المؤلفون: David S. Goldstein

المصدر: Circulation. 117:458-461

مصطلحات موضوعية: medicine.medical_specialty, Sympathetic nervous system, Neuroeffector, biology, business.industry, Tyramine, Pharmacology, Reuptake, chemistry.chemical_compound, Norepinephrine, Endocrinology, medicine.anatomical_structure, chemistry, Norepinephrine transporter, Physiology (medical), Internal medicine, medicine, Catecholamine, biology.protein, Cardiology and Cardiovascular Medicine, Neurotransmitter, business, medicine.drug

الوصف: In this issue of Circulation , Fung and coworkers1 report associations between hand venous responses to the indirectly acting sympathomimetic amine tyramine and single nucleotide polymorphisms (SNPs) of genes encoding particular proteins related to the synthesis, release, reuptake, and metabolism of catecholamines. The importance of these associations lies in their illustrating how genotypic differences may contribute to phenotypic differences in circulatory functions in healthy adults via sympathetic neuroeffector mechanisms. More generally, identification of SNPs related to catecholamine systems may provide insights into the pathophysiology, diagnosis, and treatment of a variety of cardiovascular disorders.2 Article p 517 To provide perspective about these findings, this editorial compares and contrasts tyramine-induced changes and sympathetic neuroeffector functions; discusses strengths and weaknesses of the dorsal hand vein model; emphasizes the potential of clinical catecholamine neurochemistry to link genotype with cardiovascular phenotype; and conveys a viewpoint on observational versus hypothesis-driven genotyping. Tyramine produces vasoconstriction via release of endogenous norepinephrine, the main neurotransmitter of the sympathetic nervous system mediating cardiovascular responses to stressors. The authors relied on the local vascular actions of tyramine as an indirectly acting sympathomimetic amine to draw inferences about sympathetic neuroeffector functions. Mechanisms of tyramine-induced norepinephrine release differ in several respects from those of sympathetically mediated norepinephrine release. The Figure depicts some of these differences. Figure. Mechanisms of sympathetically mediated and tyramine-induced norepinephrine release. NE indicates norepinephrine; TYR, tyramine; AR, aldehyde reductase; VMAT, vesicular monoamine transporter; and MAO, monoamine oxidase. First, tyramine releases norepinephrine in a calcium-independent manner3 that is not exocytotic,4 in contrast to calcium-dependent exocytosis in response to sympathetic nerve stimulation. Tyramine displaces norepinephrine from storage vesicles, possibly by alkalinizing them.5 Because most of the vesicles would not be expected to be in communication with the extracellular fluid under resting conditions, most of the displaced norepinephrine …

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::44d6fb52c48bb46ed1e621437718de4aTest
https://doi.org/10.1161/circulationaha.107.745737Test

المؤلفون: Jody J. Haigh, Patrik Verstreken, Ger M.J. Janssen, Diether Lambrechts, Peter Carmeliet, Paul M. H. Schiffers, Greet Vanhoutte, Massimiliano Mazzone, Carmen Ruiz de Almodovar, Hermann Rohrer, Jo G. R. De Mey, Gregorio E. Fazzi, Koen Poesen, Stefan Vinckier, Merlijn J. Meens, Annemie Van der Linden, Serena Zacchigna, Katarzyna Miskiewicz, Erik Storkebaum

المساهمون: Promovendi CD, Ondersteunend personeel CD, Farmacologie & Toxicologie, Bedrijfsbureau CD, RS: CARIM School for Cardiovascular Diseases, Storkebaum, Erik, Ruiz De Almodovar, Carmen, Meens, Merlijn, Zacchigna, Serena, Mazzone, Massimiliano, Vanhoutte, Greet, Vinckier, Stefan, Miskiewicz, Katarzyna, Poesen, Koen, Lambrechts, Diether, Janssen, Ger M. J., Fazzi, Gregorio E., Verstreken, Patrik, Haigh, Jody, Schiffers, Paul M., Rohrer, Hermann, Van Der Linden, Annemie, De Mey, Jo G. R., Carmeliet, Peter

المصدر: Circulation
Circulation, 122(3), 273-U107. LIPPINCOTT WILLIAMS & WILKINS
CIRCULATION

