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| August 2004 | Inside IOVS | Volume 45/8 |
Specific BRAF Mutation in Some Conjunctival Melanomas Offers a Potential New Drug Target
The BRAF T1799A mutation is common in cutaneous melanoma but absent in uveal melanoma. Gear et al. (p. 2484) found the BRAF T1799A mutation in 5 out of 22 conjunctival melanomas. This finding has two important implications. Firstly, it reflects the closer clinical relationship of cutaneous and conjunctival melanoma compared with uveal melanoma and may indicate a common genetic basis for some conjunctival and cutaneous melanomas. Secondly, specific inhibitors of b-Raf and the associated MAPK pathway are currently undergoing clinical trials for the treatment of cutaneous melanomas amongst other malignancies and may be effective in the treatment of some conjunctival melanomas.
Drug-Loaded Hydrogel Iontophoresis
Eljarrat-Binstock et al. (p. 2543) demonstrated the ability of iontophoresis to deliver high doses of charged drugs like gentamicin to different segments of the eye using an easy-to-operate iontophoretic device with disposable drug-loaded hydrogel. A low and harmless current of up to 1 mA for 60 seconds enhanced gentamicin penetration into the eye resulting in therapeutic drug levels at the cornea for more than eight hours. The achieved levels were ten-fold higher than those obtained with extensive eye drop instillation or subconjunctival injection. This non-invasive convenient procedure may have an immediate use in prophylactic and acute delivery of antibiotics and other charged drugs.
Enhanced In Vitro Anti-angiogenic Activity of Human Limbal Epithelial Cells Cultivated on Amniotic Membrane
Ma et al. (p. 2586) reported that human limbo-corneal epithelial cells (HLE) cultivated on amniotic membrane (AM) expressed an enhanced inhibitory effect on the proliferation, migration, and differentiation of vascular endothelial cells. Such inhibitory activities were further augmented when HLE on denuded AM were cocultured with 3T3 fibroblasts and were correlated with the release of endostatin. The phenomenon highlights the significance of cell-matrix and cell-cell interactions in the production of anti-angiogenic factors by HLE, and also justifies combined limbal and AM transplantation or the transplantation of cultivated HLE on AM in limbal stem cell deficiency diseases associated with inflammation and neovascularization.
Modulation of Hemangiogenesis and Lymphangiogenesis after Corneal Transplantation Promotes Graft Survival
Whereas corneal grafts placed into avascular recipient beds enjoy 90% 2-year survival rates, corneas placed into vascularized recipient beds are rejected in more than 50%. Pre-existing corneal blood vessels have previously been identified as risk factors for immune rejections after corneal transplantation. But even in preoperatively avascular recipient beds, mild corneal hemangiogenesis develops after keratoplasty. Using the mouse model of normal-risk keratoplasty, the study by Cursiefen et al. (p. 2666) provides novel evidence that lymphangiogenesis accompanies hemangiogenesis after normal-risk keratoplasty and that this process can be inhibited by VEGF Trap and establishes postkeratoplasty heme- and lymphangiogenesis as novel risk factors for immune rejections after keratoplasty. This study provides proof-of-principle that corneal graft survival can be improved by modulation of heme- and lymphangiogenesis after transplantation.
Neuroprotection of Minocycline in Retinal Light Damage
Microglial cells are known to play pivotal roles in various neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. Minocycline, a microglial inhibitor, has recently been shown to be neuroprotective in models of cerebral ischemia and degenerative diseases of the brain and is in clinical trial for Parkinson’s disease. Zhang et al. (p. 2753) show that minocycline treatment provided marked neuroprotective effect on photoreceptors in light-induced retinal degeneration as evidenced by morphologic, morphometric, and electrophysiologic criteria. Because of its pharmacokinetic properties, desirable pharmacologic actions, and proven safety, minocycline might be considered for photoreceptor degenerative diseases such as retinitis pigmentosa or possibly age-related macular degeneration.
Abnormal Retinal Development in Mice Deficient in Semaphorin 4A
Semaphorins represent a diverse family of proteins that are important during nervous system development and immune functions. Secreted semaphorins and their receptors are known to play a role in retinal ganglion cell development. However, very little is known regarding the function of transmembrane semaphorins in the visual system. Rice et al. (p. 2767) used a retroviral gene-trap approach to generate mice deficient in Semaphorin 4A. Adult mice lacking this transmembrane semaphorin exhibit a profound loss of both rod and cone photoreceptors. Developmental studies revealed a failure in the normal interactions that occur between outer segments and the retinal pigment epithelium. This study identifies Semaphorin 4A as an important regulator of outer retina development in mice.
Corneal Dehydration and Rehydration Measured by Optical Coherence Tomography
Hosseini et al. (p. 2555) measured the dynamic of corneal dehydration and rehydration following the application of a topical dehydrating agent using optical coherence tomography (OCT). This novel application enables the non-invasive quantitative assessment of the corneal response to dehydrating agents by continuously monitoring the dynamic of changes in corneal thickness and the backscatter light profile. An inverse relationship was found between the backscatter intensity of the cornea and the degree of rabbit corneal hydration. The study demonstrates the potential application of OCT for functional assessment of cornea and may provide an effective tool for developing a better understanding of drug-corneal interaction and water transport within the cornea.
Memantine Treatment in Experimental Glaucoma Monkeys
Excessive stimulation of NMDA-type glutamatergic ion channels is thought to contribute to neuronal injury in a wide range of CNS degenerative disorders. Vehicle-treated ocular hypertensive monkeys exhibit functional and anatomical changes which are consistent with a selective injury to retinal ganglion cells. As shown by Hare et al. (p. 2625 and p. 2640), daily oral dosing with 4 mg/kg memantine, an uncompetitive NMDA-type channel blocker that does not act to lower intraocular pressure, was associated with a reduction of these glaucoma-induced changes but was not associated with any effect on the function or histological appearance of normotensive eyes. Memantine may thus provide a safe and effective treatment for chronic glaucoma and other diseases of the retina and optic nerve.
II. [Abstract] [Full Text]
Effect of TNF Receptor Expression on Corneal Graft Survival
As reported by Niederkorn et al. (p. 2674), tumor necrosis factor-a (TNF-a) has been implicated in corneal allograft rejection. Murine corneal cells were found to express TNF-a receptors I and II and were susceptible to TNF-a-induced apoptosis. Corneal allografts from TNFRI knockout (KO) donors and wild-type donors were rejected in 50% of the hosts. By contrast, 100% of the corneal allografts from C57BL/6 TNFRII KO donors underwent rejection. Thus, the expression of TNFRII on corneal cells appears to convey a degree of protection against immune rejection by a yet-to-be-identified mechanism.
Insulin-like Growth Factor-1, the Retinal Pigment Epithelium, and Choroidal Neovascularization
The retinal pigment epithelium (RPE) plays a central role as a source of angiogenic factors in the development of choroidal neovascularization (CNV). Slomiany and Rosenzweig (p. 2838) demonstrate that insulin-like growth factor-1 (IGF-1) stimulates hypoxia-inducible factor-1 (HIF-1) protein expression, HIF-1 transcriptional activity, vascular endothelial growth factor (VEGF) and IGF-binding protein-3 (IGFBP-3) secretion in the RPE cell line D407. VEGF and IGFBP-3 were secreted from the apical domain of polarized monolayers grown on transwell inserts, irrespective of which compartment IGF-1 was added to. Immunocytochemical staining of IGF-1 receptors confirmed their non-polarized distribution. These studies define a potential role for the IGF system in contributing to the etiology of CNV by stimulating RPE VEGF production.
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