Loading…
A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor Blocks Mechanical Allodynia after Spinal Nerve Ligation: Respective Roles of JNK Activation in Primary Sensory Neurons and Spinal Astrocytes for Neuropathic Pain Development and Maintenance
Optimal management of neuropathic pain is a major clinical challenge. We investigated the involvement of c-Jun N-terminal kinase (JNK) in neuropathic pain produced by spinal nerve ligation (SNL) (L5). SNL induced a slow (>3 d) and persistent (>21 d) activation of JNK, in particular JNK1, in GF...
Saved in:
| Published in: | The Journal of neuroscience 2006-03, Vol.26 (13), p.3551-3560 |
|---|---|
| Main Authors: | , , , , , , , |
| Format: | Article |
| Language: | English |
| Subjects: | |
| Citations: | Items that this one cites Items that cite this one |
| Online Access: | Get full text |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| cited_by | cdi_FETCH-LOGICAL-c594t-4e172f1ba33d74320f62a83d09ef55d93774fb45e21afdd4e3f7d8fc6bde8cb63 |
|---|---|
| cites | cdi_FETCH-LOGICAL-c594t-4e172f1ba33d74320f62a83d09ef55d93774fb45e21afdd4e3f7d8fc6bde8cb63 |
| container_end_page | 3560 |
| container_issue | 13 |
| container_start_page | 3551 |
| container_title | The Journal of neuroscience |
| container_volume | 26 |
| creator | Zhuang, Zhi-Ye Wen, Yeong-Ray Zhang, De-Ren Borsello, Tiziana Bonny, Christophe Strichartz, Gary R Decosterd, Isabelle Ji, Ru-Rong |
| description | Optimal management of neuropathic pain is a major clinical challenge. We investigated the involvement of c-Jun N-terminal kinase (JNK) in neuropathic pain produced by spinal nerve ligation (SNL) (L5). SNL induced a slow (>3 d) and persistent (>21 d) activation of JNK, in particular JNK1, in GFAP-expressing astrocytes in the spinal cord. In contrast, p38 mitogen-activated protein kinase activation was found in spinal microglia after SNL, which had fallen to near basal level by 21 d. Intrathecal infusion of a JNK peptide inhibitor, D-JNKI-1, did not affect normal pain responses but potently prevented and reversed SNL-induced mechanical allodynia, a major symptom of neuropathic pain. Intrathecal D-JNKI-1 also suppressed SNL-induced phosphorylation of the JNK substrate, c-Jun, in spinal astrocytes. However, SNL-induced upregulation of GFAP was not attenuated by spinal D-JNKI-1 infusion. Furthermore, SNL induced a rapid ( |
| doi_str_mv | 10.1523/JNEUROSCI.5290-05.2006 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6673862</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>17120266</sourcerecordid><originalsourceid>FETCH-LOGICAL-c594t-4e172f1ba33d74320f62a83d09ef55d93774fb45e21afdd4e3f7d8fc6bde8cb63</originalsourceid><addsrcrecordid>eNqFkttuEzEQhlcIREvhFSpfcbjY4MOunXCBFEKBpGkaJe215Xhns6Ybe7E3ifLUvALOgQJX3MxIM9__a0b6k-SS4A7JKXs_mlzdz27ng2Enpz2c4rxDMeZPkvO47aU0w-Rpco6pwCnPRHaWvAjhO8ZYYCKeJ2eE54IIzs6Tn300haY1BSCdjtYWTdI78CtjVY2uYw2A3o4m1-_Q0FZmYVrn0afa6YeAbkBXyhodwX5du2JnjUKqbMGjeXPQT8BvAI3NUrXG2Q9oBqEB3Zo4nLkaAnIlit6ov58dGGQsmnqzUn6H5mCDi30Ca-9sQMoWv437ofVO79poUcaDDkSj2spoNFXR4jNsoHbNCmx7kN3EYQtWWQ0vk2elqgO8OvWL5P7L1d3gWzq-_Toc9MepzntZm2ZABC3JQjFWiIxRXHKquqzAPSjzvOgxIbJykeVAiSqLIgNWiqJbar4ooKsXnF0kH4--zXqxgkLHU7yqZXN8Tjpl5L8bayq5dBvJuWBdTqPB65OBdz_WEFq5MkFDXSsLbh0kF12CSc7_CxJBKKZ8D_IjqL0LwUP5eA3Bch8q-RgquQ-VxLnchyoKL__-5Y_slKIIvDkClVlWW-NBhpWq64gTud1uKZeESZbnhP0COhrcnA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>17120266</pqid></control><display><type>article</type><title>A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor Blocks Mechanical Allodynia after Spinal Nerve Ligation: Respective Roles of JNK Activation in Primary Sensory Neurons and Spinal Astrocytes for Neuropathic Pain