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Cyclosporine Attenuates Pressure-Overload Hypertrophy in Mice While Enhancing Susceptibility to Decompensation and Heart Failure
Left ventricular hypertrophy (LVH) is a compensatory mechanism to cope with pressure overload. Recently, a calcineurin pathway mediating LVH and its prevention by cyclosporine was reported. We examined whether calcineurin mediates LVH due to pressure overload in mice. Pressure overload was induced b...
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| Published in: | Circulation research 1999-04, Vol.84 (6), p.735-740 |
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| creator | Meguro, Tomomi Hong, Chull Asai, Kuniya Takagi, Gen McKinsey, Timothy A Olson, Eric N Vatner, Stephen F |
| description | Left ventricular hypertrophy (LVH) is a compensatory mechanism to cope with pressure overload. Recently, a calcineurin pathway mediating LVH and its prevention by cyclosporine was reported. We examined whether calcineurin mediates LVH due to pressure overload in mice. Pressure overload was induced by aortic banding in 53 mice (32 treated with cyclosporine [25 mg [middle dot] kg [middle dot] d], 21 treated with vehicle). There were 17 sham-operated mice (9 treated with vehicle, 8 treated with cyclosporine). At 3 weeks after surgery, LV weight to body weight was greater in the nontreatment banded group (4.39 +/- 0.16 mg/g) than in the cyclosporine-treated banded group (3.95 +/- 0.14 mg/g, P |
| doi_str_mv | 10.1161/01.res.84.6.735 |
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Recently, a calcineurin pathway mediating LVH and its prevention by cyclosporine was reported. We examined whether calcineurin mediates LVH due to pressure overload in mice. Pressure overload was induced by aortic banding in 53 mice (32 treated with cyclosporine [25 mg [middle dot] kg [middle dot] d], 21 treated with vehicle). There were 17 sham-operated mice (9 treated with vehicle, 8 treated with cyclosporine). At 3 weeks after surgery, LV weight to body weight was greater in the nontreatment banded group (4.39 +/- 0.16 mg/g) than in the cyclosporine-treated banded group (3.95 +/- 0.14 mg/g, P<0.05), with both groups being greater compared with the entire group of sham-operated mice (3.02 +/- 0.04 mg/g). The pressure gradient between the ascending and abdominal aorta was not different between the cyclosporine-treated (49.6 +/- 6.1 mm Hg) and nontreatment groups (48.7 +/- 4.6 mm Hg). Although LV systolic pressure was lower in the cyclosporine-treated banded animals, LV systolic wall stress was similar in the nontreatment banded group and in the cyclosporine-treated group. However, LV dP/dt was lower (P=0.05) in the cyclosporine-treated banded group (4774 +/- 656 mm Hg/s) than in the nontreatment banded group (6604 +/- 516 mm Hg/s). During the protocol, 23 of 32 mice in the cyclosporine-treated group and 9 of 21 mice in the nontreatment group died. All deaths occurred within 10 days after surgery. Deaths caused by heart failure were 7.2-fold higher (P<0.05) in the cyclosporine-treated group, whereas deaths due to other causes were not different between the 2 groups. In addition, LV function of mice was assessed at 48 hours after banding; LV ejection fraction measured with echocardiography was lower (P<0.05) in the cyclosporine-treated banded group (66 +/- 3.0%) than in the nontreatment banded group (79 +/- 1.5%), whereas LV systolic wall stresses were similar. Calcineurin phosphatase activity was depressed similarly in both cyclosporine-treated groups compared with both nontreatment groups. Thus, cyclosporine could attenuate, but not prevent, LVH at the expense of inhibiting an important compensatory mechanism in response to pressure overload, resulting in reduced LV wall stress and function and increased susceptibility to decompensation and heart failure. (Circ Res. 1999;84:735-740.)