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  • 1
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    #4372 TYK2-INDUCED STAT ACTIVATION IS ESSENTIAL FOR VASCULAR PRO-CALCIFIC EFFECTS OF LEUKEMIA INHIBITORY FACTOR
    Oxford University Press (OUP) ; 2023
    In:  Nephrology Dialysis Transplantation Vol. 38, No. Supplement_1 ( 2023-06-14)
    Details
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 38, No. Supplement_1 ( 2023-06-14)
    Abstract: Hyperphosphatemia in chronic kidney disease (CKD) is closely linked to medial vascular calcification. Phosphate is able to induce pro-inflammatory effects in vascular smooth muscle cells (VSMC), which could actively augment calcification processes. This study investigated the role of the IL-6 family member leukemia inhibitory factor (LIF) during vascular calcification. Method Experiments were performed in primary human aortic VSMCs, ex vivo mouse aortic rings and cholecalciferol treated mice, as well as serum samples from CKD patients and healthy controls. Results Phosphate exposure induced LIF release in VSMCs, while supplementation of LIF aggravated calcification and expression of pro-calcific markers in VSMCs. Silencing of LIF or addition of soluble LIF receptor (LIFR) as putative LIF antagonist ameliorated the pro-calcific effects of phosphate. Similarly, effects of phosphate or LIF were blunted by silencing of LIFR or its coreceptor GP130 in VSMCs. Mechanistically, LIF induced phosphorylation of TYK2, which was required for STAT1/3 activation. TYK2 overexpression augmented VSMC calcification, while silencing of either TYK2 or STAT1/3 ameliorated phosphate- and LIF-induced expression of pro-calcific markers. Pharmacological inhibition of TYK2 ameliorated calcification in VSMCs, mouse aortic rings and mice after cholecalciferol treatment. Furthermore, calcification was ameliorated in TYK2-deficient mouse aortic rings and mice after cholecalciferol overload. In a pilot study, LIFR was reduced in serum from patients with CKD and LIFR levels were associated with serum calcification propensity. Conclusion Vascular calcification is augmented by LIF, which identifies a crucial role of TYK2 in the pro-calcific reprogramming of VSMCs. Inhibition of this signalling axis might be able to reduce the burden of vascular calcification in CKD.
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    URL: Article
    DOI: 10.1093/ndt/gfad063c_4372
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1465709-0
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  • 2
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    Prevention of Oxidative Damage in Spinal Cord Ischemia Upon Aortic Surgery: First‐In‐Human Results of Shock Wave Therapy Prove Safety and Feasibility
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Journal of the American Heart Association Vol. 11, No. 20 ( 2022-10-18)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 11, No. 20 ( 2022-10-18)
    Abstract: Spinal cord ischemia (SCI) remains a devastating complication after aortic dissection or repair. A primary hypoxic damage is followed by a secondary damage resulting in further cellular loss via apoptosis. Affected patients have a poor prognosis and limited therapeutic options. Shock wave therapy (SWT) improves functional outcome, neuronal degeneration and survival in murine spinal cord injury. In this first‐in‐human study we treated 5 patients with spinal cord ischemia with SWT aiming to prove safety and feasibility. Methods and Results Human neurons were subjected to ischemic injury with subsequent SWT. Reactive oxygen species and cellular apoptosis were quantified using flow cytometry. Signaling of the antioxidative transcription factor NRF2 (nuclear factor erythroid 2‐related factor 2) and immune receptor Toll‐like receptor 3 (TLR3) were analyzed. To assess whether SWT act via a conserved mechanism, transgenic tlr3 −/− zebrafish created via CRISPR/Cas9 were subjected to spinal cord injury. To translate our findings into a clinical setting, 5 patients with SCI underwent SWT. Baseline analysis and follow‐up (6 months) included assessment of American Spinal Cord Injury Association (ASIA) impairment scale, evaluation of Spinal Cord Independence Measure score and World Health Organization Quality of Life questionnaire. SWT reduced the number of reactive oxygen species positive cells and apoptosis upon ischemia via induction of the antioxidative factor nuclear factor erythroid 2‐related factor 2. Inhibition or deletion of tlr3 impaired axonal growth after spinal cord lesion in zebrafish, whereas tlr3 stimulation enhanced spinal regeneration. In a first‐in‐human study, we treated 5 patients with SCI using SWT (mean age, 65.3 years). Four patients presented with acute