37 results on '"OPTIC-NERVE"'
Search Results
2. Immune stimulation recruits a subset of pro-regenerative macrophages to the retina that promotes axonal regrowth of injured neurons
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Lien Andries, Daliya Kancheva, Luca Masin, Isabelle Scheyltjens, Hannah Van Hove, Karen De Vlaminck, Steven Bergmans, Marie Claes, Lies De Groef, Lieve Moons, Kiavash Movahedi, Brussels Heritage Lab, Department of Bio-engineering Sciences, Cellular and Molecular Immunology, Laboratory of Molecullar and Cellular Therapy, Faculty of Sciences and Bioengineering Sciences, and Basic (bio-) Medical Sciences
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Retinal Ganglion Cells ,MONOCYTE-DERIVED MACROPHAGES ,Neuroscience(all) ,Immunology ,ONCOMODULIN ,Retina ,Pathology and Forensic Medicine ,MICROGLIA ,Cellular and Molecular Neuroscience ,INFLAMMATION ,Animals ,Mammals ,Science & Technology ,IDENTIFICATION ,Macrophages ,Neurosciences ,INHIBITOR ,Axons ,inflammation ,Optic Nerve Injuries ,Neurosciences & Neurology ,SULFATE PROTEOGLYCAN ,FUNCTIONAL RECOVERY ,Neurology (clinical) ,SPINAL-CORD ,Life Sciences & Biomedicine ,OPTIC-NERVE - Abstract
The multifaceted nature of neuroinflammation is highlighted by its ability to both aggravate and promote neuronal health. While in mammals retinal ganglion cells (RGCs) are unable to regenerate following injury, acute inflammation can induce axonal regrowth. However, the nature of the cells, cellular states and signalling pathways that drive this inflammation-induced regeneration have remained elusive. Here, we investigated the functional significance of macrophages during RGC de- and regeneration, by characterizing the inflammatory cascade evoked by optic nerve crush (ONC) injury, with or without local inflammatory stimulation in the vitreous. By combining single-cell RNA sequencing and fate mapping approaches, we elucidated the response of retinal microglia and recruited monocyte-derived macrophages (MDMs) to RGC injury. Importantly, inflammatory stimulation recruited large numbers of MDMs to the retina, which exhibited long-term engraftment and promoted axonal regrowth. Ligand-receptor analysis highlighted a subset of recruited macrophages that exhibited expression of pro-regenerative secreted factors, which were able to promote axon regrowth via paracrine signalling. Our work reveals how inflammation may promote CNS regeneration by modulating innate immune responses, providing a rationale for macrophage-centred strategies for driving neuronal repair following injury and disease. ispartof: ACTA NEUROPATHOLOGICA COMMUNICATIONS vol:11 issue:1 ispartof: location:England status: published
- Published
- 2023
3. Microstructural Visual Pathway White Matter Alterations in Primary Open-Angle Glaucoma
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S. Haykal, A. Invernizzi, J. Carvalho, N.M. Jansonius, F.W. Cornelissen, and Perceptual and Cognitive Neuroscience (PCN)
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genetic structures ,DTI PARAMETERS ,Leukoaraiosis ,SEGMENTATION ,White Matter ,eye diseases ,DIFFUSION ,ATROPHY ,INTEGRITY ,Diffusion Magnetic Resonance Imaging ,Diffusion Tensor Imaging ,SEVERITY ,Neurites ,Humans ,Radiology, Nuclear Medicine and imaging ,Visual Pathways ,Neurology (clinical) ,sense organs ,LATERAL GENICULATE-NUCLEUS ,BRAIN CONNECTIVITY ,Head & Neck ,Glaucoma, Open-Angle ,OPTIC-NERVE ,MRI - Abstract
BACKGROUND AND PURPOSE: DTI studies of patients with primary open-angle glaucoma have demonstrated that glaucomatous degeneration is not confined to the retina but involves the entire visual pathway. Due to the lack of direct biologic interpretation of DTI parameters, the structural nature of this degeneration is still poorly understood. We used neurite orientation dispersion and density imaging (NODDI) to characterize the microstructural changes in the pregeniculate optic tracts and the postgeniculate optic radiations of patients with primary open-angle glaucoma, to better understand the mechanisms underlying these changes. MATERIALS AND METHODS: T1- and multishell diffusion-weighted scans were obtained from 23 patients with primary open-angle glaucoma and 29 controls. NODDI parametric maps were produced from the diffusion-weighted scans, and probabilistic tractography was used to track the optic tracts and optic radiations. NODDI parameters were computed for the tracked pathways, and the measures were compared between both groups. The retinal nerve fiber layer thickness and visual field loss were assessed for the patients with glaucoma. RESULTS: The optic tracts of the patients with glaucoma showed a higher orientation dispersion index and a lower neurite density index compared with the controls (P
- Published
- 2022
4. Impacts of <scp> Camellia sinensis </scp> fermentation end‐product (black tea) on retinal microvasculature: an updated <scp>OCTA</scp> analysis
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Ozgur Erogul, Anar Alizada, Mehmet Akif Seylan, Mustafa Dogan, Furkan Fatih Gulyesil, Hamidu Hamisi Gobeka, Muberra Akdogan, Mehmet Cem Sabaner, and Belirlenecek
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Male ,Acute effects ,030309 nutrition & dietetics ,Camellia sinensis ,Ocular physiology ,chemistry.chemical_compound ,Foveal ,Macula Lutea ,Prospective Studies ,0303 health sciences ,Nutrition and Dietetics ,Angiography ,Antioxidant Activity ,04 agricultural and veterinary sciences ,040401 food science ,Optic-Nerve ,Female ,OCTA ,Tomography, Optical Coherence ,Biotechnology ,Morphology ,Adult ,medicine.medical_specialty ,Race ,Foveal Avascular Zone ,Retina ,Perimeter ,Young Adult ,03 medical and health sciences ,Age ,0404 agricultural biotechnology ,Vessel density ,vessel density ,Caffeine ,Ophthalmology ,medicine ,Humans ,Black tea ,Tea ,business.industry ,Microcirculation ,black tea consumption ,Retinal ,retinal microcirculation ,Plant Leaves ,FAZ ,chemistry ,Green ,Microvessels ,sense organs ,business ,Agronomy and Crop Science ,Food Science - Abstract
Background Tea, second only to water, is one of the most regularly consumed drinks in the world. Its potentially beneficial effects on general health may be enormously important. Optical coherence tomography angiography (OCTA) now allows clinicians to examine the acute retinal morphological changes caused by black tea consumption. The purpose of this study was to investigate the acute impacts of a Camellia sinensis fermentation end-product (black tea) on retinal microvasculature in healthy individuals using OCTA. Results In this study, 60 healthy people were divided into two groups: group 1 (n=30) received black tea (2 mg/250 ml of water) and group 2 (n=30) received only 250 ml of water. Following consumption, AngioVue Analytics software automatically analyzed the foveal, parafoveal, perifoveal macular superficial and deep vascular plexus densities, foveal avascular zone (FAZ) area, FAZ perimeter, and foveal vessel density in a 300 μm wide region around the FAZ (FD-300). Male to female ratios were 19:11 and 15:15 in groups 1 and 2, respectively (P=0.217). Mean age was 33.27±7.92 years in group 1 and 31.00±7.30 years in group 2 (P=0.254). Changes in foveal, perifoveal, and parafoveal macular vessel density between groups 1 and 2 were not statistically significant. In addition, no significant differences regarding FAZ, FAZ perimeter and FD-300 were observed. Conclusion There were no acute effects of black tea on macular microcirculation in healthy individuals. The authors, however, believe that this study could serve as a model for future researches on the relationship between regular tea consumption and general ocular physiology. This article is protected by copyright. All rights reserved.
