Differential regulation of glucose transporter 1 and 2 mRNA expression by epidermal growth factor and transforming growth factor-beta in rat hepatocytes

We have examined by Northern blot analysis the expression of two members of the glucose transporter family of genes (GLUT‐1 and GLUT‐2) in regenerating liver and in hepatocytes cultured under various conditions. GLUT‐1, although thought to be a growth‐associated gene, is not expressed in normal or r...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of cellular physiology 1992-11, Vol.153 (2), p.288-296
Hauptverfasser: Mischoulon, David, Rana, Basabi, Kotliar, Natalio, Pilch, Paul F., Bucher, Nancy L. R., Farmer, Stephen R.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 296
container_issue 2
container_start_page 288
container_title Journal of cellular physiology
container_volume 153
creator Mischoulon, David
Rana, Basabi
Kotliar, Natalio
Pilch, Paul F.
Bucher, Nancy L. R.
Farmer, Stephen R.
description We have examined by Northern blot analysis the expression of two members of the glucose transporter family of genes (GLUT‐1 and GLUT‐2) in regenerating liver and in hepatocytes cultured under various conditions. GLUT‐1, although thought to be a growth‐associated gene, is not expressed in normal or regenerating liver, whereas GLUT‐2, a liver‐specific gene, is abundant in normal liver and gradually up‐regulated during liver regeneration. Conversely, in hepatocytes cultured conventionally on dried rat tail collagen (RTC) in the presence of EGF and insulin, which potentiate proliferation, GLUT‐1 mRNA is rapidly and abundantly expressed, whereas GLUT‐2 is depressed. To investigate the causes of this “switch” in glucose transporter expression seen when hepatocytes are removed from the liver and cultured under the conventional proliferative conditions, we examined the effects of specific growth factors and extracellular matrices on cultured hepatocytes. EGF, a potent liver mitogen, although causing a threefold induction of GLUT‐1, was found to have no effect on GLUT‐2 expression, suggesting that the increase in GLUT‐2 seen in regenerating liver is not due to EGF. Inhibition of protein synthesis by cycloheximide in cultured hepatocytes does not prevent the induction of GLUT‐1 mRNA. In addition, treatment of cells with cycloheximide appears to stabilize the GLUT‐2 mRNA, preventing the usual down‐regulation of this gene in cultured hepatocvtes. The expression of the two glucose transporter mRNAs also differed when the hepatocytes were adherent to particular cell matrices. Culture of hepatocytes on a reconstituted basement membrane gel matrix (EHS) is known to restrain their growth and mediate high levels of differentiated hepatocytic functions that are lost under conventional culture conditions. Unlike cells on RTC, hepatocytes on EHS expressed low levels of GLUT‐1 mRNA, and decreased GLUT‐2 mRNA. TGF‐β, an attenuator of DNA synthesis, when added to cultures on RTC, substantially down‐regulated GLUT‐2 but had no effect on GLUT‐1. We propose that the effectors, EGF, TGF‐β and basement membrane components, play a significant role in the regulation of expression of GLUT‐1 and GLUT‐2 in hepatocytes. © 1992 Wiley‐Liss, Inc.
