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Irreversible Blindness (irreversible + blindness)
Selected AbstractsDexamethasone alters F-actin architecture and promotes cross-linked actin network formation in human trabecular meshwork tissueCYTOSKELETON, Issue 2 2005Abbot F. Clark Abstract Elevated intraocular pressure is an important risk factor for the development of glaucoma, a leading cause of irreversible blindness. This ocular hypertension is due to increased hydrodynamic resistance to the drainage of aqueous humor through specialized outflow tissues, including the trabecular meshwork (TM) and the endothelial lining of Schlemm's canal. We know that glucocorticoid therapy can cause increased outflow resistance and glaucoma in susceptible individuals, that the cytoskeleton helps regulate aqueous outflow resistance, and that glucocorticoid treatment alters the actin cytoskeleton of cultured TM cells. Our purpose was to characterize the actin cytoskeleton of cells in outflow pathway tissues in situ, to characterize changes in the cytoskeleton due to dexamethasone treatment in situ, and to compare these with changes observed in cell culture. Human ocular anterior segments were perfused with or without 10,7 M dexamethasone, and F-actin architecture was investigated by confocal laser scanning microscopy. We found that outflow pathway cells contained stress fibers, peripheral actin staining, and occasional actin "tangles." Dexamethasone treatment caused elevated IOP in several eyes and increased overall actin staining, with more actin tangles and the formation of cross-linked actin networks (CLANs). The actin architecture in TM tissues was remarkably similar to that seen in cultured TM cells. Although CLANs have been reported previously in cultured cells, this is the first report of CLANs in tissue. These cytoskeletal changes may be associated with increased aqueous humor outflow resistance after ocular glucocorticoid treatment. Cell Motil. Cytoskeleton 60:83,95, 2005. © 2004 Wiley-Liss, Inc. [source] Calpain-mediated degradation of G-substrate plays a critical role in retinal excitotoxicity for amacrine cellsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2009Toru Nakazawa Abstract The role of neuronal N-methyl-D-aspartate (NMDA) receptor-mediated intracellular signaling has been elucidated in both physiological and pathological conditions. However, the details of relative vulnerability for excitotoxicity remain unknown. Retinal excitotoxicity is involved in various diseases leading to irreversible blindness. Here, we used the visual system and explored the mechanistic details of the NMDA-elicited intracellular events, especially in the amacrine cells, which are the most vulnerable type of neuron in the retina. G-substrate, a specific substrate of cyclic guanosine 3,,5,-monophosphate (cGMP)-dependent protein kinase, is colocalized with amacrine cells and acts as an endogenous inhibitor of protein phosphatase. To elucidate how G-substrate was involved in NMDA-induced amacrine cell death, the immunohistochemical analysis with G-substrate antibody was performed following NMDA injury. In vivo, NMDA immediately decreased G-substrate immunoreactivity, and the suppression of calpain activation using ALLN or calpain III, an inhibitor of calpain, blocked this decrease. In vitro, degraded fragments of G-substrate were detected within 10 min after coincubation of G-substrate and calpain. Moreover, G-substrate knockout (G-substrate,/,) mice were more susceptible to NMDA injury than wild-type mice. ALLN did not have a neuroprotective effect in G-substrate,/, mice. These data strongly suggest that calpain-mediated loss of G-substrate represents an important mechanism contributing to NMDA-induced amacrine cell death. © 2008 Wiley-Liss, Inc. [source] 2161: Development of a next-generation sequencing platform for retinal dystrophies, with LCA and RP as proof of conceptACTA OPHTHALMOLOGICA, Issue 2010F COPPIETERS Purpose Retinal dystrophies represent an emerging group of hereditary disorders that lead to degeneration of the photoreceptors and/or the retinal pigment epithelium, resulting in irreversible blindness. They are genetically complex, with over 200 disease loci identified so far. Current genetic screening consists of microarray analysis (Asper Ophthalmics) for the most recurrent mutations, and subsequent Sanger sequencing. However, the high cost and low throughput of the latter technology limits testing to only the most recurrent genes. This project aims to develop a high throughput and cost-effective platform for screening of all known disease genes for Leber Congenital Amaurosis (LCA) and retinitis pigmentosa (RP), using the next-generation sequencing (NGS) technology. Methods A NGS panel will be developed for all 16 and 47 known LCA and RP genes, respectively, including coding and untranslated regions, regulatory regions and microRNA binding sites. The protocol will consist of the following steps: 1) high throughput