- Published
- 2021
5. MMP2 Modulates Inflammatory Response during Axonal Regeneration in the Murine Visual System
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Marie Claes, Samantha Zaunz, Kiavash Movahedi, Lieve Moons, Luca Masin, Catherine M. Verfaillie, Lies De Groef, Steven Bergmans, Evy Lefevere, Lien Andries, Manuel Salinas Navarro, Véronique Brouwers, Laboratory of Molecullar and Cellular Therapy, and Basic (bio-) Medical Sciences
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0301 basic medicine ,STIMULATION ,RETINAL GANGLION-CELLS ,MATRIX METALLOPROTEINASES ,Mice ,GAP-43 Protein ,0302 clinical medicine ,matrix metalloproteinases ,optic nerve injury ,myeloid cells ,axonal regeneration ,inflammatory stimulation ,expression profiling ,Cell Movement ,GLAUCOMA ,Antigens, Ly ,Biology (General) ,Bone Marrow Transplantation ,Mice, Knockout ,Medicine(all) ,General Medicine ,Phenotype ,Cell biology ,medicine.anatomical_structure ,Optic nerve ,Matrix Metalloproteinase 2 ,medicine.symptom ,Life Sciences & Biomedicine ,Whole-Body Irradiation ,QH301-705.5 ,Transplantation, Heterologous ,Central nervous system ,CX3C Chemokine Receptor 1 ,Inflammation ,Biology ,NEURITE OUTGROWTH ,Retina ,Article ,Glial scar ,DIFFERENTIAL EXPRESSION ,03 medical and health sciences ,Immunology and Microbiology(all) ,medicine ,Animals ,PROMOTE ,Neuroinflammation ,ENVIRONMENT ,Innate immune system ,Science & Technology ,GUIDANCE ,Regeneration (biology) ,Optic Nerve ,Cell Biology ,Axons ,Immunity, Innate ,Nerve Regeneration ,Mice, Inbred C57BL ,030104 developmental biology ,Gene Expression Regulation ,Optic Nerve Injuries ,Leukocyte Common Antigens ,030217 neurology & neurosurgery ,OPTIC-NERVE - Abstract
Neuroinflammation has been put forward as a mechanism triggering axonal regrowth in the mammalian central nervous system (CNS), yet little is known about the underlying cellular and molecular players connecting these two processes. In this study, we provide evidence that MMP2 is an essential factor linking inflammation to axonal regeneration by using an in vivo mouse model of inflammation-induced axonal regeneration in the optic nerve. We show that infiltrating myeloid cells abundantly express MMP2 and that MMP2 deficiency results in reduced long-distance axonal regeneration. However, this phenotype can be rescued by restoring MMP2 expression in myeloid cells via a heterologous bone marrow transplantation. Furthermore, while MMP2 deficiency does not affect the number of infiltrating myeloid cells, it does determine the coordinated expression of pro- and anti-inflammatory molecules. Altogether, in addition to its role in axonal regeneration via resolution of the glial scar, here, we reveal a new mechanism via which MMP2 facilitates axonal regeneration, namely orchestrating the expression of pro- and anti-inflammatory molecules by infiltrating innate immune cells. ispartof: Cells vol:10 issue:7 pages:1-19 ispartof: location:Switzerland status: Published online
- Published
- 2021
6. Persisting Embryonal Infundibular Recess in Morning Glory Syndrome: Clinical Report of a Novel Association
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Mario Cirillo, A. Grandone, Renata Conforti, Lorenzo Ugga, Renato Cuocolo, Alessandra D'Amico, D'Amico, A., Ugga, L., Cuocolo, R., Cirillo, M., Grandone, A., Conforti, R., D'Amico, A, Ugga, L, Cuocolo, Maria Rosaria, Cirillo, M, Grandone, A, and Conforti, R
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Male ,Adolescent ,Morning glory disc anomaly ,Optic Disk ,Infundibular recess ,Glory ,Pediatrics ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,Optic Nerve Disease ,0302 clinical medicine ,Clinical report ,Optic Nerve Diseases ,medicine ,Humans ,Abnormalities, Multiple ,Radiology, Nuclear Medicine and imaging ,Third Ventricle ,Morning ,Pituitary stalk ,business.industry ,Syndrome ,Anatomy ,medicine.anatomical_structure ,Child, Preschool ,Pituitary Gland ,Neurology (clinical) ,Differential diagnosis ,business ,030217 neurology & neurosurgery ,OPTIC-NERVE ,Human ,Optic disc - Abstract
SUMMARY: Morning glory syndrome is characterized by a congenital optic disc defect that resembles the eponymous flower. We present the MR imaging findings of 2 pediatric patients with morning glory disc anomaly and persisting embryonal infundibular recess, another rare malformative finding, a previously unreported association. Neuroradiologists should be aware of the possible presence of a persisting embryonal infundibular recess in patients with morning glory syndrome, to aid in the differential diagnosis including other pituitary malformations such as pituitary stalk duplication.
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- 2019
7. İdyopatik intrakraniyal hipertansiyona yaklaşımda güncel bakış
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Bayir, Buse Rahime Hasirci, Baykan, Betul, and Celebisoy, Nesse
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Pseudotumor Cerebri ,Complications ,treatment ,Headache ,Bariatric Surgery ,medical ,Pathophysiology ,Management ,Acetazolamide ,surgical ,Optic-Nerve ,Risk-Factors ,idiopathic intracranial hypertension ,Placement - Abstract
Pseudotumor cerebri, also known as idiopathic intracranial hypertension (IIH), is an increment in the intracranial pressure without identifiable causal factors. The disorder is frequently seen in obese women of childbearing age. Due to both permanent vision loss and higher risk of recurrence than previously thought, patients with IIH should be followed closely using a multidisciplinary approach. IIH treatment should be arranged considering the severity of headache and papilledema, presence of vision loss, response to medical treatment, and comorbid conditions, with individual planning for each patient. In patients where weight loss and acetazolamide are insufficient for symptoms' resolution, other medical and surgical treatment options should be evaluated rapidly. Because the pathogenesis of IIH is not fully known, treatment options support different theories. With the increase in clinical experience, the aim is to prevent the risk of developing irreversible complications in patients using different treatments, which have recently been developed. This review aimed to evaluate IIH treatment options using current approaches and help physicians in the decision-making process.
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- 2021
8. Stress-induced changes in neuronal Aquaporin-9 (AQP9) in a retinal ganglion cell-line
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Dibas, Adnan, Yang, Ming-Hui, Bobich, Joseph, and Yorio, Thomas
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RETINAL ganglion cells , *NERVOUS system , *NEURONS , *ISCHEMIA - Abstract
Abstract: The water channel, Aquaporin-9 (AQP9) is enriched in selected neuronal populations and is unique its ability to act as a lactate-glycerol channel supplying neurons with alternative fuel under ischaemic conditions. AQP9 was detected in RGC-5 cells, a retinal ganglion cell-line, primary RGCs, and retina by Western blotting, real-time PCR (RT-PCR) and immunohistochemistry. RGC-5 cells subjected to a hypotonic stress increased their cell volume that was blocked by known inhibitor of AQP9 (phloretin (40μM)). RGC-5 cells subjected to hypoxia, showed an up-regulation in AQP9 expression as judged by Western blotting and RT-PCR. Similarly, hypotonic shock (50%) increased AQP9 expression as determined by RT-PCR. AQP9 is involved in energy balance as a glycerol–lactate channel and also appears to regulate cell volume in retinal ganglion neurons. This water channel may play a key role in retinal ganglion pathology. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
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9. Fast circulation of cerebrospinal fluid: an alternative perspective on the protective role of high intracranial pressure in ocular hypertension
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Peter Paul De Deyn, Peter Wostyn, Hanspeter E. Killer, Debby Van Dam, Kurt Audenaert, and Veva De Groot
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Retinal Ganglion Cells ,medicine.medical_specialty ,Intraocular pressure ,MENINGOTHELIAL CELLS ,genetic structures ,Open angle glaucoma ,cerebrospinal fluid clearance ,PATHOGENESIS ,intracranial pressure ,Ocular hypertension ,Glaucoma ,INTRAOCULAR-PRESSURE ,SENESCENT CHANGES ,03 medical and health sciences ,0302 clinical medicine ,Cerebrospinal fluid ,Internal medicine ,Normal tension glaucoma ,TRANSPORTER EXPRESSION ,medicine ,Humans ,NORMAL-TENSION GLAUCOMA ,Intracranial pressure ,Amyloid beta-Peptides ,business.industry ,Optic Nerve ,Alzheimer's disease ,AMYLOID-BETA ,medicine.disease ,eye diseases ,ALZHEIMERS-DISEASE ,Ophthalmology ,glaucoma ,Anesthesia ,030221 ophthalmology & optometry ,Cardiology ,Optic nerve ,ocular hypertension ,Human medicine ,sense organs ,OPEN-ANGLE GLAUCOMA ,business ,030217 neurology & neurosurgery ,OPTIC-NERVE ,Optometry - Abstract
As ocular hypertension refers to a condition in which the intraocular pressure is consistently elevated but without development of glaucoma, study of it may provide important clues to factors that may play a protective role in glaucoma. β-amyloid, one of the key histopathological findings in Alzheimer's disease, has been reported to increase by chronic elevation of intraocular pressure in animals with experimentally induced ocular hypertension and to cause retinal ganglion cell death, pointing to similarities in molecular cell death mechanisms between glaucoma and Alzheimer's disease. On the other hand, recent studies have reported that intracranial pressure is higher in patients with ocular hypertension compared with controls, giving rise to the idea that elevated intracranial pressure may provide a protective effect for the optic nerve by decreasing the trans-lamina cribrosa pressure difference. The speculation that the higher intracranial pressure reported in ocular hypertension patients may protect against glaucoma mainly through a lower trans-lamina cribrosa pressure difference remains at least questionable. Here, we present an alternative viewpoint, according to which the protective effect of higher intracranial pressure could be due, at least in part, to a pressure-independent mechanism, namely faster cerebrospinal fluid production leading to increased cerebrospinal fluid turnover with enhanced removal of potentially neurotoxic waste products that accumulate in the optic nerve. This suggests a new hypothesis for glaucoma, which, just like Alzheimer's disease, may be considered then as an imbalance between production and clearance of neurotoxins, including β-amyloid. If confirmed, then strategies to improve cerebrospinal fluid flow are reasonable and could provide a new therapeutic approach for stopping the neurotoxic β-amyloid pathway in glaucoma.
- Published
- 2016
10. Fast circulation of cerebrospinal fluid
- Subjects
MENINGOTHELIAL CELLS ,cerebrospinal fluid clearance ,PATHOGENESIS ,intracranial pressure ,Alzheimer's disease ,AMYLOID-BETA ,INTRAOCULAR-PRESSURE ,SENESCENT CHANGES ,ALZHEIMERS-DISEASE ,glaucoma ,TRANSPORTER EXPRESSION ,ocular hypertension ,NORMAL-TENSION GLAUCOMA ,OPEN-ANGLE GLAUCOMA ,OPTIC-NERVE - Abstract
As ocular hypertension refers to a condition in which the intraocular pressure is consistently elevated but without development of glaucoma, study of it may provide important clues to factors thatmay play a protective role in glaucoma. beta-amyloid, one of the key histopathological findings in Alzheimer's disease, has been reported to increase by chronic elevation of intraocular pressure in animals with experimentally induced ocular hypertension and to cause retinal ganglion cell death, pointing to similarities in molecular cell death mechanisms between glaucoma and Alzheimer's disease. On the other hand, recent studies have reported that intracranial pressure is higher in patients with ocular hypertension compared with controls, giving rise to the idea that elevated intracranial pressure may provide a protective effect for the optic nerve by decreasing the trans-lamina cribrosa pressure difference. The speculation that the higher intracranial pressure reported in ocular hypertension patients may protect against glaucomamainly through a lower trans-lamina cribrosa pressure difference remains at least questionable. Here, we present an alternative viewpoint, according to which the protective effect of higher intracranial pressure could be due, at least in part, to a pressure-independent mechanism, namely faster cerebrospinal fluid production leading to increased cerebrospinal fluid turnover with enhanced removal of potentially neurotoxic waste products that accumulate in the optic nerve. This suggests a new hypothesis for glaucoma, which, just like Alzheimer's disease, may be considered then as an imbalance between production and clearance of neurotoxins, including beta-amyloid. If confirmed, then strategies to improve cerebrospinal fluid flow are reasonable and could provide a new therapeutic approach for stopping the neurotoxic beta-amyloid pathway in glaucoma.
