Plasminogen activator inhibitor-1 influences cerebrovascular complications and death in pneumococcal meningitis
Cerebrovascular complications are common in pneumococcal meningitis and are a main determinant of unfavourable outcome and death. We hypothesized that plasminogen activator inhibitor-1 (PAI-1) is a major contributor to cerebrovascular complications and death in pneumococcal meningitis. In a nationwi...
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| Veröffentlicht in: | Acta neuropathologica 2014-04, Vol.127 (4), p.553-564 |
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| creator | Brouwer, Matthijs C. Meijers, Joost C. M. Baas, Frank van der Ende, Arie Pfister, Hans-Walter Giese, Armin van de Beek, Diederik Koedel, Uwe |
| description | Cerebrovascular complications are common in pneumococcal meningitis and are a main determinant of unfavourable outcome and death. We hypothesized that plasminogen activator inhibitor-1 (PAI-1) is a major contributor to cerebrovascular complications and death in pneumococcal meningitis. In a nationwide prospective cohort study we evaluated the effect of the 4G/5G polymorphism (rs1799889) in
SERPINE1
(coding for PAI-1) on cerebrovascular complications and outcome in adults with pneumococcal meningitis proven by cerebrospinal fluid (CSF) culture. From 2006 to 2011, a total of 991 adult patients with community-acquired bacterial meningitis were included in the cohort and 712 had pneumococcal meningitis. The rs1799889 5G/5G genotype was associated with an increased risk of unfavourable outcome [odds ratio (OR) 1.69, 95 % confidence interval (CI) 1.03–2.78] and mortality (OR 2.20, 95 % CI 1.02–4.86) in white adults with pneumococcal meningitis. rs1799889 was associated with CSF PAI-1 concentrations (
P
= 0.048), and white patients homozygous for the low PAI-1 producing genotype (5G/5G) had a significantly higher risk for cerebral infarctions (
P
= 0.015) and haemorrhages (
P
= 0.005). Subsequently, we assessed the functionality of PAI-1 in a pneumococcal meningitis mouse model, using
Serpine1
knockout mice. Consistent with the human data,
Serpine1
-deficient mice had increased mortality and cerebral haemorrhages compared to wild-type mice. We conclude PAI-1 is protective for death in humans and mice with pneumococcal meningitis by reducing cerebrovascular complications. |
| doi_str_mv | 10.1007/s00401-013-1216-4 |
| format | Article |
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SERPINE1
(coding for PAI-1) on cerebrovascular complications and outcome in adults with pneumococcal meningitis proven by cerebrospinal fluid (CSF) culture. From 2006 to 2011, a total of 991 adult patients with community-acquired bacterial meningitis were included in the cohort and 712 had pneumococcal meningitis. The rs1799889 5G/5G genotype was associated with an increased risk of unfavourable outcome [odds ratio (OR) 1.69, 95 % confidence interval (CI) 1.03–2.78] and mortality (OR 2.20, 95 % CI 1.02–4.86) in white adults with pneumococcal meningitis. rs1799889 was associated with CSF PAI-1 concentrations (
P
= 0.048), and white patients homozygous for the low PAI-1 producing genotype (5G/5G) had a significantly higher risk for cerebral infarctions (
P
= 0.015) and haemorrhages (
P
= 0.005). Subsequently, we assessed the functionality of PAI-1 in a pneumococcal meningitis mouse model, using
Serpine1
knockout mice. Consistent with the human data,
Serpine1
-deficient mice had increased mortality and cerebral haemorrhages compared to wild-type mice. We conclude PAI-1 is protective for death in humans and mice with pneumococcal meningitis by reducing cerebrovascular complications.