aortic dissection (80%), 2 of them exhibited preoperative neurological symptoms (40%). Impairment was ASIA A in 1 patient (20%), ASIA B in 3 patients (60%), and ASIA D in 1 patient (20%) at baseline. At follow‐up, 2 patients were graded as ASIA A (40%) and 3 patients as ASIA B (60%). Spinal cord independence measure score showed significant improvement. Examination of World Health Organization Quality of Life questionnaires revealed increased scores at follow‐up. Conclusions SWT reduces oxidative damage upon SCI via immune receptor TLR3. The first‐in‐human application proved safety and feasibility in patients with SCI. SWT could therefore become a powerful regenerative treatment option for this devastating injury.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.122.026076
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2653953-6
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  • 3
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    Adenylyl cyclase 6 in acid-base balance – adding complexity
    Portland Press Ltd. ; 2018
    In:  Clinical Science Vol. 132, No. 17 ( 2018-09-14), p. 1995-1997
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 132, No. 17 ( 2018-09-14), p. 1995-1997
    Abstract: Systemic acid-base balance is tightly controlled within a narrow range of pH. Disturbances in systemic acid-base homeostasis are associated with diverse detrimental effects. The kidney is a key regulator of acid-base balance, capable of excreting HCO3− or H+, and chronic kidney disease invariably leads to acidosis. However, the regulatory pathways underlying the fine-tuned acid-base sensing and regulatory mechanisms are still incompletely understood. In the article published recently in Clinical Science (vol 132 (16) 1779-1796), Poulson and colleagues investigated the role of adenylyl cyclase 6 (AC6) in acid-base homeostasis. They uncovered a complex role of AC6, specifically affecting acid-base balance during HCO3− load, which causes pronounced alkalosis in AC6-deficient mice. However, the phenotype of AC6-deficient mice appears much more complex, involving systemic effects associated with increased energy expenditure. These observations remind us that there is much to be learned about the intricate signaling pathways involved in renal control of acid-base balance and the complex ramifications of acid-base regulation.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20180572
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2018
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  • 4
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    CD44 sensitivity of platelet activation, membrane scrambling and adhesion under high arterial shear rates
    Georg Thieme Verlag KG ; 2016
    In:  Thrombosis and Haemostasis Vol. 115, No. 01 ( 2016-01), p. 99-108
    Details
    In: Thrombosis and Haemostasis, Georg Thieme Verlag KG, Vol. 115, No. 01 ( 2016-01), p. 99-108
    Abstract: CD44 is required for signalling of macrophage migration inhibitory factor (MIF), an anti-apoptotic pro-inflammatory cytokine. MIF is expressed and released from blood platelets, key players in the orchestration of occlusive vascular disease. Nothing is known about a role of CD44 in the regulation of platelet function. The present study thus explored whether CD44 modifies degranulation (P-selectin exposure), integrin activation, caspase activity, phosphatidylserine exposure on the platelet surface, platelet volume, Orai1 protein abundance and cytosolic Ca2+-activity ([Ca2+]i). Platelets from mice lacking CD44 (cd44-/- ) were compared to platelets from corresponding wild-type mice (cd44+/+ ). In resting platelets, P-selectin abundance, αllbβ3 inte-grin activation, caspase-3 activity and phosphatidylserine exposure were negligible in both genotypes and Orai1 protein abundance, [Ca2+] i, and volume were similar in cd44-/- and cd44+/+ platelets. Platelet degranulation and αllbβ3 integrin activation were significantly increased by thrombin (0.02 U/ml), collagen related peptide (CRP, 2 µg/ml and Ca2+-store depletion with thapsigargin (1 µM), effects more pronounced in cd44-/- than in cd44+/+ platelets. Thrombin (0.02 U/ml) increased platelet [Ca2+]i, caspase-3 activity, phosphatidylserine exposure and Orai1 surface abundance, effects again significantly stronger in cd44-/- than in cd44+/+ platelets. Thrombin further decreased forward scatter in cd44-/- and cd44+/+ platelets, an effect which tended to be again more pronounced in cd44-/- than in cd44+/+ platelets. Platelet adhesion and in vitro thrombus formation under high arterial shear rates (1,700 s-1) were significantly augmented in cd44-/- mice. In conclusion, genetic deficiency of CD44 augments activation, apoptosis and prothrombotic potential of platelets.
