110 results on '"José Vilar"'
Search Results
2. Data from Angiotensinogen Delays Angiogenesis and Tumor Growth of Hepatocarcinoma in Transgenic Mice
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Evelyne Dupuy, Pierre Corvol, Gérard Tobelem, Patricia Hainaud, José Vilar, Jean-Marie Gasc, Noël Lamandé, Jean-Olivier Contrerès, Maud Clemessy, Philippe Bonnin, and François Vincent
- Abstract
Angiotensinogen, a member of the serpin family, is involved in the suppression of tumor growth and metastasis. To investigate whether human angiotensinogen protects against tumor progression in vivo, we established an original bitransgenic model in which transgenic mice expressing human angiotensinogen (Hu-AGT-TG mice) were crossed with a transgenic mouse model of hepatocellular carcinoma (HCC-TG mice). Bitransgenic mice overexpressing human angiotensinogen (HCC/Hu-AGT-TG) had a significantly longer survival time than the HCC-TG mice and a reduction of both tumor growth and blood flow velocities in the liver. This antitumor effect of angiotensinogen is related to a reduced angiogenesis, impaired expression of endothelial arterial markers (active Notch4, Delta-like 4 ligand, and ephrin B2) with a decrease of arterial vessel density in HCC/Hu-AGT-TG mice liver. Overexpression of human angiotensinogen decreases angiogenesis, and prevents tumor sinusoids from remodeling and arterialization, thus delaying tumor progression in vivo. [Cancer Res 2009;69(7):2853–60]
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- 2023
3. Supplementary Figure 1 from Angiotensinogen Delays Angiogenesis and Tumor Growth of Hepatocarcinoma in Transgenic Mice
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Evelyne Dupuy, Pierre Corvol, Gérard Tobelem, Patricia Hainaud, José Vilar, Jean-Marie Gasc, Noël Lamandé, Jean-Olivier Contrerès, Maud Clemessy, Philippe Bonnin, and François Vincent
- Abstract
Supplementary Figure 1 from Angiotensinogen Delays Angiogenesis and Tumor Growth of Hepatocarcinoma in Transgenic Mice
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- 2023
4. EphrinA4/EphA4 controls blood pressure via arterial sympathetic innervation
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Emilie Simonnet, Sabrina Martin, José Vilar, Emilie Vessieres, Sonia Taib, Virginie Monceau, Luc Pardanaud, Nadine Bouby, Anne Eichmann, Jean-Sébastien Silvestre, Daniel Henrion, and Isabelle Brunet
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The autonomic sympathetic nervous system innervates peripheral resistance arteries, thereby controlling arterial diameter and modulating blood supply to organs and arterial tone. Despite its fundamental role in blood flow regulation and adaptive response of the cardiovascular system to challenging situations, how sympathetic arterial innervation develops remains poorly understood.We here show that sympathetic arterial innervation is regulated by the axonal guidance molecule EphrinA4 in arterial Smooth Muscle Cells (SMCs), which repels sympathetic axons via the EphA4 receptor. Specific inactivation of EphA4 in sympathetic axons induced a loss of repulsion and increased sympathetic innervation of peripheral arteries throughout life. Functional consequences were a significant increase in arterial tone (resistivity and vasoconstriction), leading to an elevated systemic arterial blood pressure that reached to hypertension under stressful circumstances. These findings identify a novel pathway that negatively regulates sympathetic arterial innervation, and could participate to the appearance of idiopathic resistant hypertension.
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- 2023
5. Psychological factors and healthy sleep in a Portuguese sample of employees with regular working hours
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Beatriz Marques Silva, Sandra Carvalho Bos, António José Vilar Queirós, and António Ferreira Macedo
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Physiology ,Physiology (medical) ,Ecology, Evolution, Behavior and Systematics - Published
- 2022
6. Differences in the clinical management of women and men after detection of a solitary pulmonary nodule in clinical practice
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Maria Pastor-Valero, José Vilar, Lucy Anne Parker, Ildefonso Hernández-Aguado, Blanca Lumbreras, Elisa Chilet-Rosell, Fermina Lorente-Fernández, Isabel González-Álvarez, M. Luisa Domingo, and José María Salinas-Serrano
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Male ,Delayed Diagnosis ,Lung Neoplasms ,Multivariate analysis ,Comorbidity ,030218 nuclear medicine & medical imaging ,Cohort Studies ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Interquartile range ,Lung ,Neuroradiology ,Incidental Findings ,medicine.diagnostic_test ,Smoking ,Men ,General Medicine ,Middle Aged ,030220 oncology & carcinogenesis ,Female ,Radiography, Thoracic ,Radiology ,Risk ,medicine.medical_specialty ,Clinical Decision-Making ,Radiation Dosage ,03 medical and health sciences ,Sex Factors ,Internal medicine ,medicine ,Humans ,Women ,Radiology, Nuclear Medicine and imaging ,Healthcare Disparities ,Mortality ,Lung cancer ,Aged ,Retrospective Studies ,Solitary pulmonary nodule ,business.industry ,Solitary Pulmonary Nodule ,Retrospective cohort study ,medicine.disease ,Logistic Models ,Spain ,Relative risk ,Multivariate Analysis ,Tomography, X-Ray Computed ,business ,Chest radiograph - Abstract
To explore differences in the clinical management of men and women in the 5 years after detecting a solitary pulmonary nodule (SPN) by chest radiograph or CT in routine clinical practice. We followed up 545 men and 347 women with an SPN detected by chest radiograph or CT in a retrospective cohort of 25,422 individuals undergoing routine thoracic imaging in 2010–2011. We compared the frequency of each management strategy (no further test, immediate intervention or follow up) according to sex by means of chi-squared. We estimated the relative risk of women versus men of having been followed up instead of an immediate intervention using multivariate logistic regression. We compared by sex the time between detection of the nodule and lung cancer diagnosis, the time between diagnosis and death by means of Mann-Whitney U test and the cumulative effective dose of radiation in each management strategy by means of t test. Women were more likely than men to have follow-up rather than immediate intervention (aRR = 1.8, CI 1.3–2.7, p = 0.002), particularly in those who underwent CT (aRR = 4.2, CI 1.9–9.3, p
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- 2020
7. Extracellular vesicles from human cardiovascular progenitors trigger a reparative immune response in infarcted hearts
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Sisareuth Tan, Jean-Sébastien Silvestre, Kamaleswaran Keirththana, Alain Brisson, Thi Anh-Dao Tran, José Vilar, Philippe Menasché, Paul Alayrac, Thomas Hamada, Maria Franca Perotto, Nadia El Harane, Reem Al-Daccak, Dominique Charron, Laetitia Pidial, Valérie Bellamy, Nisa Renault, Hocine Rachid Hocine, Chloé Guillas, Manon Desgres, Ingrid Gomez, Bruna Lima Correa, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Curie [Paris], Chimie et Biologie des Membranes et des Nanoobjets (CBMN), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Fujifilm Cellular Dynamics Inc [Madison, WI, USA], Service de Chirurgie Cardiovasculaire [Hôpital Européen Georges Pompidou - APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), LIMA CORREA, Bruna, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
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Male ,0301 basic medicine ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,Neutrophils ,Physiology ,T cell ,Lymphocyte ,Induced Pluripotent Stem Cells ,Myocardial Infarction ,030204 cardiovascular system & hematology ,Monocytes ,Cell Line ,Extracellular Vesicles ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,Immune system ,Interferon ,Physiology (medical) ,medicine ,Animals ,Humans ,Regeneration ,Myocytes, Cardiac ,Progenitor cell ,Cell Proliferation ,Heart Failure ,Chemistry ,Macrophages ,Myocardium ,NKG2D ,Coculture Techniques ,Rats ,[SDV.BIO] Life Sciences [q-bio]/Biotechnology ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,Phenotype ,030104 developmental biology ,medicine.anatomical_structure ,Immunology ,Cytokines ,Inflammation Mediators ,Cardiology and Cardiovascular Medicine ,CD80 ,medicine.drug - Abstract
AimsThe cardioprotective effects of human induced pluripotent stem cell-derived cardiovascular progenitor cells (CPC) are largely mediated by the paracrine release of extracellular vesicles (EV). We aimed to assess the immunological behaviour of EV-CPC, which is a prerequisite for their clinical translation.Methods and resultsFlow cytometry demonstrated that EV-CPC expressed very low levels of immune relevant molecules including HLA Class I, CD80, CD274 (PD-L1), and CD275 (ICOS-L); and moderate levels of ligands of the natural killer (NK) cell activating receptor, NKG2D. In mixed lymphocyte reactions, EV-CPC neither induced nor modulated adaptive allogeneic T cell immune responses. They also failed to induce NK cell degranulation, even at high concentrations. These in vitro effects were confirmed in vivo as repeated injections of EV-CPC did not stimulate production of immunoglobulins or affect the interferon (IFN)-γ responses from primed splenocytes. In a mouse model of chronic heart failure, intra-myocardial injections of EV-CPC, 3 weeks after myocardial infarction, decreased both the number of cardiac pro-inflammatory Ly6Chigh monocytes and circulating levels of pro-inflammatory cytokines (IL-1α, TNF-α, and IFN-γ). In a model of acute infarction, direct cardiac injection of EV-CPC 2 days after infarction reduced pro-inflammatory macrophages, Ly6Chigh monocytes, and neutrophils in heart tissue as compared to controls. EV-CPC also reduced levels of pro-inflammatory cytokines IL-1α, IL-2, and IL-6, and increased levels of the anti-inflammatory cytokine IL-10. These effects on human macrophages and monocytes were reproduced in vitro; EV-CPC reduced the number of pro-inflammatory monocytes and M1 macrophages, while increasing the number of anti-inflammatory M2 macrophages.ConclusionsEV-CPC do not trigger an immune response either in in vitro human allogeneic models or in immunocompetent animal models. The capacity for orienting the response of monocyte/macrophages towards resolution of inflammation strengthens the clinical attractiveness of EV-CPC as an acellular therapy for cardiac repair.
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- 2020
8. Extracellular vesicles fail to trigger the generation of new cardiomyocytes in chronically infarcted hearts
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Bruna, Lima Correa, Nadia, El Harane, Manon, Desgres, Maria, Perotto, Paul, Alayrac, Chloé, Guillas, Laetitia, Pidial, Valérie, Bellamy, Emilie, Baron, Gwennhael, Autret, Keirththana, Kamaleswaran, Chloé, Pezzana, Marie-Cécile, Perier, José, Vilar, Antonio, Alberdi, Alain, Brisson, Nisa, Renault, Massimiliano, Gnecchi, Jean-Sébastien, Silvestre, and Philippe, Menasché
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Heart Failure ,Guided Tissue Regeneration ,Myocardium ,Induced Pluripotent Stem Cells ,Cell- and Tissue-Based Therapy ,Myocardial Infarction ,Mice, Transgenic ,Fibrosis ,Disease Models, Animal ,Extracellular Vesicles ,Mice ,MicroRNAs ,Heart Function Tests ,Animals ,Humans ,Myocytes, Cardiac ,Cells, Cultured ,Cell Proliferation ,Research Paper - Abstract
Background: Extracellular vesicles (EV) mediate the therapeutic effects of stem cells but it is unclear whether this involves cardiac regeneration mediated by endogenous cardiomyocyte proliferation. Methods: Bi-transgenic MerCreMer/ZEG (n = 15/group) and Mosaic Analysis With Double Markers (MADM; n = 6/group) mouse models underwent permanent coronary artery ligation and received, 3 weeks later, 10 billion EV (from human iPS-derived cardiovascular progenitor cells [CPC]), or saline, injected percutaneously under echo guidance in the peri-infarcted myocardium. Endogenous cardiomyocyte proliferation was tracked by EdU labeling and biphoton microscopy. Other end points, including cardiac function (echocardiography and MRI), histology and transcriptomics were blindly assessed 4-6 weeks after injections. Results: There was no proliferation of cardiomyocytes in either transgenic mouse strains. Nevertheless, EV improved cardiac function in both models. In MerCreMer/ZEG mice, LVEF increased by 18.3 ± 0.2% between baseline and the end-study time point in EV-treated hearts which contrasted with a decrease by 2.3 ± 0.2% in the PBS group; MADM mice featured a similar pattern as intra-myocardial administration of EV improved LVEF by 13.3 ± 0.16% from baseline whereas it decreased by 14.4 ± 0.16% in the control PBS-injected group. This functional improvement was confirmed by MRI and associated with a reduction in infarct size, the decreased expression of several pro-fibrotic genes and an overexpression of the anti-fibrotic miRNA 133-a1 compared to controls. Experiments with an anti-miR133-a demonstrated that the cardio-reparative effects of EV were partly abrogated. Conclusions: EV-CPC do not trigger cardiomyocyte proliferation but still improve cardiac function by other mechanisms which may include the regulation of fibrosis.
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- 2021
9. Role of tissue resident VSIG4+ macrophages in cardiac remodeling after acute myocardial infarction in mice
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Paul Alayrac, Yanyi Sun, Vincent Duval, Alexandra Achab Ali, Mathilde Lemitre, José Vilar, Angelique Levoye, Stephane Camus, Clément Cochain, and Jean-Sébastien Silvestre
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Cardiology and Cardiovascular Medicine - Published
- 2022
10. Endothelial Cell Indoleamine 2, 3-Dioxygenase 1 Alters Cardiac Function After Myocardial Infarction Through Kynurenine
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Alain Tedgui, Nada Joe Melhem, Jean-Sébastien Silvestre, Mathilde Lemitre, Ludivine Laurans, Mouna Chajadine, Ingrid Gomez, Soraya Taleb, Marie Rouanet, Jacques Callebert, Ziad Mallat, Jean-Sébastien Hulot, Camille Knosp, Hafid Ait-Oufella, Olivier Cazorla, José Vilar, Marion Bouvet, Jean-Marie Launay, Kiave-Yune Howangyin, Yanyi Sun, Jérémy Fauconnier, Mallat, Ziad [0000-0003-0443-7878], and Apollo - University of Cambridge Repository
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Cardiac function curve ,030204 cardiovascular system & hematology ,Pharmacology ,Article ,IDO ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Physiology (medical) ,medicine ,Animals ,Humans ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,tryptophan ,Myocardial infarction ,Indoleamine 2,3-dioxygenase ,Kynurenine ,030304 developmental biology ,0303 health sciences ,business.industry ,apoptosis ,Endothelial Cells ,medicine.disease ,Endothelial stem cell ,myocardial infarction ,chemistry ,Apoptosis ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background: Ischemic cardiovascular diseases, particularly acute myocardial infarction (MI), is one of the leading causes of mortality worldwide. Indoleamine 2, 3-dioxygenase 1 (IDO) catalyzes 1 rate-limiting step of L-tryptophan metabolism, and emerges as an important regulator of many pathological conditions. We hypothesized that IDO could play a key role to locally regulate cardiac homeostasis after MI. Methods: Cardiac repair was analyzed in mice harboring specific endothelial or smooth muscle cells or cardiomyocyte or myeloid cell deficiency of IDO and challenged with acute myocardial infarction. Results: We show that kynurenine generation through IDO is markedly induced after MI in mice. Total genetic deletion or pharmacological inhibition of IDO limits cardiac injury and cardiac dysfunction after MI. Distinct loss of function of IDO in smooth muscle cells, inflammatory cells, or cardiomyocytes does not affect cardiac function and remodeling in infarcted mice. In sharp contrast, mice harboring endothelial cell–specific deletion of IDO show an improvement of cardiac function as well as cardiomyocyte contractility and reduction in adverse ventricular remodeling. In vivo kynurenine supplementation in IDO-deficient mice abrogates the protective effects of IDO deletion. Kynurenine precipitates cardiomyocyte apoptosis through reactive oxygen species production in an aryl hydrocarbon receptor–dependent mechanism. Conclusions: These data suggest that IDO could constitute a new therapeutic target during acute MI.
