Association of Neuroimmune Guidance Cue Netrin-1 and Its Chemorepulsive Receptor UNC5B With Atherosclerotic Plaque Expression Signatures and Stability in Human(s): Tampere Vascular Study (TVS)
BACKGROUND—Macrophage (MΦ) infiltration and smooth muscle cell (SMC) proliferation are hallmarks of atherosclerosis and unstable plaques. Neuroimmune guidance cue 1 (netrin-1 [NTN1]) plays a critical role controlling MΦ trafficking and SMC activation. Characterization of expression of NTN1 and its r...
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| Veröffentlicht in: | Circulation. Cardiovascular genetics 2013-12, Vol.6 (6), p.579-587 |
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| creator | Oksala, Niku Pärssinen, Jenita Seppälä, Ilkka Raitoharju, Emma Ivana, Kholova Hernesniemi, Jussi Lyytikäinen, Leo-Pekka Levula, Mari Mäkelä, Kari-Matti Sioris, Thanos Kähönen, Mika Laaksonen, Reijo Hytönen, Vesa Lehtimäki, Terho |
| description | BACKGROUND—Macrophage (MΦ) infiltration and smooth muscle cell (SMC) proliferation are hallmarks of atherosclerosis and unstable plaques. Neuroimmune guidance cue 1 (netrin-1 [NTN1]) plays a critical role controlling MΦ trafficking and SMC activation. Characterization of expression of NTN1 and its receptors and their association with plaque stability in human(s) is lacking.
METHODS AND RESULTS—The expression of NTN1 and its receptors did not differ in either whole blood or circulating monocytes from patients with coronary artery disease (n=55) compared with healthy controls (n=45). However, NTN1 was downregulated (−2.9-fold; P |
| doi_str_mv | 10.1161/CIRCGENETICS.113.000141 |
| format | Article |
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METHODS AND RESULTS—The expression of NTN1 and its receptors did not differ in either whole blood or circulating monocytes from patients with coronary artery disease (n=55) compared with healthy controls (n=45). However, NTN1 was downregulated (−2.9-fold; P<0.0001) and UNC5B upregulated (2.2-fold; P<0.0001) in atherosclerotic plaques (n=68), whereas there were no differences in other NTN1 receptors compared with histologically normal controls (n=28). Increased UNC5B expression is associated with histologically more stable plaques (P=0.011). NTN1 expression correlated positively with SMC markers and signatures and negatively with inflammatory markers and M1 and especially M2 signatures in the atherosclerotic plaques. UNC5B clustering correlated positively with inflammatory and MΦ markers. NTN1 protein colocalized with CD68-positive cells of monocytic origin and muscle-actin-specific-antibody (HHF3)-positive cells indicative of SMCs in the plaques and only with SMCs in the control samples. NTN1 protein was highly expressed in the intimal layer of the control vessels.
CONCLUSIONS—Present findings provide support for the hypothesis that dysregulation of expression of NTN1 in SMCs and its chemorepulsive receptor UNC5B in macrophages are involved in the development of atherosclerosis and unstable plaques.</description><identifier>ISSN: 1942-325X</identifier><identifier>EISSN: 1942-3268</identifier><identifier>DOI: 10.1161/CIRCGENETICS.113.000141</identifier><identifier>PMID: 24122613</identifier><language>eng</language><publisher>United States: American Heart Association, Inc</publisher><subject>Actins - genetics ; Actins - metabolism ; Aged ; Aged, 80 and over ; Cluster Analysis ; Down-Regulation ; Female ; Gene Expression Profiling ; Humans ; Inflammation - genetics ; Inflammation - metabolism ; Macrophages - metabolism ; Male ; Microscopy, Confocal ; Middle Aged ; Monocytes - metabolism ; Myocytes, Smooth Muscle - metabolism ; Nerve Growth Factors - genetics ; Nerve Growth Factors - metabolism ; Netrin-1 ; Oligonucleotide Array Sequence Analysis ; Plaque, Atherosclerotic - genetics ; Plaque, Atherosclerotic - metabolism ; Receptors, Cell Surface - genetics ; Receptors, Cell Surface - metabolism ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Up-Regulation</subject><ispartof>Circulation. Cardiovascular genetics, 2013-12, Vol.6 (6), p.579-587</ispartof><rights>2013 American Heart Association, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c3111-d62a7110f665763deadfd3f7827fb6d67ba348ecbd2a0f6374222d5759f7c7203</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3673,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24122613$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Oksala, Niku</creatorcontrib><creatorcontrib>Pärssinen, Jenita</creatorcontrib><creatorcontrib>Seppälä, Ilkka</creatorcontrib><creatorcontrib>Raitoharju, Emma</creatorcontrib><creatorcontrib>Ivana, Kholova</creatorcontrib><creatorcontrib>Hernesniemi, Jussi</creatorcontrib><creatorcontrib>Lyytikäinen, Leo-Pekka</creatorcontrib><creatorcontrib>Levula, Mari</creatorcontrib><creatorcontrib>Mäkelä, Kari-Matti</creatorcontrib><creatorcontrib>Sioris, Thanos</creatorcontrib><creatorcontrib>Kähönen, Mika</creatorcontrib><creatorcontrib>Laaksonen, Reijo</creatorcontrib><creatorcontrib>Hytönen, Vesa</creatorcontrib><creatorcontrib>Lehtimäki, Terho</creatorcontrib><title>Association of Neuroimmune Guidance Cue Netrin-1 and Its Chemorepulsive Receptor UNC5B With Atherosclerotic Plaque Expression Signatures and Stability in Human(s): Tampere Vascular Study (TVS)</title><title>Circulation. Cardiovascular genetics</title><addtitle>Circ Cardiovasc Genet</addtitle><description>BACKGROUND—Macrophage (MΦ) infiltration and smooth muscle cell (SMC) proliferation are hallmarks of atherosclerosis and unstable plaques. Neuroimmune guidance cue 1 (netrin-1 [NTN1]) plays a critical role controlling MΦ trafficking and SMC activation. Characterization of expression of NTN1 and its receptors and their association with plaque stability in human(s) is lacking.
METHODS AND RESULTS—The expression of NTN1 and its receptors did not differ in either whole blood or circulating monocytes from patients with coronary artery disease (n=55) compared with healthy controls (n=45). However, NTN1 was downregulated (−2.9-fold; P<0.0001) and UNC5B upregulated (2.2-fold; P<0.0001) in atherosclerotic plaques (n=68), whereas there were no differences in other NTN1 receptors compared with histologically normal controls (n=28). Increased UNC5B expression is associated with histologically more stable plaques (P=0.011). NTN1 expression correlated positively with SMC markers and signatures and negatively with inflammatory markers and M1 and especially M2 signatures in the atherosclerotic plaques. UNC5B clustering correlated positively with inflammatory and MΦ markers. NTN1 protein colocalized with CD68-positive cells of monocytic origin and muscle-actin-specific-antibody (HHF3)-positive cells indicative of SMCs in the plaques and only with SMCs in the control samples. NTN1 protein was highly expressed in the intimal layer of the control vessels.
CONCLUSIONS—Present findings provide support for the hypothesis that dysregulation of expression of NTN1 in SMCs and its chemorepulsive receptor UNC5B in macrophages are involved in the development of atherosclerosis and unstable plaques.</description><subject>Actins - genetics</subject><subject>Actins - metabolism</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Cluster Analysis</subject><subject>Down-Regulation</subject><subject>Female</subject><subject>Gene Expression Profiling</subject><subject>Humans</subject><subject>Inflammation - genetics</subject><subject>Inflammation - metabolism</subject><subject>Macrophages - metabolism</subject><subject>Male</subject><subject>Microscopy, Confocal</subject><subject>Middle Aged</subject><subject>Monocytes - metabolism</subject><subject>Myocytes, Smooth Muscle - metabolism</subject><subject>Nerve Growth Factors - genetics</subject><subject>Nerve Growth Factors - metabolism</subject><subject>Netrin-1</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Plaque, Atherosclerotic - genetics</subject><subject>Plaque, Atherosclerotic - metabolism</subject><subject>Receptors, Cell Surface - genetics</subject><subject>Receptors, Cell Surface - metabolism</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Up-Regulation</subject><issn>1942-325X</issn><issn>1942-3268</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9u1DAQxiMEoqXwCuDj9pAS24mzgdMSbbcrVQvqbgu3yLEnxODEwX9o9-14NFy2VNy4eDwzv_lGoy9J3uDsDGOG39brq3q13Cx363obK_QsyzKc4yfJMa5yklLC5k8f_8WXo-SFc9-yjOWUsufJEckxIQzT4-TXwjkjFPfKjMh0aAPBGjUMYQS0CkryUQCqA8SGt2pMMeKjRGvvUN3DYCxMQTv1E9AVCJi8seh6Uxcf0Gfle7TwPVjjhI6vVwJ90vxHlFreTRacu9-4VV9H7kNM_-huPW-VVn6P1IguwsDHmTt9h3Z8mMACuuFOBM1t5ILco9nuZnv6MnnWce3g1UM8Sa7Pl7v6Ir38uFrXi8tUUIxxKhnhJcZZx1hRMiqBy07SrpyTsmuZZGXLaT4H0UrCI0TLnBAii7KoulKUJKMnyeygO1kTj3C-GZQToDUfwQTX4JxVrKiyah7R8oCKeLyz0DWTVQO3-wZnzb19zb_2xQptDvbFydcPS0I7gHyc--tXBN4fgFujPVj3XYdbsE0PXPv-v_K_AXHdrFo</recordid><startdate>201312</startdate><enddate>201312</enddate><creator>Oksala, Niku</creator><creator>Pärssinen, Jenita</creator><creator>Seppälä, Ilkka</creator><creator>Raitoharju, Emma</creator><creator>Ivana, Kholova</creator><creator>Hernesniemi, Jussi</creator><creator>Lyytikäinen, Leo-Pekka</creator><creator>Levula, Mari</creator><creator>Mäkelä, Kari-Matti</creator><creator>Sioris, Thanos</creator><creator>Kähönen, Mika</creator><creator>Laaksonen, Reijo</creator><creator>Hytönen, Vesa</creator><creator>Lehtimäki, Terho</creator><general>American Heart Association, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201312</creationdate><title>Association of Neuroimmune Guidance Cue Netrin-1 and Its Chemorepulsive Receptor UNC5B With Atherosclerotic Plaque Expression Signatures and Stability in Human(s): Tampere Vascular Study (TVS)</title><author>Oksala, Niku ; Pärssinen, Jenita ; Seppälä, Ilkka ; Raitoharju, Emma ; Ivana, Kholova ; Hernesniemi, Jussi ; Lyytikäinen, Leo-Pekka ; Levula, Mari ; Mäkelä, Kari-Matti ; Sioris, Thanos ; Kähönen, Mika ; Laaksonen, Reijo ; Hytönen, Vesa ; Lehtimäki, Terho</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3111-d62a7110f665763deadfd3f7827fb6d67ba348ecbd2a0f6374222d5759f7c7203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Actins - genetics</topic><topic>Actins - metabolism</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Cluster Analysis</topic><topic>Down-Regulation</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Humans</topic><topic>Inflammation - genetics</topic><topic>Inflammation - metabolism</topic><topic>Macrophages - metabolism</topic><topic>Male</topic><topic>Microscopy, Confocal</topic><topic>Middle Aged</topic><topic>Monocytes - metabolism</topic><topic>Myocytes, Smooth Muscle - metabolism</topic><topic>Nerve Growth Factors - genetics</topic><topic>Nerve Growth Factors - metabolism</topic><topic>Netrin-1</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Plaque, Atherosclerotic - genetics</topic><topic>Plaque, Atherosclerotic - metabolism</topic><topic>Receptors, Cell Surface - genetics</topic><topic>Receptors, Cell Surface - metabolism</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Oksala, Niku</creatorcontrib><creatorcontrib>Pärssinen, Jenita</creatorcontrib><creatorcontrib>Seppälä, Ilkka</creatorcontrib><creatorcontrib>Raitoharju, Emma</creatorcontrib><creatorcontrib>Ivana, Kholova</creatorcontrib><creatorcontrib>Hernesniemi, Jussi</creatorcontrib><creatorcontrib>Lyytikäinen, Leo-Pekka</creatorcontrib><creatorcontrib>Levula, Mari</creatorcontrib><creatorcontrib>Mäkelä, Kari-Matti</creatorcontrib><creatorcontrib>Sioris, Thanos</creatorcontrib><creatorcontrib>Kähönen, Mika</creatorcontrib><creatorcontrib>Laaksonen, Reijo</creatorcontrib><creatorcontrib>Hytönen, Vesa</creatorcontrib><creatorcontrib>Lehtimäki, Terho</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation. Cardiovascular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Oksala, Niku</au><au>Pärssinen, Jenita</au><au>Seppälä, Ilkka</au><au>Raitoharju, Emma</au><au>Ivana, Kholova</au><au>Hernesniemi, Jussi</au><au>Lyytikäinen, Leo-Pekka</au><au>Levula, Mari</au><au>Mäkelä, Kari-Matti</au><au>Sioris, Thanos</au><au>Kähönen, Mika</au><au>Laaksonen, Reijo</au><au>Hytönen, Vesa</au><au>Lehtimäki, Terho</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Association