Pravastatin Improves Function in Hibernating Myocardium by Mobilizing CD133+ and cKit+ Bone Marrow Progenitor Cells and Promoting Myocytes to Reenter the Growth Phase of the Cardiac Cell Cycle
3-Hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors have been reported to increase circulating bone marrow progenitor cells and variably improve global function in heart failure. The potential role of improved perfusion versus direct effects of statins on cardiac myocytes has not been establ...
Gespeichert in:
| Veröffentlicht in: | Circulation research 2009-01, Vol.104 (2), p.255-264 |
|---|---|
| Hauptverfasser: | , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 264 |
|---|---|
| container_issue | 2 |
| container_start_page | 255 |
| container_title | Circulation research |
| container_volume | 104 |
| creator | Suzuki, Gen Iyer, Vijay Cimato, Thomas Canty, John M |
| description | 3-Hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors have been reported to increase circulating bone marrow progenitor cells and variably improve global function in heart failure. The potential role of improved perfusion versus direct effects of statins on cardiac myocytes has not been established. We chronically instrumented swine with a left anterior descending artery (LAD) stenosis to produce chronic hibernating myocardium with regional contractile dysfunction in the absence of heart failure. Hemodynamics, function, perfusion, and histopathology were assessed in pigs treated for 5 weeks with pravastatin (n=12) versus untreated controls (n=10). Regional LAD wall thickening was depressed under baseline conditions (LAD 3.7±0.3 versus 6.6±0.3 in remote regions, P |
| doi_str_mv | 10.1161/CIRCRESAHA.108.188730 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2666151</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>19096024</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5877-153ad17c1b6302c5e7326486742c8789d0a0f439ad7d7eadea4957bc078555cf3</originalsourceid><addsrcrecordid>eNpVks2O0zAUhSMEYsrAI4C8YTVKuTeO42SDVMLMtGJGVAXWkeM4jSGNK9ttVZ6OR8P9UQdWls4957uWj6PoLcIYMcMP5WxRLm6_TaaTMUI-xjznFJ5FI2RJGqeM4_NoBABFzCmFq-iVcz8BMKVJ8TK6wgKKDJJ0FP2ZW7EVzguvBzJbra3ZKkfuNoP02gwkiFNdKzsc5kvyuDdS2EZvVqTek0dT617_PgzKz0jpDRFDQ-QX7W_IJzMo8iisNTsyt2apBu2NJaXqe3e0BXFlLtC9D1u9IQulBq8s8Z0i9yHrOzLvhFPEtEetPGwX8sgh5V726nX0ohW9U2_O53X04-72ezmNH77ez8rJQyxZznmMjIoGucQ6o5BIpjhNsjTPeJrInOdFAwLalBai4Q1XolEiLRivJfCcMSZbeh19PHHXm3qlGhnuaUVfra1eCbuvjNDV_5NBd9XSbKskyzJkGADsBJDWOGdVe8kiVIdKq6dKg5RXp0pD7t2_i59S5w6D4f3ZIJwUfWvFILW7-BIMsMAJvvTk25k-vLH71W92yladEr3vqvBXgAImcRI-DSAFiIOCnP4Ft7C9cw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Pravastatin Improves Function in Hibernating Myocardium by Mobilizing CD133+ and cKit+ Bone Marrow Progenitor Cells and Promoting Myocytes to Reenter the Growth Phase of the Cardiac Cell Cycle</title><source>MEDLINE</source><source>American Heart Association Journals</source><source>Journals@Ovid Complete</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Suzuki, Gen ; Iyer, Vijay ; Cimato, Thomas ; Canty, John M</creator><creatorcontrib>Suzuki, Gen ; Iyer, Vijay ; Cimato, Thomas ; Canty, John M</creatorcontrib><description>3-Hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors have been reported to increase circulating bone marrow progenitor cells and variably improve global function in heart failure. The potential role of improved perfusion versus direct effects of statins on cardiac myocytes has not been established. We chronically instrumented swine with a left anterior descending artery (LAD) stenosis to produce chronic hibernating myocardium with regional contractile dysfunction in the absence of heart failure. Hemodynamics, function, perfusion, and histopathology were assessed in pigs treated for 5 weeks with pravastatin (n=12) versus untreated controls (n=10). Regional LAD wall thickening