- Published
- 2016
11. Neurodegeneration beyond the primary visual pathways in a population with a high incidence of normal-pressure glaucoma
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Masaki Yoshida, Branislava Ćurčić-Blake, Frans W. Cornelissen, Sandra Hanekamp, Christine C. Boucard, Masahiro Ida, Perceptual and Cognitive Neuroscience (PCN), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), and Clinical Cognitive Neuropsychiatry Research Program (CCNP)
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Male ,Intraocular pressure ,genetic structures ,TENSION GLAUCOMA ,Glaucoma ,Corpus callosum ,INTRAOCULAR-PRESSURE ,0302 clinical medicine ,Japan ,magnetic resonance imaging ,POSTERIOR CORTICAL ATROPHY ,Medicine ,Low Tension Glaucoma ,education.field_of_study ,CLINICAL SEVERITY ,Incidence ,neurodegeneration ,Brain ,Anatomy ,Middle Aged ,Sensory Systems ,3. Good health ,ALZHEIMERS-DISEASE ,Diffusion Tensor Imaging ,VOXEL-BASED MORPHOMETRY ,Optic nerve ,Heredodegenerative Disorders, Nervous System ,Female ,OPEN-ANGLE GLAUCOMA ,medicine.medical_specialty ,Open angle glaucoma ,Population ,normal-pressure glaucoma ,03 medical and health sciences ,Ophthalmology ,Fractional anisotropy ,Humans ,Visual Pathways ,education ,Intraocular Pressure ,business.industry ,DIFFUSION-TENSOR ,medicine.disease ,eye diseases ,glaucoma ,030221 ophthalmology & optometry ,LATERAL GENICULATE-NUCLEUS ,sense organs ,business ,030217 neurology & neurosurgery ,OPTIC-NERVE ,Optometry - Abstract
Purpose: Glaucoma is the most common age-related neurodegenerative eye disease in western society. It is an insidious disease that, when untreated or detected too late, leads inevitably to blindness. An outstanding issue is whether glaucoma should be considered exclusively an eye disease or also a brain disease. To further examine it, we used Diffusion Tensor Imaging (DTI) to study white matter integrity in a Japanese glaucoma population. This population has a very high incidence of normal-pressure glaucoma, in which optic nerve damage occurs in the absence of the elevated eye pressure that characterises the more common form of glaucoma.Methods: We performed DTI in 30 participants with normal-pressure glaucoma and 21 age-matched healthy controls. We used voxel-wise tract-based spatial statistics to compare fractional anisotropy and mean diffusivity of the white matter of the brain between patients and control group. Whole-brain and region of interest-based analyses served to find associations between diffusion indices and clinical measures of glaucomatous damage.Results: Fractional Anisotropy was significantly lower in glaucoma patients in a cluster in the right occipital lobe (p Conclusions: In this specific population, glaucoma is associated with lower Fractional Anisotropy in the optic radiations, forceps major and corpus callosum. We interpret these reductions as evidence for white matter degeneration in these loci. In particular, the degeneration of the corpus callosum suggests the presence of neurodegeneration of the brain beyond what can be explained on the basis of propagated retinal and pre-geniculate damage. We discuss how this finding links to the emerging view that a brain component that is independent from the eye damage plays a role in the aetiology of glaucoma.
- Published
- 2016
12. The retinal nerve fiber layer as a window to the glymphatic system
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Peter Wostyn, Peter Paul De Deyn, and Molecular Neuroscience and Ageing Research (MOLAR)
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Nerve fiber layer ,Retina ,chemistry.chemical_compound ,Nerve Fibers ,medicine ,Humans ,Aquaporin 4 ,business.industry ,PATHWAYS ,Window (computing) ,Neurodegenerative Diseases ,Retinal ,Organ Size ,General Medicine ,IMPAIRMENT ,medicine.anatomical_structure ,chemistry ,Optic nerve ,Surgery ,Glymphatic system ,Human medicine ,Neurology (clinical) ,business ,Glymphatic System ,Tomography, Optical Coherence ,OPTIC-NERVE ,Biomedical engineering - Published
- 2020
13. Compromised Integrity of Central Visual Pathways in Patients With Macular Degeneration
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Malania, Maka, Konrad, Julia, Jägle, Herbert, Werner, John S., and Greenlee, Mark W.
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Retinal Ganglion Cells ,Male ,genetic structures ,juvenile macular dystrophy ,610 Medizin ,Bioengineering ,Neurodegenerative ,Eye ,Ophthalmology & Optometry ,Medical and Health Sciences ,NERVE-FIBER LAYER ,VOXEL-BASED MORPHOMETRY ,HUMAN CEREBRAL-CORTEX ,OPTIC-NERVE ,NEURAL DEGENERATION ,STARGARDT DISEASE ,NATURAL-HISTORY ,DIFFUSION MRI ,WHITE-MATTER ,DOMAIN OCT ,diffusion tensor imaging ,white matter tracts ,age-related macular degeneration ,Macular Degeneration ,Nerve Fibers ,Clinical Research ,Humans ,2.1 Biological and endogenous factors ,Visual Pathways ,Aetiology ,Tomography ,Eye Disease and Disorders of Vision ,Aged ,ddc:610 ,Neurosciences ,Middle Aged ,Biological Sciences ,eye diseases ,Diffusion Magnetic Resonance Imaging ,Optical Coherence ,150 Psychologie ,Neurological ,ddc:150 ,Biomedical Imaging ,Female ,sense organs - Abstract
PURPOSE. Macular degeneration (MD) affects the central retina and leads to gradual loss of foveal vision. Although, photoreceptors are primarily affected in MD, the retinal nerve fiber layer (RNFL) and central visual pathways may also be altered subsequent to photoreceptor degeneration. Here we investigate whether retinal damage caused by MD alters microstructural properties of visual pathways using diffusion-weighted magnetic resonance imaging. METHODS. Six MD patients and six healthy control subjects participated in the study. Retinal images were obtained by spectral-domain optical coherence tomography (SD-OCT). Diffusion tensor images (DTI) and high-resolution T1-weighted structural images were collected for each subject. We used diffusion-based tensor modeling and probabilistic fiber tractography to identify the optic tract (OT) and optic radiations (OR), as well as nonvisual pathways (corticospinal tract and anterior fibers of corpus callosum). Fractional anisotropy (FA) and axial and radial diffusivity values (AD, RD) were calculated along the nonvisual and visual pathways. RESULTS. Measurement of RNFL thickness reveals that the temporal circumpapillary retinal nerve fiber layer was significantly thinner in eyes with macular degeneration than normal. While we did not find significant differences in diffusion properties in nonvisual pathways, patients showed significant changes in diffusion scalars (FA, RD, and AD) both in OT and OR. CONCLUSIONS. The results indicate that the RNFL and the white matter of the visual pathways are significantly altered in MD patients. Damage to the photoreceptors in MD leads to atrophy of the ganglion cell axons and to corresponding changes in microstructural properties of central visual pathways.
- Published
- 2017
14. Quantification of the efficacy of collagen cross-linking agents to induce stiffening of rat sclera
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Joseph M. Sherwood, C. Ross Ethier, A. Thomas Read, Bailey G. Hannon, Stephen A. Schwaner, and Ian C. Campbell
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0301 basic medicine ,collagen ,Intraocular pressure ,genetic structures ,Glaucoma ,Strain (injury) ,Corrections ,Biochemistry ,INTRAOCULAR-PRESSURE ,chemistry.chemical_compound ,0302 clinical medicine ,GLAUCOMA ,Medicine ,Iridoids ,rat ,PORCINE SCLERA ,TREE SHREW ,Methylglyoxal ,Pyruvaldehyde ,musculoskeletal system ,GLYCERALDEHYDE ,Sclera ,Multidisciplinary Sciences ,Cross-Linking Reagents ,medicine.anatomical_structure ,Science & Technology - Other Topics ,sclera ,Biotechnology ,circulatory and respiratory physiology ,medicine.medical_specialty ,General Science & Technology ,Biomedical Engineering ,Biophysics ,Bioengineering ,LAMINA-CRIBROSA ,GENIPIN ,biomechanics ,Biomaterials ,03 medical and health sciences ,In vivo ,DEFORMATION ,Ophthalmology ,MD Multidisciplinary ,Animals ,digital image correlation ,Intraocular Pressure ,Life Sciences–Engineering interface ,Science & Technology ,Dose-Response Relationship, Drug ,business.industry ,medicine.disease ,eye diseases ,Rats ,Stiffening ,Surgery ,030104 developmental biology ,chemistry ,BIOMECHANICAL PROPERTIES ,030221 ophthalmology & optometry ,Genipin ,sense organs ,business ,cross-linking ,OPTIC-NERVE - Abstract
The concept of scleral stiffening therapies has emerged as a novel theoretical approach for treating the ocular disorders glaucoma and myopia. Deformation of specific regions of the posterior eye is innately involved in the pathophysiology of these diseases, and thus targeted scleral stiffening could resist these changes and slow or prevent progression of these diseases. Here, we present the first systematic screen and direct comparison of the stiffening effect of small molecule collagen cross-linking agents in the posterior globe, namely using glyceraldehyde, genipin and methylglyoxal (also called pyruvaldehyde). To establish a dose–response relationship, we used inflation testing to simulate the effects of increasing intraocular pressure in freshly harvested rat eyes stiffened with multiple concentrations of each agent. We used digital image correlation to compute the mechanical strain in the tissue as a metric of stiffness, using a novel treatment paradigm for screening relative stiffening by incubating half of each eye in cross-linker and using the opposite half as an internal control. We identified the doses necessary to increase stiffness by approximately 100%, namely 30 mM for glyceraldehyde, 1 mM for genipin and 7 mM for methylglyoxal, and we also identified the range of stiffening it was possible to achieve with such agents. Such findings will inform development of in vivo studies of scleral stiffening to treat glaucoma and myopia.
