Ultrasound Detection of Myocardial Ischemic Memory Using an E-Selectin Targeting Peptide Amenable to Human Application.
Identifieur interne : 000A31 ( Main/Exploration ); précédent : 000A30; suivant : 000A32Ultrasound Detection of Myocardial Ischemic Memory Using an E-Selectin Targeting Peptide Amenable to Human Application.
Auteurs : Xiaoping Leng [États-Unis] ; Jianjun Wang [États-Unis] ; Andrew Carson [États-Unis] ; Xucai Chen [États-Unis] ; Huili Fu [États-Unis] ; Susanne Ottoboni [États-Unis] ; William R. Wagner [États-Unis] ; Flordeliza S. Villanueva [États-Unis]Source :
- Molecular imaging [ 1536-0121 ] ; 2014.
Abstract
Vascular endothelial leukocyte adhesion molecules, such as E-selectin, are acutely upregulated in myocardial ischemia/reperfusion and are thus "ischemic memory" biomarkers for recent cardiac ischemia. We sought to develop an ultrasound molecular imaging agent composed of microbubbles (MBs) targeted to E-selectin to enable the differential diagnosis of myocardial ischemia in patients presenting with chest pain of unclear etiology. Biodegradable polymer MBs were prepared bearing a peptide with specific human E-selectin affinity (MBESEL). Control MBs had scrambled peptide (MBCTL) or nonspecific IgG (MBIgG). MBESEL adhesion to activated rat endothelial cells (ECs) was confirmed in vitro in a flow system and in vivo with intravital microscopy of rat cremaster microcirculation. Ultrasound molecular imaging of recent myocardial ischemia was performed in rats 4 hours after transient (15 minutes) coronary occlusion. MBESEL adhesion was higher to inflamed versus normal ECs in vitro; there was no difference in MBCTL or MBIgG adhesion to inflamed versus normal ECs. There was greater adhesion of MBESEL to inflamed versus noninflamed microcirculation and minimal adhesion of MBCTL or MBIgG under any condition. Ultrasound imaging after injection of MBSEL demonstrated persistent contrast enhancement of the previously ischemic region. Videointensity in postischemic myocardium after MBESEL was higher than that in the nonischemic bed (11.6 ± 2.7 dB vs 3.6 ± 0.8 dB, p < .02) and higher than that after MBCTL (4.0 ± 1.0 dB, p < .03) or MBIgG (1.7 ± 0.1 dB, p < .03). MBs targeted to E-selectin via a short synthetic peptide with human E-selectin binding affinity enables echocardiographic detection of recent ischemia, setting the stage for clinical myocardial ischemic memory imaging to identify acute coronary syndromes.
DOI: 10.2310/7290.2014.00006
PubMed: 28650290
Affiliations:
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Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Wang, Jianjun" sort="Wang, Jianjun" uniqKey="Wang J" first="Jianjun" last="Wang">Jianjun Wang</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Carson, Andrew" sort="Carson, Andrew" uniqKey="Carson A" first="Andrew" last="Carson">Andrew Carson</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Chen, Xucai" sort="Chen, Xucai" uniqKey="Chen X" first="Xucai" last="Chen">Xucai Chen</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Fu, Huili" sort="Fu, Huili" uniqKey="Fu H" first="Huili" last="Fu">Huili Fu</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Ottoboni, Susanne" sort="Ottoboni, Susanne" uniqKey="Ottoboni S" first="Susanne" last="Ottoboni">Susanne Ottoboni</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Wagner, William R" sort="Wagner, William R" uniqKey="Wagner W" first="William R" last="Wagner">William R. Wagner</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Villanueva, Flordeliza S" sort="Villanueva, Flordeliza S" uniqKey="Villanueva F" first="Flordeliza S" last="Villanueva">Flordeliza S. Villanueva</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2014">2014</date><idno type="RBID">pubmed:28650290</idno><idno type="pmid">28650290</idno><idno type="doi">10.2310/7290.2014.00006</idno><idno type="wicri:Area/PubMed/Corpus">002903</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">002903</idno><idno type="wicri:Area/PubMed/Curation">002890</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">002890</idno><idno type="wicri:Area/PubMed/Checkpoint">002890</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">002890</idno><idno type="wicri:Area/Ncbi/Merge">004A55</idno><idno type="wicri:Area/Ncbi/Curation">004A55</idno><idno type="wicri:Area/Ncbi/Checkpoint">004A55</idno><idno type="wicri:Area/Main/Merge">000A39</idno><idno type="wicri:Area/Main/Curation">000A31</idno><idno type="wicri:Area/Main/Exploration">000A31</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Ultrasound Detection of Myocardial Ischemic Memory Using an E-Selectin Targeting Peptide Amenable to Human Application.