Characterization of [123I]FP-CIT binding to the dopamine transporter in the striatum of tree shrews by quantitative in vitro autoradiography
ABSTRACT Objectives Aim of this study was to quantify the binding of [123I]FP‐CIT in striatum of healthy tree shrews. [123I]FP‐CIT is widely used in clinical SPECT imaging to reveal nigrostriatal degeneration in aid of the diagnosis of clinically uncertain parkinsonian syndromes. Despite its wide cl...
Gespeichert in:
| Veröffentlicht in: | Synapse (New York, N.Y.) N.Y.), 2015-10, Vol.69 (10), p.497-504 |
|---|---|
| Hauptverfasser: | , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 504 |
|---|---|
| container_issue | 10 |
| container_start_page | 497 |
| container_title | Synapse (New York, N.Y.) |
| container_volume | 69 |
| creator | Geisler, Stefanie Beindorff, Nicola Cremer, Markus Hoffmann, Kerstin Brenner, Winfried Cumming, Paul Meyer, Philipp T. Langen, Karl-Josef Fuchs, Eberhard Buchert, Ralph |
| description | ABSTRACT
Objectives
Aim of this study was to quantify the binding of [123I]FP‐CIT in striatum of healthy tree shrews. [123I]FP‐CIT is widely used in clinical SPECT imaging to reveal nigrostriatal degeneration in aid of the diagnosis of clinically uncertain parkinsonian syndromes. Despite its wide clinical use, the saturation binding parameters of [123I]FP‐CIT for the dopamine transporter (DAT) have not yet been determined in any mammalian brain. Tree shrews are genetically and neuroanatomically more similar to humans than are rodents and might therefore be a valuable animal model for research of neurological disorders involving brain dopamine.
Experimental Design
Quantitative in vitro autoradiography with [123I]FP‐CIT was performed with brains of healthy tree shrews and, for comparison, brains of healthy rats. Dopamine D2/3 receptor autoradiography with [3H]raclopride was also performed.
Principal observations
Saturation analysis revealed high specificity of [123I]FP‐CIT for DAT in the striatum with considerably higher affinity in tree shrews than in rats (KD = 10.3 versus 36.4 nM). The density of DAT binding sites also was higher in tree shrews than in rats (Bmax = 2499 versus 1495 pmol/g wet weight (ww)). [3H]raclopride revealed D2/3 receptors in the tree shrew striatum with about the same density as in rats (Bmax = 78.4 versus 84.1 pmol/g ww), but with slightly lower affinity in tree shrews (KD = 1.27 versus 0.59 nM).
Conlusions
The higher affinity in combination with the higher abundance of DAT binding sites compared to rat striatum predicts substantially higher binding of [123I]FP‐CIT in SPECT studies of living tree shrews. Synapse 69:497–504, 2015. © 2015 Wiley Periodicals, Inc.
Using in vitro autoradiography, the authors characterize the binding of [123I]FP‐CIT to striatal dopamine transporters in tree shrew compared to rat. This is the first report of the dissociation constant of [123I]FP‐CIT for the dopamine transporter in mammalian brain. |
