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1. Harmonization of sensorimotor deficit assessment in a registered multicentre pre-clinical randomized controlled trial using two models of ischemic stroke

Author

Valente, A, Mariani, J, Seminara, S, Tettamanti, M, Pignataro, G, Perego, C, Sironi, L, Pedata, F, Amantea, D, Bacigaluppi, M, Vinciguerra, A, Diamanti, S, Vigano, M, Santangelo, F, Zoia, C, Rodriguez-Menendez, V, Castiglioni, L, Rzemieniec, J, Dettori, I, Bulli, I, Coppi, E, Di Santo, C, Cuomo, O, Gullotta, G, Butti, E, Bagetta, G, Martino, G, De Simoni, M, Ferrarese, C, Fumagalli, S, Beretta, S, Valente A., Mariani J., Seminara S., Tettamanti M., Pignataro G., Perego C., Sironi L., Pedata F., Amantea D., Bacigaluppi M., Vinciguerra A., Diamanti S., Vigano M., Santangelo F., Zoia C. P., Rodriguez-Menendez V., Castiglioni L., Rzemieniec J., Dettori I., Bulli I., Coppi E., Di Santo C., Cuomo O., Gullotta G. S., Butti E., Bagetta G., Martino G., De Simoni M. -G., Ferrarese C., Fumagalli S., Beretta S., Valente, A, Mariani, J, Seminara, S, Tettamanti, M, Pignataro, G, Perego, C, Sironi, L, Pedata, F, Amantea, D, Bacigaluppi, M, Vinciguerra, A, Diamanti, S, Vigano, M, Santangelo, F, Zoia, C, Rodriguez-Menendez, V, Castiglioni, L, Rzemieniec, J, Dettori, I, Bulli, I, Coppi, E, Di Santo, C, Cuomo, O, Gullotta, G, Butti, E, Bagetta, G, Martino, G, De Simoni, M, Ferrarese, C, Fumagalli, S, Beretta, S, Valente A., Mariani J., Seminara S., Tettamanti M., Pignataro G., Perego C., Sironi L., Pedata F., Amantea D., Bacigaluppi M., Vinciguerra A., Diamanti S., Vigano M., Santangelo F., Zoia C. P., Rodriguez-Menendez V., Castiglioni L., Rzemieniec J., Dettori I., Bulli I., Coppi E., Di Santo C., Cuomo O., Gullotta G. S., Butti E., Bagetta G., Martino G., De Simoni M. -G., Ferrarese C., Fumagalli S., and Beretta S.

Abstract

Multicentre preclinical randomized controlled trials (pRCTs) are a valuable tool to improve experimental stroke research, but are challenging and therefore underused. A common challenge regards the standardization of procedures across centres. We here present the harmonization phase for the quantification of sensorimotor deficits by composite neuroscore, which was the primary outcome of two multicentre pRCTs assessing remote ischemic conditioning in rodent models of ischemic stroke. Ischemic stroke was induced by middle cerebral artery occlusion for 30, 45 or 60 min in mice and 50, 75 or 100 min in rats, allowing sufficient variability. Eleven animals per species were video recorded during neurobehavioural tasks and evaluated with neuroscore by eight independent raters, remotely and blindly. We aimed at reaching an intraclass correlation coefficient (ICC) ≥0.60 as satisfactory interrater agreement. After a first remote training we obtained ICC = 0.50 for mice and ICC = 0.49 for rats. Errors were identified in animal handling and test execution. After a second remote training, we reached the target interrater agreement for mice (ICC = 0.64) and rats (ICC = 0.69). In conclusion, a multi-step, online harmonization phase proved to be feasible, easy to implement and highly effective to align each centre’s behavioral evaluations before project’s interventional phase.

Published
2023

4. Harmonization of sensorimotor deficit assessment in a registered multicentre pre-clinical randomized controlled trial using two models of ischemic stroke

Author

Valente, A., Mariani, J., Seminara, S., Tettamanti, M., Pignataro, G., Perego, C., Sironi, L., Pedata, F., Amantea, D., Bacigaluppi, M., Vinciguerra, A., Diamanti, S., Vigano, M., Santangelo, F., Zoia, C.P., Rodriguez-Menendez, V., Castiglioni, L., Rzemieniec, J., Dettori, I., Bulli, I., Coppi, E., Di Santo, C., Cuomo, O., Gullotta, G.S., Butti, E., Bagetta, G., Martino, G., De Simoni, M.-., Ferrarese, C., Fumagalli, S., and Beretta, S.

Subjects
interrater agreement, Ischemic stroke, neurobehavior, preclinical multicentre trial, quality check, Neurology, Settore BIO/14 - Farmacologia, Settore MED/26 - Neurologia, Neurology (clinical), Cardiology and Cardiovascular Medicine
Abstract

Multicentre preclinical randomized controlled trials (pRCTs) are a valuable tool to improve experimental stroke research, but are challenging and therefore underused. A common challenge regards the standardization of procedures across centres. We here present the harmonization phase for the quantification of sensorimotor deficits by composite neuroscore, which was the primary outcome of two multicentre pRCTs assessing remote ischemic conditioning in rodent models of ischemic stroke. Ischemic stroke was induced by middle cerebral artery occlusion for 30, 45 or 60 min in mice and 50, 75 or 100 min in rats, allowing sufficient variability. Eleven animals per species were video recorded during neurobehavioural tasks and evaluated with neuroscore by eight independent raters, remotely and blindly. We aimed at reaching an intraclass correlation coefficient (ICC) ≥0.60 as satisfactory interrater agreement. After a first remote training we obtained ICC = 0.50 for mice and ICC = 0.49 for rats. Errors were identified in animal handling and test execution. After a second remote training, we reached the target interrater agreement for mice (ICC = 0.64) and rats (ICC = 0.69). In conclusion, a multi-step, online harmonization phase proved to be feasible, easy to implement and highly effective to align each centre’s behavioral evaluations before project’s interventional phase.

Published
2023

8. ‘We are the nobodies': youth violence, marginality and social cleansing in Colombia

Author

Butti, E and Pirie, F

Subjects
Anthropology, Socio-Legal Studies
Abstract

Colombia’s ‘transition to peace’ faces various challenges. One is the activity of drug- related criminal organisations, which use adolescents to carry out low-level tasks. Based on 18 months of ethnographic fieldwork, this thesis explores the lives and perspectives of a group of adolescents who are starting to engage in criminal activities and the violence associated with them in the town of San Carlos and in the close-by city Medellín. Informal conversations with these youths and regular observation of their activities, as well as engagement with their families and communities, reveal aspects of their lives that mainstream discourses and statistics about violence cannot account for. The central question I ask is why and how some youths engage in organised crime and violence, despite the enthusiasm for peace currently permeating their country. I propose that these youths’ involvement in crime and violence is shaped by the precarity and ontological insecurity that characterise their lives. First, this thesis describes the process whereby these youths are progressively marginalised and come to be conceived as worthless and killable, through a number of practices ranging from stigmatisation and corporal punishment to police harassment and social cleansing. It then explores how they react to marginalisation by both embracing an oppositional identity and striving to overcome it. Having been made to feel like ‘nobodies’, they see joining a criminal group as the only way of ‘becoming somebody’, in social, economic and moral terms. However, I also show that the process of deciding to engage in crime and violence is experienced with a great deal of ambivalence and hesitation, as evidenced by these youths’ contradictory moral discourses about violence. By contextualising these findings within Colombia’s political juncture, this thesis questions clear-cut distinctions between conflict and its aftermath, and points towards further transformations that need to take place for peace to last.

Published
2019

9. Subventricular zone neural progenitors protect striatal neurons from glutamatergic excitotoxicity

Author

Butti, E., Bacigaluppi, M., Rossi, S., Cambiaghi, M., Bari, M., Silla, A.C., Brambilla, E., Musella, A., Teneud, L., De Chiara, Garcia Verdugo, J.M. , Comi, LEOCANI , ANNUNZIATA MARIA LETIZIA, Maccarrone, M., Centonze, D., Martino, G., Butti, E., Bacigaluppi, M., Rossi, S., Cambiaghi, M., Bari, M., Silla, A. C., Brambilla, E., Musella, A., Teneud, L., De, Chiara, Garcia, Verdugo, J. M., Comi, Leocani, ANNUNZIATA MARIA LETIZIA, Maccarrone, M., Centonze, D., and Martino, G.

Published
2012

11. Poster session 2THE IMAGING EXAMINATIONP536Appropriate use criteria of transthoracic echocardiography and its clinical impact: a continuous challengeP537Implementation of proprietary plug-ins in the DICOM-based computerized echo reporting system fuels the use of 3D echo and deformation imaging in the clinical routine of a multivendor laboratoryP538Exercise stress echocardiography appropriate use criteria: real-life cases classification ease and agreement among cardiologistsANATOMY AND PHYSIOLOGY OF THE HEART AND GREAT VESSELSP539Functional capacity in older people with normal ejection fraction correlates with left ventricular functional reserve and carotid-femoral pulse wave velocity but not with E/e and augmentation indexP540Survey of competency of practitioners for diagnosis of acute cardiopulmonary diseases manifest on chest x-rayASSESSMENT OF DIAMETERS, VOLUMES AND MASSP541Left atrium remodeling in dialysis patients with normal ejection fractionP542The prediction of postinfarction left ventricular remodeling and the role of of leptin and MCP-1 in regard to the presence of metabolic syndromeP543Ascending aorta and common carotid artery: diameters and stiffness in a group of 584 healthy subjectsAssessments of haemodynamicsP544Alternate echo parameters in patients without estimable RVSPAssessment of systolic functionP545Reduced contractile performance in heart failure with preserved ejection fraction: determination using novel preload-adjusted maximal left ventricular ejection forceP546Left ventricular dimensions and prognosis in acute coronary syndromesP547Time course of myocardial alterations in a murine model of high fat diet: A strain rate imaging studyP548Subclinical left ventricular systolic dysfunction in patients with premature ventricular contractionsP549Global myocardial strain by CMR-based feature tracking (FT) and tagging to predict development of severe left ventricular systolic dysfunction after acute st-elevation myocardial infarctionP550Echocardiographic analysis of left and right ventricular function in patients after mitral valve reconstructionP551The role of regional longitudinal strain assessment in predicting response to cardiac resynchronization therapy in patients with left ventricular systolic dysfunction and left bundle branch blockP552Speckle tracking automatic border detection improves echocardiographic evaluation of right ventricular systolic function in repaired tetralogy of fallot patients: comparison with MRI findingsP553Echocardiography: a reproducible and relevant tool in pah? intermediate results of the multicentric efort echogardiographic substudy (evaluation of prognostic factors and therapeutic targets in pah)Assessment of diastolic functionP554Relationship between left ventricular filling pressures and myocardial fibrosis in patients with uncomplicated arterial hypertensionP555Cardiac rehabilitation improves echocardiographic parameters of diastolic function in patients with ischemic heart diseaseP556Diastolic parameters in the calcified mitral annulusP557Biomarkers and echocardiography - combined weapon to diagnose and prognose heart failure with and without preserved ejection fractionP558Diastolic function changes of the maternal heart in twin and singleton pregnancyIschemic heart diseaseP559Syntax score as predictor for the correlation between epicardial adipose tissue and the severity of coronary lesions in patients with significant coronary diseaseP560Impact of strain analysis in ergonovine stress echocardiography for diagnosis vasospastic anginaP561Cardiac magnetic resonance tissue tracking: a novel method to predict infarct transmurality in acute myocardial infarctionP562Infarct size is correlated to global longitudinal strain but not left ventricular ejection fraction in the early stage of acute myocardial infarctionP563Magnetic resonance myocardial deformation assessment with tissue tracking and risk stratification in acute myocardial infarction patientsP564Increase in regional end-diastolic wall thickness by transthoracic echocardiography as a biomarker of successful reperfusion in anterior ST elevation acute myocardial infarctionP565Mitral regurgitation is associated with worse long-term prognosis in ST-segment elevation myocardial infarction treated with primary percutaneous coronary interventionP566Statistical significance of 3D motion and deformation indexes for the analysis of LAD infarctionHeart valve DiseasesP567Paradoxical low gradient aortic stenosis: echocardiographic progression from moderate to severe diseaseP568The beneficial effects of TAVI in mitral insufficiencyP569Impact of thoracic aortic calcification on the left ventricular hypertrophy and its regression after aortic valve replacement in patients with severe aortic stenosisP570Additional value of exercise-stress echocardiography in asymptomatic patients with aortic valve stenosisP571Valvulo-arterial impedance in severe aortic stenosis: a dual imaging modalities studyP572Left ventricular mechanics: novel tools to evaluate left ventricular performance in patients with aortic stenosisP573Comparison of long-term outcome after percutaneous mitral valvuloplasty versus mitral valve replacement in moderate to severe mitral stenosis with left ventricular dysfunctionP574Incidence of de novo left ventricular dysfunction in patient treated with aortic valve replacement for severe aortic regurgitationP575Transforming growth factor-beta dependant progression of the mitral valve prolapseP576Quantification of mitral regurgitation with multiple jets: in vitro validation of three-dimensional PISA techniqueP577Impaired pre-systolic contraction and saddle-shape deepening of mitral annulus contributes to atrial functional regurgitation: a three-dimensional echocardiographic studyP578Incidence and determinants of left ventricular (lv) reverse remodeling after MitraClip implantation in patients with moderate-to severe or severe mitral regurgitation and reduced lv ejection fractionP579Severe functional tricuspid regurgitation in rheumatic heart valve disease. New insights from 3D transthoracic echocardiographyP58015 years of evolution of the etiologic profile for prosthetic heart valve replacement through an echocardiography laboratoryP581The role of echocardiography in the differential diagnosis of prolonged fever of unknown originP582Predictive value for paravalvular regurgitation of 3-dimensional anatomic aortic annulus shape assessed by multidetector computed tomography post-transcatheter aortic valve replacementP583The significance and advantages of echo and CT imaging & measurement at transcatherter aortic valve implantation through the left common carotid accessP584Comparison of the self-expandable Medtronic CoreValve versus the balloon-expandable Edwards SAPIEN bioprostheses in high-risk patients undergoing transfemoral aortic valve implantationP585The impact of transcatheter aortic valve implantation on mitral regurgitation severityP586Echocardiographic follow up of children with valvular lesions secondary to rheumatic heart disease: Data from a prospective registryP587Valvular heart disease and different circadian blood pressure profilesCardiomyopathiesP588Comparison of transthoracic echocardiography versus cardiac magnetic for implantable cardioverter defibrillator therapy in primary prevention strategy dilated cardiomyopathy patientsP589Incidence and prognostic significance of left ventricle reverse remodeling in a cohort of patients with idiopathic dilated cardiomyopathyP590Early evaluation of diastolic function in fabry diseaseP591Echocardiographic predictors of atrial fibrillation development in hypertrophic cardiomyopathyP592Altered Torsion mechanics in patients with hypertrophic cardiomyopathy: LVOT-obstruction is the topdog?P593Prevention of sudden cardiac death in hypertrophic cardiomyopathy: what has changed in the guidelines?P594Coronary microcirculatory function as determinator of longitudinal systolic left ventricular function in hypertrophic cardiomyopathyP595Detection of subclinical myocardial dysfunction by tissue Doppler ehocardiography in patients with muscular dystrophiesP596Speckle tracking myocardial deformation analysis and three dimensional echocardiography for early detection of chemotherapy induced cardiac dysfunction in bone marrow transplantation patientsP597Left ventricular non compaction or hypertrabeculation: distinguishing between physiology and pathology in top-level athletesP598Role of multi modality imaging in familiar screening of Danon diseaseP599Early impairment of global longitudinal left ventricular systolic function independently predicts incident atrial fibrillation in type 2 diabetes mellitusP600Fetal cardiovascular programming in maternal diabetes mellitus and obesity: insights from deformation imagingP601Longitudinal strain stress echo evaluation of aged marginal donor hearts: feasibility in the Adonhers project.P602Echocardiographic evaluation of left ventricular size and function following heart transplantation - Gender mattersSystemic diseases and other conditionsP603The impact of septal kinetics on adverse ventricular-ventricular interactions in pulmonary stenosis and pulmonary arterial hypertensionP604Improvement in right ventricular mechanics after inhalation of iloprost in pulmonary hypertensionP605Does the treatment of patients with metabolic syndrome correct the right ventricular diastolic dysfunction?P606Predictors of altered cardiac function in breast cancer survivors who were treated with anthracycline-based therapyP607Prevalence and factors related to left ventricular systolic dysfunction in asymptomatic patients with rheumatoid arthritis: a prospective tissue-doppler echocardiography studyP608Diastolic and systolic left ventricle dysfunction presenting different prognostic implications in cardiac amyloidosisP609Diagnostic accuracy of Bedside Lung Ultrasonography in Emergency (BLUE) protocol for the diagnosis of pulmonary embolismP610Right ventricular systolic dysfunction and its incidence in breast cancer patients submitted to anthracycline therapyP611Right ventricular dysfunction is an independent predictor of survival among cirrhotic patients undergoing liver transplantCongenital heart diseaseP612Hypoplasia or absence of posterior leaflet: a rare congenital anomaly of the mitral valveP613ECHO screening for Barlow disease in proband's relativesDiseases of the aortaP614Aortic size distribution and prognosis in an unselected population of patients referred for standard transthoracic echocardiographyP615Abdominal aorta aneurysm ultrasonographic screening in a large cohort of asympromatic volounteers in an Italian urban settingP616Thoracic aortic aneurysm and left ventricular systolic functionStress echocardiographyP617Wall motion score index, systolic mitral annulus velocity and left ventricular mass predicted global longitudinal systolic strain in 238 patients examined by stress echocardiographyP618Prognostic parameters of exercise-induced severe mitral valve regurgitation and exercise-induced systolic pulmonary hypertensionP619Risk stratification after myocardial infarction: prognostic value of dobutamine stress echocardiographyP620relationship between LV and RV myocardial contractile reserve and metabolic parameters during incremental exercise and recovery in healthy children using 2-D strain analysisP621Increased peripheral extraction as a mechanism compensatory to reduced cardiac output in high risk heart failure patients with group 2 pulmonary hypertension and exercise oscillatory ventilationP622Can exercise induced changes in cardiac synchrony predict response to CRT?Transesophageal echocardiographyP623Fully-automated software for mitral valve assessment in chronic mitral regurgitation by three-dimensional transesophageal echocardiographyP624Real-time 3D transesophageal echocardiography provides more accurate orifice measurement in percutaneous transcatheter left atrial appendage closureP625Percutaneous closure of left atrial appendage: experience of 36 casesReal-time three-dimensional TEEP626Real-time three-dimensional transesophageal echocardiography during pulmonary vein cryoballoon ablation for atrial fibrilationP627Three dimensional ultrasound anatomy of intact mitral valve and in the case of type 2 disfunctionTissue Doppler and speckle trackingP629Left ventricle wall motion tracking from echocardiographic images by a non-rigid image registrationP630The first experience with the new prototype of a robotic system for remote echocardiographyP631Non-invasive PCWP influence on a loop diuretics regimen monitoring model in ADHF patients.P632Normal range of left ventricular strain, dimensions and ejection fraction using three-dimensional speckle-tracking echocardiography in neonatesP633Circumferential ascending aortic strain: new parameter in the assessment of arterial stiffness in systemic hypertensionP634Aortic vascular properties in pediatric osteogenesis imperfecta: a two-dimensional echocardiography derived aortic strain studyP635Assessment of cardiac functions in children with sickle cell anemia: doppler tissue imaging studyP636Assessment of left ventricular function in type 1 diabetes mellitus patients by two-dimensional speckle tracking echocardiography: relation to duration and control of diabetesP637A study of left ventricular torsion in l-loop ventricles using speckle-tracking echocardiographyP638Despite No-Reflow, global and regional longitudinal strains assessed by two-dimensional speckle tracking echocardiography are predictive indexes of left ventricular remodeling in patients with STEMIP639The function of reservoir of the left atrium in patients with medicaly treated arterial hypertensionP640The usefulness of speckle tracking analysis for predicting the recovery of regional systolic function after myocardial infarctionP641Two dimensional speckle tracking echocardiography in assessment of left ventricular systolic function in patients with rheumatic severe mitral regurgitation and normal ejection fractionP642The prediction of left-main and tripple vessel coronary artery disease by tissue doppler based longitudinal strain and strain rate imagingP643Role of speckle tracking in predicting arrhythmic risk and occurrence of appropriate implantable defibrillator Intervention in patients with ischemic and non-ischemic cardiomyopathyComputed Tomography & Nuclear CardiologyP644Cardiac adrenergic activity in patients with nonischemic dilated cardiomyopathy. Correlation with echocardiographyP645Different vascular territories and myocardial ischemia, there is a gradient of association?

