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| August 2003 | Inside IOVS | Volume 44/8 |
Potential Susceptibility Gene for the Development of Ocular Telangiectasias
Mauget-Faÿsse et al. (p. 3257) examined whether the gene mutated in patients with the rare cancer-prone disease ataxia telangiectasia, the ATM gene, could be modified in individuals who developed idiopathic or radiation-induced ocular telangiectasias. A high frequency of sequence variants was found in such individuals, implicating the ATM gene in a non-neoplastic clinical disorder outside the setting of AT families, and identifying a potential susceptibility gene for the development of ocular telangiectasias of either choroidal or retinal origin.
Survival in Uveal Melanoma Patients
From the population-based Swedish Cancer Registry, with an inclusion rate of 95% of cancer cases, the survival rates in uveal melanoma patients were estimated over a 39-year period. As reported by Bergman et al. (p. 3282), the 5-year relative survival rates for uveal melanoma improved over time, in spite of falling incidence rates for this ocular tumor in the Swedish population. This suggests that explanatory causes other than early detection must be sought. As regards overall survival of patients with uveal melanomas, the introduction of eye-sparing treatments has not adversely affected prognosis.
Repeatability of ETDRS Visual Acuity in Children
The clinician must often determine if the visual acuity (VA) of a patient has changed over time. For a change to be significant and important in the management of the patient, the change must exceed the measurement variability. Manny et al. (p. 3294) report that, based on a group of myopic children (6-11 years) enrolled in COMET (Correction of Myopia Evaluation Trial), the criterion for a statistically significant change in VA is no more than ± 0.15 logMAR (± 8 letters). This value is similar to that reported for adults and provides a guideline to determine if the visual acuity of a child has changed significantly.
Viral Clearance without Destruction of Infected Retina
Since recovery from viral retinitis can occur without permanent retinal damage, noncytolytic mechanisms of clearance must exist. To investigate these mechanisms, the animal model system, experimental coronavirus retinopathy (ECOR) was used. These studies by Hooks et al. (p. 3402) revealed that CD4 and CD8 T cells and macrophages infiltrate the infected retina. Noncytolytic T cell-mediated control of virus replication was associated with a cytokine–mediated process and IFN-g was identified as a critical cytokine. These studies define an important immune component for recovery from viral retinitis.
Glucose Transporters in Diabetes
In diabetic cataract, elevated glucose concentrations result in osmotic and oxidative stresses that produce a distinct zone of fiber cell damage that is restricted to the outer cortex of the lens. Previous work by Merriman-Smith et al. show that the glucose transporter isoform, GLUT3, is expressed in lens fiber cells. In this current study, Merriman-Smith et al. (p. 3458) showed that GLUT3 was up-regulated in the diabetic lens at both the transcript and protein levels. Furthermore GLUT3 up-regulation was localized to the zone of tissue damage. Thus the up-regulation of GLUT3 should be considered as one of the molecular mechanisms involved in the pathogenesis of diabetic cataract.
AP-1 Activation: A New Mechanism to Treat Glaucoma?
Interleukin (IL)-1a, when introduced into the anterior chamber of the rat in vivo or the human ex vivo, lowers intraocular pressure (IOP). Its effect may be mediated by the activation of matrix metalloproteinases (MMPs), which can hydrolyze the excessive extracellular matrix in the trabecular meshwork (TM) and improve aqueous outflow. Pang et al. (p. 3485) and Fleenor et al. (p. 3494) have dissected the IL-1a signaling pathway in the TM, and discovered a novel IOP-lowering mechanism. In cultured human TM cells, IL-1a stimulated the production of MMP-3. This effect was mediated mainly by activation of the AP-1 signaling pathway. Finally, as reported in Pang et al. (p. 3502), certain small molecule AP-1 activators were found to up-regulate MMP-3 expression in TM cells and improve aqueous outflow in perfused human eyes. The compound tert-butylhydroquinone did not affect the morphology of the perfused eyes, suggesting that it may be safe for clinical use. These findings may lead to the development of new drugs for glaucoma, which directly target the compromised outflow pathway.
Macrophage Depletion and Choroidal Neovascularization
Macrophages have been detected in choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD) and in experimental models. Sakurai et al. (p. 3578) show that pharmacological depletion of macrophages using clodronate liposomes nearly abolishes laser-induced CNV in mice and is associated with decreased vascular endothelial growth factor expression. This demonstration of a causal role for macrophages in CNV provides a mechanistic rationale for clinical trials of anti-inflammatory drugs in exudative AMD.
Experimental CNV and Macrophage Depletion in the Mouse
Macrophages have been shown to be present in both dry and wet age-related macular degeneration (AMD), but their contribution to disease pathogenesis is unknown. Espinosa-Heidmann et al. (p. 3586) report that macrophage depletion diminishes the severity of experimental CNV in mice. CNV lesions in aged mice depleted of macrophages were smaller, thinner, and less vascular than those in aged-matched controls. The results suggest that local immune factors may contribute to the severity of CNV lesions.
Corneal Grafts – How Long Will They Last?
The continued long-term loss of endothelial cells from corneal grafts is not typically a cell-mediated rejection response. It can, however, lead eventually to late endothelial failure and loss of graft function. Armitage et al. (p. 3326) have used a bi-exponential mathematical model to describe this loss of cells. They found that the rate of loss is 10-fold higher than in normal eyes, even 20 years after transplantation. Intriguingly, the long-term loss in grafts is very similar to that seen after cataract surgery, which could imply a common mechanism. Accordingly, a non-specific, innate response is proposed. The model also provides a rationale for a minimum donor endothelial cell density.
Mutational Hotspot in the RP1 Gene
Retinitis pigmentosa (RP) is a genetically heterogeneous group of retinal degenerations. Mutations in the RP1 gene, and especially Arg677ter, are a common cause of the autosomal dominant form of RP. Is the high frequency of the Arg677ter RP1 mutation due to a founder effect or a mutational hotspot? Schwartz et al. (p. 3593) observed a de novo Arg677ter RP1 mutation in an isolated (simplex) RP patient. This provides direct evidence for a mutational hotspot theory and has implications for accurate genetic counseling of individuals diagnosed with simplex RP.
Combretastatin Causes Regression of Choroidal Neovascularization
Several agents have been identified that suppress the development of choroidal neovascularization (CNV). A more desirable outcome is for an agent to cause CNV to regress, which would have greater potential for causing improvement. Nambu et al. (p. 3650) have demonstrated that a tubulin binding agent, combretastatin-A-4-phosphate, causes regression of CNV in mice. It binds to the colchicine binding site on microtubules, but in a reversible fashion, and thereby does not manifest the same toxicity as colchicine. It differentially affects endothelial cells participating in neovascularization and by changing their shape promotes thrombosis in neovascular tissue. Future studies will investigate its effects in patients with CNV.
Proteome Analysis of Human RPE Lipofuscin: Evidence for Posttranslational Modifications of Protein Compounds
Lipofuscin accumulation in the RPE is a common downstream pathogenetic pathway in various retinal diseases of heterogeneous etiology. Schutt et al. (p. 3663) performed proteome analysis of human lipofuscin granules and showed that many of the compounds were altered by aberrant covalent modifications of malondialdehyde (MDA), hydroxynonenal (4-HNE) and advanced glycosylation end products (AGE’s). These lipidperoxidation and glucoxidation products may result from lifelong UV-light and oxygen exposure and may be involved in lipofuscinogenesis and contribute to secondary cellular dysfunction. Their identification helps to identify potential future treatment targets.
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