doi_str_mv 10.1002/jcp.1041530208
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_73298521</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>73298521</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3228-36c33d9a914e88a7d6ae440b70893748670f77d605a137f13e08d44b9280182d3</originalsourceid><addsrcrecordid>eNqFkc1u1DAUhSMEKkNhyw7JC8QuxX-J7WUZYAqqBjQCsbQc52bqksTB9qidN-nj1m1GrbpiZcvnO-da9xTFW4JPCMb046Wd8oWTimGK5bNiQbASJa8r-rxYZICUquLkZfEqxkuMsVKMHRVHhFMluVoUN59d10GAMTnTowDbXW-S8yPyHdr2O-sjoBTMGCcfEgREkBlbRNGwWZ8iuJ4CxHiHN3sEk2shDDlmG_xVukCdscmHe8N9ROfD4MbtU7lsIBnkRhRMQhcwmeTtPkF8XbzoTB_hzeE8Ln5__fJreVae_1h9W56el5ZRKktWW8ZaZRThIKURbW2Ac9wILBUTXNYCdyK_4soQJjrCAMuW80ZRiYmkLTsuPsy5U_D_dhCTHly00PdmBL-LWrC8qYqSDJ7MoA0-xgCdnoIbTNhrgvVdFTpXoR-ryIZ3h-RdM0D7iM-7z_r7g26iNX2XV2RdfMA4l1jKKmNqxq5cD_v_DNXflz-ffKGcvS4muH7wmvBX14KJSv9ZrzRZf1qdsQ3TG3YLWJWycA</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>73298521</pqid></control><display><type>article</type><title>Differential regulation of glucose transporter 1 and 2 mRNA expression by epidermal growth factor and transforming growth factor-beta in rat hepatocytes</title><source>MEDLINE</source><source>Access via Wiley Online Library</source><creator>Mischoulon, David ; Rana, Basabi ; Kotliar, Natalio ; Pilch, Paul F. ; Bucher, Nancy L. R. ; Farmer, Stephen R.</creator><creatorcontrib>Mischoulon, David ; Rana, Basabi ; Kotliar, Natalio ; Pilch, Paul F. ; Bucher, Nancy L. R. ; Farmer, Stephen R.</creatorcontrib><description>We have examined by Northern blot analysis the expression of two members of the glucose transporter family of genes (GLUT‐1 and GLUT‐2) in regenerating liver and in hepatocytes cultured under various conditions. GLUT‐1, although thought to be a growth‐associated gene, is not expressed in normal or regenerating liver, whereas GLUT‐2, a liver‐specific gene, is abundant in normal liver and gradually up‐regulated during liver regeneration. Conversely, in hepatocytes cultured conventionally on dried rat tail collagen (RTC) in the presence of EGF and insulin, which potentiate proliferation, GLUT‐1 mRNA is rapidly and abundantly expressed, whereas GLUT‐2 is depressed. To investigate the causes of this “switch” in glucose transporter expression seen when hepatocytes are removed from the liver and cultured under the conventional proliferative conditions, we examined the effects of specific growth factors and extracellular matrices on cultured hepatocytes. EGF, a potent liver mitogen, although causing a threefold induction of GLUT‐1, was found to have no effect on GLUT‐2 expression, suggesting that the increase in GLUT‐2 seen in regenerating liver is not due to EGF. Inhibition of protein synthesis by cycloheximide in cultured hepatocytes does not prevent the induction of GLUT‐1 mRNA. In addition, treatment of cells with cycloheximide appears to stabilize the GLUT‐2 mRNA, preventing the usual down‐regulation of this gene in cultured hepatocvtes. The expression of the two glucose transporter mRNAs also differed when the hepatocytes were adherent to particular cell matrices. Culture of hepatocytes on a reconstituted basement membrane gel matrix (EHS) is known to restrain their growth and mediate high levels of differentiated hepatocytic functions that are lost under conventional culture conditions. Unlike cells on RTC, hepatocytes on EHS expressed low levels of GLUT‐1 mRNA, and decreased GLUT‐2 mRNA. TGF‐β, an attenuator of DNA synthesis, when added to cultures on RTC, substantially down‐regulated GLUT‐2 but had no effect on GLUT‐1. We propose that the effectors, EGF, TGF‐β and basement membrane components, play a significant role in the regulation of expression of GLUT‐1 and GLUT‐2 in hepatocytes. © 1992 Wiley‐Liss, Inc.