Chemokine-related gene expression in the brain following ischemic stroke: No role for CXCR2 in outcome
Abstract This study sought to identify potential targets for acute stroke therapy that can be exploited pharmacologically beyond the current 4.5 h time limit for clinical administration of recombinant tissue-plasminogen activator. We used PCR arrays to initially screen the temporal expression profil...
Gespeichert in:
Veröffentlicht in: | Brain research 2011-02, Vol.1372, p.169-179 |
---|---|
Hauptverfasser: | , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 179 |
---|---|
container_issue | |
container_start_page | 169 |
container_title | Brain research |
container_volume | 1372 |
creator | Brait, Vanessa H Rivera, Jennifer Broughton, Brad R.S Lee, Seyoung Drummond, Grant R Sobey, Christopher G |
description | Abstract This study sought to identify potential targets for acute stroke therapy that can be exploited pharmacologically beyond the current 4.5 h time limit for clinical administration of recombinant tissue-plasminogen activator. We used PCR arrays to initially screen the temporal expression profiles of several chemokine-related genes in the brain at 4, 24 and 72 h after stroke. We identified large increases (> 10-fold) in mRNA at 24 or 72 h for the neutrophil CXCR2 receptor, and for CXCL1 and CXCL2—two chemokine ligands expressed by monocytes and neutrophils with strong neutrophil chemoattractant activity via CXCR2. We then tested the efficacy of a CXCR2 antagonist as a therapeutic. Mice were treated with vehicle (1% DMSO) or SB225002 (2 mg/kg per day, ip) commencing at reperfusion, and we evaluated chemokine gene expression, neutrophil infiltration and functional and histological endpoints of stroke outcome. Expression levels of CXCL1, CXCL2 and CXCR2 after 24 h were markedly reduced to near normal levels in SB225002-treated mice. Myeloperoxidase-positive cell infiltration was significantly reduced in SB225002-treated mice compared with vehicle-treated mice, and was similar to levels in sham-operated mice. However, although SB225002 evidently antagonised the interaction between CXCR2 and its chemokine ligands in the ischemic brain, mice treated with either SB225002 or vehicle had similar motor impairment and infarct volume at 72 h. Thus, the reduced expression of CXC chemokine subfamily genes and neutrophil-related infiltration following SB225002 administration did not improve outcome after cerebral ischemia–reperfusion. CXCR2 antagonists are therefore unlikely to be a potential therapy for ischemic stroke. |
doi_str_mv | 10.1016/j.brainres.2010.11.087 |
format | Article |
fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_860376516</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0006899310026004</els_id><sourcerecordid>847286286</sourcerecordid><originalsourceid>FETCH-LOGICAL-c423t-c3f71e2c7569fd1104a2ad78cfc24b98f5de1d057e19e0721991c05e6f5bde2f3</originalsourceid><addsrcrecordid>eNqFklFrFDEUhQdR7Fr9CzUv4tOsuclMMuODKINWoShYC76FbOZmm93ZZE1m1P77Ztytgi-FQEj4zr2He25RnAFdAgXxarNcRe18xLRkdP6EJW3kg2IBjWSlYBV9WCwopaJs2pafFE9S2uQn5y19XJwwAN5IXi8K213jLmydxzLioEfsyRo9Evy9z7WTC544T8ZrJH_6ERuGIfxyfk1cMlnqDEljDFt8TT4HEsOAGYmk-959ZbMyTKMJO3xaPLJ6SPjseJ8WVx_ef-s-lhdfzj917y5KUzE-loZbCciMrEVrewBaaaZ72RhrWLVqG1v3CD2tJUKLVDJoWzC0RmHrVY_M8tPi5aHuPoYfE6ZR7bJPHAbtMUxJNYJyKWoQ95OVZI3IJ5PiQJoYUopo1T66nY43Cqiaw1AbdReGmsNQACqHkYVnxxbTaof9X9nd9DPw4gjoZPRgo_bGpX8cb0QlK8jc8wNndVB6HTNzdZk71TnRloOcPb49EJiH-9NhVMk49AZ7F9GMqg_ufrdv_ithBudd9rXFG0ybMEWfo1OgElNUXc7LNe8WUMoEpRW_BVp1yUQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>847286286</pqid></control><display><type>article</type><title>Chemokine-related gene expression in the brain following ischemic stroke: No role for CXCR2 in outcome</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals Complete</source><creator>Brait, Vanessa H ; Rivera, Jennifer ; Broughton, Brad R.S ; Lee, Seyoung ; Drummond, Grant R ; Sobey, Christopher