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- 2021
11. Abstract 13427: Extracellular Vesicles Improve Heart Function Without Inducing the Generation of New Cardiomyocytes
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Massimiliano Gnecchi, noemie tence, Emilie Baron, Philippe Menasché, Nadia El Harane, Bruna Lima Correa, Chloé Guillas, Jean-Sébastien Silvestre, Manon Desgres, Maria Perotto, Antonio Alberdi, Keirththana Kamaleswaran, José Vilar, Valérie Bellamy, Laetitia Pidial, Nisa Renault, Gwennhael Autret, and Paul Alayrac
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business.industry ,medicine.medical_treatment ,Stem-cell therapy ,medicine.disease ,Extracellular vesicles ,Cell biology ,Cell therapy ,Mechanism of action ,Fibrosis ,Physiology (medical) ,Heart failure ,Medicine ,Heart repair ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Function (biology) - Abstract
Introduction: Extracellular Vesicles (EV) recapitulate the benefits of cell therapy for heart repair. Their mechanism of action remains unsettled. Hypothesis: EV may contribute to heart repair by de novo cardiogenesis. Methods: To answer this question, we used 2 bi-transgenic mouse models: the fate-mapping MerCreMer/ZEG and the Mosaic Analysis With Double Markers (MADM). Myocardial infarction was induced by permanent coronary artery ligation. Those with a LVEF ≤ 45% were treated 3 weeks later with EV (from human iPS-derived cardiovascular progenitor cells; 10x10 9 particles) or PBS, injected under echo guidance in the peri-infarcted area (MerCreMer/ZEG: n=15/group and MADM: n=6/group). To track endogenous cardiomyocyte (CM) proliferation, we used EdU labeling in MerCreMer/ZEG delivered by osmotic pumps implanted for 7-10 days post-injection and biphoton microscopy in MADM models. Cardiac function was assessed 4-6 weeks after injection by echocardiography and MRI, blinded to treatment group. Hearts were then subjected to histological and transcriptomic analyses (qPCR and genome-wide microarray). Results: In PBS controls, EF remained stable over time in MerCreMer/ZEG mice and decreased from 34.5% ± 6.0% to 30.7% ± 7.5% in MADM mice by the end of the study. Conversely, EV injections increased EF from 32.1% ± 9.5% to 36.1% ± 7.45 % in MerCreMer/ZEG and from 36.2 %± 8.7% to 40.5% ± 8.9% in MADM mice. A significant difference in the change from baseline was found between EV and controls: 20.7% ± 10.5 % (p=0.048) and 28.0% ± 11.0 %, (p=0.045) for MerCreMer/ZEG and MADM groups, respectively. This improvement was confirmed by MRI in MerCreMer/ZEG mice (p=0.05). Improvement in EF was unrelated to the appearance of new CM, as shown by the absence of difference in TnT+/EdU+/GFP+ cell numbers and the lack of activation of the YAP/TAZ pathway between control and EV groups. However, EV reduced infarct size by 11.9% ± 5.75% (p=0.04), which was accompanied by decreased expression of 4 pro-fibrotic genes (Col1a2, Col3a1, Lox, Col1a2 by qPCR) in heart tissue and a 2.13X overexpression of the anti-fibrotic miRNA 133a-1 compared to controls (n=3/group; p=0.001). Conclusions: EV likely improve cardiac function by modulation of fibrosis rather than by de novo cardiogenesis.
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- 2020
12. Dynamics of Cardiac Neutrophil Diversity in Murine Myocardial Infarction
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Panagiota Arampatzi, Jean-Sébastien Silvestre, Anahi-Paula Arias-Loza, Ehsan Vafadarnejad, Giuseppe Rizzo, Dirk J.J Schulz, Sourish Reddy Bandi, Melanie Roesch, Laura Krampert, Anna Rizakou, Antoine-Emmanuel Saliba, Alma Zernecke, Yara Nazzal, Paul Alayrac, Vallery Audy Nugroho, José Vilar, Clément Cochain, and Tim Knochenhauer
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Pathology ,medicine.medical_specialty ,Isoantigens ,Time Factors ,Physiology ,Neutrophils ,Aortic Diseases ,Myocardial Infarction ,Inflammation ,Bone Marrow Cells ,Receptors, Cell Surface ,Cell Communication ,GPI-Linked Proteins ,Mice ,neutrophils ,Lipocalin-2 ,Medicine ,Animals ,Antigens, Ly ,Myocardial infarction ,Cellular Senescence ,Autoantibodies ,Sialic Acid Binding Immunoglobulin-like Lectins ,Focal Adhesions ,business.industry ,CCAAT-Enhancer-Binding Protein-beta ,Gene Expression Profiling ,Macrophages ,medicine.disease ,Atherosclerosis ,Hypoxia-Inducible Factor 1, alpha Subunit ,Receptors, Formyl Peptide ,myocardial infarction ,Neutrophil Infiltration ,inflammation ,Organ Specificity ,Tissue healing ,Leukocyte Common Antigens ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Epitope Mapping ,Spleen - Abstract
Rationale: After myocardial infarction, neutrophils rapidly and massively infiltrate the heart, where they promote both tissue healing and damage. Objective: To characterize the dynamics of circulating and cardiac neutrophil diversity after infarction. Methods and results: We employed single-cell transcriptomics combined with cell surface epitope detection by sequencing to investigate temporal neutrophil diversity in the blood and heart after murine myocardial infarction. At day 1, 3, and 5 after infarction, cardiac Ly6G + (lymphocyte antigen 6G) neutrophils could be delineated into 6 distinct clusters with specific time-dependent patterning and proportions. At day 1, neutrophils were characterized by a gene expression profile proximal to bone marrow neutrophils ( Cd177 , Lcn2 , Fpr1 ), and putative activity of transcriptional regulators involved in hypoxic response ( Hif1a ) and emergency granulopoiesis ( Cebpb ). At 3 and 5 days, 2 major subsets of Siglecf hi (enriched for eg, Icam1 and Tnf ) and Siglecf low ( Slpi, Ifitm1 ) neutrophils were found. Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis in blood and heart revealed that while circulating neutrophils undergo a process of aging characterized by loss of surface CD62L and upregulation of Cxcr4 , heart infiltrating neutrophils acquired a unique SiglecF hi signature. SiglecF hi neutrophils were absent from the bone marrow and spleen, indicating local acquisition of the SiglecF hi signature. Reducing the influx of blood neutrophils by anti-Ly6G treatment increased proportions of cardiac SiglecF hi neutrophils, suggesting accumulation of locally aged neutrophils. Computational analysis of ligand/receptor interactions revealed putative pathways mediating neutrophil to macrophage communication in the myocardium. Finally, SiglecF hi neutrophils were also found in atherosclerotic vessels, revealing that they arise across distinct contexts of cardiovascular inflammation. Conclusions: Altogether, our data provide a time-resolved census of neutrophil diversity and gene expression dynamics in the mouse blood and ischemic heart at the single-cell level, and reveal a process of local tissue specification of neutrophils in the ischemic heart characterized by the acquisition of a SiglecF hi signature.
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- 2020
13. Cytotoxic CD8
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Icia, Santos-Zas, Jeremie, Lemarié, Ivana, Zlatanova, Marine, Cachanado, Jean-Christophe, Seghezzi, Hakim, Benamer, Pascal, Goube, Marie, Vandestienne, Raphael, Cohen, Maya, Ezzo, Vincent, Duval, Yujiao, Zhang, Jin-Bo, Su, Alain, Bizé, Lucien, Sambin, Philippe, Bonnin, Maxime, Branchereau, Christophe, Heymes, Corinne, Tanchot, José, Vilar, Clement, Delacroix, Jean-Sebastien, Hulot, Clement, Cochain, Patrick, Bruneval, Nicolas, Danchin, Alain, Tedgui, Ziad, Mallat, Tabassome, Simon, Bijan, Ghaleh, Jean-Sébastien, Silvestre, and Hafid, Ait-Oufella
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Heart Failure ,Homeodomain Proteins ,Male ,Mice, Knockout ,Ventricular Remodeling ,Swine ,Myocardium ,Myocardial Infarction ,Apoptosis ,Heart ,CD8-Positive T-Lymphocytes ,Granzymes ,Article ,Mice, Inbred C57BL ,Disease Models, Animal ,Mice ,Animals ,Humans ,Female ,cardiovascular diseases ,Lymphocytes ,Transcriptome - Abstract
Acute myocardial infarction is a common condition responsible for heart failure and sudden death. Here, we show that following acute myocardial infarction in mice, CD8+ T lymphocytes are recruited and activated in the ischemic heart tissue and release Granzyme B, leading to cardiomyocyte apoptosis, adverse ventricular remodeling and deterioration of myocardial function. Depletion of CD8+ T lymphocytes decreases apoptosis within the ischemic myocardium, hampers inflammatory response, limits myocardial injury and improves heart function. These effects are recapitulated in mice with Granzyme B-deficient CD8+ T cells. The protective effect of CD8 depletion on heart function is confirmed by using a model of ischemia/reperfusion in pigs. Finally, we reveal that elevated circulating levels of GRANZYME B in patients with acute myocardial infarction predict increased risk of death at 1-year follow-up. Our work unravels a deleterious role of CD8+ T lymphocytes following acute ischemia, and suggests potential therapeutic strategies targeting pathogenic CD8+ T lymphocytes in the setting of acute myocardial infarction., Immune cells contribute to adverse remodeling following myocardial infarction. Here the authors show in mice and pigs that CD8+ lymphocytes release Granzyme B in the infarcted heart leading to cardiomyocyte death, enhanced inflammation and deterioration of cardiac function.
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- 2020
14. Protocolos clínicos: rotinas de atendimento nas principais urgências e emergências
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Jairo de Faria Paiva Júnior, Hélcio Vitor Pandini Siqueira, Romeo Lages Simões, Artur José Vilar Sette, Thaisa Gabriele da Silva Belan, Paulo Roberto Rodrigues Bicalho, and Paula Costa Machado
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- 2020
15. Intoxicações exógenas
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Thaisa Gabriele da Silva Belan, Artur José Vilar Sette, and Elenilton Souza Rodrigues Júnior
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- 2020
16. Selective EGFR (Epidermal Growth Factor Receptor) Deletion in Myeloid Cells Limits Atherosclerosis—Brief Report
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Ludivine Laurans, Christoph J. Binder, José Vilar, Yujiao Zhang, Léa Guyonnet, Alain Tedgui, Nikolina Papac-Milicevic, Lynda Zeboudj, Bruno Esposito, Andreas Giraud, Ziad Mallat, Pierre-Louis Tharaux, Anna Chipont, Hafid Ait-Oufella, Mallat, Ziad [0000-0003-0443-7878], and Apollo - University of Cambridge Repository
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CD36 Antigens ,Male ,0301 basic medicine ,mice ,Myeloid ,CD36 ,Inflammation ,030204 cardiovascular system & hematology ,Diet, High-Fat ,Necrosis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Epidermal growth factor receptor ,Scavenger receptor ,Cytoskeleton ,Bone Marrow Transplantation ,Mice, Knockout ,biology ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,Chemistry ,Macrophages ,Atherosclerosis ,foam cells ,Plaque, Atherosclerotic ,ErbB Receptors ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Receptors, LDL ,inflammation ,LDL receptor ,biology.protein ,Cancer research ,Tumor necrosis factor alpha ,Bone marrow ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Gene Deletion ,Whole-Body Irradiation - Abstract
Objective— To determine the consequences of specific inhibition of EGFR (epidermal growth factor receptor) in myeloid cells in atherosclerosis development. Approach and Results— Atherosclerotic lesion size was significantly reduced in irradiated Ldlr −/− mice reconstituted with LysM Cre+ Egfr lox/lox bone marrow, compared with chimeric Ldlr −/− mice reconstituted with LysM Cre− Egfr lox/lox bone marrow, after 4 (−43%; P P P Egfr in myeloid cells reduced TNF-α (tumor necrosis factor-α) and IL (interleukin)-6 production by stimulated macrophages but had no effect on IL-10 and IL-12p70 secretion. Finally, we found that myeloid deletion of Egfr limited cytoskeletal rearrangements and also lipid uptake by macrophages through a downregulation of the scavenger receptor CD36 (cluster of differentiation 36). Conclusions— Gene deletion of Egfr in myeloid cells limits IL-6 and TNF-α production, lipid uptake, and consecutively reduces atherosclerosis development.