</description><identifier>ISSN: 0021-9541</identifier><identifier>EISSN: 1097-4652</identifier><identifier>DOI: 10.1002/jcp.1041530208</identifier><identifier>PMID: 1429849</identifier><identifier>CODEN: JCLLAX</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Animals ; Basement Membrane ; Biological and medical sciences ; Cell Adhesion - physiology ; Cell physiology ; Cells, Cultured ; Epidermal Growth Factor - pharmacology ; Fundamental and applied biological sciences. Psychology ; Gels ; Glucose Transporter Type 1 ; Hepatectomy - methods ; Liver - cytology ; Liver - metabolism ; Male ; Membrane and intracellular transports ; Molecular and cellular biology ; Monosaccharide Transport Proteins - genetics ; Rats ; Rats, Sprague-Dawley ; RNA, Messenger - antagonists &amp; inhibitors ; RNA, Messenger - metabolism ; Transforming Growth Factor beta - pharmacology ; Transforming Growth Factors - pharmacology</subject><ispartof>Journal of cellular physiology, 1992-11, Vol.153 (2), p.288-296</ispartof><rights>Copyright © 1992 Wiley‐Liss, Inc.</rights><rights>1993 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3228-36c33d9a914e88a7d6ae440b70893748670f77d605a137f13e08d44b9280182d3</citedby><cites>FETCH-LOGICAL-c3228-36c33d9a914e88a7d6ae440b70893748670f77d605a137f13e08d44b9280182d3</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%2Fjcp.1041530208$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjcp.1041530208$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=4480885$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1429849$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mischoulon, David</creatorcontrib><creatorcontrib>Rana, Basabi</creatorcontrib><creatorcontrib>Kotliar, Natalio</creatorcontrib><creatorcontrib>Pilch, Paul F.</creatorcontrib><creatorcontrib>Bucher, Nancy L. R.</creatorcontrib><creatorcontrib>Farmer, Stephen R.</creatorcontrib><title>Differential regulation of glucose transporter 1 and 2 mRNA expression by epidermal growth factor and transforming growth factor-beta in rat hepatocytes</title><title>Journal of cellular physiology</title><addtitle>J. Cell. Physiol</addtitle><description>We have examined by Northern blot analysis the expression of two members of the glucose transporter family of genes (GLUT‐1 and GLUT‐2) in regenerating liver and in hepatocytes cultured under various conditions. GLUT‐1, although thought to be a growth‐associated gene, is not expressed in normal or regenerating liver, whereas GLUT‐2, a liver‐specific gene, is abundant in normal liver and gradually up‐regulated during liver regeneration. Conversely, in hepatocytes cultured conventionally on dried rat tail collagen (RTC) in the presence of EGF and insulin, which potentiate proliferation, GLUT‐1 mRNA is rapidly and abundantly expressed, whereas GLUT‐2 is depressed. To investigate the causes of this “switch” in glucose transporter expression seen when hepatocytes are removed from the liver and cultured under the conventional proliferative conditions, we examined the effects of specific growth factors and extracellular matrices on cultured hepatocytes. EGF, a potent liver mitogen, although causing a threefold induction of GLUT‐1, was found to have no effect on GLUT‐2 expression, suggesting that the increase in GLUT‐2 seen in regenerating liver is not due to EGF. Inhibition of protein synthesis by cycloheximide in cultured hepatocytes does not prevent the induction of GLUT‐1 mRNA. In addition, treatment of cells with cycloheximide appears to stabilize the GLUT‐2 mRNA, preventing the usual down‐regulation of this gene in cultured hepatocvtes. The expression of the two glucose transporter mRNAs also differed when the hepatocytes were adherent to particular cell matrices. Culture of hepatocytes on a reconstituted basement membrane gel matrix (EHS) is known to restrain their growth and mediate high levels of differentiated hepatocytic functions that are lost under conventional culture conditions. Unlike cells on RTC, hepatocytes on EHS expressed low levels of GLUT‐1 mRNA, and decreased GLUT‐2 mRNA. TGF‐β, an attenuator of DNA synthesis, when added to cultures on RTC, substantially down‐regulated GLUT‐2 but had no effect on GLUT‐1. We propose that the effectors, EGF, TGF‐β and basement membrane components, play a significant role in the regulation of expression of GLUT‐1 and GLUT‐2 in hepatocytes. © 1992 Wiley‐Liss, Inc.