Author

Martins Fernandes, S, primary, Badano, L, primary, Garcia Campos, A, primary, Erdei, T, primary, Mehdipoor, G, primary, Hanboly, N, primary, Michalski, BW, primary, Vriz, O, primary, Mo, VY, primary, Le, T T, primary, Ribeiro, JM, primary, Ternacle, J, primary, Yurdakul, SELEN, primary, Shetye, A, primary, Stoebe, S, primary, Lisowska, A, primary, Chinali, M, primary, Orabona, M, primary, Contaldi, C, primary, De La Chica, JA, primary, Codolosa, JN, primary, Trzcinski, P, primary, Prado Diaz, S, primary, Morales Portano, J D, primary, Ha, SJ, primary, Valente, F, primary, Joseph, G, primary, Scali, MC, primary, Cordeiro, F, primary, Duchateau, N, primary, Fabris, E, primary, Costantino, MF, primary, Cho, I J, primary, Goublaire, C, primary, Lam, W, primary, Galli, E, primary, Kim, KH, primary, Mariani, M, primary, Malev, E, primary, Zuercher, F, primary, Tang, Z, primary, Cimino, S, primary, Mahia, P, primary, Petrovic, J, primary, Ciobotaru, V, primary, Remsey- Semmelweiss, E, primary, Kogoj, P, primary, Guerreiro, S, primary, Saxena, A, primary, Mozenska, O, primary, Pontone, G, primary, Macaya Ten, F, primary, Caballero, L, primary, Avegliano, G, primary, Halmai, L, primary, Reis, L, primary, Trifunovic, D, primary, Gospodinova, M, primary, Makavos, G, primary, D'ascenzi, F, primary, Dantas Tavares De Melo, M, primary, Bonapace, S, primary, Kulkarni, A, primary, Cameli, M, primary, Ingvarsson, A, primary, Driessen, MMP, primary, Tufekcioglu, O, primary, Radulescu, D, primary, Barac, A, primary, Cioffi, G, primary, Almeida Morais, L, primary, Ledakowicz-Polak, A, primary, Portugal, G, primary, Naksuk, N, primary, Parato, V M, primary, Kovalova, S, primary, Cherubini, A, primary, Corrado, G, primary, Wierzbowska-Drabik, K, primary, Lesevic, H, primary, Laredj, N, primary, Pieles, G E, primary, Generati, G, primary, Van Zalen, JJ, primary, Aquila, I, primary, Cheng, H-L, primary, Lanzoni, L, primary, Asmarats Serra, L, primary, Kadrabulatova, S, primary, Ranjbar, S, primary, Szczesniak-Stanczyk, D, primary, Sharka, I, primary, Di Salvo, G, primary, Ben Kahla, S, primary, Li, L, primary, Hadeed, HA, primary, Habeeb, H A, primary, Toscano, A, primary, Granata, F, primary, Djikic, D, primary, Wdowiak-Okrojek, K, primary, Girgis, H Y A, primary, Sharma, A, primary, Soro, C, primary, Gallego Page, J C, primary, Corneli, M, primary, Teixeira, R, additional, Roussin, I, additional, Lynch, M, additional, Muraru, D, additional, Romeo, G, additional, Ermacora, D, additional, Marotta, C, additional, Aruta, P, additional, Cucchini, U, additional, Iliceto, S, additional, Martin-Fernandez, M, additional, De La Hera Galarza, JM, additional, Corros-Vicente, C, additional, Colunga Blanco, S, additional, Velasco-Alonso, E, additional, Leon-Aguero, V, additional, Rodriguez-Suarez, ML, additional, Moris De La Tassa, C, additional, Edwards, J, additional, Braim, D, additional, Price, C, additional, Fraser, AG, additional, Salmani, F, additional, Arjmand Shabestari, A, additional, Szymczyk, E, additional, Kupczynska, K, additional, Peczek, L, additional, Nawrot, B, additional, Lipiec, P, additional, Kasprzak, JD, additional, Driussi, C, additional, Ferrara, F, additional, Brosolo, G, additional, Antonini-Canterin, F, additional, Magne, J, additional, Aboyans, V, additional, Bossone, E, additional, Bellucci, BM, additional, Fisher, JM, additional, Balekian, AA, additional, Idapalapati, S, additional, Huang, F, additional, Wong, JI, additional, Tan, RS, additional, Madeira, M, additional, Almeida, I, additional, Reis, L, additional, Siserman, A, additional, Dinis, P, additional, Dias, L, additional, Ramos, AP, additional, Goncalves, L, additional, Wan, FW, additional, Sawaki, DS, additional, Dubois-Rande, JLDR, additional, Adnot, SA, additional, Czibik, GC, additional, Derumeaux, GD, additional, Ercan, G, additional, Tekkesin, ILKER, additional, Sahin, ST, additional, Cengiz, B, additional, Celik, G, additional, Demircan, S, additional, Aytekin, SAIDE, additional, Razvi, NA, additional, Nazir, SA, additional, Price, N, additional, Khan, JN, additional, Kanagala, P, additional, Singh, A, additional, Squire, I, additional, Mccann, GP, additional, Langel, M, additional, Pfeiffer, D, additional, Hagendorff, A, additional, Ptaszynska-Kopczynska, K, additional, Marcinkiewicz-Siemion, M, additional, Knapp, M, additional, Witkowski, M, additional, Musial, WJ, additional, Kaminski, K, additional, Natali, B, additional, D' Anna, C, additional, Leonardi, B, additional, Secinaro, A, additional, Pongiglione, G, additional, Rinelli, G, additional, Renard, S, additional, Michel, N, additional, Mancini, J, additional, Haentjens, J, additional, Sitbon, O, additional, Habib, G, additional, Imbriaco, M, additional, Alcidi, G, additional, Santoro, C, additional, Buonauro, A, additional, Lo Iudice, F, additional, Lembo, M, additional, Cuocolo, A, additional, Trimarco, B, additional, Galderisi, M, additional, Mora Robles, J, additional, Roldan Jimenez, MA, additional, Mancisidor, MA, additional, De Mora, MA, additional, Alnabelsi, T, additional, Goykhman, I, additional, Koshkelashvili, N, additional, Romero-Corral, A, additional, Pressman, GS, additional, Michalski, BW, additional, Miskowiec, D, additional, Montoro Lopez, N, additional, Refoyo Salicio, E, additional, Valbuena Lopez, SC, additional, Gonzalez, O, additional, Alvarez, C, additional, Moreno Yanguela, M, additional, Bartha Rasero, JL, additional, De La Calle, M, additional, Guzman Martinez, G, additional, Suarez-Cuenca, JA, additional, Merino, JA, additional, Gomez Alvarez, E B, additional, Delgado, LG, additional, Woo, YM, additional, Bang, WD, additional, Sohn, GH, additional, Cheong, SS, additional, Yoo, SY, additional, Rodriguez Palomares, JF, additional, Gutierrez, L, additional, Maldonado, G, additional, Pineda, V, additional, Galian, L, additional, Teixido, G, additional, Gonzalez Allujas, MT, additional, Evangelista, A, additional, Garcia Dorado, D, additional, Zaremba, T, additional, Ekeloef, S, additional, Heiberg, E, additional, Engblom, H, additional, Jensen, SE, additional, Sogaard, P, additional, Garcia, G, additional, Dini, FL, additional, Galli, F, additional, Lattanzi, F, additional, Picano, E, additional, Marzilli, M, additional, Leao, S, additional, Moz, M, additional, Magalhaes, P, additional, Trigo, J, additional, Mateus, PS, additional, Ferreira, A, additional, Moreira, JI, additional, De Craene, M, additional, Legallois, D, additional, Labombarda, F, additional, Pellissier, A, additional, Sermesant, M, additional, Saloux, E, additional, Merlo, M, additional, Moretti, M, additional, Barbati, G, additional, Stolfo, D, additional, Gigli, M, additional, Pinamonti, B, additional, Sinagra, G, additional, Dores, E, additional, Matera, A, additional, Innelli, P, additional, Lopizzo, A, additional, Violini, R, additional, Fiorilli, R, additional, Cappabianca, G, additional, Tarsia, G, additional, Seo, J, additional, Chang, HJ, additional, Heo, R, additional, Kim, IC, additional, Shim, CY, additional, Hong, GR, additional, Chung, N, additional, Melissopoulou, MM, additional, Nguyen, V, additional, Brochet, E, additional, Cimadevilla, C, additional, Codogno, I, additional, Vahanian, A, additional, Messika-Zeitoun, D, additional, Pontana, F, additional, Vassiliou, V, additional, Prasad, S, additional, Leclercq, C, additional, Samset, E, additional, Donal, E, additional, Lim, DS, additional, Bianchi, G, additional, Rossi, F, additional, Gianetti, J, additional, Marchi, F, additional, Cerone, E, additional, Nardelli, A, additional, Terrazzi, M, additional, Solinas, M, additional, Maffei, S, additional, Pshepiy, A, additional, Vasina, L, additional, Timofeev, E, additional, Reeva, S, additional, Zemtsovsky, E, additional, Brugger, N, additional, Jahren, S, additional, De Marchi, SF, additional, Seiler, C, additional, Jin, CN, additional, Tang, H, additional, Fan, K, additional, Kam, K, additional, Yan, BP, additional, Yu, CM, additional, Lee, PW, additional, Reali, M, additional, Silvetti, E, additional, Salatino, T, additional, Mancone, M, additional, Pennacchi, M, additional, Giordano, A, additional, Sardella, G, additional, Agati, L, additional, Tirado, G, additional, Nogales-Romo, MT, additional, Marcos-Alberca, P, additional, De Agustin, A, additional, Almeria, C, additional, Rodrigo, JL, additional, Garcia Fernandez, MA, additional, Macaya, C, additional, Perez De Isla, L, additional, Mancisidor, M, additional, Lara Garcia, C, additional, Vivancos, R, additional, De Mora, M, additional, Petrovic, M, additional, Vujisic-Tesic, B, additional, Trifunovic, D, additional, Boricic-Kostic, M, additional, Petrovic, I, additional, Draganic, G, additional, Petrovic, O, additional, Tomic-Dragovic, M, additional, Furlan, T, additional, Ambrozic, J, additional, Mohorko Pleskovic, PN, additional, Bunc, M, additional, Ribeiras, R, additional, Abecasis, J, additional, Andrade, MJ, additional, Mendes, M, additional, Ramakrishnan, S, additional, Gupta, SK, additional, Juneja, R, additional, Kothari, SS, additional, Zaleska, M, additional, Segiet, A, additional, Chwesiuk, S, additional, Kroc, A, additional, Kosior, DA, additional, Andreini, D, additional, Solbiati, A, additional, Guglielmo, M, additional, Mushtaq, S, additional, Baggiano, A, additional, Beltrama, V, additional, Rota, C, additional, Guaricci, AI, additional, Pepi, M, additional, Pons Llinares, J, additional, Asmarats Serra, L, additional, Pericas Ramis, P, additional, Caldes Llull, O, additional, Grau Sepulveda, A, additional, Frontera, G, additional, Vaquer Segui, A, additional, Noris, M, additional, Bethencourt Gonzalez, A, additional, Climent Paya, V, additional, Martinez Moreno, M, additional, Saura, D, additional, Oliva, MJ, additional, Sanchez Quinones, J, additional, Garcia Honrubia, A, additional, Valdes, M, additional, De La Morena, G, additional, Terricabras, M, additional, Costabel, JP, additional, Ronderos, R, additional, Venturini, C, additional, Galve, E, additional, Nemes, A, additional, Neubauer, S, additional, Rahman Haley, S, additional, Banner, N, additional, Caetano, F, additional, Botelho, A, additional, Silva, J, additional, Nascimento, J, additional, Tesic, M, additional, Jovanovic, I, additional, Dragovic, M, additional, Stepanovic, J, additional, Banovic, M, additional, Guergelcheva, V, additional, Chamova, T, additional, Sarafov, S, additional, Tournev, I, additional, Denchev, S, additional, Ikonomidis, I, additional, Psarogiannakopoulos, P, additional, Tsirigotis, P, additional, Paraskevaidis, I, additional, Lekakis, J, additional, Pelliccia, A, additional, Natali, BM, additional, Cameli, M, additional, Focardi, M, additional, Bonifazi, M, additional, Mondillo, S, additional, Lima, C, additional, Assed, L, additional, Kalil Filho, R, additional, Mady, C, additional, Bochi, E A, additional, Salemi, V M C, additional, Targher, G, additional, Valbusa, F, additional, Rossi, A, additional, Lanzoni, L, additional, Lipari, P, additional, Zenari, L, additional, Molon, G, additional, Canali, G, additional, Barbieri, E, additional, Li, L, additional, Craft, M, additional, Nanda, M, additional, Lorenzo, JM, additional, Kutty, S, additional, Bombardini, T, additional, Sparla, S, additional, Di Tommaso, C, additional, Losito, M, additional, Incampo, E, additional, Maccherini, M, additional, Werther Evaldsson, A, additional, Radegran, G, additional, Stagmo, M, additional, Waktare, J, additional, Roijer, A, additional, Meurling, CJ, additional, Hui, W, additional, Meijboom, FJ, additional, Bijnens, B, additional, Dragulescu, A, additional, Mertens, L, additional, Friedberg, MK, additional, Sensoy, B, additional, Suleymanoglu, M, additional, Akin, Y, additional, Sahan, E, additional, Sasmaz, H, additional, Pasca, L, additional, Buzdugan, E, additional, Chis, B, additional, Stoicescu, L, additional, Lynce, FC, additional, Smith, KL, additional, Mete, M, additional, Isaacs, C, additional, Viapiana, O, additional, Di Nora, C, additional, Ognibeni, F, additional, Fracassi, E, additional, Giollo, A, additional, Mazzone, C, additional, Faganello, G, additional, Di Lenarda, A, additional, Rossini, M, additional, Galrinho, A, additional, Branco, L, additional, Timoteo, A T, additional, Rodrigues, I, additional, Daniel, P, additional, Rosa, S, additional, Ferreira, L, additional, Ferreira, R, additional, Polak, L, additional, Krauza, G, additional, Stokfisz, K, additional, Zielinska, M, additional, Branco, L M, additional, Mota Carmo, M, additional, Teresa Timoteo, A, additional, Aguiar Rosa, S, additional, Abreu, J, additional, Pinto Teixeira, P, additional, Viveiros Monteiro, A, additional, Cruz Ferreira, R, additional, Peeraphatdit, T, additional, Chaiteerakij, R, additional, Klarich, KW, additional, Masia, S, additional, Necas, J, additional, Nistri, S, additional, Negri, F, additional, Cioffi, G, additional, Russo, G, additional, Pandullo, C, additional, Durante, A, additional, Rovelli, E, additional, Genchi, V, additional, Trabattoni, L, additional, Zerboni, SC, additional, Cattaneo, L, additional, Butti, E, additional, Ferrari, G, additional, Luneva, E, additional, Mitrofanova, L, additional, Uspensky, V, additional, Rosner, S, additional, Karl, M, additional, Ott, I, additional, Sonne, C, additional, Ali Lahmar, HM, additional, Hammou, L, additional, Forsey, J, additional, Gowing, L, additional, Miller, F, additional, Ramanujam, P, additional, Stuart, AG, additional, Williams, CA, additional, Bandera, F, additional, Pellegrino, M, additional, Carbone, F, additional, Labate, V, additional, Alfonzetti, E, additional, Guazzi, M, additional, Patel, NR, additional, Raju, P, additional, Beale, L, additional, Brickley, G, additional, Lloyd, GW, additional, Fernandez-Golfin, C, additional, Gonzalez, A, additional, Rincon, LM, additional, Hinojar, R, additional, Garcia, A, additional, Megias, A, additional, Jimenez-Nacher, JJ, additional, Moya, JL, additional, Zamorano, JL, additional, Bonapace, S, additional, Chiampan, A, additional, Albrigi, L, additional, Noris Mora, M, additional, Rodriguez Fernandez, A, additional, Exposito Pineda, C, additional, Grande, C, additional, Gonzalez Colino, R, additional, Macaya Ten, F, additional, Fernandez Vazquez, X, additional, Fortuny Frau, E, additional, Karvandi, M, additional, Blaszczyk, R, additional, Zarczuk, R, additional, Brzozowski, W, additional, Janowski, M, additional, Wysokinski, A, additional, Stanczyk, B, additional, Myftiu, S, additional, Teferici, D, additional, Quka, A, additional, Dado, E, additional, Djamandi, J, additional, Kresto, L, additional, Duka, A, additional, Kristo, A, additional, Balla, I, additional, Issa, Z, additional, Moiduddin, N, additional, Siblini, G, additional, Bulbul, Z, additional, Abid, L, additional, Abid, D, additional, Kammoun, S, additional, Rush, E, additional, Goodwin, J, additional, Kreikemeier, R, additional, Cantinotti, M, additional, Zolaly, M A, additional, Khoshhal, SQ, additional, El-Harbi, K, additional, Tarawah, A, additional, Al-Hawsawi, Z, additional, Al-Mozainy, I, additional, Bakhoum, S W G, additional, Nabil, M N, additional, Elebrashy, I N, additional, Chinali, M, additional, Albanese, S, additional, Carotti, A, additional, Iacobelli, R, additional, Esposito, C, additional, Moscogiuri, G, additional, Pasquini, L, additional, Malvezzi Caracciolo, M, additional, Bianchi, RM, additional, Caso, P, additional, Arenga, F, additional, Riegler, L, additional, Scarafile, R, additional, D'andrea, A, additional, Russo, MG, additional, Calabro', P, additional, Simic, DS, additional, Peric, VP, additional, Mujovic, NM, additional, Marinkovic, MM, additional, Jankovic, NJ, additional, Shim, A, additional, Wejner-Mik, P, additional, Jain, N, additional, Kharwar, R, additional, Saran, RK, additional, Narain, VS, additional, Dwivedi, SK, additional, Sethi, R, additional, Chandra, S, additional, Pradhan, A, additional, Safal, S, additional, Marchetti, MF, additional, Cacace, C, additional, Congia, M, additional, Nissardi, V, additional, Ruscazio, M, additional, Meloni, L, additional, Montisci, R, additional, Gallego Sanchez, G, additional, Calero, S, additional, Portero, JJ, additional, Tercero, A, additional, Garcia, JC, additional, Barambio, M, additional, Martinez Lazaro, R, additional, Meretta, AH, additional, Perea, GO, additional, Belcastro, F, additional, Aguirre, E, additional, De Luca, I, additional, Henquin, R, additional, and Masoli, O, additional