مصطلحات موضوعية: Vascular Endothelial Growth Factor A, SYMPATHETIC-NERVOUS-SYSTEM, Vascular smooth muscle, muscle, SMOOTH-MUSCLE-CELLS, Gene Expression, Transgenic, Muscle, Smooth, Vascular, Neuroeffector junction, arteries, chemistry.chemical_compound, Mesenteric Arterie, Mice, Cardiovascular Disease, vasoconstriction, vascular endothelial growth factor, Medicine (all), nervous system, Gene Transfer Techniques, arterie, Autonomic Nervous System Disease, MESENTERIC-ARTERIES, VEGF, Common, Mesenteric Arteries, Vascular endothelial growth factor B, Vascular endothelial growth factor, Vascular endothelial growth factor A, DIFFERENTIATION, medicine.anatomical_structure, Lac Operon, Cardiovascular Diseases, SURVIVAL, Smooth, Cardiology and Cardiovascular Medicine, smooth, Signal Transduction, EXPRESSION, medicine.medical_specialty, Neuroeffector, Carotid Artery, Common, Mice, Transgenic, RATS, Internal medicine, Vascular, Physiology (medical), muscle, smooth, medicine, Animals, Autonomic Nervous System Diseases, Vascular Endothelial Growth Factor Receptor-1, Vascular Endothelial Growth Factor Receptor-2, Vascular Resistance, Vasoconstriction, ERYTHRODYSESTHESIA, RECEPTOR, business.industry, Animal, Biology and Life Sciences, Kinase insert domain receptor, Gene Transfer Technique, Endocrinology, chemistry, Vascular resistance, Human medicine, Carotid Artery, business

الوصف: Background— Control of peripheral resistance arteries by autonomic nerves is essential for the regulation of blood flow. The signals responsible for the maintenance of vascular neuroeffector mechanisms in the adult, however, remain largely unknown. Methods and Results— Here, we report that VEGF ∂/∂ mice with low vascular endothelial growth factor (VEGF) levels suffer defects in the regulation of resistance arteries. These defects are due to dysfunction and structural remodeling of the neuroeffector junction, the equivalent of a synapse between autonomic nerve endings and vascular smooth muscle cells, and to an impaired contractile smooth muscle cell phenotype. Notably, short-term delivery of a VEGF inhibitor to healthy mice also resulted in functional and structural defects of neuroeffector junctions. Conclusions— These findings uncover a novel role for VEGF in the maintenance of arterial neuroeffector function and may help us better understand how VEGF inhibitors cause vascular regulation defects in cancer patients.

وصف الملف: pdf; application/pdf

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::869af034c9a5edf6c835c5019c41bc07Test
https://hdl.handle.net/10067/883510151162165141Test

المؤلفون: Patti Larrabee, J D Port, Wayne Minobe, M White, D Campbell, A M Feldman, R Roden, Fred L. Anderson, M F Khan, M Wollmering

المصدر: Circulation. 90(3)

مصطلحات موضوعية: Agonist, Adult, Male, medicine.medical_specialty, Aging, Neuroeffector, Adrenergic receptor, Adolescent, medicine.drug_class, Population, In Vitro Techniques, Binding, Competitive, Beta-1 adrenergic receptor, Heart Conduction System, Physiology (medical), Internal medicine, Receptors, Adrenergic, beta, Neuroeffector Junction, Medicine, Humans, Iodocyanopindolol, Beta (finance), education, Child, education.field_of_study, business.industry, Myocardium, Isoproterenol, Infant, Heart, Middle Aged, Denervation, Myocardial Contraction, medicine.anatomical_structure, Endocrinology, Ventricle, Child, Preschool, Pindolol, Circulatory system, Female, Cardiology and Cardiovascular Medicine, business, Adenylyl Cyclases

