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  • 1
    Online Resource
    Online Resource
    Different roles of myocardial ROCK1 and ROCK2 in cardiac dysfunction and postcapillary pulmonary hypertension in mice
    Proceedings of the National Academy of Sciences ; 2018
    In:  Proceedings of the National Academy of Sciences Vol. 115, No. 30 ( 2018-07-24)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 115, No. 30 ( 2018-07-24)
    Abstract: Although postcapillary pulmonary hypertension (PH) is an important prognostic factor for patients with heart failure (HF), its pathogenesis remains to be fully elucidated. To elucidate the different roles of Rho-kinase isoforms, ROCK1 and ROCK2, in cardiomyocytes in response to chronic pressure overload, we performed transverse aortic constriction (TAC) in cardiac-specific ROCK1-deficient ( cROCK1 −/− ) and ROCK2-deficient ( cROCK2 −/− ) mice. Cardiomyocyte-specific ROCK1 deficiency promoted pressure-overload-induced cardiac dysfunction and postcapillary PH, whereas cardiomyocyte-specific ROCK2 deficiency showed opposite results. Histological analysis showed that pressure-overload-induced cardiac hypertrophy and fibrosis were enhanced in cROCK1 −/− mice compared with controls, whereas cardiac hypertrophy was attenuated in cROCK2 −/− mice after TAC. Consistently, the levels of oxidative stress were up-regulated in cROCK1 −/− hearts and down-regulated in cROCK2 −/− hearts compared with controls after TAC. Furthermore, cyclophilin A (CyPA) and basigin (Bsg), both of which augment oxidative stress, enhanced cardiac dysfunction and postcapillary PH in cROCK1 −/− mice, whereas their expressions were significantly lower in cROCK2 −/− mice. In clinical studies, plasma levels of CyPA were significantly increased in HF patients and were higher in patients with postcapillary PH compared with those without it. Finally, high-throughput screening demonstrated that celastrol, an antioxidant and antiinflammatory agent, reduced the expressions of CyPA and Bsg in the heart and the lung, ameliorating cardiac dysfunction and postcapillary PH induced by TAC. Thus, by differentially affecting CyPA and Bsg expressions, ROCK1 protects and ROCK2 jeopardizes the heart from pressure-overload HF with postcapillary PH, for which celastrol may be a promising agent.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1721298115
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2018
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Circulation Research Vol. 119, No. 2 ( 2016-07-08), p. 197-209
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 119, No. 2 ( 2016-07-08), p. 197-209
    Abstract: Endothelial AMP-activated protein kinase (AMPK) plays an important role for vascular homeostasis, and its role is impaired by vascular inflammation. However, the role of endothelial AMPK in the pathogenesis of pulmonary arterial hypertension (PAH) remains to be elucidated. Objective: To determine the role of endothelial AMPK in the development of PAH. Methods and Results: Immunostaining showed that endothelial AMPK is downregulated in the pulmonary arteries of patients with PAH and hypoxia mouse model of pulmonary hypertension (PH). To elucidate the role of endothelial AMPK in PH, we used endothelial-specific AMPK-knockout mice ( eAMPK –/– ), which were exposed to hypoxia. Under normoxic condition, eAMPK –/– mice showed the normal morphology of pulmonary arteries compared with littermate controls ( eAMPK flox/flox ). In contrast, development of hypoxia-induced PH was accelerated in eAMPK –/– mice compared with controls. Furthermore, the exacerbation of PH in eAMPK –/– mice was accompanied by reduced endothelial function, upregulation of growth factors, and increased proliferation of pulmonary artery smooth muscle cells. Importantly, conditioned medium from endothelial cells promoted pulmonary artery smooth muscle cell proliferation, which was further enhanced by the treatment with AMPK inhibitor. Serum levels of inflammatory cytokines, including tumor necrosis factor-α and interferon-γ were significantly increased in patients with PAH compared with healthy controls. Consistently, endothelial AMPK and cell proliferation were significantly reduced by the treatment with serum from patients with PAH compared with controls. Importantly, long-term treatment with metformin, an AMPK activator, significantly attenuated hypoxia-induced PH in mice. Conclusions: These results indicate that endothelial AMPK is a novel therapeutic target for the treatment of PAH.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.115.308178