</description><subject>Animals</subject><subject>Basement Membrane</subject><subject>Biological and medical sciences</subject><subject>Cell Adhesion - physiology</subject><subject>Cell physiology</subject><subject>Cells, Cultured</subject><subject>Epidermal Growth Factor - pharmacology</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gels</subject><subject>Glucose Transporter Type 1</subject><subject>Hepatectomy - methods</subject><subject>Liver - cytology</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Membrane and intracellular transports</subject><subject>Molecular and cellular biology</subject><subject>Monosaccharide Transport Proteins - genetics</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>RNA, Messenger - antagonists &amp; inhibitors</subject><subject>RNA, Messenger - metabolism</subject><subject>Transforming Growth Factor beta - pharmacology</subject><subject>Transforming Growth Factors - pharmacology</subject><issn>0021-9541</issn><issn>1097-4652</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1992</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1u1DAUhSMEKkNhyw7JC8QuxX-J7WUZYAqqBjQCsbQc52bqksTB9qidN-nj1m1GrbpiZcvnO-da9xTFW4JPCMb046Wd8oWTimGK5bNiQbASJa8r-rxYZICUquLkZfEqxkuMsVKMHRVHhFMluVoUN59d10GAMTnTowDbXW-S8yPyHdr2O-sjoBTMGCcfEgREkBlbRNGwWZ8iuJ4CxHiHN3sEk2shDDlmG_xVukCdscmHe8N9ROfD4MbtU7lsIBnkRhRMQhcwmeTtPkF8XbzoTB_hzeE8Ln5__fJreVae_1h9W56el5ZRKktWW8ZaZRThIKURbW2Ac9wILBUTXNYCdyK_4soQJjrCAMuW80ZRiYmkLTsuPsy5U_D_dhCTHly00PdmBL-LWrC8qYqSDJ7MoA0-xgCdnoIbTNhrgvVdFTpXoR-ryIZ3h-RdM0D7iM-7z_r7g26iNX2XV2RdfMA4l1jKKmNqxq5cD_v_DNXflz-ffKGcvS4muH7wmvBX14KJSv9ZrzRZf1qdsQ3TG3YLWJWycA</recordid><startdate>199211</startdate><enddate>199211</enddate><creator>Mischoulon, David</creator><creator>Rana, Basabi</creator><creator>Kotliar, Natalio</creator><creator>Pilch, Paul F.</creator><creator>Bucher, Nancy L. R.</creator><creator>Farmer, Stephen R.</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley-Liss</general><scope>BSCLL</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></search><sort><creationdate>199211</creationdate><title>Differential regulation of glucose transporter 1 and 2 mRNA expression by epidermal growth factor and transforming growth factor-beta in rat hepatocytes</title><author>Mischoulon, David ; Rana, Basabi ; Kotliar, Natalio ; Pilch, Paul F. ; Bucher, Nancy L. R. ; Farmer, Stephen R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3228-36c33d9a914e88a7d6ae440b70893748670f77d605a137f13e08d44b9280182d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1992</creationdate><topic>Animals</topic><topic>Basement Membrane</topic><topic>Biological and medical sciences</topic><topic>Cell Adhesion - physiology</topic><topic>Cell physiology</topic><topic>Cells, Cultured</topic><topic>Epidermal Growth Factor - pharmacology</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gels</topic><topic>Glucose Transporter Type 1</topic><topic>Hepatectomy - methods</topic><topic>Liver - cytology</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Membrane and intracellular transports</topic><topic>Molecular and cellular biology</topic><topic>Monosaccharide Transport Proteins - genetics</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>RNA, Messenger - antagonists &amp; inhibitors</topic><topic>RNA, Messenger - metabolism</topic><topic>Transforming Growth Factor beta - pharmacology</topic><topic>Transforming Growth Factors - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mischoulon, David</creatorcontrib><creatorcontrib>Rana, Basabi</creatorcontrib><creatorcontrib>Kotliar, Natalio</creatorcontrib><creatorcontrib>Pilch, Paul F.</creatorcontrib><creatorcontrib>Bucher, Nancy L. R.</creatorcontrib><creatorcontrib>Farmer, Stephen R.</creatorcontrib><collection>Istex</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><jtitle>Journal of cellular physiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mischoulon, David</au><au>Rana, Basabi</au><au>Kotliar, Natalio</au><au>Pilch, Paul F.</au><au>Bucher, Nancy L. R.