Published
2015
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14. PREAMI: Perindopril and remodelling in elderly with acute myocardial infarction: Study rationale and design

Author

Battaglia, A., Ferraro, L., Lo Monaco, M., Palumbo, A., Mariani, M., Biadi, O., Boccalatte, A., Polimeno, S., Rosa, V., Liguori, L., Cuomo, S., Boccanelli, A., Morosetti, P., D Angelo, G., Bottiglieri, P., Brunelli, C., Spallarossa, P., Rolandi, A., Rossettini, Pf, Campa, P., Francesco BARILLA', Biase, L., Biscosi, C., Zampino, D., Capponi, E., Buccolieri, M., Gattobigio, R., Capucci, A., Passerini, F., Piepoli, M., Castello, A., Chiariello, M., Betocchi, S., Ciampi, Q., Losi, M., Corsini, G., Melorio, S., Dalle Mule, J., Mazzella, M., Cristinziani, Gr, Mario, L., Luca, I., Fusco, F., Del Salvatore, B., Sorino, M., Delise, P., Mozzato, Mg, Bilardo, G., Coro, L., Fantinel, M., Zasso, A., Fedele, F., Di Donato, D., Romano, S., Pascale, F., Giasi, M., Ciarcia, L., Lizzardo, A., Mastursi, M., Giordano, A., Benigno, M., Zanelli, E., Campana, M., Giovannini, E., Lacche, A., Pulignano, G., Giuffrida, G., Montana, G., Licciardello, G., L Abbate, A., Carpeggiani, C., Morales, A., Leghissa, R., Mandorla, S., Del Pinto, M., Borgioni, C., Mininni, N., Petrillo, Me, Moretti, G., Bonaglia, M., Zoni, A., Piscicelli, C., Orlandi, M., Panciroli, C., Oddone, A., Caizzi, V., Tartarini, G., Lattanzi, F., Reisenhofer, B., Pascotto, P., Zanocco, A., Dabizzi, Rp, Bini, L., Mondanelli, D., Frascarelli, F., Pitscheider, W., Erlicher, A., Rauhe, W., Bonsante, E., Polimeni, M., Catananti, F., Guerrisi, G., Magnani, B., Rapezzi, C., Ferlito, M., Amati, S., Di Leo, L., Manzo, M., Baldi, C., Cristofaro, M., Citro, R., Raviele, A., Turiano, G., Zuin, G., Rengo, F., Furgi, G., Papa, A., Rotiroti, D., Rosato, G., Siano, F., Pagliuca, MR, Rovelli, G., Heyman, J., Locati, I., Sanguinetti, M., Tomassini, F., Mantovani, R., Sanna, A., Marras, L., Crabu, E., Locci, G., Moio, N., Scilla, C., Tavazzi, L., Magrini, G., Bersano, C., Laudisa, Ml, Trimarco, B., Argenziano, L., Silvestri, S., Valagussa, F., Ciro, E., Cantu, E., Trocino, G., Rossillo, A., Valagussa, L., Finocchi, G., Benvenuto, Gm, Bonanno, C., Ometto, R., Risica, G., Gualandi, G., Facchin, L., Tenderini, P., Nicolosi, Gl, Burelli, C., Macor, F., Bellone, E., Laiso, D., Carvalho, P., Peila, C., Fagiano, A., Gardiol, S., Ganci, B., Presutto, P., Fontanelli, A., Morgera, T., Scarpino, L., Barbuzzi, S., Capogrosso, V., Terrosu, Pf, Contini, Gm, Sabino, G., Pes, R., Uneddu, F., Mecca, D., Tommaso, I., Rusconi, C., Brunazzi, Mc, Codeluppi, P., Pasqualini, M., Gorni, R., Negrelli, M., Paparoni, S., Core, A., Pecce, P., Petrella, L., Zennaro, Rg, Garuti, W., Alfano, G., Bacca, F., Petrucci, G., Paci, Am, Bigalli, G., Mangiameli, S., Gulizia, M., Cardillo, R., Ferrari, G., Tettamanti, F., Butti, E., Picchione, N., Sulla, A., Stroder, P., Perna, Gp, Ricci, S., Generali, Ca, Adornato, E., Ghisio, A., Tidu, M., Ferrari, R., Mele, D., Cicchitelli, G., Merli, E., Russa, O., Azcarate, Jma, Gonzales, Pz, Vilchez, F., Alonso, Lfi, Montero, Jmm, Zarzosa, Cd, Martin, Es, Ros, Jo, Martinez, Mh, Palau, Vm, Carranza, Mst, Mayor, Djlb, Cocina, Eg, Valderrama, Jc, Jimenez, Rp, Pardo, Jam, Cortada, Jb, Lorente, Lj, Guerrero, Jjg, Martinez, A., Coronado, Jlb, Casado, Rs, Cendon, Aa, Cokkinos, D., Maounis, T., Karatasakis, G., Kremastinos, D., Iliodromitis, S., Karatzas, D., Georgiadis, M., Paraskevaidis, I., Toutouzas, P., Antoniadis, P., Angeli, C., Vadas, P., Kaleboubas, M., Stamatelopoulos, S., Nanas, I., Kanakakis, A., Dalianis, A., Zacharoulis, A., Fotiadis, I., Pyrgakis, V., Liata, O., Mazen, B., Kardaras, F., Kardara, D., Krokos, V., Sioras, H., Fousas, S., Stefanidis, A., Papadopoulos, G., Papadopoulos, C., Papagiannis, I., Karidas, I., Zobolos, S., Preami, Investigators, A., Battaglia, L., Ferraro, M. L., Monaco, A., Palumbo, M., Mariani, O., Biadi, A., Boccalatte, S., Polimeno, V. D., Rosa, L., Liguori, S., Cuomo, A., Boccanelli, P., Morosetti, G., D'Angelo, P., Bottiglieri, C., Brunelli, P., Spallarossa, A., Rolandi, P. F., Rossettini, P., Campa, F., Barilla, L. D., Biase, C., Biscosi, D., Zampino, E., Capponi, M., Buccolieri, R., Gattobigio, A., Capucci, F., Passerini, M., Piepoli, A., Castello, M., Chiariello, Betocchi, Sandro, Q., Ciampi, Losi, MARIA ANGELA, G., Corsini, S., Melorio, J. D., Mule, M., Mazzella, G. R., Cristinziani, L., Mario, I. D., Luca, F., Fusco, B. D., Salvatore, M., Sorino, P., Delise, M. G., Mozzato, G., Bilardo, L., Coro', M., Fantinel, A., Zasso, F., Fedele, D. D., Donato, S., Romano, F. D., Pascale, M., Giasi, L., Ciarcia, A., Lizzardo, M., Mastursi, A., Giordano, M., Benigno, E., Zanelli, M., Campana, E., Giovannini, A., Lacche, G., Pulignano, G., Giuffrida, G., Montana, G., Licciardello, A., L'Abbate, C., Carpeggiani, A., Morale, R., Leghissa, S., Mandorla, M. D., Pinto, C., Borgioni, N., Mininni, M. E., Petrillo, G., Moretti, M., Bonaglia, A., Zoni, C., Piscicelli, M., Orlandi, C., Panciroli, A., Oddone, V., Caizzi, G., Tartarini, F., Lattanzi, B., Reisenhofer, P., Pascotto, A., Zanocco, R. P., Dabizzi, L., Bini, D., Mondanelli, F., Frascarelli, W., Pitscheider, A., Erlicher, W., Rauhe, E., Bonsante, M., Polimeni, F., Catananti, G., Guerrisi, B., Magnani, C., Rapezzi, M., Ferlito, S., Amati, L. D., Leo, M., Manzo, C., Baldi, M. D., Cristofaro, R., Citro, A., Raviele, G., Turiano, G., Zuin, F., Rengo, G., Furgi, A., Papa, D., Rotiroti, G., Rosato, F., Siano, M. R., Pagliuca, G., Rovelli, J., Heyman, I., Locati, M., Sanguinetti, F., Tomassini, R., Mantovani, A., Sanna, L., Marra, E., Crabu, G., Locci, N., Moio, C., Scilla, L., Tavazzi, G., Magrini, C., Bersano, M. L., Laudisa, Trimarco, Bruno, L., Argenziano, S., Silvestri, F., Valagussa, E., Ciro, E., Cantu, G., Trocino, A., Rossillo, L., Valagussa, G., Finocchi, G. M., Benvenuto, C., Bonanno, R., Ometto, G., Risica, G., Gualandi, L., Facchin, P., Tenderini, G. L., Nicolosi, C., Burelli, F., Macor, E., Bellone, D., Laiso, P., Carvalho, C., Peila, A., Fagiano, S., Gardiol, B., Ganci, P., Presutto, A., Fontanelli, T., Morgera, L., Scarpino, S., Barbuzzi, V., Capogrosso, P. F., Terrosu, G. M., Contini, G., Sabino, R., Pe, F., Uneddu, D., Mecca, I. D., Tommaso, C., Rusconi, M. C., Brunazzi, P., Codeluppi, M., Pasqualini, R., Gorni, M., Negrelli, S., Paparoni, A., Core, P., Pecce, L., Petrella, R. G., Zennaro, W., Garuti, G., Alfano, F., Bacca, G., Petrucci, A. M., Paci, G., Bigalli, S., Mangiameli, M., Gulizia, R., Cardillo, G., Ferrari, F., Tettamanti, E., Butti, N., Picchione, A., Sulla, P., Stroder, G. P., Perna, S., Ricci, C. A., Generali, E., Adornato, A., Ghisio, M., Tidu, R., Ferrari, D., Mele, G., Cicchitelli, E., Merli, O., Russa, J. M., A., P. Z., Gonzale, F., Vilchez, L. F. I., J. M. M., C. D., Zarzosa, E. S., Martin, J. O., De, M. H., Martinez, V. M., Palau, M. S. T., D. J. L., E. G., Cocina, J. C., Valderrama, R. P., Jimenez, J. A., M., J. B., Cortada, L. J., Lorente, J. J., G., A., Martinez, J. L., B., R. S., Casado, A. A., Cendon, D., Cokkino, T., Maouni, G., Karatasaki, D., Kremastino, S., Iliodromiti, D., Karatza, M., Georgiadi, I., Paraskevaidi, P., Toutouza, P., Antoniadi, C., Angeli, P., Vada, M., Kalebouba, S., Stamatelopoulo, I., Nana, A., Kanakaki, A., Daliani, A., Zacharouli, I., Fotiadi, V., Pyrgaki, O., Liata, B., Mazen, F., Kardara, D., Kardara, V., Kroko, H., Siora, S., Fousa, A., Stefanidi, G., Papadopoulo, C., Papadopoulo, I., Papagianni, I., Karida, and S., Zobolos