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1467838-X
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  • 3
    Online Resource
    Online Resource
    Selenoprotein P Promotes the Development of Pulmonary Arterial Hypertension : Possible Novel Therapeutic Target
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation Vol. 138, No. 6 ( 2018-08-07), p. 600-623
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 138, No. 6 ( 2018-08-07), p. 600-623
    Abstract: Excessive proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs) are key mechanisms of pulmonary arterial hypertension (PAH). Despite the multiple combination therapy, a considerable number of patients develop severe pulmonary hypertension (PH) because of the lack of diagnostic biomarker and antiproliferative therapies for PASMCs. Methods: Microarray analyses were used to identify a novel therapeutic target for PAH. In vitro experiments, including lung and serum samples from patients with PAH, cultured PAH-PASMCs, and high-throughput screening of 3336 low-molecular-weight compounds, were used for mechanistic study and exploring a novel therapeutic agent. Five genetically modified mouse strains, including PASMC-specific selenoprotein P (SeP) knockout mice and PH model rats, were used to study the role of SeP and therapeutic capacity of the compounds for the development of PH in vivo. Results: Microarray analysis revealed a 32-fold increase in SeP in PAH-PASMCs compared with control PASMCs. SeP is a widely expressed extracellular protein maintaining cellular metabolism. Immunoreactivity of SeP was enhanced in the thickened media of pulmonary arteries in PAH. Serum SeP levels were also elevated in patients with PH compared with controls, and high serum SeP predicted poor outcome. SeP-knockout mice ( SeP –/– ) exposed to chronic hypoxia showed significantly reduced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary artery remodeling compared with controls. In contrast, systemic SeP-overexpressing mice showed exacerbation of hypoxia-induced PH. Furthermore, PASMC-specific SeP –/– mice showed reduced hypoxia-induced PH compared with controls, whereas neither liver-specific SeP knockout nor liver-specific SeP-overexpressing mice showed significant differences with controls. Altogether, protein levels of SeP in the lungs were associated with the development of PH. Mechanistic experiments demonstrated that SeP promotes PASMC proliferation and resistance to apoptosis through increased oxidative stress and mitochondrial dysfunction, which were associated with activated hypoxia-inducible factor-1α and dysregulated glutathione metabolism. It is important to note that the high-throughput screening of 3336 compounds identified that sanguinarine, a plant alkaloid with antiproliferative effects, reduced SeP expression and proliferation in PASMCs and ameliorated PH in mice and rats. Conclusions: These results indicate that SeP promotes the development of PH, suggesting that it is a novel biomarker and therapeutic target of the disorder.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.117.033113
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1466401-X
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  • 4
    Online Resource
    Online Resource
    Diagnostic and Prognostic Significance of Serum Levels of SeP (Selenoprotein P) in Patients With Pulmonary Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 39, No. 12 ( 2019-12), p. 2553-2562
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 39, No. 12 ( 2019-12), p. 2553-2562
    Abstract: Despite the recent progress in upfront combination therapy for pulmonary arterial hypertension (PAH), useful biomarkers for the disorder still remain to be developed. SeP (Selenoprotein P) is a glycoprotein secreted from various kinds of cells including pulmonary artery smooth muscle cells to maintain cellular metabolism. We have recently demonstrated that SeP production from pulmonary artery smooth muscle cells is upregulated and plays crucial roles in the pathogenesis of PAH. However, it remains to be elucidated whether serum SeP levels could be a useful biomarker for PAH. Approach and Results: We measured serum SeP levels and evaluated their prognostic impacts in 65 consecutive patients with PAH and 20 controls during follow-up (mean, 1520 days; interquartile range, 1393–1804 days). Serum SeP levels were measured using a newly developed sol particle homogeneous immunoassay. The patients with PAH showed significantly higher