of Neuroimmune Guidance Cue Netrin-1 and Its Chemorepulsive Receptor UNC5B With Atherosclerotic Plaque Expression Signatures and Stability in Human(s): Tampere Vascular Study (TVS)</atitle><jtitle>Circulation. Cardiovascular genetics</jtitle><addtitle>Circ Cardiovasc Genet</addtitle><date>2013-12</date><risdate>2013</risdate><volume>6</volume><issue>6</issue><spage>579</spage><epage>587</epage><pages>579-587</pages><issn>1942-325X</issn><eissn>1942-3268</eissn><abstract>BACKGROUND—Macrophage (MΦ) infiltration and smooth muscle cell (SMC) proliferation are hallmarks of atherosclerosis and unstable plaques. Neuroimmune guidance cue 1 (netrin-1 [NTN1]) plays a critical role controlling MΦ trafficking and SMC activation. Characterization of expression of NTN1 and its receptors and their association with plaque stability in human(s) is lacking.
METHODS AND RESULTS—The expression of NTN1 and its receptors did not differ in either whole blood or circulating monocytes from patients with coronary artery disease (n=55) compared with healthy controls (n=45). However, NTN1 was downregulated (−2.9-fold; P<0.0001) and UNC5B upregulated (2.2-fold; P<0.0001) in atherosclerotic plaques (n=68), whereas there were no differences in other NTN1 receptors compared with histologically normal controls (n=28). Increased UNC5B expression is associated with histologically more stable plaques (P=0.011). NTN1 expression correlated positively with SMC markers and signatures and negatively with inflammatory markers and M1 and especially M2 signatures in the atherosclerotic plaques. UNC5B clustering correlated positively with inflammatory and MΦ markers. NTN1 protein colocalized with CD68-positive cells of monocytic origin and muscle-actin-specific-antibody (HHF3)-positive cells indicative of SMCs in the plaques and only with SMCs in the control samples. NTN1 protein was highly expressed in the intimal layer of the control vessels.
CONCLUSIONS—Present findings provide support for the hypothesis that dysregulation of expression of NTN1 in SMCs and its chemorepulsive receptor UNC5B in macrophages are involved in the development of atherosclerosis and unstable plaques.</abstract><cop>United States</cop><pub>American Heart Association, Inc</pub><pmid>24122613</pmid><doi>10.1161/CIRCGENETICS.113.000141</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1942-325X |
| ispartof | Circulation. Cardiovascular genetics, 2013-12, Vol.6 (6), p.579-587 |
| issn | 1942-325X 1942-3268 |
| language | eng |
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| source | MEDLINE; American Heart Association Journals |
| subjects | Actins - genetics Actins - metabolism Aged Aged, 80 and over Cluster Analysis Down-Regulation Female Gene Expression Profiling Humans Inflammation - genetics Inflammation - metabolism Macrophages - metabolism Male Microscopy, Confocal Middle Aged Monocytes - metabolism Myocytes, Smooth Muscle - metabolism Nerve Growth Factors - genetics Nerve Growth Factors - metabolism Netrin-1 Oligonucleotide Array Sequence Analysis Plaque, Atherosclerotic - genetics Plaque, Atherosclerotic - metabolism Receptors, Cell Surface - genetics Receptors, Cell Surface - metabolism Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Up-Regulation |
| title | Association of Neuroimmune Guidance Cue Netrin-1 and Its Chemorepulsive Receptor UNC5B With Atherosclerotic Plaque Expression Signatures and Stability in Human(s): Tampere Vascular Study (TVS) |
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