Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression
Murine hepatic cytochrome P450 2a5 (Cyp2a5) is induced during hepatotoxicity and hepatitis, however, the specific regulatory mechanisms have not been determined. We compared the influence of acute inflammation elicited in vivo by bacterial endotoxin lipopolysaccharide (LPS) and liver injury caused b...
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| Veröffentlicht in: | Toxicology (Amsterdam) 2003-03, Vol.184 (2), p.211-226 |
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| creator | Gilmore, W.James Hartmann, Georgy Piquette-Miller, Micheline Marriott, Jason Kirby, Gordon M |
| description | Murine hepatic cytochrome P450 2a5 (Cyp2a5) is induced during hepatotoxicity and hepatitis, however, the specific regulatory mechanisms have not been determined. We compared the influence of acute inflammation elicited in vivo by bacterial endotoxin lipopolysaccharide (LPS) and liver injury caused by the hepatotoxin pyrazole on hepatic Cyp2a5 expression in mice. Pyrazole treatment resulted in statistically significant increases in levels of Cyp2a5 mRNA, protein and catalytic activity by 540, 273 and 711%, respectively (
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| doi_str_mv | 10.1016/S0300-483X(02)00581-4 |
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P<0.05). In LPS-treated livers Cyp2a5 expression was significantly reduced compared to controls at the mRNA (46%) protein (35%), and activity (23%) levels (
P<0.05). Treatment of mice with recombinant murine interleukin-1 beta and interleukin-6 had no significant effect on Cyp2a5 mRNA and protein levels. Liver injury, as assessed by serum alanine aminotransferase, was greater with pyrazole than with LPS treatment (609 vs 354% of control levels respectively). ER stress, determined by hepatic glucose regulated protein 78 (grp78) levels, was greater with pyrazole (185% of controls) than with LPS (128% of controls). In pyrazole-treated liver, overexpression of immunoreactive grp78 protein revealed that ER stress was localized to pericentral hepatocytes in which Cyp2a5 was induced. Evidence of glycogen loss and membrane damage in these cells was suggestive of oxidative damage. Moreover, vitamin E attenuated Cyp2a5 induction by pyrazole in vivo. These results suggest that induction of Cyp2a5 that has been observed in mouse models of hepatitis and hepatoxicity may be related to oxidative injury to the endoplasmic reticulum of pericentral hepatocytes rather than exposure to pro-inflammatory cytokines.</description><identifier>ISSN: 0300-483X</identifier><identifier>EISSN: 1879-3185</identifier><identifier>DOI: 10.1016/S0300-483X(02)00581-4</identifier><identifier>PMID: 12499123</identifier><identifier>CODEN: TXICDD</identifier><language>eng</language><publisher>Shannon: Elsevier Ireland Ltd</publisher><subject>Alanine Transaminase - blood ; Amyloid beta-Peptides - metabolism ; Analytical, structural and metabolic biochemistry ; Animals ; Aryl Hydrocarbon Hydroxylases - metabolism ; Biological and medical sciences ; Blotting, Northern ; Blotting, Western ; Carrier Proteins - metabolism ; Cell injury ; Chemical and Drug Induced Liver Injury - enzymology ; Chemical and Drug Induced Liver Injury - pathology ; Cytochrome P-450 CYP2A6 ; Cytochrome P450 ; Cytochrome P450 Family 2 ; Cytokines ; Cytokines - metabolism ; Enzymes and enzyme inhibitors ; Fundamental and applied biological sciences. Psychology ; Gastroenterology. Liver. Pancreas. Abdomen ; Heat-Shock Proteins ; Hepatocytes - drug effects ; Hepatocytes - enzymology ; Hepatocytes - ultrastructure ; Immunohistochemistry ; Inflammation - chemically induced ; Inflammation - enzymology ; Interleukin-1 - pharmacology ; Interleukin-6 - pharmacology ; Lipopolysaccharide ; Lipopolysaccharides - pharmacology ; Liver - drug effects ; Liver - enzymology ; Liver - pathology ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Male ; Medical sciences ; Mice ; Mice, Inbred DBA ; Microscopy, Electron ; Mixed Function Oxygenases - metabolism ; Molecular