was depressed under baseline conditions (LAD 3.7±0.3 versus 6.6±0.3 in remote regions, P<0.01). It remained unchanged in untreated animals but increased from 3.8±0.6 to 5.2±0.5 mm after pravastatin (P<0.01). There was no increase in myocardial perfusion at rest or during vasodilation. Pravastatin mobilized circulating CD133/cKit bone marrow progenitor cells and increased myocardial tissue levels (LAD CD133 cells from 140±33 to 884±167 cells/10 myocyte nuclei and cKit cells from 223±49 to 953±123 cells/10 myocyte nuclei). Pravastatin increased myocytes in mitosis (phospho–histone-H3; 9±5 to 43±7 nuclei/10 myocyte nuclei, P<0.05) and the growth phase of the cell cycle (Ki67; 410±82 to 1261±235 nuclei/10 myocyte nuclei, P<0.05) in diseased but not normal hearts. As a result, pravastatin increased LAD myocyte nuclear density from 830±41 to 1027±55 nuclei/mm (P<0.05). These data indicate that, in the absence of impaired endothelial function and heart failure, dysfunctional hibernating myocardium improves after pravastatin. This effect is independent of myocardial perfusion and related to mobilization of CD133/cKit bone marrow progenitor cells which stimulate myocyte proliferation resulting in quantitative increases in myocyte nuclear density.</description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/CIRCRESAHA.108.188730</identifier><identifier>PMID: 19096024</identifier><identifier>CODEN: CIRUAL</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>AC133 Antigen ; Animals ; Antigens, CD - metabolism ; Biological and medical sciences ; Bone Marrow Cells - drug effects ; Bone Marrow Cells - immunology ; Bone Marrow Cells - pathology ; Cell Movement - drug effects ; Cell Proliferation - drug effects ; Coronary Circulation - drug effects ; Coronary Stenosis - drug therapy ; Coronary Stenosis - pathology ; Coronary Stenosis - physiopathology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Fundamental and applied biological sciences. Psychology ; GATA4 Transcription Factor - metabolism ; Glycoproteins - metabolism ; Hemodynamics - drug effects ; Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology ; Mitosis - drug effects ; Muscle Development - drug effects ; Myocardial Contraction - drug effects ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - immunology ; Myocytes, Cardiac - pathology ; Peptides - metabolism ; Pravastatin - pharmacology ; Proto-Oncogene Proteins c-kit - metabolism ; Regeneration - drug effects ; Stem Cells - drug effects ; Stem Cells - immunology ; Stem Cells - pathology ; Swine ; Vertebrates: cardiovascular system</subject><ispartof>Circulation research, 2009-01, Vol.104 (2), p.255-264</ispartof><rights>2009 American Heart Association, Inc.</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5877-153ad17c1b6302c5e7326486742c8789d0a0f439ad7d7eadea4957bc078555cf3</citedby><cites>FETCH-LOGICAL-c5877-153ad17c1b6302c5e7326486742c8789d0a0f439ad7d7eadea4957bc078555cf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3687,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=21108303$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19096024$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Suzuki, Gen</creatorcontrib><creatorcontrib>Iyer, Vijay</creatorcontrib><creatorcontrib>Cimato, Thomas</creatorcontrib><creatorcontrib>Canty, John M</creatorcontrib><title>Pravastatin Improves Function in Hibernating Myocardium by Mobilizing CD133+ and cKit+ Bone Marrow Progenitor Cells and Promoting Myocytes to Reenter the Growth Phase of the Cardiac Cell Cycle</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description>3-Hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors have been reported to increase circulating bone marrow progenitor cells and variably improve global function in heart failure. The potential role of improved perfusion versus direct effects of