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- 2018
17. Updated effective doses in radiology
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Isabel González-Alvarez, Blanca Lumbreras, José Vilar, Jorge Vilar-Palop, and Ildefonso Hernández-Aguado
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Diagnostic Imaging ,medicine.medical_specialty ,Population ,MEDLINE ,Cochrane Library ,Radiation Dosage ,Effective dose (radiation) ,Standard deviation ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Medical imaging ,medicine ,Humans ,Dosimetry ,Fluoroscopy ,Radiometry ,education ,Waste Management and Disposal ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Public Health, Environmental and Occupational Health ,General Medicine ,030220 oncology & carcinogenesis ,Radiology ,business - Abstract
The aim of this study was to review recent literature in order to provide updated values of the typical effective doses associated with the top 20 imaging tests for adults and children and for the most widely used set of weights (ICRP60) as well as for the most recent one (ICRP103). We performed a systematic research on radiation dosimetry in radiology published from 2007 onwards through the Medline, Embase and Cochrane Library Plus databases. We also included studies backed by scientific or governmental organizations. Other variables included: year and type of study (survey or descriptive), country, method and sample used for the measurement. Mean effective dose, minimum, maximum and standard deviation were calculated. We compared our results with previous evidence and with data from DDM2. We included 27 articles and 5 web references in the study. A total of 378 values from the 20 procedures included were obtained, 280 (74%) using ICRP60 and 98 (26%) using ICRP103. Effective doses for CT procedures in children were very similar to those for adults, with the exception of CT Trunk, but fluoroscopy procedures had consistently lower dose. There were differences between the current data with either ICRP60 or ICRP103, and the previous published data. In conclusion, we provided the best available evidence from literature to evaluate the effective dose received by each patient for the most typical examinations. According to the recommendations from the Report 154 and from the European Council Directive, these results could also be useful to estimate the range of average exposures to the population.
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- 2016
18. P6292Role of CXCL12gamma isoform and its interactions with heparan-sulfates in post-ischemic cardiac remodeling
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Ivana Zlatanova, Jean-Sébastien Silvestre, Mathilde Lemitre, V Duval, José Vilar, Yanyi Sun, Paul Alayrac, Ingrid Gomez, and A Levoye
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Gene isoform ,business.industry ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,Cell biology - Abstract
Introduction Myocardial infarction (MI) is a severe ischemic disease precipitating long-term adverse remodeling and heart failure. The chemokine CXCL12/SDF-1 is essential for cardiovascular system development and plays a prominent role in physio-pathological processes such as inflammation, angiogenesis and tissue fibrosis. In addition to the binding to its cognate receptors CXCR4 and CXCR7, CXCL12 interacts with heparan-sulfates (HS) which coordinate its biological activity. We have previously highlighted the essential role of CXCL12/HS interactions in vascular growth and remodeling in the setting of critical limb ischemia. In addition, studies in experimental model of MI revealed a protective role for the CXCL12α isoform, through the regulation of cardiomyocyte survival and recruitment of inflammatory cells. However, in mice, three CXCL12 isoforms (α, β and γ) have been identified and, among them, the CXCL12γ isoform shows an unchallenged ability to cooperate with HS, suggesting a putative pivotal role in tissue repair. Objectives The aim of the study is to analyze the role of CXCL12γ isoform and the importance of CXCL12/HS interactions in post-ischemic cardiac remodeling in an acute model of MI. Methods MI was induced by permanent ligation of the left ascending coronary artery in mice carrying a Cxcl12 gene mutation that precludes interactions with HS (Cxcl12Gagtm) and in Cxcl12γ knock-in animals (Cxcl12γ-KI) harboring CXCL12γ deficiency. Alternatively, the impact of CXCL12γ overexpression and the importance of its interactions with HS was also evaluated in wild-type (WT) mice receiving transcutaneous echo-guided injections of adenovirus encoding WT Cxcl12γ or HS-binding-disabled Cxcl12γ in cardiac tissue. Cardiac function and remodeling have been assessed through echocardiography analysis, evaluation of infarct size, interstitial fibrosis, vascular growth (capillary and arteriole densities) and inflammatory cell infiltration into the cardiac tissue. Results After MI, Cxcl12Gagtm and Cxcl12γ-KI animals exhibit reduction in cardiac function and adverse left ventricular remodeling when compared to their respective WT littermates. Interestingly, overexpression of CXCL12γ in WT mice cardiac restored cardiac function by reducing the size of the infarcted area, interstitial fibrosis and promoting vascular growth. In sharp contrast, HS–binding disabled CXCL12gamma mutants failed to improve cardiac function and to abrogate adverse left ventricular remodeling. Conclusion We show that CXCL12γ isoform plays an important role in the regulation of post-ischemic cardiac function and remodeling and that its interactions with HS are essential for adequate cardiac repair in the setting of acute MI.
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- 2019
19. P6598MicroRNA 21 and Hypoxia Inducible Factor 1 synchronize the impact of B lymphocytes on cardiac function after acute myocardial infarction
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Ingrid Gomez, Xavier Loyer, Hafid Ait-Oufella, Ziad Mallat, Mathilde Lemitre, V Duval, A Levoye, Cristina Pinto, Jean-Sébastien Silvestre, José Vilar, Yanyi Sun, and Paul Alayrac
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Cardiac function curve ,medicine.medical_specialty ,Hypoxia-Inducible Factor 1 ,business.industry ,Internal medicine ,Cardiology ,Medicine ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,medicine.disease - Abstract
Background Myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Mature B lymphocytes have been shown to exacerbate tissue injury and deterioration of cardiac function after MI. However, the cellular and molecular mechanisms governing B cell deleterious effects in the ischemic milieu remain to be defined. Purpose In this study, we speculate that endogenous activation of the miR21/HIFα-related pathways mediates the effect of B lymphocytes on post-ischemic cardiac remodeling. Methods Acute MI was induced by permanent ligation of the left anterior descending artery in mice. Cardiac function and remodeling was determined by echocardiography and immunohistochemistry. Inflammatory cell number and phenotype were defined by FACS analysis. To evaluate the role of HIFα isoforms in B cells, we generated mice with B cell lineage specific (Cd79aCre/+) conditional deletion of HIF1α (HIF1αflox/flox), HIF2α (HIF2αflox/flox), or both isoforms (HIF1α-HIF2αflox/flox). Results Acute MI increased miR21 levels in B cells. miR21 deficient mice showed reduced B cell numbers in the spleen, blood and subsequently in the injured cardiac tissue. Transplantation of bone marrow derived cells isolated from miR21-deficient mice (miR21−/−) improved cardiac function and remodeling when compared to administration of wild-type (WT) bone marrow cells. Similarly, in Rag1−/− immunodeficient mice with acute MI, re-supplementation with miR21−/− B lymphocytes restored cardiac repair and function when compared to injection of WT B cells. miR21 abrogated PTEN contents and subsequently enhanced HIF1α levels in cultured B cells. B cell deletion of HIF1α, but not that of HIF2α, reduced B cell accumulation and improved cardiac function after MI. Mice, which were equally deficient in HIF1α and HIF2α, also exhibited abrogation of adverse ventricular remodeling and showed recovery of cardiac function after MI. Toll like receptor agonist, CpG, fostered the release of the monocyte chemo-attractant protein, Ccl7, in cultured WT B cells but not in miR21- or HIF1α- deficient B cells. Ccl7 circulating levels were also reduced in miR21−/− and Cd79aCre/+/HIF1α flox/flox animals after acute MI. Ccl7 down-regulation hampered Ly6Chigh monocyte infiltration in the ischemic myocardium, leading to decreased infarct size and interstitial fibrosis, supporting cardiac repair. Conclusion This work reveals a novel function for miR21/HIF1α related pathways in B lymphocyte dependent effect on cardiac function and remodeling in the setting of acute MI.
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- 2019
20. Time-resolved single-cell transcriptomics uncovers dynamics of cardiac neutrophil diversity in murine myocardial infarction
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Jean-Sébastien Silvestre, Melanie Roesch, Alma Zernecke, Vallery Audy Nugroho, José Vilar, Ehsan Vafadarnejad, Antoine-Emmanuel Saliba, Giuseppe Rizzo, Laura Krampert, Dirk J.J Schulz, Panagiota Arampatzi, Clément Cochain, and Paul Alayrac
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Chemokine ,biology ,Infarction ,Inflammation ,medicine.disease ,Granulopoiesis ,CCL6 ,Immunology ,medicine ,biology.protein ,CEBPB ,Tumor necrosis factor alpha ,medicine.symptom ,SLPI - Abstract
ObjectiveAfter myocardial infarction, neutrophils rapidly and massively infiltrate the heart, where they can promote both tissue healing and damage. Here, we investigated the dynamics of cardiac neutrophil heterogeneity after infarction.Methods and resultsWe employed single-cell transcriptomics (scRNA-seq) to investigate temporal neutrophil heterogeneity in the heart after murine myocardial infarction. At day 1, 3, and 5 after infarction, neutrophils could be delineated into six distinct clusters with specific time-dependent patterning and proportions. While the majority of neutrophils at day 1 were characterized by high expression of chemokines (e.g.Cxcl3,Ccl6), and putative activity of transcriptional regulators involved in hypoxic response (Hif1a) and emergency granulopoiesis (Cebpb), two major subsets ofSiglecfhi(enriched for e.g.Icam1andTnf) andSiglecflow(Slpi, Ifitm1) neutrophils were found at 3 and 5 days. Flow cytometry analysis confirmed the presence of LY6G+SIGLECFhiand LY6G+SIGLECFlowneutrophils in the heart from 3 days after infarction onwards. LY6G+SIGLECFhineutrophils were absent from the bone marrow, blood and spleen, suggesting local acquisition of surface SIGLECF. Acquisition of the SIGLECFhistate was paralleled by features of neutrophil ageing and activation (ICAM1hiCXCR4hiCD49dhiCD62Llow). scRNA-seq of atherosclerotic aortas revealed two neutrophil subsets with gene expression patterns reminiscent of the majorSiglecfhiandSiglecflowcardiac neutrophil subpopulations, revealing that these populations may be present across distinct contexts of cardiovascular inflammation.ConclusionAltogether, our data provide a time-resolved census of neutrophil diversity and gene expression dynamics in the mouse ischemic heart at the single-cell level, and suggests that temporal neutrophil heterogeneity is in part driven by local transition to a SIGLECFhistate.
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- 2019
21. The determinants of lung cancer after detecting a solitary pulmonary nodule are different in men and women, for both chest radiograph and CT
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Elisa Chilet-Rosell, Isabel González-Álvarez, José María Salinas-Serrano, José Vilar, Ildefonso Hernández-Aguado, Lucy Anne Parker, M. Luisa Domingo, Blanca Lumbreras, Maria Pastor-Valero, and Fermina Lorente-Fernández
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Male ,Lung Neoplasms ,Pulmonology ,Social Sciences ,Lung and Intrathoracic Tumors ,030218 nuclear medicine & medical imaging ,Diagnostic Radiology ,Habits ,0302 clinical medicine ,Outpatients ,Medicine and Health Sciences ,Smoking Habits ,Psychology ,Cumulative incidence ,Tomography ,Aged, 80 and over ,Multidisciplinary ,medicine.diagnostic_test ,Mortality rate ,Radiology and Imaging ,Middle Aged ,Pulmonary Imaging ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,Female ,Radiography, Thoracic ,Research Article ,Adult ,medicine.medical_specialty ,Patients ,Death Rates ,Imaging Techniques ,Science ,Chronic Obstructive Pulmonary Disease ,Clinical Decision-Making ,Neuroimaging ,Research and Analysis Methods ,Diagnosis, Differential ,03 medical and health sciences ,Sex Factors ,Population Metrics ,Diagnostic Medicine ,Internal medicine ,medicine ,Cancer Detection and Diagnosis ,Humans ,Lung cancer ,Aged ,Retrospective Studies ,Solitary pulmonary nodule ,Behavior ,Population Biology ,business.industry ,Cancer ,Solitary Pulmonary Nodule ,Cancers and Neoplasms ,Biology and Life Sciences ,Retrospective cohort study ,medicine.disease ,Computed Axial Tomography ,Health Care ,Relative risk ,business ,Chest radiograph ,Tomography, X-Ray Computed ,Neuroscience - Abstract
ObjectivesTo determine the factors associated with lung cancer diagnosis and mortality after detecting a solitary pulmonary nodule (SPN) in routine clinical practice, in men and in women for both chest radiograph and CT.Materials and methodsA 5-year follow-up of a retrospective cohort of of 25,422 (12,594 men, 12,827 women) patients aged ≥35 years referred for chest radiograph or CT in two hospitals in Spain (2010-2011). SPN were detected in 893 (546 men, 347 women) patients. We estimated the cumulative incidence of lung cancer at 5-years, the association of patient and nodule characteristics with SPN malignancy using Poisson logistic regression, stratifying by sex and type of imaging test. We calculated lung cancer specific mortality rate by sex and SPN detection and hazard rates by cox regression.Results133 (14.9%) out of 893 patients with an SPN and 505 (2.06%) of the 24,529 patients without SPN were diagnosed with lung cancer. Median diameter of SPN in women who developed cancer was larger than in men. Men who had a chest radiograph were more likely to develop a lung cancer if the nodule was in the upper-lobes, which was not the case for women. In patients with an SPN, smoking increased the risk of lung cancer among men (chest radiograph: RR = 11.3, 95%CI 1.5-83.3; CT: RR = 7.5, 95%CI 2.2, 26.0) but smoking was not significantly associated with lung cancer diagnosis or mortality among women with an SPN. The relative risk of lung cancer diagnosis in women with SPN versus those without was much higher compared to men (13.7; 95%CI 9.2, 20.4 versus 6.2; 95%CI 4.9,7.9).ConclusionThe factors associated with SPN malignancy and 5-year lung cancer mortality were different among men and women, especially regarding smoking history and SPN characteristics, where we observed a relatively high rate of lung cancer diagnosis among female non-smokers.