serum SeP levels compared with controls. Higher SeP levels (cutoff point, 3.47 mg/L) were associated with the outcome (composite end point of all-cause death and lung transplantation) in patients with PAH (hazard ratio, 4.85 [1.42–16.6]; P 〈 0.01). Importantly, we found that the absolute change in SeP of patients with PAH (ΔSeP) in response to the initiation of PAH-specific therapy significantly correlated with the absolute change in mean pulmonary artery pressure, pulmonary vascular resistance (ΔPVR), and cardiac index (ΔCI; R =0.78, 0.76, and −0.71 respectively, all P 〈 0.0001). Moreover, increase in ΔSeP during the follow-up predicted poor outcome of PAH. Conclusions: Serum SeP is a novel biomarker for diagnosis and assessment of treatment efficacy and long-term prognosis in patients with PAH.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.119.313267
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1494427-3
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  • 5
    Online Resource
    Online Resource
    Abstract 541: SmgGDS as a Crucial Mediator of the Inhibitory Effects of Statins on Cardiac Hypertrophy and Fibrosis -Novel Mechanism of the Pleiotropic Effects of Statins-
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. suppl_1 ( 2015-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. suppl_1 ( 2015-05)
    Abstract: Background: Statins are widely known to exert beneficial pleiotropic effects mediated by anti-oxidative and anti-inflammatory mechanisms, independent of their LDL-cholesterol lowering effect. However, the detailed molecular mechanisms of the pleiotropic effects of statins remain to be fully elucidated. Here, we demonstrate that small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins. Methods and Results: SmgGDS +/- and wild-type (WT) mice were treated with continuous infusion of angiotensin II (AngII) for 2 weeks with and without oral treatment with atorvastatin (10 mg/kg/day) or pravastatin (50 mg/kg/day). At 2 weeks, the extents of AngII-induced cardiac hypertrophy and fibrosis were comparable between the 2 genotypes. However, statins significantly attenuated cardiomyocyte hypertrophy, fibrosis and left ventricular diastolic dysfunction in WT mice, but not in SmgGDS +/- mice. Since SmgGDS was highly expressed in cardiac fibroblasts (CFs) in the heart, we then examined the role of SmgGDS in cultured CFs from WT and SmgGDS +/- mice. In SmgGDS +/- CFs, Rac1 expression, ERK1/2 activity, Rho-kinase activity and inflammatory cytokines secretion in response to AngII were significantly increased as compared with WT CFs. Atorvastatin significantly reduced Rac1 expression and oxidative stress in WT CFs, but not in SmgGDS +/- CFs. Furthermore, Bio-plex analysis revealed significant up-regulations of inflammatory cytokines/chemokines and growth factors in SmgGDS +/- CFs as compared with WT CFs. Importantly, conditioned medium from SmgGDS +/- CFs increased BNP expression in neonatal rat cardiomyocytes to a greater extent than that from WT CFs. Furthermore, atorvastatin significantly increased SmgGDS secretion from mouse and human CFs. Finally, treatment with recombinant SmgGDS significantly reduced Rac1 expression in SmgGDS +/- CFs. Conclusion: These results indicate that both intracellular and extracellular SmgGDS play a crucial role in the inhibitory effects of statins on cardiac hypertrophy and fibrosis, partly through inhibition of Rac1, Rho-kinase and ERK1/2 pathways, demonstrating the novel mechanism of the pleiotropic effects of statins.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.35.suppl_1.541
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1494427-3
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  • 6
    Online Resource
    Online Resource
    Abstract 62: Selenoprotein P Promotes Vascular Smooth Muscle Cell Proliferation and Pulmonary Hypertension -A Possible Novel Therapeutic Target-
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. suppl_1 ( 2016-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. suppl_1 ( 2016-05)
