{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,16]],"date-time":"2025-12-16T12:20:17Z","timestamp":1765887617504},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2014,6,3]],"date-time":"2014-06-03T00:00:00Z","timestamp":1401753600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2014,6,3]],"date-time":"2014-06-03T00:00:00Z","timestamp":1401753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arthritis Res Ther"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Introduction<\/jats:title>\n                        <jats:p>Gelatinous Heberden\u2019s nodes (HNs), also termed synovial cysts, are a common form of generalized osteoarthritis (OA). We sought to determine whether HN cases at clinical presentation contained multipotential stromal cells (MSCs) and to explore whether such cells were more closely related to bone marrow (BM) or synovial fluid (SF) MSCs by transcriptional analysis.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>At clinical presentation, gelatinous material was extracted\/extruded from the distal phalangeal joint of OA patients with HNs. From this, plastic adherent cells were culture-expanded for phenotypic and functional characterization and comparison with BM- and SF-MSCs. Mesenchymal related gene expression was studied by using a custom-designed TaqMan Low Density Array to determine transcriptional similarities between different MSC groups and skin fibroblasts.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>In all cases, HN material produced MSC-like colonies. Adherent cultures displayed an MSC phenotype (CD29<jats:sup>+<\/jats:sup>, CD44<jats:sup>+<\/jats:sup>, CD73<jats:sup>+<\/jats:sup>, CD81<jats:sup>+<\/jats:sup>, and CD90<jats:sup>+<\/jats:sup> and CD14<jats:sup>-<\/jats:sup> CD19<jats:sup>-<\/jats:sup>, CD31<jats:sup>-<\/jats:sup>, CD34<jats:sup>-<\/jats:sup>, CD45<jats:sup>-<\/jats:sup>, and HLADR<jats:sup>-<\/jats:sup>) and exhibited osteogenic, chondrogenic lineage differentiation but weak adipogenesis. Gene cluster analysis showed that HN-MSCs were more closely related to SF- than normal or OA BM-MSCs with significantly higher expression of synovium-related gene markers such as bone morphogenic protein 4 (<jats:italic>BMP4<\/jats:italic>), bone morphogenetic protein receptor type 1A (<jats:italic>BMPR1A<\/jats:italic>), protein\/leucine-rich end leucine-rich repeat protein (<jats:italic>PRELP<\/jats:italic>), secreted frizzled-related protein 4 (<jats:italic>SFRP4<\/jats:italic>), and tumor necrosis factor alpha-induced protein 6 (<jats:italic>TNFAIP6<\/jats:italic>) (<jats:italic>P<\/jats:italic> &lt;0.05).<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>Gelatinous HNs derived from hand OA at clinical presentation contain a population of MSCs that share transcriptional similarities with SF-derived MSCs. Their aberrant entrapment within the synovial cysts may impact on their normal role in joint homeostasis.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/ar4574","type":"journal-article","created":{"date-parts":[[2014,6,3]],"date-time":"2014-06-03T10:00:25Z","timestamp":1401789625000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Intrinsic multipotential mesenchymal stromal cell activity in gelatinous Heberden\u2019s nodes in osteoarthritis at clinical presentation"],"prefix":"10.1186","volume":"16","author":[{"given":"Thomas G","family":"Baboolal","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sally A","family":"Boxall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah M","family":"Churchman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Conor T","family":"Buckley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis","family":"McGonagle","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2014,6,3]]},"reference":[{"key":"4201_CR1","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1136\/bmj.1.4751.181","volume":"1","author":"JH Kellgren","year":"1952","unstructured":"Kellgren JH, Moore R: Generalized osteoarthritis and Heberden\u2019s nodes. Br Med J. 1952, 1: 181-187. 