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Cardiac Overexpression of the Norepinephrine Transporter Uptake-1 Results in Marked Improvement of Heart Failure
A hyperadrenergic state is one of the key features of human and experimental heart failure. Decreased densities and activities of the presynaptic neuronal norepinephrine (NE) transporter uptake-1 occur both in patients and animal models. It is currently unclear to what extent the reduction of uptake...
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| Published in: | Circulation research 2005-10, Vol.97 (9), p.928-936 |
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| creator | Münch, Götz Rosport, Kai Bültmann, Andreas Baumgartner, Christine Li, Zhongmin Laacke, Lien Ungerer, Martin |
| description | A hyperadrenergic state is one of the key features of human and experimental heart failure. Decreased densities and activities of the presynaptic neuronal norepinephrine (NE) transporter uptake-1 occur both in patients and animal models. It is currently unclear to what extent the reduction of uptake-1 contributes to the deterioration of heart failure. Therefore, we investigated the effects of myocardial overexpression of uptake-1 in both nonfailing rabbit hearts and in an animal model of heart failure. Heart failure was induced in rabbits by rapid ventricular pacing. Adenoviral gene transfer was used to overexpress uptake-1 in the myocardium. Uptake-1 overexpression led to increased NE uptake capacity into the myocardium. In contrast, systemic plasma NE levels in uptake-1-overexpressing failing rabbits (uptake-1–CHF) did not differ from controls. Downregulation of SERCA-2 and β-adrenergic receptors in the failing myocardium was significantly reversed after uptake-1 overexpression. Uptake-1 overexpression significantly improved left ventricular (LV) diameters (LV end-diastolic diameterin GCP-overexpressing failing rabbits (GFP-CHF), 17.4±0.4 mm; in uptake-1–CHF rabbits, 15.6±0.6 mm) and systolic contractility (fractional shorteningGFP-CHF, 20.7±0.6%; uptake-1–CHF, 27.3±0.7%), as assessed by echocardiography at the end of the heart failure protocol. Intraventricular tip catheter measurements revealed enhanced contractile reserve (dP/dt max with isoproterenol 1.0 μg/kgGFP-CHF, 6964±230 mm Hg/sec; uptake-1–CHF, 7660±315 mm Hg/sec) and LV relaxation (dP/dt min with isoproterenol 1.0 μg/kgGFP-CHF−3960±260 mm Hg/sec; uptake-1–CHF, −4910±490 mm Hg/sec). End-diastolic filling pressures (GFP-CHF, 8.5±1.2 mm Hg; uptake-1–CHF, 5.6±0.7 mm Hg) tended to be lower in uptake-1 overexpressing animals. In summary, local overexpression of uptake-1 in the myocardium results in marked structural and functional improvement of heart failure, thus underlining the importance of uptake-1 as a key protein in heart failure. |
| doi_str_mv | 10.1161/01.RES.0000186685.46829.E5 |
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Decreased densities and activities of the presynaptic neuronal norepinephrine (NE) transporter uptake-1 occur both in patients and animal models. It is currently unclear to what extent the reduction of uptake-1 contributes to the deterioration of heart failure. Therefore, we investigated the effects of myocardial overexpression of uptake-1 in both nonfailing rabbit hearts and in an animal model of heart failure. Heart failure was induced in rabbits by rapid ventricular pacing. Adenoviral gene transfer was used to overexpress uptake-1 in the myocardium. Uptake-1 overexpression led to increased NE uptake capacity into the myocardium. In contrast, systemic plasma NE levels in uptake-1-overexpressing failing rabbits (uptake-1–CHF) did not differ from controls. Downregulation of SERCA-2 and β-adrenergic receptors in the failing myocardium was significantly reversed after uptake-1 overexpression. Uptake-1 overexpression significantly improved left ventricular (LV) diameters (LV end-diastolic diameterin GCP-overexpressing failing rabbits (GFP-CHF), 17.4±0.4 mm; in uptake-1–CHF rabbits, 15.6±0.6 mm) and systolic contractility (fractional shorteningGFP-CHF, 20.7±0.6%; uptake-1–CHF, 27.3±0.7%), as assessed by echocardiography at the end of the heart failure protocol. Intraventricular tip catheter measurements revealed enhanced contractile reserve (dP/dt max with isoproterenol 1.0 μg/kgGFP-CHF, 6964±230 mm Hg/sec; uptake-1–CHF, 7660±315 mm Hg/sec) and LV relaxation (dP/dt min with isoproterenol 1.0 μg/kgGFP-CHF−3960±260 mm Hg/sec; uptake-1–CHF, −4910±490 mm Hg/sec). End-diastolic filling pressures (GFP-CHF, 8.5±1.2 mm Hg; uptake-1–CHF, 5.6±0.7 mm Hg) tended to be lower in uptake-1 overexpressing animals. In summary, local overexpression of uptake-1 in the myocardium results in marked structural and functional improvement of heart failure, thus underlining the importance of uptake-1 as a key protein in heart failure.</description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/01.RES.0000186685.46829.E5</identifier><identifier>PMID: 16166553</identifier><identifier>CODEN: CIRUAL</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>Adenoviridae - genetics ; Animals ; Biological and medical sciences ; Cardiology. Vascular system ; Fundamental and applied biological sciences. Psychology ; Genetic Therapy ; Heart ; Heart Failure - physiopathology ; Heart Failure - therapy ; Heart failure, cardiogenic pulmonary edema, cardiac enlargement ; HeLa Cells ; Humans ; Medical sciences ; Myocardial Contraction ; Myocardium - metabolism ; Norepinephrine - metabolism ; Norepinephrine Plasma Membrane Transport Proteins - genetics ; PC12 Cells ; Rabbits ; Rats ; Transgenes ; Ventricular Dysfunction, Left - therapy ; Vertebrates: cardiovascular system ; Weight Gain</subject><ispartof>Circulation research, 2005-10, Vol.97 (9), p.928-936</ispartof><rights>2005 American Heart Association, Inc.</rights><rights>2005 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5252-a8930ec45cc9c7dc1734572b7c041d221ec0dc095516fea8a6cf6197aca9a8653</citedby><cites>FETCH-LOGICAL-c5252-a8930ec45cc9c7dc1734572b7c041d221ec0dc095516fea8a6cf6197aca9a8653</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17255841$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16166553$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Münch, Götz</creatorcontrib><creatorcontrib>Rosport, Kai</creatorcontrib><creatorcontrib>Bültmann, Andreas</creatorcontrib><creatorcontrib>Baumgartner, Christine</creatorcontrib><creatorcontrib>Li, Zhongmin</creatorcontrib><creatorcontrib>Laacke, Lien</creatorcontrib><creatorcontrib>Ungerer, Martin</creatorcontrib><title>Cardiac Overexpression of the Norepinephrine Transporter Uptake-1 Results in Marked Improvement of Heart Failure</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description>A hyperadrenergic state is one of the key features of human and experimental heart failure. Decreased densities and activities of the presynaptic neuronal norepinephrine (NE) transporter uptake-1 occur both in patients and animal models. It is currently unclear to what extent the reduction of uptake-1 contributes to the deterioration of heart failure. Therefore, we investigated the effects of myocardial overexpression of uptake-1 in both nonfailing rabbit hearts and in an animal model of heart failure. Heart failure was induced in rabbits by rapid ventricular pacing. Adenoviral gene transfer was used to overexpress uptake-1 in the myocardium. Uptake-1 overexpression led to increased NE uptake capacity into the myocardium. In contrast, systemic plasma NE levels in uptake-1-overexpressing failing rabbits (uptake-1–CHF) did not differ from controls. Downregulation of SERCA-2 and β-adrenergic receptors in the failing myocardium was significantly reversed after uptake-1 overexpression. Uptake-1 overexpression significantly improved left ventricular (LV) diameters (LV end-diastolic diameterin GCP-overexpressing failing rabbits (GFP-CHF), 17.4±0.4 mm; in uptake-1–CHF rabbits, 15.6±0.6 mm) and systolic contractility (fractional shorteningGFP-CHF, 20.7±0.6%; uptake-1–CHF, 27.3±0.7%), as assessed by echocardiography at the end