Subjects
Male, Ventricular Remodeling, Myocardial Infarction, Angiotensin-Converting Enzyme Inhibitors, Electrocardiography, ace inhibitors, elderly, heart rate variability, left ventricular remodeling, myocardial infarction, perindopril, Double-Blind Method, Echocardiography, Research Design, Perindopril, Electrocardiography, Ambulatory, Humans, Female, Aged
Abstract

Angiotensin-converting enzyme (ACE) inhibitors reduce mortality, the development of remodeling, left ventricular (LV) dysfunction, and ischemic events, both when administered alone as long-term treatment in patients with impaired LV function and/or heart failure (HF) and as short-term treatment, early after acute myocardial infarction (AMI) and/or HF. The few data available on the use of ACE inhibitors in the elderly after AMI are conflicting. Nothing is known about the effects of ACE inhibitors in elderly postinfarction patients with preserved LV function: these patients have a remarkable medium- to long-term mortality and HF incidence after infarction. The aim of this study is to evaluate, in patients with AMI agedor =65 years, the effects of Perindopril on the combined outcome of death, hospitalization for HF, and heart remodeling, considered to be aor =8% increase in LV end-diastolic volume (LVEDV). Secondary objectives include the same factors listed in the primary end points but considered separately. In addition, safety of the drug, ventricular remodeling, and adaptation are being evaluated. A total of 1100 patients with AMI (first episode or reinfarction), agedor =65 years, and preserved or only moderately depressed LV (LV ejection fractionor =40%), are to be enrolled and randomly assigned to treatment (8 mg for 12 months of Perindopril or placebo, in double-blind conditions). Clinical assessment is performed at fixed times, and periodic evaluations of (1) ventricular shape, dimensions, and function by quantitative 2-D echocardiography, and (2) heart rate variability and arrhythmias by ambulatory electrocardiographic monitoring are anticipated. The results and conclusions will be available by 2002 year.

Published
2000

15. Inflammation Triggers Synaptic Alteration and Degeneration in Experimental Autoimmune Encephalomyelitis

Author

Centonze, D., primary, Muzio, L., additional, Rossi, S., additional, Cavasinni, F., additional, De Chiara, V., additional, Bergami, A., additional, Musella, A., additional, D'Amelio, M., additional, Cavallucci, V., additional, Martorana, A., additional, Bergamaschi, A., additional, Cencioni, M. T., additional, Diamantini, A., additional, Butti, E., additional, Comi, G., additional, Bernardi, G., additional, Cecconi, F., additional, Battistini, L., additional, Furlan, R., additional, and Martino, G., additional

Published
2009
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20. HSV-1-mediated IL-1 receptor antagonist gene therapy ameliorates MOG35–55-induced experimental autoimmune encephalomyelitis in C57BL/6 mice.

Author

Furlan, R., Bergami, A., Brambilla, E., Butti, E., De Simoni, M. G., Campagnoli, M., Marconi, P., Comi, G., and Martino, G.

Subjects
CYTOKINES, GENE therapy, MULTIPLE sclerosis, ENCEPHALOMYELITIS, CENTRAL nervous system, MACROPHAGES, ANTIGEN presenting cells
Abstract

Primary proinflammatory cytokines, such as IL-1β, play a crucial pathogenic role in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE), and may represent, therefore, a suitable therapeutic target. We have previously established the delivery of anti-inflammatory cytokine genes within the central nervous system (CNS), based on intracisternal (i.c.) injection of non-replicative HSV-1-derived vectors. Here we show the therapeutic efficacy of i.c. administration of an HSV-1-derived vector carrying the interleukin-1receptor antagonist (IL-1ra) gene, the physiological antagonist of the proinflammatory cytokine IL-1, in C57BL/6 mice affected by myelin oligodendrocyte glycoprotein-induced EAE. IL-1ra gene therapy is effective preventively, delaying EAE onset by almost 1 week (22.4±1.4 days post-immunization vs 15.9±2.1 days in control mice; P=0.0229 log-rank test), and decreasing disease severity. Amelioration of EAE course was associated with a reduced number of macrophages infiltrating the CNS and in a decreased level of proinflammatory cytokine mRNA in the CNS, suggesting an inhibitory activity of IL-1ra on effector cell recruitment, as antigen-specific peripheral T-cell activation and T-cell recruitment to the CNS is unaffected. Thus, local IL-1ra gene therapy may represent a therapeutic alternative for the inhibition of immune-mediated demyelination of the CNS.Gene Therapy (2007) 14, 93–98. doi:10.1038/sj.gt.3302805; published online 24 August 2006 [ABSTRACT FROM AUTHOR]

Published
2007
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23. Poster session 2

Author

Martins Fernandes, S, Teixeira, R, Roussin, I, Lynch, M, Badano, L, Muraru, D, Romeo, G, Ermacora, D, Marotta, C, Aruta, P, Cucchini, U, Iliceto, S, Garcia Campos, A, Martin-Fernandez, M, De La Hera Galarza, JM, Corros-Vicente, C, Colunga Blanco, S, Velasco-Alonso, E, Leon-Aguero, V, Rodriguez-Suarez, ML, Moris De La Tassa, C, Erdei, T, Edwards, J, Braim, D, Price, C, Fraser, AG, Cardiff, Investigators, MEDIA, Mehdipoor, G, Salmani, F, Arjmand Shabestari, A, Hanboly, N, Michalski, BW, Szymczyk, E, Kupczynska, K, Peczek, L, Nawrot, B, Lipiec, P, Kasprzak, JD, Vriz, O, Driussi, C, Ferrara, F, Brosolo, G, Antonini-Canterin, F, Magne, J, Aboyans, V, Bossone, E, Mo, VY, Bellucci, BM, Fisher, JM, Balekian, AA, Le, T T, Idapalapati, S, Huang, F, Wong, JI, Tan, RS, Ribeiro, JM, Teixeira, R, Madeira, M, Almeida, I, Reis, L, Siserman, A, Dinis, P, Dias, L, Ramos, AP, Goncalves, L, Ternacle, J, Wan, FW, Sawaki, DS, Dubois-Rande, JLDR, Adnot, SA, Czibik, GC, Derumeaux, GD, Yurdakul, SELEN, Ercan, G, Tekkesin, ILKER, Sahin, ST, Cengiz, B, Celik, G, Demircan, S, Aytekin, SAIDE, Shetye, A, Razvi, NA, Nazir, SA, Price, N, Khan, JN, Kanagala, P, Singh, A, Squire, I, Mccann, GP, Stoebe, S, Langel, M, Pfeiffer, D, Hagendorff, A, Lisowska, A, Ptaszynska-Kopczynska, K, Marcinkiewicz-Siemion, M, Knapp, M, Witkowski, M, Musial, WJ, Kaminski, K, Chinali, M, Natali, B, D' Anna, C, Leonardi, B, Secinaro, A, Pongiglione, G, Rinelli, G, Orabona, M, Renard, S, Michel, N, Mancini, J, Haentjens, J, Sitbon, O, Habib, G, Contaldi, C, Imbriaco, M, Alcidi, G, Santoro, C, Buonauro, A, Lo Iudice, F, Lembo, M, Cuocolo, A, Trimarco, B, Galderisi, M, De La Chica, JA, Mora Robles, J, Roldan Jimenez, MA, Mancisidor, MA, De Mora, MA, Codolosa, JN, Alnabelsi, T, Goykhman, I, Koshkelashvili, N, Romero-Corral, A, Pressman, GS, Trzcinski, P, Michalski, BW, Kupczynska, K, Miskowiec, D, Lipiec, P, Kasprzak, JD, Prado Diaz, S, Montoro Lopez, N, Refoyo Salicio, E, Valbuena Lopez, SC, Gonzalez, O, Alvarez, C, Moreno Yanguela, M, Bartha Rasero, JL, De La Calle, M, Guzman Martinez, G, Morales Portano, J D, Suarez-Cuenca, JA, Merino, JA, Gomez Alvarez, E B, Delgado, LG, Ha, SJ, Woo, YM, Bang, WD, Sohn, GH, Cheong, SS, Yoo, SY, Valente, F, Rodriguez Palomares, JF, Gutierrez, L, Maldonado, G, Pineda, V, Galian, L, Teixido, G, Gonzalez Allujas, MT, Evangelista, A, Garcia Dorado, D, Joseph, G, Zaremba, T, Ekeloef, S, Heiberg, E, Engblom, H, Jensen, SE, Sogaard, P, Valente, F, Rodriguez Palomares, JF, Gutierrez, L, Garcia, G, Pineda, V, Galian, L, Teixido, G, Gonzalez Allujas, MT, Evangelista, A, Garcia Dorado, D, Scali, MC, Dini, FL, Galli, F, Lattanzi, F, Picano, E, Marzilli, M, Cordeiro, F, Leao, S, Moz, M, Magalhaes, P, Trigo, J, Mateus, PS, Ferreira, A, Moreira, JI, Duchateau, N, De Craene, M, Legallois, D, Labombarda, F, Pellissier, A, Sermesant, M, Saloux, E, Fabris, E, Merlo, M, Moretti, M, Barbati, G, Stolfo, D, Gigli, M, Pinamonti, B, Sinagra, G, Costantino, MF, Dores, E, Matera, A, Innelli, P, Innelli, P, Lopizzo, A, Violini, R, Fiorilli, R, Cappabianca, G, Picano, E, Tarsia, G, Cho, I J, Seo, J, Chang, HJ, Heo, R, Kim, IC, Shim, CY, Hong, GR, Chung, N, Goublaire, C, Melissopoulou, MM, Nguyen, V, Brochet, E, Cimadevilla, C, Codogno, I, Vahanian, A, Messika-Zeitoun, D, Lam, W, Pontana, F, Vassiliou, V, Prasad, S, Galli, E, Leclercq, C, Samset, E, Donal, E, Kim, KH, Lim, DS, Mariani, M, Bianchi, G, Rossi, F, Gianetti, J, Marchi, F, Cerone, E, Nardelli, A, Terrazzi, M, Solinas, M, Maffei, S, Malev, E, Pshepiy, A, Vasina, L, Timofeev, E, Reeva, S, Zemtsovsky, E, Zuercher, F, Brugger, N, Jahren, S, De Marchi, SF, Seiler, C, Tang, Z, Jin, CN, Tang, H, Fan, K, Kam, K, Yan, BP, Yu, CM, Lee, PW, Cimino, S, Reali, M, Silvetti, E, Salatino, T, Mancone, M, Pennacchi, M, Giordano, A, Sardella, G, Agati, L, Mahia, P, Tirado, G, Nogales-Romo, MT, Marcos-Alberca, P, De Agustin, A, Almeria, C, Rodrigo, JL, Garcia Fernandez, MA, Macaya, C, Perez De Isla, L, De La Chica, JA, Mancisidor, M, Lara Garcia, C, Vivancos, R, De Mora, M, Petrovic, J, Petrovic, M, Vujisic-Tesic, B, Trifunovic, D, Boricic-Kostic, M, Petrovic, I, Draganic, G, Petrovic, O, Tomic-Dragovic, M, Ciobotaru, V, Remsey- Semmelweiss, E, Kogoj, P, Furlan, T, Ambrozic, J, Mohorko Pleskovic, PN, Bunc, M, Guerreiro, S, Ribeiras, R, Abecasis, J, Andrade, MJ, Mendes, M, Saxena, A, Ramakrishnan, S, Gupta, SK, Juneja, R, Kothari, SS, Mozenska, O, Zaleska, M, Segiet, A, Chwesiuk, S, Kroc, A, Kosior, DA, Pontone, G, Andreini, D, Solbiati, A, Guglielmo, M, Mushtaq, S, Baggiano, A, Beltrama, V, Rota, C, Guaricci, AI, Pepi, M, Macaya Ten, F, Pons Llinares, J, Asmarats Serra, L, Pericas Ramis, P, Caldes Llull, O, Grau Sepulveda, A, Frontera, G, Vaquer Segui, A, Noris, M, Bethencourt Gonzalez, A, Caballero, L, Climent Paya, V, Martinez Moreno, M, Saura, D, Oliva, MJ, Sanchez Quinones, J, Garcia Honrubia, A, Valdes, M, De La Morena, G, Avegliano, G, Terricabras, M, Costabel, JP, Ronderos, R, Evangelista, A, Venturini, C, Galve, E, Halmai, L, Nemes, A, Neubauer, S, Rahman Haley, S, Banner, N, Reis, L, Teixeira, R, Caetano, F, Almeida, I, Trigo, J, Botelho, A, Silva, J, Nascimento, J, Goncalves, L, Trifunovic, D, Tesic, M, Jovanovic, I, Petrovic, O, Boricic-Kostic, M, Dragovic, M, Petrovic, M, Stepanovic, J, Banovic, M, Vujisic-Tesic, B, Gospodinova, M, Guergelcheva, V, Chamova, T, Sarafov, S, Tournev, I, Denchev, S, Makavos, G, Ikonomidis, I, Psarogiannakopoulos, P, Tsirigotis, P, Paraskevaidis, I, Lekakis, J, D'ascenzi, F, Pelliccia, A, Natali, BM, Cameli, M, Focardi, M, Bonifazi, M, Mondillo, S, Dantas Tavares De Melo, M, Lima, C, Assed, L, Kalil Filho, R, Mady, C, Bochi, E A, Salemi, V M C, Bonapace, S, Targher, G, Valbusa, F, Rossi, A, Lanzoni, L, Lipari, P, Zenari, L, Molon, G, Canali, G, Barbieri, E, Kulkarni, A, Li, L, Craft, M, Nanda, M, Lorenzo, JM, Kutty, S, Cameli, M, Bombardini, T, Sparla, S, Di Tommaso, C, Losito, M, Incampo, E, Maccherini, M, Mondillo, S, Ingvarsson, A, Werther Evaldsson, A, Radegran, G, Stagmo, M, Waktare, J, Roijer, A, Meurling, CJ, Driessen, MMP, Hui, W, Meijboom, FJ, Bijnens, B, Dragulescu, A, Mertens, L, Friedberg, MK, Tufekcioglu, O, Sensoy, B, Suleymanoglu, M, Akin, Y, Sahan, E, Sasmaz, H, Radulescu, D, Pasca, L, Buzdugan, E, Chis, B, Stoicescu, L, Barac, A, Lynce, FC, Smith, KL, Mete, M, Isaacs, C, Cioffi, G, Viapiana, O, Di Nora, C, Ognibeni, F, Fracassi, E, Giollo, A, Mazzone, C, Faganello, G, Di Lenarda, A, Rossini, M, Almeida Morais, L, Galrinho, A, Branco, L, Timoteo, A T, Rodrigues, I, Daniel, P, Rosa, S, Ferreira, L, Ferreira, R, Ledakowicz-Polak, A, Polak, L, Krauza, G, Stokfisz, K, Zielinska, M, Portugal, G, Branco, L M, Galrinho, A, Mota Carmo, M, Teresa Timoteo, A, Aguiar Rosa, S, Abreu, J, Pinto Teixeira, P, Viveiros Monteiro, A, Cruz Ferreira, R, Naksuk, N, Peeraphatdit, T, Chaiteerakij, R, Klarich, KW, Parato, V M, Masia, S, Kovalova, S, Necas, J, Cherubini, A, Nistri, S, Negri, F, Barbati, G, Cioffi, G, Russo, G, Mazzone, C, Faganello, G, Pandullo, C, Di Lenarda, A, Corrado, G, Durante, A, Rovelli, E, Genchi, V, Trabattoni, L, Zerboni, SC, Cattaneo, L, Butti, E, Ferrari, G, Malev, E, Luneva, E, Mitrofanova, L, Uspensky, V, Zemtsovsky, E, Wierzbowska-Drabik, K, Kasprzak, JD, Lesevic, H, Rosner, S, Karl, M, Ott, I, Sonne, C, Laredj, N, Ali Lahmar, HM, Hammou, L, Pieles, G E, Forsey, J, Gowing, L, Miller, F, Ramanujam, P, Stuart, AG, Williams, CA, Generati, G, Bandera, F, Pellegrino, M, Carbone, F, Labate, V, Alfonzetti, E, Guazzi, M, Van Zalen, JJ, Patel, NR, Raju, P, Beale, L, Brickley, G, Lloyd, GW, Aquila, I, Fernandez-Golfin, C, Gonzalez, A, Rincon, LM, Hinojar, R, Garcia, A, Megias, A, Jimenez-Nacher, JJ, Moya, JL, Zamorano, JL, Cheng, H-L, Lanzoni, L, Molon, G, Canali, G, Bonapace, S, Chiampan, A, Albrigi, L, Barbieri, E, Asmarats Serra, L, Noris Mora, M, Rodriguez Fernandez, A, Exposito Pineda, C, Grande, C, Gonzalez Colino, R, Macaya Ten, F, Fernandez Vazquez, X, Fortuny Frau, E, Bethencourt Gonzalez, A, Kadrabulatova, S, Ranjbar, S, Karvandi, M, Szczesniak-Stanczyk, D, Blaszczyk, R, Zarczuk, R, Brzozowski, W, Janowski, M, Wysokinski, A, Stanczyk, B, Consortium, ReMeDi, Sharka, I, Myftiu, S, Teferici, D, Quka, A, Dado, E, Djamandi, J, Kresto, L, Duka, A, Kristo, A, Balla, I, Di Salvo, G, Issa, Z, Moiduddin, N, Siblini, G, Bulbul, Z, Ben Kahla, S, Abid, L, Abid, D, Kammoun, S, Li, L, Rush, E, Craft, M, Goodwin, J, Kreikemeier, R, Cantinotti, M, Kutty, S, Hadeed, HA, Zolaly, M A, Khoshhal, SQ, El-Harbi, K, Tarawah, A, Al-Hawsawi, Z, Al-Mozainy, I, Habeeb, H A, Bakhoum, S W G, Nabil, M N, Elebrashy, I N, Toscano, A, Chinali, M, Albanese, S, Carotti, A, Iacobelli, R, Esposito, C, Secinaro, A, Moscogiuri, G, Pasquini, L, Granata, F, Malvezzi Caracciolo, M, Bianchi, RM, Caso, P, Arenga, F, Riegler, L, Scarafile, R, D'andrea, A, Russo, MG, Calabro', P, Djikic, D, Simic, DS, Peric, VP, Mujovic, NM, Marinkovic, MM, Jankovic, NJ, Wdowiak-Okrojek, K, Shim, A, Wejner-Mik, P, Kasprzak, JD, Lipiec, P, Girgis, H Y A, Sharma, A, Jain, N, Kharwar, R, Saran, RK, Narain, VS, Dwivedi, SK, Sethi, R, Chandra, S, Pradhan, A, Safal, S, Soro, C, Marchetti, MF, Cacace, C, Congia, M, Nissardi, V, Ruscazio, M, Meloni, L, Montisci, R, Gallego Page, J C, Gallego Sanchez, G, Calero, S, Portero, JJ, Tercero, A, Garcia, JC, Barambio, M, Martinez Lazaro, R, Corneli, M, Meretta, AH, Perea, GO, Belcastro, F, Aguirre, E, De Luca, I, Henquin, R, and Masoli, O