| doi_str_mv | 10.1002/syn.21838 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1712562510</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3782317091</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4948-2a266fba870361aac3f6367b6441d59acf4ea08efbc3f44e500d219e65f36e853</originalsourceid><addsrcrecordid>eNqNkV9rFDEUxYModlt98AtIwJf6MG3-TSbzaBfbLixVbEVFJNyZyXRTdybTJNN2_Qx-aLO7bR8EwacL9_7OuRwOQq8oOaCEsMOw6g8YVVw9QRNKSpUxXsqnaEKUKjIhCrmDdkO4IoRwSsRztMMkZbIUbIJ-TxfgoY7G218Qreuxa_F3yvjsx_HHbDq7wJXtG9tf4uhwXBjcuAE62xscPfRhcD5Jse03txC9hTh2a4_oTVosvLkNuFrh6xH6aGN6cWPW-I2N3mEYo_PQWHfpYVisXqBnLSyDeXk_99Dn4_cX09Ns_uFkNn03z2pRipQOmJRtBaogXFKAmreSy6KSQtAmL6FuhQGiTFulixAmJ6RhtDQyb7k0Kud7aH_rO3h3PZoQdWdDbZZL6I0bg6YFZblkOSX_gZK8YKqURULf_IVeudH3KciG4iVj5Zp6u6Vq70LwptWDtx34laZEr9vUqU29aTOxr-8dx6ozzSP5UF8CDrfArV2a1b-d9Pm3swfLbKuwIZq7RwX4nzpFKHL95exEq_NPR-rr0Vyf8j-ZGLlZ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1705392297</pqid></control><display><type>article</type><title>Characterization of [123I]FP-CIT binding to the dopamine transporter in the striatum of tree shrews by quantitative in vitro autoradiography</title><source>MEDLINE</source><source>Wiley Online Library (Online service)</source><creator>Geisler, Stefanie ; Beindorff, Nicola ; Cremer, Markus ; Hoffmann, Kerstin ; Brenner, Winfried ; Cumming, Paul ; Meyer, Philipp T. ; Langen, Karl-Josef ; Fuchs, Eberhard ; Buchert, Ralph</creator><creatorcontrib>Geisler, Stefanie ; Beindorff, Nicola ; Cremer, Markus ; Hoffmann, Kerstin ; Brenner, Winfried ; Cumming, Paul ; Meyer, Philipp T. ; Langen, Karl-Josef ; Fuchs, Eberhard ; Buchert, Ralph</creatorcontrib><description>ABSTRACT
Objectives
Aim of this study was to quantify the binding of [123I]FP‐CIT in striatum of healthy tree shrews. [123I]FP‐CIT is widely used in clinical SPECT imaging to reveal nigrostriatal degeneration in aid of the diagnosis of clinically uncertain parkinsonian syndromes. Despite its wide clinical use, the saturation binding parameters of [123I]FP‐CIT for the dopamine transporter (DAT) have not yet been determined in any mammalian brain. Tree shrews are genetically and neuroanatomically more similar to humans than are rodents and might therefore be a valuable animal model for research of neurological disorders involving brain dopamine.
Experimental Design
Quantitative in vitro autoradiography with [123I]FP‐CIT was performed with brains of healthy tree shrews and, for comparison, brains of healthy rats. Dopamine D2/3 receptor autoradiography with [3H]raclopride was also performed.
Principal observations
Saturation analysis revealed high specificity of [123I]FP‐CIT for DAT in the striatum with considerably higher affinity in tree shrews than in rats (KD = 10.3 versus 36.4 nM). The density of DAT binding sites also was higher in tree shrews than in rats (Bmax = 2499 versus 1495 pmol/g wet weight (ww)). [3H]raclopride revealed D2/3 receptors in the tree shrew striatum with about the same density as in rats (Bmax = 78.4 versus 84.1 pmol/g ww), but with slightly lower affinity in tree shrews (KD = 1.27 versus 0.59 nM).
Conlusions
The higher affinity in combination with the higher abundance of DAT binding sites compared to rat striatum predicts substantially higher binding of [123I]FP‐CIT in SPECT studies of living tree shrews. Synapse 69:497–504, 2015. © 2015 Wiley Periodicals, Inc.