    Type of Medium: Online Resource
    ISSN: 0340-6245 , 2567-689X
    URL: Article
    DOI: 10.1160/TH14-10-0847
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2016
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  • 5
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    Up-Regulation of Hepatic Alpha-2-HS-Glycoprotein Transcription by Testosterone via Androgen Receptor Activation
    S. Karger AG ; 2014
    In:  Cellular Physiology and Biochemistry Vol. 33, No. 6 ( 2014), p. 1911-1920
    Details
    In: Cellular Physiology and Biochemistry, S. Karger AG, Vol. 33, No. 6 ( 2014), p. 1911-1920
    Type of Medium: Online Resource
    ISSN: 1421-9778 , 1015-8987
    URL: Article
    DOI: 10.1159/000362968
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2014
    detail.hit.zdb_id: 1482056-0
    SSG: 12
    SSG: 15,3
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  • 6
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    SGK1 induces vascular smooth muscle cell calcification through NF-κB signaling
    American Society for Clinical Investigation ; 2018
    In:  Journal of Clinical Investigation Vol. 128, No. 7 ( 2018-7-2), p. 3024-3040
    Details
    In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 128, No. 7 ( 2018-7-2), p. 3024-3040
    Type of Medium: Online Resource
    ISSN: 0021-9738 , 1558-8238
    URL: Article
    URL: Article
    DOI: 10.1172/JCI96477
    DOI: 10.1172/JCI96477DS1
    Language: English
    Publisher: American Society for Clinical Investigation
    Publication Date: 2018
    detail.hit.zdb_id: 2018375-6
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  • 7
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    Pivotal Role of Serum- and Glucocorticoid-Inducible Kinase 1 in Vascular Inflammation and Atherogenesis
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. 3 ( 2015-03), p. 547-557
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. 3 ( 2015-03), p. 547-557
    Abstract: Atherosclerosis, an inflammatory disease of arterial vessel walls, requires migration and matrix metalloproteinase (MMP)-9–dependent invasion of monocytes/macrophages into the vascular wall. MMP-9 expression is stimulated by transcription factor nuclear factor-κB, which is regulated by inhibitor κB (IκB) and thus IκB kinase. Regulators of nuclear factor-κB include serum- and glucocorticoid-inducible kinase 1 (SGK1). The present study explored involvement of SGK1 in vascular inflammation and atherogenesis. Approach and Results— Gene-targeted apolipoprotein E (ApoE)–deficient mice without ( apoe −/− sgk1 +/+ ) or with ( apoe −/− sgk1 −/− ) additional SGK1 knockout received 16-week cholesterol-rich diet. According to immunohistochemistry atherosclerotic lesions in aorta and carotid artery, vascular CD45 + leukocyte infiltration, Mac-3 + macrophage infiltration, vascular smooth muscle cell content, MMP-2, and MMP-9 positive areas in atherosclerotic tissue were significantly less in apoe −/− sgk1 −/− mice than in apoe −/− sgk1 +/+ mice. As determined by Boyden chamber, thioglycollate-induced peritonitis and air pouch model, migration of SGK1-deficient CD11b + F4/80 + macrophages was significantly diminished in vitro and in vivo. Zymographic MMP-2 and MMP-9 production, MMP-9 activity and invasion through matrigel in vitro were significantly less in sgk1 −/− than in sgk1 +/+ macrophages and in control plasmid–transfected or inactive K127N SGK1-transfected than in constitutively active S422D SGK1-transfected THP-1 cells. Confocal microscopy revealed reduced macrophage number and macrophage MMP-9 content in plaques of apoe −/− sgk1 −/− mice. In THP-1 cells, MMP-inhibitor GM6001 (25 μmol/L) abrogated