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  1. Article ; Online: von Willebrand factor and inflammation.

    Kawecki, C / Lenting, P J / Denis, C V

    Journal of thrombosis and haemostasis : JTH

    2017  Volume 15, Issue 7, Page(s) 1285–1294

    Abstract: Von Willebrand factor (VWF) is a plasma glycoprotein best known for its crucial hemostatic role in serving as a molecular bridge linking platelets to subendothelial components following vascular injury. In addition, VWF functions as chaperone for ... ...

    Abstract Von Willebrand factor (VWF) is a plasma glycoprotein best known for its crucial hemostatic role in serving as a molecular bridge linking platelets to subendothelial components following vascular injury. In addition, VWF functions as chaperone for coagulation factor VIII. In pathological settings, VWF is recognized as a risk factor for both arterial and venous thrombosis, as well as a molecular player that directly promotes the thrombotic process. Recent years have seen the emergence of the concept of immuno-thrombosis by which inflammatory cells participate in thrombotic processes. In return, reports about the involvement of hemostatic proteins or cells (such as platelets) in inflammatory responses have become increasingly common, emphasizing the intricate link between hemostasis and inflammation. However, evidence of a link between VWF and inflammation arose much earlier than these recent developments. At first, VWF was considered only as a marker of inflammation in various pathologies, due to its acute release by the activated endothelium. Later on, a more complex role of VWF in inflammation was uncovered, owing to its capacity to direct the biogenesis of specific endothelial organelles, the Weibel-Palade bodies that contain known inflammation players such as P-selectin. Finally, a more direct link between VWF and inflammation has become apparent with the discovery that VWF is able to recruit leukocytes, either via direct leukocyte binding or by recruiting platelets which in turn will attract leukocytes. This review will focus on these different aspects of the connection between VWF and inflammation, with particular emphasis on VWF-leukocyte interactions.
    MeSH term(s) ADAMTS13 Protein/metabolism ; Animals ; Blood Platelets/metabolism ; Endothelial Cells/metabolism ; Endothelium, Vascular/metabolism ; Glycoproteins/metabolism ; Hemostasis ; Humans ; Inflammation ; Leukocytes/cytology ; Ligands ; Mice ; Neutrophils/metabolism ; P-Selectin/metabolism ; Platelet Glycoprotein GPIb-IX Complex/metabolism ; Risk Factors ; Venous Thrombosis/metabolism ; Weibel-Palade Bodies ; von Willebrand Factor/metabolism
    Chemical Substances Glycoproteins ; Ligands ; P-Selectin ; Platelet Glycoprotein GPIb-IX Complex ; SELP protein, human ; von Willebrand Factor ; ADAMTS13 Protein (EC 3.4.24.87) ; ADAMTS13 protein, human (EC 3.4.24.87)
    Language English
    Publishing date 2017-08-17
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1111/jth.13696
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: ADAMTS-13: double trouble for von Willebrand factor.

    Lenting, P J / Rastegarlari, G

    Journal of thrombosis and haemostasis : JTH

    2010  Volume 8, Issue 12, Page(s) 2775–2777

    MeSH term(s) ADAM Proteins/blood ; ADAMTS13 Protein ; Humans ; Substrate Specificity ; von Willebrand Factor/metabolism
    Chemical Substances von Willebrand Factor ; ADAM Proteins (EC 3.4.24.-) ; ADAMTS13 Protein (EC 3.4.24.87) ; ADAMTS13 protein, human (EC 3.4.24.87)
    Language English
    Publishing date 2010-06-14
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1111/j.1538-7836.2010.04124.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: von Willebrand factor A1 domain: stuck in the middle.

    Lenting, P J / Denis, C V

    Journal of thrombosis and haemostasis : JTH

    2007  Volume 5, Issue 7, Page(s) 1361–1362

    MeSH term(s) ADAM Proteins/blood ; ADAMTS13 Protein ; Animals ; Binding Sites ; Hemostasis/physiology ; Humans ; In Vitro Techniques ; Metalloendopeptidases/blood ; Mice ; Platelet Aggregation/physiology ; Protein Structure, Tertiary ; von Willebrand Factor/chemistry ; von Willebrand Factor/metabolism
    Chemical Substances von Willebrand Factor ; ADAM Proteins (EC 3.4.24.-) ; ADAMTS13 protein, mouse (EC 3.4.24.-) ; Metalloendopeptidases (EC 3.4.24.-) ; ADAMTS13 Protein (EC 3.4.24.87) ; ADAMTS13 protein, human (EC 3.4.24.87)
    Language English
    Publishing date 2007-04-07
    Publishing country England
    Document type Journal Article ; Comment
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1111/j.1538-7836.2007.02573.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Shear stress-independent binding of von Willebrand factor-type 2B mutants p.R1306Q & p.V1316M to LRP1 explains their increased clearance.