of the heart failure protocol. Intraventricular tip catheter measurements revealed enhanced contractile reserve (dP/dt max with isoproterenol 1.0 μg/kgGFP-CHF, 6964±230 mm Hg/sec; uptake-1–CHF, 7660±315 mm Hg/sec) and LV relaxation (dP/dt min with isoproterenol 1.0 μg/kgGFP-CHF−3960±260 mm Hg/sec; uptake-1–CHF, −4910±490 mm Hg/sec). End-diastolic filling pressures (GFP-CHF, 8.5±1.2 mm Hg; uptake-1–CHF, 5.6±0.7 mm Hg) tended to be lower in uptake-1 overexpressing animals. In summary, local overexpression of uptake-1 in the myocardium results in marked structural and functional improvement of heart failure, thus underlining the importance of uptake-1 as a key protein in heart failure.</description><subject>Adenoviridae - genetics</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cardiology. Vascular system</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetic Therapy</subject><subject>Heart</subject><subject>Heart Failure - physiopathology</subject><subject>Heart Failure - therapy</subject><subject>Heart failure, cardiogenic pulmonary edema, cardiac enlargement</subject><subject>HeLa Cells</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Myocardial Contraction</subject><subject>Myocardium - metabolism</subject><subject>Norepinephrine - metabolism</subject><subject>Norepinephrine Plasma Membrane Transport Proteins - genetics</subject><subject>PC12 Cells</subject><subject>Rabbits</subject><subject>Rats</subject><subject>Transgenes</subject><subject>Ventricular Dysfunction, Left - therapy</subject><subject>Vertebrates: cardiovascular system</subject><subject>Weight Gain</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><recordid>eNqFkUtv1DAURi0EokPhLyALCXYJfsSPsEOjKa1UqFTatXXr3GjCOA_spIV_j6cz0izxwt4cf_ezDyEfOCs51_wz4-Xt5mfJ8uJWa6vKSltRlxv1gqy4ElVRKcNfklUG6sJIyc7Im5R-ZbySon5NznKK1krJFZnWEJsOPL15xIh_pogpdeNAx5bOW6Q_xohTN-C0jXmndxGGNI1xxkjvpxl2WHB6i2kJc6LdQL9D3GFDr_opjo_Y4zDvgy4R4kwvoAtLxLfkVQsh4bvjeU7uLzZ368vi-ubb1frrdeGVUKIAW0uGvlLe1940nhuZHyUejGcVb4Tg6FnjWa0U1y2CBe1bzWsDHmqwWslz8umQm6v8XjDNru-SxxBgwHFJTlsjhdH2v6BgptbMsAx-OYA-jilFbN0Uux7iX8eZ24txjLssxp3EuGcxbrOv8_44ZXnosTldPZrIwMcjAMlDaPNP-y6dOCOUshXPXHXgnsaQNaRdWJ4wui1CmLfPoyXjohCMKc6EZcW-jJD_AN1Jp0g</recordid><startdate>20051028</startdate><enddate>20051028</enddate><creator>Münch, Götz</creator><creator>Rosport, Kai</creator><creator>Bültmann, Andreas</creator><creator>Baumgartner, Christine</creator><creator>Li, Zhongmin</creator><creator>Laacke, Lien</creator><creator>Ungerer, Martin</creator><general>American Heart Association, Inc</general><general>Lippincott</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>7QP</scope><scope>7X8</scope></search><sort><creationdate>20051028</creationdate><title>Cardiac Overexpression of the Norepinephrine Transporter Uptake-1 Results in Marked Improvement of Heart Failure</title><author>Münch, Götz ; Rosport, Kai ; Bültmann, Andreas ; Baumgartner, Christine ; Li, Zhongmin ; Laacke, Lien ; Ungerer, Martin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5252-a8930ec45cc9c7dc1734572b7c041d221ec0dc095516fea8a6cf6197aca9a8653</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Adenoviridae - genetics</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cardiology. Vascular system</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genetic Therapy</topic><topic>Heart</topic><topic>Heart Failure - physiopathology</topic><topic>Heart Failure - therapy</topic><topic>Heart failure, cardiogenic pulmonary edema, cardiac enlargement</topic><topic>HeLa Cells</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Myocardial Contraction</topic><topic>Myocardium - metabolism</topic><topic>Norepinephrine - metabolism</topic><topic>Norepinephrine Plasma Membrane Transport Proteins - genetics</topic><topic>PC12 Cells</topic><topic>Rabbits</topic><topic>Rats</topic><topic>Transgenes</topic><topic>Ventricular Dysfunction, Left - therapy</topic><topic>Vertebrates: cardiovascular system</topic><topic>Weight