Using in vitro autoradiography, the authors characterize the binding of [123I]FP‐CIT to striatal dopamine transporters in tree shrew compared to rat. This is the first report of the dissociation constant of [123I]FP‐CIT for the dopamine transporter in mammalian brain.</description><identifier>ISSN: 0887-4476</identifier><identifier>EISSN: 1098-2396</identifier><identifier>DOI: 10.1002/syn.21838</identifier><identifier>PMID: 26126942</identifier><identifier>CODEN: SYNAET</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>[123I]FP-CIT ; Animals ; Autoradiography ; Corpus Striatum - diagnostic imaging ; Corpus Striatum - metabolism ; dissociation constant ; Dopamine Antagonists - pharmacokinetics ; Dopamine Plasma Membrane Transport Proteins - metabolism ; dopamine receptor ; dopamine transporter ; Humans ; In Vitro Techniques ; Male ; mammalian brain ; Protein Binding - drug effects ; raclopride ; Raclopride - pharmacokinetics ; Rats ; Tomography, Emission-Computed, Single-Photon ; tree shrew ; Tropanes - pharmacokinetics ; Tupaia ; Tupaiidae</subject><ispartof>Synapse (New York, N.Y.), 2015-10, Vol.69 (10), p.497-504</ispartof><rights>2015 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4948-2a266fba870361aac3f6367b6441d59acf4ea08efbc3f44e500d219e65f36e853</citedby><cites>FETCH-LOGICAL-c4948-2a266fba870361aac3f6367b6441d59acf4ea08efbc3f44e500d219e65f36e853</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fsyn.21838$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fsyn.21838$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26126942$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Geisler, Stefanie</creatorcontrib><creatorcontrib>Beindorff, Nicola</creatorcontrib><creatorcontrib>Cremer, Markus</creatorcontrib><creatorcontrib>Hoffmann, Kerstin</creatorcontrib><creatorcontrib>Brenner, Winfried</creatorcontrib><creatorcontrib>Cumming, Paul</creatorcontrib><creatorcontrib>Meyer, Philipp T.</creatorcontrib><creatorcontrib>Langen, Karl-Josef</creatorcontrib><creatorcontrib>Fuchs, Eberhard</creatorcontrib><creatorcontrib>Buchert, Ralph</creatorcontrib><title>Characterization of [123I]FP-CIT binding to the dopamine transporter in the striatum of tree shrews by quantitative in vitro autoradiography</title><title>Synapse (New York, N.Y.)</title><addtitle>Synapse</addtitle><description>ABSTRACT
Objectives
Aim of this study was to quantify the binding of [123I]FP‐CIT in striatum of healthy tree shrews. [123I]FP‐CIT is widely used in clinical SPECT imaging to reveal nigrostriatal degeneration in aid of the diagnosis of clinically uncertain parkinsonian syndromes. Despite its wide clinical use, the saturation binding parameters of [123I]FP‐CIT for the dopamine transporter (DAT) have not yet been determined in any mammalian brain. Tree shrews are genetically and neuroanatomically more similar to humans than are rodents and might therefore be a valuable animal model for research of neurological disorders involving brain dopamine.
Experimental Design
Quantitative in vitro autoradiography with [123I]FP‐CIT was performed with brains of healthy tree shrews and, for comparison, brains of healthy rats. Dopamine D2/3 receptor autoradiography with [3H]raclopride was also performed.
Principal observations
Saturation analysis revealed high specificity of [123I]FP‐CIT for DAT in the striatum with considerably higher affinity in tree shrews than in rats (KD = 10.3 versus 36.4 nM). The density of DAT binding sites also was higher in tree shrews than in rats (Bmax = 2499 versus 1495 pmol/g wet weight (ww)). [3H]raclopride revealed D2/3 receptors in the tree shrew striatum with about the same density as in rats (Bmax = 78.4 versus 84.1 pmol/g ww), but with slightly lower affinity in tree shrews (KD = 1.27 versus 0.59 nM).
Conlusions
The higher affinity in combination with the higher abundance of DAT binding sites compared to rat striatum predicts substantially higher binding of [123I]FP‐CIT in SPECT studies of living tree shrews. Synapse 69:497–504, 2015. © 2015 Wiley Periodicals, Inc.
