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| June 2003 | Inside IOVS | Volume 44/6 |
A Mouse Model with Similarities to Human Pigment Dispersion Syndrome
Collagen XVIII and endostatin are components of ocular basement membranes. Marneros and Olsen (p. 2367) find that mice lacking collagen XVIII/endostatin show severe iris defects, with disruption of the iris pigment epithelium and morphological basement membrane changes. These observations suggest that collagen XVIII/endostatin has an important role for the function of iris basement membranes. Pigmented cells, characterized as macrophage-like iris clump cells, migrate out of the iris and cover the retina. The abnormalities in these mutant mice show similarities to changes seen in human pigment dispersion syndrome. Col18a1-/- mice might serve as a model for this disease.
Lutein and Zeaxanthin Status and Risk of Age-Related Macular Degeneration
The carotenoids lutein and zeaxanthin are the main constituents of macular pigment which protects the retina from phototoxic short-wavelength visible light and oxidative stress. The variation in their distribution within the retina—lutein dominant at the periphery and zeaxanthin in the central macular—suggests a difference in function. In a study of 380 elderly people by Gale et al. (p. 2461), those with the lowest plasma concentrations of zeaxanthin were twice as likely to have age-related macular degeneration as those with the highest concentrations. Low concentrations of lutein were not associated with increased risk. Improving zeaxanthin status may protect against age-related macular degeneration.
Differentially Expressed Genes in Keratoconus Epithelium
DNA microarrays provide the ability to measure the gene expression of thousands of genes simultaneously. This technique was used by Nielsen et al. (p. 2466) to identify 56 differentially expressed genes in corneal epithelium of keratoconus patients. Genes with distinct expression patterns may serve as a diagnostic tool, or as drug targets in a medical treatment. The altered genes belonged to groups of genes encoding the cytoskeleton, extracellular matrix remodeling, transmembrane signaling, and cell-to-cell/matrix interaction. Some of the alterations were also observed at the protein level using immunohistochemistry. The candidate genes identified in this study will be subjected to further studies.
Corneal Innervation and Morphology in Primary Sjögren’s Syndrome
Tuominen et al. (p. 2545) investigated corneal innervation and morphology in dry eye patients with verified primary Sjögren’s syndrome by in vivo confocal microscopy. The interesting morphological finding was nerve sprouting-like pattern that was found in subbasal nerve plexus in 40% of patients with primary SS, but in none of the controls. This finding may result from an ongoing corneal surface inflammation and subsequent neural de- and regeneration. This finding has implications for the pathophysiology of dry eye and for corneal hyperalgesia often experienced by these patients.
Multi-Sampling Suprathreshold Perimetry
High variability is a key problem in visual field testing. Also, novice patients find threshold tests difficult tasks to perform, so that the first results are often unreliable. In this paper, Artes et al. (p. 2582) introduce a new test, based on several suprathreshold presentations at each field location. Using computer simulation, they show that this "multi-sampling suprathreshold strategy" can detect field loss with similar sensitivity and specificity as the full-threshold strategy. Moreover, it gives more accurate and less variable estimates of the defect area. The authors speculate that the multi-sampling suprathreshold test may provide an easier and more reliable alternative to conventional field tests in detecting and monitoring glaucoma.
Gene Expression Profile in the Human TM
Mutation or altered expression of genes expressed in TM could interfere with normal function of the tissue, thereby leading to glaucoma. Tomarev et al. (p. 2588) used Expressed Sequence Tag (EST) analysis to investigate the expression profile of the human TM tissue. Over 4000 clones were analyzed. Transcripts for the myocilin gene, a locus for inherited glaucoma, formed the third most abundant cluster in the TM collection, while several other genes implicated in glaucoma (PITX2, CYP1B1 and optineurin) were also represented. These data may help to increase our understanding of the function of the TM and help in the selection of candidate genes for inherited glaucoma.