Gain</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Münch, Götz</creatorcontrib><creatorcontrib>Rosport, Kai</creatorcontrib><creatorcontrib>Bültmann, Andreas</creatorcontrib><creatorcontrib>Baumgartner, Christine</creatorcontrib><creatorcontrib>Li, Zhongmin</creatorcontrib><creatorcontrib>Laacke, Lien</creatorcontrib><creatorcontrib>Ungerer, Martin</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>Calcium & Calcified Tissue Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Münch, Götz</au><au>Rosport, Kai</au><au>Bültmann, Andreas</au><au>Baumgartner, Christine</au><au>Li, Zhongmin</au><au>Laacke, Lien</au><au>Ungerer, Martin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cardiac Overexpression of the Norepinephrine Transporter Uptake-1 Results in Marked Improvement of Heart Failure</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>2005-10-28</date><risdate>2005</risdate><volume>97</volume><issue>9</issue><spage>928</spage><epage>936</epage><pages>928-936</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><coden>CIRUAL</coden><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>A hyperadrenergic state is one of the key features of human and experimental heart failure. Decreased densities and activities of the presynaptic neuronal norepinephrine (NE) transporter uptake-1 occur both in patients and animal models. It is currently unclear to what extent the reduction of uptake-1 contributes to the deterioration of heart failure. Therefore, we investigated the effects of myocardial overexpression of uptake-1 in both nonfailing rabbit hearts and in an animal model of heart failure. Heart failure was induced in rabbits by rapid ventricular pacing. Adenoviral gene transfer was used to overexpress uptake-1 in the myocardium. Uptake-1 overexpression led to increased NE uptake capacity into the myocardium. In contrast, systemic plasma NE levels in uptake-1-overexpressing failing rabbits (uptake-1–CHF) did not differ from controls. Downregulation of SERCA-2 and β-adrenergic receptors in the failing myocardium was significantly reversed after uptake-1 overexpression. Uptake-1 overexpression significantly improved left ventricular (LV) diameters (LV end-diastolic diameterin GCP-overexpressing failing rabbits (GFP-CHF), 17.4±0.4 mm; in uptake-1–CHF rabbits, 15.6±0.6 mm) and systolic contractility (fractional shorteningGFP-CHF, 20.7±0.6%; uptake-1–CHF, 27.3±0.7%), as assessed by echocardiography at the end of the heart failure protocol. Intraventricular tip catheter measurements revealed enhanced contractile reserve (dP/dt max with isoproterenol 1.0 μg/kgGFP-CHF, 6964±230 mm Hg/sec; uptake-1–CHF, 7660±315 mm Hg/sec) and LV relaxation (dP/dt min with isoproterenol 1.0 μg/kgGFP-CHF−3960±260 mm Hg/sec; uptake-1–CHF, −4910±490 mm Hg/sec). End-diastolic filling pressures (GFP-CHF, 8.5±1.2 mm Hg; uptake-1–CHF, 5.6±0.7 mm Hg) tended to be lower in uptake-1 overexpressing animals. In summary, local overexpression of uptake-1 in the myocardium results in marked structural and functional improvement of heart failure, thus underlining the importance of uptake-1 as a key protein in heart failure.</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>16166553</pmid><doi>10.1161/01.RES.0000186685.46829.E5</doi><tpages>9</tpages></addata></record> |
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| subjects | Adenoviridae - genetics Animals Biological and medical sciences Cardiology. Vascular system Fundamental and applied biological sciences. Psychology Genetic Therapy Heart Heart Failure - physiopathology Heart Failure - therapy Heart failure, cardiogenic pulmonary edema, cardiac enlargement HeLa Cells Humans Medical sciences Myocardial Contraction Myocardium - metabolism Norepinephrine - metabolism Norepinephrine Plasma Membrane Transport Proteins - genetics PC12 Cells Rabbits Rats Transgenes Ventricular Dysfunction, Left - therapy Vertebrates: cardiovascular system Weight Gain |
| title | Cardiac Overexpression of the Norepinephrine Transporter Uptake-1 Results in Marked Improvement of Heart Failure |
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