Using in vitro autoradiography, the authors characterize the binding of [123I]FP‐CIT to striatal dopamine transporters in tree shrew compared to rat. This is the first report of the dissociation constant of [123I]FP‐CIT for the dopamine transporter in mammalian brain.</description><subject>[123I]FP-CIT</subject><subject>Animals</subject><subject>Autoradiography</subject><subject>Corpus Striatum - diagnostic imaging</subject><subject>Corpus Striatum - metabolism</subject><subject>dissociation constant</subject><subject>Dopamine Antagonists - pharmacokinetics</subject><subject>Dopamine Plasma Membrane Transport Proteins - metabolism</subject><subject>dopamine receptor</subject><subject>dopamine transporter</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Male</subject><subject>mammalian brain</subject><subject>Protein Binding - drug effects</subject><subject>raclopride</subject><subject>Raclopride - pharmacokinetics</subject><subject>Rats</subject><subject>Tomography, Emission-Computed, Single-Photon</subject><subject>tree shrew</subject><subject>Tropanes - pharmacokinetics</subject><subject>Tupaia</subject><subject>Tupaiidae</subject><issn>0887-4476</issn><issn>1098-2396</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkV9rFDEUxYModlt98AtIwJf6MG3-TSbzaBfbLixVbEVFJNyZyXRTdybTJNN2_Qx-aLO7bR8EwacL9_7OuRwOQq8oOaCEsMOw6g8YVVw9QRNKSpUxXsqnaEKUKjIhCrmDdkO4IoRwSsRztMMkZbIUbIJ-TxfgoY7G218Qreuxa_F3yvjsx_HHbDq7wJXtG9tf4uhwXBjcuAE62xscPfRhcD5Jse03txC9hTh2a4_oTVosvLkNuFrh6xH6aGN6cWPW-I2N3mEYo_PQWHfpYVisXqBnLSyDeXk_99Dn4_cX09Ns_uFkNn03z2pRipQOmJRtBaogXFKAmreSy6KSQtAmL6FuhQGiTFulixAmJ6RhtDQyb7k0Kud7aH_rO3h3PZoQdWdDbZZL6I0bg6YFZblkOSX_gZK8YKqURULf_IVeudH3KciG4iVj5Zp6u6Vq70LwptWDtx34laZEr9vUqU29aTOxr-8dx6ozzSP5UF8CDrfArV2a1b-d9Pm3swfLbKuwIZq7RwX4nzpFKHL95exEq_NPR-rr0Vyf8j-ZGLlZ</recordid><startdate>201510</startdate><enddate>201510</enddate><creator>Geisler, Stefanie</creator><creator>Beindorff, Nicola</creator><creator>Cremer, Markus</creator><creator>Hoffmann, Kerstin</creator><creator>Brenner, Winfried</creator><creator>Cumming, Paul</creator><creator>Meyer, Philipp T.</creator><creator>Langen, Karl-Josef</creator><creator>Fuchs, Eberhard</creator><creator>Buchert, Ralph</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</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>7QP</scope><scope>7TK</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201510</creationdate><title>Characterization of [123I]FP-CIT binding to the dopamine transporter in the striatum of tree shrews by quantitative in vitro autoradiography</title><author>Geisler, Stefanie ; Beindorff, Nicola ; Cremer, Markus ; Hoffmann, Kerstin ; Brenner, Winfried ; Cumming, Paul ; Meyer, Philipp T. ; Langen, Karl-Josef ; Fuchs, Eberhard ; Buchert, Ralph</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4948-2a266fba870361aac3f6367b6441d59acf4ea08efbc3f44e500d219e65f36e853</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>[123I]FP-CIT</topic><topic>Animals</topic><topic>Autoradiography</topic><topic>Corpus Striatum - diagnostic imaging</topic><topic>Corpus Striatum - metabolism</topic><topic>dissociation constant</topic><topic>Dopamine Antagonists - pharmacokinetics</topic><topic>Dopamine Plasma Membrane Transport Proteins - metabolism</topic><topic>dopamine receptor</topic><topic>dopamine transporter</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Male</topic><topic>mammalian brain</topic><topic>Protein Binding - drug effects</topic><topic>raclopride</topic><topic>Raclopride - pharmacokinetics</topic><topic>Rats</topic><topic>Tomography, Emission-Computed, Single-Photon</topic><topic>tree shrew</topic><topic>Tropanes - pharmacokinetics</topic><topic>Tupaia</topic><topic>Tupaiidae</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Geisler, Stefanie</creatorcontrib><creatorcontrib>Beindorff, Nicola</creatorcontrib><creatorcontrib>Cremer, Markus</creatorcontrib><creatorcontrib>Hoffmann, Kerstin</creatorcontrib><creatorcontrib>Brenner, Winfried</creatorcontrib><creatorcontrib>Cumming, Paul</creatorcontrib><creatorcontrib>Meyer, Philipp T.</creatorcontrib><creatorcontrib>Langen, Karl-Josef</creatorcontrib><creatorcontrib>Fuchs, Eberhard</creatorcontrib><creatorcontrib>Buchert, Ralph</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Synapse (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Geisler, Stefanie</au><au>Beindorff, Nicola</au><au>Cremer, Markus</au><au>Hoffmann, Kerstin</au><au>Brenner, Winfried</au><au>Cumming, Paul</au><au>Meyer, Philipp T.</au><au>Langen, Karl-Josef</au><au>Fuchs, Eberhard</au><au>Buchert, Ralph</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Characterization of [123I]FP-CIT binding to the dopamine transporter in the striatum of tree shrews by quantitative in vitro autoradiography</atitle><jtitle>Synapse (New York, N.Y.)</jtitle><addtitle>Synapse</addtitle><date>2015-10</date><risdate>2015</risdate><volume>69</volume><issue>10</issue><spage>497</spage><epage>504</epage><pages>497-504</pages><issn>0887-4476</issn><eissn>1098-2396</eissn><coden>SYNAET</coden><abstract>ABSTRACT
Objectives
Aim of this study was to quantify the binding of [123I]FP‐CIT in striatum of healthy tree shrews. [123I]FP‐CIT is widely used in clinical SPECT imaging to reveal nigrostriatal degeneration in aid of the diagnosis of clinically uncertain parkinsonian syndromes. Despite its wide clinical use, the saturation binding parameters of [123I]FP‐CIT for the dopamine transporter (DAT) have not yet been determined in any mammalian brain. Tree shrews are genetically and neuroanatomically more similar to humans than are rodents and might therefore be a valuable animal model for research of neurological disorders involving brain dopamine.
