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Article ; Online: Role of extracellular vesicles in de novo mineralization: an additional novel mechanism of cardiovascular calcification.

New, Sophie E P / Aikawa, Elena

Arteriosclerosis, thrombosis, and vascular biology

2013 Volume 33, Issue 8, Page(s) 1753–1758

Abstract: Extracellular vesicles are membrane micro/nanovesicles secreted by many cell types into the circulation and the extracellular milieu in physiological and pathological conditions. Evidence suggests that extracellular vesicles, known as matrix vesicles, ... ...

Abstract	Extracellular vesicles are membrane micro/nanovesicles secreted by many cell types into the circulation and the extracellular milieu in physiological and pathological conditions. Evidence suggests that extracellular vesicles, known as matrix vesicles, play a role in the mineralization of skeletal tissue, but emerging ultrastructural and in vitro studies have demonstrated their contribution to cardiovascular calcification as well. Cells involved in the progression of cardiovascular calcification release active vesicles capable of nucleating hydroxyapatite on their membranes. This review discusses the role of extracellular vesicles in cardiovascular calcification and elaborates on this additional mechanism of calcification as an alternative pathway to the currently accepted mechanism of biomineralization via osteogenic differentiation.
MeSH term(s)	Animals ; Calcification, Physiologic/physiology ; Calcinosis/physiopathology ; Cell-Derived Microparticles/physiology ; Extracellular Space/physiology ; Heart Diseases/physiopathology ; Humans ; Osteogenesis/physiology
Language	English
Publishing date	2013-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.112.300128
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Article ; Online: Molecular imaging insights into early inflammatory stages of arterial and aortic valve calcification.

New, Sophie E P / Aikawa, Elena

Circulation research

2011 Volume 108, Issue 11, Page(s) 1381–1391

Abstract: ... to cardiovascular calcification and to develop new therapeutic strategies to prevent or reverse calcification has ...

Abstract	Traditional imaging modalities such as computed tomography, although perfectly adept at identifying and quantifying advanced calcification, cannot detect the early stages of this disorder and offer limited insight into the mechanisms of mineral dysregulation. This review presents optical molecular imaging as a promising tool that simultaneously detects pathobiological processes associated with inflammation and early stages of calcification in vivo at the (sub)cellular levels. Research into treatment of cardiovascular calcification is lacking, as shown by clinical trials that have failed to demonstrate the reduction of calcific aortic stenosis. Hence, the need to elucidate the pathways that contribute to cardiovascular calcification and to develop new therapeutic strategies to prevent or reverse calcification has driven investigations into the use of molecular imaging. This review discusses studies that have used molecular imaging methods to advance knowledge of cardiovascular calcification, focusing in particular on the inflammation-dependent mechanisms of arterial and aortic valve calcification.
MeSH term(s)	Aortic Valve Stenosis/diagnosis ; Aortic Valve Stenosis/immunology ; Atherosclerosis/diagnosis ; Atherosclerosis/immunology ; Calcinosis/diagnosis ; Calcinosis/immunology ; Humans ; Magnetic Resonance Imaging ; Tomography, X-Ray Computed ; Ultrasonography, Interventional ; Vasculitis/diagnosis ; Vasculitis/immunology
Language	English
Publishing date	2011-05-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/CIRCRESAHA.110.234146
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Article ; Online: Cardiovascular calcification: an inflammatory disease.

New, Sophie E P / Aikawa, Elena

Circulation journal : official journal of the Japanese Circulation Society

2011 Volume 75, Issue 6, Page(s) 1305–1313

Abstract: Cardiovascular calcification is an independent risk factor for cardiovascular morbidity and mortality. This disease of dysregulated metabolism is no longer viewed as a passive degenerative disease, but instead as an active process triggered by pro- ... ...