- Published
- 2017
15. The two faces of the translaminar pressure difference : the biomechanical one and the biochemical one
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Veva De Groot, Hanspeter E. Killer, Peter Paul De Deyn, Debby Van Dam, Kurt Audenaert, Peter Wostyn, and Molecular Neuroscience and Ageing Research (MOLAR)
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Intraocular pressure ,medicine.medical_specialty ,INTRACRANIAL-PRESSURE ,INTRAOCULAR-PRESSURE ,Biomechanical Phenomena ,03 medical and health sciences ,0302 clinical medicine ,Normal tension glaucoma ,Ophthalmology ,Pressure ,medicine ,Humans ,NORMAL-TENSION GLAUCOMA ,Intracranial pressure ,business.industry ,Pressure difference ,Review article ,Anesthesia ,030221 ophthalmology & optometry ,Optic nerve ,Human medicine ,business ,030217 neurology & neurosurgery ,Optometry ,OPTIC-NERVE - Abstract
EDITOR: We read with great interest the paper recently published in Clinical and Experimental Optometry by McMonnies.2016 We are grateful to the author for sharing his valuable review article with ...
- Published
- 2017
16. The Glymphatic Hypothesis of Glaucoma
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OCULAR HYPERTENSION ,INTRACRANIAL-PRESSURE ,CENTRAL-NERVOUS-SYSTEM ,CEREBROSPINAL-FLUID PRESSURE ,NORMAL-TENSION GLAUCOMA ,OPEN-ANGLE GLAUCOMA ,LAMINA-CRIBROSA ,INTRAOCULAR-PRESSURE ,RETINAL VEIN PULSATION ,OPTIC-NERVE - Abstract
The pathophysiology of primary open-angle glaucoma is still largely unknown, although a joint contribution of vascular, biomechanical, and biochemical factors is widely acknowledged. Since glaucoma is a leading cause of irreversible blindness worldwide, exploring its underlying pathophysiological mechanisms is extremely important and challenging. Evidence from recent studies appears supportive of the hypothesis that a "glymphatic system" exists in the eye and optic nerve, analogous to the described "glymphatic system" in the brain. As discussed in the present paper, elucidation of a glymphatic clearance pathway in the eye could provide a new unifying hypothesis of glaucoma that can incorporate many aspects of the vascular, biomechanical, and biochemical theories of the disease. It should be stressed, however, that the few research data currently available cannot be considered as proof of the existence of an "ocular glymphatic system" and that much more studies are needed to validate this possibility. Even though nothing conclusive can yet be said, the recent reports suggesting a paravascular transport system in the eye and optic nerve are encouraging and, if confirmed, may offer new perspectives for the development of novel diagnostic and therapeutic strategies for this devastating disorder.
- Published
- 2017
17. Cardiovascular risk factors as determinants of retinal and skin microvascular function: The Maastricht Study
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Miranda T. Schram, Abraham A. Kroon, Annemarie Koster, Jan S. A. G. Schouten, Nicolaas C. Schaper, Ben M Sörensen, Coen D.A. Stehouwer, Alfons J.H.M. Houben, Carla J.H. van der Kallen, Pieter C. Dagnelie, Ronald M.A. Henry, Tos T. J. M. Berendschot, Medical Image Analysis, Interne Geneeskunde, Promovendi CD, MUMC+: MA Alg Interne Geneeskunde (9), RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, RS: MHeNs - R3 - Neuroscience, Oogheelkunde, MUMC+: MA UECM Oogartsen MUMC (9), RS: NUTRIM - R1 - Metabolic Syndrome, MUMC+: MA UECM Oogartsen ZL (9), RS: CARIM - R3.02 - Hypertension and target organ damage, MUMC+: HVC Pieken Maastricht Studie (9), Sociale Geneeskunde, RS: CAPHRI - R4 - Health Inequities and Societal Participation, Epidemiologie, RS: CAPHRI - R5 - Optimising Patient Care, MUMC+: MA Endocrinologie (9), RS: CAPHRI - R2 - Creating Value-Based Health Care, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, and MUMC+: MA Interne Geneeskunde (3)
- Subjects
0301 basic medicine ,Male ,FLOW ,lcsh:Medicine ,BLOOD-PRESSURE ,Blood Pressure ,Type 2 diabetes ,030204 cardiovascular system & hematology ,SDG 3 – Goede gezondheid en welzijn ,Vascular Medicine ,Biochemistry ,VESSEL DIAMETER ,0302 clinical medicine ,Endocrinology ,Risk Factors ,Medicine and Health Sciences ,Endothelial dysfunction ,lcsh:Science ,Skin ,INSULIN-RESISTANCE ,education.field_of_study ,Multidisciplinary ,Drugs ,Lipids ,Skin/blood supply ,Type 2 Diabetes ,Cholesterol ,Cardiovascular Diseases ,OBESITY ,Cardiology ,Female ,Research Article ,medicine.medical_specialty ,Waist ,Endocrine Disorders ,Lipoproteins ,Population ,Guinea Pigs ,03 medical and health sciences ,AGE ,Insulin resistance ,SDG 3 - Good Health and Well-being ,Internal medicine ,Journal Article ,medicine ,Diabetes Mellitus ,Animals ,Humans ,Risk factor ,education ,Pharmacology ,Cardiovascular Diseases/physiopathology ,NITRIC-OXIDE ,business.industry ,lcsh:R ,Biology and Life Sciences ,Proteins ,Health Risk Analysis ,Retinal Vessels ,medicine.disease ,Health Care ,PATHOLOGY ,030104 developmental biology ,Blood pressure ,Metabolic Disorders ,ENDOTHELIAL DYSFUNCTION ,lcsh:Q ,Retinal Vessels/physiology ,business ,Dyslipidemia ,OPTIC-NERVE ,Antihypertensives - Abstract
ObjectiveMicrovascular dysfunction is an important underlying mechanism of microvascular diseases. Determinants (age, sex, hypertension, dyslipidemia, hyperglycemia, obesity, and smoking) of macrovascular diseases affect large-artery endothelial function. These risk factors also associate with microvascular diseases. We hypothesized that they are also determinants of microvascular (endothelial) function. MethodsIn The Maastricht Study, a type 2 diabetes-enriched population-based cohort study (n = 1991, 51% men, aged 59.7±8.2 years), we determined microvascular function as flicker light-induced retinal arteriolar %-dilation and heat-induced skin %-hyperemia. Multiple linear regression analyses were used to assess the associations of cardiovascular risk factors (age, sex, waist circumference, total-to-high-density lipoprotein (HDL) cholesterol ratio, fasting plasma glucose (FPG), 24-h systolic blood pressure, and cigarette smoking) with retinal and skin microvascular function. ResultsIn multivariate analyses, age and FPG were inversely associated with retinal and skin microvascular function (regression coefficients per standard deviation (SD) were -0.11SD (95%CI: -0.15;-0.06) and -0.12SD (-0.17;-0.07) for retinal arteriolar %-dilation and -0.10SD (-0.16;-0.05) and -0.11SD (-0.17;-0.06) for skin %-hyperemia, respectively. Men and current smokers had -0.43SD (-0.58;-0.27) and -0.32SD (-0.49;-0.15) lower skin %-hyperemia, respectively. 24-h systolic blood pressure, waist circumference, and total-to-HDL cholesterol ratio were not statistically significantly associated with these microvascular functions. ConclusionsAssociations between cardiovascular risk factors and retinal and skin microvascular function show a pattern that is partly similar to the associations between cardiovascular risk factors and macrovascular function. Impairment of microvascular function may constitute a pathway through which an adverse cardiovascular risk factor pattern may increase risk of diseases that are partly or wholly of microvascular origin.
- Published
- 2017
18. The glymphatic hypothesis of glaucoma : a unifying concept incorporating vascular, biomechanical, and biochemical aspects of the disease
- Author
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Hanspeter E. Killer, Kurt Audenaert, Veva De Groot, Debby Van Dam, Peter Wostyn, and Peter Paul De Deyn
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,genetic structures ,INTRACRANIAL-PRESSURE ,Models, Neurological ,lcsh:Medicine ,Glaucoma ,Disease ,Review Article ,LAMINA-CRIBROSA ,INTRAOCULAR-PRESSURE ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Normal tension glaucoma ,medicine ,Animals ,Humans ,CEREBROSPINAL-FLUID PRESSURE ,NORMAL-TENSION GLAUCOMA ,Biology ,Research data ,General Immunology and Microbiology ,business.industry ,CENTRAL-NERVOUS-SYSTEM ,lcsh:R ,Models, Cardiovascular ,Optic Nerve ,General Medicine ,medicine.disease ,eye diseases ,RETINAL VEIN PULSATION ,030104 developmental biology ,OCULAR HYPERTENSION ,030221 ophthalmology & optometry ,Optic nerve ,Glymphatic system ,Cerebrospinal fluid pressure ,sense organs ,Human medicine ,OPEN-ANGLE GLAUCOMA ,business ,Neuroscience ,Engineering sciences. Technology ,Transport system ,OPTIC-NERVE - Abstract
The pathophysiology of primary open-angle glaucoma is still largely unknown, although a joint contribution of vascular, biomechanical, and biochemical factors is widely acknowledged. Since glaucoma is a leading cause of irreversible blindness worldwide, exploring its underlying pathophysiological mechanisms is extremely important and challenging. Evidence from recent studies appears supportive of the hypothesis that a “glymphatic system” exists in the eye and optic nerve, analogous to the described “glymphatic system” in the brain. As discussed in the present paper, elucidation of a glymphatic clearance pathway in the eye could provide a new unifying hypothesis of glaucoma that can incorporate many aspects of the vascular, biomechanical, and biochemical theories of the disease. It should be stressed, however, that the few research data currently available cannot be considered as proof of the existence of an “ocular glymphatic system” and that much more studies are needed to validate this possibility. Even though nothing conclusive can yet be said, the recent reports suggesting a paravascular transport system in the eye and optic nerve are encouraging and, if confirmed, may offer new perspectives for the development of novel diagnostic and therapeutic strategies for this devastating disorder.
