Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke
Multi-protein complexes called inflammasomes have recently been identified and shown to contribute to cell death in tissue injury. Intravenous immunoglobulin (IVIg) is an FDA-approved therapeutic modality used for various inflammatory diseases. The objective of this study is to investigate dynamic r...
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| creator | Yang-Wei Fann, D Lee, S-Y Manzanero, S Tang, S-C Gelderblom, M Chunduri, P Bernreuther, C Glatzel, M Cheng, Y-L Thundyil, J Widiapradja, A Lok, K-Z Foo, S L Wang, Y-C Li, Y-I Drummond, G R Basta, M Magnus, T Jo, D-G Mattson, M P Sobey, C G Arumugam, T V |
| description | Multi-protein complexes called inflammasomes have recently been identified and shown to contribute to cell death in tissue injury. Intravenous immunoglobulin (IVIg) is an FDA-approved therapeutic modality used for various inflammatory diseases. The objective of this study is to investigate dynamic responses of the NLRP1 and NLRP3 inflammasomes in stroke and to determine whether the NLRP1 and NLRP3 inflammasomes can be targeted with IVIg for therapeutic intervention. Primary cortical neurons were subjected to glucose deprivation (GD), oxygen–glucose deprivation (OGD) or simulated ischemia-reperfusion (I/R). Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion. Neurological assessment was performed, brain tissue damage was quantified, and NLRP1 and NLRP3 inflammasome protein levels were evaluated. NLRP1 and NLRP3 inflammasome components were also analyzed in postmortem brain tissue samples from stroke patients. Ischemia-like conditions increased the levels of NLRP1 and NLRP3 inflammasome proteins, and IL-1
β
and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1
β
and IL-18 were elevated in ipsilateral brain tissues of cerebral I/R mice and stroke patients. Caspase-1 inhibitor treatment protected cultured cortical neurons and brain cells
in vivo
in experimental stroke models. IVIg treatment protected neurons in experimental stroke models by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Our findings provide evidence that the NLRP1 and NLRP3 inflammasomes have a major role in neuronal cell death and behavioral deficits in stroke. We also identified NLRP1 and NLRP3 inflammasome inhibition as a novel mechanism by which IVIg can protect brain cells against ischemic damage, suggesting a potential clinical benefit of therapeutic interventions that target inflammasome assembly and activity. |
| doi_str_mv | 10.1038/cddis.2013.326 |
| format | Article |
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β
and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1
β
and IL-18 were elevated in ipsilateral brain tissues of cerebral I/R mice and stroke patients. Caspase-1 inhibitor treatment protected cultured cortical neurons and brain cells
in vivo
in experimental stroke models. IVIg treatment protected neurons in experimental stroke models by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Our findings provide evidence that the NLRP1 and NLRP3 inflammasomes have a major role in neuronal cell death and behavioral deficits in stroke. We also identified NLRP1 and NLRP3 inflammasome inhibition as a novel mechanism by which IVIg can protect brain cells against ischemic damage, suggesting a potential clinical benefit of therapeutic interventions that target inflammasome assembly and activity.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/cddis.2013.326</identifier><identifier>PMID: 24008734</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/154/51/1568 ; 631/250/256/2177 ; 631/378/1689/534 ; 631/80/82 ; Adaptor Proteins, Signal Transducing - metabolism ; Animals ; Antibodies ; Apoptosis Regulatory Proteins - metabolism ; Biochemistry ; Biomedical and Life Sciences ; Brain Ischemia - complications ; Brain Ischemia - metabolism ; Brain Ischemia - pathology ; Carrier Proteins - metabolism ; Caspase 1 - metabolism ; Caspase Inhibitors - pharmacology ; Cell Biology ; Cell Culture ; Cell Death - drug effects ; Cells, Cultured ; Cerebral Cortex - pathology ; Cytoprotection - drug effects ; Disease Models, Animal ; Humans ; Immunoglobulins, Intravenous - pharmacology ; Immunology ; Inflammasomes - metabolism ; Interleukin-18 - metabolism ; Interleukin-1beta - metabolism ; Life Sciences ; Mice ; Mice, Inbred