9 results on '"Wynants S"'
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2. Spontaneous corneal perforation and endophtalmitis in pseudomonas aeruginosa infection in a ventilated patient: a case report
- Author
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Wynants S, Koppen C, and Marie-José Tassignon
- Subjects
Male ,Endophthalmitis ,Multiple Trauma ,Multiple Organ Failure ,Sepsis ,Pseudomonas aeruginosa ,Humans ,Pseudomonas Infections ,Middle Aged ,Corneal Ulcer ,Respiration, Artificial ,Respiratory Tract Infections - Abstract
We report a case of Pseudomonas keratitis and endophthalmitis after inoculation from the respiratory tract in a mechanically ventilated patient. In these (semi)comatose and more vulnerable patients, colonisation of the upper respiratory tract by Pseudomonas occurs frequently, and this can lead to inoculation of the eyes. Emphasis lies on careful prevention of ocular inoculation and aggressive therapy as soon as keratitis is noticed.
3. Deciphering Distinct Genetic Risk Factors for FTLD-TDP Pathological Subtypes via Whole-Genome Sequencing.
- Author
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Pottier C, Küçükali F, Baker M, Batzler A, Jenkins GD, van Blitterswijk M, Vicente CT, De Coster W, Wynants S, Van de Walle P, Ross OA, Murray ME, Faura J, Haggarty SJ, van Rooij JG, Mol MO, Hsiung GR, Graff C, Öijerstedt L, Neumann M, Asmann Y, McDonnell SK, Baheti S, Josephs KA, Whitwell JL, Bieniek KF, Forsberg L, Heuer H, Lago AL, Geier EG, Yokoyama JS, Oddi AP, Flanagan M, Mao Q, Hodges JR, Kwok JB, Domoto-Reilly K, Synofzik M, Wilke C, Onyike C, Dickerson BC, Evers BM, Dugger BN, Munoz DG, Keith J, Zinman L, Rogaeva E, Suh E, Gefen T, Geula C, Weintraub S, Diehl-Schmid J, Farlow MR, Edbauer D, Woodruff BK, Caselli RJ, Donker Kaat LL, Huey ED, Reiman EM, Mead S, King A, Roeber S, Nana AL, Ertekin-Taner N, Knopman DS, Petersen RC, Petrucelli L, Uitti RJ, Wszolek ZK, Ramos EM, Grinberg LT, Gorno Tempini ML, Rosen HJ, Spina S, Piguet O, Grossman M, Trojanowski JQ, Keene DC, Lee-Way J, Prudlo J, Geschwind DH, Rissman RA, Cruchaga C, Ghetti B, Halliday GM, Beach TG, Serrano GE, Arzberger T, Herms J, Boxer AL, Honig LS, Vonsattel JP, Lopez OL, Kofler J, White CL, Gearing M, Glass J, Rohrer JD, Irwin DJ, Lee EB, Van Deerlin V, Castellani R, Mesulam MM, Tartaglia MC, Finger EC, Troakes C, Al-Sarraj S, Miller BL, Seelaar H, Graff-Radford NR, Boeve BF, Mackenzie IR, van Swieten JC, Seeley WW, Sleegers K, Dickson DW, Biernacka JM, and Rademakers R
- Abstract
Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyses, we further identify for the first time genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified VIPR1 , RBPJL , and L3MBTL1 as novel subtype specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signalling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.
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- 2024
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4. Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.