</description><identifier>ISSN: 0009-7330</identifier><identifier>EISSN: 1524-4571</identifier><identifier>DOI: 10.1161/01.res.84.6.735</identifier><identifier>PMID: 10189362</identifier><identifier>CODEN: CIRUAL</identifier><language>eng</language><publisher>Hagerstown, MD: American Heart Association, Inc</publisher><subject>Animals ; Aorta - physiology ; Aorta, Abdominal - physiology ; Aorta, Thoracic - physiology ; Biological and medical sciences ; Cardiovascular system ; Cyclosporine - blood ; Cyclosporine - pharmacology ; Disease Susceptibility ; Enzyme Inhibitors - blood ; Enzyme Inhibitors - pharmacology ; Heart Failure - etiology ; Heart Failure - mortality ; Heart Failure - physiopathology ; Hypertension - mortality ; Hypertension - physiopathology ; Hypertrophy, Left Ventricular - mortality ; Hypertrophy, Left Ventricular - pathology ; Hypertrophy, Left Ventricular - physiopathology ; Ligation ; Male ; Medical sciences ; Mice ; Pharmacology. Drug treatments ; Vascular wall</subject><ispartof>Circulation research, 1999-04, Vol.84 (6), p.735-740</ispartof><rights>1999 American Heart Association, Inc.</rights><rights>1999 INIST-CNRS</rights><rights>Copyright American Heart Association, Inc. Apr 2, 1999</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5373-914f0e288b5582d129558b49dd6efd129c57975efdd5cf07f2cd49b24d6fa3363</citedby><cites>FETCH-LOGICAL-c5373-914f0e288b5582d129558b49dd6efd129c57975efdd5cf07f2cd49b24d6fa3363</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1772882$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10189362$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Meguro, Tomomi</creatorcontrib><creatorcontrib>Hong, Chull</creatorcontrib><creatorcontrib>Asai, Kuniya</creatorcontrib><creatorcontrib>Takagi, Gen</creatorcontrib><creatorcontrib>McKinsey, Timothy A</creatorcontrib><creatorcontrib>Olson, Eric N</creatorcontrib><creatorcontrib>Vatner, Stephen F</creatorcontrib><title>Cyclosporine Attenuates Pressure-Overload Hypertrophy in Mice While Enhancing Susceptibility to Decompensation and Heart Failure</title><title>Circulation research</title><addtitle>Circ Res</addtitle><description>Left ventricular hypertrophy (LVH) is a compensatory mechanism to cope with pressure overload. Recently, a calcineurin pathway mediating LVH and its prevention by cyclosporine was reported. We examined whether calcineurin mediates LVH due to pressure overload in mice. Pressure overload was induced by aortic banding in 53 mice (32 treated with cyclosporine [25 mg [middle dot] kg [middle dot] d], 21 treated with vehicle). There were 17 sham-operated mice (9 treated with vehicle, 8 treated with cyclosporine). At 3 weeks after surgery, LV weight to body weight was greater in the nontreatment banded group (4.39 +/- 0.16 mg/g) than in the cyclosporine-treated banded group (3.95 +/- 0.14 mg/g, P<0.05), with both groups being greater compared with the entire group of sham-operated mice (3.02 +/- 0.04 mg/g). The pressure gradient between the ascending and abdominal aorta was not different between the cyclosporine-treated (49.6 +/- 6.1 mm Hg) and nontreatment groups (48.7 +/- 4.6 mm Hg). Although LV systolic pressure was lower in the cyclosporine-treated banded animals, LV systolic wall stress was similar in the nontreatment banded group and in the cyclosporine-treated group. However, LV dP/dt was lower (P=0.05) in the cyclosporine-treated banded group (4774 +/- 656 mm Hg/s) than in the nontreatment banded group (6604 +/- 516 mm Hg/s). During the protocol, 23 of 32 mice in the cyclosporine-treated group and 9 of 21 mice in the nontreatment group died. All deaths occurred within 10 days after surgery. Deaths caused by heart failure were 7.2-fold higher (P<0.05) in the cyclosporine-treated group, whereas deaths due to other causes were not different between the 2 groups. In addition, LV function of mice was assessed at 48 hours after banding; LV ejection fraction measured with echocardiography was lower (P<0.05) in the cyclosporine-treated banded group (66 +/- 3.0%) than in the nontreatment banded group (79 +/- 1.5%), whereas LV systolic wall stresses were similar. Calcineurin phosphatase activity was depressed similarly in both cyclosporine-treated groups compared with both nontreatment groups. Thus, cyclosporine could attenuate, but not prevent, LVH at the expense of inhibiting an important compensatory mechanism in response to pressure overload, resulting in reduced LV wall stress and function and increased susceptibility to decompensation and heart failure. (Circ Res. 1999;84:735-740.)