</title><author><name sortKey="Leng, Xiaoping" sort="Leng, Xiaoping" uniqKey="Leng X" first="Xiaoping" last="Leng">Xiaoping Leng</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Wang, Jianjun" sort="Wang, Jianjun" uniqKey="Wang J" first="Jianjun" last="Wang">Jianjun Wang</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Carson, Andrew" sort="Carson, Andrew" uniqKey="Carson A" first="Andrew" last="Carson">Andrew Carson</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Chen, Xucai" sort="Chen, Xucai" uniqKey="Chen X" first="Xucai" last="Chen">Xucai Chen</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Fu, Huili" sort="Fu, Huili" uniqKey="Fu H" first="Huili" last="Fu">Huili Fu</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Ottoboni, Susanne" sort="Ottoboni, Susanne" uniqKey="Ottoboni S" first="Susanne" last="Ottoboni">Susanne Ottoboni</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Wagner, William R" sort="Wagner, William R" uniqKey="Wagner W" first="William R" last="Wagner">William R. Wagner</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author><author><name sortKey="Villanueva, Flordeliza S" sort="Villanueva, Flordeliza S" uniqKey="Villanueva F" first="Flordeliza S" last="Villanueva">Flordeliza S. Villanueva</name><affiliation wicri:level="2"><nlm:affiliation>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark, CA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>From the Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, the Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, China; Center for Ultrasound Molecular Imaging and Therapeutics and McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA; and Depomed, Inc., Newark</wicri:cityArea></affiliation></author></analytic><series><title level="j">Molecular imaging</title><idno type="eISSN">1536-0121</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Vascular endothelial leukocyte adhesion molecules, such as E-selectin, are acutely upregulated in myocardial ischemia/reperfusion and are thus "ischemic memory" biomarkers for recent cardiac ischemia. We sought to develop an ultrasound molecular imaging agent composed of microbubbles (MBs) targeted to E-selectin to enable the differential diagnosis of myocardial ischemia in patients presenting with chest pain of unclear etiology. Biodegradable polymer MBs were prepared bearing a peptide with specific human E-selectin affinity (MBESEL). Control MBs had scrambled peptide (MBCTL) or nonspecific IgG (MBIgG). MBESEL adhesion to activated rat endothelial cells (ECs) was confirmed in vitro in a flow system and in vivo with intravital microscopy of rat cremaster microcirculation. Ultrasound molecular imaging of recent myocardial ischemia was performed in rats 4 hours after transient (15 minutes) coronary occlusion. MBESEL adhesion was higher to inflamed versus normal ECs in vitro; there was no difference in MBCTL or MBIgG adhesion to inflamed versus normal ECs. There was greater adhesion of MBESEL to inflamed versus noninflamed microcirculation and minimal adhesion of MBCTL or MBIgG under any condition. Ultrasound imaging after injection of MBSEL demonstrated persistent contrast enhancement of the previously ischemic region. Videointensity in postischemic myocardium after MBESEL was higher than that in the nonischemic bed (11.6 ± 2.7 dB vs 3.6 ± 0.8 dB, p < .02) and higher than that after MBCTL (4.0 ± 1.0 dB, p < .03) or MBIgG (1.7 ± 0.1 dB, p < .03). MBs targeted to E-selectin via a short synthetic peptide with human E-selectin binding affinity enables echocardiographic detection of recent ischemia, setting the stage for clinical myocardial ischemic memory imaging to identify acute coronary syndromes.</div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Californie</li></region></list><tree><country name="États-Unis"><region name="Californie"><name sortKey="Leng, Xiaoping" sort="Leng, Xiaoping" uniqKey="Leng X" first="Xiaoping" last="Leng">Xiaoping Leng</name></region><name sortKey="Carson, Andrew" sort="Carson, Andrew" uniqKey="Carson A" first="Andrew" last="Carson">Andrew Carson</name><name sortKey="Chen, Xucai" sort="Chen, Xucai" uniqKey="Chen X" first="Xucai" last="Chen">Xucai Chen</name><name sortKey="Fu, Huili" sort="Fu, Huili" uniqKey="Fu H" first="Huili" last="Fu">Huili Fu</name><name sortKey="Ottoboni, Susanne" sort="Ottoboni, Susanne" uniqKey="Ottoboni S" first="Susanne" last="Ottoboni">Susanne Ottoboni</name><name sortKey="Villanueva, Flordeliza S" sort="Villanueva, Flordeliza S" uniqKey="Villanueva F" first="Flordeliza S" last="Villanueva">Flordeliza S. Villanueva</name><name sortKey="Wagner, William R" sort="Wagner, William R" uniqKey="Wagner W" first="William R" last="Wagner">William R. Wagner</name><name sortKey="Wang, Jianjun" sort="Wang, Jianjun" uniqKey="Wang J" first="Jianjun" last="Wang">Jianjun Wang</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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