statins on cardiac myocytes has not been established. We chronically instrumented swine with a left anterior descending artery (LAD) stenosis to produce chronic hibernating myocardium with regional contractile dysfunction in the absence of heart failure. Hemodynamics, function, perfusion, and histopathology were assessed in pigs treated for 5 weeks with pravastatin (n=12) versus untreated controls (n=10). Regional LAD wall thickening was depressed under baseline conditions (LAD 3.7±0.3 versus 6.6±0.3 in remote regions, P<0.01). It remained unchanged in untreated animals but increased from 3.8±0.6 to 5.2±0.5 mm after pravastatin (P<0.01). There was no increase in myocardial perfusion at rest or during vasodilation. Pravastatin mobilized circulating CD133/cKit bone marrow progenitor cells and increased myocardial tissue levels (LAD CD133 cells from 140±33 to 884±167 cells/10 myocyte nuclei and cKit cells from 223±49 to 953±123 cells/10 myocyte nuclei). Pravastatin increased myocytes in mitosis (phospho–histone-H3; 9±5 to 43±7 nuclei/10 myocyte nuclei, P<0.05) and the growth phase of the cell cycle (Ki67; 410±82 to 1261±235 nuclei/10 myocyte nuclei, P<0.05) in diseased but not normal hearts. As a result, pravastatin increased LAD myocyte nuclear density from 830±41 to 1027±55 nuclei/mm (P<0.05). These data indicate that, in the absence of impaired endothelial function and heart failure, dysfunctional hibernating myocardium improves after pravastatin. This effect is independent of myocardial perfusion and related to mobilization of CD133/cKit bone marrow progenitor cells which stimulate myocyte proliferation resulting in quantitative increases in myocyte nuclear density.</description><subject>AC133 Antigen</subject><subject>Animals</subject><subject>Antigens, CD - metabolism</subject><subject>Biological and medical sciences</subject><subject>Bone Marrow Cells - drug effects</subject><subject>Bone Marrow Cells - immunology</subject><subject>Bone Marrow Cells - pathology</subject><subject>Cell Movement - drug effects</subject><subject>Cell Proliferation - drug effects</subject><subject>Coronary Circulation - drug effects</subject><subject>Coronary Stenosis - drug therapy</subject><subject>Coronary Stenosis - pathology</subject><subject>Coronary Stenosis - physiopathology</subject><subject>Disease Models, Animal</subject><subject>Dose-Response Relationship, Drug</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>GATA4 Transcription Factor - metabolism</subject><subject>Glycoproteins - metabolism</subject><subject>Hemodynamics - drug effects</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology</subject><subject>Mitosis - drug effects</subject><subject>Muscle Development - drug effects</subject><subject>Myocardial Contraction - drug effects</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - immunology</subject><subject>Myocytes, Cardiac - pathology</subject><subject>Peptides - metabolism</subject><subject>Pravastatin - pharmacology</subject><subject>Proto-Oncogene Proteins c-kit - metabolism</subject><subject>Regeneration - drug effects</subject><subject>Stem Cells - drug effects</subject><subject>Stem Cells - immunology</subject><subject>Stem Cells - pathology</subject><subject>Swine</subject><subject>Vertebrates: cardiovascular system</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVks2O0zAUhSMEYsrAI4C8YTVKuTeO42SDVMLMtGJGVAXWkeM4jSGNK9ttVZ6OR8P9UQdWls4957uWj6PoLcIYMcMP5WxRLm6_TaaTMUI-xjznFJ5FI2RJGqeM4_NoBABFzCmFq-iVcz8BMKVJ8TK6wgKKDJJ0FP2ZW7EVzguvBzJbra3ZKkfuNoP02gwkiFNdKzsc5kvyuDdS2EZvVqTek0dT617_PgzKz0jpDRFDQ-QX7W_IJzMo8iisNTsyt2apBu2NJaXqe3e0BXFlLtC9D1u9IQulBq8s8Z0i9yHrOzLvhFPEtEetPGwX8sgh5V726nX0ohW9U2_O53X04-72ezmNH77ez8rJQyxZznmMjIoGucQ6o5BIpjhNsjTPeJrInOdFAwLalBai4Q1XolEiLRivJfCcMSZbeh19PHHXm3qlGhnuaUVfra1eCbuvjNDV_5NBd9XSbKskyzJkGADsBJDWOGdVe8kiVIdKq6dKg5RXp0pD7t2_i59S5w6D4f3ZIJwUfWvFILW7-BIMsMAJvvTk25k-vLH71W92yladEr3vqvBXgAImcRI-DSAFiIOCnP4Ft7C9cw</recordid><startdate>20090130</startdate><enddate>20090130</enddate><creator>Suzuki, Gen</creator><creator>Iyer, Vijay</creator><creator>Cimato, Thomas</creator><creator>Canty, John