</description><subject>Animals</subject><subject>Aorta - physiology</subject><subject>Aorta, Abdominal - physiology</subject><subject>Aorta, Thoracic - physiology</subject><subject>Biological and medical sciences</subject><subject>Cardiovascular system</subject><subject>Cyclosporine - blood</subject><subject>Cyclosporine - pharmacology</subject><subject>Disease Susceptibility</subject><subject>Enzyme Inhibitors - blood</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Heart Failure - etiology</subject><subject>Heart Failure - mortality</subject><subject>Heart Failure - physiopathology</subject><subject>Hypertension - mortality</subject><subject>Hypertension - physiopathology</subject><subject>Hypertrophy, Left Ventricular - mortality</subject><subject>Hypertrophy, Left Ventricular - pathology</subject><subject>Hypertrophy, Left Ventricular - physiopathology</subject><subject>Ligation</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Pharmacology. Drug treatments</subject><subject>Vascular wall</subject><issn>0009-7330</issn><issn>1524-4571</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1999</creationdate><recordtype>article</recordtype><recordid>eNpdkU1v1DAQhiMEokvhzA1ZCHFL6q848bFathSpqIiCOFpeZ0JcvHawHaq98dPxalcCcZqx9fjReN6qeklwQ4ggF5g0EVLT80Y0HWsfVSvSUl7ztiOPqxXGWNYdY_isepbSPcaEMyqfVmcEk14yQVfV7_XeuJDmEK0HdJkz-EVnSOhT8aYlQn37C6ILekDX-xlijmGe9sh69NEaQN8m6wBt_KS9sf47uluSgTnbrXU271EO6B2YsJvBJ51t8Ej7IgIdM7rS1hX_8-rJqF2CF6d6Xn292nxZX9c3t-8_rC9vatOyjtWS8BED7ftt2_Z0IFSWuuVyGASMh6NpO9m1pR9aM-JupGbgckv5IEbNmGDn1dujd47h5wIpq50tszqnPYQlKSGFEB2nBXz9H3gflujLbIoSyonoJSnQxREyMaQUYVRztDsd94pgdUhGYaI-b-5Uz5VQJZny4tVJu2x3MPzDH6MowJsToJPRboyHlaa_XNeV3x8wfsQegssQ0w-3PEBUE2iXJ1USxwwTWhMpJeaY4rrcEMb-AIyup7k</recordid><startdate>19990402</startdate><enddate>19990402</enddate><creator>Meguro, Tomomi</creator><creator>Hong, Chull</creator><creator>Asai, Kuniya</creator><creator>Takagi, Gen</creator><creator>McKinsey, Timothy A</creator><creator>Olson, Eric N</creator><creator>Vatner, Stephen F</creator><general>American Heart Association, Inc</general><general>Lippincott</general><general>Lippincott Williams & Wilkins Ovid Technologies</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>7T5</scope><scope>7TK</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>19990402</creationdate><title>Cyclosporine Attenuates Pressure-Overload Hypertrophy in Mice While Enhancing Susceptibility to Decompensation and Heart Failure</title><author>Meguro, Tomomi ; Hong, Chull ; Asai, Kuniya ; Takagi, Gen ; McKinsey, Timothy A ; Olson, Eric N ; Vatner, Stephen F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5373-914f0e288b5582d129558b49dd6efd129c57975efdd5cf07f2cd49b24d6fa3363</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1999</creationdate><topic>Animals</topic><topic>Aorta - physiology</topic><topic>Aorta, Abdominal - physiology</topic><topic>Aorta, Thoracic - physiology</topic><topic>Biological and medical sciences</topic><topic>Cardiovascular system</topic><topic>Cyclosporine - blood</topic><topic>Cyclosporine - pharmacology</topic><topic>Disease Susceptibility</topic><topic>Enzyme Inhibitors - blood</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Heart Failure - etiology</topic><topic>Heart Failure - mortality</topic><topic>Heart Failure - physiopathology</topic><topic>Hypertension - mortality</topic><topic>Hypertension - physiopathology</topic><topic>Hypertrophy, Left Ventricular - mortality</topic><topic>Hypertrophy, Left Ventricular - pathology</topic><topic>Hypertrophy, Left Ventricular - physiopathology</topic><topic>Ligation</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Pharmacology. Drug treatments</topic><topic>Vascular wall</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Meguro, Tomomi</creatorcontrib><creatorcontrib>Hong, Chull</creatorcontrib><creatorcontrib>Asai, Kuniya</creatorcontrib><creatorcontrib>Takagi, Gen</creatorcontrib><creatorcontrib>McKinsey, Timothy A</creatorcontrib><creatorcontrib>Olson, Eric N</creatorcontrib><creatorcontrib>Vatner, Stephen F</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>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Circulation