C57BL ; Neurons - drug effects ; Neurons - enzymology ; Neurons - metabolism ; Neurons - pathology ; NLR Family, Pyrin Domain-Containing 3 Protein ; Original ; original-article ; Stroke - complications ; Stroke - metabolism ; Stroke - pathology ; Treatment Outcome</subject><ispartof>Cell death & disease, 2013-09, Vol.4 (9), p.e790-e790</ispartof><rights>The Author(s) 2013</rights><rights>Copyright Nature Publishing Group Sep 2013</rights><rights>Copyright © 2013 Macmillan Publishers Limited 2013 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c536t-cf526148bba844a53d1b3c475c7010c947d726ab992c627922b26afd707d28f33</citedby><cites>FETCH-LOGICAL-c536t-cf526148bba844a53d1b3c475c7010c947d726ab992c627922b26afd707d28f33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789184/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789184/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24008734$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang-Wei Fann, D</creatorcontrib><creatorcontrib>Lee, S-Y</creatorcontrib><creatorcontrib>Manzanero, S</creatorcontrib><creatorcontrib>Tang, S-C</creatorcontrib><creatorcontrib>Gelderblom, M</creatorcontrib><creatorcontrib>Chunduri, P</creatorcontrib><creatorcontrib>Bernreuther, C</creatorcontrib><creatorcontrib>Glatzel, M</creatorcontrib><creatorcontrib>Cheng, Y-L</creatorcontrib><creatorcontrib>Thundyil, J</creatorcontrib><creatorcontrib>Widiapradja, A</creatorcontrib><creatorcontrib>Lok, K-Z</creatorcontrib><creatorcontrib>Foo, S L</creatorcontrib><creatorcontrib>Wang, Y-C</creatorcontrib><creatorcontrib>Li, Y-I</creatorcontrib><creatorcontrib>Drummond, G R</creatorcontrib><creatorcontrib>Basta, M</creatorcontrib><creatorcontrib>Magnus, T</creatorcontrib><creatorcontrib>Jo, D-G</creatorcontrib><creatorcontrib>Mattson, M P</creatorcontrib><creatorcontrib>Sobey, C G</creatorcontrib><creatorcontrib>Arumugam, T V</creatorcontrib><title>Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>Multi-protein complexes called inflammasomes have recently been identified and shown to contribute to cell death in tissue injury. Intravenous immunoglobulin (IVIg) is an FDA-approved therapeutic modality used for various inflammatory diseases. The objective of this study is to investigate dynamic responses of the NLRP1 and NLRP3 inflammasomes in stroke and to determine whether the NLRP1 and NLRP3 inflammasomes can be targeted with IVIg for therapeutic intervention. Primary cortical neurons were subjected to glucose deprivation (GD), oxygen–glucose deprivation (OGD) or simulated ischemia-reperfusion (I/R). Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion. Neurological assessment was performed, brain tissue damage was quantified, and NLRP1 and NLRP3 inflammasome protein levels were evaluated. NLRP1 and NLRP3 inflammasome components were also analyzed in postmortem brain tissue samples from stroke patients. Ischemia-like conditions increased the levels of NLRP1 and NLRP3 inflammasome proteins, and IL-1
β
and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1
β
and IL-18 were elevated in ipsilateral brain tissues of cerebral I/R mice and stroke patients. Caspase-1 inhibitor treatment protected cultured cortical neurons and brain cells
in vivo
in experimental stroke models. IVIg treatment protected neurons in experimental stroke models by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Our findings provide evidence that the NLRP1 and NLRP3 inflammasomes have a major role in neuronal cell death and behavioral deficits in stroke. We also identified NLRP1 and NLRP3 inflammasome inhibition as a novel mechanism by which IVIg can protect brain cells against ischemic damage, suggesting a potential clinical benefit of therapeutic interventions that target inflammasome assembly and activity.