</au><au>Farmer, Stephen R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Differential regulation of glucose transporter 1 and 2 mRNA expression by epidermal growth factor and transforming growth factor-beta in rat hepatocytes</atitle><jtitle>Journal of cellular physiology</jtitle><addtitle>J. Cell. Physiol</addtitle><date>1992-11</date><risdate>1992</risdate><volume>153</volume><issue>2</issue><spage>288</spage><epage>296</epage><pages>288-296</pages><issn>0021-9541</issn><eissn>1097-4652</eissn><coden>JCLLAX</coden><abstract>We have examined by Northern blot analysis the expression of two members of the glucose transporter family of genes (GLUT‐1 and GLUT‐2) in regenerating liver and in hepatocytes cultured under various conditions. GLUT‐1, although thought to be a growth‐associated gene, is not expressed in normal or regenerating liver, whereas GLUT‐2, a liver‐specific gene, is abundant in normal liver and gradually up‐regulated during liver regeneration. Conversely, in hepatocytes cultured conventionally on dried rat tail collagen (RTC) in the presence of EGF and insulin, which potentiate proliferation, GLUT‐1 mRNA is rapidly and abundantly expressed, whereas GLUT‐2 is depressed. To investigate the causes of this “switch” in glucose transporter expression seen when hepatocytes are removed from the liver and cultured under the conventional proliferative conditions, we examined the effects of specific growth factors and extracellular matrices on cultured hepatocytes. EGF, a potent liver mitogen, although causing a threefold induction of GLUT‐1, was found to have no effect on GLUT‐2 expression, suggesting that the increase in GLUT‐2 seen in regenerating liver is not due to EGF. Inhibition of protein synthesis by cycloheximide in cultured hepatocytes does not prevent the induction of GLUT‐1 mRNA. In addition, treatment of cells with cycloheximide appears to stabilize the GLUT‐2 mRNA, preventing the usual down‐regulation of this gene in cultured hepatocvtes. The expression of the two glucose transporter mRNAs also differed when the hepatocytes were adherent to particular cell matrices. Culture of hepatocytes on a reconstituted basement membrane gel matrix (EHS) is known to restrain their growth and mediate high levels of differentiated hepatocytic functions that are lost under conventional culture conditions. Unlike cells on RTC, hepatocytes on EHS expressed low levels of GLUT‐1 mRNA, and decreased GLUT‐2 mRNA. TGF‐β, an attenuator of DNA synthesis, when added to cultures on RTC, substantially down‐regulated GLUT‐2 but had no effect on GLUT‐1. We propose that the effectors, EGF, TGF‐β and basement membrane components, play a significant role in the regulation of expression of GLUT‐1 and GLUT‐2 in hepatocytes. © 1992 Wiley‐Liss, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>1429849</pmid><doi>10.1002/jcp.1041530208</doi><tpages>9</tpages></addata></record>
fulltext fulltext
identifier ISSN: 0021-9541
ispartof Journal of cellular physiology, 1992-11, Vol.153 (2), p.288-296
issn 0021-9541
1097-4652
language eng
recordid cdi_proquest_miscellaneous_73298521
source MEDLINE; Access via Wiley Online Library
subjects Animals
Basement Membrane
Biological and medical sciences
Cell Adhesion - physiology
Cell physiology
Cells, Cultured
Epidermal Growth Factor - pharmacology
Fundamental and applied biological sciences. Psychology
Gels
Glucose Transporter Type 1
Hepatectomy - methods
Liver - cytology
Liver - metabolism
Male
Membrane and intracellular transports
Molecular and cellular biology
Monosaccharide Transport Proteins - genetics
Rats
Rats, Sprague-Dawley
RNA, Messenger - antagonists & inhibitors
RNA, Messenger - metabolism
Transforming Growth Factor beta - pharmacology
Transforming Growth Factors - pharmacology
title Differential regulation of glucose transporter 1 and 2 mRNA expression by epidermal growth factor and transforming growth factor-beta in rat hepatocytes
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T04%3A18%3A45IST&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=Differential%20regulation%20of%20glucose%20transporter%201%20and%202%20mRNA%20expression%20by%20epidermal%20growth%20factor%20and%20transforming%20growth%20factor-beta%20in%20rat%20hepatocytes&rft.jtitle=Journal%20of%20cellular%20physiology&rft.au=Mischoulon,%20David&rft.date=1992-11&rft.volume=153&rft.issue=2&rft.spage=288&rft.epage=296&rft.pages=288-296&rft.issn=0021-9541&rft.eissn=1097-4652&rft.coden=JCLLAX&rft_id=info:doi/10.1002/jcp.1041530208&rft_dat=%3Cproquest_cross%3E73298521%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=73298521&rft_id=info:pmid/1429849&rfr_iscdi=true