10.1136\/bmj.1.4751.181.","journal-title":"Br Med J"},{"key":"4201_CR2","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1136\/ard.16.2.238","volume":"16","author":"DG Jackson","year":"1957","unstructured":"Jackson DG, Kellgren JH: Hyaluronic acid in Heberden\u2019s nodes. Ann Rheum Dis. 1957, 16: 238-240. 10.1136\/ard.16.2.238.","journal-title":"Ann Rheum Dis"},{"key":"4201_CR3","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1002\/acr.21586","volume":"64","author":"F Rees","year":"2012","unstructured":"Rees F, Doherty S, Hui M, Maciewicz R, Muir K, Zhang W, Doherty M: Distribution of finger nodes and their association with underlying radiographic features of osteoarthritis. Arthritis Care Res. 2012, 64: 533-538.","journal-title":"Arthritis Care Res"},{"key":"4201_CR4","doi-asserted-by":"publisher","first-page":"1214","DOI":"10.1136\/ard.2004.031450","volume":"64","author":"A Thaper","year":"2005","unstructured":"Thaper A: Relationship between Heberden\u2019s nodes and underlying radiographic changes of osteoarthritis. Ann Rheum Dis. 2005, 64: 1214-1216. 10.1136\/ard.2004.031450.","journal-title":"Ann Rheum Dis"},{"key":"4201_CR5","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1038\/nrrheum.2013.109","volume":"9","author":"F Barry","year":"2013","unstructured":"Barry F, Murphy M: Mesenchymal stem cells in joint disease and repair. Nat Rev Rheumatol. 2013, 9: 584-594. 10.1038\/nrrheum.2013.109.","journal-title":"Nat Rev Rheumatol"},{"key":"4201_CR6","unstructured":"ClinicalTrials.gov homepage. [http:\/\/clinicaltrials.gov\/]"},{"key":"4201_CR7","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1002\/art.20203","volume":"50","author":"EA Jones","year":"2004","unstructured":"Jones EA, English A, Henshaw K, Kinsey SE, Markham AF, Emery P, McGonagle D: Enumeration and phenotypic characterization of synovial fluid multipotential mesenchymal progenitor cells in inflammatory and degenerative arthritis. Arthritis Rheum. 2004, 50: 817-827. 10.1002\/art.20203.","journal-title":"Arthritis Rheum"},{"key":"4201_CR8","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1093\/rheumatology\/ken114","volume":"47","author":"T Morito","year":"2008","unstructured":"Morito T, Muneta T, Hara K, Ju Y-J, Mochizuki T, Makino H, Umezawa A, Sekiya I: Synovial fluid-derived mesenchymal stem cells increase after intra-articular ligament injury in humans. Rheumatology (Oxford). 2008, 47: 1137-1143. 10.1093\/rheumatology\/ken114.","journal-title":"Rheumatology (Oxford)"},{"key":"4201_CR9","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1002\/jor.22029","volume":"30","author":"I Sekiya","year":"2012","unstructured":"Sekiya I, Ojima M, Suzuki S, Yamaga M, Horie M, Koga H, Tsuji K, Miyaguchi K, Ogishima S, Tanaka H, Muneta T: Human mesenchymal stem cells in synovial fluid increase in the knee with degenerated cartilage and osteoarthritis. J Orthop Res. 2012, 30: 943-949. 10.1002\/jor.22029.","journal-title":"J Orthop Res"},{"key":"4201_CR10","doi-asserted-by":"publisher","first-page":"2253","DOI":"10.1002\/stem.1477","volume":"31","author":"Q Harris","year":"2013","unstructured":"Harris Q, Seto J, O\u2019Brien K, Lee PS, Kondo C, Heard BJ, Hart DA, Krawetz RJ: Monocyte chemotactic protein-1 inhibits chondrogenesis of synovial mesenchymal progenitor cells: an in vitro study. Stem Cells. 2013, 31: 2253-2265. 10.1002\/stem.1477.","journal-title":"Stem Cells"},{"key":"4201_CR11","doi-asserted-by":"publisher","first-page":"1441","DOI":"10.1136\/ard.2010.142364","volume":"70","author":"F Intema","year":"2011","unstructured":"Intema F, Van Roermund PM, Marijnissen AC, Cotofana S, Eckstein F, Castelein RM, Bijlsma JW, Mastbergen SC, Lafeber FP: Tissue structure modification in knee osteoarthritis by use of joint distraction: an open 1-year pilot study. Ann Rheum Dis. 2011, 70: 1441-1446. 