- Author
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Vandebergh M, Ramos EM, Corriveau-Lecavalier N, Ramanan VK, Kornak J, Mester C, Kolander T, Brushaber D, Staffaroni AM, Geschwind D, Wolf A, Kantarci K, Gendron TF, Petrucelli L, Van den Broeck M, Wynants S, Baker MC, Borrego-Écija S, Appleby B, Barmada S, Bozoki A, Clark D, Darby RR, Dickerson BC, Domoto-Reilly K, Fields JA, Galasko DR, Ghoshal N, Graff-Radford N, Grant IM, Honig LS, Hsiung GR, Huey ED, Irwin D, Knopman DS, Kwan JY, Léger GC, Litvan I, Masdeu JC, Mendez MF, Onyike C, Pascual B, Pressman P, Ritter A, Roberson ED, Snyder A, Sullivan AC, Tartaglia MC, Wint D, Heuer HW, Forsberg LK, Boxer AL, Rosen HJ, Boeve BF, and Rademakers R
- Abstract
Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients., Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP , symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR
® +NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted., Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model., Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms., Competing Interests: The ALLFTD consortium is funded by the National Institute on Aging (NIA) and the National Institute of Neurological Diseases and Stroke (NINDS) (U19: AG063911). The former ARTFL and LEFFTDS consortia received funding from the NIA, NINDS and National Center for Advancing Translational Science (U54 NS092089, U01 AG045390). Samples from the National Centralized Repository for Alzheimer Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24 AG021886) awarded by the National Institute on Aging (NIA), were used in this study. M. Vandebergh received funding from the Queen Elisabeth Medical Foundation of Neurosciences (GSKE). E.M. Ramos receives research support from the NIH. N. Corriveau-Lecavalier reports no disclosures relevant to the manuscript. V.K. Ramanan has received research funding from the NIH and the Mangurian Foundation for Lewy Body disease research, has provided educational content for Medscape, has received speaker and conference session honoraria from the American Academy of Neurology Institute, is co-PI for a clinical trial supported by the Alzheimer’s Association, is site Co-I for the Alzheimer’s Clinical Trials Consortium, and is a site clinician for clinical trials supported by Eisai, the Alzheimer’s Treatment and Research Institute at USC, and Transposon Therapeutics, Inc. J. Kornak has provided expert witness testimony for Teva Pharmaceuticals in Forest Laboratories Inc. et al. v. Teva Pharmaceuticals USA, Inc., case numbers 1:14-cv-00121 and 1:14-cv-00686 (D. Del. filed 31 January 2014 and 30 May 2014 regarding the drug Memantine) and for Apotex/HEC/Ezra in Novartis AG et al. v. Apotex Inc., case number 1:15-cv-975 (D. Del. filed 26 October 2015 regarding the drug Fingolimod). He has also given testimony on behalf of Puma Biotechnology in Hsingching Hsu et al, vs. Puma Biotechnology, Inc., et al. 2018 regarding the drug Neratinib. He receives research support from the NIH. C. Mester reports no disclosures relevant to the manuscript. T. Kolander reports no disclosures relevant to the manuscript. D. Brushaber reports no disclosures relevant to the manuscript. A.M. Staffaroni received research support from the NIA/NIH, the Bluefield Project to Cure FTD, the Association for Frontotemporal Dementia, the ALS Association, the Rainwater Charitable Foundation, and the Larry L. Hillblom Foundation. He has provided consultation to Alector, Lilly/Prevail Therapeutics, Passage Bio, and Takeda. He serves on the scientific review board for ADDF. D. Geschwind reports no disclosures relevant to the manuscript. A. Wolf reports no disclosures relevant to the manuscript. K. Kantarci served on the Data Safety Monitoring Board for Takeda Global Research & Development Center and data monitoring boards of Pfizer and Janssen Alzheimer Immunotherapy and received research support from Avid Radiopharmaceuticals, Eli Lilly, the Alzheimer’s Drug Discovery Foundation and the NIH. T.F. Gendron receives research support from the NIH. L. Petrucelli receives research support from the NIH. M. Van den Broeck reports no disclosures relevant to the manuscript. S. Wynants reports no disclosures relevant to the manuscript. M.C. Baker reports no disclosures relevant to the manuscript. S. Borrego-Écija is a recipient of the Joan Rodés Josep Baselga grant from the FBBVA. B. Appleby receives research support from the Centers for Disease Control and Prevention, the National Institutes of Health (NIH), Ionis, Alector and the CJD Foundation. He has provided consultation to Acadia, Ionis and Sangamo. S. Barmada reports no