</description><subject>631/154/51/1568</subject><subject>631/250/256/2177</subject><subject>631/378/1689/534</subject><subject>631/80/82</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Apoptosis Regulatory Proteins - metabolism</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Brain Ischemia - complications</subject><subject>Brain Ischemia - metabolism</subject><subject>Brain Ischemia - pathology</subject><subject>Carrier Proteins - metabolism</subject><subject>Caspase 1 - metabolism</subject><subject>Caspase Inhibitors - pharmacology</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell Death - drug effects</subject><subject>Cells, Cultured</subject><subject>Cerebral Cortex - pathology</subject><subject>Cytoprotection - drug effects</subject><subject>Disease Models, Animal</subject><subject>Humans</subject><subject>Immunoglobulins, Intravenous - pharmacology</subject><subject>Immunology</subject><subject>Inflammasomes - metabolism</subject><subject>Interleukin-18 - metabolism</subject><subject>Interleukin-1beta - metabolism</subject><subject>Life Sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Neurons - drug effects</subject><subject>Neurons - enzymology</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>NLR Family, Pyrin Domain-Containing 3 Protein</subject><subject>Original</subject><subject>original-article</subject><subject>Stroke - complications</subject><subject>Stroke - metabolism</subject><subject>Stroke - pathology</subject><subject>Treatment Outcome</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNqFkc1rFDEYxoMottRePUrAi5fZ5muSzEWQYrWw2FL0HDJJZjd1kqzJTMH_vpluLasUzCVveH953o8HgLcYrTCi8sxY68uKIExXlPAX4JgghhsmZffyID4Cp6XconooRaTlr8ERYQhJQdkxCJdxyvrOxTQX6EOYY9qMqZ9HH2GZd7vsSnEFflvfXGOoo32IKPRxGHUIuqTgmuCs15OzMLo5p6hHaJ2ethWCvpitC97AMuX0070BrwY9Fnf6eJ-AHxefv59_bdZXXy7PP60b01I-NWZoCcdM9r2WjOmWWtxTw0RrBMLIdExYQbjuu44YTkRHSF-fgxVIWCIHSk_Ax73ubu5rd8YtQ45ql33Q-bdK2qu_M9Fv1SbdKSpkhyWrAh8eBXL6NbsyqVBHceOoo6ubUlh0qOOMtvz_KKNIti3ii-r7f9DbNOe6sEVQckIJpqJSqz1lciolu-Gpb4zU4rt68F0tvqvqe_3w7nDaJ_yPyxU42wOlpuLG5YO6z0veA9TAucw</recordid><startdate>20130901</startdate><enddate>20130901</enddate><creator>Yang-Wei Fann, D</creator><creator>Lee, S-Y</creator><creator>Manzanero, S</creator><creator>Tang, S-C</creator><creator>Gelderblom, M</creator><creator>Chunduri, P</creator><creator>Bernreuther, C</creator><creator>Glatzel, M</creator><creator>Cheng, Y-L</creator><creator>Thundyil, J</creator><creator>Widiapradja, A</creator><creator>Lok, K-Z</creator><creator>Foo, S L</creator><creator>Wang, Y-C</creator><creator>Li, Y-I</creator><creator>Drummond, G R</creator><creator>Basta, M</creator><creator>Magnus, T</creator><creator>Jo, D-G</creator><creator>Mattson, M P</creator><creator>Sobey, C G</creator><creator>Arumugam, T V</creator><general>Nature Publishing Group UK</general><general>Springer Nature B.V</general><general>Nature Publishing Group</general><scope>C6C</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>7T5</scope><scope>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20130901</creationdate><title>Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke</title><author>Yang-Wei Fann, D ; Lee, S-Y ; Manzanero, S ; Tang, S-C ; Gelderblom, M ; Chunduri, P ; Bernreuther, C ; Glatzel, M ; Cheng, Y-L ; Thundyil, J ; Widiapradja, A ; Lok, K-Z ; Foo, S L ; Wang, Y-C ; Li, Y-I ; Drummond, G R ; Basta, M ; Magnus, T ; Jo, D-G ; Mattson, M P ; Sobey, C G ; Arumugam, T V</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c536t-cf526148bba844a53d1b3c475c7010c947d726ab992c627922b26afd707d28f33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>631/154/51/1568</topic><topic>631/250/256/2177</topic><topic>631/378/1689/534</topic><topic>631/80/82</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Apoptosis Regulatory Proteins - metabolism</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Brain Ischemia - complications</topic><topic>Brain Ischemia - metabolism</topic><topic>Brain Ischemia - pathology</topic><topic>Carrier Proteins - metabolism</topic><topic>Caspase 1 - metabolism</topic><topic>Caspase Inhibitors - pharmacology</topic><topic>Cell Biology</topic><topic>Cell Culture</topic><topic>Cell Death - drug effects</topic><topic>Cells, Cultured</topic><topic>Cerebral Cortex - pathology</topic><topic>Cytoprotection - drug effects</topic><topic>Disease Models, Animal</topic><topic>Humans</topic><topic>Immunoglobulins, Intravenous - pharmacology</topic><topic>Immunology</topic><topic>Inflammasomes - metabolism</topic><topic>Interleukin-18 - metabolism</topic><topic>Interleukin-1beta - metabolism</topic><topic>Life Sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Neurons - 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Academic</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang-Wei Fann, D</au><au>Lee, S-Y</au><au>Manzanero, S</au><au>Tang, S-C</au><au>Gelderblom, M</au><au>Chunduri, P</au><au>Bernreuther, C</au><au>Glatzel, M</au><au>Cheng, Y-L</au><au>Thundyil, J</au><au>Widiapradja, A</au><au>Lok, K-Z</au><au>Foo, S