- Published
- 2017
19. Next generation sequencing identifies mutations in Atonal homolog 7 (ATOH7) in families with global eye developmental defects
- Author
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Eamonn Sheridan, Graham R. Taylor, Joanne E. Morgan, Narcis Fernandez-Fuentes, Hussain Jafri, Ahmed Al-Maskari, Özlem Yenice, Colin A. Johnson, Clare V. Logan, Carmel Toomes, Nursel Elcioglu, Manir Ali, Yasmin Raashid, David A. Parry, Martin McKibbin, Chris F. Inglehearn, Kamron N. Khan, Moin Mohamed, Zakia Abdelhamed, James A. Poulter, Ian M. Carr, Khan, Kamron, Logan, Clare V., McKibbin, Martin, Sheridan, Eamonn, Elcioglu, Nursel H., Yenice, Ozlem, Parry, David A., Fernandez-Fuentes, Narcis, Abdelhamed, Zakia I. A., Al-Maskari, Ahmed, Poulter, James A., Mohamed, Moin D., Carr, Ian M., Morgan, Joanne E., Jafri, Hussain, Raashid, Yasmin, Taylor, Graham R., Johnson, Colin A., Inglehearn, Chris F., Toomes, Carmel, and Ali, Manir
- Subjects
Male ,Eye Diseases ,genetic structures ,DNA Mutational Analysis ,Nerve Tissue Proteins ,Biology ,Eye ,Microphthalmia ,Retina ,Consanguinity ,03 medical and health sciences ,0302 clinical medicine ,NORRIE-DISEASE ,VASCULATURE ,Basic Helix-Loop-Helix Transcription Factors ,Genetics ,medicine ,Humans ,Eye Abnormalities ,GENOME-WIDE ASSOCIATION ,Eye Proteins ,FZD4 MUTATIONS ,Persistent fetal vasculature ,Molecular Biology ,beta Catenin ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Optic nerve hypoplasia ,Articles ,General Medicine ,EXUDATIVE VITREORETINOPATHY ,medicine.disease ,eye diseases ,ATONAL HOMOLOG ,Microcornea ,medicine.anatomical_structure ,Persistent hyperplastic primary vitreous ,Mutation ,030221 ophthalmology & optometry ,Congenital cataracts ,Optic nerve ,RETINAL GANGLION-CELL ,FATE DETERMINATION ,sense organs ,OPEN-ANGLE GLAUCOMA ,OPTIC-NERVE - Abstract
The atonal homolog 7 (ATOH7) gene encodes a transcription factor involved in determining the fate of retinal progenitor cells and is particularly required for optic nerve and ganglion cell development. Using a combination of autozygosity mapping and next generation sequencing, we have identified homozygous mutations in this gene, p.E49V and p.P18RfsX69, in two consanguineous families diagnosed with multiple ocular developmental defects, including severe vitreoretinal dysplasia, optic nerve hypoplasia, persistent fetal vasculature, microphthalmia, congenital cataracts, microcornea, corneal opacity and nystagmus. Most of these clinical features overlap with defects in the Norrin/beta-catenin signalling pathway that is characterized by dysgenesis of the retinal and hyaloid vasculature. Our findings document Mendelian mutations within ATOH7 and imply a role for this molecule in the development of structures at the front as well as the back of the eye. This work also provides further insights into the function of ATOH7, especially its importance in retinal vascular development and hyaloid regression.
- Published
- 2011
20. Alzheimer's disease and glaucoma - Reply
- Subjects
SPACE ,CEREBROSPINAL-FLUID PRESSURE ,NORMAL-TENSION GLAUCOMA ,OPEN-ANGLE GLAUCOMA ,LAMINA-CRIBROSA ,GENE ,INTRAOCULAR-PRESSURE ,TRANSPORT ,OPTIC-NERVE - Published
- 2014
21. Changes in cortical grey matter density associated with long-standing retinal visual field defects
- Author
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Nomdo M. Jansonius, Aditya Tri Hernowo, Jos B. T. M. Roerdink, Christine C. Boucard, Johanna M. M. Hooymans, R. Paul Maguire, Frans W. Cornelissen, Scientific Visualization and Computer Graphics, Intelligent Systems, and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
- Subjects
visual field ,Male ,CORTEX ,macular degeneration ,genetic structures ,PATHOGENESIS ,Retinal implant ,Vision Disorders ,Lateral geniculate nucleus ,ATROPHY ,chemistry.chemical_compound ,Cortex (anatomy) ,medicine ,voxel-based morphometry ,Humans ,visual cortex ,Aged ,grey matter density ,Aged, 80 and over ,Retina ,Vision, Binocular ,LESIONS ,business.industry ,Retinal ,Original Articles ,Macular degeneration ,Middle Aged ,medicine.disease ,Magnetic Resonance Imaging ,eye diseases ,Tissue Degeneration ,HUMAN GLAUCOMA ,VISION ,medicine.anatomical_structure ,Visual cortex ,glaucoma ,chemistry ,Female ,LATERAL GENICULATE-NUCLEUS ,Neurology (clinical) ,Sensory Deprivation ,Visual Fields ,business ,Neuroscience ,REORGANIZATION ,Glaucoma, Open-Angle ,OPTIC-NERVE - Abstract
Retinal lesions caused by eye diseases such as glaucoma and age-related macular degeneration can, over time, eliminate stimulation of parts of the visual cortex. This could lead to degeneration of inactive cortical neuronal tissue, but this has not been established in humans. Here, we used magnetic resonance imaging to assess the effects of prolonged sensory deprivation in human visual cortex. High-resolution anatomical magnetic resonance images were obtained in subjects with foveal (age-related macular degeneration) and peripheral (glaucoma) retinal lesions as well as age-matched controls. Comparison of grey matter between patient and control groups revealed density reductions in the approximate retinal lesion projection zones in visual cortex. This indicates that long-term cortical deprivation, due to retinal lesions acquired later in life, is associated with retinotopic-specific neuronal degeneration of visual cortex. Such degeneration could interfere with therapeutic strategies such as the future application of artificial retinal implants to overcome lesion-induced visual impairment.
- Published
- 2009
22. The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury
- Author
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Gizem Inak, Luming Zhou, Jeanne Christophe Marine, Magali Cucchiarini, Arnau Hervera, Yashashree Joshi, Khizr I. Rathore, Mohamed Y. Elnaggar, Simone Di Giovanni, Giorgia Quadrato, Radhika Puttagunta, Marilia Grando Sória, Wings for Life Spinal Cord Research Foundation, and International Spinal Research Trust
- Subjects
p53 ,metabolism [Axons] ,CORTICOSPINAL TRACT ,metabolism [Spinal Cord Injuries] ,ACTIVATION ,Mice ,Mdm4 protein, mouse ,Ubiquitin ,spinal cord injury, regeneration ,IGF1R ,physiopathology [Spinal Cord Injuries] ,SPINAL-CORD-INJURY ,Insulin-Like Growth Factor I ,metabolism [Insulin-Like Growth Factor I] ,Spinal cord injury ,IN-VIVO ,pathology [Axons] ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,metabolism [Proto-Oncogene Proteins c-mdm2] ,P53 PATHWAY ,Proto-Oncogene Proteins c-mdm2 ,11 Medical And Health Sciences ,Flow Cytometry ,ADULT CNS ,Immunohistochemistry ,FAMILY-MEMBERS ,medicine.anatomical_structure ,Optic nerve ,Mdm2 ,Mdm2 protein, mouse ,pathology [Spinal Cord Injuries] ,Life Sciences & Biomedicine ,Signal Transduction ,physiopathology [Optic Nerve Injuries] ,GROWTH CONE COLLAPSE ,Nerve Crush ,Ubiquitin-Protein Ligases ,Central nervous system ,Immunoblotting ,Clinical Neurology ,NEURITE OUTGROWTH ,Retinal ganglion ,optic nerve ,17 Psychology And Cognitive Sciences ,MDM4 ,metabolism [Ubiquitin-Protein Ligases] ,MDM2 ,Proto-Oncogene Proteins ,physiology [Signal Transduction] ,medicine ,Animals ,Immunoprecipitation ,metabolism [Proto-Oncogene Proteins] ,ddc:610 ,Spinal Cord Injuries ,metabolism [Optic Nerve Injuries] ,Science & Technology ,Neurology & Neurosurgery ,Regeneration (biology) ,Neurosciences ,Computational Biology ,Recovery of Function ,pathology [Optic Nerve Injuries] ,Spinal cord ,medicine.disease ,insulin-like growth factor-1, mouse ,spinal cord injury ,Axons ,Mice, Mutant Strains ,Nerve Regeneration ,Mice, Inbred C57BL ,Disease Models, Animal ,physiology [Recovery of Function] ,physiology [Nerve Regeneration] ,regeneration ,Optic Nerve Injuries ,biology.protein ,metabolism [Tumor Suppressor Protein p53] ,Neurology (clinical) ,Neurosciences & Neurology ,Tumor Suppressor Protein p53 ,Transcriptome ,Neuroscience ,OPTIC-NERVE - Abstract
Regeneration of injured central nervous system axons is highly restricted, causing neurological impairment. To date, although the lack of intrinsic regenerative potential is well described, a key regulatory molecular mechanism for the enhancement of both axonal regrowth and functional recovery after central nervous system injury remains elusive. While ubiquitin ligases coordinate neuronal morphogenesis and connectivity during development as well as after axonal injury, their role specifically in axonal regeneration is unknown. Following a bioinformatics network analysis combining ubiquitin ligases with previously defined axonal regenerative proteins, we found a triad composed of the ubiquitin ligases MDM4, MDM2 and the transcription factor p53 (encoded by TP53) as a putative central signalling complex restricting the regeneration program. Indeed, conditional deletion of MDM4 or pharmacological inhibition of MDM2/p53 interaction in the eye and spinal cord promote axonal regeneration and sprouting of the optic nerve after crush and of supraspinal tracts after spinal cord injury. The double conditional deletion of MDM4-p53 as well as MDM2 inhibition in p53-deficient mice blocks this regenerative phenotype, showing its dependence upon p53. Genome-wide gene expression analysis from ex vivo fluorescence-activated cell sorting in MDM4-deficient retinal ganglion cells identifies the downstream target IGF1R, whose activity and expression was found to be required for the regeneration elicited by MDM4 deletion. Importantly, we demonstrate that pharmacological enhancement of the MDM2/p53-IGF1R axis enhances axonal sprouting as well as functional recovery after spinal cord injury. Thus, our results show MDM4-MDM2/p53-IGF1R as an original regulatory mechanism for CNS regeneration and offer novel targets to enhance neurological recovery.media-1vid110.1093/brain/awv125_video_abstractawv125_video_abstract.