primerdesign and qPCR, 2) ligation, 3) shearing and 4) sequencing on the Illumina Genome Analyser IIx (GAIIx). This innovative protocol overcomes the need for short amplicons in order to render short-read sequences by the GAIIx. This sequencing instrument was chosen because of its high capacity, low cost per base and the absence of interpretation problems at homopolymeric regions. Analysis of the variants will be performed using in-house developed and commercial software, which ranks all variants according to their pathogenic potential. Conclusion Using the proposed protocol, comprehensive screening for all known disease genes for LCA and RP will be available for the first time. [source] Ocular perfusion and age-related macular degenerationACTA OPHTHALMOLOGICA, Issue 2 2001Thomas A. Ciulla ABSTRACT. Purpose: To review the role of ocular perfusion in the pathophysiology of age-related macular degeneration (AMD), the leading cause of irreversible blindness in the industrialized world. Methods: Medline search of the literature published in English or with English abstracts from 1966 to 2000 was performed using various combinations of relevant key words. Results: Vascular defects have been identified in both nonexudative and exudative AMD patients using fluorescein angiographic methods, laser Doppler flowmetry, indocyanine green angiography, and color Doppler imaging. Conclusion: Although these studies lend some support to the vascular pathogenesis of AMD, it is not possible to determine if the choroidal perfusion abnormalities play a causative role in nonexudative AMD, if they are simply an association with another primary alteration, such as a primary RPE defect or a genetic defect at the photoreceptor level, or if they are more strongly associated with one particular form of this heterogeneous disease. Further study is warranted. [source] Association of a single nucleotide polymorphism in the TIGR/MYOCILIN gene promoter with the severity of primary open-angle glaucomaCLINICAL GENETICS, Issue 3 2001E Colomb Primary open-angle glaucoma (POAG) is a highly prevalent optic neuropathy and a major cause of irreversible blindness, with elevation of intraocular pressure (IOP) being a primary risk factor. The trabecular meshwork-inducible glucocorticoid response (TIGR)/MYOCILIN (MYOC) gene coding region is mutated in 3,4% of POAG patients. Here, in a retrospective study of 142 POAG patients, we evaluated the influence on glaucoma phenotype of a novel biallelic polymorphism (,1000C/G) located in the upstream region of the MYOC gene. Allele frequencies were similar among patients and controls. However, the G allele (frequency 17.6%), also designated as MYOC.mt1, was associated with an increased IOP (+4.9 mmHg, p=0.0004) and a more damaged visual field (p=0.02). Both effects were predominant in females. Moreover, whereas IOP in MYOC.mt1 noncarriers decreased very markedly to the normal range between diagnosis and inclusion in the study (p=3×10,5 in both males and females), reflecting successful therapy, it decreased less noticeably in MYOC.mt1+ male patients (p=0.005) and not at all in MYOC.mt1+ female patients. MYOC.mt1 appears therefore to be an indicator of poor IOP control and greater visual field damage in diagnosed POAG patients, potentially due to a lack of response to therapeutic intervention. Its typing might help in the selection of treatment paradigms for the management of POAG patients. [source] REVIEW: An Approach for Neuroprotective Therapies of Secondary Brain Damage after Excitotoxic Retinal Injury in MiceCNS: NEUROSCIENCE AND THERAPEUTICS, Issue 5 2010Yasushi Ito SUMMARY Background: Many current therapeutic strategies for several eye diseases, such as glaucoma, retinal ischemia, and optic neuropathy, are focused on protection of the retinal ganglion cells (RGCs). In fact, loss of visual field, including irreversible blindness, is caused by RGC damage in these diseases. However, recent evidence suggests that the RGC damage extends to visual center in brain: the visual impairment induced by these diseases may result not only from RGC loss, but also from neuronal degeneration within the visual center in brain. Objective: To protect neurons within the visual center in the brain, as well as retinal treatment, for the prevention of visual disorder in these diseases. Methods: Once considered difficult to study the visual center in brain following RGCs loss, because obtaining the human samples that are suitable for the study may be difficult. In addition, the monkey, mainly used as glaucomatous model, is relatively high cost and needs to long experiment-span. Here, we focused on mice, because of their high degree of availability, relatively low cost, and amenability to experimental and genetic manipulation. Conclusion: In this review, we describe time-dependent alterations in the visual center in brain following RGCs loss, and whether some drugs prevent the neuronal damage of the visual center in the brain. [source] | ||||||||||