Abstract

Introduction: The relationship between the appropriateness of the transthoracic echocardiography (TTE) and its clinical impact is still a matter of debate. Objective: The aim of this study was to assess the degree of adherence to the appropriate use criteria for echocardiography, in a tertiary public hospital in the United Kingdom, as well as the clinical impact of the exam on patient management. Methods: 859 TTE’s performed consecutively during January 2014 were reviewed to assess its appropriateness, and were classified as appropriate, uncertain or inappropriate using the 2011 guidelines. Subsequently, patient’s files were examined to determine the clinical impact of the TTE which was assigned to one of the following three categories: (1) active change in care, (2) continuation of current care, or (3) no change in care. Patients which files were not available were excluded (259). All classifications were evaluated by two independent cardiologists, with no direct relation to the study. Results: Our sample had a mean age of 63 ± 17 years with a gender balance. The majority of the exams were requested at the outpatient (81.4%) clinic, by cardiologists (50.3%) and general practitioners (13.4%). Regarding the main findings, in 7.6% of the studies there were moderate to severe systolic dysfunction; 4.0% showed severe valvular heart disease and 5.1% had significant pulmonary hypertension. Relatively to the appropriateness of the TTE requests, 76.5% were considered appropriate, 7.1% inappropriate and 12.6% uncertain. With respect to the clinical impact of the TTE’s, 42.7% of the exams led to an active change in care, 15.6% to a continuation of the care and 11.5% revealed no change in care. Age (β0.90, P=0.05) and outpatient setting (β4.4, P<0.01) were the most important predictors of an active change of care exam. On the contrary, the appropriateness of the TTE’s requests (β1.1, P=0.56) and the specialist ordering the exams (β0.81, P=0.26) were not independently associated. Conclusion: Our data showed that almost 8 out of 10 TTE were considered appropriate, and 4 out of 10 exams had an active clinical impact.

Published
2015
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24. TLR3 preconditioning induces anti-inflammatory and anti-ictogenic effects in mice mediated by the IRF3/IFN-β axis

Author

Annamaria Vezzani, E. Butti, Sergio Marchini, Cecilia Garlanda, L. Carmant, Valentina Iori, Eleonora Aronica, T. Shaker, Teresa Ravizza, Chrysaugi Kostoula, Rosaria Pascente, Ilaria Craparotta, Milica Cerovic, Gianvito Martino, Pathology, ANS - Cellular & Molecular Mechanisms, APH - Aging & Later Life, APH - Mental Health, Kostoula, C., Shaker, T., Cerovic, M., Craparotta, I., Marchini, S., Butti, E., Pascente, R., Iori, V., Garlanda, C., Aronica, E., Martino, G., Ravizza, T., Carmant, L., and Vezzani, A.

Subjects
Male, 0301 basic medicine, viruses, Immunology, Anti-Inflammatory Agents, Hippocampus, Receptors, Cell Surface, Stimulation, Pharmacology, Inhibitory postsynaptic potential, Proinflammatory cytokine, Mice, 03 medical and health sciences, Behavioral Neuroscience, Epilepsy, 0302 clinical medicine, Seizures, medicine, Animals, Inflammation, C [Poly I], Endocrine and Autonomic Systems, Chemistry, NF-kappa B, virus diseases, Population spike, Interferon-beta, Viral encephalitis, medicine.disease, Toll-like receptors, Toll-Like Receptor 3, Mice, Inbred C57BL, Poly I-C, 030104 developmental biology, nervous system, Interferon, Anticonvulsants, Interferon Regulatory Factor-3, Signal transduction, IRF3, Neuroglia, 030217 neurology & neurosurgery, Signal Transduction
Abstract

Activation of Toll-like receptor 3 (TLR3) was previously shown to contribute to the generation of epileptic seizures in rodents by evoking a proinflammatory response in the forebrain. This suggests that TLR3 blockade may provide therapeutic effects in epilepsy. We report that brain activation of TLR3 using the synthetic receptor ligand Poly I:C may also result in remarkable dose- and time-dependent inhibitory effects on acute seizures in mice without inducing inflammation. These inhibitory effects are associated with reduced neuronal excitability in the hippocampus as shown by a decrease in the population spike amplitude of CA1 pyramidal neurons following Schaffer collaterals stimulation. TLR3 activation which results in seizure inhibition does not evoke NF-kB-dependent inflammatory molecules or morphological activation of glia, however, it induces the alternative interferon (IFN) regulatory factor (IRF)-3/IFN-β signaling pathway. IFN-β reproduced the inhibitory effects of Poly I:C on neuronal excitability in hippocampal slices. Seizure inhibition attained with activation the TLR3-IRF3/IFN-β axis should be carefully considered when TLR3 are targeted for therapeutic purposes.

Published
2019

25. Neural Stem Cells of the Subventricular Zone Contribute to Neuroprotection of the Corpus Callosum after Cuprizone-Induced Demyelination

Author

Linda Chaabane, Elena Brambilla, Marco Bacigaluppi, Erica Butti, Gianvito Martino, Carolina Montonati, Giulia Berera, Francesca Ruffini, Angelo Quattrini, Butti, E., Bacigaluppi, M., Chaabane, L., Ruffini, F., Brambilla, E., Berera, G., Montonati, C., Quattrini, A., and Martino, G.

Subjects
0301 basic medicine, Axonal loss, Subventricular zone, Ablation, Biology, Neuroprotection, Corpus Callosum, Multiple sclerosis, Cuprizone, Mice, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, Cell Movement, Lateral Ventricles, Precursor cell, medicine, Transgenic mice, Animals, Remyelination, Demyelinating Disorder, Research Articles, Myelin Sheath, Neural stem cells, Sub ventricular zone, General Neuroscience, medicine.disease, Neural stem cell, Mice, Inbred C57BL, Oligodendroglia, 030104 developmental biology, medicine.anatomical_structure, nervous system, Female, Neuroscience, 030217 neurology & neurosurgery, Demyelinating Diseases
Abstract

Myelin loss occurring in demyelinating diseases, including multiple sclerosis, is the leading cause of long-lasting neurological disability in adults. While endogenous remyelination, driven by resident oligodendrocyte precursor cells (OPCs), might partially compensate myelin loss in the early phases of demyelinating disorders, this spontaneous reparative potential fails at later stages. To investigate the cellular mechanisms sustaining endogenous remyelination in demyelinating disorders, we focused our attention on endogenous neural precursor cells (eNPCs) located within the subventricular zone (SVZ) since this latter area is considered one of the primary sources of new OPCs in the adult forebrain. First, we fate mapped SVZ-eNPCs in cuprizone-induced demyelination and found that SVZ endogenous neural stem/precursor cells are recruited during the remyelination phase to the corpus callosum (CC) and are capable of forming new oligodendrocytes. When we ablated SVZ-derived eNPCs during cuprizone-induced demyelination in female mice, the animals displayed reduced numbers of oligodendrocytes within the lesioned CC. Although this reduction in oligodendrocytes did not impact the ensuing remyelination, eNPC-ablated mice experienced increased axonal loss. Our results indicate that, in toxic models of demyelination, SVZ-derived eNPCs contribute to support axonal survival. SIGNIFICANCE STATEMENT One of the significant challenges in MS research is to understand the detrimental mechanisms leading to the failure of CNS tissue regeneration during disease progression. One possible explanation is the inability of recruited oligodendrocyte precursor cells (OPCs) to complete remyelination and to sustain axonal survival. The contribution of endogenous neural precursor cells (eNPCs) located in the subventricular zone (SVZ) to generate new OPCs in the lesion site has been debated. Using transgenic mice to fate map and to selectively kill SVZ-derived eNPCs in the cuprizone demyelination model, we observed migration of SVZ-eNPCs after injury and their contribution to oligodendrogenesis and axonal survival. We found that eNPCs are dispensable for remyelination but protect partially from increased axonal loss.

Published
2019

26. Endogenous neural precursor cells in health and disease

Author

Marco Bacigaluppi, Gianvito Martino, Giacomo Sferruzza, Linda Ottoboni, Erica Butti, Bacigaluppi, M., Sferruzza, G., Butti, E., Ottoboni, L., and Martino, G.

Subjects
0301 basic medicine, Aging, Non neurogenesis, Subventricular zone, Neurogenesis, Biology, Subgranular zone, Bystander effect, 03 medical and health sciences, Lateral ventricles, 0302 clinical medicine, Neural Stem Cells, Precursor cell, otorhinolaryngologic diseases, medicine, Animals, Homeostasis, Humans, Progenitor cell, Molecular Biology, Neural stem cells, Brain Diseases, Role of neurogenesis, Therapeutic plasticity, General Neuroscience, Dentate gyrus, Brain, Neurodegenerative Diseases, Neural stem cell, stomatognathic diseases, 030104 developmental biology, medicine.anatomical_structure, Neurology (clinical), Neuroscience, 030217 neurology & neurosurgery, Developmental Biology
Abstract

Neurogenesis persists in the adult brain of mammals in the subventricular zone (SVZ) of the lateral ventricles and in the subgranular zone (SGZ) of the dentate gyrus (DG). The complex interactions between intrinsic and extrinsic signals provided by cells in the niche but also from distant sources regulate the fate of neural stem/progenitor cells (NPCs) in these sites. This fine regulation is perturbed in aging and in pathological conditions leading to a different NPC behavior, tailored to the specific physio-pathological features. Indeed, NPCs exert in physiological and pathological conditions important neurogenic and non-neurogenic regulatory functions and participate in maintaining and protecting brain tissue homeostasis. In this review, we discuss intrinsic and extrinsic signals that regulate NPC activation and NPC functional role in various homeostatic and non-homeostatic conditions.