M</creator><general>American Heart Association, Inc</general><general>Lippincott Williams & Wilkins</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>5PM</scope></search><sort><creationdate>20090130</creationdate><title>Pravastatin Improves Function in Hibernating Myocardium by Mobilizing CD133+ and cKit+ Bone Marrow Progenitor Cells and Promoting Myocytes to Reenter the Growth Phase of the Cardiac Cell Cycle</title><author>Suzuki, Gen ; Iyer, Vijay ; Cimato, Thomas ; Canty, John M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5877-153ad17c1b6302c5e7326486742c8789d0a0f439ad7d7eadea4957bc078555cf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>AC133 Antigen</topic><topic>Animals</topic><topic>Antigens, CD - metabolism</topic><topic>Biological and medical sciences</topic><topic>Bone Marrow Cells - drug effects</topic><topic>Bone Marrow Cells - immunology</topic><topic>Bone Marrow Cells - pathology</topic><topic>Cell Movement - drug effects</topic><topic>Cell Proliferation - drug effects</topic><topic>Coronary Circulation - drug effects</topic><topic>Coronary Stenosis - drug therapy</topic><topic>Coronary Stenosis - pathology</topic><topic>Coronary Stenosis - physiopathology</topic><topic>Disease Models, Animal</topic><topic>Dose-Response Relationship, Drug</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>GATA4 Transcription Factor - metabolism</topic><topic>Glycoproteins - metabolism</topic><topic>Hemodynamics - drug effects</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology</topic><topic>Mitosis - drug effects</topic><topic>Muscle Development - drug effects</topic><topic>Myocardial Contraction - drug effects</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - immunology</topic><topic>Myocytes, Cardiac - pathology</topic><topic>Peptides - metabolism</topic><topic>Pravastatin - pharmacology</topic><topic>Proto-Oncogene Proteins c-kit - metabolism</topic><topic>Regeneration - drug effects</topic><topic>Stem Cells - drug effects</topic><topic>Stem Cells - immunology</topic><topic>Stem Cells - pathology</topic><topic>Swine</topic><topic>Vertebrates: cardiovascular system</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Suzuki, Gen</creatorcontrib><creatorcontrib>Iyer, Vijay</creatorcontrib><creatorcontrib>Cimato, Thomas</creatorcontrib><creatorcontrib>Canty, John 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>PubMed Central (Full Participant titles)</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Suzuki, Gen</au><au>Iyer, Vijay</au><au>Cimato, Thomas</au><au>Canty, John M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pravastatin Improves Function in Hibernating Myocardium by Mobilizing CD133+ and cKit+ Bone Marrow Progenitor Cells and Promoting Myocytes to Reenter the Growth Phase of the Cardiac Cell Cycle</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>2009-01-30</date><risdate>2009</risdate><volume>104</volume><issue>2</issue><spage>255</spage><epage>264</epage><pages>255-264</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><coden>CIRUAL</coden><abstract>3-Hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors have been reported to increase circulating bone marrow progenitor cells and variably improve global function in heart failure. The potential role of improved perfusion versus direct effects of statins on cardiac myocytes has not been established. We chronically instrumented swine with a left anterior descending artery (LAD) stenosis to produce chronic hibernating myocardium with regional contractile dysfunction in the absence of heart failure. Hemodynamics, function, perfusion, and