- Published
- 2014
23. Glaucoma Considered as an Imbalance Between Production and Clearance of Neurotoxins
- Author
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Peter Paul De Deyn, Veva De Groot, Hanspeter E. Killer, Kurt Audenaert, Debby Van Dam, Peter Wostyn, and Molecular Neuroscience and Ageing Research (MOLAR)
- Subjects
Open angle glaucoma ,business.industry ,INTRACRANIAL-PRESSURE ,Glaucoma ,Ocular hypertension ,medicine.disease ,OCULAR HYPERTENSION ,Cerebrospinal Fluid Pressure ,Anesthesia ,Optic Nerve Diseases ,Optic nerve ,medicine ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Animals ,CEREBROSPINAL-FLUID PRESSURE ,Cerebrospinal fluid pressure ,Human medicine ,OPEN-ANGLE GLAUCOMA ,business ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Intracranial pressure ,Clearance ,OPTIC-NERVE - Published
- 2014
24. A Comparison of Topical or Retrobulbar Anesthesia for 23-Gauge Posterior Vitrectomy
- Author
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Ozlem Sahin, Hande Celiker, Levent Karabaş, Celiker, Hande, Karabas, Levent, and Sahin, Ozlem
- Subjects
medicine.medical_specialty ,PHACOEMULSIFICATION ,Article Subject ,medicine.medical_treatment ,Sedation ,Vitrectomy ,lcsh:Ophthalmology ,Medicine ,Severe pain ,In patient ,Retrobulbar anesthesia ,business.industry ,Significant difference ,PERIBULBAR ANESTHESIA ,Vitreoretinal surgery ,Surgery ,Ophthalmology ,GLOBE PERFORATION ,lcsh:RE1-994 ,Anesthesia ,Anesthetic ,medicine.symptom ,INJECTION ,business ,INTRAOCULAR-LENS IMPLANTATION ,Research Article ,medicine.drug ,OPTIC-NERVE - Abstract
Background. To compare the efficacy and safety of topical anesthesia versus retrobulbar anesthesia in 23-gauge vitreoretinal surgery.Materials and Methods. A total of 63 patients scheduled for 23 G posterior vitrectomy without scleral buckling procedures were included in the study. The patients were randomly assigned to receive either topical (Group 1,n=31) or retrobulbar anesthesia (Group 2,n=32). Postoperatively, patients were shown a visual analogue pain scale (VAPS) from 1 (no pain or discomfort) to 4 (severe pain or discomfort) to rate the levels of pain.Results. There was more discomfort in patients in Group 2 while anesthetic was administered (Group 1: 1.0±0, Group 2:2.3±0.7,P=0.0001). Between the two groups the level of pain during surgery (Group 1:1.4±0.5, Group 2:1.5±0.5;P=0.85) was noted. There was also no significant difference between two groups postoperatively (Group 1:1.2±0.4, Group 2:1.3±0.4;P=0.28). There were no complications in either group related to the anesthetic technique. No patient needed sedation or anesthesia supplement during the surgery or postoperative period.Conclusion. Topical anesthesia in posterior vitrectomy procedures is an effective and safe method that is alternative to retrobulbar anesthesia.
- Published
- 2014
25. Perturbation of myelination by activation of distinct signaling pathways: an in vitro study in a myelinating culture derived from fetal rat brain
- Author
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Dick Hoekstra, Wia Baron, de Hans Vries, J. de Jonge, Nanotechnology and Biophysics in Medicine (NANOBIOMED), and Molecular Neuroscience and Ageing Research (MOLAR)
- Subjects
GROWTH-FACTOR ,O-2A PROGENITORS ,ELECTRICAL-ACTIVITY ,medicine.medical_treatment ,CYCLIC-AMP ,Cell Culture Techniques ,FGF-2 ,Biology ,Embryonic and Fetal Development ,Cellular and Molecular Neuroscience ,Myelin ,medicine ,Animals ,Rats, Wistar ,Myelin Sheath ,Protein Kinase C ,Protein kinase C ,Neurons ,Platelet-Derived Growth Factor ,Growth factor ,CENTRAL-NERVOUS-SYSTEM ,PROLIFERATION ,Oligodendrocyte differentiation ,myelination ,Brain ,differentiation ,MULTIPLE-SCLEROSIS ,PDGF ,Embryo, Mammalian ,Cyclic AMP-Dependent Protein Kinases ,Oligodendrocyte ,Rats ,Cell biology ,Oligodendroglia ,medicine.anatomical_structure ,PROGENITOR CELLS ,nervous system ,Myelinogenesis ,biology.protein ,Fibroblast Growth Factor 2 ,Signal transduction ,OLIGODENDROCYTE DIFFERENTIATION ,Neuroscience ,oligodendrocyte ,Platelet-derived growth factor receptor ,OPTIC-NERVE ,Signal Transduction - Abstract
An in vitro myelinating mouse-derived model system has been adapted and optimized for fetal rat brain. In these mixed brain cell (MBC) cultures, myelinogenesis was studied by examining the effect of signaling pathways that are involved in the timing of oligodendrocyte differentiation. When PMA, a protein kinase C (PKC) activator, was kept present during development, the early myelin protein, CNP, was expressed in oligodendrocytes as promptly as in control MBC cultures. In contrast, continuous activation of signaling pathways triggered by FGF-2 caused a delay in the expression of CNP. The expression of the late myelin proteins MBP and PLP in oligodendrocytes was impeded by both PMA- and FGFP-treatment, and, as a consequence, also myelin formation. Surprisingly, the continuous presence of PDGF during development also prevented myelin formation, even though ail myelin-specific proteins were significantly expressed. Taken together, the data indicate that this in vitro myelinating culture system represents an excellent system to study signaling events necessary for the onset of myelination. Moreover, the present results demonstrate that oligodendrocyte differentiation in the presence of neurons and astrocytes can be manipulated both by extracellular and intracellular signaling factors. Importantly, differentiation per se is not necessarily culminating into myelination. (C) 2000 Wiley-Liss, Inc.
- Published
- 2000
26. Perturbation of myelination by activation of distinct signaling pathways
- Subjects
GROWTH-FACTOR ,O-2A PROGENITORS ,ELECTRICAL-ACTIVITY ,CENTRAL-NERVOUS-SYSTEM ,CYCLIC-AMP ,PROLIFERATION ,myelination ,FGF-2 ,differentiation ,MULTIPLE-SCLEROSIS ,PDGF ,nervous system ,PROGENITOR CELLS ,OLIGODENDROCYTE DIFFERENTIATION ,oligodendrocyte ,protein kinase C ,OPTIC-NERVE - Abstract
An in vitro myelinating mouse-derived model system has been adapted and optimized for fetal rat brain. In these mixed brain cell (MBC) cultures, myelinogenesis was studied by examining the effect of signaling pathways that are involved in the timing of oligodendrocyte differentiation. When PMA, a protein kinase C (PKC) activator, was kept present during development, the early myelin protein, CNP, was expressed in oligodendrocytes as promptly as in control MBC cultures. In contrast, continuous activation of signaling pathways triggered by FGF-2 caused a delay in the expression of CNP. The expression of the late myelin proteins MBP and PLP in oligodendrocytes was impeded by both PMA- and FGFP-treatment, and, as a consequence, also myelin formation. Surprisingly, the continuous presence of PDGF during development also prevented myelin formation, even though ail myelin-specific proteins were significantly expressed. Taken together, the data indicate that this in vitro myelinating culture system represents an excellent system to study signaling events necessary for the onset of myelination. Moreover, the present results demonstrate that oligodendrocyte differentiation in the presence of neurons and astrocytes can be manipulated both by extracellular and intracellular signaling factors. Importantly, differentiation per se is not necessarily culminating into myelination. (C) 2000 Wiley-Liss, Inc.