10.1136\/ard.2010.142364.","journal-title":"Ann Rheum Dis"},{"key":"4201_CR12","first-page":"249","volume":"48","author":"PM van Roermund","year":"1999","unstructured":"van Roermund PM, Lafeber FP: Joint distraction as treatment for ankle osteoarthritis. Instr Course Lect. 1999, 48: 249-254.","journal-title":"Instr Course Lect"},{"key":"4201_CR13","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1016\/j.stem.2009.01.015","volume":"4","author":"S Koelling","year":"2009","unstructured":"Koelling S, Kruegel J, Irmer M, Path JR, Sadowski B, Miro X, Miosge N: Migratory chondrogenic progenitor cells from repair tissue during the later stages of human osteoarthritis. Cell Stem Cell. 2009, 4: 324-335. 10.1016\/j.stem.2009.01.015.","journal-title":"Cell Stem Cell"},{"key":"4201_CR14","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1136\/ard.25.2.145","volume":"25","author":"M Begg","year":"1966","unstructured":"Begg M, Scott J: Hyaluronic acid and protein in simple ganglia and Heberden\u2019s nodes. Ann Rheum Dis. 1966, 25: 145-148.","journal-title":"Ann Rheum Dis"},{"key":"4201_CR15","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1016\/j.bone.2011.07.016","volume":"50","author":"G Cox","year":"2012","unstructured":"Cox G, Boxall SA, Giannoudis PV, Buckley CT, Roshdy T, Churchman SM, McGonagle D, Jones E: High abundance of CD271(+) multipotential stromal cells (MSCs) in intramedullary cavities of long bones. Bone. 2012, 50: 510-517. 10.1016\/j.bone.2011.07.016.","journal-title":"Bone"},{"key":"4201_CR16","doi-asserted-by":"publisher","first-page":"1944","DOI":"10.1002\/art.27595","volume":"62","author":"E Jones","year":"2010","unstructured":"Jones E, English A, Churchman SM, Kouroupis D, Boxall SA, Kinsey S, Giannoudis PG, Emery P, McGonagle D: Large-scale extraction and characterization of CD271+ multipotential stromal cells from trabecular bone in health and osteoarthritis: implications for bone regeneration strategies based on uncultured or minimally cultured multipotential stromal cells. Arthritis Rheum. 2010, 62: 1944-1954.","journal-title":"Arthritis Rheum"},{"key":"4201_CR17","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1002\/art.23485","volume":"58","author":"EA Jones","year":"2008","unstructured":"Jones EA, Crawford A, English A, Henshaw K, Mundy J, Corscadden D, Chapman T, Emery P, Hatton P, McGonagle D: Synovial fluid mesenchymal stem cells in health and early osteoarthritis: detection and functional evaluation at the single-cell level. Arthritis Rheum. 2008, 58: 1731-1740. 10.1002\/art.23485.","journal-title":"Arthritis Rheum"},{"key":"4201_CR18","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1002\/term.357","volume":"5","author":"T Vinardell","year":"2011","unstructured":"Vinardell T, Buckley CT, Thorpe SD, Kelly DJ: Composition-function relations of cartilaginous tissues engineered from chondrocytes and mesenchymal stem cells isolated from bone marrow and infrapatellar fat pad. J Tissue Eng Regen Med. 2011, 5: 673-683. 10.1002\/term.357.","journal-title":"J Tissue Eng Regen Med"},{"key":"4201_CR19","doi-asserted-by":"publisher","first-page":"2632","DOI":"10.1002\/art.34434","volume":"64","author":"SM Churchman","year":"2012","unstructured":"Churchman SM, Ponchel F, Boxall SA, Cuthbert R, Kouroupis D, Roshdy T, Giannoudis PV, Emery P, McGonagle D, Jones EA: Transcriptional profile of native CD271+ multipotential stromal cells: evidence for multiple fates, with prominent osteogenic and Wnt pathway signaling activity. Arthritis Rheum. 2012, 64: 2632-2643. 10.1002\/art.34434.","journal-title":"Arthritis Rheum"},{"key":"4201_CR20","doi-asserted-by":"publisher","first-page":"14863","DOI":"10.1073\/pnas.95.25.14863","volume":"95","author":"MB Eisen","year":"1998","unstructured":"Eisen MB, Spellman PT, Brown PO, Botstein D: Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A. 1998, 95: 14863-14868. 10.1073\/pnas.95.25.14863.