disclosures relevant to the manuscript. A. Bozoki reports no disclosures relevant to the manuscript. D. Clark reports no disclosures relevant to the manuscript. R.R Darby reports no disclosures relevant to the manuscript. B.C. Dickerson is a consultant for Acadia, Alector, Arkuda, Biogen, Denali, Eisai, Genentech, Lilly, Merck, Novartis, Takeda and Wave Lifesciences, receives royalties from Cambridge University Press, Elsevier and Oxford University Press, and receives grant funding from the NIA, the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health and the Bluefield Foundation. K. Domoto-Reilly receives research support from the NIH and serves as an investigator for a clinical trial sponsored by Lawson Health Research Institute. J.A. Fields receives research support from the NIH. D. R. Galasko reports no disclosures relevant to the manuscript. N.Ghoshal has participated or is currently participating in clinical trials of anti-dementia drugs sponsored by Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals, Janssen Immunotherapy, Novartis, Pfizer, Wyeth, SNIFF (The Study of Nasal Insulin to Fight Forgetfulness) and the A4 (The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease) trial. She receives research support from Tau Consortium and the Association for Frontotemporal Dementia and is funded by the NIH. N. Graff-Radford receives royalties from UpToDate and has participated in multicenter therapy studies by sponsored by Biogen, TauRx, and Lilly. He receives research support from the NIH. I.M. Grant reports no disclosures relevant to the manuscript. L.S. Honig receives research funding from Abbvie, Acumen, Alector, Biogen, BMS, Eisai, Genentech/Roche, Janssen/J&J, Transposon, UCB, Vaccinex, and consulting fees from Biogen, Cortexyme, Eisai, Medscape, Prevail/Lilly. G-Y R Hsiung has served as an investigator for clinical trials sponsored by AstraZeneca, Eli Lilly and Roche/Genentech. He receives research support from the Canadian Institutes of Health Research and the Alzheimer Society of British Columbia. E.D. Huey receives research support from the NIH. D. Irwin receives support from the NIH, BrightFocus Foundation and Penn Institute on Aging. D.S. Knopman serves on the data and safety monitoring board of the DIAN-TU study; is a site principal investigator for clinical trials sponsored by Biogen, Lilly and the University of Southern California; and is funded by the NIH. J. Kwan reports no disclosures relevant to the manuscript. G.C. Léger reports no disclosures relevant to the manuscript. I. Litvan is supported by the National Institutes of Health grants: 2R01AG038791-06A, U01NS100610, U01NS80818, R25NS098999; U19 AG063911-1 and 1R21NS114764-01A1; the Michael J Fox Foundation, Parkinson Foundation, Lewy Body Association, CurePSP, Roche, Abbvie, Biogen, Centogene. EIP-Pharma, Biohaven Pharmaceuticals, Novartis, Brain Neurotherapy Bio and United Biopharma SRL - UCB. She is a Scientific advisor for Amydis and Rossy Center for Progressive Supranuclear Palsy University of Toronto. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. J.S. Masdeu reports no disclosures relevant to the manuscript. M.F. Mendez receives research support from the NIH. C.U Onyike receives research funding from the NIH, Lawton Health Research Institute, National Ataxia Foundation, Alector and Transposon. He is also supported by the Robert and Nancy Hall Brain Research Fund, the Jane Tanger Black Fund for Young-Onset Dementias and a gift from Joseph Trovato. He is a consultant with Alector Inc., Acadia Pharmaceuticals, and Reata Pharmaceuticals. B. Pascual reports no disclosures relevant to the manuscript. P. Pressman reports no disclosures relevant to the manuscript. A. Ritter reports no disclosures relevant to the manuscript. E.D. Roberson has received research support from the NIH, the Bluefield Project to Cure Frontotemporal Dementia, the Alzheimer’s Association, the Alzheimer’s Drug Discovery Foundation, the BrightFocus Foundation, and Alector; has served as a consultant for AGTC and on a data monitoring committee for Lilly; and owns intellectual property related to tau and progranulin. A. Snyder reports no disclosures relevant to the manuscript. A Campbell Sullivan reports no disclosures relevant to the manuscript. M.C. Tartaglia has served as an investigator for clinical trials sponsored by Biogen, Avanex, Green Valley, Roche/Genentech, Bristol Myers Squibb, Eli Lilly/Avid Radiopharmaceuticals and Janssen. She receives research support from the Canadian Institutes of Health Research. D. Wint reports no disclosures relevant to the manuscript. H.W. Heuer reports no disclosures relevant