- Published
- 2000
27. BDNF impairment is associated with age-related changes in the inner retina and exacerbates experimental glaucoma
- Author
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Gupta, V, You, Y, Li, J, Gupta, Veer, Golzan, M, Klistorner, A, van den Buuse, M, Graham, S, Gupta, V, You, Y, Li, J, Gupta, Veer, Golzan, M, Klistorner, A, van den Buuse, M, and Graham, S
- Published
- 2014
28. Visual cortex in aging and Alzheimer's disease: changes in visual field maps and population receptive fields
- Author
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Alyssa A. Brewer and Brian Barton
- Subjects
vision ,genetic structures ,Brain activity and meditation ,lcsh:BF1-990 ,Population ,lewy bodies ,Social and Behavioral Sciences ,optic-nerve ,Visual processing ,brain activity ,Medicine and Health Sciences ,medicine ,Dementia ,Psychology ,functional mri ,Original Research Article ,education ,General Psychology ,education.field_of_study ,aging ,population receptive field modeling mild cognitive impairment ,areas ,Life Sciences ,spatial contrast sensitivity ,Alzheimer's disease ,medicine.disease ,Visual field ,population receptive field modeling ,lcsh:Psychology ,Visual cortex ,medicine.anatomical_structure ,age ,cerebral-cortex ,Receptive field ,Cerebral cortex ,visual field mapping ,cortical atrophy ,Alzheimer’s disease ,Neuroscience - Abstract
Although several studies have suggested that cortical alterations underlie such age-related visual deficits as decreased acuity, little is known about what changes actually occur in visual cortex during healthy aging. Two recent studies showed changes in primary visual cortex (V1) during normal aging; however, no studies have characterized the effects of aging on visual cortex beyond V1, important measurements both for understanding the aging process and for comparison to changes in age-related diseases. Similarly, there is almost no information about changes in visual cortex in Alzheimer's disease (AD), the most common form of dementia. Because visual deficits are often reported as one of the first symptoms of AD, measurements of such changes in the visual cortex of AD patients might improve our understanding of how the visual system is affected by neurodegeneration as well as aid early detection, accurate diagnosis and timely treatment of AD. Here we use fMRI to first compare the visual field map (VFM) organization and population receptive fields (pRFs) between young adults and healthy aging subjects for occipital VFMs V1, V2, V3, and hV4. Healthy aging subjects do not show major VFM organizational deficits, but do have reduced surface area and increased pRF sizes in the foveal representations of V1, V2, and hV4 relative to healthy young control subjects. These measurements are consistent with behavioral deficits seen in healthy aging. We then demonstrate the feasibility and first characterization of these measurements in two patients with mild AD, which reveal potential changes in visual cortex as part of the pathophysiology of AD. Our data aid in our understanding of the changes in the visual processing pathways in normal aging and provide the foundation for future research into earlier and more definitive detection of AD.
- Published
- 2012
29. Type VII Collagen Expression in the Human Vitreoretinal Interface, Corpora Amylacea and Inner Retinal Layers
- Author
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Leonoor I. Los, Roel Kuijer, Bart Wullink, Hendri H. Pas, Roelofje J. van der Worp, Microbes in Health and Disease (MHD), Translational Immunology Groningen (TRIGR), and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Collagen Type VII ,Immunoelectron microscopy ,BASAL LAMINA ,lcsh:Medicine ,Epithelium ,Retina ,Young Adult ,Anchoring fibrils ,medicine ,Humans ,lcsh:Science ,Ganglion cell layer ,Aged ,Dermoepidermal junction ,Inclusion Bodies ,Basement membrane ,Multidisciplinary ,Chemistry ,lcsh:R ,COMPONENTS ,IN-VITRO ,Middle Aged ,Inner plexiform layer ,ANCHORING FIBRILS ,EPIRETINAL MEMBRANES ,Vitreous Body ,CONNECTIVE-TISSUE ,Collagen, type I, alpha 1 ,medicine.anatomical_structure ,Gene Expression Regulation ,Astrocytes ,BASEMENT-MEMBRANE ,CELLS ,lcsh:Q ,Female ,DERMAL-EPIDERMAL JUNCTION ,Corpora amylacea ,OPTIC-NERVE ,Research Article - Abstract
Type VII collagen, as a major component of anchoring fibrils found at basement membrane zones, is crucial in anchoring epithelial tissue layers to their underlying stroma. Recently, type VII collagen was discovered in the inner human retina by means of immunohistochemistry, while proteomic investigations demonstrated type VII collagen at the vitreoretinal interface of chicken. Because of its potential anchoring function at the vitreoretinal interface, we further assessed the presence of type VII collagen at this site. We evaluated the vitreoretinal interface of human donor eyes by means of immunohistochemistry, confocal microscopy, immunoelectron microscopy, and Western blotting. Firstly, type VII collagen was detected alongside vitreous fibers6 at the vitreoretinal interface. Because of its known anchoring function, it is likely that type VII collagen is involved in vitreoretinal attachment. Secondly, type VII collagen was found within cytoplasmic vesicles of inner retinal cells. These cells resided most frequently in the ganglion cell layer and inner plexiform layer. Thirdly, type VII collagen was found in astrocytic cytoplasmic inclusions, known as corpora amylacea. The intraretinal presence of type VII collagen was confirmed by Western blotting of homogenized retinal preparations. These data add to the understanding of vitreoretinal attachment, which is important for a better comprehension of common vitreoretinal attachment pathologies.
- Published
- 2015
30. Automated morphometry of the visual pathway in primary open-angle glaucoma
- Author
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Johanna M. M. Hooymans, Frans W. Cornelissen, Christine C. Boucard, Nomdo M. Jansonius, Aditya Tri Hernowo, and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
- Subjects
Male ,medicine.medical_specialty ,RETINAL GANGLION-CELLS ,genetic structures ,Optic tract ,Optic chiasm ,Glaucoma ,Lateral geniculate nucleus ,INTRAOCULAR-PRESSURE ,GRONINGEN LONGITUDINAL GLAUCOMA ,Ophthalmology ,Normal tension glaucoma ,Optic Nerve Diseases ,FREQUENCY-DOUBLING PERIMETRY ,medicine ,Humans ,Visual Pathways ,NORMAL-TENSION GLAUCOMA ,Scotoma ,Intraocular Pressure ,NERVE-FIBER LAYER ,Aged ,Aged, 80 and over ,business.industry ,Blind spot ,Geniculate Bodies ,Optic Nerve ,Middle Aged ,PASS RESOLUTION PERIMETRY ,medicine.disease ,Magnetic Resonance Imaging ,eye diseases ,medicine.anatomical_structure ,Optic Chiasm ,Optic nerve ,SCANNING LASER POLARIMETRY ,Visual Field Tests ,Female ,LATERAL GENICULATE-NUCLEUS ,sense organs ,Visual Fields ,business ,Glaucoma, Open-Angle ,OPTIC-NERVE ,Optic radiation - Abstract
PURPOSE. To establish whether primary open-angle glaucoma (POAG) is associated with a change in volume of the visual pathway structures between the eyes and the visual cortex.METHODS. To answer this question, magnetic resonance imaging (MRI) was used in combination with automated segmentation and voxel-based morphometry (VBM). Eight patients with POAG and 12 age-matched control subjects participated in the study. Only POAG patients with bilateral glaucomatous visual field loss were admitted to the study. The scotoma in both eyes had to include the paracentral region and had to, at least partially, overlap. All participants underwent high-resolution, T(1)-weighted, 3-T MRI scanning[b]. Subsequently, VBM was used to determine the volume of the optic nerves, the optic chiasm, the optic tracts, the lateral geniculate nuclei (LGN), and the optic radiations. Analysis of covariance was used to compare these volumes in the POAG and control groups. The main outcome parameter of the measurement was the volume of visual pathway structures.RESULTS. Compared with the controls, subjects with glaucoma showed reduced volume (P CONCLUSIONS. POAG adversely affects structures along the full visual pathway, from the optic nerve to the optic radiation. Moreover, MRI in combination with automated morphometry can be used to aid the detection and assessment of glaucomatous damage in the brain. (Invest Ophthalmol Vis Sci. 2011;52:2758-2766) DOI:10.1167/iovs.10-5682
- Published
- 2011
31. TrkB receptor signalling: Implications in neurodegenerative, psychiatric and proliferative disorders
- Author
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Gupta, VK, You, Y, Gupta, Veer, Klistorner, A, Graham, SL, Gupta, VK, You, Y, Gupta, Veer, Klistorner, A, and Graham, SL
- Published
- 2013
32. THE EFFECTS OF AN ALDOSE REDUCTASE INHIBITOR ON THE PROGRESSION OF DIABETIC-RETINOPATHY
- Subjects
BLOOD-RETINAL BARRIER ,SORBITOL METABOLISM ,ALDOSE REDUCTASE INHIBITOR ,DIABETIC RETINOPATHY ,NEUROPATHY ,PERMEABILITY ,SURAL NERVE ,SORBINIL ,OPTIC-NERVE ,RATS - Abstract
The polyol pathway has long been associated with diabetic retinopathy. Glucose is converted to sorbitol with the aid of the enzyme aldose reductase. Aldose reductase inhibitors can prevent changes induced by diabetes. A total of 30 patients with minimal background retinopathy were randomly divided into a ponalrestat-taking group and a placebo-taking group. All were followed for 6 months and twenty-three were followed for 12 months. The baseline microaneurysm count was 2.6 +/- 1.9 (mean +/- SD) for the ponalrestat group and 3.5 +/- 2.9 for the placebo group. At 6 months the counts were 3.1 +/- 3.5 and 2.9 +/- 3.6 and after 12 months 3.0 +/- 4.1 and 2.9 +/- 3.4. There is no statistically significant difference between the groups at 0, 6 or 12 months of study. The change in retinopathy severity level did not significantly differ between the two groups at either 6 or 12 months. Ponalrestat administration at a dosage of 600 mg daily for 12 months has no significant effect on the course of minimal retinopathy in diabetic patients.
- Published
- 1991
33. THE EFFECTS OF AN ALDOSE REDUCTASE INHIBITOR ON THE PROGRESSION OF DIABETIC-RETINOPATHY
- Author
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TROMP, A, HOOYMANS, JMM, BARENDSEN, BC, VONDOORMAAL, JJ, and Restoring Organ Function by Means of Regenerative Medicine (REGENERATE)
- Subjects
BLOOD-RETINAL BARRIER ,SORBITOL METABOLISM ,ALDOSE REDUCTASE INHIBITOR ,DIABETIC RETINOPATHY ,NEUROPATHY ,PERMEABILITY ,SURAL NERVE ,SORBINIL ,OPTIC-NERVE ,RATS - Abstract
The polyol pathway has long been associated with diabetic retinopathy. Glucose is converted to sorbitol with the aid of the enzyme aldose reductase. Aldose reductase inhibitors can prevent changes induced by diabetes. A total of 30 patients with minimal background retinopathy were randomly divided into a ponalrestat-taking group and a placebo-taking group. All were followed for 6 months and twenty-three were followed for 12 months. The baseline microaneurysm count was 2.6 +/- 1.9 (mean +/- SD) for the ponalrestat group and 3.5 +/- 2.9 for the placebo group. At 6 months the counts were 3.1 +/- 3.5 and 2.9 +/- 3.6 and after 12 months 3.0 +/- 4.1 and 2.9 +/- 3.4. There is no statistically significant difference between the groups at 0, 6 or 12 months of study. The change in retinopathy severity level did not significantly differ between the two groups at either 6 or 12 months. Ponalrestat administration at a dosage of 600 mg daily for 12 months has no significant effect on the course of minimal retinopathy in diabetic patients.