    Abstract: Background: Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) is the main characteristics in pulmonary arterial hypertension (PAH); however, its mechanism still remains unclear. Methods & Results: To explore a novel therapeutic target in PAH, we performed a gene expression microarray screening using PASMCs from patients with PAH (PAH-PASMCs) and those from controls and found up-regulation of selenoprotein P (SeP) in PAH-PASMCs ( 〉 5-fold, P 〈 0.01). SeP is a widely expressed extracellular protein, which transports selenium to whole body. Immunostaining showed strong expression of SeP in thickened pulmonary arteries (PA) in PAH. Chronic exposure of mice to hypoxia (O 2 10%) increased SeP expression in the lung. In PAH-PASMCs, hypoxia (O 2 2%, 24 hours) increased SeP expression compared with normoxic controls (O 2 21%) (1.6-fold, P 〈 0.05). Treatment with human recombinant SeP (10μg/mL) up-regulated pro-proliferative genes, activated signals associated with cell-cycle, and increased PAH-PASMCs proliferation (P 〈 0.05, n=8 each). SeP siRNA suppressed pro-proliferative signals with a resultant reduction in PASMCs proliferation. Next, SeP-deficient mice ( SeP -/- ) were exposed to hypoxia (O 2 10%) for 4 weeks, which resulted in suppression of right ventricular systolic pressure (RVSP), RV hypertrophy and PA remodeling compared with controls (all P 〈 0.05, n=11 each). PASMCs proliferation was reduced in SeP -/- PASMCs compared with SeP +/+ PASMCs (P 〈 0.05). SeP -/- PASMCs showed ERK1/2 inactivation, AMPK activation, and reduced secretion of pro-inflammatory cytokines. SMC-targeted deletion of SeP suppressed the development of hypoxia-induced PH compared with controls (all P 〈 0.05, n=10). In contrast, liver-specific deletion of SeP did not affect the development of hypoxia-induced PH (all P 〉 0.05, n=8-9). In the clinical study, serum SeP levels were significantly elevated in PAH patients (n=203) compared with controls (n=20) (P 〈 0.001). Event-free curve revealed that high plasma SeP (≥27μg/ml) predicted poor outcome in PH patients (death or lung transplantation, P 〈 0.01). Conclusions: These results indicate that SeP, especially in PASMCs, promotes PA remodeling, suggesting that it is a novel therapeutic target for PAH.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.36.suppl_1.62
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 1494427-3
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  • 7
    Online Resource
    Online Resource
    Abstract 313: Protective Roles of Small GTP-Binding Protein GDP Dissociation Stimulator Against Angiotensin II-Induced Thoracic Aortic Aneurysm Formation and Rupture in Mice -A Possible Novel Therapeutic Target
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 37, No. suppl_1 ( 2017-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 37, No. suppl_1 ( 2017-05)
    Abstract: Background: Statins reduce the incidence and development of thoracic aortic aneurysm (TAA) and rupture. We have previously identified that small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins. Methods and Results: To examine the role of SmgGDS in TAA formation, Apoe -/- and Apoe -/- SmgGDS +/- (DKO) mice were infused with angiotensin II (AngII, 1,000 ng/min/kg) for 4 weeks. There was no significant difference in blood pressure between the 2 genotypes in response to the AngII treatment. However, during the follow-up, 36% of DKO mice died suddenly due to TAA rupture, whereas there was no TAA rupture in Apoe -/- mice ( P 〈 0.05, n =14 each). Histological analysis of DKO mice showed dissections of major thoracic aorta in the early phase of AngII infusion (day 3~5). We performed ultrasound imaging every week to follow the serial changes in aortic diameters. Diameter of the ascending aorta was progressively and significantly increased in DKO mice compared with Apoe -/- mice (1.64±0.06 vs. 1.43±0.05 mm at 4 weeks, P 〈 0.05, n =14 each), whereas that of the abdominal aorta was comparable between the 2 genotypes. Indeed, there was no significant difference in the incidence of AngII-induced abdominal aortic aneurysm (AAA) formation between the 2 genotypes (both 75%). Western blotting demonstrated that AngII-induced activations of JNK and ERK were significantly higher in the thoracic aorta of DKO mice compared with Apoe -/- mice ( P 〈 0.01, n =6 each). For mechanistic analyses, we primary cultured aortic smooth muscle cells (AoSMCs) from the 2 genotypes. After AngII (100 nM) treatment for 24 hours, DKO AoSMCs showed significantly increased JNK activity, cyclophilin A secretion, and oxidative stress levels compared with Apoe -/- AoSMCs ( P 〈 0.01, n =6 each). Interestingly, AngII-induced upregulation of Nrf2, a master regulator of cellular responses against environmental stresses, was significantly less in DKO AoSMCs compared with Apoe -/- AoSMCs ( P 〈 0.01, n =6). Finally, expressions of matrix metalloproteinase-2 and -9 were significantly increased in DKO AoSMCs compared with Apoe -/- AoSMCs. Conclusions: These results suggest that SmgGDS is a novel therapeutic target for the prevention and treatment of TAA.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.37.suppl_1.313