الوصف: BACKGROUND Aging decreases cardiac beta-adrenergic responsiveness in model systems and in humans in vivo. The purpose of this study was to comprehensively evaluate the age-related changes in the beta-receptor-G protein-adenylyl cyclase complex in nonfailing human hearts. METHODS AND RESULTS Twenty-six nonfailing explanted human hearts aged 1 to 71 years were obtained from organ donors and subjected to pharmacological investigation of beta-adrenergic neuroeffector systems. When the population was subdivided into the 13 youngest and 13 oldest subjects, total beta-receptor density assessed by maximum [125I]ICYP binding (beta max) was reduced in older hearts by 37% in left ventricles and 31% in right ventricles (both P < .05), and the downregulation was confined to the beta 1 subtype (r = .78 left ventricle beta 1 density versus donor age). Older donor hearts exhibited a 3- to 4-fold rightward shift of ICYP-isoproterenol (ISO) competition curves and demonstrated 43% fewer receptors in a high-affinity agonist binding state (P < .05). Older hearts exhibited decreased adenylyl cyclase stimulation by ISO, by zinterol (beta 2-agonist), and by the G protein-sensitive probes forskolin, Gpp(NH)p, and NaF. In contrast, there was no change in response to manganese, a specific activator of the adenylyl cyclase catalytic subunit. Toxin-catalyzed ADP ribosylation in membranes prepared from older versus younger hearts revealed a 29% to 30% reduction (P < .05) with cholera toxin (Gs) but no difference with pertussis toxin (Gi). The systolic contractile response of isolated right ventricular trabeculae to ISO was decreased by 46%, with a 10-fold increase in ISO EC50 in older relative to younger donor hearts. CONCLUSIONS There is a profound decrease in cardiac beta-adrenergic responsiveness with aging. This occurs by multiple mechanisms including downregulation and decreased agonist binding of beta 1-receptors, uncoupling of beta 2-receptors, and abnormal G protein-mediated signal transduction.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c0b7fb9c8182eedda97b054411b53b25Test
https://pubmed.ncbi.nlm.nih.gov/8087932Test

المؤلفون: Eugene E. Wolfel, William T. Abraham, Robert J. Wiechmann, J. David Port, Michael R. Bristow, JoAnn Lindenfeld, Mary Beth Hagan, Mary M. Wollmering, Michel White, Elizabeth H. Hammond, David A. Fullerton, Robert L. Roden

المصدر: Circulation. 92(8)

مصطلحات موضوعية: Adult, Male, medicine.medical_specialty, Brain Death, Neuroeffector, Iodocyanopindolol, Adrenergic, Cyclase, Adenylyl cyclase, chemistry.chemical_compound, Ventricular Dysfunction, Left, Catecholamines, GTP-Binding Proteins, Physiology (medical), Internal medicine, Receptors, Adrenergic, beta, Medicine, Humans, Zinterol, Forskolin, business.industry, Myocardium, medicine.disease, Myocardial Contraction, Tissue Donors, Endocrinology, chemistry, Echocardiography, Heart failure, Case-Control Studies, Female, Cardiology and Cardiovascular Medicine, business, medicine.drug, Adenylyl Cyclases, Signal Transduction

الوصف: Background Ten percent to 20% of potential cardiac donors with brain injury and no previous cardiac history have myocardial dysfunction. We assessed components of the β-receptor–G-protein–adenylyl cyclase complex as well as the contractile response in 10 explanted acutely failing human hearts (donor heart dysfunction [DHD]) and compared the results with 13 age-matched nonfailing (NF) organ donor controls. Methods and Results As measured by echocardiography, all DHD hearts exhibited a decreased shortening fraction (16±2%, mean±SEM). Although total and subpopulation β-receptor densities measured by [ 125 I]iodocyanopindolol (ICYP) were similar in the DHD and NF groups, DHD hearts exhibited a 30% decrease in maximum isoproterenol-stimulated adenylyl cyclase activity and a 50% decrease in the maximal response to zinterol. DHD hearts also exhibited decreases in adenylyl cyclase maximal stimulation by forskolin (211±25 [DHD] versus 295±23 [NF] pmol cAMP · min −1 · mg −1 , P −1 · mg −1 , P 2+ , a direct activator of adenylyl cyclase. Right ventricular trabeculae removed from DHD hearts exhibited a profound decrease in the contractile response to isoproterenol (8.7±1 [DHD] versus 22±2 [NF] mN, P P =.03). Morphological examination of two hearts revealed some ultrastructural evidence suggestive of catecholamine-mediated injury, but there was no difference in tissue creatine kinase activity between the two groups. Conclusions Compared with NF hearts, DHD hearts exhibit marked uncoupling of β 1 - and β 2 -adrenergic receptors from adenylyl cyclase and contractile response stimulation as well as decreased intrinsic systolic function. Thus, acute myocardial dysfunction accompanying brain injury is characterized by marked alterations in β-adrenergic signal transduction as well as changes in the contractile apparatus, and this profile is markedly different from what occurs in the chronically failing human heart.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a891b2f927dca65f2d5a88b9a1fb0307Test
https://pubmed.ncbi.nlm.nih.gov/7554200Test