S422D SGK1-induced MMP-9 production and invasion. According to reverse transcription polymerase chain reaction, MMP-9 transcript levels were significantly reduced in sgk1 −/− macrophages and strongly upregulated in S422D SGK1-transfected THP-1 cells compared with control plasmid–transfected or K127N SGK1-transfected THP-1 cells. According to immunoblotting and confocal microscopy, phosphorylation of IκB kinase and inhibitor κB and nuclear translocation of p50 were significantly lower in sgk1 −/− macrophages than in sgk1 +/+ macrophages and significantly higher in S422D SGK1-transfected THP-1 cells than in control plasmid–transfected or K127N SGK1-transfected THP-1 cells. Treatment of S422D SGK1-transfected THP-1 cells with IκB kinase-inhibitor BMS-345541 (10 μmol/L) abolished S422D SGK1-induced increase of MMP-9 transcription and gelatinase activity. Conclusions— SGK1 plays a pivotal role in vascular inflammation during atherogenesis. SGK1 participates in the regulation of monocyte/macrophage migration and MMP-9 transcription via regulation of nuclear factor-κB.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.114.304454
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1494427-3
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  • 8
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    Stimulation of Suicidal Erythrocyte Death by Increased Extracellular Phosphate Concentrations
    S. Karger AG ; 2013
    In:  Kidney and Blood Pressure Research Vol. 38, No. 1 ( 2013), p. 42-51
    Details
    In: Kidney and Blood Pressure Research, S. Karger AG, Vol. 38, No. 1 ( 2013), p. 42-51
    Abstract: 〈 b 〉 〈 i 〉 Background/Aim 〈 /i 〉 〈 /b 〉 〈 i 〉 : 〈 /i 〉 Anemia in renal insufficiency results in part from impaired erythrocyte formation due to erythropoietin and iron deficiency. Beyond that, renal insufficiency enhances eryptosis, the suicidal erythrocyte death characterized by phosphatidylserine-exposure at the erythrocyte surface. Eryptosis may be stimulated by increase of cytosolic Ca 〈 sup 〉 2+ 〈 /sup 〉 -activity ([Ca 〈 sup 〉 2+ 〈 /sup 〉 ] 〈 sub 〉 i 〈 /sub 〉 ). Several uremic toxins have previously been shown to stimulate eryptosis. Renal insufficiency is further paralleled by increase of plasma phosphate concentration. The present study thus explored the effect of phosphate on erythrocyte death. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 Cell volume was estimated from forward scatter, phosphatidylserine-exposure from annexin V binding, and [Ca 〈 sup 〉 2+ 〈 /sup 〉 ] 〈 sub 〉 i 〈 /sub 〉 from Fluo3-fluorescence. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Following a 48 hours incubation, the percentage of phosphatidylserine exposing erythrocytes markedly increased as a function of extracellular phosphate concentration (from 0-5 mM). The exposure to 2 mM or 5 mM phosphate was followed by slight but significant hemolysis. [Ca 〈 sup 〉 2+ 〈 /sup 〉 ] 〈 sub 〉 i 〈 /sub 〉 did not change significantly up to 2 mM phosphate but significantly decreased at 5 mM phosphate. The effect of 2 mM phosphate on phosphatidylserine exposure was significantly augmented by increase of extracellular Ca 〈 sup 〉 2+ 〈 /sup 〉 to 1.7 mM, and significantly blunted by nominal absence of extracellular Ca 〈 sup 〉 2+ 〈 /sup 〉 , by additional presence of pyrophosphate as well as by presence of p38 inhibitor SB203580. 〈 b 〉 〈 i 〉 Conclusion 〈 /i 〉 〈 /b 〉 〈 i 〉 : 〈 /i 〉 Increasing phosphate concentration stimulates erythrocyte membrane scrambling, an effect depending on extracellular but not intracellular Ca 〈 sup 〉 2+ 〈 /sup 〉 concentration. It is hypothesized that suicidal erythrocyte death is triggered by complexed CaHPO 〈 sub 〉 4 〈 /sub 〉 .