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- 2019
22. The ECHO model proved to be a useful tool to increase clinicians' self-effectiveness for care of patients with Hepatitis C in Argentina
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Valeria Moreno, Ariel Billordo, Carlos Mendoza, Estela Manero, Silvia Mengarelli, Susana Ceballos, Marcelo Fernandez, Claudia Gadea, Manuel Mendizabal, Federico Piñero, Verónica Deltrozzo, Martin O´Flaherty, José Vilar, Marcelo Silva, Sanjeev Arora, Fernando Barreyro, Ana Palazzo, Sebastián Figueroa, Luis De María, Ezequiel Ridruejo, Andres Bruno, Marcela Sixto, Daniela Perez, Dolores Murga, Marina Villa, and Cristina Alonso
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Adult ,Male ,medicine.medical_specialty ,CIENCIAS MÉDICAS Y DE LA SALUD ,Sustained Virologic Response ,barriers ,Argentina ,Medicina Clínica ,Medical care ,Antiviral Agents ,Virology ,medicine ,Clinical endpoint ,Humans ,In patient ,Viral hepatitis C ,Gastroenterología y Hepatología ,antiviral therapies ,Practice Patterns, Physicians' ,Prospective cohort study ,ECHO ,Aged ,Hepatology ,Geography ,business.industry ,virus diseases ,Hepatitis C ,Middle Aged ,Models, Theoretical ,University hospital ,medicine.disease ,digestive system diseases ,Telemedicine ,Infectious Diseases ,Virologic response ,Emergency medicine ,Drug Therapy, Combination ,Female ,Clinical Competence ,Patient Care ,business ,Healthcare providers - Abstract
The ECHO model was developed to expand access to medical care for populations with HCV infection in underserved areas. We aimed to compare HCV treatment outcomes in community‐based clinics with the Austral University Hospital (AUH) and to assess improvement in physician knowledge and skills. In October 2015, we established an HCV ECHO clinic at the AUH in Buenos Aires. To evaluate the impact of this programme, we conducted a prospective cohort study comparing treatment for HCV infection at the AUH with healthcare providers from different Argentinean provinces. A survey evaluating skills and competence in HCV care was administered, and results were compared. The primary endpoint was sustained virologic response (SVR) and under direct‐acting antivirals. Since the implementation of ECHO clinics, a total of 25 physicians participated in at least one session (median 10.0; IQR 3.0‐18.0). SVR rates (n = 437 patients) were 94.2% (95% CI 90.4‐96.8) in patients treated at AUH clinic (n = 227/242) and 96.4% (95% CI 92.7‐98.5) in those treated at ECHO sites (n = 188/195), with a nonsignificant difference between sites, 2.2% SVR difference (95% CI −0.24‐0.06; P = 0.4). We also found a significant improvement in all the evaluated skills and abilities. Replicating the ECHO model helped to improve participants´ skills in the management of HCV achieving similar SVR rates. ECHO model was demonstrated to be an effective intervention able to multiply and expand HCV treatment, a critical barrier to access to care that needs to be solved if we are committed with WHO goals to eliminate HCV by 2030 Fil: Mendizabal, Manuel. Gobierno de la Provincia de Buenos Aires. Hospital Universitario Austral; Argentina Fil: Ridruejo, Ezequiel. Gobierno de la Provincia de Buenos Aires. Hospital Universitario Austral; Argentina Fil: Ceballos, Susana. Gobierno de la Provincia de Jujuy. Hospital San Roque; Argentina Fil: Sixto, Marcela. Gobierno de la Provincia de Santa Fe. Hospital José M. Cullen; Argentina Fil: Billordo, Ariel. Gobierno de la Provincia del Chaco. Hospital Julio C. Perrando; Argentina Fil: Gadea, Claudia. Sanatorio Pasquini de la Provincia de Tucumán; Argentina Fil: Mengarelli, Silvia. Gobierno de la Provincia de Cordoba. Nuevo Hospital San Roque.; Argentina Fil: Alonso, Cristina. Gobierno de la Provincia de Buenos Aires. Hospital Universitario Austral; Argentina Fil: Palazzo, Ana. Gobierno de la Provincia de Tucumán. Hospital Padilla; Argentina Fil: De María, Luis. Gobierno de la Provincia de Santa Fe. Hospital José M. Cullen; Argentina Fil: Bruno, Andrés. Gobierno de la Provincia de Buenos Aires. Hospital Argerich; Argentina Fil: Perez, Daniela. Gobierno de la Provincia de Tucumán. Hospital Padilla; Argentina. Gobierno de la Provincia de Buenos Aires. Hospital Universitario Austral; Argentina Fil: Piñero, Federico. Gobierno de la Provincia de Buenos Aires. Hospital Universitario Austral; Argentina Fil: Deltrozzo, Verónica. Dual Medica de la Provincia de Santiago del Estero; Argentina Fil: Mendoza, Carlos. Gobierno de la Provincia de Río Cuarto. Hospital Central de Río Cuarto; Argentina Fil: Figueroa, Sebastián. Hospital Dr. Arturo Oñativia - Salta Capital.; Argentina Fil: Manero, Estela. Gobierno de la Provincia de Jujuy. Hospital Pablo Soria; Argentina Fil: Villa, Marina. Instituto Oulton de Córdoba; Argentina Fil: Barreyro, Fernando Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste; Argentina Fil: Moreno, Valeria. Gobierno de la Provincia de Cordoba. Nuevo Hospital San Roque.; Argentina Fil: Vilar, José. Asociación Argentina para el Estudio de las Enfermedades del Hígado; Argentina Fil: Murga, Dolores. Gobierno de la Provincia de Tucumán. Hospital Padilla; Argentina Fil: Fernandez, Marcelo. Gobierno de la Provincia de Entre Ríos. Hospital Bicentenario; Argentina Fil: O´Flaherty, Martin. University of Liverpool; Reino Unido Fil: Arora, Sanjeev. University of New Mexico; Estados Unidos Fil: Silva, Marcelo. Hospital Universitario Austral; Argentina
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- 2019
23. Iron Regulator Hepcidin Impairs Macrophage-Dependent Cardiac Repair After Injury
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Jacques Mathieu, Jean-Sébastien Silvestre, Philippe Bonnin, Sophie Vaulont, José Vilar, Wineke Bakker, David Voehringer, Mathilde Lemitre, Cristina Pinto, Ivana Zlatanova, and Carole Peyssonnaux
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Regulator ,Myocardial Infarction ,Inflammation ,Bone Marrow Cells ,Mice, Transgenic ,Mesenchymal Stem Cell Transplantation ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Hepcidins ,Hepcidin ,Physiology (medical) ,Medicine ,Macrophage ,Animals ,Regeneration ,Myocytes, Cardiac ,Myocardial infarction ,Cardiac disorders ,030304 developmental biology ,0303 health sciences ,Interleukin-13 ,biology ,Ventricular Remodeling ,business.industry ,Regeneration (biology) ,Macrophages ,Heart ,Mesenchymal Stem Cells ,Atrial Remodeling ,medicine.disease ,Mice, Inbred C57BL ,Animals, Newborn ,030220 oncology & carcinogenesis ,Cardiac repair ,Cancer research ,biology.protein ,Interleukin-4 ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background: Defective systemic and local iron metabolism correlates with cardiac disorders. Hepcidin, a master iron sensor, actively tunes iron trafficking. We hypothesized that hepcidin could play a key role to locally regulate cardiac homeostasis after acute myocardial infarction. Methods: Cardiac repair was analyzed in mice harboring specific cardiomyocyte or myeloid cell deficiency of hepcidin and challenged with acute myocardial infarction. Results: We found that the expression of hepcidin was elevated after acute myocardial infarction and the specific deletion of hepcidin in cardiomyocytes failed to improve cardiac repair and function. However, transplantation of bone marrow–derived cells from hepcidin-deficient mice ( Hamp −/− ) or from mice with specific deletion of hepcidin in myeloid cells (LysM CRE/+ / Hamp f/f ) improved cardiac function. This effect was associated with a robust reduction in the infarct size and tissue fibrosis in addition to favoring cardiomyocyte renewal. Macrophages lacking hepcidin promoted cardiomyocyte proliferation in a prototypic model of apical resection–induced cardiac regeneration in neonatal mice. Interleukin (IL)–6 increased hepcidin levels in inflammatory macrophages. Hepcidin deficiency enhanced the number of CD45 + /CD11b + /F4/80 + /CD64 + /MHCII Low /chemokine (C–C motif) receptor 2 (CCR2) + inflammatory macrophages and fostered signal transducer and activator of transcription factor-3 (STAT3) phosphorylation, an instrumental step in the release of IL-4 and IL-13. The combined genetic suppression of hepcidin and IL-4/IL-13 in macrophages failed to improve cardiac function in both adult and neonatal injured hearts. Conclusions: Hepcidin refrains macrophage-induced cardiac repair and regeneration through modulation of IL-4/IL-13 pathways.
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- 2018
24. Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction
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Luca Danelli, Maxime Branchereau, Eric Camerer, Mathilde Lemitre, Nisa Renault, Béatrice Cousin, Pauline Marck, Adèle Richart, Elodie Luche, Pierre Launay, Sylvain M. Le Gall, Coralie L. Guerin, Jean-Sébastien Silvestre, Anta Ngkelo, Philippe Bonnin, Anaïs Kervadec, Jonathan A. Kirk, Hans Reimer Rodewald, Philippe Menasché, Mark J. Ranek, Patrick Bruneval, Christophe Heymes, José Vilar, Ulrich Blank, David A. Kass, Gregory Gautier, and Louis Casteilla
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0301 basic medicine ,Cardiac function curve ,medicine.medical_specialty ,CPA3 ,Carboxypeptidases A ,Immunology ,Myocardial Infarction ,Tryptase ,Sudden death ,Article ,Contractility ,Mice ,03 medical and health sciences ,Myofibrils ,Internal medicine ,medicine ,Animals ,Receptor, PAR-2 ,Immunology and Allergy ,Calcium Signaling ,Mast Cells ,Myocardial infarction ,Research Articles ,Mice, Knockout ,biology ,Myocardium ,medicine.disease ,Cyclic AMP-Dependent Protein Kinases ,Myocardial Contraction ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,Endocrinology ,Heart failure ,Proteolysis ,cardiovascular system ,biology.protein ,Mast cell sarcoma ,Calcium - Abstract
Ngkelo et al. use a mast cell–deficient mouse model to reveal a protective role of mast cells in myocardial infarction, through regulation of the cardiac contractile machinery., Acute myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Inflammatory cells orchestrate postischemic cardiac remodeling after MI. Studies using mice with defective mast/stem cell growth factor receptor c-Kit have suggested key roles for mast cells (MCs) in postischemic cardiac remodeling. Because c-Kit mutations affect multiple cell types of both immune and nonimmune origin, we addressed the impact of MCs on cardiac function after MI, using the c-Kit–independent MC-deficient (Cpa3Cre/+) mice. In response to MI, MC progenitors originated primarily from white adipose tissue, infiltrated the heart, and differentiated into mature MCs. MC deficiency led to reduced postischemic cardiac function and depressed cardiomyocyte contractility caused by myofilament Ca2+ desensitization. This effect correlated with increased protein kinase A (PKA) activity and hyperphosphorylation of its targets, troponin I and myosin-binding protein C. MC-specific tryptase was identified to regulate PKA activity in cardiomyocytes via protease-activated receptor 2 proteolysis. This work reveals a novel function for cardiac MCs modulating cardiomyocyte contractility via alteration of PKA-regulated force–Ca2+ interactions in response to MI. Identification of this MC-cardiomyocyte cross-talk provides new insights on the cellular and molecular mechanisms regulating the cardiac contractile machinery and a novel platform for therapeutically addressable regulators.
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- 2016
25. Myeloid-Epithelial-Reproductive Receptor Tyrosine Kinase and Milk Fat Globule Epidermal Growth Factor 8 Coordinately Improve Remodeling After Myocardial Infarction via Local Delivery of Vascular Endothelial Growth Factor
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Ivana Zlatanova, Christian Stockmann, Ziad Mallat, Jean-Sébastien Silvestre, Cristina Pinto, Marie Rouanet, José Vilar, Clément Cochain, Mathilde Lemitre, Anta Ngkelo, Kiave-Yune Howangyin, Bernd K. Fleischmann, Mallat, Ziad [0000-0003-0443-7878], and Apollo - University of Cambridge Repository
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Vascular Endothelial Growth Factor A ,0301 basic medicine ,Myeloid ,Myocardial Infarction ,030204 cardiovascular system & hematology ,Receptor tyrosine kinase ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Epidermal growth factor ,Coronary Heart Disease ,Mice, Knockout ,Ventricular Remodeling ,biology ,Milk Proteins ,3. Good health ,Cell biology ,Vascular endothelial growth factor ,Vascular endothelial growth factor A ,medicine.anatomical_structure ,Antigens, Surface ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Mice, Transgenic ,Inflammation ,03 medical and health sciences ,Phagocytosis ,Proto-Oncogene Proteins ,Physiology (medical) ,medicine ,Animals ,ddc:610 ,Ventricular remodeling ,c-Mer Tyrosine Kinase ,business.industry ,Macrophages ,Receptor Protein-Tyrosine Kinases ,Original Articles ,medicine.disease ,Mice, Inbred C57BL ,030104 developmental biology ,chemistry ,inflammation ,Heart failure ,Immunology ,biology.protein ,neovascularization, physiologic ,myocarditis ,business - Abstract
Supplemental Digital Content is available in the text., Background— In infarcted heart, improper clearance of dying cells by activated neighboring phagocytes may precipitate the transition to heart failure. We analyzed the coordinated role of 2 major mediators of efferocytosis, the myeloid-epithelial-reproductive protein tyrosine kinase (Mertk) and the milk fat globule epidermal growth factor (Mfge8), in directing cardiac remodeling by skewing the inflammatory response after myocardial infarction. Methods and Results— We generated double-deficient mice for Mertk and Mfge8 (Mertk−/−/Mfge8−/−) and challenged them with acute coronary ligature. Compared with wild-type, Mertk-deficient (Mertk−/−), or Mfge8-deficient (Mfge8−/−) animals, Mertk−/−/Mfge8−/− mice displayed greater alteration in cardiac function and remodeling. Mertk and Mfge8 were expressed mainly by cardiac Ly6CHigh and Low monocytes and macrophages. In parallel, Mertk−/−/Mfge8−/− bone marrow chimeras manifested increased accumulation of apoptotic cells, enhanced fibrotic area, and larger infarct size, as well as reduced angiogenesis. We found that the abrogation of efferocytosis affected neither the ability of circulating monocytes to infiltrate cardiac tissue nor the number of resident Ly6CHigh and Ly6CHow monocytes/macrophages populating the infarcted milieu. In contrast, combined Mertk and Mfge8 deficiency in Ly6CHigh/Ly6CLow monocytes/macrophages either obtained from in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted vascular endothelial growth factor A (VEGFA) release. Using LysMCre+/VEGFAfl/fl mice, we further identified an important role for myeloid-derived VEGFA in improving cardiac function and angiogenesis. Conclusions— After myocardial infarction, Mertk- and Mfge8-expressing monocyte/macrophages synergistically engage the clearance of injured cardiomyocytes, favoring the secretion of VEGFA to locally repair the dysfunctional heart.
