Institute National Of La Sante Et Of La Recherche Medical

Sainte-Foy-lès-Lyon, France

Institute National Of La Sante Et Of La Recherche Medical

Sainte-Foy-lès-Lyon, France
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Ricard N.,National Health Research Institute | Ricard N.,University Paris - Sud | Tu L.,National Health Research Institute | Tu L.,University Paris - Sud | And 23 more authors.
Circulation | Year: 2014

Background: Pericytes and their crosstalk with endothelial cells are critical for the development of a functional microvasculature and vascular remodeling. It is also known that pulmonary endothelial dysfunction is intertwined with the initiation and progression of pulmonary arterial hypertension (PAH). We hypothesized that pulmonary endothelial dysfunction, characterized by abnormal fibroblast growth factor-2 and interleukin-6 signaling, leads to abnormal microvascular pericyte coverage causing pulmonary arterial medial thickening. Methods and results: In human lung tissues, numbers of pericytes are substantially increased (up to 2-fold) in distal PAH pulmonary arteries compared with controls. Interestingly, human pulmonary pericytes exhibit, in vitro, an accentuated proliferative and migratory response to conditioned media from human idiopathic PAH endothelial cells compared with conditioned media from control cells. Importantly, by using an anti-fibroblast growth factor-2 neutralizing antibody, we attenuated these proliferative and migratory responses, whereas by using an anti-interleukin-6 neutralizing antibody, we decreased the migratory response without affecting the proliferative response. Furthermore, in our murine retinal angiogenesis model, both fibroblast growth factor-2 and interleukin-6 administration increased pericyte coverage. Finally, using idiopathic PAH human and NG2DsRedBAC mouse lung tissues, we demonstrated that this increased pericyte coverage contributes to pulmonary vascular remodeling as a source of smooth muscle-like cells. Furthermore, we found that transforming growth factor-β, in contrast to fibroblast growth factor-2 and interleukin-6, promotes human pulmonary pericyte differentiation into contractile smooth muscle-like cells. Conclusions: To the best of our knowledge, this is the first report of excessive pericyte coverage in distal pulmonary arteries in human PAH. We also show that this phenomenon is directly linked with pulmonary endothelial dysfunction. © 2014 American Heart Association, Inc.


Calvino E.,CSIC - Biological Research Center | Estan M.C.,CSIC - Biological Research Center | Simon G.P.,CSIC - Biological Research Center | Sancho P.,University of Alcalá | And 4 more authors.
Biochemical Pharmacology | Year: 2011

Lonidamine is a safe, clinically useful anti-tumor drug, but its efficacy is generally low when used in monotherapy. We here demonstrate that lonidamine efficaciously cooperates with the anti-leukemic agent arsenic trioxide (ATO, Trisenox™) to induce apoptosis in HL-60 and other human leukemia cell lines, with low toxicity in non-tumor peripheral blood lymphocytes. Apoptosis induction by lonidamine/ATO involves mitochondrial dysfunction, as indicated by early mitochondrial permeability transition pore opening and late mitochondrial transmembrane potential dissipation, as well as activation of the intrinsic apoptotic pathway, as indicated by Bcl-X L and Mcl-1 down-regulation, Bax translocation to mitochondria, cytochrome c and Omi/HtrA2 release to the cytosol, XIAP down-regulation, and caspase-9 and -3 cleavage/activation, with secondary (Bcl-2-inhibitable) activation of the caspase-8/Bid axis. Lonidamine stimulates reactive oxygen species production, and lonidamine/ATO toxicity is attenuated by antioxidants. Lonidamine/ATO stimulates JNK phosphorylation/ activation, and apoptosis is attenuated by the JNK inhibitor SP600125. In addition, lonidamine elicits ERK and Akt/mTOR pathway activation, as indicated by increased ERK, Akt, p70S6K and rpS6 phosphorylation, and these effects are reduced by co-treatment with ATO. Importantly, co-treatment with MEK/ERK inhibitor (U0126) and PI3K/Akt (LY294002) or mTOR (rapamycin) inhibitors, instead of ATO, also potentiates lonidamine-provoked apoptosis. These results indicate that: (i) lonidamine efficacy is restrained by drug-provoked activation of MEK/ERK and Akt/mTOR defensive pathways, which therefore represent potential therapeutic targets. (ii) Co-treatment with ATO efficaciously potentiates lonidamine toxicity via defensive pathway inhibition and JNK activation. And (iii) conversely, the pro-oxidant action of lonidamine potentiates the apoptotic efficacy of ATO as an anti-leukemic agent. © 2011 Elsevier Inc.


van Endert P.,Institute National Of La Sante Et Of La Recherche Medical | van Endert P.,French National Center for Scientific Research | van Endert P.,University of Paris Descartes | Mauvais F.-X.,Institute National Of La Sante Et Of La Recherche Medical | And 5 more authors.
F1000Research | Year: 2016