G</creator><creatorcontrib>Brait, Vanessa H ; Rivera, Jennifer ; Broughton, Brad R.S ; Lee, Seyoung ; Drummond, Grant R ; Sobey, Christopher G</creatorcontrib><description>Abstract This study sought to identify potential targets for acute stroke therapy that can be exploited pharmacologically beyond the current 4.5 h time limit for clinical administration of recombinant tissue-plasminogen activator. We used PCR arrays to initially screen the temporal expression profiles of several chemokine-related genes in the brain at 4, 24 and 72 h after stroke. We identified large increases (> 10-fold) in mRNA at 24 or 72 h for the neutrophil CXCR2 receptor, and for CXCL1 and CXCL2—two chemokine ligands expressed by monocytes and neutrophils with strong neutrophil chemoattractant activity via CXCR2. We then tested the efficacy of a CXCR2 antagonist as a therapeutic. Mice were treated with vehicle (1% DMSO) or SB225002 (2 mg/kg per day, ip) commencing at reperfusion, and we evaluated chemokine gene expression, neutrophil infiltration and functional and histological endpoints of stroke outcome. Expression levels of CXCL1, CXCL2 and CXCR2 after 24 h were markedly reduced to near normal levels in SB225002-treated mice. Myeloperoxidase-positive cell infiltration was significantly reduced in SB225002-treated mice compared with vehicle-treated mice, and was similar to levels in sham-operated mice. However, although SB225002 evidently antagonised the interaction between CXCR2 and its chemokine ligands in the ischemic brain, mice treated with either SB225002 or vehicle had similar motor impairment and infarct volume at 72 h. Thus, the reduced expression of CXC chemokine subfamily genes and neutrophil-related infiltration following SB225002 administration did not improve outcome after cerebral ischemia–reperfusion. CXCR2 antagonists are therefore unlikely to be a potential therapy for ischemic stroke.</description><identifier>ISSN: 0006-8993</identifier><identifier>EISSN: 1872-6240</identifier><identifier>DOI: 10.1016/j.brainres.2010.11.087</identifier><identifier>PMID: 21138735</identifier><identifier>CODEN: BRREAP</identifier><language>eng</language><publisher>Amsterdam: Elsevier B.V</publisher><subject>Analysis of Variance ; Animals ; antagonists ; Biological and medical sciences ; brain ; Brain - drug effects ; Brain - metabolism ; Brain - pathology ; Brain Edema - drug therapy ; Brain Edema - etiology ; Brain Infarction - drug therapy ; Brain Infarction - etiology ; chemoattractants ; Chemokines ; Chemokines - genetics ; Chemokines - metabolism ; CXCL1 ; CXCL2 ; CXCR2 ; Disease Models, Animal ; gene expression ; Gene Expression Regulation - drug effects ; Gene Expression Regulation - physiology ; genes ; infarction ; Infarction, Middle Cerebral Artery - drug therapy ; Infarction, Middle Cerebral Artery - mortality ; Infarction, Middle Cerebral Artery - pathology ; Laser-Doppler Flowmetry - methods ; Male ; Medical sciences ; Mice ; Mice, Inbred C57BL ; monocytes ; Mouse ; Neurology ; neutrophils ; Neutrophils - drug effects ; Phenylurea Compounds - therapeutic use ; Recovery of Function - drug effects ; RNA, Messenger - metabolism ; Stroke ; therapeutics ; Time Factors ; Vascular diseases and vascular malformations of the nervous system</subject><ispartof>Brain research, 2011-02, Vol.1372, p.169-179</ispartof><rights>Elsevier B.V.</rights><rights>2010 Elsevier B.V.