PulmoBind Imaging Measures Reduction of Vascular Adrenomedullin Receptor Activity with Lack of effect of Sildenafil in Pulmonary Hypertension

International audienceEndothelial dysfunction is a core pathophysiologic process in pulmonary arterial hypertension (PAH). We developed PulmoBind (PB), a novel imaging biomarker of the pulmonary vascular endothelium. 99mTechnetium (99mTc)-labelled PB binds to adrenomedullin receptors (AM1) densely expressed in the endothelium of alveolar capillaries. We evaluated the effect of sildenafil on AM1 receptors activity using 99mTc-PB. PAH was induced in rats using the Sugen/hypoxia model and after 3 weeks, animals were allocated to sildenafil (25 or 100 mg/kg/day) for 4 weeks. 99mTc-PB uptake kinetics was assessed by single-photon emission computed tomography. PAH caused right ventricular (RV) hypertrophy that was decreased by low and high sildenafil doses. Sildenafil low and high dose also improved RV function measured from the tricuspid annulus plane systolic excursion. Mean integrated pulmonary uptake of 99mTc-PB was reduced in PAH (508% · min ± 37, p < 0.05) compared to controls (630% · min ± 30), but unchanged by sildenafil at low and high doses. Lung tissue expressions of the AM1 receptor components were reduced in PAH and also unaffected by sildenafil. In experimental angio-proliferative PAH, sildenafil improves RV dysfunction and remodeling, but does not modify pulmonary vascular endothelium dysfunction assessed by the adrenomedullin receptor ligand 99mTc-PB

Rôle d'autotaxine (ATX) dans le développement du rétrécissement aortique calcifié (RAC)

Le rétrécissement aortique calcifié (RAC), pathologie valvulaire la plus fréquente, est une maladie caractérisée par une minéralisation progressive de la valve. À l’heure actuelle, il n’existe aucun traitement médical efficace pouvant empêcher ou ralentir sa progression. Le remplacement valvulaire aortique (RVA) est le seul traitement disponible du RAC. Par conséquent, l'identification des principaux facteurs de risque ainsi que les processus moléculaires impliqués dans la pathogenèse du RAC représentent une nécessité primordiale pour développer des approches pharmacologiques. Le RAC est une maladie progressive caractérisée par une calcification ectopique des feuillets valvulaires. Pendant plusieurs années, elle était considérée comme une atteinte dégénérative liée au vieillissement. Néanmoins, de nombreuses études récentes ont révélé qu’il s’agit d’une maladie active. En effet, les premiers stades de cette maladie, nommée sclérose aortique, partagent plusieurs similitudes avec l’athérosclérose en termes de facteurs de risque associés. Il s’agit donc d’une pathologie complexe mettant en jeu plusieurs processus pathologiques, notamment la rétention des lipides et leur oxydation, l’inflammation chronique, le remodelage fibrotique et la calcification de la VA. À cet égard, l'identification des principaux facteurs de risque ainsi que les processus moléculaires par lesquelles les lipides favorisent la minéralisation de la valve aortique (VA) représentent une nécessité primordiale pour comprendre le mécanisme physiopathologique du RAC. Cela pourrait également aider à identifier de nouvelles cibles thérapeutiques et ouvre d’autres perspectives de recherche afin de développer de nouvelles thérapies médicales. Les objectifs généraux de mon projet de doctorat sont : (1) Étudier le rôle des lipides, en particulier l’axe lipoprotéine Lp (a)-autotaxine (ATX), dans la progression et le développement du RAC; (2) Élucider le mécanisme d’action par lequel l’acide lysophosphatidique (LPA), le produit final de l’enzyme ATX, favorise l’inflammation et la réponse ostéogénique des cellules interstitielles de la valve aortique (CIVs); (3) Déterminer le rôle de l’axe ATX-LPA dans un modèle murin du RAC.Calcific aortic valve disease (CAVD) is the most common valvular disease, which is characterized by a progressive mineralization of aortic valve. So far, there is no effective medical therapy able to stop or slow the natural course of this disease. Surgical aortic valve replacement is the only available treatments of severe symptomatic aortic stenosis. Therefore, identify the key factors as well as molecular processes involved in the pathogenesis of CAVD is crucial to develop efficient pharmaceutical approaches able to prevent or to slow the progression of aortic stenosis. CAVD is a progressive disease characterized by ectopic calcification of the aortic valve leaflets. It has long been considered as a degenerative process of the aortic valve linked to aging. However, a growing number of studies have revealed that this disease is an active process likely related to atherosclerosis. Therefore, CAVD seems to be a complex pathology involving several pathological processes, including lipid retention, oxidation, chronic inflammation, fibrotic remodeling and calcification. In this regard, assessment of the molecular process whereby lipids promote the mineralization of aortic valve is required to understand the pathophysiological mechanisms leading to CAVD. Furthermore, investigations are needed to identify therapeutic targets and to open novel therapeutic avenues for the treatment of CAVD. The general objectives of my PhD project are: (1) To determine the role of ATX in mediating lipid-induced mineralization of valve interstitial cells (VICs); (2) To understand the mechanisms and signaling pathways by which lysophosphatidic acid (LPA) promotes inflammation and the mineralization of the aortic valve; (3) To determine the role of ATX-LPA in a mouse model of CAVD