Published
2020

27. Inflammation Triggers Synaptic Alteration and Degeneration in Experimental Autoimmune Encephalomyelitis

Author

Gianvito Martino, Valentina De Chiara, Giorgio Bernardi, Silvia Rossi, Alessandra Bergami, Diego Centonze, Giancarlo Comi, Alessandra Musella, Andrea Bergamaschi, Francesca Cavasinni, Marcello D'Amelio, Alessandro Martorana, Roberto Furlan, Luca Muzio, Maria Teresa Cencioni, Adamo Diamantini, Erica Butti, Francesco Cecconi, Luca Battistini, Virve Cavallucci, Centonze, D, Muzio, L, Rossi, S, Cavasinni, F, De Chiara, V, Bergami, A, Musella, A, D'Amelio, M, Cavallucci, V, Martorana, A, Bergamaschi, A, Cencioni, Mt, Diamantini, A, Butti, E, Bernardi, G, Cecconi, F, Battistini, L, Furlan, R, Comi, G, and Martino, G

Subjects
protein p55, microglia, animal cell, multiple sclerosis, Inbred C57BL, AMPA receptor, CD45 antigen, gamma interferon receptor 1, glutamate receptor 1, glutamic acid, histone H3, messenger RNA, myelin, postsynaptic density protein 95, tumor necrosis factor alpha, allergic encephalomyelitis, animal experiment, animal model, animal tissue, Arc gene, Arg3.1 gene, article, central nervous system, controlled study, corpus striatum, cytokine release, demyelination, dendrite, down regulation, female, gene, gene expression, immunocompetent cell, inflammation, mouse, nerve degeneration, nonhuman, priority journal, protein phosphorylation, synaptic transmission, Animals, Cell Line, Transformed, Encephalomyelitis, Autoimmune, Experimental, Female, Inflammation, Mice, Mice, Inbred C57BL, Nerve Degeneration, Receptors, AMPA, Synapses, Receptors, AMPA, Encephalomyelitis, Microglia, General Neuroscience, Neurodegeneration, Experimental autoimmune encephalomyelitis, Glutamate receptor, Articles, medicine.anatomical_structure, Settore MED/26 - Neurologia, Synaptopathy, experimental autoimmune encephalomyeliti, Biology, Neuroprotection, Cell Line, Experimental, medicine, Neuroinflammation, medicine.disease, Transformed, synaptic alteration, Immunology, Neuroscience, Autoimmune
Abstract

Neurodegeneration is the irremediable pathological event occurring during chronic inflammatory diseases of the CNS. Here we show that, in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, inflammation is capable in enhancing glutamate transmission in the striatum and in promoting synaptic degeneration and dendritic spine loss. These alterations occur early in the disease course, are independent of demyelination, and are strongly associated with massive release of tumor necrosis factor-α from activated microglia. CNS invasion by myelin-specific blood-borne immune cells is the triggering event, and the downregulation of the early geneArc/Arg3.1, leading to the abnormal expression and phosphorylation of AMPA receptors, represents a culminating step in this cascade of neurodegenerative events. Accordingly, EAE-induced synaptopathy subsided during pharmacological blockade of AMPA receptors. Our data establish a link between neuroinflammation and synaptic degeneration and calls for early neuroprotective therapies in chronic inflammatory diseases of the CNS.

Published
2009

28. Persistent modification of forebrain networks and metabolism in rats following adolescent exposure to a 5-HT7 receptor agonist

Author

Rossella Canese, Gianvito Martino, Luisa Altabella, Francesco de Pasquale, Francesca Zoratto, Enza Lacivita, Laura Mercurio, Giovanni Laviola, Paola Porcari, Erica Butti, Marcello Leopoldo, Walter Adriani, Canese, R, Zoratto, F, Altabella, L, Porcari, P, Mercurio, L, de Pasquale, F, Butti, E, Martino, Gianvito, Lacivita, E, Leopoldo, M, Laviola, G, and Adriani, W.

Subjects
Male, Agonist, medicine.medical_specialty, medicine.drug_class, Hippocampus, Amygdala, Piperazines, 5-HT7 receptor, Prosencephalon, Internal medicine, medicine, Animals, Rats, Wistar, Receptor, Pharmacology, Age Factors, Magnetic Resonance Imaging, Rats, Serotonin Receptor Agonists, medicine.anatomical_structure, Endocrinology, Receptors, Serotonin, Forebrain, 5-HT6 receptor, Serotonin, Nerve Net, Psychology, Neuroscience
Abstract

The serotonin 7 receptor (5-HT7-R) is part of a neuro-transmission system with a proposed role in neural plasticity and in mood, cognitive or sleep regulation.We investigated long-term consequences of sub-chronic treatment, during adolescence (43-45 to 47-49 days old) in rats, with a novel 5-HT7-R agonist (LP-211, 0 or 0.250 mg/kg/day).We evaluated behavioural changes as well as forebrain structural/functional modifications by in vivo magnetic resonance (MR) in a 4.7 T system, followed by ex vivo histology.Adult rats pre-treated during adolescence showed reduced anxiety-related behaviour, in terms of reduced avoidance in the light/dark test and a less fragmented pattern of exploration in the novel object recognition test. Diffusion tensor imaging (DTI) revealed decreased mean diffusivity (MD) in the amygdala, increased fractional anisotropy (FA) in the hippocampus (Hip) and reduced axial (D||) together with increased radial (D⊥) diffusivity in the nucleus accumbens (NAcc). An increased neural dendritic arborization was confirmed in the NAcc by ex vivo histology. Seed-based functional MR imaging (fMRI) identified increased strength of connectivity within and between "limbic" and "cortical" loops, with affected cross-correlations between amygdala, NAcc and Hip. The latter displayed enhanced connections through the dorsal striatum (dStr) to dorso-lateral prefrontal cortex (dl-PFC) and cerebellum. Functional connection also increased between amygdala and limbic elements such as NAcc, orbito-frontal cortex (OFC) and hypothalamus. MR spectroscopy (1H-MRS) indicated that adolescent LP-211 exposure increased glutamate and total creatine in the adult Hip.Persistent MR-detectable modifications indicate a rearrangement within forebrain networks, accounting for long-lasting behavioural changes as a function of developmental 5-HT7-R stimulation.

Published
2015

29. HSV-1-mediated IL-1 receptor antagonist gene therapy ameliorates MOG35–55-induced experimental autoimmune encephalomyelitis in C57BL/6 mice

Author

Peggy Marconi, Elena Brambilla, Erica Butti, M.G. De Simoni, Alessandra Bergami, M Campagnoli, Roberto Furlan, G. Comi, Gianvito Martino, Furlan, R, Bergami, A, Brambilla, E, Butti, E, De Simoni, Mg, Campagnoli, M, Marconi, P, Martino, Gianvito, and Comi, Giancarlo

Subjects
Central Nervous System, Encephalomyelitis, Autoimmune, Experimental, Time Factors, T-Lymphocytes, medicine.medical_treatment, Encephalomyelitis, Genetic Vectors, Central nervous system, Gene Expression, Herpesvirus 1, Human, Injections, Proinflammatory cytokine, Interferon-gamma, Mice, Myelin, Cisterna Magna, Genetics, medicine, Animals, RNA, Messenger, Molecular Biology, Interleukin-6, Tumor Necrosis Factor-alpha, business.industry, Macrophages, Multiple sclerosis, Experimental autoimmune encephalomyelitis, Genetic Therapy, medicine.disease, Oligodendrocyte, Mice, Inbred C57BL, Interleukin 1 Receptor Antagonist Protein, Myelin-Associated Glycoprotein, Cytokine, medicine.anatomical_structure, Immunology, Molecular Medicine, Myelin-Oligodendrocyte Glycoprotein, business, Myelin Proteins, Interleukin-1
Abstract

Primary proinflammatory cytokines, such as IL-1beta, play a crucial pathogenic role in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE), and may represent, therefore, a suitable therapeutic target. We have previously established the delivery of anti-inflammatory cytokine genes within the central nervous system (CNS), based on intracisternal (i.c.) injection of non-replicative HSV-1-derived vectors. Here we show the therapeutic efficacy of i.c. administration of an HSV-1-derived vector carrying the interleukin-1receptor antagonist (IL-1ra) gene, the physiological antagonist of the proinflammatory cytokine IL-1, in C57BL/6 mice affected by myelin oligodendrocyte glycoprotein-induced EAE. IL-1ra gene therapy is effective preventively, delaying EAE onset by almost 1 week (22.4+/-1.4 days post-immunization vs 15.9+/-2.1 days in control mice; P=0.0229 log-rank test), and decreasing disease severity. Amelioration of EAE course was associated with a reduced number of macrophages infiltrating the CNS and in a decreased level of proinflammatory cytokine mRNA in the CNS, suggesting an inhibitory activity of IL-1ra on effector cell recruitment, as antigen-specific peripheral T-cell activation and T-cell recruitment to the CNS is unaffected. Thus, local IL-1ra gene therapy may represent a therapeutic alternative for the inhibition of immune-mediated demyelination of the CNS.

Published
2006

30. Neurogenic and non neurogenic functions of endogenous neural stem cells

Author

Gianvito Martino, Melania Cusimano, Erica Butti, Marco Bacigaluppi, Butti, E, Cusimano, M, Bacigaluppi, M, and Martino, Gianvito

Subjects
Inflammation, Transplantation, General Neuroscience, Dentate gyrus, Neurogenesis, Subventricular zone, Review Article, Bystander Effect, Biology, germinal niches, Neural stem cell, Subgranular zone, lcsh:RC321-571, Lateral ventricles, medicine.anatomical_structure, Neural Stem Cells, medicine, Progenitor cell, Neuroscience, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry
Abstract

Adult neurogenesis is a lifelong process that occurs in two main neurogenic niches of the brain, namely in the subventricular zone (SVZ) of the lateral ventricles and in the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus. In the 1960s, studies on adult neurogenesis have been hampered by the lack of established phenotypic markers. The precise tracing of neural stem/progenitor cells (NPCs) was therefore, not properly feasible. After the (partial) identification of those markers, it was the lack of specific tools that hindered a proper experimental elimination and tracing of those cells to demonstrate their terminal fate and commitment. Nowadays, irradia-tion, cytotoxic drugs as well as genetic tracing/ablation procedures have moved the field forward and increased our understanding of neurogenesis processes in both physiological and pathological conditions. Newly formed NPC progeny from the SVZ can replace granule cells in the olfactory bulbs of rodents, thus contributing to orchestrate sophisticated odour behaviour. SGZ-derived new granule cells, instead, integrate within the DG where they play an essential role in memory functions. Furthermore, converging evidence claim that endogenous NPCs not only exert neurogenic functions, but might also have non-neurogenic homeostatic functions by the release of different types of neuroprotective molecules. Remarkably, these non-neurogenic homeostatic functions seem to be necessary, both in healthy and diseased conditions, for example for preventing or limiting tissue damage. In this review, we will discuss the neurogenic and the non-neurogenic functions of adult NPCs both in physiological and pathological conditions.

Published
2014

31. Subventricular zone neural progenitors protect striatal neurons from glutamatergic excitotoxicity

Author

Silvia Rossi, Marco Bacigaluppi, Alessandra Musella, Luca Muzio, Arantxa Cebrian Silla, Monica Bari, Mauro Maccarrone, José Manuel García-Verdugo, Erica Butti, Giancarlo Comi, Roberta De Ceglia, Angelo Quattrini, Patrizia D'Adamo, Gianvito Martino, Diego Centonze, Marco Cambiaghi, Letizia Leocani, Luis Teneud, Valentina De Chiara, Elena Brambilla, Butti, E, Bacigaluppi, M, Rossi, S, Cambiaghi, M, Bari, M, Cebrian Silla, A, Brambilla, E, Musella, A, De Ceglia, R, Teneud, L, De Chiara, V, D'Adamo, Patrizia, Verdugo, G, Comi, Giancarlo, Muzio, L, Quattrini, A, Leocani, ANNUNZIATA MARIA LETIZIA, Maccarrone, L, Centonze, D, and Martino, Gianvito

Subjects
Lipopolysaccharides, Polyunsaturated Alkamides, Subventricular zone, Glutamic Acid, Mice, Transgenic, Arachidonic Acids, Biology, Amidohydrolases, Glutamatergic, Mice, Neural Stem Cells, Lateral Ventricles, medicine, Animals, Dronabinol, Progenitor cell, 4-Aminopyridine, neurogenesis, ischaemia, neural stem cells, excitotoxicity, endocannabinoids, Ganciclovir, Epilepsy, Stem Cells, Neurogenesis, Excitatory Postsynaptic Potentials, Neural stem cell, Corpus Striatum, Neuroepithelial cell, Mice, Inbred C57BL, Stroke, Disease Models, Animal, medicine.anatomical_structure, Neuroprotective Agents, Benzamides, Settore MED/26 - Neurologia, Neurology (clinical), Carbamates, Stem cell, Neuroscience, Excitatory Amino Acid Antagonists, Adult stem cell, Endocannabinoids
Abstract

The functional significance of adult neural stem and progenitor cells in hippocampal-dependent learning and memory has been well documented. Although adult neural stem and progenitor cells in the subventricular zone are known to migrate to, maintain and reorganize the olfactory bulb, it is less clear whether they are functionally required for other processes. Using a conditional transgenic mouse model, selective ablation of adult neural stem and progenitor cells in the subventricular zone induced a dramatic increase in morbidity and mortality of central nervous system disorders characterized by excitotoxicity-induced cell death accompanied by reactive inflammation, such as 4-aminopyridine-induced epilepsy and ischaemic stroke. To test the role of subventricular zone adult neural stem and progenitor cells in protecting central nervous system tissue from glutamatergic excitotoxicity, neurophysiological recordings of spontaneous excitatory postsynaptic currents from single medium spiny striatal neurons were measured on acute brain slices. Indeed, lipopolysaccharide-stimulated, but not unstimulated, subventricular zone adult neural stem and progenitor cells reverted the increased frequency and duration of spontaneous excitatory postsynaptic currents by secreting the endocannabinod arachidonoyl ethanolamide, a molecule that regulates glutamatergic tone through type 1 cannabinoid receptor (CB(1)) binding. In vivo restoration of cannabinoid levels, either by administration of the type 1 cannabinoid receptor agonist HU210 or the inhibitor of the principal catabolic enzyme fatty acid amide hydrolase, URB597, completely reverted the increased morbidity and mortality of adult neural stem and progenitor cell-ablated mice suffering from epilepsy and ischaemic stroke. Our results provide the first evidence that adult neural stem and progenitor cells located within the subventricular zone exert an 'innate' homeostatic regulatory role by protecting striatal neurons from glutamate-mediated excitotoxicity.

Published
2012

32. In vivo fate analysis reveals the multipotent and self-renewal features of embryonic AspM expressing cells

Author

Andrea Bergamaschi, Cinzia Marinaro, Roberto Furlan, Erica Butti, Luca Muzio, Giancarlo Comi, Gianvito Martino, Alessandro Papale, Marinaro, C, Butti, E, Bergamaschi, A, Papale, A, Furlan, R, Comi, Giancarlo, Martino, Gianvito, and Muzio, L.

Subjects
Central Nervous System, Time Factors, Anatomy and Physiology, Mouse, Cell Culture Techniques, lcsh:Medicine, Cell Fate Determination, Mice, Neural Stem Cells, Stem Cell Niche, lcsh:Science, Cerebral Cortex, Multidisciplinary, Stem Cells, Neurogenesis, Cell Differentiation, Animal Models, Anatomy, Neural stem cell, Cell biology, Neuroepithelial cell, medicine.anatomical_structure, Neuroglia, Research Article, Cell Potency, Green Fluorescent Proteins, Mice, Transgenic, Nerve Tissue Proteins, Biology, Neurological System, ASPM, Prosencephalon, Model Organisms, Developmental Neuroscience, Neuroblast, Neurosphere, medicine, Animals, Cell Lineage, Radial glia, Neural Stem Cells, AspM, Alleles, Embryonic Stem Cells, Cell Proliferation, lcsh:R, Embryonic stem cell, nervous system, Calmodulin-Binding Proteins, lcsh:Q, Developmental Biology, Neuroscience
Abstract

Radial Glia (RG) cells constitute the major population of neural progenitors of the mouse developing brain. These cells are located in the ventricular zone (VZ) of the cerebral cortex and during neurogenesis they support the generation of cortical neurons. Later on, during brain maturation, RG cells give raise to glial cells and supply the adult mouse brain of Neural Stem Cells (NSC). Here we used a novel transgenic mouse line expressing the CreER(T2) under the control of AspM promoter to monitor the progeny of an early cohort of RG cells during neurogenesis and in the post natal brain. Long term fate mapping experiments demonstrated that AspM-expressing RG cells are multi-potent, as they can generate neurons, astrocytes and oligodendrocytes of the adult mouse brain. Furthermore, AspM descendants give also rise to proliferating progenitors in germinal niches of both developing and post natal brains. In the latter--i.e. the Sub Ventricular Zone--AspM descendants acquired several feature of neural stem cells, including the capability to generate neurospheres in vitro. We also performed the selective killing of these early progenitors by using a Nestin-GFP(flox)-TK allele. The forebrain specific loss of early AspM expressing cells caused the elimination of most of the proliferating cells of brain, a severe derangement of the ventricular zone architecture, and the impairment of the cortical lamination. We further demonstrated that AspM is expressed by proliferating cells of the adult mouse SVZ that can generate neuroblasts fated to become olfactory bulb neurons.