Development and Maintenance</title><source>Open Access: PubMed Central</source><creator>Zhuang, Zhi-Ye ; Wen, Yeong-Ray ; Zhang, De-Ren ; Borsello, Tiziana ; Bonny, Christophe ; Strichartz, Gary R ; Decosterd, Isabelle ; Ji, Ru-Rong</creator><creatorcontrib>Zhuang, Zhi-Ye ; Wen, Yeong-Ray ; Zhang, De-Ren ; Borsello, Tiziana ; Bonny, Christophe ; Strichartz, Gary R ; Decosterd, Isabelle ; Ji, Ru-Rong</creatorcontrib><description>Optimal management of neuropathic pain is a major clinical challenge. We investigated the involvement of c-Jun N-terminal kinase (JNK) in neuropathic pain produced by spinal nerve ligation (SNL) (L5). SNL induced a slow (>3 d) and persistent (>21 d) activation of JNK, in particular JNK1, in GFAP-expressing astrocytes in the spinal cord. In contrast, p38 mitogen-activated protein kinase activation was found in spinal microglia after SNL, which had fallen to near basal level by 21 d. Intrathecal infusion of a JNK peptide inhibitor, D-JNKI-1, did not affect normal pain responses but potently prevented and reversed SNL-induced mechanical allodynia, a major symptom of neuropathic pain. Intrathecal D-JNKI-1 also suppressed SNL-induced phosphorylation of the JNK substrate, c-Jun, in spinal astrocytes. However, SNL-induced upregulation of GFAP was not attenuated by spinal D-JNKI-1 infusion. Furthermore, SNL induced a rapid (<12 h) but transient activation of JNK in the L5 (injured) but not L4 (intact) DRG. JNK activation in the DRG was mainly found in small-sized C-fiber neurons. Infusion of D-JNKI-1 into the L5 DRG prevented but did not reverse SNL-induced mechanical allodynia. Finally, intrathecal administration of an astroglial toxin, l-alpha-aminoadipate, reversed mechanical allodynia. Our data suggest that JNK activation in the DRG and spinal cord play distinct roles in regulating the development and maintenance of neuropathic pain, respectively, and that spinal astrocytes contribute importantly to the persistence of mechanical allodynia. Targeting the JNK pathway in spinal astroglia may present a new and efficient way to treat neuropathic pain symptoms.</description><identifier>ISSN: 0270-6474</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/JNEUROSCI.5290-05.2006</identifier><identifier>PMID: 16571763</identifier><language>eng</language><publisher>United States: Soc Neuroscience</publisher><subject>Animals ; Astrocytes - drug effects ; Astrocytes - enzymology ; Enzyme Activation - drug effects ; Ganglia, Spinal - drug effects ; Ganglia, Spinal - enzymology ; Hyperalgesia - complications ; Hyperalgesia - enzymology ; Hyperalgesia - prevention & control ; Male ; MAP Kinase Kinase 4 - antagonists & inhibitors ; MAP Kinase Kinase 4 - metabolism ; Neuralgia - complications ; Neuralgia - enzymology ; Neuralgia - prevention & control ; Neurons, Afferent - drug effects ; Neurons, Afferent - enzymology ; Peptides - administration & dosage ; Rats ; Rats, Sprague-Dawley ; Spinal Nerves - drug effects ; Spinal Nerves - injuries</subject><ispartof>The Journal of neuroscience, 2006-03, Vol.26 (13), p.3551-3560</ispartof><rights>Copyright © 2006 Society for Neuroscience 0270-6474/06/263551-10$15.00/0 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c594t-4e172f1ba33d74320f62a83d09ef55d93774fb45e21afdd4e3f7d8fc6bde8cb63</citedby><cites>FETCH-LOGICAL-c594t-4e172f1ba33d74320f62a83d09ef55d93774fb45e21afdd4e3f7d8fc6bde8cb63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673862/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673862/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16571763$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhuang, Zhi-Ye</creatorcontrib><creatorcontrib>Wen, Yeong-Ray</creatorcontrib><creatorcontrib>Zhang, De-Ren</creatorcontrib><creatorcontrib>Borsello, Tiziana</creatorcontrib><creatorcontrib>Bonny, Christophe</creatorcontrib><creatorcontrib>Strichartz, Gary