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- 2016
26. How do Extracellular Vesicles Protect the Ischemic Myocardium?
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Gwennhael Autret, Jean-Sébastien Silvestre, B. Lima Correa, Keirththana Kamaleswaran, N. El Harane, Massimiliano Gnecchi, Antonio Alberdi, Nisa Renault, Philippe Menasché, Maria Perotto, Chloé Guillas, Manon Desgres, noemie tence, Valérie Bellamy, Emilie Baron, Laetitia Pidial, and José Vilar
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Cardioprotection ,Cardiac function curve ,Cancer Research ,Transplantation ,Ejection fraction ,business.industry ,Immunology ,Cell Biology ,medicine.disease ,Andrology ,Cell therapy ,Oncology ,Fibrosis ,Heart failure ,Immunology and Allergy ,Medicine ,Myocardial infarction ,business ,Ligation ,Genetics (clinical) - Abstract
Background & Aim Introduction Cell therapy for chronic heart failure has demonstrated that Cardiac Progenitor Cells (CPCs) delivered to the heart exert their beneficial effects through a paracrine mechanism harnessing endogenous repair pathways largely mediated by extracellular vesicles (EVs). We used a bi-transgenic fate-mapping MerCreMer/ZEG mouse model to assess whether the cardioprotection could be partly explained by de novo cardiogenesis. Methods, Results & Conclusion Methods Myocardial infarction (MI) was induced by permanent left anterior descending coronary artery ligation in MerCreMer/ZEG mice. Surviving animals (n=30) with a left ventricular ejection fraction (LVEF) ≤ 45% were treated 3 weeks after MI with either EV (from 1.4 × 106 human iPS-derived CPC; 10 × 109 particles; n=15) or PBS (n=15) delivered by echo-guided intra-myocardial injections targeted to the peri-infarcted area. To track a putative proliferation of endogenous cardiomyocytes, osmotic pumps delivering EdU were implanted for 10-13 days after EV or PBS treatnent. Cardiac function was assessed 4-6 weeks after injections by echocardiography (n=15 p/group) and MRI (n=6-7 p/group), blinded to treatment group. Hearts were harvested and subjected to histological and transcriptomic analyses by qRT-PCR and genome-wide microarrays (Affymetrix). Results In controls, echocardiographically assessed EF slightly decreased over time whereas in the EV-treated group, it increased so that at the end-study time point, the between-group difference in changes from baseline averaged 20.7 % ± 10.5 % (p=0.048). This improvement was confirmed by MRI (11%, p=0.05). EV-treated hearts did not show a different number of new cardiomyocytes (TnT+/EdU+/GFP+) compared to controls (32 analyzed sections/mouse). However, EV-treatment was associated with a reduction in infarct size (-11.9% ± 5.75%), and reduced expression of 4 pro-fibrotic genes (Col1a2, Col3a1, Lox, Col1a2) as assessed by qRT-PCR (n=5-6 p/group). Further, the EV-treatment group showed an over-expression of the anti-fibrotic miRNA 133a-1 (2.13 fold) as compared to controls (n=3 p/group; p=0.0015). Conclusions EV secreted by iPSC-CPC improve cardiac function in chronic heart failure by mechanisms which seem to be largely related to the modulation of fibrosis without participation of a de novo cardiogenesis. Funding Labex Revive, Fondation pour la Recherche Medicale, Fonds Marion Elizabeth BRANCHER
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- 2020
27. El futuro de la Educación Física
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Arturo Díaz Suárez, Antonio García de Alcaraz Serrano, Enrique Ortega Toro, and Juan José Vilar Abellaneda
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Los trabajos que se presentan en este volumen, bebiendo y siendo parte del sobresaliente y positivo devenir que acompaña en las últimas décadas al ámbito motriz del ser humano y más concretamente a la parcela de la Educación Física están insertas contextualmente y forman parte de un nuevo proceso renovador que se está dando en el ámbito citado, que va a marcar una nueva etapa en ese devenir y por tanto un salto cualitativo en la interpretación, en el sentido, en la direccionalidad, y en los propios efectos que el movimiento libre y voluntario ejecutado conforme a pautas educativas pueda provocar en las personas.
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- 2018
28. Lung cancer risk and cancer-specific mortality in subjects undergoing routine imaging test when stratified with and without identified lung nodule on imaging study
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Blanca Lumbreras, Isabel González-Alvarez, José Vilar, Ildefonso Hernández-Aguado, María Fermina Lorente, Maria Luisa Domingo, María Pastor Valero, Noemi Gómez-Sáez, and Lucy Anne Parker
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Male ,Risk ,medicine.medical_specialty ,Lung Neoplasms ,Comorbidity ,Malignancy ,Cohort Studies ,Pulmonary Disease, Chronic Obstructive ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Prospective Studies ,Lung cancer ,Prospective cohort study ,Lung ,Aged ,COPD ,medicine.diagnostic_test ,business.industry ,Incidence ,Incidence (epidemiology) ,Smoking ,Solitary Pulmonary Nodule ,General Medicine ,Odds ratio ,Middle Aged ,respiratory system ,medicine.disease ,respiratory tract diseases ,medicine.anatomical_structure ,Female ,Radiology ,Tomography, X-Ray Computed ,business ,Chest radiograph ,Follow-Up Studies - Abstract
To assess the risk of lung cancer and specific mortality rate in patients with and without solitary pulmonary nodules (SPN) on chest radiograph and CT. This prospective study included 16,078 patients ≥35 years old (893 of them had an SPN detected with either chest radiograph or CT) and 15,185 without SPN. Patients were followed up for 18 months or until being diagnosed with lung cancer. Risk and mortality lung cancer were calculated in both groups with Poisson regression. In patients with SPN, incidence of lung cancer was 8.3 % (95 % CI 6.0–11.2) on radiograph and 12.4 % (95 % CI 9.3–15.9) on CT. A chronic obstructive pulmonary disease in patients with radiographs (odds ratio 2.62; 95 % CI 1.03, 6.67) and smoking habit (odds ratio 20.63; 95 % CI 3.84, 110.77) in patients with CT were associated with a higher probability of lung cancer. Large nodule size and spiculated edge were associated with lung cancer on both CT and radiograph. Lung cancer-specific mortality was lower in patients with SPN than in those without SPN (1.73/1000 person-years, 95 % CI 1.08–2.88 vs. 2.15/1000 person-years, 95 % CI 1.25–3.96). The risk of lung cancer for patients with SPN is higher in clinical populations than in screening studies. Moreover, patients with SPN showed lower mortality than those without SPN. • Lung cancer risk is 8 % for SPN detected on routine radiographs. • Lung cancer risk is 12.4 % for SPN detected in routine chest CT. • Smoking, COPD, SPN diameter and edge were predictors of malignancy. • Lung cancer risk of SPN in routine practice seems higher than in screening.
- Published
- 2015
29. Pacemakers and implantable cardioverter defibrillators, unknown to chest radiography: Review, complications and systematic reading
- Author
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Maria Luisa Domingo Montañana, José Vilar Samper, Salvador Alandete Germán, Santiago Isarria Vidal, and Esperanza de la Vía Oraá
- Subjects
Pacemaker, Artificial ,medicine.medical_specialty ,business.industry ,Radiography ,media_common.quotation_subject ,General Medicine ,Patient Positioning ,Defibrillators, Implantable ,Radiological weapon ,Reading (process) ,medicine ,Humans ,Equipment Failure ,Radiography, Thoracic ,Radiology, Nuclear Medicine and imaging ,Patient Safety ,Imaging technique ,Intensive care medicine ,business ,Cardiac device ,Follow-Up Studies ,media_common - Abstract
Chest X-ray is the imaging technique of choice for an initial study of pacemakers and implantable cardio-defibrillators (ICD). Radiologists have an important role in the evaluation of its initial placement and in the assessment during its follow-up. For this reason, it is necessary to know not only the different existing devices and its components but also the reasons of malfunction or possible complications. The purpose of this article is to do a systematic review of the different types of pacemakers and ICD. We review their usual radiological appearances, the possible complications which might take place and its causes of malfunctioning.
- Published
- 2015
30. P2568Another advantage of extracellular vesicles for the treatment of chronic heart failure: their immune privilege
- Author
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Jean-Sébastien Silvestre, Valérie Bellamy, Nisa Renault, H R Rachid, N. El Harane, Ingrid Gomez, Philippe Menasché, Anaïs Kervadec, Dominique Charron, José Vilar, Laetitia Pidial, F. Lay, and Reem Al-Daccak
- Subjects
Pathology ,medicine.medical_specialty ,Immune privilege ,business.industry ,Heart failure ,Immunology ,medicine ,Cardiology and Cardiovascular Medicine ,medicine.disease ,business ,Extracellular vesicles - Published
- 2017
31. Gingival fibroblasts protect against experimental abdominal aortic aneurysm development and rupture through tissue inhibitor of metalloproteinase-1 production
- Author
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José Vilar, Ziad Mallat, Lynda Zeboudj, Bruno Esposito, Stephane Potteaux, Alain Tedgui, Sylvie Seguier, Antoine Lafont, Marie Vandestienne, Andreas Giraud, Johannes Kluwe, Jérémie Joffre, Hafid Ait-Oufella, and Daniela Cabuzu
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Pathology ,Physiology ,Aortic Rupture ,Gingiva ,030204 cardiovascular system & hematology ,Protective Agents ,03 medical and health sciences ,Aortic aneurysm ,0302 clinical medicine ,Aneurysm ,Transforming Growth Factor beta ,Physiology (medical) ,Adventitia ,Internal medicine ,medicine.artery ,medicine ,Animals ,cardiovascular diseases ,Aorta, Abdominal ,Aortic rupture ,Aortic dissection ,Mice, Knockout ,Tissue Inhibitor of Metalloproteinase-1 ,business.industry ,Angiotensin II ,Abdominal aorta ,Fibroblasts ,medicine.disease ,Abdominal aortic aneurysm ,Extracellular Matrix ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,cardiovascular system ,Cardiology ,Cardiology and Cardiovascular Medicine ,business ,Aortic Aneurysm, Abdominal - Abstract
Aims Abdominal aortic aneurysm (AAA), frequently diagnosed in old patients, is characterized by chronic inflammation, vascular cell apoptosis and metalloproteinase-mediated extracellular matrix destruction. Despite improvement in the understanding of the pathophysiology of aortic aneurysm, no pharmacological treatment is yet available to limit dilatation and/or rupture. We previously reported that human gingival fibroblasts (GFs) can reduce carotid artery dilatation in a rabbit model of elastase-induced aneurysm. Here, we sought to investigate the mechanisms of GF-mediated vascular protection in two different models of aortic aneurysm growth and rupture in mice. Methods and results In vitro, mouse GFs proliferated and produced large amounts of anti-inflammatory cytokines and tissue inhibitor of metalloproteinase-1 (Timp-1). GFs deposited on the adventitia of abdominal aorta survived, proliferated, and organized as a layer structure. Furthermore, GFs locally produced Il-10, TGF-β, and Timp-1. In a mouse elastase-induced AAA model, GFs prevented both macrophage and lymphocyte accumulations, matrix degradation, and aneurysm growth. In an Angiotensin II/anti-TGF-β model of aneurysm rupture, GF cell-based treatment limited the extent of aortic dissection, prevented abdominal aortic rupture, and increased survival. Specific deletion of Timp-1 in GFs abolished the beneficial effect of cell therapy in both AAA mouse models. Conclusions GF cell-based therapy is a promising approach to inhibit aneurysm progression and rupture through local production of Timp-1.
- Published
- 2017
32. HIF-Prolyl Hydroxylase 2 Inhibition Enhances the Efficiency of Mesenchymal Stem Cell-Based Therapies for the Treatment of Critical Limb Ischemia
- Author
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Kiave-Yune, HoWangYin, Céline, Loinard, Wineke, Bakker, Coralie L, Guérin, José, Vilar, Clément, d'Audigier, Clément, D'Audigier, Laetitia, Mauge, Patrick, Bruneval, Joseph, Emmerich, Bernard I, Lévy, Jacques, Pouysségur, David M, Smadja, Jean-Sébastien, Silvestre, Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut de Radioprotection et de Sûreté Nucléaire (IRSN/PRP-HOM/SRBE), Institut de Radioprotection et de Sûreté Nucléaire (IRSN), Risque Thrombotique et Mecanismes de l'Hemostase (U765), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), University of Nice, and AstraZeneca
- Subjects
Male ,Cell Transplantation ,Angiogenesis ,[SDV]Life Sciences [q-bio] ,medicine.medical_treatment ,Ischemia ,Mice, Nude ,Apoptosis ,030204 cardiovascular system & hematology ,Biology ,Transfection ,Hypoxia-Inducible Factor-Proline Dioxygenases ,Neovascularization ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,medicine ,Animals ,Humans ,Gene silencing ,Aged ,030304 developmental biology ,0303 health sciences ,Growth factor ,Endovascular Procedures ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Prolyl-Hydroxylase Inhibitors ,Cell Biology ,Middle Aged ,Limb Salvage ,medicine.disease ,Hindlimb ,Mice, Inbred C57BL ,Disease Models, Animal ,Case-Control Studies ,Cancer research ,Molecular Medicine ,medicine.symptom ,Developmental Biology - Abstract
Upregulation of hypoxia-inducible transcription factor-1α (HIF-1α), through prolyl-hydroxylase domain protein (PHD) inhibition, can be thought of as a master switch that coordinates the expression of a wide repertoire of genes involved in regulating vascular growth and remodeling. We aimed to unravel the effect of specific PHD2 isoform silencing in cell-based strategies designed to promote therapeutic revascularization in patients with critical limb ischemia (CLI). PHD2 mRNA levels were upregulated whereas that of HIF-1α were downregulated in blood cells from patients with CLI. We therefore assessed the putative beneficial effects of PHD2 silencing on human bone marrow-derived mesenchymal stem cells (hBM-MSC)-based therapy. PHD2 silencing enhanced hBM-MSC therapeutic effect in an experimental model of CLI in Nude mice, through an upregulation of HIF-1α and its target gene, VEGF-A. In addition, PHD2-transfected hBM-MSC displayed higher protection against apoptosis in vitro and increased rate of survival in the ischemic tissue, as assessed by Fluorescence Molecular Tomography. Cotransfection with HIF-1α or VEGF-A short interfering RNAs fully abrogated the beneficial effect of PHD2 silencing on the proangiogenic capacity of hBM-MSC. We finally investigated the effect of PHD2 inhibition on the revascularization potential of ischemic targeted tissues in the diabetic pathological context. Inhibition of PHD-2 with shRNAs increased postischemic neovascularization in diabetic mice with CLI. This increase was associated with an upregulation of proangiogenic and proarteriogenic factors and was blunted by concomitant silencing of HIF-1α. In conclusion, silencing of PHD2, by the transient upregulation of HIF-1α and its target gene VEGF-A, might improve the efficiency of hBM-MSC-based therapies. Stem Cells 2014;32:231–243
- Published
- 2014
33. 2Path: A terpenoid metabolic network modeled as graph database
- Author
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Maristela Holanda, Waldeyr Mendes Cordeiro da Silva, Maria Emilia M. T. Walter, Danilo José Vilar, Marcelo M. Brigido, and Daniel da S. Souza
- Subjects
0301 basic medicine ,Biological data ,Graph database ,Systems biology ,Metabolic network ,Computational biology ,Biology ,NoSQL ,computer.software_genre ,Data modeling ,03 medical and health sciences ,Metabolic pathway ,030104 developmental biology ,Biochemistry ,Scalability ,computer - Abstract
Terpenoids are involved in interactions as signaling for communication intra/inter species, signal molecules to attract pollinating insects, and defense against herbivores and microbes. Due to their chemical composition, many terpenoids possess vast pharmacological applicability in medicine and biotechnology, besides important roles in ecology, industry and commerce. The biosynthesis of terpenes has been widely studied over the years, and it is well known that they can be synthesized from two metabolic pathways: mevalonate pathway (MVA) and non-mevalonate pathway (MEP). On the other hand, genome-scale reconstruction of metabolic networks faces many challenges, including organizational data storage and data modeling, to properly represent the complexity of systems biology. Recent NoSQL database paradigms have introduced new concepts of scalable storage and data queries. Among them graph databases, which are versatile enough to cope with biological data. In this paper, we propose 2Path, a graph database model designed to represent terpenoid metabolic networks, with thousands of secondary metabolism reactions, such that it preserves important terpenoid biosynthesis characteristics.