    Wohner, N / Legendre, P / Casari, C / Christophe, O D / Lenting, P J / Denis, C V

    Journal of thrombosis and haemostasis : JTH

    2015  Volume 13, Issue 5, Page(s) 815–820

    Abstract: Background: von Willebrand factor (VWF) is cleared in a shear stress- and macrophage-dependent manner by LRP1. von Willebrand disease (VWD)-type 2B mutants are endocytosed more efficiently than wild-type (wt)-VWF by macrophages.: Objective: To ... ...

    Abstract Background: von Willebrand factor (VWF) is cleared in a shear stress- and macrophage-dependent manner by LRP1. von Willebrand disease (VWD)-type 2B mutants are endocytosed more efficiently than wild-type (wt)-VWF by macrophages.
    Objective: To investigate if VWD-type 2B mutations in the VWF A1-domain affect LRP1 binding and LRP1-dependent clearance.
    Methods: Recombinant Fc-tagged A1 domain (A1-Fc, A2-Fc, A3-Fc) and full-length VWF (wt or mutants thereof) were tested for binding to LRP1 or a recombinant fragment thereof in a static immunosorbent assay. Mutant and wt-VWF were also compared for clearance in mice lacking macrophage LRP1 (macLRP1(-) ) and control mice (macLRP1(+) ).
    Results: We found that A1-Fc but not A2-Fc or A3-Fc binds dose-dependently to LRP1. Binding of A1-Fc to LRP1 was markedly enhanced by the VWD-type 2B mutation p.V1316M. As expected, full-length wt-VWF was unable to bind LRP1 under static conditions unless ristocetin was added. In contrast, the presence of the p.V1316M or p.R1306Q mutation induced spontaneous binding to LRP1 without the need for ristocetin or shear stress. Both mutants were cleared more rapidly than wt-VWF in control macLRP1(+) mice. Surprisingly, deletion of macrophage LRP1 abrogated the increased clearance of the VWF/p.R1306Q and VWF/p.V1316M mutant.
    Conclusion: The VWF A1-domain contains a binding site for LRP1. Certain VWD-type 2B mutations relieve the need for shear stress to induce LRP1 binding. Enhanced LRP1 binding coincides with a reduced survival of VWF/p.R1306Q and VWF/p.V1316M. Our data provide a rationale for reduced VWF levels in at least some VWD-type 2B patients.
    MeSH term(s) Animals ; Female ; Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; Male ; Mice ; Mutation ; Protein Binding ; Shear Strength ; Stress, Mechanical ; von Willebrand Factor/genetics ; von Willebrand Factor/metabolism
    Chemical Substances LRP1 protein, human ; Low Density Lipoprotein Receptor-Related Protein-1 ; von Willebrand Factor
    Language English
    Publishing date 2015-03-31
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1111/jth.12885
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Circulatory support devices: fundamental aspects and clinical management of bleeding and thrombosis.

    Susen, S / Rauch, A / Van Belle, E / Vincentelli, A / Lenting, P J

    Journal of thrombosis and haemostasis : JTH

    2015  Volume 13, Issue 10, Page(s) 1757–1767

    Abstract: Circulatory support devices are increasingly being used to overcome cardiac or respiratory failure. Long-term devices are used either as a 'bridge to transplant' to support patients who are unable to wait any longer for a heart transplant, or, more ... ...