Published
2011

33. IL4 gene delivery to the CNS recruits regulatory T cells and induces clinical recovery in mouse models of multiple sclerosis

Author

Elena Brambilla, Alessandra Bergami, Gianvito Martino, Marianna Esposito, Fulvio Mavilio, G. Comi, U Del Carro, Anna Stornaiuolo, Alessandra Recchia, Stefano Amadio, Roberto Furlan, A Cattalini, Stefano Pluchino, Erica Butti, Butti, E, Bergami, A, Recchia, A, Brambilla, E, Del Carro, U, Amadio, S, Cattalini, A, Esposito, M, Stornaiuolo, A, Comi, G, Pluchino, S, Mavilio, F, Martino, G, and Furlan, R

Subjects
Central Nervous System, Multiple Sclerosis, Regulatory T cell, Genetic enhancement, Animal Female Gene Therapy/*methods Genetic Vectors/administration & dosage Green Fluorescent Proteins/analysis/genetics Helper Viruses/genetics Humans Interleukin-4/analysis/*genetics/immunology Mice Mice, Genetic Vectors, Green Fluorescent Proteins, Regulatory/*immunology, CCL1, Gene delivery, Biology, T-Lymphocytes, Regulatory, Leukocyte Disease Models, Viral vector, Adenoviridae, Inbred C57BL Multiple Sclerosis/immunology/pathology/*therapy Reverse Transcriptase Polymerase Chain Reaction T-Lymphocytes, Mice, immune system diseases, Transduction, Genetic, Genetics, medicine, Animals, Humans, Molecular Biology, Reverse Transcriptase Polymerase Chain Reaction, Multiple sclerosis, Experimental autoimmune encephalomyelitis, FOXP3, hemic and immune systems, Genetic Therapy, medicine.disease, Adenoviridae/genetics Animals Central Nervous System/*immunology/pathology Chemokines/immunology Chemotaxis, Mice, Inbred C57BL, Chemotaxis, Leukocyte, Disease Models, Animal, medicine.anatomical_structure, Immunology, Molecular Medicine, Female, Interleukin-4, Chemokines, Helper Viruses
Abstract

Central nervous system (CNS) delivery of anti-inflammatory cytokines, such as interleukin 4 (IL4), holds promise as treatment for multiple sclerosis (MS). We have previously shown that short-term herpes simplex virus type 1-mediated IL4 gene therapy is able to inhibit experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in mice and non-human primates. Here, we show that a single administration of an IL4-expressing helper-dependent adenoviral vector (HD-Ad) into the cerebrospinal fluid (CSF) circulation of immunocompetent mice allows persistent transduction of neuroepithelial cells and long-term (up to 5 months) CNS transgene expression without toxicity. Mice affected by chronic and relapsing EAE display clinical and neurophysiological recovery from the disease once injected with the IL4-expressing HD-Ad vector. The therapeutic effect is due to the ability of IL4 to increase, in inflamed CNS areas, chemokines (CCL1, CCL17 and CCL22) capable of recruiting regulatory T cells (CD4+CD69- CD25+Foxp3+) with suppressant functions. CSF delivery of HD-Ad vectors expressing anti-inflammatory molecules might represent a valuable therapeutic option for CNS inflammatory disorders.

Published
2008

34. Absence of an intrathecal immune reaction to a helper-dependent adenoviral vector delivered into the cerebrospinal fluid of non-human primates

Author

F Lachapelle, Erica Butti, Roberto Furlan, Elena Brambilla, Alessandra Recchia, Gianvito Martino, Fulvio Mavilio, Alessandra Bergami, A Cattalini, G. Comi, Diego Franciotta, Anna Stornaiuolo, Butti, E, Bergami, A, Recchia, A, Brambilla, E, Franciotta, D, Cattalini, A, Stornaiuolo, A, Lachapelle, F, Mavilio, F, Furlan, R., Comi, G, and Martino, G

Subjects
Male, Genetic enhancement, Central nervous system, Genetic Vectors, Neuroepithelial Cells, Gene Expression, Inflammation, Biology, medicine.disease_cause, Spinal Puncture, Viral vector, Adenoviridae, Adenoviridae/*genetics, Animals, Cerebrospinal Fluid/*virology, Gene Therapy/*methods, Interleukin-4/genetics, Macaca fascicularis, Cerebrospinal fluid, Immunity, Transduction, Genetic, Genetics, medicine, Vector (molecular biology), Molecular Biology, Cerebrospinal Fluid, Parkinson Disease, Genetic Therapy, medicine.anatomical_structure, Immunology, Models, Animal, Molecular Medicine, Interleukin-4, medicine.symptom, Genetic Engineering, Helper Viruses
Abstract

Inflammation and immune reaction, or pre-existing immunity towards commonly used viral vectors for gene therapy severely impair long-term gene expression in the central nervous system (CNS), impeding the possibility to repeat the therapeutic intervention. Here, we show that injection of a helper-dependent adenoviral (HD-Ad) vector by lumbar puncture into the cerebrospinal fluid (CSF) of non-human primates allows long-term (three months) infection of neuroepithelial cells, also in monkeys bearing a pre-existing anti-adenoviral immunity. Intrathecal injection of the HD-Ad vector was not associated with any sign of systemic or local toxicity, nor by signs of a CNS-specific immune reaction towards the HD-Ad vector. Injection of HD-Ad vectors into the CSF circulation may thus represent a valuable approach for CNS gene therapy allowing for long-term expression and re-administration.

Published
2007

35. Gene and Stem Cell Therapy for Autoimmune Demyelination

Author

Lucia Zanotti, Michela Deleidi, Gianvito Martino, S. Bucello, Roberto Furlan, Stefano Pluchino, Marco Bacigaluppi, Erica Butti, Perez D., Mitrovic B., Baron Van Evercooren A., Pluchino, Bacigaluppi, M, Bucello, S, Butti, E, Deleidi, M, Zanotti, L, Martino, Gianvito, and Furlan, G.

Subjects
business.industry, Multiple sclerosis, medicine.medical_treatment, Genetic enhancement, Experimental autoimmune encephalomyelitis, Central nervous system, Stem-cell therapy, Biology, medicine.disease, Text mining, medicine.anatomical_structure, medicine, Cancer research, Stem cell, business, Gene
Published
2006

36. The ependymal route for central nervous system gene therapy

Author

Roberto Furlan, Gianvito Martino, Erica Butti, T. Tatlisumak, M. Fisher, Butti, E, Martino, Gianvito, and Furlan, R.

Subjects
medicine.anatomical_structure, Intracerebroventricular injection, Genetic enhancement, Central nervous system, medicine, Gene transfer, Biology, Neuroscience, Experimental neurology
Published
2006

37. A nitric oxide releasing derivative of flurbiprofen inhibits experimental autoimmune encephalomyelitis

Author

Laura Gasparini, Alessandra Bergami, Giancarlo Comi, Ennio Ongini, Asli Kurne, Roberto Furlan, Gianvito Martino, Raffaella Maucci, Erica Butti, Elena Brambilla, Furlan, R, Kurne, A, Bergami, A, Brambilla, E, Maucci, R, Gasparini, L, Butti, E, Ongini, E, Comi, G, and Martino, G

Subjects
Antigens, Differentiation, T-Lymphocyte, CD4-Positive T-Lymphocytes, Central Nervous System, Adoptive cell transfer, Flurbiprofen, Administration, Oral, Epitopes, T-Lymphocyte, chemistry.chemical_compound, Mice, Cell Movement, T-Lymphocyte Subsets, Immunology and Allergy, Medicine, IL-2 receptor, Mice, Knockout, biology, Experimental autoimmune encephalomyelitis, Adoptive Transfer, Growth Inhibitors, Interleukin-10, Interleukin 10, medicine.anatomical_structure, Neurology, Cytokines, Female, Immunosuppressive Agents, medicine.drug, medicine.medical_specialty, Encephalomyelitis, Autoimmune, Experimental, Immunology, Spleen, Nitric Oxide, Nitric oxide, Myelin oligodendrocyte glycoprotein, Antigens, CD, Internal medicine, Animals, Lectins, C-Type, Lymphocyte Count, RNA, Messenger, Glycoproteins, business.industry, Receptors, Interleukin-2, medicine.disease, Peptide Fragments, Mice, Inbred C57BL, Endocrinology, chemistry, biology.protein, Myelin-Oligodendrocyte Glycoprotein, Neurology (clinical), business
Abstract

Nitric oxide (NO)-releasing non-steroidal anti-inflammatory drugs (NSAIDs) have been reported to have a safer profile and additional anti-inflammatory and immuno-modulatory properties compared to parent compounds. Preventive treatment of experimental autoimmune encephalomyelitis (EAE)-induced in C57BL/6 mice by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55-with the NO-releasing derivative of flurbiprofen HCT1026 delayed disease onset and significantly decreased disease severity. HCT1026 treatment was associated to (i) decreased mRNA levels of pro-inflammatory cytokines, caspase-1, and iNOS in blood cells; (ii) decreased ability of encephalitogenic T cells to proliferate; (iii) reduced number of central nervous system (CNS)-infiltrating T cells; (iv) decreased axonal loss and demyelination; (v) increased CD4(+) CD69(-) CD25(+) regulatory T cells in the spleen.

Published
2003

39. Subventricular zone neural progenitors reverse TNF-alpha effects in cortical neurons

Author

Michela Matteoli, Gianvito Martino, Elsa Ghirardini, Raffaella Morini, Erica Butti, Claudia Verderio, Morini, R, Ghirardini, E, Butti, E, Verderio, C, Martino, Gianvito, and Matteoli, M.

Subjects
Neurogenesis, Central nervous system, Medicine (miscellaneous), Subventricular zone, Neurotransmission, Biology, Synaptic Transmission, Biochemistry, Genetics and Molecular Biology (miscellaneous), Mice, 03 medical and health sciences, 0302 clinical medicine, Neural Stem Cells, Lateral Ventricles, medicine, Animals, Receptor, Cells, Cultured, 030304 developmental biology, Neurons, 0303 health sciences, Tumor Necrosis Factor-alpha, Research, Glutamate receptor, Cell Biology, Neural stem cell, Cell biology, medicine.anatomical_structure, nervous system, Immunology, Molecular Medicine, Tumor necrosis factor alpha, 030217 neurology & neurosurgery
Abstract

Introduction Tumor necrosis factor alpha (TNFα) plays a physiological role in controlling synaptic transmission and plasticity in the healthy central nervous system by modulating glutamate receptor trafficking to the plasma membrane. TNFα expression is also rapidly induced in response to tissue injury and infection. By promoting the insertion of Ca2+ permeable-AMPA receptors into the neuronal plasma membrane, this cytokine may cause excessive Ca2+ influx into neurons, thus enhancing neuronal death. Methods Primary cultures of cortical neurons were obtained from E18 foetal mice and incubated for 24 h with adult neural stem cells (aNPCs) either stimulated with lipopolysaccharide (LPS+aNPCs) or not (aNPCs). Cultures were treated with TNFα (100 ng/ml), and electrophysiological recordings were performed in different conditions to evaluate the effect of the cytokine on neuronal transmission. Results In this study, we demonstrate that aNPCs from the subventricular zone reverse the effects induced by the cytokine. Moreover, we show that the effect of aNPCs on cortical neurons is mediated by cannabinoid CB1 receptor activation. Conclusion These data suggest that the role of aNPCs in preventing excitatory neurotransmission potentiation induced by TNFα on cortical neurons may have important implications for pathologies characterized by an inflammatory component affecting cortical neurons such as Alzheimer’s disease.

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40. Neural precursor cells rescue symptoms of Rett syndrome by activation of the Interferon γ pathway.

Author

Frasca A, Miramondi F, Butti E, Indrigo M, Balbontin Arenas M, Postogna FM, Piffer A, Bedogni F, Pizzamiglio L, Cambria C, Borello U, Antonucci F, Martino G, and Landsberger N

Abstract

The beneficial effects of Neural Precursor Cell (NPC) transplantation in several neurological disorders are well established and they are generally mediated by the secretion of immunomodulatory and neurotrophic molecules. We therefore investigated whether Rett syndrome (RTT), that represents the first cause of severe intellectual disability in girls, might benefit from NPC-based therapy. Using in vitro co-cultures, we demonstrate that, by sensing the pathological context, NPC-secreted factors induce the recovery of morphological and synaptic defects typical of Mecp2 deficient neurons. In vivo, we prove that intracerebral transplantation of NPCs in RTT mice significantly ameliorates neurological functions. To uncover the molecular mechanisms underpinning the mediated benefic effects, we analyzed the transcriptional profile of the cerebellum of transplanted animals, disclosing the possible involvement of the Interferon γ (IFNγ) pathway. Accordingly, we report the capacity of IFNγ to rescue synaptic defects, as well as motor and cognitive alterations in Mecp2 deficient models, thereby suggesting this molecular pathway as a potential therapeutic target for RTT., (© 2024. The Author(s).)

Published
2024
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41. A glia-enriched stem cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis.

Author

Fagiani F, Pedrini E, Taverna S, Brambilla E, Murtaj V, Podini P, Ruffini F, Butti E, Braccia C, Andolfo A, Magliozzi R, Smirnova L, Kuhlmann T, Quattrini A, Calabresi PA, Reich DS, Martino G, Panina-Bordignon P, and Absinta M

Subjects
Humans, Oligodendroglia metabolism, Oligodendroglia pathology, Neural Stem Cells metabolism, Neural Stem Cells pathology, Microglia metabolism, Microglia pathology, Multiple Sclerosis pathology, Multiple Sclerosis metabolism, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells pathology, Organoids pathology, Organoids metabolism, Neuroglia metabolism, Neuroglia pathology, Brain pathology, Brain metabolism, Cell Differentiation, Phenotype
Abstract

The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor (SOX10)-based protocol to accelerate oligodendrocyte differentiation from human induced pluripotent stem cell (hiPSC)-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from patients with MS, organoids properly mimic macroglia-microglia neurodegenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support the implementation of this organoid model for drug screening to halt inflammatory neurodegeneration., Competing Interests: Declaration of interests D.S.R.: research funding from Abata Therapeutics and Sanofi-Genzyme. P.A.C.: research funding from Genentech and previously Principia; consulting honoraria for serving on SABs for NervGen, Idorsia, Biogen, Vaccitech, and Lilly. L.S.: original organoid model(6) is under a patent by Johns Hopkins University, which is licensed to AxoSim, New Orleans, US; she consults for AxoSim. M.A.: consultancy fees from GSK, Sanofi, Biogen, Immunic Therapeutics, and Abata Therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
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42. Glia-enriched stem-cell 3D model of the human brain mimics the glial-immune neurodegenerative phenotypes of multiple sclerosis.

Author

Fagiani F, Pedrini E, Taverna S, Brambilla E, Murtaj V, Podini P, Ruffini F, Butti E, Braccia C, Andolfo A, Magliozzi R, Smirnova L, Kuhlmann T, Quattrini A, Calabresi PA, Reich DS, Martino G, Panina-Bordignon P, and Absinta M

Abstract

The role of central nervous system (CNS) glia in sustaining self-autonomous inflammation and driving clinical progression in multiple sclerosis (MS) is gaining scientific interest. We applied a single transcription factor ( SOX10 )-based protocol to accelerate oligodendrocyte differentiation from hiPSC-derived neural precursor cells, generating self-organizing forebrain organoids. These organoids include neurons, astrocytes, oligodendroglia, and hiPSC-derived microglia to achieve immunocompetence. Over 8 weeks, organoids reproducibly generated mature CNS cell types, exhibiting single-cell transcriptional profiles similar to the adult human brain. Exposed to inflamed cerebrospinal fluid (CSF) from MS patients, organoids properly mimic macroglia-microglia neuro-degenerative phenotypes and intercellular communication seen in chronic active MS. Oligodendrocyte vulnerability emerged by day 6 post-MS-CSF exposure, with nearly 50% reduction. Temporally-resolved organoid data support and expand on the role of soluble CSF mediators in sustaining downstream events leading to oligodendrocyte death and inflammatory neurodegeneration. Such findings support implementing this organoid model for drug screening to halt inflammatory neurodegeneration.