to the manuscript. L.K. Forsberg reports no disclosures relevant to the manuscript. A.L. Boxer receives research support from the NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer’s Drug Discovery Foundation and the Alzheimer’s Association. He has served as a consultant for Aeovian, AGTC, Alector, Arkuda, Arvinas, Boehringer Ingelheim, Denali, GSK, Life Edit, Humana, Oligomerix, Oscotec, Roche, TrueBinding, Wave, Merck and received research support from Biogen, Eisai and Regeneron. H.J. Rosen has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience, Ionis Pharmaceuticals, Eisai Pharmaceuticals, and Genentech, and receives research support from the NIH and the state of California. B.F. Boeve has served as an investigator for clinical trials sponsored by Alector, Biogen, Transposon and Cognition Therapeutics. He serves on the Scientific Advisory Board of the Tau Consortium which is funded by the Rainwater Charitable Foundation. He receives research support from NIH. R.R. receives research funding from the NIH and the Bluefield Project to Cure Frontotemporal Dementia. R.R. is on the scientific advisory board of Arkuda Therapeutics and receives royalties from progranulin-related patent. She is also on the scientific advisory board of the Foundation Alzheimer.- Published
- 2024
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5. C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes.
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T Vicente C, Perneel J, Wynants S, Heeman B, Van den Broeck M, Baker M, Cheung S, Faura J, Mackenzie IRA, and Rademakers R
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- Humans, Haplotypes, Cryoelectron Microscopy, Membrane Proteins genetics, Membrane Proteins metabolism, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Brain pathology, Frontotemporal Dementia pathology, Frontotemporal Lobar Degeneration pathology
- Abstract
Transmembrane protein 106B (TMEM106B) is a tightly regulated glycoprotein predominantly localized to endosomes and lysosomes. Genetic studies have implicated TMEM106B haplotypes in the development of multiple neurodegenerative diseases with the strongest effect in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), especially in progranulin (GRN) mutation carriers. Recently, cryo-electron microscopy studies showed that a C-terminal fragment (CTF) of TMEM106B (amino acid residues 120-254) forms amyloid fibrils in the brain of patients with FTLD-TDP, but also in brains with other neurodegenerative conditions and normal ageing brain. The functional implication of these fibrils and their relationship to the disease-associated TMEM106B haplotype remain unknown. We performed immunoblotting using a newly developed antibody to detect TMEM106B CTFs in the sarkosyl-insoluble fraction of post-mortem human brain tissue from patients with different proteinopathies (n = 64) as well as neuropathologically normal individuals (n = 10) and correlated the results with age and TMEM106B haplotype. We further compared the immunoblot results with immunohistochemical analyses performed in the same study population. Immunoblot analysis showed the expected ∼30 kDa band in the sarkosyl-insoluble fraction of frontal cortex tissue in at least some individuals with each of the conditions evaluated. Most patients with GRN mutations showed an intense band representing TMEM106B CTF, whereas in most neurologically normal individuals it was absent or much weaker. In the overall cohort, the presence of TMEM106B CTFs correlated strongly with both age (rs = 0.539, P < 0.001) and the presence of the TMEM106B risk haplotype (rs = 0.469, P < 0.001). Although there was a strong overall correlation between the results of immunoblot and immunohistochemistry (rs = 0.662, P < 0.001), 27 cases (37%) were found to have higher amounts of TMEM106B CTFs detected by immunohistochemistry, including most of the older individuals who were neuropathologically normal and individuals who carried two protective TMEM106B haplotypes. Our findings suggest that the formation of sarkosyl-insoluble TMEM106B CTFs is an age-related feature which is modified by TMEM106B haplotype, potentially underlying its disease-modifying effect. The discrepancies between immunoblot and immunohistochemistry in detecting TMEM106B pathology suggests the existence of multiple species of TMEM106B CTFs with possible biological relevance and disease implications., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2023
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6. Limbic-predominant age-related TDP-43 proteinopathy (LATE-NC) is associated with abundant TMEM106B pathology.