L</au><au>Wang, Y-C</au><au>Li, Y-I</au><au>Drummond, G R</au><au>Basta, M</au><au>Magnus, T</au><au>Jo, D-G</au><au>Mattson, M P</au><au>Sobey, C G</au><au>Arumugam, T V</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2013-09-01</date><risdate>2013</risdate><volume>4</volume><issue>9</issue><spage>e790</spage><epage>e790</epage><pages>e790-e790</pages><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>Multi-protein complexes called inflammasomes have recently been identified and shown to contribute to cell death in tissue injury. Intravenous immunoglobulin (IVIg) is an FDA-approved therapeutic modality used for various inflammatory diseases. The objective of this study is to investigate dynamic responses of the NLRP1 and NLRP3 inflammasomes in stroke and to determine whether the NLRP1 and NLRP3 inflammasomes can be targeted with IVIg for therapeutic intervention. Primary cortical neurons were subjected to glucose deprivation (GD), oxygen–glucose deprivation (OGD) or simulated ischemia-reperfusion (I/R). Ischemic stroke was induced in C57BL/6J mice by middle cerebral artery occlusion, followed by reperfusion. Neurological assessment was performed, brain tissue damage was quantified, and NLRP1 and NLRP3 inflammasome protein levels were evaluated. NLRP1 and NLRP3 inflammasome components were also analyzed in postmortem brain tissue samples from stroke patients. Ischemia-like conditions increased the levels of NLRP1 and NLRP3 inflammasome proteins, and IL-1
β
and IL-18, in primary cortical neurons. Similarly, levels of NLRP1 and NLRP3 inflammasome proteins, IL-1
β
and IL-18 were elevated in ipsilateral brain tissues of cerebral I/R mice and stroke patients. Caspase-1 inhibitor treatment protected cultured cortical neurons and brain cells
in vivo
in experimental stroke models. IVIg treatment protected neurons in experimental stroke models by a mechanism involving suppression of NLRP1 and NLRP3 inflammasome activity. Our findings provide evidence that the NLRP1 and NLRP3 inflammasomes have a major role in neuronal cell death and behavioral deficits in stroke. We also identified NLRP1 and NLRP3 inflammasome inhibition as a novel mechanism by which IVIg can protect brain cells against ischemic damage, suggesting a potential clinical benefit of therapeutic interventions that target inflammasome assembly and activity.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>24008734</pmid><doi>10.1038/cddis.2013.326</doi><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3789184 |
| source | Nature Open Access; MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Springer Nature OA/Free Journals |
| subjects | 631/154/51/1568 631/250/256/2177 631/378/1689/534 631/80/82 Adaptor Proteins, Signal Transducing - metabolism Animals Antibodies Apoptosis Regulatory Proteins - metabolism Biochemistry Biomedical and Life Sciences Brain Ischemia - complications Brain Ischemia - metabolism Brain Ischemia - pathology Carrier Proteins - metabolism Caspase 1 - metabolism Caspase Inhibitors - pharmacology Cell Biology Cell Culture Cell Death - drug effects Cells, Cultured Cerebral Cortex - pathology Cytoprotection - drug effects Disease Models, Animal Humans Immunoglobulins, Intravenous - pharmacology Immunology Inflammasomes - metabolism Interleukin-18 - metabolism Interleukin-1beta - metabolism Life Sciences Mice Mice, Inbred C57BL Neurons - drug effects Neurons - enzymology Neurons - metabolism Neurons - pathology NLR Family, Pyrin Domain-Containing 3 Protein Original original-article Stroke - complications Stroke - metabolism Stroke - pathology Treatment Outcome |
| title | Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-06T04%3A43%3A06IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Intravenous%20immunoglobulin%20suppresses%20NLRP1%20and%20NLRP3%20inflammasome-mediated%20neuronal%20death%20in%20ischemic%20stroke&rft.jtitle=Cell%20death%20&%20disease&rft.au=Yang-Wei%20Fann,%20D&rft.date=2013-09-01&rft.volume=4&rft.issue=9&rft.spage=e790&rft.epage=e790&rft.pages=e790-e790&rft.issn=2041-4889&rft.eissn=2041-4889&rft_id=info:doi/10.1038/cddis.2013.326&rft_dat=%3Cproquest_pubme%3E4042576211%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1786232137&rft_id=info:pmid/24008734&rfr_iscdi=true |