Abstract	Cardiovascular calcification is an independent risk factor for cardiovascular morbidity and mortality. This disease of dysregulated metabolism is no longer viewed as a passive degenerative disease, but instead as an active process triggered by pro-inflammatory cues. Furthermore, a positive feedback loop of calcification and inflammation is hypothesized to drive disease progression in arterial calcification. Both calcific aortic valve disease and atherosclerotic arterial calcification may possess similar underlying mechanisms. Early histopathological studies first highlighted the contribution of inflammation to cardiovascular calcification by demonstrating the accumulation of macrophages and T lymphocytes in `early' lesions within the aortic valves and arteries. A series of in vitro work followed, which gave a mechanistic insight into the stimulation of smooth muscle cells to undergo osteogenic differentiation and mineralization. The emergence of novel technology, in the form of animal models and more recently molecular imaging, has enabled accelerated progression of this field, by providing strong evidence regarding the concept of this disorder as an inflammatory disease. Although there are still gaps in our knowledge of the mechanisms behind this disorder, this review discusses the various studies that have helped form the concept of the inflammation-dependent cardiovascular calcification paradigm.
MeSH term(s)	Animals ; Bone Remodeling ; Calcinosis/immunology ; Calcinosis/metabolism ; Calcinosis/pathology ; Cardiovascular Diseases/immunology ; Cardiovascular Diseases/metabolism ; Cardiovascular Diseases/pathology ; Humans ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/pathology ; Inflammation Mediators/metabolism ; Molecular Imaging ; Signal Transduction
Chemical Substances	Inflammation Mediators
Language	English
Publishing date	2011-05-12
Publishing country	Japan
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2068090-9
ISSN	1347-4820 ; 1346-9843
ISSN (online)	1347-4820
ISSN	1346-9843
DOI	10.1253/circj.cj-11-0395
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Article ; Online: Visualizing novel concepts of cardiovascular calcification.

Hjortnaes, Jesper / New, Sophie E P / Aikawa, Elena

Trends in cardiovascular medicine

2013 Volume 23, Issue 3, Page(s) 71–79

Abstract: ... to understand the process of calcification is therefore warranted and requires new imaging modalities which are ... able to visualize early cardiovascular calcification. This review focuses on the use of new imaging ...

Abstract	Cardiovascular calcification is currently viewed as an active disease process similar to embryonic bone formation. Cardiovascular calcification mainly affects the aortic valve and arteries and is associated with increased mortality risk. Aortic valve and arterial calcification share similar risk factors, including age, gender, diabetes, chronic renal disease, and smoking. However, the exact cellular and molecular mechanism of cardiovascular calcification is unknown. Late-stage cardiovascular calcification can be visualized with conventional imaging modalities such as echocardiography and computed tomography. However, these modalities are limited in their ability to detect the development of early calcification and the progression of calcification until advanced tissue mineralization is apparent. Due to the subsequent late diagnosis of cardiovascular calcification, treatment is usually comprised of invasive interventions such as surgery. The need to understand the process of calcification is therefore warranted and requires new imaging modalities which are able to visualize early cardiovascular calcification. This review focuses on the use of new imaging techniques to visualize novel concepts of cardiovascular calcification.
MeSH term(s)	Animals ; Calcinosis/diagnosis ; Calcinosis/diagnostic imaging ; Calcinosis/metabolism ; Calcinosis/pathology ; Cardiomyopathies/diagnosis ; Cardiomyopathies/diagnostic imaging ; Cardiomyopathies/metabolism ; Cardiomyopathies/pathology ; Diagnostic Imaging/methods ; Early Diagnosis ; Echocardiography ; Endothelial Cells/metabolism ; Endothelial Cells/pathology ; Humans ; Inflammation Mediators/metabolism ; Molecular Imaging ; Predictive Value of Tests ; Prognosis ; Tomography, X-Ray Computed ; Vascular Calcification/diagnosis ; Vascular Calcification/diagnostic imaging ; Vascular Calcification/metabolism ; Vascular Calcification/pathology
Chemical Substances	Inflammation Mediators
Language	English
Publishing date	2013-01-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1097434-9
ISSN	1873-2615 ; 1050-1738
ISSN (online)	1873-2615
ISSN	1050-1738
DOI	10.1016/j.tcm.2012.09.003
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Article ; Online: Three-dimensional environment and vascularization induce osteogenic maturation of human adipose-derived stem cells comparable to that of bone-derived progenitors.

