المؤلفون: Keil,Jason M, Zhao,Peter Y, Durrani,Asad F, Azzouz,Lyna, Huvard,Michael J, Dedania,Vaidehi S, Zacks,David N

مصطلحات موضوعية: Clinical Ophthalmology

الوصف: Jason M Keil,1 Peter Y Zhao,1 Asad F Durrani,1 Lyna Azzouz,1 Michael J Huvard,1 Vaidehi S Dedania,2 David N Zacks1 1Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA; 2Department of Ophthalmology, New York University Langone Health, New York University School of Medicine, New York, NY, USACorrespondence: David N Zacks, Email davzacks@med.umich.eduPurpose: Ocular trauma with intraocular foreign body (IOFB) can have devastating visual consequences. Management and antimicrobial strategies remain variable due to the infrequency and heterogeneity of presentation. Our goal was to identify risk factors for endophthalmitis and poor visual outcomes in cases of IOFB and investigate management strategies.Patients and Methods: A retrospective chart review was conducted in 88 eyes of 88 patients suffering traumatic injury with IOFB at the University of Michigan between January 2000 and December 2019. Medical records were reviewed to characterize the injuries and IOFBs as well as how clinical presentation and treatment modalities were associated with outcomes.Results: Delayed presentation (P=0.016) and organic IOFB (P=0.044) were associated with development of endophthalmitis. Retinal detachment (P=0.012), wound length greater than 5 mm (P=0.041), and poor presenting visual acuity (P=0.003) correlated with poor final visual outcome. Antibiotic prophylaxis was given to all patients, though agents and routes of delivery varied. Endophthalmitis developed in 4.9% of the eyes after initial management, with primary and secondary removal of posterior segment IOFBs associated with similar rates of endophthalmitis (P=1.000).Conclusion: Poor presenting visual acuity and severity of injury, as measured by large wound and retinal detachment, correlate with poor visual outcome. Prompt globe closure and antimicrobial prophylaxis are critical for infection prevention. In cases where IOFB removal and globe closure cannot be performed concurrently, primary globe closure with ...

وصف الملف: text/html

العلاقة: https://www.dovepress.com/endophthalmitis-visual-outcomes-and-management-strategies-in-eyes-with-peer-reviewed-fulltext-article-OPTHTest

الإتاحة: https://doi.org/10.2147/OPTH.S358064Test
https://www.dovepress.com/endophthalmitis-visual-outcomes-and-management-strategies-in-eyes-with-peer-reviewed-fulltext-article-OPTHTest

المؤلفون: Keil, Jason M, Zhao, Peter Y, Durrani, Asad F, Azzouz, Lyna, Huvard, Michael J, Dedania, Vaidehi S, Zacks, David N

المصدر: Clinical Ophthalmology ; volume Volume 16, page 1401-1411 ; ISSN 1177-5483

الإتاحة: https://doi.org/10.2147/opth.s358064Test
https://www.dovepress.com/getfile.php?fileID=80474Test

المؤلفون: Durrani,Asad F, Zhao,Peter Y, Zhou,Yunshu, Huvard,Michael, Azzouz,Lyna, Keil,Jason M, Armenti,Stephen T, Dedania,Vaidehi S, Musch,David C, Zacks,David N

مصطلحات موضوعية: Clinical Ophthalmology

الوصف: Asad F Durrani,1 Peter Y Zhao,1 Yunshu Zhou,1 Michael Huvard,2 Lyna Azzouz,3 Jason M Keil,3 Stephen T Armenti,1 Vaidehi S Dedania,4 David C Musch,1,5 David N Zacks1 1Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, MI, USA; 2Department of Ophthalmology, University of Colorado School of Medicine, Aurora, CO, USA; 3University of Michigan Medical School, Ann Arbor, MI, USA; 4Department of Ophthalmology, NYU Grossman School of Medicine, New York, NY, USA; 5Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USACorrespondence: David N ZacksDepartment of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, 1000 Wall Street, Ann Arbor, MI, 48105, USATel +1 734-232-8404Email Davzacks@med.umich.eduBackground/Aims: To determine the rate of endophthalmitis and assess risk factors for development of endophthalmitis following open globe injury (OGI).Methods: A retrospective chart review of all patients treated for OGI at the University of Michigan from January 2000 to July 2017 was conducted. Exclusion criteria included intravitreal injection or intraocular surgery in the 30 days prior to injury or less than 30 days of follow-up. A total of 586 out of 993 open globe injuries were included in the study. The main outcome measure was the rate of endophthalmitis.Results: In this study, 25/586 eyes (4.3%) had endophthalmitis. Of these, 12/25 eyes (48.0%) presented with endophthalmitis and 13/25 eyes (52.0%) developed endophthalmitis after globe closure. Multivariate analysis identified time to globe repair (OR 4.5, CI 1.9– 10.7, p = 0.0008), zone I injury (OR 3.6, CI 1.1– 11.0, p = 0.0282), and need for additional surgery (OR 5.5, CI 1.5– 19.7, p = 0.0092) as factors associated with increased risk of developing endophthalmitis. Subconjunctival antibiotic injection at the time of globe closure (OR 0.3, CI 0.1– 0.7, p = 0.0036) was associated with decreased risk of developing endophthalmitis.Conclusion: ...

