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| November 2007 | Inside IOVS | Volume 48/11 |
BRAF Gene Mutations: Different Prevalence in Iris and Choroidal Melanomas?
Mutations in the BRAF gene, which encodes a protein kinase, have been shown to be important in melanoma of the skin. They have also been identified in a proportion of conjunctival melanomas. This mutation has, however, rarely been identified in choroidal melanoma. Henriquez et al. (p. 4897) report the presence of this activating point mutation in 9 of 19 iris melanomas and show that its presence is significantly associated with recurrent tumors. This suggests that there may be genetic as well as clinical differences between iris and posterior uveal melanomas. Inhibitors of the mutated BRAF protein are already undergoing clinical trials and may offer an alternative therapeutic strategy for iris melanoma.
Light-Induced AP-1 Activation in Müller Cells
The T4R rhodopsin mutant photoreceptors degenerate with light exposures comparable to those used in clinical eye examinations of human patients. Gu et al. (p. 4907) show that light exposures of mutant canine retinas significantly increased AP-1 DNA binding activity by 1 hour after exposure, and there was parallel phosphorylation of c-Fos and ERK1/2. Immunohistochemistry showed that the components of this signaling pathway were localized in Müller cells and not photoreceptors. These results suggest that light-induced AP-1 activation in the T4R rhodopsin mutant retina is a retinal cell survival response rather than a photoreceptor death signal.
Driving Is an Important Activity for Low Vision Patients
Massof et al. (p. 4955) report that more than half of the patients seen at an outpatient low vision clinic in a large urban academic medical center potentially are eligible to drive a motor vehicle in 80% of the states in the U.S. More than a quarter of the patients were driving at the time of their clinic appointment. However, 40% of those patients reported that driving was difficult. Driving was rated as an extremely important goal by more than half of the low vision patients. The data suggest that it takes more than two years after patients stop driving before they adapt to that loss of function and driving ceases to be important to them.
Keratocyte Networks, "Cellular Highways" for Neutrophil Trafficking
In response to corneal epithelial injury, emigrated leukocytes (neutrophils) facilitate wound healing, but the mechanism of leukocyte migration within the corneal stroma is poorly understood. Using a mouse model of corneal epithelial scrape injury, Petrescu et al. (p. 5023) found that neutrophils form close surface contacts not only with the extracellular matrix (e.g., collagen) but also with keratocytes. Moreover, the leukocyte integrin adhesion molecule, CD18, mediates neutrophil contact with keratocytes, but not collagen. Since keratocytes form a cellular network within the stroma, this study identifies a novel role for the keratocyte network as a "cellular highway" for leukocyte trafficking during corneal inflammation.
Defensin RC-2 and the Prevention of Experimental HSV-1 Keratitis
Defensins, small peptides that have inhibitory effects on several microbes, play an important role in innate defenses. Although defensins have been known for some time to inhibit viruses in culture, little is known about their utility in treating infections. Using various treatment regimens, Brandt et al. (p. 5118) tested the in vivo activity of a theta defensin, RC-2, in a mouse model of HSV-1 keratitis. The RC-2 was most effective when mixed with virus before infection. When RC-2 was used prophylactically by placing it on the cornea before virus, there was a significant reduction in the severity of corneal clouding. The RC-2 was not effective when given post-infection. These results suggest that defensins may be therapeutically useful, but improvements will be needed, including further studies on formulation and pharmacokinetics.
Aerosolized Nanoparticle Drug Delivery in Gas-Filled, Vitrectomized Eyes
Drug delivery to posterior segment tissues is gaining importance as new pharmacotherapies become available to modify posterior segment disease. For example, proliferative vitreoretinopathy (PVR) is primarily a surgical disease that may require post-operative intraocular gas tamponade. The ability to introduce standard pharmacotherapeutic agents during the surgical procedure is limited by the gas-phase media. Zhang et al. (p. 5243) propose a novel drug delivery system by introducing aerosolized nanoparticles in the gas-phase of pars plana vitrectomy, thereby influencing the disease process. Many other applications are feasible. Fluorescein is used to demonstrate the methodology, pilot-stage pharmacokinetics, and establish parameters for modeling systems.