</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2010 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c423t-c3f71e2c7569fd1104a2ad78cfc24b98f5de1d057e19e0721991c05e6f5bde2f3</citedby><cites>FETCH-LOGICAL-c423t-c3f71e2c7569fd1104a2ad78cfc24b98f5de1d057e19e0721991c05e6f5bde2f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.brainres.2010.11.087$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23864741$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21138735$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brait, Vanessa H</creatorcontrib><creatorcontrib>Rivera, Jennifer</creatorcontrib><creatorcontrib>Broughton, Brad R.S</creatorcontrib><creatorcontrib>Lee, Seyoung</creatorcontrib><creatorcontrib>Drummond, Grant R</creatorcontrib><creatorcontrib>Sobey, Christopher G</creatorcontrib><title>Chemokine-related gene expression in the brain following ischemic stroke: No role for CXCR2 in outcome</title><title>Brain research</title><addtitle>Brain Res</addtitle><description>Abstract This study sought to identify potential targets for acute stroke therapy that can be exploited pharmacologically beyond the current 4.5 h time limit for clinical administration of recombinant tissue-plasminogen activator. We used PCR arrays to initially screen the temporal expression profiles of several chemokine-related genes in the brain at 4, 24 and 72 h after stroke. We identified large increases (> 10-fold) in mRNA at 24 or 72 h for the neutrophil CXCR2 receptor, and for CXCL1 and CXCL2—two chemokine ligands expressed by monocytes and neutrophils with strong neutrophil chemoattractant activity via CXCR2. We then tested the efficacy of a CXCR2 antagonist as a therapeutic. Mice were treated with vehicle (1% DMSO) or SB225002 (2 mg/kg per day, ip) commencing at reperfusion, and we evaluated chemokine gene expression, neutrophil infiltration and functional and histological endpoints of stroke outcome. Expression levels of CXCL1, CXCL2 and CXCR2 after 24 h were markedly reduced to near normal levels in SB225002-treated mice. Myeloperoxidase-positive cell infiltration was significantly reduced in SB225002-treated mice compared with vehicle-treated mice, and was similar to levels in sham-operated mice. However, although SB225002 evidently antagonised the interaction between CXCR2 and its chemokine ligands in the ischemic brain, mice treated with either SB225002 or vehicle had similar motor impairment and infarct volume at 72 h. Thus, the reduced expression of CXC chemokine subfamily genes and neutrophil-related infiltration following SB225002 administration did not improve outcome after cerebral ischemia–reperfusion. CXCR2 antagonists are therefore unlikely to be a potential therapy for ischemic stroke.</description><subject>Analysis of Variance</subject><subject>Animals</subject><subject>antagonists</subject><subject>Biological and medical sciences</subject><subject>brain</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Brain Edema - drug therapy</subject><subject>Brain Edema - etiology</subject><subject>Brain Infarction - drug therapy</subject><subject>Brain Infarction - etiology</subject><subject>chemoattractants</subject><subject>Chemokines</subject><subject>Chemokines - genetics</subject><subject>Chemokines - metabolism</subject><subject>CXCL1</subject><subject>CXCL2</subject><subject>CXCR2</subject><subject>Disease Models, Animal</subject><subject>gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Gene Expression Regulation - physiology</subject><subject>genes</subject><subject>infarction</subject><subject>Infarction, Middle Cerebral Artery - drug therapy</subject><subject>Infarction, Middle Cerebral Artery - mortality</subject><subject>Infarction, Middle Cerebral Artery - pathology</subject><subject>Laser-Doppler Flowmetry - methods</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>monocytes</subject><subject>Mouse</subject><subject>Neurology</subject><subject>neutrophils</subject><subject>Neutrophils - drug effects</subject><subject>Phenylurea Compounds - therapeutic use</subject><subject>Recovery of Function - drug effects</subject><subject>RNA, Messenger - metabolism</subject><subject>Stroke</subject><subject>therapeutics</subject><subject>Time Factors</subject><subject>Vascular diseases and vascular malformations of the nervous