case of warning signs of complications. If patients are selected carefully and monitored effectively, many patients who experience acute VTE can be cared for safely at home.Les patients hospitalisés pour une maladie thromboembolique veineuse aiguë (MTEV), et notamment les patients souffrant d’une embolie pulmonaire, restent souvent à l’hôpital pendant de longues périodes en raison du risque perçu de complications. Cependant, plusieurs études ont montré que le traitement à domicile de patients sélectionnés est faisable et sûr, avec une faible incidence d’événements indésirables. Cela peut présenter des avantages évidents pour la qualité de vie des patients, la planification hospitalière et le coût pour les services de santé. Néanmoins, il est nécessaire de disposer d’un outil de stratification du risque de MTEV qui prenne en compte le pronostic des patients atteints de cancer. Cet outil pourrait aider à sélectionner les patients à faible risque atteints d’un cancer et d’une MTEV qui peuvent bénéficier d’un traitement ambulatoire. Bien que plusieurs scores pronostiques aient été proposés, nous suggérons d’utiliser un outil pragmatique de prise de décision clinique tel que les critères Hestia, afin de sélectionner les patients devant recevoir des soins à domicile dans la pratique clinique quotidienne. Une fois les patients sortis de l’hôpital, il est indispensable de les surveiller régulièrement (nous suggérons après 3 jours, 10 jours, 1 mois et 3 mois, ou plus fréquemment si nécessaire) avec l’implication d’une équipe multidisciplinaire, afin que des mesures correctives appropriées puissent être prises en temps voulu, en cas de signes avant-coureurs de complications. Si les patients sont sélectionnés avec soin et suivis efficacement, de nombreux cas de MTEV aiguë peuvent être soignés en toute sécurité à domicile

Home treatment for patients with cancer-associated venous thromboembolism

International audiencePatients hospitalised with acute venous thromboembolism (VTE), and notably patients with pulmonary embolism, often remain in hospital for extended periods due to the perceived risk of complications. However, several studies have shown that home treatment of selected patients is feasible and safe, with a low incidence of adverse events. This may offer clear benefits for patients’ quality of life, hospital planning and cost to the health service. Nonetheless, there is a need for a VTE risk-stratification tool specifically addressing prognosis in patients with cancer. This may aid in the selection of low-risk patients with cancer and VTE who are suitable for outpatient treatment. Although several prognostic scores have been proposed, we suggest using a pragmatic clinical decision-making tool such as the Hestia criteria for selecting patients for home care in everyday clinical practice. Once patients have been discharged, it is mandatory to monitor patients regularly (we suggest after 3 days, 10 days, 1 month and 3 months, or more frequently if needed) with the involvement of a multidisciplinary team, so that appropriate and timely remedial action can be taken in case of warning signs of complications. If patients are selected carefully and monitored effectively, many patients who experience acute VTE can be cared for safely at home

Exercise-Induced Vasculitis: A Review with Illustrated Cases

International audienceAlthough exercise-induced vasculitis (EIV) is usually misdiagnosed, it is not uncommon. Occurring mostly after prolonged exercise, especially in hot weather, EIV is an isolated cutaneous vasculitis with stereotypical presentation. This article reviews the clinical characteristics, treatments, and outcomes of EIV based on the published literature. We report 99 patients who developed EIV after walking, dancing, swimming, or hiking especially during hot weather, including the records of 16 patients with EIV treated at our hospital from 2007 to 2015. Erythematous or purpuric plaques arise on the lower legs, without the involvement of compression socks or stockings. Symptoms include itch, pain, and a burning sensation. EIV is an isolated cutaneous vasculitis. Lesions resolve spontaneously after 10 days. When triggering conditions persist, relapses are frequent (77.5 %). Histopathology demonstrates leukocytoclastic vasculitis in 95 % of cases with C3 or immunoglobulin M deposits in 88 and 46 % of cases, respectively. Blood investigations are negative. EIV appears to be a consequence of venous stasis induced by an acute failure of the muscle pump of the calf and thermoregulation decompensation. Both appear after prolonged and unusual exercise in hot weather. Treatment is not codified; topical corticosteroids may reduce symptoms and wearing light clothes might limit lesion occurrence

Semi-Quantitative [¹⁸F]FDG-PET/CT ROC-Analysis-Based Cut-Offs for Aortitis Definition in Giant Cell Arteritis

[18F]fluorodeoxyglucose-positron emission tomography/computed tomography ([18F]FDG-PET/CT) is used to diagnose large vessel vasculitis in giant cell arteritis (GCA). We aimed to define a semi-quantitative threshold for identifying GCA aortitis from aortic atheroma or the control. Contrast enhanced computed tomography (CECT) was used as the reference imaging for aortic evaluation and to define aortitis, aortic atheroma and control aortas. [18F]FDG-PET/CT was performed on 35 GCA patients and in two different control groups (aortic atheroma (n = 70) and normal control (n = 35)). Aortic semi-quantitative features were compared between the three groups. GCA patients without aortitis on CECT were excluded. Of the GCA patients, 19 (54.3%) were not on glucocorticoids (GC) prior to [18F]FDG-PET/CT. The SUVmax, TBRblood and TBRliver aortic values were significantly higher in the GCA aortitis group than in the aortic atheroma and control groups (p max threshold of 3.25 and a TBRblood threshold of 1.75 had a specificity of 83% and 75%, respectively, a sensitivity of 81% and 81%, respectively, and the area under the ROC curve (AUC) was 0.86 and 0.83, respectively, for aortitis detection compared to control groups in GCA cases with GC. A SUVmax threshold of 3.45 and a TBRblood threshold of 1.97 had a specificity of 90% and 93%, respectively, a sensitivity of 89% and 89%, respectively, with an AUC of 0.89 and 0.96, respectively, for aortitis detection compared to the control in GC-free GCA cases. Discriminative thresholds of SUVmax and TBRblood for the diagnosis of GCA aortitis were established using CECT as the reference imaging