- Published
- 1991
34. Atherosclerosis, C-Reactive Protein, and Risk for Open-Angle Glaucoma: The Rotterdam Study
- Author
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Paulus T. V. M. de Jong, Albert Hofman, Nomdo M. Jansonius, Roger C. W. Wolfs, Jacqueline C.M. Witteman, Simone de Voogd, Epidemiology, and Ophthalmology
- Subjects
Male ,medicine.medical_specialty ,VISUAL-FIELD LOSS ,Population ,PROGRESSION ,Cohort Studies ,Rotterdam Study ,Risk Factors ,GENERAL ELDERLY POPULATION ,Internal medicine ,Humans ,Medicine ,Aorta, Abdominal ,Prospective Studies ,MEDIATOR ,Risk factor ,education ,Prospective cohort study ,Aged ,Netherlands ,Ultrasonography ,LOW-TENSION GLAUCOMA ,education.field_of_study ,BLOOD-FLOW ,biology ,business.industry ,MORTALITY ,C-reactive protein ,Odds ratio ,Middle Aged ,Atherosclerosis ,Confidence interval ,PREVALENCE ,Surgery ,Radiography ,C-Reactive Protein ,Carotid Arteries ,Cardiology ,biology.protein ,Female ,Tunica Intima ,CAROTID-ARTERY ,business ,Glaucoma, Open-Angle ,OPTIC-NERVE ,Cohort study - Abstract
PURPOSE. To test the hypotheses that atherosclerosis and elevated serum C-reactive protein ( CRP) levels are risk factors for open-angle glaucoma ( OAG).METHODS. In a prospective, population-based cohort study, all participants 55 years and older and at risk for incident OAG underwent, at baseline ( 1990 - 1993) and at follow-up ( 1997 1999), the same ophthalmic examination, including visual field testing and optic disc photography. Baseline atherosclerosis was assessed by means of echography of the carotid arteries, abdominal x-ray examination, and ankle-arm index; baseline serum CRP levels were used in the analyses. The diagnosis of OAG was based on an algorithm using optic disc measures and visual field loss. Odds ratios of OAG were computed with logistic regression analyses. Risk factors were categorized in tertiles and according to standard deviation.RESULTS. After a mean follow-up of 6.5 years, incident OAG was diagnosed in 87 of 3842 ( 2.3%) participants at risk for OAG. Carotid artery plaques, carotid intima-media thickness, aortic calcifications, ankle-arm index, and CRP levels were not significant risk factors for OAG. The odds ratio, given for the highest and lowest tertiles, for carotid plaques was 1.43 ( 95% confidence interval [ CI], 0.68 - 2.99), for carotid intima-media thickness 0.86 ( 95% CI, 0.47 - 1.57), for aortic calcifications 1.02 ( 95% CI, 0.60 - 1.75), for ankle-arm index 0.69 ( 95% CI, 0.38 - 1.25), and for CRP 1.19 ( 95% CI, 0.68 - 2.07).CONCLUSIONS. In this prospective, population-based study, neither atherosclerosis nor serum CRP level was an important risk factor for OAG.
- Published
- 2006
35. Postsurgical Assessment and Long-term Safety of Recombinant Adeno-Associated Virus–Mediated Gene Transfer Into the Retinas of Dogs and Primates
- Author
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Yann Péréon, Guylène Le Meur, Jack-Yves Deschamps, Alexandra Mendes-Madeira, Michel Weber, D. Nivard, Philippe Moullier, Fabienne Rolling, UMR649, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'ophtalmologie, Développement et Pathologie du Tissu Musculaire (DPTM), and Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes
- Subjects
Pathology ,[SDV]Life Sciences [q-bio] ,viruses ,Genetic enhancement ,Recombinant virus ,medicine.disease_cause ,AAV SEROTYPES ,Green fluorescent protein ,chemistry.chemical_compound ,0302 clinical medicine ,Transgenes ,Fluorescein Angiography ,SPECIFICITY ,Adeno-associated virus ,0303 health sciences ,medicine.diagnostic_test ,Gene Transfer Techniques ,Defective Viruses ,VIRAL VECTOR ,Dependovirus ,3. Good health ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Safety ,medicine.medical_specialty ,Transgene ,EPITHELIUM-DERIVED FACTOR ,Genetic Vectors ,Green Fluorescent Proteins ,Biology ,TRANSDUCTION ,Retina ,TRANSGENE EXPRESSION ,PIGMENTED EPITHELIUM ,TYPE-2 ,03 medical and health sciences ,Dogs ,RETINITIS-PIGMENTOSA ,Electroretinography ,medicine ,Animals ,030304 developmental biology ,Postoperative Care ,Retinal ,Macaca fascicularis ,Ophthalmology ,Gene Expression Regulation ,chemistry ,OPTIC-NERVE ,Follow-Up Studies - Abstract
International audience; Objective: To evaluate, in dogs and primates, the short-term effects of subretinal injection and the safety of long-term recombinant adeno-associated virus (rAAV)mediated transgene expression with respect to retinal morphology and function. Methods: Subretinal delivery of rAAV (serotype 2, 4, or 5) was performed unilaterally in 14 beagles and 9 macaques. Postsurgical condition was evaluated during a 2-month follow-up study. Three dogs and I primate were examined for the long-term study. Green fluorescent protein expression was monitored by fluorescent retinal imaging. Retinal anatomy and function were assessed by angiography and electroretinography, respectively. Results: Transgene expression was observed in 20 of 23 subretinally injected animals (both with and without vitrectomy). We did not detect an inflammatory response in any of the 23 treated subjects. In the long-term study, transgene expression was detected at the latest points evaluated: 36 months for the rAAV-2-injected dog, 24 months for the rAAV-4 and rAAV-5 dogs, and more than 18 months for the rAAV-4-injected primate. Angiography examinations were performed and showed no retinal abnormalities. Functional evaluation showed normal electroretinographic amplitude responses that were similar to those of the noninjected contralateral eyes. Conclusions: Subretinal injection of the rAAV vector in dogs and primates is a safe procedure with no perioperative complications and a high rate of successful retinal gene transfer. The retinal anatomy and function remained unchanged, despite persistent transgene expression up to 36 months postinjection with rAAV-2, -4, or -5. Additionally, we observed no other adverse effects, such as tumor formation due to possible insertional mutagenesis. These short- and long-term studies on rAAV transgene expression using large animals are encouraging for the prospects of ocular gene therapy applications in humans. Clinical Relevance: These short- and long-term studies on rAAV transgene expression using large animals are encouraging for the prospects of ocular gene therapy applications in humans.
- Published
- 2005
36. Combined inhibition of Cdk5 and ROCK additively increase cell survival, but not the regenerative response in regenerating retinal ganglion cells
- Author
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Bermel, Christina, Toenges, Lars, Planchamp, Veronique, Gillardon, Frank, Weishaupt, Jochen H., Dietz, Gunnar P. H., Baehr, Mathias, and Lingor, Paul
- Subjects
Optic nerve crush ,Cdk5 ,Spinal-Cord ,Axonal Regeneration ,rho kinase ,Retinal ganglion cells ,Central-Nervous-System ,Signaling Pathways ,Adult-Rats ,nervous system ,Neurite Outgrowth ,Rho ,Retinal explants ,Optic-Nerve ,Regeneration ,Cyclin-Dependent Kinase-5 ,Death In-Vivo - Abstract
CNS regeneration is limited by lesion-induced neuronal apoptosis and an environment inhibiting axonal elongation. Inhibition of ROCK has been previously shown to promote regeneration in retinal ganglion cells (RGC) whereas Cdk5 inhibition mainly promoted survival. Therefore, we have evaluated the effects of combined treatment with inhibitors of ROCK and Cdk5. We show that in vitro, the co-application of the Cdk5 inhibitor, Indolinone A, and the ROCK inhibitor, Y-27632, potentiated the survival-promoting effect of either substance alone. However, neurite outgrowth in vitro was promoted only by the presence of Y-27632, not by Indolinone A alone. In the ex vivo explant and the in vivo optic nerve crush model the combination of both inhibitors significantly increased neurite outgrowth at small distances, but this effect leveled off for longer neurites. In Summary, the combined treatment with the Cdk5 inhibitor Indolinone A and the ROCK inhibitor Y-27632 results in a strong additive effect on neuronal survival, but is not able to increase the regenerative response beyond the effect of the ROCK inhibitor. (C) 2009 Elsevier Inc. All rights reserved.
37. Alzheimer's disease and glaucoma - Reply
- Author
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Janssen, Sarah F., Gorgels, Theo G. M. F., Ramdas, Wishal D., Klaver, Caroline C. W., Duijn, Cornelia M., Nomdo Jansonius, Bergen, Arthur A. B., Perceptual and Cognitive Neuroscience (PCN), MUMC+: *AB Onderzoekers (9), RS: MHeNs - R3 - Neuroscience, and Oogheelkunde
- Subjects
SPACE ,CEREBROSPINAL-FLUID PRESSURE ,NORMAL-TENSION GLAUCOMA ,OPEN-ANGLE GLAUCOMA ,LAMINA-CRIBROSA ,GENE ,INTRAOCULAR-PRESSURE ,TRANSPORT ,OPTIC-NERVE
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