المؤلفون: M. D. Esler, I T Meredith, rd R O Cannon, Garry L. Jennings, Arshed A. Quyyumi, J Chin, Graeme Eisenhofer, Anthony M. Dart, G Lambert, David S. Goldstein

المصدر: Scopus-Elsevier

مصطلحات موضوعية: Cardiac output, medicine.medical_specialty, Sympathetic nervous system, Sympathetic Nervous System, Neuroeffector, Cardiac Output, Low, Catechols, Reuptake, Methoxyhydroxyphenylglycol, Norepinephrine (medication), Norepinephrine, Heart Conduction System, Reference Values, Physiology (medical), Desipramine, Internal medicine, medicine, Humans, business.industry, Myocardium, Osmolar Concentration, Coronary Vessels, Yohimbine, Endocrinology, medicine.anatomical_structure, Catecholamine, Cardiology and Cardiovascular Medicine, business, medicine.drug

الوصف: BACKGROUND Measurement of cardiac norepinephrine spillover may indicate the amount of transmitter at neuroeffector sites but does not distinguish neuronal release or reuptake in determining this amount or provide information about other aspects of sympathetic function. This report examines how cardiac spillover of the norepinephrine metabolite dihydroxyphenylglycol (DHPG) provides additional distinct information about cardiac sympathetic function. METHODS AND RESULTS Arterial and coronary venous blood samples were taken during cardiac catheterization and intravenous infusion of [3H]norepinephrine in 57 subjects. Subjects were given intravenous yohimbine or underwent mental stress, handgrip exercise, and cycling exercise to activate sympathetic nerves or were given intravenous desipramine to block norepinephrine reuptake. Cardiac DHPG spillover (601 +/- 41 pmol/min) was eightfold greater than norepinephrine spillover (78 +/- 10 pmol/min) at rest and increased during sympathetic activation by 65% of the increase of norepinephrine. This and the desipramine-sensitive cardiac production of [3H]-labeled DHPG from [3H]norepinephrine indicated that 10.5 times more endogenous norepinephrine is recaptured than escapes into plasma; that more than 90% of recaptured norepinephrine is sequestered into storage vesicles; and that under resting conditions, most cardiac spillover of DHPG and turnover of norepinephrine are from metabolism of transmitter leaking from vesicles; the latter process is independent of exocytotic transmitter release with a rate at rest over 100-fold that of norepinephrine spillover and over 10-fold that of norepinephrine reuptake. CONCLUSIONS Cardiac spillover of DHPG provides information about processes close to or within sympathetic nerve endings that cannot be provided by measurements of norepinephrine spillover alone. This includes quantitative information about the role of neuronal uptake in terminating the actions of norepinephrine at neuroeffector sites and the importance of vesicular-axoplasmic exchange of norepinephrine as a dynamic process contributing to norepinephrine turnover.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a6f2965ab9ffad8d9142297b38cf5a63Test
https://pubmed.ncbi.nlm.nih.gov/1572033Test

المؤلفون: J D Port, Ray E. Hershberger, John B. O'Connell, Fred L. Anderson, Michael R. Bristow, J Murray, L Skerl, Patti Larrabee, Dale G. Renlund, Kirk Volkman

المصدر: Circulation. 84(3)

مصطلحات موضوعية: Inotrope, Adult, Cardiomyopathy, Dilated, Male, medicine.medical_specialty, Adrenergic receptor, Neuroeffector, Cardiomyopathy, Adrenergic, Down-Regulation, Iodine Radioisotopes, Catecholamines, GTP-Binding Proteins, Physiology (medical), Internal medicine, Idiopathic dilated cardiomyopathy, Receptors, Adrenergic, beta, medicine, Humans, Neuropeptide Y, Iodocyanopindolol, Creatine Kinase, business.industry, Dilated cardiomyopathy, Heart, Middle Aged, medicine.disease, Endocrinology, Heart failure, Pindolol, Female, Cardiology and Cardiovascular Medicine, business, Adenylyl Cyclases