</description><identifier>ISSN: 0001-6322</identifier><identifier>EISSN: 1432-0533</identifier><identifier>DOI: 10.1007/s00401-013-1216-4</identifier><identifier>PMID: 24248324</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adolescent ; Adult ; Adults ; Animals ; Bacterial meningitis ; Cerebrovascular Disorders - drug therapy ; Cerebrovascular Disorders - etiology ; Cerebrovascular Disorders - mortality ; Cohort analysis ; Cohort Studies ; Disease Models, Animal ; Female ; Genotype ; Health aspects ; Humans ; Infections ; Infectious diseases ; Male ; Medicine ; Medicine & Public Health ; Meningitis ; Meningitis, Pneumococcal - cerebrospinal fluid ; Meningitis, Pneumococcal - complications ; Meningitis, Pneumococcal - genetics ; Mice ; Mice, Knockout ; Middle Aged ; Mortality ; Mutation - genetics ; Neurosciences ; Original Paper ; Pathology ; Plasminogen Activator Inhibitor 1 - cerebrospinal fluid ; Plasminogen Activator Inhibitor 1 - genetics ; Plasminogen Activator Inhibitor 1 - metabolism ; Pneumonia ; Polymorphism ; Proteins ; Sepsis ; Streptococcus pneumoniae ; Stroke ; Young Adult</subject><ispartof>Acta neuropathologica, 2014-04, Vol.127 (4), p.553-564</ispartof><rights>Springer-Verlag Berlin Heidelberg 2013</rights><rights>COPYRIGHT 2014 Springer</rights><rights>Springer-Verlag Berlin Heidelberg 2014</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c472t-a1f6fc6c2a7b7507c02f3836db0afef521bd54a64ad630ab31c571f028886bc53</citedby><cites>FETCH-LOGICAL-c472t-a1f6fc6c2a7b7507c02f3836db0afef521bd54a64ad630ab31c571f028886bc53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00401-013-1216-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00401-013-1216-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27923,27924,41487,42556,51318</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24248324$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brouwer, Matthijs C.</creatorcontrib><creatorcontrib>Meijers, Joost C. M.</creatorcontrib><creatorcontrib>Baas, Frank</creatorcontrib><creatorcontrib>van der Ende, Arie</creatorcontrib><creatorcontrib>Pfister, Hans-Walter</creatorcontrib><creatorcontrib>Giese, Armin</creatorcontrib><creatorcontrib>van de Beek, Diederik</creatorcontrib><creatorcontrib>Koedel, Uwe</creatorcontrib><title>Plasminogen activator inhibitor-1 influences cerebrovascular complications and death in pneumococcal meningitis</title><title>Acta neuropathologica</title><addtitle>Acta Neuropathol</addtitle><addtitle>Acta Neuropathol</addtitle><description>Cerebrovascular complications are common in pneumococcal meningitis and are a main determinant of unfavourable outcome and death. We hypothesized that plasminogen activator inhibitor-1 (PAI-1) is a major contributor to cerebrovascular complications and death in pneumococcal meningitis. In a nationwide prospective cohort study we evaluated the effect of the 4G/5G polymorphism (rs1799889) in
SERPINE1
(coding for PAI-1) on cerebrovascular complications and outcome in adults with pneumococcal meningitis proven by cerebrospinal fluid (CSF) culture. From 2006 to 2011, a total of 991 adult patients with community-acquired bacterial meningitis were included in the cohort and 712 had pneumococcal meningitis. The rs1799889 5G/5G genotype was associated with an increased risk of unfavourable outcome [odds ratio (OR) 1.69, 95 % confidence interval (CI) 1.03–2.78] and mortality (OR 2.20, 95 % CI 1.02–4.86) in white adults with pneumococcal meningitis. rs1799889 was associated with CSF PAI-1 concentrations (
P
= 0.048), and white patients homozygous for the low PAI-1 producing genotype (5G/5G) had a significantly higher risk for cerebral infarctions (
P
= 0.015) and haemorrhages (
P
= 0.005). Subsequently, we assessed the functionality of PAI-1 in a pneumococcal meningitis mouse model, using
Serpine1
knockout mice. Consistent with the human data,
Serpine1
-deficient mice had increased mortality and cerebral haemorrhages compared to wild-type mice. We conclude PAI-1 is protective for death in humans and mice with pneumococcal meningitis by reducing cerebrovascular complications.