R</creatorcontrib><creatorcontrib>Decosterd, Isabelle</creatorcontrib><creatorcontrib>Ji, Ru-Rong</creatorcontrib><title>A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor Blocks Mechanical Allodynia after Spinal Nerve Ligation: Respective Roles of JNK Activation in Primary Sensory Neurons and Spinal Astrocytes for Neuropathic Pain Development and Maintenance</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>Optimal management of neuropathic pain is a major clinical challenge. We investigated the involvement of c-Jun N-terminal kinase (JNK) in neuropathic pain produced by spinal nerve ligation (SNL) (L5). SNL induced a slow (>3 d) and persistent (>21 d) activation of JNK, in particular JNK1, in GFAP-expressing astrocytes in the spinal cord. In contrast, p38 mitogen-activated protein kinase activation was found in spinal microglia after SNL, which had fallen to near basal level by 21 d. Intrathecal infusion of a JNK peptide inhibitor, D-JNKI-1, did not affect normal pain responses but potently prevented and reversed SNL-induced mechanical allodynia, a major symptom of neuropathic pain. Intrathecal D-JNKI-1 also suppressed SNL-induced phosphorylation of the JNK substrate, c-Jun, in spinal astrocytes. However, SNL-induced upregulation of GFAP was not attenuated by spinal D-JNKI-1 infusion. Furthermore, SNL induced a rapid (<12 h) but transient activation of JNK in the L5 (injured) but not L4 (intact) DRG. JNK activation in the DRG was mainly found in small-sized C-fiber neurons. Infusion of D-JNKI-1 into the L5 DRG prevented but did not reverse SNL-induced mechanical allodynia. Finally, intrathecal administration of an astroglial toxin, l-alpha-aminoadipate, reversed mechanical allodynia. Our data suggest that JNK activation in the DRG and spinal cord play distinct roles in regulating the development and maintenance of neuropathic pain, respectively, and that spinal astrocytes contribute importantly to the persistence of mechanical allodynia. Targeting the JNK pathway in spinal astroglia may present a new and efficient way to treat neuropathic pain symptoms.</description><subject>Animals</subject><subject>Astrocytes - drug effects</subject><subject>Astrocytes - enzymology</subject><subject>Enzyme Activation - drug effects</subject><subject>Ganglia, Spinal - drug effects</subject><subject>Ganglia, Spinal - enzymology</subject><subject>Hyperalgesia - complications</subject><subject>Hyperalgesia - enzymology</subject><subject>Hyperalgesia - prevention & control</subject><subject>Male</subject><subject>MAP Kinase Kinase 4 - antagonists & inhibitors</subject><subject>MAP Kinase Kinase 4 - metabolism</subject><subject>Neuralgia - complications</subject><subject>Neuralgia - enzymology</subject><subject>Neuralgia - prevention & control</subject><subject>Neurons, Afferent - drug effects</subject><subject>Neurons, Afferent - enzymology</subject><subject>Peptides - administration & dosage</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Spinal Nerves - drug effects</subject><subject>Spinal Nerves - injuries</subject><issn>0270-6474</issn><issn>1529-2401</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><recordid>eNqFkttuEzEQhlcIREvhFSpfcbjY4MOunXCBFEKBpGkaJe215Xhns6Ybe7E3ifLUvALOgQJX3MxIM9__a0b6k-SS4A7JKXs_mlzdz27ng2Enpz2c4rxDMeZPkvO47aU0w-Rpco6pwCnPRHaWvAjhO8ZYYCKeJ2eE54IIzs6Tn300haY1BSCdjtYWTdI78CtjVY2uYw2A3o4m1-_Q0FZmYVrn0afa6YeAbkBXyhodwX5du2JnjUKqbMGjeXPQT8BvAI3NUrXG2Q9oBqEB3Zo4nLkaAnIlit6ov58dGGQsmnqzUn6H5mCDi30Ca-9sQMoWv437ofVO79poUcaDDkSj2spoNFXR4jNsoHbNCmx7kN3EYQtWWQ0vk2elqgO8OvWL5P7L1d3gWzq-_Toc9MepzntZm2ZABC3JQjFWiIxRXHKquqzAPSjzvOgxIbJykeVAiSqLIgNWiqJbar4ooKsXnF0kH4--zXqxgkLHU7yqZXN8Tjpl5L8bayq5dBvJuWBdTqPB65OBdz_WEFq5MkFDXSsLbh0kF12CSc7_CxJBKKZ8D_IjqL0LwUP5eA3Bch8q-RgquQ-VxLnchyoKL__-5Y_slKIIvDkClVlWW-NBhpWq64gTud1uKZeESZbnhP0COhrcnA</recordid><startdate>20060329</startdate><enddate>20060329</enddate><creator>Zhuang, Zhi-Ye</creator><creator>Wen, Yeong-Ray</creator><creator>Zhang, De-Ren</creator><creator>Borsello, Tiziana</creator><creator>Bonny, Christophe</creator><creator>Strichartz, Gary R</creator><creator>Decosterd, Isabelle</creator><creator>Ji, Ru-Rong</creator><general>Soc Neuroscience</general><general>Society for Neuroscience</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>7TK</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20060329</creationdate><title>A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor Blocks Mechanical Allodynia after Spinal Nerve Ligation: Respective Roles of JNK Activation in Primary Sensory Neurons and Spinal Astrocytes for Neuropathic Pain Development and Maintenance</title><author>Zhuang, Zhi-Ye ; Wen, Yeong-Ray ; Zhang, De-Ren ; Borsello, Tiziana ; Bonny, Christophe ; Strichartz, Gary R ; Decosterd, Isabelle ; Ji, Ru-Rong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c594t-4e172f1ba33d74320f62a83d09ef55d93774fb45e21afdd4e3f7d8fc6bde8cb63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Animals</topic><topic>Astrocytes - drug effects</topic><topic>Astrocytes - enzymology</topic><topic>Enzyme Activation - drug effects</topic><topic>Ganglia, Spinal - drug effects</topic><topic>Ganglia, Spinal - enzymology</topic><topic>Hyperalgesia - complications</topic><topic>Hyperalgesia - enzymology</topic><topic>Hyperalgesia - prevention & control</topic><topic>Male</topic><topic>MAP Kinase Kinase 4 - antagonists & inhibitors</topic><topic>MAP Kinase Kinase 4 - metabolism</topic><topic>Neuralgia - complications</topic><topic>Neuralgia - enzymology</topic><topic>Neuralgia - prevention & control</topic><topic>Neurons, Afferent - drug effects</topic><topic>Neurons, Afferent - enzymology</topic><topic>Peptides - administration & dosage</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Spinal Nerves - drug effects</topic><topic>Spinal Nerves - injuries</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhuang, Zhi-Ye</creatorcontrib><creatorcontrib>Wen, Yeong-Ray</creatorcontrib><creatorcontrib>Zhang, De-Ren</creatorcontrib><creatorcontrib>Borsello, Tiziana</creatorcontrib><creatorcontrib>Bonny, Christophe</creatorcontrib><creatorcontrib>Strichartz, Gary R</creatorcontrib><creatorcontrib>Decosterd, Isabelle</creatorcontrib><creatorcontrib>Ji, Ru-Rong</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhuang, Zhi-Ye</au><au>Wen, Yeong-Ray</au><au>Zhang, De-Ren</au><au>Borsello, Tiziana</au><au>Bonny, Christophe</au><au>Strichartz, Gary R</au><au>Decosterd, Isabelle</au><au>Ji, Ru-Rong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor Blocks Mechanical Allodynia after Spinal Nerve Ligation: Respective Roles of JNK Activation in Primary Sensory Neurons and Spinal Astrocytes for Neuropathic Pain Development and Maintenance</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2006-03-29</date><risdate>2006</risdate><volume>26</volume><issue>13</issue><spage>3551</spage><epage>3560</epage><pages>3551-3560</pages><issn>0270-6474</issn><eissn>1529-2401</eissn><abstract>Optimal management of neuropathic pain is a major clinical challenge. We investigated the involvement of c-Jun N-terminal kinase (JNK) in neuropathic pain produced by spinal nerve ligation (SNL) (L5). SNL induced a slow (>3 d) and persistent (>21 d) activation of JNK, in particular JNK1, in GFAP-expressing astrocytes in the spinal cord. In contrast, p38 mitogen-activated protein kinase activation was found in spinal microglia after SNL, which had fallen to near basal level by 21 d. Intrathecal infusion of a JNK peptide inhibitor, D-JNKI-1, did not affect normal pain responses but potently prevented and reversed SNL-induced mechanical allodynia, a major symptom of neuropathic pain. Intrathecal D-JNKI-1 also suppressed SNL-induced phosphorylation of the JNK substrate, c-Jun, in spinal astrocytes. However, SNL-induced upregulation of GFAP was not attenuated by spinal D-JNKI-1 infusion. Furthermore, SNL induced a rapid (<12 h) but transient activation of JNK in the L5 (injured) but not L4 (intact) DRG. JNK activation in the DRG was mainly found in small-sized C-fiber neurons. Infusion of D-JNKI-1 into the L5 DRG prevented but did not reverse SNL-induced mechanical allodynia. Finally, intrathecal administration of an astroglial toxin, l-alpha-aminoadipate, reversed mechanical allodynia. Our data suggest that JNK activation in the DRG and spinal cord play distinct roles in regulating the development and maintenance of neuropathic pain, respectively, and that spinal astrocytes contribute importantly to the persistence of mechanical allodynia. Targeting the JNK pathway in spinal astroglia may present a new and efficient way to treat neuropathic pain symptoms.</abstract><cop>United States</cop><pub>Soc Neuroscience</pub><pmid>16571763</pmid><doi>10.1523/JNEUROSCI.5290-05.2006</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0270-6474 |
| ispartof | The Journal of neuroscience, 2006-03, Vol.26 (13), p.3551-3560 |
| issn | 0270-6474 1529-2401 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6673862 |
| source | Open Access: PubMed Central |
| subjects | Animals Astrocytes - drug effects Astrocytes - enzymology Enzyme Activation - drug effects Ganglia, Spinal - drug effects Ganglia, Spinal - enzymology Hyperalgesia - complications Hyperalgesia - enzymology Hyperalgesia - prevention & control Male MAP Kinase Kinase 4 - antagonists & inhibitors MAP Kinase Kinase 4 - metabolism Neuralgia - complications Neuralgia - enzymology Neuralgia - prevention & control Neurons, Afferent - drug effects Neurons, Afferent - enzymology Peptides - administration & dosage Rats Rats, Sprague-Dawley Spinal Nerves - drug effects Spinal Nerves - injuries |
| title | A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor Blocks Mechanical Allodynia after Spinal Nerve Ligation: Respective Roles of JNK Activation in Primary Sensory Neurons and Spinal Astrocytes for Neuropathic Pain Development and Maintenance |
| url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-26T21%3A35%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20Peptide%20c-Jun%20N-Terminal%20Kinase%20(JNK)%20Inhibitor%20Blocks%20Mechanical%20Allodynia%20after%20Spinal%20Nerve%20Ligation:%20Respective%20Roles%20of%20JNK%20Activation%20in%20Primary%20Sensory%20Neurons%20and%20Spinal%20Astrocytes%20for%20Neuropathic%20Pain%20Development%20and%20Maintenance&rft.jtitle=The%20Journal%20of%20neuroscience&rft.au=Zhuang,%20Zhi-Ye&rft.date=2006-03-29&rft.volume=26&rft.issue=13&rft.spage=3551&rft.epage=3560&rft.pages=3551-3560&rft.issn=0270-6474&rft.eissn=1529-2401&rft_id=info:doi/10.1523/JNEUROSCI.5290-05.2006&rft_dat=%3Cproquest_pubme%3E17120266%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c594t-4e172f1ba33d74320f62a83d09ef55d93774fb45e21afdd4e3f7d8fc6bde8cb63%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=17120266&rft_id=info:pmid/16571763&rfr_iscdi=true |