A New Therapeutic Target for Retinal Neovascularization
A critical step during retinal neovascularization is the breakdown of the extracellular matrix by proteinase enzymes allowing cell migration. McGuire et al. (p. 2736) demonstrate that the cell surface receptor of one of the key proteinase enzymes, urokinase, is upregulated during this process. The inhibition of the binding of urokinase to this receptor by a novel peptide, A6, significantly suppresses retinal neovascularization in an animal model. The current study suggests that the interaction of urokinase and its receptor may be an important therapeutic target in the management of proliferative retinopathies.
The Retinal Mitochondrial ATP-Sensitive K+ Channel: A Target for Neuroprotection?
In retinal ischemia, a large quantity of glutamate is released and mediates excitotoxicity via the NMDA receptor. Yamauchi et al. (p. 2750) show that opening the mitochondrial ATP-sensitive potassium channel [Mit K (ATP)] protects cultured retinal neurons against glutamate excitotoxicity, and that the protective effect of bradykinin against glutamate toxicity is mediated through Mit K (ATP). These results suggest that opening of Mit K (ATP) inhibits the initial calcium entry into mitochondria following NMDA receptor activation that causes superoxide generation. Mit K (ATP) may therefore be a novel target for neuroprotection against ischemic neuronal diseases.
Inhibitors of Apoptosis in Retinal Gene Therapy
In most cases of retinal degeneration, the outcome is apoptotic cell death of the photoreceptors. Petrin et al. (p. 2757) show that a gene that inhibits apoptosis (XIAP) provides photoreceptor protection in an acute chemotoxic model of retinal degeneration. Protection is seen both histologically and functionally. This suggests that increasing the apoptotic threshold may protect photoreceptors from dying and preserve their functional capability, regardless of the underlying cause of the disease.
Genetic Modification of Retinal Light Damage Susceptibility
Photoreceptors of mice lacking c-Fos, a component of the pro-apoptotic transcription factor AP-1, resist light induced apoptosis even at extreme illuminance levels. At position 450 of RPE65, presence of either Leu or Met is a genetic modifier of light damage sensitivity: Leu increases while Met reduces sensitivity. Wenzel et al. (p. 2798) introduced RPE65Leu450 to test whether this modification would overcome the protection given by lack of c-Fos. Light damage sensitivity was restored. c-Fos, normally needed to promote apoptosis, was replaced by other Fos family members, which are otherwise not activated by damaging light.
Genetic Loci That Protect against Age-Related Retinal Degeneration
Danciger et al. (p. 2442) have identified one very strong genetic locus on mouse Chromosome 6, and two additional loci representing variants of genes that protect the mouse from age-related retinal degeneration. This is the first step toward finding the actual genes and their protective variants. The human orthologs of these genes may serve as candidates for study in age-related macular degeneration (AMD) since mouse and human retinal genes are so much alike. Future identification of genes in play in AMD will open avenues of study that may lead to treatment or prevention of this blinding disease so prevalent in the older population.
Visual Fields in Newly Diagnosed Glaucoma Patients – the CIGTS Experience
For 607 newly diagnosed glaucoma patients enrolled in the Collaborative Initial Glaucoma Treatment Study (CIGTS), visual field (VF) characteristics based on automated perimetry are described in Gillespie et al. (p. 2613). A comparison among three visual field measures (the CIGTS VF score, the AGIS VF score, and the Mean Deviation) shows striking similarity among results. Learning effects were assessed, and some interesting predictors of both initial field loss and test-retest variability were found. Patient reported alertness had an impact on both measures. As one of the few modifiable characteristics that could improve performance in automated perimetry, this study suggests that the manufacturers might consider a video game format to raise the enjoyment level and thus, perhaps, improve alertness.
An RGC Response to Injury: Upregulation of PKC
The mammalian central nervous system is thought to have little capacity for regeneration, but increasing evidence argues that retinal ganglion cells (RGCs) have an intrinsic ability for repair if a permissive environment is present. Wu et al. (p. 2783) report neurite outgrowth from cultured RGCs is enhanced by prior injury to optic nerves. The injury increases the levels of PKCa and b mRNAs and these isozymes in neurites and growth cones. Stimulating PKC activity further increases neurite outgrowth, while blocking PKC activity strongly suppresses neurite outgrowth. Thus, RGCs actively respond to injury by specifically upregulating components of signaling cascades needed for survival and regrowth.
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