research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Meguro, Tomomi</au><au>Hong, Chull</au><au>Asai, Kuniya</au><au>Takagi, Gen</au><au>McKinsey, Timothy A</au><au>Olson, Eric N</au><au>Vatner, Stephen F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cyclosporine Attenuates Pressure-Overload Hypertrophy in Mice While Enhancing Susceptibility to Decompensation and Heart Failure</atitle><jtitle>Circulation research</jtitle><addtitle>Circ Res</addtitle><date>1999-04-02</date><risdate>1999</risdate><volume>84</volume><issue>6</issue><spage>735</spage><epage>740</epage><pages>735-740</pages><issn>0009-7330</issn><eissn>1524-4571</eissn><coden>CIRUAL</coden><abstract>Left ventricular hypertrophy (LVH) is a compensatory mechanism to cope with pressure overload. Recently, a calcineurin pathway mediating LVH and its prevention by cyclosporine was reported. We examined whether calcineurin mediates LVH due to pressure overload in mice. Pressure overload was induced by aortic banding in 53 mice (32 treated with cyclosporine [25 mg [middle dot] kg [middle dot] d], 21 treated with vehicle). There were 17 sham-operated mice (9 treated with vehicle, 8 treated with cyclosporine). At 3 weeks after surgery, LV weight to body weight was greater in the nontreatment banded group (4.39 +/- 0.16 mg/g) than in the cyclosporine-treated banded group (3.95 +/- 0.14 mg/g, P<0.05), with both groups being greater compared with the entire group of sham-operated mice (3.02 +/- 0.04 mg/g). The pressure gradient between the ascending and abdominal aorta was not different between the cyclosporine-treated (49.6 +/- 6.1 mm Hg) and nontreatment groups (48.7 +/- 4.6 mm Hg). Although LV systolic pressure was lower in the cyclosporine-treated banded animals, LV systolic wall stress was similar in the nontreatment banded group and in the cyclosporine-treated group. However, LV dP/dt was lower (P=0.05) in the cyclosporine-treated banded group (4774 +/- 656 mm Hg/s) than in the nontreatment banded group (6604 +/- 516 mm Hg/s). During the protocol, 23 of 32 mice in the cyclosporine-treated group and 9 of 21 mice in the nontreatment group died. All deaths occurred within 10 days after surgery. Deaths caused by heart failure were 7.2-fold higher (P<0.05) in the cyclosporine-treated group, whereas deaths due to other causes were not different between the 2 groups. In addition, LV function of mice was assessed at 48 hours after banding; LV ejection fraction measured with echocardiography was lower (P<0.05) in the cyclosporine-treated banded group (66 +/- 3.0%) than in the nontreatment banded group (79 +/- 1.5%), whereas LV systolic wall stresses were similar. Calcineurin phosphatase activity was depressed similarly in both cyclosporine-treated groups compared with both nontreatment groups. Thus, cyclosporine could attenuate, but not prevent, LVH at the expense of inhibiting an important compensatory mechanism in response to pressure overload, resulting in reduced LV wall stress and function and increased susceptibility to decompensation and heart failure. (Circ Res. 1999;84:735-740.)</abstract><cop>Hagerstown, MD</cop><pub>American Heart Association, Inc</pub><pmid>10189362</pmid><doi>10.1161/01.res.84.6.735</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Circulation research, 1999-04, Vol.84 (6), p.735-740 |
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| subjects | Animals Aorta - physiology Aorta, Abdominal - physiology Aorta, Thoracic - physiology Biological and medical sciences Cardiovascular system Cyclosporine - blood Cyclosporine - pharmacology Disease Susceptibility Enzyme Inhibitors - blood Enzyme Inhibitors - pharmacology Heart Failure - etiology Heart Failure - mortality Heart Failure - physiopathology Hypertension - mortality Hypertension - physiopathology Hypertrophy, Left Ventricular - mortality Hypertrophy, Left Ventricular - pathology Hypertrophy, Left Ventricular - physiopathology Ligation Male Medical sciences Mice Pharmacology. Drug treatments Vascular wall |
| title | Cyclosporine Attenuates Pressure-Overload Hypertrophy in Mice While Enhancing Susceptibility to Decompensation and Heart Failure |
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