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Adults</subject><subject>Animals</subject><subject>Bacterial meningitis</subject><subject>Cerebrovascular Disorders - drug therapy</subject><subject>Cerebrovascular Disorders - etiology</subject><subject>Cerebrovascular Disorders - mortality</subject><subject>Cohort analysis</subject><subject>Cohort Studies</subject><subject>Disease Models, Animal</subject><subject>Female</subject><subject>Genotype</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Meningitis</subject><subject>Meningitis, Pneumococcal - cerebrospinal fluid</subject><subject>Meningitis, Pneumococcal - complications</subject><subject>Meningitis, Pneumococcal - genetics</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Middle Aged</subject><subject>Mortality</subject><subject>Mutation - genetics</subject><subject>Neurosciences</subject><subject>Original Paper</subject><subject>Pathology</subject><subject>Plasminogen Activator Inhibitor 1 - cerebrospinal fluid</subject><subject>Plasminogen Activator Inhibitor 1 - genetics</subject><subject>Plasminogen Activator Inhibitor 1 - metabolism</subject><subject>Pneumonia</subject><subject>Polymorphism</subject><subject>Proteins</subject><subject>Sepsis</subject><subject>Streptococcus pneumoniae</subject><subject>Stroke</subject><subject>Young Adult</subject><issn>0001-6322</issn><issn>1432-0533</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkk1v1DAQhi0EosvCD-CCInHpJcXjz-yxqiggVaIHOFsTx966SuzFTir13-Noy6dAqnzw2PO8oxn7JeQ10DOgVL8rlAoKLQXeAgPViidkA4KzlkrOn5INpTWrOGMn5EUpt_XEtJDPyQkTTHSciQ1J1yOWKcS0d7FBO4c7nFNuQrwJfahRCzX24-KidaWxLrs-pzssdhkxNzZNhzFYnEOKpcE4NIPD-aZKmkN0y5RsshbHZnIxxH2YQ3lJnnkci3v1sG_J18v3Xy4-tlefP3y6OL9qrdBsbhG88lZZhrrXkmpLmecdV0NP0TsvGfSDFKgEDopT7DlYqcFT1nWd6q3kW3J6rHvI6dviymymUKwbR4wuLcWApJ2WtaJ6DKphB4yKir79C71NS451kJVSnMNOyV_UHkdn6vOlOaNdi5pzrnccJK__syVn_6DqGtwUbIrOh3r_hwCOAptTKdl5c8hhwnxvgJrVD-boB1P9YFY_mLXhNw8NL_3khp-KHwaoADsCpabi3uXfJvpv1e-a979e</recordid><startdate>20140401</startdate><enddate>20140401</enddate><creator>Brouwer, Matthijs C.</creator><creator>Meijers, Joost C. M.</creator><creator>Baas, Frank</creator><creator>van der Ende, Arie</creator><creator>Pfister, Hans-Walter</creator><creator>Giese, Armin</creator><creator>van de Beek, Diederik</creator><creator>Koedel, Uwe</creator><general>Springer Berlin Heidelberg</general><general>Springer</general><general>Springer Nature B.V</general><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>7TK</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope><scope>7QL</scope><scope>C1K</scope></search><sort><creationdate>20140401</creationdate><title>Plasminogen activator inhibitor-1 influences cerebrovascular complications and death in pneumococcal meningitis</title><author>Brouwer, Matthijs C. ; Meijers, Joost C. M. ; Baas, Frank ; van der Ende, Arie ; Pfister, Hans-Walter ; Giese, Armin ; van de Beek, Diederik ; Koedel, Uwe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c472t-a1f6fc6c2a7b7507c02f3836db0afef521bd54a64ad630ab31c571f028886bc53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Adults</topic><topic>Animals</topic><topic>Bacterial meningitis</topic><topic>Cerebrovascular Disorders - drug therapy</topic><topic>Cerebrovascular Disorders - etiology</topic><topic>Cerebrovascular Disorders - mortality</topic><topic>Cohort analysis</topic><topic>Cohort Studies</topic><topic>Disease Models, Animal</topic><topic>Female</topic><topic>Genotype</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Infections</topic><topic>Infectious diseases</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Meningitis</topic><topic>Meningitis, Pneumococcal - cerebrospinal fluid</topic><topic>Meningitis, Pneumococcal - complications</topic><topic>Meningitis, Pneumococcal - genetics</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Middle Aged</topic><topic>Mortality</topic><topic>Mutation - genetics</topic><topic>Neurosciences</topic><topic>Original Paper</topic><topic>Pathology</topic><topic>Plasminogen Activator Inhibitor 1 - cerebrospinal fluid</topic><topic>Plasminogen Activator Inhibitor 1 - genetics</topic><topic>Plasminogen Activator Inhibitor 1 - metabolism</topic><topic>Pneumonia</topic><topic>Polymorphism</topic><topic>Proteins</topic><topic>Sepsis</topic><topic>Streptococcus pneumoniae</topic><topic>Stroke</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brouwer, Matthijs C.</creatorcontrib><creatorcontrib>Meijers, Joost C. M.