- Published
- 2016
34. CXCL12γ isoform inhibits adverse left ventricular remodeling after acute myocardial infarction
- Author
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Mathilde Lemitre, Jean-Sébastien Silvestre, V Duval, A Levoye, Yanyi Sun, José Vilar, Ivana Zlatanova, Paul Alayrac, and Cristina Pinto
- Subjects
Gene isoform ,Cardiac function curve ,medicine.medical_specialty ,business.industry ,Inflammation ,Gene mutation ,medicine.disease ,Endocrinology ,Arteriole ,Internal medicine ,medicine.artery ,medicine ,Myocardial infarction ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Ventricular remodeling ,business ,Receptor - Abstract
Introduction The chemokine CXCL12 is essential for cardiovascular system development and plays a major role in physio-pathological processes such as inflammation, angiogenesis but also tissue remodeling after an ischemic insult. In addition to the binding to its receptors, CXCR4 and CXCR7, CXCL12 interaction with heparan-sulfates (HS) commands its biological activity. Studies in experimental models of myocardial infarction (MI) revealed a protective role for CXCL12α. However, in mice, three CXCL12 isoforms (α, β and γ) have been identified and the CXCL12γ isoform shows an unchallenged ability to cooperate with HS, suggesting a pivotal role in tissue repair. Objective The aim of the study is to analyze the role of CXCL12γ isoform and the importance of CXCL12/HS interactions in post-ischemic cardiac remodeling in an acute model of MI. Method MI are induced in mice carrying a Cxcl12 gene mutation that precludes interactions with HS (Cxcl12Gagtm) and in Cxcl12γ knock-in animals (Cxcl12γ-KI), harboring CXCL12γ deficiency. Alternatively, the impact of CXCL12γ overexpression is also evaluated in wild-type (WT) mice receiving transcutaneous echo-guided injections of adenovirus encoding Cxcl12γ in cardiac tissue. Cardiac function and remodeling have been assessed through echocardiography analysis and evaluation of infarct size, interstitial fibrosis, capillary and arteriole densities and as well as inflammatory cell infiltration. Results After MI, Cxcl12Gagtm and Cxcl12γ-KI animals exhibit reduction in cardiac function and adverse left ventricular remodeling when compared to their respective WT littermates. Interestingly, overexpression of CXCL12γ in WT mice normalizes cardiac function by reducing the size of the infarcted area, interstitial fibrosis and promoting vascular growth. Conclusion We show that CXCL12γ isoform plays an important role in the regulation of cardiac function after MI and that its interactions with HS seems essential for adequate cardiac repair.
- Published
- 2019
35. Evaluation of Rat Heart Microvasculature with High-Spatial-Resolution Susceptibility-weighted MR Imaging
- Author
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Etienne Audureau, E. Blondiaux, Laetitia Pidial, Alain Bel, Olivier Clément, Patrick Bruneval, Gwennhael Autret, Daniel Balvay, Jean-Sébastien Silvestre, Charles-André Cuénod, and José Vilar
- Subjects
medicine.medical_specialty ,business.industry ,Microcirculation ,Reproducibility of Results ,Rat heart ,Image Enhancement ,Coronary Vessels ,Sensitivity and Specificity ,Mr imaging ,Rats ,Contrast medium ,Image Interpretation, Computer-Assisted ,Microvessels ,High spatial resolution ,Animals ,Medicine ,Female ,Radiology, Nuclear Medicine and imaging ,Radiology ,Rats, Wistar ,business ,Algorithms ,Magnetic Resonance Angiography - Abstract
To demonstrate that strandlike hypointense signals seen in the myocardium of normal rat hearts correspond to myocardial microvessels with high-spatial-resolution susceptibility-weighted (SW) magnetic resonance (MR) imaging without injection of contrast medium.Animal experiments were performed with institutional animal care committee approval. Ex vivo cardiac MR imaging was performed in 10 normal Wistar rats with a 4.7-T imager and a cryogenic probe. The hypothesis that thin tubular hypointense signals in the myocardium of rat hearts at SW MR imaging sequences (group 1, n = 6; in-plane resolution, 39 μm) represent intramyocardial microvessels was tested. A superparamagnetic intravascular contrast agent (ferumoxsil; Lumirem) was used to explore the distribution of the intramyocardial microvessels (group 2, n = 4; three-dimensional fast imaging with steady-state free precession sequences). Nonparametric Mann-Whitney tests were performed to compare groups 1 and 2 both for microvascular densities (MVD) on histologic sections and for MR imaging signal intensities (SIs). Wilcoxon signed rank tests were used for paired comparison of subepicardial and subendocardial MVD and SI within groups.Ferumoxsil opacified the coronary microvasculature (group 2) on MR-matched histologic sections. No statistically significant difference was found between groups 1 and 2 for either MVD or MR imaging SI expressed as ratios between subendocardium and subepicardium (P = .40 and P = .46, respectively). The comparison of mean subendocardial and subepicardial SI within groups revealed significantly more microvessels in the subepicardium with MR (group 1: P = .01; group 2: P = .004).Myocardial microvessels appear as strandlike structures on high-spatial-resolution SW MR images without the aid of contrast medium injection.
- Published
- 2013
36. VEGA, Jesusa, Pasado y tradición. La construcción visual del imaginario español en el siglo XIX, Madrid, Ediciones Polifemo, 2016, 192 pp
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María José Vilar
- Subjects
History ,lcsh:History (General) and history of Europe ,lcsh:D ,Tradición ,España ,Siglo XIX ,Nación ,Identidad - Published
- 2016
37. The Chemokine Decoy Receptor D6 Prevents Excessive Inflammation and Adverse Ventricular Remodeling After Myocardial Infarction
- Author
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Edouard Dumeau, Yasmine Zouggari, Lucie Poupel, Gilles Renault, Adèle Richart, José Vilar, Christophe Combadière, Clément Cochain, Jean-Sébastien Silvestre, Philippe Bonnin, A. Récalde, Constance Auvynet, Raffaella Bonecchi, Patrick Bruneval, Massimo Locati, Bernard I. Levy, Carmen Marchiol, and Kiave Yune Ho Wang Yin
- Subjects
Chemokine ,Pathology ,Neutrophils ,Myocardial Infarction ,Infarction ,Monocytes ,Ventricular Function, Left ,Mice ,Antigens, Ly ,Myocardial infarction ,Receptor ,Chemokine CCL2 ,Bone Marrow Transplantation ,Chemokine CCL3 ,Ultrasonography ,Mice, Knockout ,Ejection fraction ,Ventricular Remodeling ,biology ,Chemotaxis ,Phenotype ,Matrix Metalloproteinase 9 ,Neutrophil Infiltration ,Matrix Metalloproteinase 2 ,Hypertrophy, Left Ventricular ,Receptors, Chemokine ,Inflammation Mediators ,medicine.symptom ,Signal transduction ,Cardiology and Cardiovascular Medicine ,Signal Transduction ,medicine.medical_specialty ,Genotype ,Receptors, CCR2 ,Inflammation ,Receptors, CCR10 ,Internal medicine ,medicine ,Animals ,Humans ,Ventricular remodeling ,Heart Rupture, Post-Infarction ,business.industry ,Myocardium ,Stroke Volume ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,biology.protein ,business - Abstract
Objective— Leukocyte infiltration in ischemic areas is a hallmark of myocardial infarction, and overwhelming infiltration of innate immune cells has been shown to promote adverse remodeling and cardiac rupture. Recruitment of inflammatory cells in the ischemic heart depends highly on the family of CC-chemokines and their receptors. Here, we hypothesized that the chemokine decoy receptor D6, which specifically binds and scavenges inflammatory CC-chemokines, might limit inflammation and adverse cardiac remodeling after infarction. Methods and Results— D6 was expressed in human and murine infarcted myocardium. In a murine model of myocardial infarction, D6 deficiency led to increased chemokine (C-C motif) ligand 2 and chemokine (C-C motif) ligand 3 levels in the ischemic heart. D6-deficient (D6 −/−) infarcts displayed increased infiltration of pathogenic neutrophils and Ly6Chi monocytes, associated with strong matrix metalloproteinase-9 and matrix metalloproteinase-2 activities in the ischemic heart. D6 −/− mice were cardiac rupture prone after myocardial infarction, and functional analysis revealed that D6 −/− hearts had features of adverse remodeling with left ventricle dilation and reduced ejection fraction. Bone marrow chimera experiments showed that leukocyte-borne D6 had no role in this setting, and that leukocyte-specific chemokine (C-C motif) receptor 2 deficiency rescued the adverse phenotype observed in D6 −/− mice. Conclusion— We show for the first time that the chemokine decoy receptor D6 limits CC-chemokine–dependent pathogenic inflammation and is required for adequate cardiac remodeling after myocardial infarction.
- Published
- 2012
38. Acetazolamide and chronic hypoxia: effects on haemorheology and pulmonary haemodynamics
- Author
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Dominique Marchant, Fabrice Favret, Julien Brunet, José Vilar, Maxime Maignan, Bernard I. Levy, Patricia Quidu, Florence Cymbalista, Philippe Connes, Innocent Safeukui, Jean-Paul Richalet, and Aurélien Pichon
- Subjects
Male ,Pulmonary and Respiratory Medicine ,Pulmonary Circulation ,Cardiac output ,Hypertension, Pulmonary ,Blood viscosity ,Hemodynamics ,Altitude Sickness ,medicine ,Animals ,Rats, Wistar ,Carbonic Anhydrase Inhibitors ,Hypoxia ,Lung ,Blood Volume ,business.industry ,Heart ,Hydrogen-Ion Concentration ,Hypoxia (medical) ,Blood Viscosity ,medicine.disease ,Pulmonary hypertension ,Rats ,Acetazolamide ,medicine.anatomical_structure ,Hematocrit ,Anesthesia ,Chronic Disease ,Hemorheology ,Vascular resistance ,Stress, Mechanical ,medicine.symptom ,business ,medicine.drug - Abstract
We tested the effect of acetazolamide on blood mechanical properties and pulmonary vascular resistance (PVR) during chronic hypoxia. Six groups of rats were either treated or not treated with acetazolamide (curative: treated after 10 days of hypoxic exposure; preventive: treated before hypoxic exposure with 40 mg · kg(-1) · day(-1)) and either exposed or not exposed to 3 weeks of hypoxia (at altitude5,500 m). They were then used to assess the role of acetazolamide on pulmonary artery pressure, cardiac output, blood volume, haematological and haemorheological parameters. Chronic hypoxia increased haematocrit, blood viscosity and PVR, and decreased cardiac output. Acetazolamide treatment in hypoxic rats decreased haematocrit (curative by -10% and preventive by -11%), PVR (curative by -36% and preventive by -49%) and right ventricular hypertrophy (preventive -20%), and increased cardiac output (curative by +60% and preventive by +115%). Blood viscosity was significantly decreased after curative acetazolamide treatment (-16%) and was correlated with PVR (r=0.87, p0.05), suggesting that blood viscosity could influence pulmonary haemodynamics. The fall in pulmonary vascular hindrance (curative by -27% and preventive by -45%) after treatment suggests that acetazolamide could decrease pulmonary vessels remodelling under chronic hypoxia. The effect of acetazolamide is multifactorial by acting on erythropoiesis, pulmonary circulation, haemorheological properties and cardiac output, and could represent a pertinent treatment of chronic mountain sickness.