histopathology were assessed in pigs treated for 5 weeks with pravastatin (n=12) versus untreated controls (n=10). Regional LAD wall thickening was depressed under baseline conditions (LAD 3.7±0.3 versus 6.6±0.3 in remote regions, P<0.01). It remained unchanged in untreated animals but increased from 3.8±0.6 to 5.2±0.5 mm after pravastatin (P<0.01). There was no increase in myocardial perfusion at rest or during vasodilation. Pravastatin mobilized circulating CD133/cKit bone marrow progenitor cells and increased myocardial tissue levels (LAD CD133 cells from 140±33 to 884±167 cells/10 myocyte nuclei and cKit cells from 223±49 to 953±123 cells/10 myocyte nuclei). Pravastatin increased myocytes in mitosis (phospho–histone-H3; 9±5 to 43±7 nuclei/10 myocyte nuclei, P<0.05) and the growth phase of the cell cycle (Ki67; 410±82 to 1261±235 nuclei/10 myocyte nuclei, P<0.05) in diseased but not normal hearts. As a result, pravastatin increased LAD myocyte nuclear density from 830±41 to 1027±55 nuclei/mm (P<0.05). These data indicate that, in the absence of impaired endothelial function and heart failure, dysfunctional hibernating myocardium improves after pravastatin. This effect is independent of myocardial perfusion and related to mobilization of CD133/cKit bone marrow progenitor cells which stimulate myocyte proliferation resulting in quantitative increases in myocyte nuclear density.</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>19096024</pmid><doi>10.1161/CIRCRESAHA.108.188730</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0009-7330 |
| ispartof | Circulation research, 2009-01, Vol.104 (2), p.255-264 |
| issn | 0009-7330 1524-4571 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2666151 |
| source | MEDLINE; American Heart Association Journals; Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals |
| subjects | AC133 Antigen Animals Antigens, CD - metabolism Biological and medical sciences Bone Marrow Cells - drug effects Bone Marrow Cells - immunology Bone Marrow Cells - pathology Cell Movement - drug effects Cell Proliferation - drug effects Coronary Circulation - drug effects Coronary Stenosis - drug therapy Coronary Stenosis - pathology Coronary Stenosis - physiopathology Disease Models, Animal Dose-Response Relationship, Drug Fundamental and applied biological sciences. Psychology GATA4 Transcription Factor - metabolism Glycoproteins - metabolism Hemodynamics - drug effects Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology Mitosis - drug effects Muscle Development - drug effects Myocardial Contraction - drug effects Myocytes, Cardiac - drug effects Myocytes, Cardiac - immunology Myocytes, Cardiac - pathology Peptides - metabolism Pravastatin - pharmacology Proto-Oncogene Proteins c-kit - metabolism Regeneration - drug effects Stem Cells - drug effects Stem Cells - immunology Stem Cells - pathology Swine Vertebrates: cardiovascular system |
| title | Pravastatin Improves Function in Hibernating Myocardium by Mobilizing CD133+ and cKit+ Bone Marrow Progenitor Cells and Promoting Myocytes to Reenter the Growth Phase of the Cardiac Cell Cycle |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-29T06%3A14%3A47IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Pravastatin%20Improves%20Function%20in%20Hibernating%20Myocardium%20by%20Mobilizing%20CD133+%20and%20cKit+%20Bone%20Marrow%20Progenitor%20Cells%20and%20Promoting%20Myocytes%20to%20Reenter%20the%20Growth%20Phase%20of%20the%20Cardiac%20Cell%20Cycle&rft.jtitle=Circulation%20research&rft.au=Suzuki,%20Gen&rft.date=2009-01-30&rft.volume=104&rft.issue=2&rft.spage=255&rft.epage=264&rft.pages=255-264&rft.issn=0009-7330&rft.eissn=1524-4571&rft.coden=CIRUAL&rft_id=info:doi/10.1161/CIRCRESAHA.108.188730&rft_dat=%3Cpubmed_cross%3E19096024%3C/pubmed_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/19096024&rfr_iscdi=true |