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"4201_CR21","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1002\/jor.20786","volume":"27","author":"Y Segawa","year":"2009","unstructured":"Segawa Y, Muneta T, Makino H, Nimura A, Mochizuki T, Ju Y-J, Ezura Y, Umezawa A, Sekiya I: Mesenchymal stem cells derived from synovium, meniscus, anterior cruciate ligament, and articular chondrocytes share similar gene expression profiles. J Orthop Res. 2009, 27: 435-441. 10.1002\/jor.20786.","journal-title":"J Orthop Res"},{"key":"4201_CR22","doi-asserted-by":"publisher","first-page":"R1304","DOI":"10.1186\/ar1827","volume":"7","author":"F Djouad","year":"2005","unstructured":"Djouad F, Bony C, H\u00e4upl T, Uz\u00e9 G, Lahlou N, Louis-Plence P, Apparailly F, Canovas F, R\u00e8me T, Sany J, Jorgensen C, No\u00ebl D: Transcriptional profiles discriminate bone marrow-derived and synovium-derived mesenchymal stem cells. Arthritis Res Ther. 2005, 7: R1304-R1315. 10.1186\/ar1827.","journal-title":"Arthritis Res Ther"},{"key":"4201_CR23","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1002\/art.10126","volume":"46","author":"L Marinova-Mutafchieva","year":"2002","unstructured":"Marinova-Mutafchieva L, Williams R, Funa K, Maini R, Zvaifler N: Inflammation is preceded by tumor necrosis factor-dependent infiltration of mesenchymal cells in experimental arthritis. Arthritis Rheum. 2002, 46: 507-513. 10.1002\/art.10126.","journal-title":"Arthritis Rheum"},{"key":"4201_CR24","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1089\/ten.tea.2010.0499","volume":"17","author":"SR Herlofsen","year":"2011","unstructured":"Herlofsen SR, K\u00fcchler AM, Melvik JE, Brinchmann JE: Chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells in self-gelling alginate discs reveals novel chondrogenic signature gene clusters. Tissue Eng Part A. 2011, 17: 1003-1013. 10.1089\/ten.tea.2010.0499.","journal-title":"Tissue Eng Part A"},{"key":"4201_CR25","doi-asserted-by":"publisher","first-page":"e5846","DOI":"10.1371\/journal.pone.0005846","volume":"4","author":"W Wagner","year":"2009","unstructured":"Wagner W, Bork S, Horn P, Krunic D, Walenda T, Diehlmann A, Benes V, Blake J, Huber F-X, Eckstein V, Boukamp P, Ho AD: Aging and replicative senescence have related effects on human stem and progenitor cells. PLoS One. 2009, 4: e5846-10.1371\/journal.pone.0005846.","journal-title":"PLoS One"},{"key":"4201_CR26","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1016\/S0301-472X(00)00160-0","volume":"28","author":"A Banfi","year":"2000","unstructured":"Banfi A, Muraglia A, Dozin B, Mastrogiacomo M, Cancedda R, Quarto R: Proliferation kinetics and differentiation potential of ex vivo expanded human bone marrow stromal cells: implications for their use in cell therapy. Exp Hematol. 2000, 28: 707-715. 10.1016\/S0301-472X(00)00160-0.","journal-title":"Exp Hematol"},{"key":"4201_CR27","doi-asserted-by":"publisher","first-page":"1402","DOI":"10.1016\/j.exphem.2005.07.003","volume":"33","author":"W Wagner","year":"2005","unstructured":"Wagner W, Wein F, Seckinger A, Frankhauser M, Wirkner U, Krause U, Blake J, Schwager C, Eckstein V, Ansorge W, Ho AD: Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol. 2005, 33: 1402-1416. 10.1016\/j.exphem.2005.07.003.","journal-title":"Exp Hematol"},{"key":"4201_CR28","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.bbrc.2005.04.118","volume":"332","author":"M Ishii","year":"2005","unstructured":"Ishii M, Koike C, Igarashi A, Yamanaka K, Pan H, Higashi Y, Kawaguchi H, Sugiyama M, Kamata N, Iwata T, Matsubara T, Nakamura K, Kurihara H, Tsuji K, Kato Y: Molecular markers distinguish bone marrow mesenchymal stem cells from fibroblasts. Biochem Biophys Res Commun. 2005, 332: 297-303. 