وصف الملف: text/html

العلاقة: https://www.dovepress.com/risk-factors-for-endophthalmitis-following-open-globe-injuries-a-17-ye-peer-reviewed-fulltext-article-OPTHTest

الإتاحة: https://doi.org/10.2147/OPTH.S307718Test
https://www.dovepress.com/risk-factors-for-endophthalmitis-following-open-globe-injuries-a-17-ye-peer-reviewed-fulltext-article-OPTHTest

المؤلفون: Durrani, Asad F, Zhao, Peter Y, Zhou, Yunshu, Huvard, Michael, Azzouz, Lyna, Keil, Jason M, Armenti, Stephen T, Dedania, Vaidehi S, Musch, David C, Zacks, David N

المصدر: Clinical Ophthalmology ; volume Volume 15, page 2077-2087 ; ISSN 1177-5483

الإتاحة: https://doi.org/10.2147/opth.s307718Test
https://www.dovepress.com/getfile.php?fileID=69474Test

المؤلفون: Keil, Jason M., Doyle, Daniel Z., Qalieh, Adel, Lam, Mandy M., Funk, Owen H., Qalieh, Yaman, Shi, Lei, Mohan, Nitesh, Sorel, Alice, Kwan, Kenneth Y.

المصدر: Nature Communications ; volume 11, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: Chromatin regulates spatiotemporal gene expression during neurodevelopment, but it also mediates DNA damage repair essential to proliferating neural progenitor cells (NPCs). Here, we uncover molecularly dissociable roles for nucleosome remodeler Ino80 in chromatin-mediated transcriptional regulation and genome maintenance in corticogenesis. We find that conditional Ino80 deletion from cortical NPCs impairs DNA double-strand break (DSB) repair, triggering p53-dependent apoptosis and microcephaly. Using an in vivo DSB repair pathway assay, we find that Ino80 is selectively required for homologous recombination (HR) DNA repair, which is mechanistically distinct from Ino80 function in YY1-associated transcription. Unexpectedly, sensitivity to loss of Ino80 -mediated HR is dependent on NPC division mode: Ino80 deletion leads to unrepaired DNA breaks and apoptosis in symmetric NPC-NPC divisions, but not in asymmetric neurogenic divisions. This division mode dependence is phenocopied following conditional deletion of HR gene Brca2 . Thus, distinct modes of NPC division have divergent requirements for Ino80 -dependent HR DNA repair.

الإتاحة: https://doi.org/10.1038/s41467-020-17551-4Test
https://www.nature.com/articles/s41467-020-17551-4.pdfTest
https://www.nature.com/articles/s41467-020-17551-4Test

المؤلفون: Shi, Lei, Qalieh, Adel, Lam, Mandy M., Keil, Jason M., Kwan, Kenneth Y.

المساهمون: U.S. Department of Health & Human Services | National Institutes of Health, Autism Science Foundation, Brain Research Foundation, Simons Foundation, March of Dimes Foundation

المصدر: Nature Communications ; volume 10, issue 1 ; ISSN 2041-1723

مصطلحات موضوعية: General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary

الوصف: The brain is a genomic mosaic shaped by cellular responses to genome damage. Here, we manipulate somatic genome stability by conditional Knl1 deletion from embryonic mouse brain. KNL1 mutations cause microcephaly and KNL1 mediates the spindle assembly checkpoint, a safeguard against chromosome missegregation and aneuploidy. We find that following Knl1 deletion, segregation errors in mitotic neural progenitor cells give rise to DNA damage on the missegregated chromosomes. This triggers rapid p53 activation and robust apoptotic and microglial phagocytic responses that extensively eliminate cells with somatic genome damage, thus causing microcephaly. By leaving only karyotypically normal progenitors to continue dividing, these mechanisms provide a second safeguard against brain somatic aneuploidy. Without Knl1 or p53-dependent safeguards, genome-damaged cells are not cleared, alleviating microcephaly, but paradoxically leading to total pre-weaning lethality. Thus, mitotic genome damage activates robust responses to eliminate somatic mutant cells, which if left unpurged, can impact brain and organismal fitness.

الإتاحة: https://doi.org/10.1038/s41467-019-10411-wTest
https://www.nature.com/articles/s41467-019-10411-w.pdfTest
https://www.nature.com/articles/s41467-019-10411-wTest

المؤلفون: Lin, Cheng-mao, Titchenell, Paul M., Keil, Jason M., Garcia-Ocaña, Adolfo, Bolinger, Mark T., Abcouwer, Steven F., Antonetti, David A.