Ibrahim, Amel / Rodriguez-Florez, Naiara / Gardner, Oliver F W / Zucchelli, Eleonora / New, Sophie E P / Borghi, Alessandro / Dunaway, David / Bulstrode, Neil W / Ferretti, Patrizia

Stem cells translational medicine

2020 Volume 9, Issue 12, Page(s) 1651–1666

Abstract: While human adipose-derived stem cells (hADSCs) are known to possess osteogenic differentiation potential, the bone tissues formed are generally considered rudimentary and immature compared with those made by bone-derived precursor cells such as human ... ...

Abstract	While human adipose-derived stem cells (hADSCs) are known to possess osteogenic differentiation potential, the bone tissues formed are generally considered rudimentary and immature compared with those made by bone-derived precursor cells such as human bone marrow-derived mesenchymal stem cells (hBMSCs) and less commonly studied human calvarium osteoprogenitor cells (hOPs). Traditional differentiation protocols have tended to focus on osteoinduction of hADSCs through the addition of osteogenic differentiation media or use of stimulatory bioactive scaffolds which have not resulted in mature bone formation. Here, we tested the hypothesis that by reproducing the physical as well as biochemical bone microenvironment through the use of three-dimensional (3D) culture and vascularization we could enhance osteogenic maturation in hADSCs. In addition to biomolecular characterization, we performed structural analysis through extracellular collagen alignment and mineral density in our bone tissue engineered samples to evaluate osteogenic maturation. We further compared bone formed by hADSCs, hBMSCs, and hOPs against mature human pediatric calvarial bone, yet not extensively investigated. Although bone generated by all three cell types was still less mature than native pediatric bone, a fibrin-based 3D microenvironment together with vascularization boosted osteogenic maturation of hADSC making it similar to that of bone-derived osteoprogenitors. This demonstrates the important role of vascularization and 3D culture in driving osteogenic maturation of cells easily available but constitutively less committed to this lineage and suggests a crucial avenue for recreating the bone microenvironment for tissue engineering of mature craniofacial bone tissues from pediatric hADSCs, as well as hBMSCs and hOPs.
MeSH term(s)	Adipose Tissue/metabolism ; Humans ; Osteogenesis/physiology ; Stem Cells/metabolism ; Tissue Engineering/methods ; Tissue Scaffolds
Language	English
Publishing date	2020-07-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2642270-0
ISSN	2157-6580 ; 2157-6564
ISSN (online)	2157-6580
ISSN	2157-6564
DOI	10.1002/sctm.19-0207
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Article ; Online: Towards reconstruction of epithelialized cartilages from autologous adipose tissue-derived stem cells.

New, Sophie E P / Ibrahim, Amel / Guasti, Leonardo / Zucchelli, Eleonora / Birchall, Martin / Bulstrode, Neil W / Seifalian, Alexander M / Ferretti, Patrizia

Journal of tissue engineering and regenerative medicine

2016 Volume 11, Issue 11, Page(s) 3078–3089

Abstract: Deformities of the upper airways, including those of the nose and throat, are typically corrected by reconstructive surgery. The use of autologous somatic stem cells for repair of defects could improve quality and outcomes of such operations. The present ...