    Abstract Circulatory support devices are increasingly being used to overcome cardiac or respiratory failure. Long-term devices are used either as a 'bridge to transplant' to support patients who are unable to wait any longer for a heart transplant, or, more recently, as 'destination therapy' for older patients suffering from end-stage heart failure and who have contraindications to heart transplantation. Short-term support devices for high-risk percutaneous coronary intervention, or as a 'bridge for decision' for patients suffering from refractory cardiogenic shock, have also been developed. The clinical benefit of such assist devices has been demonstrated in several important studies, but, unfortunately, thrombotic and bleeding complications are two major clinical issues in patients requiring these devices. Overcoming these issues is of major importance to allow the safe and broad use of these devices, and to consider them as true alternatives to heart transplantation. The present review focuses on thrombotic and bleeding complications, and describes how the risk of thrombosis and bleeding may vary according to the clinical indication, but also according to the type of device. We describe the current knowledge of the mechanisms underlying the occurrence of these complications, provide some guidance for choosing the most appropriate anticoagulation regimen to prevent their occurrence for each type of device and indication, and provide some recommendations for the management of patients when the complication occurs.
    MeSH term(s) Animals ; Anticoagulants/adverse effects ; Anticoagulants/therapeutic use ; Blood Coagulation/drug effects ; Decision Support Techniques ; Heart Failure/diagnosis ; Heart Failure/mortality ; Heart Failure/physiopathology ; Heart Failure/therapy ; Heart Transplantation ; Heart-Assist Devices/adverse effects ; Hemorrhage/blood ; Hemorrhage/diagnosis ; Hemorrhage/etiology ; Hemorrhage/mortality ; Hemorrhage/prevention & control ; Humans ; Patient Selection ; Predictive Value of Tests ; Prosthesis Design ; Risk Assessment ; Risk Factors ; Thrombosis/blood ; Thrombosis/diagnosis ; Thrombosis/etiology ; Thrombosis/mortality ; Thrombosis/prevention & control ; Time Factors ; Treatment Outcome ; Ventricular Function, Left
    Chemical Substances Anticoagulants
    Language English
    Publishing date 2015-09-25
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1111/jth.13120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: The disappearing act of factor VIII.

    Lenting, P J / Christophe, O D / Guéguen, P

    Haemophilia : the official journal of the World Federation of Hemophilia

    2010  Volume 16, Issue 102, Page(s) 6–15

    Abstract: Factor VIII (FVIII) is a plasma protein critical to the haemostatic system. This notion is illustrated by the severe bleeding disorder that is associated with its functional absence, known as haemophilia A. In addition, several epidemiological studies ... ...

    Abstract Factor VIII (FVIII) is a plasma protein critical to the haemostatic system. This notion is illustrated by the severe bleeding disorder that is associated with its functional absence, known as haemophilia A. In addition, several epidemiological studies have revealed an association between the presence of elevated levels of FVIII and thrombotic complications. In view of its relation to thrombotic and haemorrhagic disorders, it is not surprising that FVIII has gained wide attention from the research community in the previous decades. This research has led to a better understanding of not only the structural, functional and physiological aspects of this intriguing protein, but also of the pathogenesis of haemostatic defects associated with FVIII. In the present review, focus will be on the interaction between FVIII and surface receptors that are able to capture FVIII. These interactions are of importance for FVIII, as they may affect both function and survival of FVIII.
    MeSH term(s) Blood Coagulation/physiology ; Factor VIII/metabolism ; Factor VIII/physiology ; Factor VIII/secretion ; Hemophilia A/metabolism ; Humans ; Low Density Lipoprotein Receptor-Related Protein-1/physiology ; von Willebrand Factor/physiology
    Chemical Substances Low Density Lipoprotein Receptor-Related Protein-1 ; von Willebrand Factor ; Factor VIII (9001-27-8)
    Language English
    Publishing date 2010-05
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1229713-6
    ISSN 1365-2516 ; 1351-8216 ; 1355-0691
    ISSN (online) 1365-2516
    ISSN 1351-8216 ; 1355-0691
    DOI 10.1111/j.1365-2516.2008.01864.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: von Willebrand factor: the old, the new and the unknown.

    Lenting, P J / Casari, C / Christophe, O D / Denis, C V

    Journal of thrombosis and haemostasis : JTH

    2012  Volume 10, Issue 12, Page(s) 2428–2437

    Abstract: von Willebrand factor (VWF) is a protein best known from its critical role in hemostasis. Indeed, any dysfunction of VWF is associated with a severe bleeding tendency known as von Willebrand disease (VWD). Since the first description of the disease by ... ...