Experimental Design
Quantitative in vitro autoradiography with [123I]FP‐CIT was performed with brains of healthy tree shrews and, for comparison, brains of healthy rats. Dopamine D2/3 receptor autoradiography with [3H]raclopride was also performed.
Principal observations
Saturation analysis revealed high specificity of [123I]FP‐CIT for DAT in the striatum with considerably higher affinity in tree shrews than in rats (KD = 10.3 versus 36.4 nM). The density of DAT binding sites also was higher in tree shrews than in rats (Bmax = 2499 versus 1495 pmol/g wet weight (ww)). [3H]raclopride revealed D2/3 receptors in the tree shrew striatum with about the same density as in rats (Bmax = 78.4 versus 84.1 pmol/g ww), but with slightly lower affinity in tree shrews (KD = 1.27 versus 0.59 nM).
Conlusions
The higher affinity in combination with the higher abundance of DAT binding sites compared to rat striatum predicts substantially higher binding of [123I]FP‐CIT in SPECT studies of living tree shrews. Synapse 69:497–504, 2015. © 2015 Wiley Periodicals, Inc.
Using in vitro autoradiography, the authors characterize the binding of [123I]FP‐CIT to striatal dopamine transporters in tree shrew compared to rat. This is the first report of the dissociation constant of [123I]FP‐CIT for the dopamine transporter in mammalian brain.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>26126942</pmid><doi>10.1002/syn.21838</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0887-4476 |
| ispartof | Synapse (New York, N.Y.), 2015-10, Vol.69 (10), p.497-504 |
| issn | 0887-4476 1098-2396 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1712562510 |
| source | MEDLINE; Wiley Online Library (Online service) |
| subjects | [123I]FP-CIT Animals Autoradiography Corpus Striatum - diagnostic imaging Corpus Striatum - metabolism dissociation constant Dopamine Antagonists - pharmacokinetics Dopamine Plasma Membrane Transport Proteins - metabolism dopamine receptor dopamine transporter Humans In Vitro Techniques Male mammalian brain Protein Binding - drug effects raclopride Raclopride - pharmacokinetics Rats Tomography, Emission-Computed, Single-Photon tree shrew Tropanes - pharmacokinetics Tupaia Tupaiidae |
| title | Characterization of [123I]FP-CIT binding to the dopamine transporter in the striatum of tree shrews by quantitative in vitro autoradiography |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T07%3A09%3A54IST&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=Characterization%20of%20%5B123I%5DFP-CIT%20binding%20to%20the%20dopamine%20transporter%20in%20the%20striatum%20of%20tree%20shrews%20by%20quantitative%20in%20vitro%20autoradiography&rft.jtitle=Synapse%20(New%20York,%20N.Y.)&rft.au=Geisler,%20Stefanie&rft.date=2015-10&rft.volume=69&rft.issue=10&rft.spage=497&rft.epage=504&rft.pages=497-504&rft.issn=0887-4476&rft.eissn=1098-2396&rft.coden=SYNAET&rft_id=info:doi/10.1002/syn.21838&rft_dat=%3Cproquest_cross%3E3782317091%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=1705392297&rft_id=info:pmid/26126942&rfr_iscdi=true |