system</subject><issn>0006-8993</issn><issn>1872-6240</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFklFrFDEUhQdR7Fr9CzUv4tOsuclMMuODKINWoShYC76FbOZmm93ZZE1m1P77Ztytgi-FQEj4zr2He25RnAFdAgXxarNcRe18xLRkdP6EJW3kg2IBjWSlYBV9WCwopaJs2pafFE9S2uQn5y19XJwwAN5IXi8K213jLmydxzLioEfsyRo9Evy9z7WTC544T8ZrJH_6ERuGIfxyfk1cMlnqDEljDFt8TT4HEsOAGYmk-959ZbMyTKMJO3xaPLJ6SPjseJ8WVx_ef-s-lhdfzj917y5KUzE-loZbCciMrEVrewBaaaZ72RhrWLVqG1v3CD2tJUKLVDJoWzC0RmHrVY_M8tPi5aHuPoYfE6ZR7bJPHAbtMUxJNYJyKWoQ95OVZI3IJ5PiQJoYUopo1T66nY43Cqiaw1AbdReGmsNQACqHkYVnxxbTaof9X9nd9DPw4gjoZPRgo_bGpX8cb0QlK8jc8wNndVB6HTNzdZk71TnRloOcPb49EJiH-9NhVMk49AZ7F9GMqg_ufrdv_ithBudd9rXFG0ybMEWfo1OgElNUXc7LNe8WUMoEpRW_BVp1yUQ</recordid><startdate>20110204</startdate><enddate>20110204</enddate><creator>Brait, Vanessa H</creator><creator>Rivera, Jennifer</creator><creator>Broughton, Brad R.S</creator><creator>Lee, Seyoung</creator><creator>Drummond, Grant R</creator><creator>Sobey, Christopher G</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</scope><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><scope>7TK</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20110204</creationdate><title>Chemokine-related gene expression in the brain following ischemic stroke: No role for CXCR2 in outcome</title><author>Brait, Vanessa H ; Rivera, Jennifer ; Broughton, Brad R.S ; Lee, Seyoung ; Drummond, Grant R ; Sobey, Christopher G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c423t-c3f71e2c7569fd1104a2ad78cfc24b98f5de1d057e19e0721991c05e6f5bde2f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Analysis of Variance</topic><topic>Animals</topic><topic>antagonists</topic><topic>Biological and medical sciences</topic><topic>brain</topic><topic>Brain - drug effects</topic><topic>Brain - metabolism</topic><topic>Brain - pathology</topic><topic>Brain Edema - drug therapy</topic><topic>Brain Edema - etiology</topic><topic>Brain Infarction - drug therapy</topic><topic>Brain Infarction - etiology</topic><topic>chemoattractants</topic><topic>Chemokines</topic><topic>Chemokines - genetics</topic><topic>Chemokines - metabolism</topic><topic>CXCL1</topic><topic>CXCL2</topic><topic>CXCR2</topic><topic>Disease Models, Animal</topic><topic>gene expression</topic><topic>Gene Expression Regulation - drug effects</topic><topic>Gene Expression Regulation - physiology</topic><topic>genes</topic><topic>infarction</topic><topic>Infarction, Middle Cerebral Artery - drug therapy</topic><topic>Infarction, Middle Cerebral Artery - mortality</topic><topic>Infarction, Middle Cerebral Artery - pathology</topic><topic>Laser-Doppler Flowmetry - methods</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>monocytes</topic><topic>Mouse</topic><topic>Neurology</topic><topic>neutrophils</topic><topic>Neutrophils - drug effects</topic><topic>Phenylurea Compounds - therapeutic use</topic><topic>Recovery of Function - drug effects</topic><topic>RNA, Messenger - metabolism</topic><topic>Stroke</topic><topic>therapeutics</topic><topic>Time Factors</topic><topic>Vascular diseases and vascular malformations of the nervous system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brait, Vanessa H</creatorcontrib><creatorcontrib>Rivera, Jennifer</creatorcontrib><creatorcontrib>Broughton, Brad R.S</creatorcontrib><creatorcontrib>Lee, Seyoung</creatorcontrib><creatorcontrib>Drummond, Grant R</creatorcontrib><creatorcontrib>Sobey, Christopher G</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><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><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Brain research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brait, Vanessa H</au><au>Rivera, Jennifer</au><au>Broughton, Brad R.S</au><au>Lee, Seyoung</au><au>Drummond, Grant R</au><au>Sobey, Christopher G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chemokine-related gene expression in the brain following ischemic stroke: No role for CXCR2 in outcome</atitle><jtitle>Brain research</jtitle><addtitle>Brain Res</addtitle><date>2011-02-04</date><risdate>2011</risdate><volume>1372</volume><spage>169</spage><epage>179</epage><pages>169-179</pages><issn>0006-8993</issn><eissn>1872-6240</eissn><coden>BRREAP</coden><abstract>Abstract