المساهمون: Juvenile Diabetes Research Foundation United States of America, Research to Prevent Blindness, National Eye Institute, National Institutes of Health

المصدر: The American Journal of Pathology ; volume 188, issue 10, page 2392-2405 ; ISSN 0002-9440

مصطلحات موضوعية: Pathology and Forensic Medicine

الإتاحة: https://doi.org/10.1016/j.ajpath.2018.06.020Test
https://api.elsevier.com/content/article/PII:S0002944018301627?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0002944018301627?httpAccept=text/plainTest

المؤلفون: Tash, Brian R., Bewley, Maria C., Russo, Mariano, Keil, Jason M., Griffin, Kathleen A., Sundstrom, Jeffrey M., Antonetti, David A., Tian, Fang, Flanagan, John M.

المصدر: Proceedings of the National Academy of Sciences of the United States of America, 2012 Jul 01. 109(27), 10855-10860.

الوصول الحر: https://www.jstor.org/stable/41601694Test

المؤلفون: Bott, Christopher J., McMahon, Lloyd P., Keil, Jason M., Chan Choo Yap, Kwan, Kenneth Y., Winckler, Bettina

المصدر: Journal of Neuroscience; 5/6/2020, Vol. 40 Issue 19, p3720-3740, 21p

مصطلحات موضوعية: INTERMEDIATE filament proteins, CONES, MORPHOLOGY, NEURONS, NESTIN

مستخلص: Nestin, an intermediate filament protein widely used as a marker of neural progenitors, was recently found to be expressed transiently in developing cortical neurons in culture and in developing mouse cortex. In young cortical cultures, nestin regulates axonal growth cone morphology. In addition, nestin, which is known to bind the neuronal cdk5/p35 kinase, affects responses to axon guidance cues upstream of cdk5, specifically, to Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, and changes in microtubules and actin filaments are well studied. In contrast, the roles of intermediate filament proteins in this process are poorly understood, even in cultured neurons. Here, we investigate the molecular mechanism by which nestin affects growth cone morphology and Sema3a sensitivity. We find that nestin selectively facilitates the phosphorylation of the lissencephaly-linked protein doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected by nestin. We uncover that this substrate selectivity is based on the ability of nestin to interact with DCX, but not with other cdk5 substrates. Nestin thus creates a selective scaffold for DCX with activated cdk5/p35. Last, we use cortical cultures derived from Dcx KO mice to show that the effects of nestin on growth cone morphology and on Sema3a sensitivity are DCX-dependent, thus suggesting a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating the intracellular kinase signaling environment in developing neurons. The sex of animal subjects is unknown. [ABSTRACT FROM AUTHOR]

: Copyright of Journal of Neuroscience is the property of Society for Neuroscience and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Titchenell, Paul M., Lin, Cheng-Mao, Keil, Jason M., Sundstrom, Jeffrey M., Smith, Charles D., Antonetti, David A.

المصدر: Biochemical Journal ; volume 446, issue 3, page 455-467 ; ISSN 0264-6021 1470-8728

الوصف: Pro-inflammatory cytokines and growth factors such as VEGF (vascular endothelial growth factor) contribute to the loss of the BRB (blood–retinal barrier) and subsequent macular oedema in various retinal pathologies. VEGF signalling requires PKCβ [conventional PKC (protein kinase C)] activity; however, PKCβ inhibition only partially prevents VEGF-induced endothelial permeability and does not affect pro-inflammatory cytokine-induced permeability, suggesting the involvement of alternative signalling pathways. In the present study, we provide evidence for the involvement of aPKC (atypical PKC) signalling in VEGF-induced endothelial permeability and identify a novel class of inhibitors of aPKC that prevent BRB breakdown in vivo. Genetic and pharmacological manipulations of aPKC isoforms were used to assess their contribution to endothelial permeability in culture. A chemical library was screened using an in vitro kinase assay to identify novel small-molecule inhibitors, and further medicinal chemistry was performed to delineate a novel pharmacophore. We demonstrate that aPKC isoforms are both sufficient and required for VEGF-induced endothelial permeability. Furthermore, these specific, potent, non-competitive, small-molecule inhibitors prevented VEGF-induced tight junction internalization and retinal endothelial permeability in response to VEGF in both primary culture and in rodent retina. The results of the present study suggest that aPKC inhibition with 2-amino-4-phenyl-thiophene derivatives may be developed to preserve the BRB in retinal diseases such as diabetic retinopathy or uveitis, and the BBB (blood–brain barrier) in the presence of brain tumours.

الإتاحة: https://doi.org/10.1042/bj20111961Test
https://portlandpress.com/biochemj/article-pdf/446/3/455/672743/bj4460455.pdfTest