</creatorcontrib><creatorcontrib>Baas, Frank</creatorcontrib><creatorcontrib>van der Ende, Arie</creatorcontrib><creatorcontrib>Pfister, Hans-Walter</creatorcontrib><creatorcontrib>Giese, Armin</creatorcontrib><creatorcontrib>van de Beek, Diederik</creatorcontrib><creatorcontrib>Koedel, Uwe</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Psychology Database (ProQuest)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Environmental Sciences and Pollution Management</collection><jtitle>Acta neuropathologica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brouwer, Matthijs C.</au><au>Meijers, Joost C. M.</au><au>Baas, Frank</au><au>van der Ende, Arie</au><au>Pfister, Hans-Walter</au><au>Giese, Armin</au><au>van de Beek, Diederik</au><au>Koedel, Uwe</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Plasminogen activator inhibitor-1 influences cerebrovascular complications and death in pneumococcal meningitis</atitle><jtitle>Acta neuropathologica</jtitle><stitle>Acta Neuropathol</stitle><addtitle>Acta Neuropathol</addtitle><date>2014-04-01</date><risdate>2014</risdate><volume>127</volume><issue>4</issue><spage>553</spage><epage>564</epage><pages>553-564</pages><issn>0001-6322</issn><eissn>1432-0533</eissn><abstract>Cerebrovascular complications are common in pneumococcal meningitis and are a main determinant of unfavourable outcome and death. We hypothesized that plasminogen activator inhibitor-1 (PAI-1) is a major contributor to cerebrovascular complications and death in pneumococcal meningitis. In a nationwide prospective cohort study we evaluated the effect of the 4G/5G polymorphism (rs1799889) in
SERPINE1
(coding for PAI-1) on cerebrovascular complications and outcome in adults with pneumococcal meningitis proven by cerebrospinal fluid (CSF) culture. From 2006 to 2011, a total of 991 adult patients with community-acquired bacterial meningitis were included in the cohort and 712 had pneumococcal meningitis. The rs1799889 5G/5G genotype was associated with an increased risk of unfavourable outcome [odds ratio (OR) 1.69, 95 % confidence interval (CI) 1.03–2.78] and mortality (OR 2.20, 95 % CI 1.02–4.86) in white adults with pneumococcal meningitis. rs1799889 was associated with CSF PAI-1 concentrations (
P
= 0.048), and white patients homozygous for the low PAI-1 producing genotype (5G/5G) had a significantly higher risk for cerebral infarctions (
P
= 0.015) and haemorrhages (
P
= 0.005). Subsequently, we assessed the functionality of PAI-1 in a pneumococcal meningitis mouse model, using
Serpine1
knockout mice. Consistent with the human data,
Serpine1
-deficient mice had increased mortality and cerebral haemorrhages compared to wild-type mice. We conclude PAI-1 is protective for death in humans and mice with pneumococcal meningitis by reducing cerebrovascular complications.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>24248324</pmid><doi>10.1007/s00401-013-1216-4</doi><tpages>12</tpages></addata></record> |
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| ispartof | Acta neuropathologica, 2014-04, Vol.127 (4), p.553-564 |
| issn | 0001-6322 1432-0533 |
| language | eng |
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| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Adolescent Adult Adults Animals Bacterial meningitis Cerebrovascular Disorders - drug therapy Cerebrovascular Disorders - etiology Cerebrovascular Disorders - mortality Cohort analysis Cohort Studies Disease Models, Animal Female Genotype Health aspects Humans Infections Infectious diseases Male Medicine Medicine & Public Health Meningitis Meningitis, Pneumococcal - cerebrospinal fluid Meningitis, Pneumococcal - complications Meningitis, Pneumococcal - genetics Mice Mice, Knockout Middle Aged Mortality Mutation - genetics Neurosciences Original Paper Pathology Plasminogen Activator Inhibitor 1 - cerebrospinal fluid Plasminogen Activator Inhibitor 1 - genetics Plasminogen Activator Inhibitor 1 - metabolism Pneumonia Polymorphism Proteins Sepsis Streptococcus pneumoniae Stroke Young Adult |
| title | Plasminogen activator inhibitor-1 influences cerebrovascular complications and death in pneumococcal meningitis |
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