This study sought to identify potential targets for acute stroke therapy that can be exploited pharmacologically beyond the current 4.5 h time limit for clinical administration of recombinant tissue-plasminogen activator. We used PCR arrays to initially screen the temporal expression profiles of several chemokine-related genes in the brain at 4, 24 and 72 h after stroke. We identified large increases (> 10-fold) in mRNA at 24 or 72 h for the neutrophil CXCR2 receptor, and for CXCL1 and CXCL2—two chemokine ligands expressed by monocytes and neutrophils with strong neutrophil chemoattractant activity via CXCR2. We then tested the efficacy of a CXCR2 antagonist as a therapeutic. Mice were treated with vehicle (1% DMSO) or SB225002 (2 mg/kg per day, ip) commencing at reperfusion, and we evaluated chemokine gene expression, neutrophil infiltration and functional and histological endpoints of stroke outcome. Expression levels of CXCL1, CXCL2 and CXCR2 after 24 h were markedly reduced to near normal levels in SB225002-treated mice. Myeloperoxidase-positive cell infiltration was significantly reduced in SB225002-treated mice compared with vehicle-treated mice, and was similar to levels in sham-operated mice. However, although SB225002 evidently antagonised the interaction between CXCR2 and its chemokine ligands in the ischemic brain, mice treated with either SB225002 or vehicle had similar motor impairment and infarct volume at 72 h. Thus, the reduced expression of CXC chemokine subfamily genes and neutrophil-related infiltration following SB225002 administration did not improve outcome after cerebral ischemia–reperfusion. CXCR2 antagonists are therefore unlikely to be a potential therapy for ischemic stroke.</abstract><cop>Amsterdam</cop><pub>Elsevier B.V</pub><pmid>21138735</pmid><doi>10.1016/j.brainres.2010.11.087</doi><tpages>11</tpages></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0006-8993 |
ispartof | Brain research, 2011-02, Vol.1372, p.169-179 |
issn | 0006-8993 1872-6240 |
language | eng |
recordid | cdi_proquest_miscellaneous_860376516 |
source | MEDLINE; Elsevier ScienceDirect Journals Complete |
subjects | Analysis of Variance Animals antagonists Biological and medical sciences brain Brain - drug effects Brain - metabolism Brain - pathology Brain Edema - drug therapy Brain Edema - etiology Brain Infarction - drug therapy Brain Infarction - etiology chemoattractants Chemokines Chemokines - genetics Chemokines - metabolism CXCL1 CXCL2 CXCR2 Disease Models, Animal gene expression Gene Expression Regulation - drug effects Gene Expression Regulation - physiology genes infarction Infarction, Middle Cerebral Artery - drug therapy Infarction, Middle Cerebral Artery - mortality Infarction, Middle Cerebral Artery - pathology Laser-Doppler Flowmetry - methods Male Medical sciences Mice Mice, Inbred C57BL monocytes Mouse Neurology neutrophils Neutrophils - drug effects Phenylurea Compounds - therapeutic use Recovery of Function - drug effects RNA, Messenger - metabolism Stroke therapeutics Time Factors Vascular diseases and vascular malformations of the nervous system |
title | Chemokine-related gene expression in the brain following ischemic stroke: No role for CXCR2 in outcome |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T13%3A26%3A53IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Chemokine-related%20gene%20expression%20in%20the%20brain%20following%20ischemic%20stroke:%20No%20role%20for%20CXCR2%20in%20outcome&rft.jtitle=Brain%20research&rft.au=Brait,%20Vanessa%20H&rft.date=2011-02-04&rft.volume=1372&rft.spage=169&rft.epage=179&rft.pages=169-179&rft.issn=0006-8993&rft.eissn=1872-6240&rft.coden=BRREAP&rft_id=info:doi/10.1016/j.brainres.2010.11.087&rft_dat=%3Cproquest_cross%3E847286286%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=847286286&rft_id=info:pmid/21138735&rft_els_id=S0006899310026004&rfr_iscdi=true |