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Neumann M, Perneel J, Cheung S, Van den Broeck M, Nygaard H, Hsiung GR, Wynants S, Heeman B, Rademakers R, and Mackenzie IRA
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- Humans, Brain pathology, Membrane Proteins, Nerve Tissue Proteins, TDP-43 Proteinopathies pathology, Alzheimer Disease pathology
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- 2023
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7. Accumulation of TMEM106B C-terminal fragments in neurodegenerative disease and aging.
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Perneel J, Neumann M, Heeman B, Cheung S, Van den Broeck M, Wynants S, Baker M, Vicente CT, Faura J, Rademakers R, and Mackenzie IRA
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- Humans, Intercellular Signaling Peptides and Proteins, Membrane Proteins genetics, Membrane Proteins metabolism, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Aging genetics, Frontotemporal Dementia genetics, Frontotemporal Dementia pathology, Neurodegenerative Diseases genetics, Frontotemporal Lobar Degeneration genetics
- Abstract
Several studies using cryogenic electron microscopy (cryo-EM) techniques recently reported the isolation and characterization of novel protein filaments, composed of a C-terminal fragment (CTF) of the endolysosomal transmembrane protein 106B (TMEM106B), from human post-mortem brain tissue with various neurodegenerative conditions and normal aging. Genetic variation in TMEM106B is known to influence the risk and presentation of several neurodegenerative diseases, especially frontotemporal dementia (FTD) caused by mutations in the progranulin gene (GRN). To further elucidate the significance of TMEM106B CTF, we performed immunohistochemistry with antibodies directed against epitopes within the filament-forming C-terminal region of TMEM106B. Accumulation of TMEM106B C-terminal immunoreactive (TMEM-ir) material was a common finding in all the conditions evaluated, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), Alzheimer's disease, tauopathies, synucleinopathies and neurologically normal aging. TMEM-ir material was present in a wide range of brain cell types and in a broad neuroanatomical distribution; however, there was no co-localization of TMEM-ir material with other neurodegenerative proteins in cellular inclusions. In most conditions, the presence and abundance of TMEM-ir aggregates correlated strongly with patient age and showed only a weak correlation with the TMEM106B haplotype or the primary pathological diagnosis. However, all patients with FTD caused by GRN mutations were found to have high levels of TMEM-ir material, including several who were relatively young (< 60 years). These findings suggest that the accumulation of TMEM106B CTF is a common age-related phenomenon, which may reflect lysosomal dysfunction. Although its significance in most neurodegenerative conditions remains uncertain, the consistent finding of extensive TMEM-ir material in cases of FTLD-TDP with GRN mutations further supports a pathomechanistic role of TMEM106B and lysosomal dysfunction in this specific disease population., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2023
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8. Correction to: Accumulation of TMEM106B C‑terminal fragments in neurodegenerative disease and aging.
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Perneel J, Neumann M, Heeman B, Cheung S, Van den Broeck M, Wynants S, Baker M, Vicente CT, Faura J, Rademakers R, and Mackenzie IRA
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- 2023
- Full Text
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9. Spontaneous corneal perforation and endophthalmitis in Pseudomonas aeruginosa infection in a ventilated patient: a case report.
- Author
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Wynants S, Koppen C, and Tassignon MJ
- Subjects
- Corneal Ulcer therapy, Endophthalmitis therapy, Humans, Male, Middle Aged, Multiple Organ Failure complications, Multiple Trauma complications, Pseudomonas Infections therapy, Respiration, Artificial, Sepsis complications, Corneal Ulcer microbiology, Endophthalmitis microbiology, Pseudomonas Infections microbiology, Pseudomonas aeruginosa isolation & purification, Respiratory Tract Infections complications
- Abstract
We report a case of Pseudomonas keratitis and endophthalmitis after inoculation from the respiratory tract in a mechanically ventilated patient. In these (semi)comatose and more vulnerable patients, colonisation of the upper respiratory tract by Pseudomonas occurs frequently, and this can lead to inoculation of the eyes. Emphasis lies on careful prevention of ocular inoculation and aggressive therapy as soon as keratitis is noticed.
- Published
- 2000
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