Abstract	Deformities of the upper airways, including those of the nose and throat, are typically corrected by reconstructive surgery. The use of autologous somatic stem cells for repair of defects could improve quality and outcomes of such operations. The present study explored the ability of paediatric adipose-derived stem cells (pADSCs), a readily available source of autologous stem cells, to generate a cartilage construct with a functional epithelium. Paediatric ADSCs seeded on the biodegradable nanocomposite polymer, polyhedral oligomeric silsesquioxane poly(ϵ-caprolactone-urea) urethane (POSS-PCL), proliferated and differentiated towards mesenchymal lineages. The ADSCs infiltrated three-dimensional POSS-PCL nanoscaffold and chondroid matrix was observed throughout chondrogenically induced samples. In ovo chorioallantoic membrane-grafted ADSC-nanoscaffold composites were enwrapped by host vessels indicating good compatibility in an in vivo system. Furthermore, pADSCs could be induced to transdifferentiate towards barrier-forming epithelial-like cells. By combining differentiation protocols, it was possible to generate epithelial cell lined chondrogenic micromasses from the same pADSC line. This proof-of-concept study appears to be the first to demonstrate that individual pADSC lines can differentiate towards two different germ lines and be successfully co-cultured. This has important implications for bioengineering of paediatric airways and further confirms the plastic nature of ADSCs. Copyright © 2016 John Wiley & Sons, Ltd.
MeSH term(s)	Adipose Tissue/cytology ; Adipose Tissue/metabolism ; Adolescent ; Cartilage/cytology ; Cartilage/metabolism ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Male ; Organosilicon Compounds/chemistry ; Polyesters/chemistry ; Polyurethanes/chemistry ; Stem Cells/cytology ; Stem Cells/metabolism ; Tissue Scaffolds/chemistry
Chemical Substances	Organosilicon Compounds ; Polyesters ; Polyurethanes ; polyhedraloligosilsesquioxane ; polycaprolactone (24980-41-4)
Language	English
Publishing date	2016-11-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2316155-3
ISSN	1932-7005 ; 1932-6254
ISSN (online)	1932-7005
ISSN	1932-6254
DOI	10.1002/term.2211
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Article ; Online: Time-dependent mechanical properties of aortic valve cusps: effect of glycosaminoglycan depletion.

Borghi, Alessandro / New, Sophie E P / Chester, Adrian H / Taylor, Patricia M / Yacoub, Magdi H

Acta biomaterialia

2013 Volume 9, Issue 1, Page(s) 4645–4652

Abstract: Aortic valve (AV) performance is closely linked to its structural components. Glycosaminoglycans (GAGs) are thought to influence the time-dependent properties of living tissues. This study investigates the effect of GAGs on the viscoelastic behaviour of ... ...

Abstract	Aortic valve (AV) performance is closely linked to its structural components. Glycosaminoglycans (GAGs) are thought to influence the time-dependent properties of living tissues. This study investigates the effect of GAGs on the viscoelastic behaviour of the AV. Fresh porcine AV cusps were either treated enzymatically to remove GAGs or left untreated (control). The specimens were tested for stress relaxation and tensile properties under equibiaxial load conditions. The stress relaxation curves were fitted using a double exponential decay equation and the early relaxation constant (τ(1)) and late relaxation constant (τ(2)) calculated for each specimen. Immunohistochemistry confirmed the successful depletion of both sulphated and non-sulphated GAGs from the AV cusps. A statistical increase in τ(1) was found for both the radial and circumferential directions between the control and -GAGs group (radial, control 17.37s vs. -GAGs 25.65 s; circumferential, control 21.47s vs. -GAGs 27.37 s). It was also found that τ(1) differed between the two directions for the control group but not after GAG depletion (control, radial 17.37s vs. circumferential 21.47 s; -GAGs, radial 25.65 s vs. circumferential 27.37s). No effect on stiffness was found. The results showed that the presence of GAGs influences the mechanical viscoelastic properties of the AV but has no effect on the stiffness. The natural anisotropy, which reflects the relaxation kinematics, is lost after GAG depletion.
MeSH term(s)	Animals ; Aortic Valve ; Biomechanical Phenomena ; Glycosaminoglycans/metabolism ; Immunohistochemistry ; Swine ; Time
Chemical Substances	Glycosaminoglycans
Language	English
Publishing date	2013-01
Publishing country	England
Document type	Journal Article
ZDB-ID	2173841-5
ISSN	1878-7568 ; 1742-7061
ISSN (online)	1878-7568
ISSN	1742-7061
DOI	10.1016/j.actbio.2012.09.001
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Article ; Online: Plasticity of human adipose-derived stem cells - relevance to tissue repair.