    Abstract von Willebrand factor (VWF) is a protein best known from its critical role in hemostasis. Indeed, any dysfunction of VWF is associated with a severe bleeding tendency known as von Willebrand disease (VWD). Since the first description of the disease by Erich von Willebrand in 1926, remarkable progress has been made with regard to our understanding of the pathogenesis of this disease. The cloning of the gene encoding VWF has allowed numerous breakthroughs, and our knowledge of the epidemiology, genetics and molecular basis of VWD has been rapidly expanding since then. These studies have taught us that VWF is rather unique in terms of its multimeric structure and the unusual mechanisms regulating its participation in the hemostatic process. Moreover, it has become increasingly clear that VWF is a more all-round protein than originally thought, given its involvement in several pathologic processes beyond hemostasis. These include angiogenesis, cell proliferation, inflammation, and tumor cell survival. In the present article, an overview of advances concerning the various structural and functional aspects of VWF will be provided.
    MeSH term(s) Apoptosis/physiology ; Cell Proliferation ; Humans ; Protein Conformation ; Thrombosis/physiopathology ; von Willebrand Factor/chemistry ; von Willebrand Factor/genetics ; von Willebrand Factor/physiology
    Chemical Substances von Willebrand Factor
    Language English
    Publishing date 2012-09-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1111/jth.12008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: LDL receptor-related protein 1 contributes to the clearance of the activated factor VII-antithrombin complex.

    Fazavana, J G / Muczynski, V / Proulle, V / Wohner, N / Christophe, O D / Lenting, P J / Denis, C V

    Journal of thrombosis and haemostasis : JTH

    2016  Volume 14, Issue 12, Page(s) 2458–2470

    Abstract: Essentials Factor VIIa is cleared principally as a complex with antithrombin. Enzyme/serpin complexes are preferred ligands for the scavenger-receptor LRP1. Factor VIIa/antithrombin but not factor VIIa alone is a ligand for LRP1. Macrophage-expressed ... ...

    Abstract Essentials Factor VIIa is cleared principally as a complex with antithrombin. Enzyme/serpin complexes are preferred ligands for the scavenger-receptor LRP1. Factor VIIa/antithrombin but not factor VIIa alone is a ligand for LRP1. Macrophage-expressed LRP1 contributes to the clearance of factor VIIa/antithrombin.
    Summary: Background Recent findings point to activated factor VII (FVIIa) being cleared predominantly (± 65% of the injected protein) as part of a complex with the serpin antithrombin. FVIIa-antithrombin complexes are targeted to hepatocytes and liver macrophages. Both cells lines abundantly express LDL receptor-related protein 1 (LRP1), a scavenger receptor mediating the clearance of protease-serpin complexes. Objectives To investigate whether FVIIa-antithrombin is a ligand for LRP1. Methods Binding of FVIIa and pre-formed FVIIa-antithrombin to purified LRP1 Fc-tagged cluster IV (rLRP1-cIV/Fc) and to human and murine macrophages was analyzed. FVIIa clearance was determined in macrophage LRP1 (macLRP1)-deficient mice. Results Solid-phase binding assays showed that FVIIa-antithrombin bound in a specific, dose-dependent and saturable manner to rLRP1-cIV/Fc. Competition experiments with human THP1 macrophages indicated that binding of FVIIa but not of FVIIa-antithrombin was reduced in the presence of annexin-V or anti-tissue factor antibodies, whereas binding of FVIIa-antithrombin but not FVIIa was inhibited by the LRP1-antagonist GST-RAP. Additional experiments revealed binding of both FVIIa and FVIIa-antithrombin to murine control macrophages. In contrast, no binding of FVIIa-antithrombin to macrophages derived from macLRP1-deficient mice could be detected. Clearance of FVIIa-antithrombin but not of active site-blocked FVIIa was delayed 1.5-fold (mean residence time of 3.3 ± 0.1 h versus 2.4 ± 0.2 h) in macLRP1-deficient mice. The circulatory presence of FVIIa was prolonged to a similar extent in macLRP1-deficient mice and in control mice. Conclusions Our data show that FVIIa-antithrombin but not FVIIa is a ligand for LRP1, and that LRP1 contributes to the clearance of FVIIa-antithrombin in vivo.
    MeSH term(s) Animals ; Antithrombins/metabolism ; Carrier Proteins/metabolism ; Catalytic Domain ; Cell Line ; Factor VIIa/metabolism ; Humans ; Ligands ; Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; Macrophages/metabolism ; Mice ; Protein Binding ; Receptors, LDL/metabolism ; Recombinant Proteins/metabolism ; Serpins/metabolism ; Thromboplastin/metabolism ; Time Factors ; Tumor Suppressor Proteins/metabolism
    Chemical Substances Antithrombins ; Carrier Proteins ; LRP1 protein, human ; Ligands ; Low Density Lipoprotein Receptor-Related Protein-1 ; Lrp1 protein, mouse ; Receptors, LDL ; Recombinant Proteins ; Serpins ; Tumor Suppressor Proteins ; Thromboplastin (9035-58-9) ; Factor VIIa (EC 3.4.21.21)
    Language English
    Publishing date 2016-10-25
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1111/jth.13502
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Clearance of von Willebrand factor.