Chaperones - metabolism ; Other diseases. Semiology ; Oxidoreductases ; Pyrazoles - toxicity ; Regulation</subject><ispartof>Toxicology (Amsterdam), 2003-03, Vol.184 (2), p.211-226</ispartof><rights>2002 Elsevier Science Ireland Ltd</rights><rights>2003 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c519t-7f6812a1f339ac2d77d0e0927ea9cc02faac4ef827114e4255035ca4358522653</citedby><cites>FETCH-LOGICAL-c519t-7f6812a1f339ac2d77d0e0927ea9cc02faac4ef827114e4255035ca4358522653</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0300-483X(02)00581-4$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=14471091$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12499123$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gilmore, W.James</creatorcontrib><creatorcontrib>Hartmann, Georgy</creatorcontrib><creatorcontrib>Piquette-Miller, Micheline</creatorcontrib><creatorcontrib>Marriott, Jason</creatorcontrib><creatorcontrib>Kirby, Gordon M</creatorcontrib><title>Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression</title><title>Toxicology (Amsterdam)</title><addtitle>Toxicology</addtitle><description>Murine hepatic cytochrome P450 2a5 (Cyp2a5) is induced during hepatotoxicity and hepatitis, however, the specific regulatory mechanisms have not been determined. We compared the influence of acute inflammation elicited in vivo by bacterial endotoxin lipopolysaccharide (LPS) and liver injury caused by the hepatotoxin pyrazole on hepatic Cyp2a5 expression in mice. Pyrazole treatment resulted in statistically significant increases in levels of Cyp2a5 mRNA, protein and catalytic activity by 540, 273 and 711%, respectively (
P<0.05). In LPS-treated livers Cyp2a5 expression was significantly reduced compared to controls at the mRNA (46%) protein (35%), and activity (23%) levels (
P<0.05). Treatment of mice with recombinant murine interleukin-1 beta and interleukin-6 had no significant effect on Cyp2a5 mRNA and protein levels. Liver injury, as assessed by serum alanine aminotransferase, was greater with pyrazole than with LPS treatment (609 vs 354% of control levels respectively). ER stress, determined by hepatic glucose regulated protein 78 (grp78) levels, was greater with pyrazole (185% of controls) than with LPS (128% of controls). In pyrazole-treated liver, overexpression of immunoreactive grp78 protein revealed that ER stress was localized to pericentral hepatocytes in which Cyp2a5 was induced. Evidence of glycogen loss and membrane damage in these cells was suggestive of oxidative damage. Moreover, vitamin E attenuated Cyp2a5 induction by pyrazole in vivo. These results suggest that induction of Cyp2a5 that has been observed in mouse models of hepatitis and hepatoxicity may be related to oxidative injury to the endoplasmic reticulum of pericentral hepatocytes rather than exposure to pro-inflammatory cytokines.</description><subject>Alanine Transaminase - blood</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Animals</subject><subject>Aryl Hydrocarbon Hydroxylases - metabolism</subject><subject>Biological and medical sciences</subject><subject>Blotting, Northern</subject><subject>Blotting, Western</subject><subject>Carrier Proteins - metabolism</subject><subject>Cell injury</subject><subject>Chemical and Drug Induced Liver Injury - enzymology</subject><subject>Chemical and Drug Induced Liver Injury - pathology</subject><subject>Cytochrome P-450 CYP2A6</subject><subject>Cytochrome P450</subject><subject>Cytochrome P450 Family 2</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Enzymes and enzyme inhibitors</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Heat-Shock Proteins</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - enzymology</subject><subject>Hepatocytes - ultrastructure</subject><subject>Immunohistochemistry</subject><subject>Inflammation - chemically induced</subject><subject>Inflammation - enzymology</subject><subject>Interleukin-1 - pharmacology</subject><subject>Interleukin-6 - pharmacology</subject><subject>Lipopolysaccharide</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Liver - drug effects</subject><subject>Liver - enzymology</subject><subject>Liver - pathology</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred DBA</subject><subject>Microscopy, Electron</subject><subject>Mixed Function Oxygenases - metabolism</subject><subject>Molecular Chaperones - metabolism</subject><subject>Other diseases. Semiology</subject><subject>Oxidoreductases</subject><subject>Pyrazoles - toxicity</subject><subject>Regulation</subject><issn>0300-483X</issn><issn>1879-3185</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtv1TAQRi1ERW8LPwGUDQgWKeNXHiuErspDqtRFQWJnDc5YdZXEwU4qwpofju9DdNmVF3O-8ac5jL3kcMGBV-9vQAKUqpE_3oJ4B6AbXqonbMObui0lb_RTtvmPnLKzlO4AQEhVPWOnXKi25UJu2N9L58jOqQiu6P0UptCvCa29xeg7KtPsh6XHmbrCj67HYcDZh7HAsSumNeKf0FM5UOf3yC1NOAdLfZ8zMSfulrgWGR_Ckugw9rbYrpNAXdDvKVJKed1zduKwT_Ti-J6z758uv22_lFfXn79uP16VVvN2LmtXNVwgd1K2aEVX1x0QtKImbK0F4RCtIteImnNFSmgNUltUUjdaiErLc_bmsHeK4ddCaTaDT7u6OFJuaHhT1RxAPg6qSjVQQwb1AbQxpBTJmSn6AeNqOJidJ7P3ZHYSDAiz92RUzr06frD8zOd7SB3FZOD1EcBksXcRR-vTA6dUbtryzH04cJTvdu8pmmQ9jTYridmr6YJ_pMo_l1Gx_A</recordid><startdate>20030303</startdate><enddate>20030303</enddate><creator>Gilmore, W.James</creator><creator>Hartmann, Georgy</creator><creator>Piquette-Miller, Micheline</creator><creator>Marriott, Jason</creator><creator>Kirby, Gordon M</creator><general>Elsevier Ireland Ltd</general><general>Elsevier Science</general><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>7ST</scope><scope>C1K</scope><scope>SOI</scope><scope>7U7</scope></search><sort><creationdate>20030303</creationdate><title>Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression</title><author>Gilmore, W.James ; Hartmann, Georgy ; Piquette-Miller, Micheline ; Marriott, Jason ; Kirby, Gordon M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c519t-7f6812a1f339ac2d77d0e0927ea9cc02faac4ef827114e4255035ca4358522653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2003</creationdate><topic>Alanine Transaminase - blood</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Analytical, structural and metabolic biochemistry</topic><topic>Animals</topic><topic>Aryl Hydrocarbon Hydroxylases - metabolism</topic><topic>Biological and medical sciences</topic><topic>Blotting, Northern</topic><topic>Blotting, Western</topic><topic>Carrier Proteins - metabolism</topic><topic>Cell injury</topic><topic>Chemical and Drug Induced Liver Injury - enzymology</topic><topic>Chemical and Drug Induced Liver Injury - pathology</topic><topic>Cytochrome P-450 CYP2A6</topic><topic>Cytochrome P450</topic><topic>Cytochrome P450 Family 2</topic><topic>Cytokines</topic><topic>Cytokines - metabolism</topic><topic>Enzymes and enzyme inhibitors</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Heat-Shock Proteins</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - enzymology</topic><topic>Hepatocytes - ultrastructure</topic><topic>Immunohistochemistry</topic><topic>Inflammation - chemically induced</topic><topic>Inflammation - enzymology</topic><topic>Interleukin-1 - pharmacology</topic><topic>Interleukin-6 - pharmacology</topic><topic>Lipopolysaccharide</topic><topic>Lipopolysaccharides - pharmacology</topic><topic>Liver - drug effects</topic><topic>Liver - enzymology</topic><topic>Liver - pathology</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred DBA</topic><topic>Microscopy, Electron</topic><topic>Mixed Function Oxygenases - metabolism</topic><topic>Molecular Chaperones - metabolism</topic><topic>Other diseases. Semiology</topic><topic>Oxidoreductases</topic><topic>Pyrazoles - toxicity</topic><topic>Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gilmore, W.James</creatorcontrib><creatorcontrib>Hartmann, Georgy</creatorcontrib><creatorcontrib>Piquette-Miller, Micheline</creatorcontrib><creatorcontrib>Marriott, Jason</creatorcontrib><creatorcontrib>Kirby, Gordon M</creatorcontrib><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>Environment Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Environment Abstracts</collection><collection>Toxicology Abstracts</collection><jtitle>Toxicology (Amsterdam)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gilmore, W.James</au><au>Hartmann, Georgy</au><au>Piquette-Miller, Micheline</au><au>Marriott, Jason</au><au>Kirby, Gordon M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression</atitle><jtitle>Toxicology (Amsterdam)</jtitle><addtitle>Toxicology</addtitle><date>2003-03-03</date><risdate>2003</risdate><volume>184</volume><issue>2</issue><spage>211</spage><epage>226</epage><pages>211-226</pages><issn>0300-483X</issn><eissn>1879-3185</eissn><coden>TXICDD</coden><abstract>Murine hepatic cytochrome P450 2a5 (Cyp2a5) is induced during hepatotoxicity and hepatitis, however, the specific regulatory mechanisms have not been determined. We compared the influence of acute inflammation elicited in vivo by bacterial endotoxin lipopolysaccharide (LPS) and liver injury caused by the hepatotoxin pyrazole on hepatic Cyp2a5 expression in mice. Pyrazole treatment resulted in statistically significant increases in levels of Cyp2a5 mRNA, protein and catalytic activity by 540, 273 and 711%, respectively (
P<0.05). In LPS-treated livers Cyp2a5 expression was significantly reduced compared to controls at the mRNA (46%) protein (35%), and activity (23%) levels (
P<0.05). Treatment of mice with recombinant murine interleukin-1 beta and interleukin-6 had no significant effect on Cyp2a5 mRNA and protein levels. Liver injury, as assessed by serum alanine aminotransferase, was greater with pyrazole than with LPS treatment (609 vs 354% of control levels respectively). ER stress, determined by hepatic glucose regulated protein 78 (grp78) levels, was greater with pyrazole (185% of controls) than with LPS (128% of controls). In pyrazole-treated liver, overexpression of immunoreactive grp78 protein revealed that ER stress was localized to pericentral hepatocytes in which Cyp2a5 was induced. Evidence of glycogen loss and membrane damage in these cells was suggestive of oxidative damage. Moreover, vitamin E attenuated Cyp2a5 induction by pyrazole in vivo. These results suggest that induction of Cyp2a5 that has been observed in mouse models of hepatitis and hepatoxicity may be related to oxidative injury to the endoplasmic reticulum of pericentral hepatocytes rather than exposure to pro-inflammatory cytokines.</abstract><cop>Shannon</cop><cop>Amsterdam</cop><pub>Elsevier Ireland Ltd</pub><pmid>12499123</pmid><doi>10.1016/S0300-483X(02)00581-4</doi><tpages>16</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Toxicology (Amsterdam), 2003-03, Vol.184 (2), p.211-226 |
| issn | 0300-483X 1879-3185 |
| language | eng |
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| subjects | Alanine Transaminase - blood Amyloid beta-Peptides - metabolism Analytical, structural and metabolic biochemistry Animals Aryl Hydrocarbon Hydroxylases - metabolism Biological and medical sciences Blotting, Northern Blotting, Western Carrier Proteins - metabolism Cell injury Chemical and Drug Induced Liver Injury - enzymology Chemical and Drug Induced Liver Injury - pathology Cytochrome P-450 CYP2A6 Cytochrome P450 Cytochrome P450 Family 2 Cytokines Cytokines - metabolism Enzymes and enzyme inhibitors Fundamental and applied biological sciences. Psychology Gastroenterology. Liver. Pancreas. Abdomen Heat-Shock Proteins Hepatocytes - drug effects Hepatocytes - enzymology Hepatocytes - ultrastructure Immunohistochemistry Inflammation - chemically induced Inflammation - enzymology Interleukin-1 - pharmacology Interleukin-6 - pharmacology Lipopolysaccharide Lipopolysaccharides - pharmacology Liver - drug effects Liver - enzymology Liver - pathology Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences Mice Mice, Inbred DBA Microscopy, Electron Mixed Function Oxygenases - metabolism Molecular Chaperones - metabolism Other diseases. Semiology Oxidoreductases Pyrazoles - toxicity Regulation |
| title | Effects of lipopolysaccharide-stimulated inflammation and pyrazole-mediated hepatocellular injury on mouse hepatic Cyp2a5 expression |
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