- Published
- 2012
39. Sympathetic Nervous System Regulates Bone Marrow–Derived Cell Egress Through Endothelial Nitric Oxide Synthase Activation
- Author
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Adèle Richart, Odile Varoquaux, Bernard I. Levy, Yasmine Zouggari, Alice Recalde, Jean-Sébastien Silvestre, Kiave Yune Ho Wang Yin, Isabelle Drouet, José Vilar, Coralie L. Guerin, and Clément Cochain
- Subjects
Sympathetic nervous system ,Sympathetic Nervous System ,Time Factors ,Angiogenesis ,Dopamine ,Mice ,Norepinephrine ,chemistry.chemical_compound ,Bone Marrow ,Cell Movement ,Ischemia ,Medicine ,Enzyme Inhibitors ,Cells, Cultured ,Bone Marrow Transplantation ,Mice, Knockout ,biology ,Cell Differentiation ,Hindlimb ,Up-Regulation ,Femoral Artery ,Endothelial stem cell ,Nitric oxide synthase ,medicine.anatomical_structure ,Dopamine Agonists ,Cardiology and Cardiovascular Medicine ,Signal Transduction ,medicine.medical_specialty ,Stromal cell ,Nitric Oxide Synthase Type III ,Tyrosine 3-Monooxygenase ,Green Fluorescent Proteins ,Neovascularization, Physiologic ,Bone Marrow Cells ,Mice, Transgenic ,Nitric oxide ,Arteriole ,medicine.artery ,Internal medicine ,Animals ,RNA, Messenger ,Muscle, Skeletal ,Adrenergic beta-2 Receptor Agonists ,Ligation ,Tyrosine hydroxylase ,business.industry ,Endothelial Cells ,Enzyme Activation ,Mice, Inbred C57BL ,Disease Models, Animal ,Endocrinology ,chemistry ,biology.protein ,Stromal Cells ,business - Abstract
Objective— Catecholamines have been shown to control bone marrow (BM)–derived cell egress, yet the cellular and molecular mechanisms involved in this effect and their subsequent participation to postischemic vessel growth are poorly understood. Methods and Results— Tyrosine hydroxylase mRNA levels, as well as dopamine (DA) and norepinephrine (NE) contents, were increased in the ischemic BM of mice with right femoral artery ligation. Angiographic score, capillary density, and arteriole number were markedly increased by treatments with DA (IP, 50 mg/kg, 5 days) or NE (IP, 2.5 mg/kg, 5 days). Using chimeric mice lethally irradiated and transplanted with BM-derived cells from green fluorescent protein mice, we showed that DA and NE enhanced by 70% ( P P N ω -nitro- l -arginine methyl ester. DA and NE also upregulated the number of CD45-positive cells in blood 3 days after ischemia and that of macrophages in ischemic tissue 21 days after ischemia. Of interest, DA and NE increased BM endothelial nitric oxide synthase (eNOS) mRNA levels and were unable to promote BM-derived cell mobilization in chimeric eNOS-deficient mice lethally irradiated and transplanted with BM-derived cells from wild-type animals. Furthermore, administration of a β2 adrenergic agonist (clenbuterol, IP, 2 mg/kg, 5 days) and that of a dopaminergic D1/D5 receptor agonist (SKF-38393, IP, 2.5 mg/kg, 5 days) also enhanced BM-derived cell mobilization and subsequently postischemic vessel growth. Conclusion— These results unravel, for the first time, a major role for the sympathetic nervous system in BM-derived cell egress through stromal eNOS activation.
- Published
- 2012
40. C/EBP Homologous Protein-10 (CHOP-10) Limits Postnatal Neovascularization Through Control of Endothelial Nitric Oxide Synthase Gene Expression
- Author
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Bhama Ramkhelawon, Adèle Richart, Patricia Rueda, Micheline Duriez, Yasmine Zouggari, Christophe Heymes, Céline Loinard, Fernando Arenzana-Seisdedos, Masataka Mori, Dominique Charue, Jean-Sébastien Silvestre, José Vilar, A. Récalde, Bernard I. Levy, and Clément Cochain
- Subjects
Transcriptional Activation ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,genetic structures ,Angiogenesis ,CHOP ,Gene Expression Regulation, Enzymologic ,Diabetes Mellitus, Experimental ,Neovascularization ,Mice ,Vasculogenesis ,hemic and lymphatic diseases ,Physiology (medical) ,Internal medicine ,Gene expression ,medicine ,Animals ,Humans ,Nuclear protein ,Cells, Cultured ,Mice, Knockout ,Neovascularization, Pathologic ,biology ,eye diseases ,Up-Regulation ,Cell biology ,Femoral Artery ,Mice, Inbred C57BL ,Nitric oxide synthase ,Endocrinology ,Animals, Newborn ,biology.protein ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Transcription Factor CHOP ,Protein C ,Protein Binding ,medicine.drug - Abstract
Background— C/EBP homologous protein-10 (CHOP-10) is a novel developmentally regulated nuclear protein that emerges as a critical transcriptional integrator among pathways regulating differentiation, proliferation, and survival. In the present study, we analyzed the role of CHOP-10 in postnatal neovascularization. Methods and Results— Ischemia was induced by right femoral artery ligation in wild-type and CHOP-10 −/− mice. In capillary structure of skeletal muscle, CHOP-10 mRNA and protein levels were upregulated by ischemia and diabetes mellitus. Angiographic score, capillary density, and foot perfusion were increased in CHOP-10 −/− mice compared with wild-type mice. This effect was associated with a reduction in apoptosis and an upregulation of endothelial nitric oxide synthase (eNOS) levels in ischemic legs of CHOP-10 −/− mice compared with wild-type mice. In agreement with these results, eNOS mRNA and protein levels were significantly upregulated in CHOP-10 short interfering RNA–transfected human endothelial cells, whereas overexpression of CHOP-10 inhibited basal transcriptional activation of the eNOS promoter. Using a chromatin immunoprecipitation assay, we also showed that CHOP-10 was bound to the eNOS promoter. Interestingly, enhanced postischemic neovascularization in CHOP-10 −/− mice was fully blunted in CHOP-10/eNOS double-knockout animals. Finally, we showed that induction of diabetes mellitus is associated with a marked upregulation of CHOP-10 that substantially inhibited postischemic neovascularization. Conclusions— This study identifies CHOP-10 as an important transcription factor modulating vessel formation and maturation.
- Published
- 2012
41. The Fate of Patients with Solitary Pulmonary Nodules: Clinical Management and Radiation Exposure Associated
- Author
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Ildefonso Hernández-Aguado, Isabel González-Álvarez, José Vilar, Noemi Gómez-Sáez, María Fermina Lorente, Maria Luisa Domingo, Blanca Lumbreras, and Maria Pastor-Valero
- Subjects
Thorax ,Male ,Lung Neoplasms ,Pulmonology ,lcsh:Medicine ,Medical care ,Lung and Intrathoracic Tumors ,030218 nuclear medicine & medical imaging ,Diagnostic Radiology ,0302 clinical medicine ,Medicine and Health Sciences ,lcsh:Science ,Lung ,Tomography ,Multidisciplinary ,Radiology and Imaging ,Radiation Exposure ,Clinical Practice ,Professions ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Female ,Radiology ,Research Article ,Adult ,medicine.medical_specialty ,Imaging Techniques ,Neuroimaging ,Surgical and Invasive Medical Procedures ,Research and Analysis Methods ,03 medical and health sciences ,Diagnostic Medicine ,Internal medicine ,Radiologists ,medicine ,Cancer Detection and Diagnosis ,Humans ,Solitary pulmonary nodule ,business.industry ,lcsh:R ,Solitary Pulmonary Nodule ,Cancers and Neoplasms ,Biology and Life Sciences ,medicine.disease ,Computed Axial Tomography ,Radiation exposure ,Tomography x ray computed ,Positron-Emission Tomography ,People and Places ,lcsh:Q ,Population Groupings ,business ,Tomography, X-Ray Computed ,Neuroscience - Abstract
Background The appropriate management of the large number of lung nodules detected during the course of routine medical care presents a challenge. We aimed to evaluate the usual clinical practice in solitary pulmonary nodule (SPN) management and associated radiation exposure. Methods We examined 893 radiology reports of consecutive patients undergoing chest computed tomography (CT) and radiography at two public hospitals in Spain. Information on diagnostic procedures from SPN detection and lung cancer diagnosis was collected prospectively for 18 months. Results More than 20% of patients with SPN detected on either chest radiograph (19.8%) or CT (26.1%) underwent no additional interventions and none developed lung cancer (100% negative predictive value). 346 (72.0%) patients with SPN detected on chest radiograph and 254 (61.5%) patients with SPN detected on CT had additional diagnostic tests and were not diagnosed with lung cancer. In patients undergoing follow-up imaging for SPNs detected on CT median number of additional imaging tests was 3.5 and the mean cumulative effective dose was 24.4 mSv; for those detected on chest radiograph the median number of additional imaging tests was 2.8 and the mean cumulative effective dose was 10.3 mSv. Conclusions Patients who did not have additional interventions were not diagnosed of lung cancer. There was an excessive amount of interventions in a high percentage of patients presenting SPN, which was associated with an excess of radiation exposure.
- Published
- 2015
42. B cell depletion reduces the development of atherosclerosis in mice
- Author
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Ziad Mallat, Jérôme Sirvent, Soraya Taleb, Ludivine Laurans, Thomas F. Tedder, Jean-David Bouaziz, Bruno Esposito, Catherine Uyttenhove, José Vilar, Olivier Herbin, Alain Tedgui, Hafid Ait-Oufella, Emily A. Van Vré, Jacques Van Snick, Christoph J. Binder, and UCL
- Subjects
Male ,T-Lymphocytes ,T cell ,Immunology ,030204 cardiovascular system & hematology ,Lymphocyte Activation ,Lymphocyte Depletion ,Immunoglobulin G ,Interferon-gamma ,Mice ,03 medical and health sciences ,Apolipoproteins E ,0302 clinical medicine ,medicine ,Animals ,Immunology and Allergy ,Secretion ,Receptor ,B cell ,Cell Proliferation ,030304 developmental biology ,Mice, Knockout ,B-Lymphocytes ,0303 health sciences ,biology ,Cell growth ,Interleukin-17 ,Brief Definitive Report ,Antibodies, Monoclonal ,Dendritic Cells ,Sinus of Valsalva ,Antigens, CD20 ,Atherosclerosis ,3. Good health ,Lipoproteins, LDL ,Mice, Inbred C57BL ,Cholesterol ,medicine.anatomical_structure ,Immunoglobulin M ,Receptors, LDL ,biology.protein ,Antibody - Abstract
B cell depletion significantly reduces the burden of several immune-mediated diseases. However, B cell activation has been until now associated with a protection against atherosclerosis, suggesting that B cell–depleting therapies would enhance cardiovascular risk. We unexpectedly show that mature B cell depletion using a CD20-specific monoclonal antibody induces a significant reduction of atherosclerosis in various mouse models of the disease. This treatment preserves the production of natural and potentially protective anti–oxidized low-density lipoprotein (oxLDL) IgM autoantibodies over IgG type anti-oxLDL antibodies, and markedly reduces pathogenic T cell activation. B cell depletion diminished T cell–derived IFN-γ secretion and enhanced production of IL-17; neutralization of the latter abrogated CD20 antibody–mediated atheroprotection. These results challenge the current paradigm that B cell activation plays an overall protective role in atherogenesis and identify new antiatherogenic strategies based on B cell modulation.
- Published
- 2010
43. Angiotensinogen Delays Angiogenesis and Tumor Growth of Hepatocarcinoma in Transgenic Mice
- Author
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Philippe Bonnin, Evelyne Dupuy, Noël Lamandé, Jean-Marie Gasc, Patricia Hainaud, François Vincent, Maud Clemessy, Pierre Corvol, José Vilar, Gérard Tobelem, Jean-Olivier Contreres, Homéostasie Cellulaire et Pathologies (HCP), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Service d'Explorations Fonctionnelles Physiologiques [CHU Limoges], CHU Limoges, Université de Limoges (UNILIM), Pathologie vasculaire et endocrinologie rénale - Chaire de médecine expérimentale (INSERM U36), and Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Male ,Cancer Research ,Angiogenesis ,Angiotensinogen ,Metastasis ,Neovascularization ,Mice ,MESH: Liver Neoplasms, Experimental ,Liver Neoplasms, Experimental ,0302 clinical medicine ,MESH: Animals ,Receptor, Notch4 ,0303 health sciences ,Neovascularization, Pathologic ,Receptors, Notch ,Intracellular Signaling Peptides and Proteins ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,3. Good health ,Liver ,Oncology ,030220 oncology & carcinogenesis ,MESH: Cell Growth Processes ,Female ,MESH: Membrane Proteins ,medicine.symptom ,hormones, hormone substitutes, and hormone antagonists ,Genetically modified mouse ,medicine.medical_specialty ,MESH: Mice, Transgenic ,Transgene ,MESH: Angiotensinogen ,Ephrin-B2 ,Mice, Transgenic ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Cell Growth Processes ,Biology ,03 medical and health sciences ,MESH: Mice, Inbred C57BL ,In vivo ,Proto-Oncogene Proteins ,MESH: Intracellular Signaling Peptides and Proteins ,Internal medicine ,Renin–angiotensin system ,medicine ,Animals ,Humans ,RNA, Messenger ,MESH: Mice ,Adaptor Proteins, Signal Transducing ,MESH: RNA, Messenger ,030304 developmental biology ,MESH: Ephrin-B2 ,MESH: Humans ,Calcium-Binding Proteins ,Membrane Proteins ,medicine.disease ,MESH: Male ,Mice, Inbred C57BL ,MESH: Proto-Oncogene Proteins ,Endocrinology ,Tumor progression ,MESH: Neovascularization, Pathologic ,MESH: Receptors, Notch ,MESH: Female ,MESH: Liver - Abstract
Angiotensinogen, a member of the serpin family, is involved in the suppression of tumor growth and metastasis. To investigate whether human angiotensinogen protects against tumor progression in vivo, we established an original bitransgenic model in which transgenic mice expressing human angiotensinogen (Hu-AGT-TG mice) were crossed with a transgenic mouse model of hepatocellular carcinoma (HCC-TG mice). Bitransgenic mice overexpressing human angiotensinogen (HCC/Hu-AGT-TG) had a significantly longer survival time than the HCC-TG mice and a reduction of both tumor growth and blood flow velocities in the liver. This antitumor effect of angiotensinogen is related to a reduced angiogenesis, impaired expression of endothelial arterial markers (active Notch4, Delta-like 4 ligand, and ephrin B2) with a decrease of arterial vessel density in HCC/Hu-AGT-TG mice liver. Overexpression of human angiotensinogen decreases angiogenesis, and prevents tumor sinusoids from remodeling and arterialization, thus delaying tumor progression in vivo. [Cancer Res 2009;69(7):2853–60]
- Published
- 2009
44. Chronic Hypoxia–Induced Angiogenesis Normalizes Blood Pressure in Spontaneously Hypertensive Rats
- Author
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Jean-Sébastien Silvestre, Micheline Duriez, Clément Cochain, Philippe Bonnin, Bernard I. Levy, Céline Loinard, José Vilar, and Ludovic Waeckel
- Subjects
Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Time Factors ,Physiology ,Angiogenesis ,Neovascularization, Physiologic ,Hemodynamics ,Blood Pressure ,Rats, Inbred WKY ,Prehypertension ,Rats, Inbred SHR ,Internal medicine ,medicine ,Animals ,cardiovascular diseases ,Cardiac Output ,Hypoxia ,Muscle, Skeletal ,business.industry ,Heart ,Hypoxia (medical) ,Chronic hypoxia ,Rats ,medicine.anatomical_structure ,Endocrinology ,Blood pressure ,Chronic Disease ,Hypertension ,Circulatory system ,Vascular resistance ,Vascular Resistance ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
We hypothesized that activation of angiogenesis by chronic hypoxia may affect vascular resistance and, subsequently, blood pressure levels in spontaneously hypertensive rats (SHRs). Five-week-old prehypertensive SHRs and age-matched normotensive Wistar–Kyoto (WKY) rats (n=8 per group) were maintained under normobaric normoxic or hypoxic (10% O 2 ) conditions for 8 weeks. Three weeks later, the systolic blood pressure was lower by 26% in hypoxic SHRs compared to normoxic SHRs ( P P P P P P
- Published
- 2008
45. Ex Vivo Priming of Endothelial Progenitor Cells With SDF-1 Before Transplantation Could Increase Their Proangiogenic Potential
- Author
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Faouzia Zemani, Arlette Bruel, Ivan Bièche, Jean-Sébastien Silvestre, Catherine Boisson-Vidal, José Vilar, Françoise Fauvel-Lafeve, Isabelle Galy-Fauroux, Anne Marie Fischer, and Ingrid Laurendeau
- Subjects
Receptors, CXCR4 ,Endothelium ,Angiogenesis ,Transplantation, Heterologous ,Mice, Nude ,Neovascularization, Physiologic ,In Vitro Techniques ,Biology ,Cell therapy ,Mice ,Ischemia ,medicine ,Animals ,Humans ,RNA, Messenger ,Progenitor cell ,Matrigel ,Cell adhesion molecule ,Stem Cells ,Endothelial Cells ,Cell migration ,Chemokine CXCL12 ,Hindlimb ,Cell biology ,Endothelial stem cell ,medicine.anatomical_structure ,Immunology ,cardiovascular system ,Cord Blood Stem Cell Transplantation ,Cardiology and Cardiovascular Medicine - Abstract
Objectives— As SDF-1 and its cognate receptor CXCR4 play a key role in the survival and mobilization of immature cells, we examined whether preconditioning of endothelial progenitor cells (EPCs) with SDF-1 could further promote their capacity to enhance angiogenesis. Methods and Results— EPC exposure to 100 ng/mL SDF-1 for 30 min induced a proangiogenic phenotype, with cell migration and differentiation into vascular cords in Matrigel and increased their therapeutic potential in a nude mouse model of hindlimb ischemia. This pretreatment enhanced EPC adhesion to activated endothelium in physiological conditions of blood flow by stimulating integrin-mediated EPCs binding to endothelial cells. Pretreated EPCs showed significantly upregulated surface α4 and αM integrin subunit expression involved in the homing of immature cells to a neovasculature and enhanced FGF-2 and promatrix metalloproteinase (MMP)-2 secretion. All these effects were significantly attenuated by EPC incubation with AMD-3100, a CXCR4 antagonist, by prior HSPGs disruption and by HUVEC incubation with anti–intercellular adhesion molecule1 (ICAM-1) and anti–vascular cell adhesion molecule (VCAM) blocking antibodies. Pretreated EPCs adhered very rapidly (within minutes) and were resistant to shear stresses of up to 2500s −1 . Conclusions— SDF-1 pretreatment during EPC expansion stimulates EPC adhesion to endothelial cells and thus augments the efficiency of cell therapy for ischemic vascular diseases.