Research focusing on type 1 diabetes (T1D) autoantigens aims to explore our understanding of these beta cell proteins in order to design assays for monitoring the pathogenic autoimmune response, as well as safe and efficient therapies preventing or stopping it. In this review, we will discuss progress made in the last 5 years with respect to mechanistic understanding, diagnostic monitoring, and therapeutic modulation of the autoantigen-specific cellular immune response in T1D. Some technical progress in monitoring tools has been made; however, the potential of recent technologies for highly multiplexed exploration of human cellular immune responses remains to be exploited in T1D research, as it may be the key to the identification of surrogate markers of disease progression that are still wanting. Detailed analysis of autoantigen recognition by T cells suggests an important role of non-conventional antigen presentation and processing in beta cell-directed autoimmunity, but the impact of this in human T1D has been little explored. Finally, therapeutic administration of autoantigens to T1D patients has produced disappointing results. The application of novel modes of autoantigen administration, careful translation of mechanistic understanding obtained in preclinical studies and in vitro with human cells, and combination therapies including CD3 antibodies may help to make autoantigen-based immunotherapy for T1D a success story in the future. © 2016 Mauvais FX et al.


Jones P.,University College London | Peters M.J.,University College London | Pinto da Costa N.,Reanimation Pediatrique | Kurth T.,Institute National Of La Sante Et Of La Recherche Medical | And 9 more authors.
PLoS ONE | Year: 2013

Background: Atropine has is currently recommended to facilitate haemodynamic stability during critical care intubation. Our objective was to determine whether atropine use at induction influences ICU mortality. Methodology/Principal Findings: A 2-year prospective, observational study of all first non-planned intubations, September 2007-9 in PICU and Intensive Care Transport team of Hôpital Robert Debré, Paris, 4 other PICUs and 5 NICUs in the Paris Region, France. Follow-up was from intubation to ICU discharge. A propensity score was used to adjust for patient specific characteristics influencing atropine prescription. 264/333 (79%) intubations were included. The unadjusted ICU mortality was 7.2% (9/124) for those who received atropine compared to 15.7% (22/140) for those who did not (OR 0.42, 95%CI 0.19-0.95, p = 0.04). One child died during intubation (1/264, 0.4%). Two age sub-groups of neonates (≤28 days) and older children (>28 days, <8 years) were examined. This difference in mortality arose from the higher mortality in children aged over one month when atropine was not used (propensity score adjusted OR 0.22, 95%CI 0.06-0.85, p = 0.028). No effect was seen in neonates (propensity score adjusted OR 1.3, 95%CI 0.31-5.1 p = 0.74). Using the propensity score, atropine maintained the mean heart rate 45.9 bpm above that observed when no atropine was used in neonates (95%CI 34.3-57.5, p<0.001) and 43.5 bpm for older children (95%CI 25.5-61.5 bpm, p<0.001). Conclusions/Significance: Atropine use during induction was associated with a reduction in ICU mortality in children over one month. This effect is independent of atropine's capacity to attenuate bradycardia during intubation which occurred similarly in neonates and older children. This result needs to be confirmed in a study using randomised methodology. © 2013 Jones et al.


Patent
Institute National Of La Sante Et Of La Recherche Medical, Etat Francais Ministere De La Defense, Assistance Publique Hopitaux De Paris and University of Paris Descartes | Date: 2014-10-15

The present invention relates to a method for determining both (a) the haematocrit value and (b) the fibrinogen content in whole blood of an individual in less than 5 minutes, as well as to associated portable apparatus.


Ogoh S.,Toyo University | Hirasawa A.,Toyo University | Raven P.B.,University of North Texas Health Science Center | Rebuffat T.,Normandie University | And 12 more authors.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2015

Systemic blood distribution is an important factor involved in regulating cerebral blood flow (CBF). However, the effect of an acute change in central blood volume (CBV) on CBF regulation remains unclear. To address our question, we sought to examine the CBF and systemic hemodynamic responses to microgravity during parabolic flight. Twelve healthy subjects were seated upright and exposed to microgravity during parabolic flight. During the brief periods of microgravity, mean arterial pressure was decreased (-26 ± 1%, P < 0.001), despite an increase in cardiac output (+21 ± 6%, P < 0.001). During microgravity, central arterial pulse pressure and estimated carotid sinus pressure increased rapidly. In addition, this increase in central arterial pulse pressure was associated with an arterial baroreflex-mediated decrease in heart rate (r = -0.888, P < 0.0001) and an increase in total vascular conductance (r = 0.711, P < 0.001). The middle cerebral artery mean blood velocity (MCA Vmean) remained unchanged throughout parabolic flight (P = 0.30). During microgravity the contribution of cardiac output to MCA Vmean was gradually reduced (P < 0.05), and its contribution was negatively correlated with an increase in total vascular conductance (r = -0.683, P < 0.0001). These findings suggest that the acute loading of the arterial and cardiopulmonary baroreceptors by increases in CBV during microgravity results in acute and marked systemic vasodilation. Furthermore, we conclude that this marked systemic vasodilation decreases the contribution of cardiac output to CBF. These findings suggest that the arterial and cardiopulmonary baroreflex-mediated peripheral vasodilation along with dynamic cerebral autoregulation counteracts a cerebral overperfusion, which otherwise would occur during acute increases in CBV. © 2015 the American Physiological Society.

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