    Casari, C / Lenting, P J / Wohner, N / Christophe, O D / Denis, C V

    Journal of thrombosis and haemostasis : JTH

    2013  Volume 11 Suppl 1, Page(s) 202–211

    Abstract: Quantitative deficiencies in von Willebrand factor (VWF) are associated with abnormal hemostasis that can manifest in bleeding or thrombotic complications. Consequently, many studies have endeavored to elucidate the mechanisms underlying the regulation ... ...

    Abstract Quantitative deficiencies in von Willebrand factor (VWF) are associated with abnormal hemostasis that can manifest in bleeding or thrombotic complications. Consequently, many studies have endeavored to elucidate the mechanisms underlying the regulation of VWF plasma levels. This review focuses on the role of VWF clearance pathways. A summary of recent developments are provided, including results from genetic studies, the relationship between glycosylation and VWF clearance, the contribution of increased VWF clearance to the pathogenesis of von Willebrand disease and the identification of VWF clearance receptors. These different studies converge in their conclusion that VWF clearance is a complex phenomenon that involves multiple mechanisms. Deciphering how such different mechanisms coordinate their role in this process is but one of the remaining challenges. Nevertheless, a better insight into the complex clearance pathways of VWF may help us to better understand the clinical implications of aberrant clearance in the pathogenesis of von Willebrand disease and perhaps other disorders as well as aid in developing alternative therapeutic approaches.
    MeSH term(s) Glycosylation ; Humans ; von Willebrand Factor/metabolism
    Chemical Substances von Willebrand Factor
    Language English
    Publishing date 2013-06-28
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1111/jth.12226
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Factor VIII and von Willebrand factor--too sweet for their own good.

    Lenting, P J / Pegon, J N / Christophe, O D / Denis, C V

    Haemophilia : the official journal of the World Federation of Hemophilia

    2010  Volume 16 Suppl 5, Page(s) 194–199

    Abstract: Summary: Although factor VIII (FVIII) and von Willebrand factor (VWF) are products of two distinct genes, they circulate in plasma as a tight non-covalent complex. Moreover, they both play a critical role in the haemostatic process, a fact that is ... ...

    Abstract Summary: Although factor VIII (FVIII) and von Willebrand factor (VWF) are products of two distinct genes, they circulate in plasma as a tight non-covalent complex. Moreover, they both play a critical role in the haemostatic process, a fact that is illustrated by the severe bleeding tendency associated with the functional absence of either protein. FVIII is an essential cofactor for coagulation factor IX, while VWF is pertinent to the recruitment of platelets to the injured vessel wall under conditions of rapid flow. FVIII and VWF have in common that they are heavily glycosylated: full-length FVIII contains 20 N-linked and at least seven O-linked glycans, while VWF contains 12 N-linked and 10 O-linked glycans. Three decades of research have revealed that the carbohydrate structures of FVIII and VWF contribute to many of the steps that can be distinguished in the life-cycle of these proteins, including biosynthesis/secretion, function and clearance. In this review, several of these aspects will be discussed. In addition, the interaction of the FVIII/VWF complex with two families of carbohydrate-binding proteins, i.e. Galectins and Siglecs, and their potential physiological relevance will be discussed.
    MeSH term(s) Amino Acid Sequence ; Factor VIII/biosynthesis ; Factor VIII/chemistry ; Glycosylation ; Humans ; Polysaccharides/chemistry ; Protein Structure, Tertiary ; von Willebrand Diseases/drug therapy ; von Willebrand Factor/biosynthesis ; von Willebrand Factor/chemistry
    Chemical Substances Polysaccharides ; von Willebrand Factor ; Factor VIII (9001-27-8)
    Language English
    Publishing date 2010-07
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1229713-6
    ISSN 1365-2516 ; 1351-8216 ; 1355-0691
    ISSN (online) 1365-2516
    ISSN 1351-8216 ; 1355-0691
    DOI 10.1111/j.1365-2516.2010.02320.x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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