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 1494427-3
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  • 8
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    Online Resource
    Beneficial Effects of Low-Intensity Pulsed Ultrasound on Right Ventricular Dysfunction in Animal Models
    Elsevier BV ; 2022
    In:  SSRN Electronic Journal
    Details
    In: SSRN Electronic Journal, Elsevier BV
    Type of Medium: Online Resource
    ISSN: 1556-5068
    URL: Article
    DOI: 10.2139/ssrn.4050029
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
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  • 9
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    Online Resource
    Identification of Novel Therapeutic Targets for Pulmonary Arterial Hypertension
    MDPI AG ; 2018
    In:  International Journal of Molecular Sciences Vol. 19, No. 12 ( 2018-12-17), p. 4081-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 19, No. 12 ( 2018-12-17), p. 4081-
    Abstract: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are fatal diseases; however, their pathogenesis still remains to be elucidated. We have recently screened novel pathogenic molecules and have performed drug discovery targeting those molecules. Pulmonary artery smooth muscle cells (PASMCs) in patients with PAH (PAH-PASMCs) have high proliferative properties like cancer cells, which leads to thickening and narrowing of distal pulmonary arteries. Thus, we conducted a comprehensive analysis of PAH-PASMCs and lung tissues to search for novel pathogenic proteins. We validated the pathogenic role of the selected proteins by using tissue-specific knockout mice. To confirm its clinical significance, we used patient-derived blood samples to evaluate the potential as a biomarker for diagnosis and prognosis. Finally, we conducted a high throughput screening and found inhibitors for the pathogenic proteins.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms19124081
    Language: English
    Publisher: MDPI AG
    Publication Date: 2018
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 10
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    Online Resource
    Identification of the Novel Variants in Patients With Chronic Thromboembolic Pulmonary Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Journal of the American Heart Association Vol. 9, No. 21 ( 2020-11-03)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 9, No. 21 ( 2020-11-03)
    Abstract: Although chronic thromboembolic pulmonary hypertension (CTEPH) and acute pulmonary embolism (APE) share some clinical manifestations, a limited proportion of patients with CTEPH have a history of APE. Moreover, in histopathologic studies, it has been revealed that pulmonary vasculature lesions similar to pulmonary arterial hypertension existed in patients with CTEPH. Thus, it remains unknown whether these 3 disorders also share genetic backgrounds. Methods and Results Whole exome screening was performed with DNA isolated from 51 unrelated patients with CTEPH of Japanese ancestry. The frequency of genetic variants associated with pulmonary arterial hypertension or APE in patients with CTEPH was compared with those in the integrative Japanese Genome Variation Database 3.5KJPN. Whole exome screening analysis showed 17 049 nonsynonymous variants in patients with CTEPH. Although we found 6 nonsynonymous variants that are associated with APE in patients with CTEPH, there was no nonsynonymous variant associated with pulmonary arterial hypertension. Patients with CTEPH with a history of APE had nonsynonymous variants of F5 , which encodes factor V. In contrast, patients with CTEPH without a history of APE had a nonsynonymous variant of THBD , which encodes thrombomodulin. Moreover, thrombin‐activatable fibrinolysis inhibitor, which is one of the pathogenic proteins in CTEPH, was significantly more activated in those who had the variants of THBD compared with those without it. Conclusions These results provide the first evidence that patients with CTEPH have some variants associated with APE, regardless of the presence or absence of a history of APE. Furthermore, the variants might be different between patients with CTEPH with and without a history of APE.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.120.015902
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2653953-6
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