Motivation and autonomy in a digital organisational communication of a swedish franchise system

This study has investigated how franchisors can implement and adapt digital organisational communication with collaborative tools and communication theories to empower their franchisees, improve their motivation and foster greater autonomy within the franchise system. The study was made possible by performing a qualitative analytical case study within a franchise company together with both franchisors and franchisees consisting of a total of 5 units and 8 participants, with the help of semi-structured interviews and the Free Listing-method.  The result shows that there is a lot of room for improvement for both franchisees and franchisors in terms of how a digital organisational communication should be implemented and adapted with the help of collaboration tools and communication theories, but that much also lies with the individuals themselves in greater inclusion, but also to enhance their motivation and foster a greater autonomy within an organisation. The study was conducted to convey the various ways that digital organisation communication can be implemented within a franchise system, organisations or businesses

The Sahel crisis since 2012

The ‘perfect storm’ that enveloped Mali in 2012 has since escalated into a protracted and widespread crisis across the Sahel. The region currently hosts multiple, moving threats, which are most active in the three states of Mali, Burkina Faso, and Niger. In those states alone, between 2012 and 2019, there have been 1,463 armed clashes, 4,723 civilians killed, at the hands of 195 violent armed groups, in 1,263 discrete locations.1 Violence reached its highest level to date in 2019 and continues at heightened frequency, suggesting a dangerous threshold has been reached and new frontlines loom. The critical lesson of this briefing is that this tsunami of conflict did not initially manifest as overtly Islamist or even ideologically coherent, but grew from opportunism. Populist rhetoric, displays of weakened state authority, a brutal—or absent—security sector, the militarization of neighbors, livelihoods and communities each constitute viable ways that the Sahel violence can metastasize through the wider region

Motivation and autonomy in a digital organisational communication of a swedish franchise system

This study has investigated how franchisors can implement and adapt digital organisational communication with collaborative tools and communication theories to empower their franchisees, improve their motivation and foster greater autonomy within the franchise system. The study was made possible by performing a qualitative analytical case study within a franchise company together with both franchisors and franchisees consisting of a total of 5 units and 8 participants, with the help of semi-structured interviews and the Free Listing-method.  The result shows that there is a lot of room for improvement for both franchisees and franchisors in terms of how a digital organisational communication should be implemented and adapted with the help of collaboration tools and communication theories, but that much also lies with the individuals themselves in greater inclusion, but also to enhance their motivation and foster a greater autonomy within an organisation. The study was conducted to convey the various ways that digital organisation communication can be implemented within a franchise system, organisations or businesses

Identification of an antiviral compound isolated from Pistacia lentiscus

This study screened mastic gum (Pistacia lentiscus L.) for antiviral activity against herpes simplex virus type 2 (HSV-2), coxsackievirus type B3, and adenovirus type 5. The organs of this plant (leaves, stem, and seed) were macerated sequentially using solvents of increasing polarity (hexane, dichloromethane, ethyl acetate, and methanol). Only the methanol extract of stem exhibited significant activity against HSV-2. This extract showed anti-HSV-2 activity with a selectivity index of 51 (50% cytotoxic concentration = 186 µg/mL; 50% inhibitory concentration = 3.63 µg/mL), and demonstrated direct inhibition against this virus with a virucidal selectivity index of 620 (50% virucidal concentration = 0.30 µg/mL). A bio-guided assay involving thin-layer chromatography led to the isolation of two active compounds, which have been identified as dammaradienone and dammaradienol using high-performance liquid chromatography-diode array detection coupled with electrospray ionization mass spectrometry. P. lentiscus has been widely studied for other biological activities. However, to our knowledge, this is the first report of P. lentiscus L. exhibiting antiviral activity

Soluble CD14 is associated with the structural failure of bioprostheses

Introduction: Aortic valve bioprostheses, which do not mandate chronic anticoagulation, are prone to structural valve degeneration (SVD). The processes involved in SVD are likely multifactorial. We hypothesized that inflammation and macrophage activation could be involved in SVD. Methods: In 203 patients with an aortic valve bioprosthesis, we evaluated the association between the macrophage activation marker soluble CD14 (sCD14) and SVD. Results: After a mean follow-up of 8 ± 3 years, 42 (21%) patients developed SVD. Patients with SVD had higher peak (44 ± 13 mmHg vs. 25 ± 12 mmHg, p < .0001) and mean (24 ± 7 mmHg vs. 12 ± 5 mmHg, p < .0001) transprosthetic gradients. On univariable analysis, low-density lipoprotein cholesterol (LDL) and sCD14 were associated with SVD. After correction for covariates, sCD14 (OR: 1.12, 95%CI: 1.02–1.23, p = .01) remained independently associated with SVD. In turn, sCD14 was associated with the HOMA index and high-density lipoprotein (HDL) level. Patients with a metabolic syndrome (MetS) had higher level of sCD14. In a model corrected for age, sex, HOMA and HDL, the MetS remained independently associated with sCD14 levels (β = 0.65, SE = 0.30, p = .03). Conclusion: Circulating level of sCD14 is an independent predictor of SVD. In turn, patients with MetS have higher sCD14 levels