الوصف: BACKGROUND We measured the content and activities of components of the beta-adrenergic receptor-G protein-adenylate cyclase complex and adrenergic neurotransmitter levels in left and right ventricular myocardial preparations derived from 77 end-stage failing human hearts from patients with idiopathic dilated cardiomyopathy (IDC) or ischemic dilated cardiomyopathy (ISCDC). METHODS AND RESULTS The results were compared with data obtained in 21 nonfailing hearts removed from organ donors. Compared with ISCDC ventricles, IDC left and right ventricles exhibited a greater degree of total beta- or beta 1-receptor downregulation. In contrast, compared with IDC right ventricles, isolated tissue preparations of ISCDC right ventricles exhibited a greater degree of subsensitivity to the inotropic effect of isoproterenol, indicating a relatively greater degree of functional uncoupling of right ventricular ISCDC beta-receptors from mechanical response. In addition, relative to IDC left ventricles, preparations of ISCDC left ventricle exhibited greater subsensitivity to beta-agonist-mediated adenylate cyclase stimulation, indicating functional uncoupling of left ventricular ISCDC beta-receptors from cyclic AMP generation. The uncoupling of beta-receptors in ISCDC left and right ventricles may have been a result of abnormalities in G protein activation of adenylate cyclase; compared with age- and cardiac function-matched respective left or right IDC ventricles, ISCDC left ventricles exhibited less stimulation of adenylate cyclase by NaF or forskolin but no change in Mn2+ stimulation, whereas ISCDC right ventricles exhibited less stimulation by the nonhydrolyzable guanine nucleotide Gpp (NH)p. Also, IDC right ventricles exhibited a "selective" (not present in IDC left ventricles or ISCDC ventricles) decrease in stimulation of adenylate cyclase by Mn2+. Tissue neurotransmitter levels and pertussis toxin-catalyzed ADP ribosylation were altered to similar extents in IDC and ISCDC: CONCLUSIONS These data indicate that potentially important differences exist in the regulatory behavior of components of the beta-adrenergic receptor-G protein-adenylate cyclase complex in IDC versus ISCDC, differences that presumably relate to the distinct pathophysiologies of these two types of heart muscle disease.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0f8c8e0d6dba475a9d8e2a00c328dfe8Test
https://pubmed.ncbi.nlm.nih.gov/1653120Test

المؤلفون: P M Vanhoutte, J T Shepherd

المصدر: Circulation. 64:655-666

مصطلحات موضوعية: Serotonin, medicine.medical_specialty, Adenosine, Adrenergic receptor, Synaptic cleft, Neurotransmission, Synaptic Transmission, Neuroeffector junction, Norepinephrine (medication), chemistry.chemical_compound, Dogs, Physiology (medical), Internal medicine, medicine, Animals, Humans, Sympathomimetics, Neurotransmitter, Nerve Endings, Adenine Nucleotides, business.industry, Angiotensin II, Osmolar Concentration, Temperature, Receptors, Adrenergic, alpha, Acetylcholine, Vasodilation, Endocrinology, chemistry, Potassium, Acidosis, Cardiology and Cardiovascular Medicine, business, Histamine, Muscle Contraction, medicine.drug