Guasti, Leonardo / New, Sophie E / Hadjidemetriou, Irene / Palmiero, Miriam / Ferretti, Patrizia

The International journal of developmental biology

2018 Volume 62, Issue 6-7-8, Page(s) 431–439

Abstract: In contrast to cold blooded vertebrates, the ability to regenerate morphologically and functionally complex structures is limited in adult mammals. Recruitment of progenitor cells is a key step in the regenerative process. The possibility of repairing ... ...

Abstract	In contrast to cold blooded vertebrates, the ability to regenerate morphologically and functionally complex structures is limited in adult mammals. Recruitment of progenitor cells is a key step in the regenerative process. The possibility of repairing missing or diseased tissues in humans has been potentiated by the increasing understanding of somatic stem cells, their plasticity and the possibility of modulating it, that could be harnessed either to stimulate endogenous repair or to engineer the required tissue. Here, we focus on human mesenchymal stem cells (MSCs), important players in tissue homeostasis in healthy organisms, with a particular emphasis on those derived from the adipose tissue (ADSCs). While a mark of MSC identity is the ability to differentiate into osteoblasts, chondrocytes and adipocytes, there is evidence that their potential goes beyond these three mesenchymal lineages. We discuss some differentiation and modulatory properties of MSCs and provide an overview of our recent work on ADSCs from paediatric patients (pADSCs) that has shown their ability to give raise to non-mesenchymal cells, consistent with a significant plasticity. Finally, we present novel data indicating that both mesenchymal lineages (adipogenic, chondrogenic and osteogenic) and neural and epithelial lineages can originate from clonal lines that like the parental line express markers of pluripotency as well as the stromal cell marker, GREM1. Together these data support the existence of pADSC multipotent stem cells.
MeSH term(s)	Adipocytes/cytology ; Adipocytes/physiology ; Adipose Tissue/cytology ; Animals ; Cell Differentiation/physiology ; Cell Polarity/physiology ; Chondrocytes/cytology ; Chondrocytes/physiology ; Humans ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/physiology ; Osteoblasts/cytology ; Osteoblasts/physiology ; Wound Healing/physiology
Language	English
Publishing date	2018-06-25
Publishing country	Spain
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1036070-0
ISSN	1696-3547 ; 0214-6282
ISSN (online)	1696-3547
ISSN	0214-6282
DOI	10.1387/ijdb.180074pf
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Zs.A 3202: Show issues

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Article ; Online: Pitavastatin Reduces Inflammation in Atherosclerotic Plaques in Apolipoprotein E-Deficient Mice with Late Stage Renal Disease.

Shibasaki, Manabu / Wang, Jian-Guo / Figueiredo, Jose-Luiz / New, Sophie E P / Quillard, Thibaut / Goettsch, Claudia / Koga, Jun-ichiro / Sonoki, Hiroyuki / Matsumoto, Jiro / Aikawa, Masanori / Aikawa, Elena

PloS one

2015 Volume 10, Issue 9, Page(s) e0138047

Abstract: ... Methods and results: CRD was induced by 5/6 nephrectomy in cholesterol-fed apolipoprotein E-deficient ...