Fractalkine Mediates Ocular Angiogenesis
You et al. (p. 5290) demonstrated that fractalkine induced migration of human umbilical vein endothelial cell (HUVEC) and bovine retinal capillary endothelial cell (BREC), formation of endothelial cell capillary tubes on Matrigel, and corneal neovascularization in rabbit corneal pocket assay. Intravitreal injection of anti-fractalkine antibody decreased retinal angiogenesis in the mouse oxygen-induced retinopathy model. Elevated vitreous level of fractalkine also was revealed in the patients with proliferative diabetic retinopathy. Fractalkine may play an important role in ocular angiogenic disorder.
Several Complement Factor H Variants Are Associated with AMD in Japanese
Ethnic variation has been reported in age-related macular degeneration (AMD)-associated Y402H polymorphism in complement factor H (CFH). Mori et al. (p. 5315) show that other coding and noncoding variants in the CFH gene, including rs1410996, moderately influenced the risk of AMD in a Japanese population. The authors provide evidence that the phenotypic and epidemiological variation present is in part attributable to differential effects of various polymorphisms in the CFH gene.
The Importance of Replication Studies in Myopia Genetics
Fifteen regions in the human genome harboring myopia genes have been identified, but the exact nature of the genes remain elusive. Impeding progress is the paucity of studies replicating these regions in independent myopic populations. To address this, Schäche et al. (p. 4924) used an Australian twin cohort to analyze previously identified myopia susceptibility loci. Results from the previous twin study were not replicated in this independently ascertained twin cohort. These findings are important as they highlight that caution is needed when interpreting myopia genetic studies and whether or not results can be applied to the wider population.
Basement Membrane Changes during Postnatal Corneal Maturation
Corneas and their basement membranes undergo postnatal maturation but the molecular mechanisms of this process remained obscure. Kabosova et al. (p 4989) have conducted a comprehensive study of basement membrane composition in infant and adult human corneas. The authors found distinct differences in the expression of type IV collagen and laminin isoforms in the infant and adult epithelial basement membranes. Additionally, many basement membrane components (type IV collagen and laminin isoforms, nidogens, perlecan, fibronectin, and netrin-4) were expressed on both sides of infant Descemet’s membrane, whereas they became confined to one side only in the adult. Some proteins (fibrillin-1, tenascin-C, SPARC, laminin-332, and matrilin-4) disappeared from adult Descemet's membrane. It is suggested that the state of cell differentiation and/or proliferation may influence basement membrane composition during transition from infant to adult state.
UBIAD1 Gene Causes Schnyder Crystalline Corneal Dystrophy
Schnyder crystalline corneal dystrophy (SCCD) is a rare autosomal dominant disease characterized by abnormal increase of cholesterol and phospholipids in the cornea leading to progressive corneal opacification and visual loss. Mutations in the UBIAD1 gene were detected by Weiss et al. (p. 5007) in six SCCD families and a potential hot spot was observed at amino acid N102S. UBIAD1, UbiA prenyltransferase domain containing 1 produces a protein that is predicted to contain several transmembrane helices and a prenyltransferase domain that could potentially play a role in cholesterol metabolism.
GDNF Acting on Dopaminergic Cells and on Rods
GDNF supports a variety of neurons, including midbrain dopaminergic neurons. Its actions in retinal development now could be further elucidated by Volpert et al. (p. 5306), using reaggregated organotypic spheres from embryonic chick retina (retinal spheroids). Supplementing their cultures with GDNF, or down-regulating inherent GDNF, they could show that GDNF promoted the differentiation of dopaminergic amacrine cells, but also strongly supported rod photoreceptors, while cones were not affected. Thus, GDNF could become a tool to extend survival of degenerating rod photoreceptors; moreover, its action on other retinal cell types deserves further attention.
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