- Published
- 2008
46. Role of human smooth muscle cell progenitors in atherosclerotic plaque development and composition
- Author
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José Vilar, Pierre Gourdy, Gérard Tobelem, Izolina Lopes-Kam, Aurélie S. Leroyer, Patrick Henry, Joffrey Zoll, Jean-François Arnal, Vincent Fontaine, Véronique Barateau, Ziad Mallat, and Alain Tedgui
- Subjects
Male ,Apolipoprotein E ,medicine.medical_specialty ,Endothelium ,Physiology ,Cell Separation ,Peripheral blood mononuclear cell ,Muscle, Smooth, Vascular ,Mice ,Apolipoproteins E ,Physiology (medical) ,Internal medicine ,Animals ,Humans ,Medicine ,Progenitor cell ,Cells, Cultured ,Aged ,business.industry ,Vascular disease ,Endothelial Cells ,Middle Aged ,Atherosclerosis ,Fetal Blood ,Hematopoietic Stem Cells ,medicine.disease ,Surgery ,DNA-Binding Proteins ,Atheroma ,medicine.anatomical_structure ,Endocrinology ,Circulatory system ,Disease Progression ,Female ,Cardiology and Cardiovascular Medicine ,business ,Blood vessel - Abstract
Aims We analysed the possible protective role of human endothelial (EPCs) and smooth muscle (SPCs) progenitor cells on atherosclerosis development in apoE−/−RAG2−/− mice. We determined plasma levels of SPCs in coronary patients. Methods and results ApoE−/−RAG2−/− mice received four intravenous injections of saline, 5 × 105 SPCs, or 5 × 105 EPCs every other week, one (preventive approach) or 12(curative approach) weeks after starting a high fat diet. Derived-SPC levels were quantified from blood mononuclear cells of patients with stable angina ( n = 10) and acute coronary syndromes (ACS, n = 9). SPCs reduced atherosclerosis development by 42% ( P < 0.001), but had no effect on lesion progression. In the SPC group, collagen and smooth muscle cell content were increased (+80%, P < 0.001, +46%, P < 0.05, respectively), and macrophage content was decreased (−41%, P < 0.05). In the curative approach, macrophage content decreased by 40.5% ( P < 0.05) after SPC injection. EPC injection had no effect on atherosclerosis development or progression. Peripheral blood-derived SPC levels were reduced in patients with ACS compared with stable angina patients ( P < 0.05). Conclusion We demonstrate that SPCs limit plaque development and promote changes in plaque composition towards a stable phenotype in mice. Our finding in patients suggests that reduced peripheral blood-derived SPC levels might represent a mechanism contributing to plaque destabilization.
- Published
- 2007
47. Effect of normovolemic hematocrit changes on blood pressure and flow
- Author
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Bernard I. Levy, José Vilar, and Philippe Bonnin
- Subjects
Male ,medicine.medical_specialty ,Blood viscosity ,030232 urology & nephrology ,Hemodynamics ,Blood Component Transfusion ,Blood Pressure ,030204 cardiovascular system & hematology ,Hematocrit ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Animals ,General Pharmacology, Toxicology and Pharmaceutics ,Rats, Wistar ,medicine.diagnostic_test ,business.industry ,Oxygen transport ,General Medicine ,medicine.disease ,Surgery ,Rats ,Blood pressure ,NG-Nitroarginine Methyl Ester ,Renal blood flow ,Blood Circulation ,Cardiology ,Hemoglobin ,business ,Kidney disease - Abstract
Aims In patients with chronic kidney disease (CKD), severe anemia is associated with increased cardiovascular risk. Although elevating hemoglobin (Hb) and hematocrit (Hct) levels with erythropoiesis-stimulating agents (ESA) improves patients' quality of life, normalization of Hb does not reduce cardiovascular risk and the reason remains unclear. Main methods We measured the effect of acute isovolumic changes in Hct from 37 ± 5 to 50 ± 2% (mean ± SD) on arterial blood pressure (BP), cardiac output (CO), and carotid and renal blood flow (BF), (1) in control rats and (2) after acute blockade of the nitric oxide (NO) pathway by l -NAME. Key findings 1) In control conditions, BP, CO and carotid and renal BF remained stable for Hct values between 38 ± 2 and 46 ± 1%; 2) for higher Hct values, BP rose together with increasing blood viscosity whereas CO and renal BF decreased; 3) during acute NO blockade, CO, and carotid and renal BF were significantly reduced and remained low whereas BP increased with Hct thus increasing blood viscosity. Our results suggest (1) the ceiling level of endothelium-mediated vasodilation for high values of blood viscosity under control conditions, and (2) the need for efficient endothelial function for vasomotor adaptation of hemodynamic resistances to blood viscosity. Significance (1) Clinical benefits of ESA in CKD patients with severe endothelial dysfunction are primarily due to increased oxygen transport and supply and, (2) normalization of Hct values in these patients may prove deleterious because of significant increases in BP and reductions in BF associated with high blood viscosity.
- Published
- 2015
48. Biomarkers of vascular dysfunction and cognitive decline in patients with Alzheimer's disease: no evidence for association in elderly subjects
- Author
-
Jacques Boddaert, Chantal M. Boulanger, Véronique Faucounau, José Vilar, Jean-Sébastien Silvestre, Marc Verny, Bénédicte Dieudonné, Christian Neri, Alice Breining, Centre de Gériatrie [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Biologie et Pathologie du Neurone (Brain-C), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), HAL-UPMC, Gestionnaire, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing ( B2A ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Biologie et Pathologie du Neurone ( Brain-C ), and Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC )
- Subjects
Oncology ,Male ,Aging ,medicine.medical_specialty ,Endothelial progenitors ,Endothelial progenitors cells ,Disease ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Alzheimer Disease ,Internal medicine ,Medicine ,Dementia ,Humans ,In patient ,Cognitive Dysfunction ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Prospective Studies ,Progenitor cell ,Cognitive decline ,Prospective cohort study ,Aged ,Aged, 80 and over ,business.industry ,Confounding ,Endothelial Cells ,medicine.disease ,[ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Immunology ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Female ,Endothelium, Vascular ,Geriatrics and Gerontology ,Alzheimer's disease ,Endothelial microparticles ,business ,030217 neurology & neurosurgery ,Biomarkers ,Circulating endothelial cells - Abstract
Background Several studies have suggested that vascular dysfunction plays an important role in Alzheimer’s disease. Aims We hypothesized that significant differences might be observed in the levels of blood endothelial biomarkers across elderly population of subjects with dementia. Methods We analyzed, in a prospective monocentric study, three different endothelial biomarkers, endothelial microparticles (EMPs), endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) in 132 older patients who underwent a full evaluation of a memory complaint. Results There was no difference in specific EMP, EPC or CEC levels between demented or non-demented patients, nor considering cognitive decline. Discussion Blood endothelial biomarkers may be too sensitive and it is likely that the multimorbidity observed in our patients may lead to opposite and confounding effects on endothelial biomarkers levels. Conclusion Unlike younger AD patients, our results suggest that endothelial biomarkers are not valuable for the diagnosis of dementia in elderly patients
- Published
- 2015
49. Update in the Diagnosis and Staging of Lung Cancer
- Author
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José Vilar and Jeremy J. Erasmus
- Subjects
Solitary pulmonary nodule ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Disease ,medicine.disease ,respiratory tract diseases ,Medicine ,National Lung Screening Trial ,Stage (cooking) ,business ,Lung cancer ,Intensive care medicine ,Developed country ,Pulmonologists - Abstract
Primary lung cancer is the leading cause of cancer mortality in the world and its incidence is expected to rise in the next several decades, especially in more recently industrialized countries such as China. This high mortality is largely explained by the fact that patients with lung cancer often present with advanced stage disease. Imaging is important in the early detection and clinical staging of lung cancer. Indeed both the therapeutic options and the management of patients with lung cancer are to a considerable degree dependent upon disease stage at presentation. Detailed knowlegde and the appropriate use of imaging in the staging evaluation of patients with non-small cell lung cancer (NSCLC) are required to avoid unnecessary procedures, excess radiation, and redundant information. This is facilitated by the use of guidelines as well as the participation of multidisciplinary teams in which radiologists, pathologists, pulmonologists, surgeons, and medical and radiation oncologists discuss and reach a consensus on individualized imaging and treatment. The main objective of this chapter is to review the basic concepts related to the detection, staging, and follow-up of patients with NSCLC.
- Published
- 2015
50. NADPH Oxidase-Derived Overproduction of Reactive Oxygen Species Impairs Postischemic Neovascularization in Mice with Type 1 Diabetes
- Author
-
Ludovic Waeckel, Bernard I. Levy, Jean-Sébastien Silvestre, Ralph P. Brandes, Olivier Blanc-Brude, Barend Mees, Dong You, Micheline Duriez, Téni G. Ebrahimian, Ajay M. Shah, José Vilar, and Christophe Heymes
- Subjects
Vascular Endothelial Growth Factor A ,medicine.medical_specialty ,Biology ,medicine.disease_cause ,Endothelial progenitor cell ,Monocytes ,Diabetes Mellitus, Experimental ,Pathology and Forensic Medicine ,Neovascularization ,Mice ,chemistry.chemical_compound ,Bone Marrow ,Ischemia ,Internal medicine ,medicine ,Animals ,Muscle, Skeletal ,NADPH oxidase ,Neovascularization, Pathologic ,Stem Cells ,Endothelial Cells ,NADPH Oxidases ,Cell Differentiation ,Rats ,Vascular endothelial growth factor ,Protein Subunits ,Vascular endothelial growth factor A ,Endocrinology ,Animals, Newborn ,chemistry ,NAD(P)H oxidase ,Apocynin ,biology.protein ,medicine.symptom ,Reactive Oxygen Species ,Oxidative stress ,Regular Articles - Abstract
We hypothesized that diabetes-induced oxidative stress may affect postischemic neovascularization. The response to unilateral femoral artery ligation was studied in wild-type or gp91(phox)-deficient control or type 1 diabetic mice or in animals treated with the anti-oxidant N-acetyl-l-cysteine (NAC) or with in vivo electrotransfer of a plasmid encoding dominant-negative Rac1 (50 microg) for 21 days. Postischemic neovascularization was reduced in diabetic mice in association with down-regulated vascular endothelial growth factor-A protein levels. In diabetic animals vascular endothelial growth factor levels and postischemic neovascularization were restored to nondiabetic levels by the scavenging of reactive oxygen species (ROS) by NAC administration or the inhibition of ROS generation by gp91(phox) deficiency or by administration of dominant-negative Rac1. Finally, diabetes reduced the ability of adherent bone marrow-derived mononuclear cells (BM-MNCs) to differentiate into endothelial progenitor cells. Treatment with NAC (3 mmol/L), apocynin (200 micromol/L), or the p38MAPK inhibitor LY333351 (10 micromol/L) up-regulated the number of endothelial progenitor cell colonies derived from diabetic BM-MNCs by 1.5-, 1.6-, and 1.5-fold, respectively (P < 0.05). In the ischemic hindlimb model, injection of diabetic BM-MNCs isolated from NAC-treated or gp91(phox)-deficient diabetic mice increased neovascularization by approximately 1.5-fold greater than untreated diabetic BM-MNCs (P < 0.05). Thus, inhibition of NADPH oxidase-derived ROS overproduction improves the angiogenic and vasculogenic processes and restores postischemic neovascularization in type 1 diabetic mice.
- Published
- 2006
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