    Type of Medium: Online Resource
    ISSN: 1420-4096 , 1423-0143
    URL: Article
    DOI: 10.1159/000355752
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2013
    detail.hit.zdb_id: 1482922-8
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  • 9
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    PKB/SGK-Resistant GSK-3 Signaling Following Unilateral Ureteral Obstruction
    S. Karger AG ; 2013
    In:  Kidney and Blood Pressure Research Vol. 38, No. 1 ( 2013), p. 156-164
    Details
    In: Kidney and Blood Pressure Research, S. Karger AG, Vol. 38, No. 1 ( 2013), p. 156-164
    Abstract: 〈 b 〉 〈 i 〉 Background/Aims: 〈 /i 〉 〈 /b 〉 Renal tissue fibrosis contributes to the development of end-stage renal disease. Causes for renal tissue fibrosis include obstructive nephropathy. The development of renal fibrosis following unilateral ureteral obstruction (UUO) is blunted in gene-targeted mice lacking functional serum- and glucocorticoid-inducible kinase SGK1. Similar to Akt isoforms, SGK1 phosphorylates and thus inactivates glycogen synthase kinase GSK-3. The present study explored whether PKB/SGK-dependent phoshorylation of GSK-3α/β impacts on pro-fibrotic signaling following UUO. 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 UUO was induced in mice carrying a PKB/SGK-resistant GSK-3α/β ( 〈 i 〉 gsk-3 〈 /i 〉 〈 sup 〉 〈 i 〉 KI 〈 /i 〉 〈 /sup 〉 ) and corresponding wild-type mice ( 〈 i 〉 gsk-3 〈 /i 〉 〈 sup 〉 〈 i 〉 WT 〈 /i 〉 〈 /sup 〉 ). Three days after the obstructive injury, expression of fibrosis markers in kidney tissues was analyzed by quantitative RT-PCR and western blotting. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 GSK-3α and GSK-3β phosphorylation was absent in both, the non-obstructed and the obstructed kidney tissues from 〈 i 〉 gsk-3 〈 /i 〉 〈 sup 〉 〈 i 〉 KI 〈 /i 〉 〈 /sup 〉 mice but was increased by UUO in kidney tissues from 〈 i 〉 gsk-3 〈 /i 〉 〈 sup 〉 〈 i 〉 WT 〈 /i 〉 〈 /sup 〉 mice. Expression of α-smooth muscle actin, type I collagen and type III collagen in the non-obstructed kidney tissues was not significantly different between 〈 i 〉 gsk-3 〈 /i 〉 〈 sup 〉 〈 i 〉 KI 〈 /i 〉 〈 /sup 〉 mice and 〈 i 〉 gsk-3 〈 /i 〉 〈 sup 〉 〈 i 〉 WT 〈 /i 〉 〈 /sup 〉 mice but was significantly less increased in the obstructed kidney tissues from 〈 i 〉 gsk-3 〈 /i 〉 〈 sup 〉 〈 i 〉 KI 〈 /i 〉 〈 /sup 〉 mice than from 〈 i 〉 gsk-3 〈 /i 〉 〈 sup 〉 〈 i 〉 WT 〈 /i 〉 〈 /sup 〉 mice. After UUO treatment, renal β-catenin protein abundance and renal expression of the β-catenin sensitive genes: 〈 i 〉 c-Myc 〈 /i 〉 , 〈 i 〉 Dkk1 〈 /i 〉 , 〈 i 〉 Twist 〈 /i 〉 and 〈 i 〉 Lef1 〈 /i 〉 were again significantly less increased in kidney tissues from 〈 i 〉 gsk-3 〈 /i 〉 〈 sup 〉 〈 i 〉 KI 〈 /i 〉 〈 /sup 〉 mice than from 〈 i 〉 gsk-3 〈 /i 〉 〈 sup 〉 〈 i 〉 WT 〈 /i 〉 〈 /sup 〉 mice. 〈 b 〉 〈 i 〉 Conclusions: 〈 /i 〉 〈 /b 〉 PKB/SGK-dependent phosphorylation of glycogen synthase kinase GSK-3 contributes to the pro-fibrotic signaling leading to renal tissue fibrosis in obstructive nephropathy.
    Type of Medium: Online Resource
    ISSN: 1420-4096 , 1423-0143
    URL: Article
    DOI: 10.1159/000355763
    Language: English
    Publisher: S. Karger AG
    Publication Date: 2013
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  • 10
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    Effect of eplerenone on parathyroid hormone levels in patients with primary hyperparathyroidism : results from the EPATH randomized, placebo-controlled trial
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Journal of Hypertension Vol. 34, No. 7 ( 2016-07), p. 1347-1356
    Details
    In: Journal of Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 34, No. 7 ( 2016-07), p. 1347-1356
    Type of Medium: Online Resource
    ISSN: 0263-6352
    URL: Article
    DOI: 10.1097/HJH.0000000000000927
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
    detail.hit.zdb_id: 2017684-3
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