Abstract	Objectives: Chronic renal disease (CRD) accelerates atherosclerosis and cardiovascular calcification. Statins reduce low-density lipoprotein-cholesterol levels in patients with CRD, however, the benefits of statins on cardiovascular disease in CRD remain unclear. This study has determined the effects of pitavastatin, the newest statin, on arterial inflammation and calcification in atherogenic mice with CRD. Methods and results: CRD was induced by 5/6 nephrectomy in cholesterol-fed apolipoprotein E-deficient mice. Mice were randomized into three groups: control mice, CRD mice, and CRD mice treated with pitavastatin. Ultrasonography showed that pitavastatin treatment significantly attenuated luminal stenosis in brachiocephalic arteries of CRD mice. Near-infrared molecular imaging and correlative Mac3 immunostaining demonstrated a significant reduction in macrophage accumulation in pitavastatin-treated CRD mice. Pitavastatin treatment reduced levels of osteopontin in plasma and atherosclerotic lesions in CRD mice, but did not produce a significant reduction in calcification in atherosclerotic plaques as assesses by histology. CRD mice had significantly higher levels of phosphate in plasma than did control mice, which did not change by pitavastatin. In vitro, pitavastatin suppressed the expression of osteopontin in peritoneal macrophages stimulated with phosphate or calcium/phosphate in concentrations similar to those found in human patients with CRD. Conclusion: Our study provides in vivo evidence that pitavastatin reduces inflammation within atherosclerotic lesions in CRD mice.
MeSH term(s)	Animals ; Apolipoproteins E/deficiency ; Atherosclerosis/blood ; Atherosclerosis/diagnostic imaging ; Atherosclerosis/drug therapy ; Atherosclerosis/genetics ; Calcium/blood ; Cholesterol/adverse effects ; Cholesterol/pharmacology ; Humans ; Kidney Failure, Chronic/blood ; Kidney Failure, Chronic/drug therapy ; Kidney Failure, Chronic/genetics ; Macrophages, Peritoneal/metabolism ; Macrophages, Peritoneal/pathology ; Mice ; Mice, Knockout ; Osteopontin/blood ; Phosphates/blood ; Plaque, Atherosclerotic/blood ; Plaque, Atherosclerotic/diagnostic imaging ; Plaque, Atherosclerotic/drug therapy ; Plaque, Atherosclerotic/genetics ; Quinolines/pharmacology ; Ultrasonography
Chemical Substances	Apolipoproteins E ; Phosphates ; Quinolines ; Osteopontin (106441-73-0) ; Cholesterol (97C5T2UQ7J) ; pitavastatin (M5681Q5F9P) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2015-09-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0138047
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Article: Time-dependent mechanical properties of aortic valve cusps: Effect of glycosaminoglycan depletion

Borghi, Alessandro / New, Sophie E.P / Chester, Adrian H / Taylor, Patricia M / Yacoub, Magdi H

Acta Biomaterialia. 2013 Jan., v. 9, no. 1

2013

Abstract	Aortic valve (AV) performance is closely linked to its structural components. Glycosaminoglycans (GAGs) are thought to influence the time-dependent properties of living tissues. This study investigates the effect of GAGs on the viscoelastic behaviour of the AV. Fresh porcine AV cusps were either treated enzymatically to remove GAGs or left untreated (control). The specimens were tested for stress relaxation and tensile properties under equibiaxial load conditions. The stress relaxation curves were fitted using a double exponential decay equation and the early relaxation constant (τ₁) and late relaxation constant (τ₂) calculated for each specimen. Immunohistochemistry confirmed the successful depletion of both sulphated and non-sulphated GAGs from the AV cusps. A statistical increase in τ₁ was found for both the radial and circumferential directions between the control and –GAGs group (radial, control 17.37s vs. –GAGs 25.65s; circumferential, control 21.47s vs. –GAGs 27.37s). It was also found that τ₁ differed between the two directions for the control group but not after GAG depletion (control, radial 17.37s vs. circumferential 21.47s; –GAGs, radial 25.65s vs. circumferential 27.37s). No effect on stiffness was found. The results showed that the presence of GAGs influences the mechanical viscoelastic properties of the AV but has no effect on the stiffness. The natural anisotropy, which reflects the relaxation kinematics, is lost after GAG depletion.
Keywords	equations ; glycosaminoglycans ; immunohistochemistry ; kinematics ; mechanical properties ; stress relaxation ; swine ; viscoelasticity
Language	English
Dates of publication	2013-01
Size	p. 4645-4652.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	2173841-5
ISSN	1878-7568 ; 1742-7061
ISSN (online)	1878-7568
ISSN	1742-7061
DOI	10.1016/j.actbio.2012.09.001
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