Published
2024
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43. Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology.

Author

Gullotta GS, De Feo D, Friebel E, Semerano A, Scotti GM, Bergamaschi A, Butti E, Brambilla E, Genchi A, Capotondo A, Gallizioli M, Coviello S, Piccoli M, Vigo T, Della Valle P, Ronchi P, Comi G, D'Angelo A, Maugeri N, Roveri L, Uccelli A, Becher B, Martino G, and Bacigaluppi M

Subjects
Mice, Animals, Neutrophils, Leukocytes, Aging, Stroke pathology, Ischemic Stroke pathology
Abstract

Aging accounts for increased risk and dismal outcome of ischemic stroke. Here, we investigated the impact of age-related changes in the immune system on stroke. Upon experimental stroke, compared with young mice, aged mice had increased neutrophil clogging of the ischemic brain microcirculation, leading to worse no-reflow and outcomes. Aged mice showed an enhanced granulopoietic response to stroke that led to the accumulation of CD101 + CD62L lo mature and CD177 hi CD101 lo CD62L lo and CD177 lo CD101 lo CD62L hi immature atypical neutrophils in the blood, endowed with increased oxidative stress, phagocytosis and procoagulant features. Production of CXCL3 by CD62L lo neutrophils of the aged had a key role in the development and pathogenicity of aging-associated neutrophils. Hematopoietic stem cell rejuvenation reverted aging-associated neutropoiesis and improved stroke outcome. In elderly patients with ischemic stroke, single-cell proteome profile of blood leukocytes identified CD62L lo neutrophil subsets associated with worse reperfusion and outcome. Our results unveil how stroke in aging leads to a dysregulated emergency granulopoiesis impacting neurological outcome., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2023
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44. Endogenous neural stem cells characterization using omics approaches: Current knowledge in health and disease.

Author

Murtaj V, Butti E, Martino G, and Panina-Bordignon P

Abstract

Neural stem cells (NSCs), an invaluable source of neuronal and glial progeny, have been widely interrogated in the last twenty years, mainly to understand their therapeutic potential. Most of the studies were performed with cells derived from pluripotent stem cells of either rodents or humans, and have mainly focused on their potential in regenerative medicine. High-throughput omics technologies, such as transcriptomics, epigenetics, proteomics, and metabolomics, which exploded in the past decade, represent a powerful tool to investigate the molecular mechanisms characterizing the heterogeneity of endogenous NSCs. The transition from bulk studies to single cell approaches brought significant insights by revealing complex system phenotypes, from the molecular to the organism level. Here, we will discuss the current literature that has been greatly enriched in the "omics era", successfully exploring the nature and function of endogenous NSCs and the process of neurogenesis. Overall, the information obtained from omics studies of endogenous NSCs provides a sharper picture of NSCs function during neurodevelopment in healthy and in perturbed environments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Murtaj, Butti, Martino and Panina-Bordignon.)

Published
2023
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45. Neural precursor cells tune striatal connectivity through the release of IGFBPL1.

Author

Butti E, Cattaneo S, Bacigaluppi M, Cambiaghi M, Scotti GM, Brambilla E, Ruffini F, Sferruzza G, Ripamonti M, Simeoni F, Cacciaguerra L, Zanghì A, Quattrini A, Fesce R, Panina-Bordignon P, Giannese F, Cittaro D, Kuhlmann T, D'Adamo P, Rocca MA, Taverna S, and Martino G

Subjects
Animals, Humans, Mice, Cardiac Electrophysiology, Insulin-Like Growth Factor Binding Proteins physiology, Neural Stem Cells physiology, Tumor Suppressor Proteins physiology, Lateral Ventricles physiology
Abstract

The adult brain retains over life endogenous neural stem/precursor cells (eNPCs) within the subventricular zone (SVZ). Whether or not these cells exert physiological functions is still unclear. In the present work, we provide evidence that SVZ-eNPCs tune structural, electrophysiological, and behavioural aspects of striatal function via secretion of insulin-like growth factor binding protein-like 1 (IGFBPL1). In mice, selective ablation of SVZ-eNPCs or selective abrogation of IGFBPL1 determined an impairment of striatal medium spiny neuron morphology, a higher failure rate in GABAergic transmission mediated by fast-spiking interneurons, and striatum-related behavioural dysfunctions. We also found IGFBPL1 expression in the human SVZ, foetal and induced-pluripotent stem cell-derived NPCs. Finally, we found a significant correlation between SVZ damage, reduction of striatum volume, and impairment of information processing speed in neurological patients. Our results highlight the physiological role of adult SVZ-eNPCs in supporting cognitive functions by regulating striatal neuronal activity., (© 2022. The Author(s).)

Published
2022
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46. Endogenous neural precursor cells in health and disease.

Author

Bacigaluppi M, Sferruzza G, Butti E, Ottoboni L, and Martino G

Subjects
Aging physiology, Animals, Brain pathology, Brain Diseases physiopathology, Homeostasis, Humans, Neurodegenerative Diseases physiopathology, Brain physiology, Neural Stem Cells physiology, Neurogenesis
Abstract

Neurogenesis persists in the adult brain of mammals in the subventricular zone (SVZ) of the lateral ventricles and in the subgranular zone (SGZ) of the dentate gyrus (DG). The complex interactions between intrinsic and extrinsic signals provided by cells in the niche but also from distant sources regulate the fate of neural stem/progenitor cells (NPCs) in these sites. This fine regulation is perturbed in aging and in pathological conditions leading to a different NPC behavior, tailored to the specific physio-pathological features. Indeed, NPCs exert in physiological and pathological conditions important neurogenic and non-neurogenic regulatory functions and participate in maintaining and protecting brain tissue homeostasis. In this review, we discuss intrinsic and extrinsic signals that regulate NPC activation and NPC functional role in various homeostatic and non-homeostatic conditions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Published
2020
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47. Neural Stem Cells of the Subventricular Zone Contribute to Neuroprotection of the Corpus Callosum after Cuprizone-Induced Demyelination.

Author

Butti E, Bacigaluppi M, Chaabane L, Ruffini F, Brambilla E, Berera G, Montonati C, Quattrini A, and Martino G

Subjects
Animals, Cell Movement, Corpus Callosum drug effects, Corpus Callosum pathology, Cuprizone toxicity, Demyelinating Diseases etiology, Demyelinating Diseases pathology, Female, Mice, Mice, Inbred C57BL, Neural Stem Cells metabolism, Neural Stem Cells physiology, Oligodendroglia cytology, Oligodendroglia metabolism, Corpus Callosum metabolism, Demyelinating Diseases metabolism, Lateral Ventricles cytology, Myelin Sheath metabolism, Neural Stem Cells cytology
Abstract

Myelin loss occurring in demyelinating diseases, including multiple sclerosis, is the leading cause of long-lasting neurological disability in adults. While endogenous remyelination, driven by resident oligodendrocyte precursor cells (OPCs), might partially compensate myelin loss in the early phases of demyelinating disorders, this spontaneous reparative potential fails at later stages. To investigate the cellular mechanisms sustaining endogenous remyelination in demyelinating disorders, we focused our attention on endogenous neural precursor cells (eNPCs) located within the subventricular zone (SVZ) since this latter area is considered one of the primary sources of new OPCs in the adult forebrain. First, we fate mapped SVZ-eNPCs in cuprizone-induced demyelination and found that SVZ endogenous neural stem/precursor cells are recruited during the remyelination phase to the corpus callosum (CC) and are capable of forming new oligodendrocytes. When we ablated SVZ-derived eNPCs during cuprizone-induced demyelination in female mice, the animals displayed reduced numbers of oligodendrocytes within the lesioned CC. Although this reduction in oligodendrocytes did not impact the ensuing remyelination, eNPC-ablated mice experienced increased axonal loss. Our results indicate that, in toxic models of demyelination, SVZ-derived eNPCs contribute to support axonal survival. SIGNIFICANCE STATEMENT One of the significant challenges in MS research is to understand the detrimental mechanisms leading to the failure of CNS tissue regeneration during disease progression. One possible explanation is the inability of recruited oligodendrocyte precursor cells (OPCs) to complete remyelination and to sustain axonal survival. The contribution of endogenous neural precursor cells (eNPCs) located in the subventricular zone (SVZ) to generate new OPCs in the lesion site has been debated. Using transgenic mice to fate map and to selectively kill SVZ-derived eNPCs in the cuprizone demyelination model, we observed migration of SVZ-eNPCs after injury and their contribution to oligodendrogenesis and axonal survival. We found that eNPCs are dispensable for remyelination but protect partially from increased axonal loss., (Copyright © 2019 the authors.)

Published
2019
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48. Neural precursor cell-secreted TGF-β2 redirects inflammatory monocyte-derived cells in CNS autoimmunity.

Author

De Feo D, Merlini A, Brambilla E, Ottoboni L, Laterza C, Menon R, Srinivasan S, Farina C, Garcia Manteiga JM, Butti E, Bacigaluppi M, Comi G, Greter M, and Martino G

Subjects
Animals, Brain immunology, Brain pathology, Cell Differentiation, Cells, Cultured, Cytokines biosynthesis, Cytokines metabolism, Dendritic Cells physiology, Female, Immunomodulation, Mice, 129 Strain, Mice, Inbred C57BL, Microglia immunology, Multiple Sclerosis immunology, Multiple Sclerosis therapy, Neural Stem Cells metabolism, T-Lymphocytes, Helper-Inducer immunology, Transcriptome, Monocytes physiology, Multiple Sclerosis metabolism, Neural Stem Cells transplantation, Transforming Growth Factor beta2 physiology
Abstract

In multiple sclerosis, the pathological interaction between autoreactive Th cells and mononuclear phagocytes in the CNS drives initiation and maintenance of chronic neuroinflammation. Here, we found that intrathecal transplantation of neural stem/precursor cells (NPCs) in mice with experimental autoimmune encephalomyelitis (EAE) impairs the accumulation of inflammatory monocyte-derived cells (MCs) in the CNS, leading to improved clinical outcome. Secretion of IL-23, IL-1, and TNF-α, the cytokines required for terminal differentiation of Th cells, decreased in the CNS of NPC-treated mice, consequently inhibiting the induction of GM-CSF-producing pathogenic Th cells. In vivo and in vitro transcriptome analyses showed that NPC-secreted factors inhibit MC differentiation and activation, favoring the switch toward an antiinflammatory phenotype. Tgfb2-/- NPCs transplanted into EAE mice were ineffective in impairing MC accumulation within the CNS and failed to drive clinical improvement. Moreover, intrathecal delivery of TGF-β2 during the effector phase of EAE ameliorated disease severity. Taken together, these observations identify TGF-β2 as the crucial mediator of NPC immunomodulation. This study provides evidence that intrathecally transplanted NPCs interfere with the CNS-restricted inflammation of EAE by reprogramming infiltrating MCs into antiinflammatory myeloid cells via secretion of TGF-β2.

Published
2017
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49. Neural Stem Cell Transplantation Induces Stroke Recovery by Upregulating Glutamate Transporter GLT-1 in Astrocytes.

Author

Bacigaluppi M, Russo GL, Peruzzotti-Jametti L, Rossi S, Sandrone S, Butti E, De Ceglia R, Bergamaschi A, Motta C, Gallizioli M, Studer V, Colombo E, Farina C, Comi G, Politi LS, Muzio L, Villani C, Invernizzi RW, Hermann DM, Centonze D, and Martino G

Subjects
Animals, Behavior, Animal, Brain Ischemia metabolism, Cerebral Infarction pathology, Excitatory Amino Acid Transporter 2 genetics, Glutamic Acid metabolism, Male, Mice, Mice, Inbred C57BL, Neuronal Plasticity, Patch-Clamp Techniques, Recovery of Function, Stroke pathology, Stroke psychology, Up-Regulation, Vascular Endothelial Growth Factor A metabolism, Astrocytes metabolism, Excitatory Amino Acid Transporter 2 biosynthesis, Neural Stem Cells transplantation, Stem Cell Transplantation methods, Stroke therapy
Abstract

Ischemic stroke is the leading cause of disability, but effective therapies are currently widely lacking. Recovery from stroke is very much dependent on the possibility to develop treatments able to both halt the neurodegenerative process as well as to foster adaptive tissue plasticity. Here we show that ischemic mice treated with neural precursor cell (NPC) transplantation had on neurophysiological analysis, early after treatment, reduced presynaptic release of glutamate within the ipsilesional corticospinal tract (CST), and an enhanced NMDA-mediated excitatory transmission in the contralesional CST. Concurrently, NPC-treated mice displayed a reduced CST degeneration, increased axonal rewiring, and augmented dendritic arborization, resulting in long-term functional amelioration persisting up to 60 d after ischemia. The enhanced functional and structural plasticity relied on the capacity of transplanted NPCs to localize in the peri-ischemic and ischemic area, to promote the upregulation of the glial glutamate transporter 1 (GLT-1) on astrocytes and to reduce peri-ischemic extracellular glutamate. The upregulation of GLT-1 induced by transplanted NPCs was found to rely on the secretion of VEGF by NPCs. Blocking VEGF during the first week after stroke reduced GLT-1 upregulation as well as long-term behavioral recovery in NPC-treated mice. Our results show that NPC transplantation, by modulating the excitatory-inhibitory balance and stroke microenvironment, is a promising therapy to ameliorate disability, to promote tissue recovery and plasticity processes after stroke., Significance Statement: Tissue damage and loss of function occurring after stroke can be constrained by fostering plasticity processes of the brain. Over the past years, stem cell transplantation for repair of the CNS has received increasing interest, although underlying mechanism remain elusive. We here show that neural stem/precursor cell transplantation after ischemic stroke is able to foster axonal rewiring and dendritic plasticity and to induce long-term functional recovery. The observed therapeutic effect of neural precursor cells seems to underlie their capacity to upregulate the glial glutamate transporter on astrocytes through the vascular endothelial growth factor inducing favorable changes in the electrical and molecular stroke microenvironment. Cell-based approaches able to influence plasticity seem particularly suited to favor poststroke recovery., (Copyright © 2016 Bacigaluppi et al.)

Published
2016
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50. Subventricular zone neural progenitors reverse TNF-alpha effects in cortical neurons.

Author

Morini R, Ghirardini E, Butti E, Verderio C, Martino G, and Matteoli M

Subjects
Animals, Cells, Cultured, Lateral Ventricles cytology, Mice, Neural Stem Cells cytology, Neural Stem Cells drug effects, Neurogenesis, Neurons cytology, Neurons drug effects, Synaptic Transmission, Neural Stem Cells physiology, Neurons physiology, Tumor Necrosis Factor-alpha pharmacology
Abstract

Introduction: Tumor necrosis factor alpha (TNFα) plays a physiological role in controlling synaptic transmission and plasticity in the healthy central nervous system by modulating glutamate receptor trafficking to the plasma membrane. TNFα expression is also rapidly induced in response to tissue injury and infection. By promoting the insertion of Ca(2+) permeable-AMPA receptors into the neuronal plasma membrane, this cytokine may cause excessive Ca(2+) influx into neurons, thus enhancing neuronal death., Methods: Primary cultures of cortical neurons were obtained from E18 foetal mice and incubated for 24 h with adult neural stem cells (aNPCs) either stimulated with lipopolysaccharide (LPS(+)aNPCs) or not (aNPCs). Cultures were treated with TNFα (100 ng/ml), and electrophysiological recordings were performed in different conditions to evaluate the effect of the cytokine on neuronal transmission., Results: In this study, we demonstrate that aNPCs from the subventricular zone reverse the effects induced by the cytokine. Moreover, we show that the effect of aNPCs on cortical neurons is mediated by cannabinoid CB1 receptor activation., Conclusion: These data suggest that the role of aNPCs in preventing excitatory neurotransmission potentiation induced by TNFα on cortical neurons may have important implications for pathologies characterized by an inflammatory component affecting cortical neurons such as Alzheimer's disease.

Published
2015
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