10.1016\/j.bbrc.2005.04.118.","journal-title":"Biochem Biophys Res Commun"},{"key":"4201_CR29","doi-asserted-by":"publisher","first-page":"245","DOI":"10.3727\/000000005783992043","volume":"12","author":"C Brendel","year":"2005","unstructured":"Brendel C, Kuklick L, Hartmann O, Kim TD, Boudriot U, Schwell D, Neubauer A: Distinct gene expression profile of human mesenchymal stem cells in comparison to skin fibroblasts employing cDNA microarray analysis of 9600 genes. Gene Expr. 2005, 12: 245-257. 10.3727\/000000005783992043.","journal-title":"Gene Expr"},{"key":"4201_CR30","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1111\/j.1365-2443.2009.01281.x","volume":"14","author":"H Kubo","year":"2009","unstructured":"Kubo H, Shimizu M, Taya Y, Kawamoto T, Michida M, Kaneko E, Igarashi A, Nishimura M, Segoshi K, Shimazu Y, Tsuji K, Aoba T, Kato Y: Identification of mesenchymal stem cell (MSC)-transcription factors by microarray and knockdown analyses, and signature molecule-marked MSC in bone marrow by immunohistochemistry. Genes Cells. 2009, 14: 407-424. 10.1111\/j.1365-2443.2009.01281.x.","journal-title":"Genes Cells"},{"key":"4201_CR31","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1016\/S0925-4773(03)00067-4","volume":"120","author":"CM Coleman","year":"2003","unstructured":"Coleman CM, Tuan RS: Functional role of growth\/differentiation factor 5 in chondrogenesis of limb mesenchymal cells. Mech Dev. 2003, 120: 823-836. 10.1016\/S0925-4773(03)00067-4.","journal-title":"Mech Dev"},{"key":"4201_CR32","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1111\/j.1432-0436.2008.00299.x","volume":"76","author":"M Pei","year":"2008","unstructured":"Pei M, He F, Vunjak-Novakovic G: Synovium-derived stem cell-based chondrogenesis. Differentiation. 2008, 76: 1044-1056. 10.1111\/j.1432-0436.2008.00299.x.","journal-title":"Differentiation"},{"key":"4201_CR33","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1002\/art.30234","volume":"63","author":"TB Kurth","year":"2011","unstructured":"Kurth TB, Dell\u2019accio F, Crouch V, Augello A, Sharpe PT, De Bari C: Functional mesenchymal stem cell niches in adult mouse knee joint synovium in vivo. Arthritis Rheum. 2011, 63: 1289-1300. 10.1002\/art.30234.","journal-title":"Arthritis Rheum"},{"key":"4201_CR34","doi-asserted-by":"publisher","first-page":"2355","DOI":"10.1002\/art.21210","volume":"52","author":"AL Tan","year":"2005","unstructured":"Tan AL, Grainger AJ, Tanner SF, Shelley DM, Pease C, Emery P, McGonagle D: High-resolution magnetic resonance imaging for the assessment of hand osteoarthritis. Arthritis Rheum. 2005, 52: 2355-2365. 10.1002\/art.21210.","journal-title":"Arthritis Rheum"},{"key":"4201_CR35","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1002\/bdrc.20189","volume":"90","author":"C De Bari","year":"2010","unstructured":"De Bari C, Kurth TB, Augello A: Mesenchymal stem cells from development to postnatal joint homeostasis, aging, and disease. Birth Defects Res C Embryo Today. 2010, 90: 257-271. 10.1002\/bdrc.20189.","journal-title":"Birth Defects Res C Embryo Today"}],"container-title":["Arthritis Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar4574.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/ar4574\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/ar4574.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T16:16:49Z","timestamp":1728922609000},"score":1,"resource":{"primary":{"URL":"https:\/\/arthritis-research.biomedcentral.com\/articles\/10.1186\/ar4574"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,6,3]]},"references-count":35,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2014,6]]}},"alternative-id":["4201"],"URL":"https:\/\/doi.org\/10.1186\/ar4574","relation":{},"ISSN":["1478-6354"],"issn-type":[{"type":"electronic","value":"1478-6354"}],"subject":[],"published":{"date-parts":[[2014,6,3]]},"assertion":[{"value":"18 December 2013","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 May 2014","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2014","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"R119"}}