الوصف: The cardiovascular reflexes, by regulating the traffic in the sympathetic nerves, govern the amount of norepinephrine released from the nerve endings. However, the final adjustments in the amount of neurotransmitter available to activate the beta 1 receptors in the heart and the alpha receptors in the blood vessels take place at the sympathetic neuroeffector junction. Thus, a decrease in pH, hyperosmolarity, moderate increases in the concentration of K+ ion, adenosine and adenine nucleotides depress the release of norepinephrine at any given level of sympathetic nerve activity. These metabolic changes, which occur in active tissues, and in particular in adenosine, have been proposed as mediators of the accompanying local hyperemia. In addition, they apparently facilitate this local dilatation by disconnecting the blood vessels in the active tissues from sympathetic control. Acetylcholine, histamine and 5-hydroxytryptamine are present in and around certain blood vessels and can activate specific receptors on the prejunctional fibers and cause vasodilatation by reducing the output of neutrotransmitter. Some of the norepinephrine released into the synaptic cleft may depress its continued release by activating prejunctional alpha receptors. In contrast, angiotensin II, by a local action on the nerve endings, can augment the release of transmitter. Decreases in local temperature reduce transmitter release but augment the affinity of the postjunctional alpha receptors for norepinephrine. The role of these local events at the neuroeffector junction, their physiologic significance and potential clinical importance are discussed in this review.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::04950bbda54aa1b51d1e6a6515b57c25Test
https://doi.org/10.1161/01.cir.64.4.655Test

المؤلفون: David W. Ferguson, D W Hayes

المصدر: Circulation. 80(2)

مصطلحات موضوعية: Adult, Male, Nitroprusside, Baroreceptor, Sympathetic Nervous System, Neuroeffector, Nifedipine, Blood Pressure, Pressoreceptors, Baroreflex, Heart Rate, Physiology (medical), Heart rate, Reflex, Medicine, Humans, Lower Body Negative Pressure, business.industry, Muscles, Cold pressor test, Central venous pressure, Blood pressure, Anesthesia, Vascular Resistance, Cardiology and Cardiovascular Medicine, business, medicine.drug

الوصف: Nifedipine augments baroreflex mechanisms in in vivo animal models. Previous studies in our laboratory demonstrate that nifedipine potentiates baroreflex control of heart rate and vascular resistance in normal human subjects. To further define the neuroeffector mechanism of the autonomic effects of nifedipine, we directly measured postganglionic sympathetic nerve activity to muscle (MSNA, microneurography), before and after drug administration, during selective unloading of cardiopulmonary baroreceptors with lower body negative pressure (-10 mm Hg, LBNP-10), and during the cold pressor test. Twenty-three normal subjects (age, 23 +/- 1 years; mean +/- SEM) were studied in the control state and 20 minutes after administration of either nifedipine (10 mg s.l., 10 subjects), during nitroprusside infusion (0.37 +/- 0.03 microgram/kg/min i.v., eight subjects), or 20 minutes after sublingual administration of placebo (five subjects). We measured systemic arterial pressure, central venous pressure, heart rate, and MSNA. Nifedipine and nitroprusside produced similar increases in resting heart rate and MSNA and similar decreases in central venous pressure, whereas placebo had no effect on resting hemodynamics. During LBNP-10, hemodynamic changes were not significantly different among the three treatment groups. However, the percentage increase in MSNA during LBNP-10 was significantly augmented from a 24 +/- 9% increase before nifedipine to a 56 +/- 7% increase after nifedipine (p less than 0.05). Decreases in central venous pressure with LBNP-10 were nearly identical before compared with after nifedipine. Thus, nifedipine increased the cardiopulmonary baroreflex sympathetic sensitivity (change in total MSNA per mm Hg decrease in central venous pressure during LBNP-10) from 26.5 +/- 10.7 units/mm Hg to 74.9 +/- 19.0 units/mm Hg (p less than 0.01). In contrast, administration of hemodynamically similar doses of nitroprusside resulted in an attenuation of MSNA responses to LBNP-10. During LBNP-10, MSNA increased 57 +/- 12% before nitroprusside but only 14 +/- 4% during nitroprusside (p less than 0.01). The cardiopulmonary baroreflex sympathetic sensitivity was not significantly altered by nitroprusside (45.1 +/- 12.4 units/mm Hg before compared with 33.1 +/- 20.8 units/mm Hg during nitroprusside, p = NS). Placebo had no effect on the responses to LBNP-10. Nifedipine did not augment MSNA responses to the cold pressor test. To evaluate the linearity of sympathetic responses to cardiopulmonary baroreceptor unloading, graded LBNP (0, -5, -10, and -15 mm Hg) was applied in three additional subjects before and after nifedipine (10 mg s.l.).(ABSTRACT TRUNCATED AT 400 WORDS)

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::87d49652ea399ccfd14b2c3752539864Test
https://pubmed.ncbi.nlm.nih.gov/2752557Test