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| January 2003 | Inside IOVS | Volume 44/1 |
High Resolution MRI Reveals Optic Chiasmal Abnormalities in Human Albinos
Human albinos have subtle differences in configuration of the optic chiasm that reflect the predominant crossing of optic fibers. Schmitz et al. (p. 16) show that these abnormalities can be revealed by multiplanar reformations of high resolution MRI scans as well as voxelwise statistical comparisons. These MRI techniques can easily be included in the routine clinical workup of albinism. The method is suitable to look for changes in the architecture of the optic chiasm in a wide variety of disorders involving the optic pathways. Voxelwise statistical comparisons are especially useful in scientific settings, because the method can attribute significance measures to morphological changes.
Role of Retinal Microglia in Experimental Uveitis
In uveitis, the inflammatory tissue damage was previously thought to derive from the macrophages. Rao et al. (p. 22) present evidence that resident retinal microglia, rather than macrophages, may be the cellular entities that initiate the inflammation. Using fluorescent dye labeling, OX42 staining, and Y-chromosome detection in Y→X chimeric rats to distinguish microglia from macrophages, Rao et al. demonstrate that in the early phase of EAU, microglia migrate to the photoreceptor cell layer, where they generate TNFa and peroxynitrite. These findings indicate a novel mechanism of EAU, in which retinal microglia may initiate retinitis with subsequent recruitment of circulation-derived phagocytes, leading to amplification of uveoretinitis.
Functional Estrogen Receptors in Human RPE
Estrogen deficiency in post-menopausal women may cause dysregulation of extracellular matrix (ECM) turnover, contributing to severity of age-related macular degeneration (ARMD). Not much is known about the presence of functional estrogen receptor (ER) subtypes a and b in RPE and their ability to regulate RPE synthesis of molecules important in the maintenance of ECM. Marin-Castaño et al. (p. 50) have demonstrated that both (ER) subtypes are expressed in human RPE and are regulated in a dose-dependent fashion by 17b-estradiol. Estrogens similarly regulated MMP-2, a gelatinase potentially important in maintaining RPE basement membrane. These data suggest that estrogen regulation of ECM synthesis and turnover may, in part, explain the gender differences and severity of ARMD.
O-Glycosylation of Mucins in the Ocular Surface Epithelia
Mucins are extraordinarily large and highly O-glycosylated glycoproteins synthesized by all wet-surfaced epithelia, including those of the cornea and conjunctiva. Argüeso et al. (p. 86) show that members of the group of isoenzymes that initiate mucin O-glycosylation have a cell-layer and a cell-type specific distribution in the corneal and conjunctival epithelia. In the keratinized epithelia of patients with dry eye (ocular cicatricial pemphigoid), the enzymes are lost within the apical cells, suggesting that O-linked glycans on mucins contribute to maintenance of a wet-surfaced phenotype. Therapies based on the modulation of mucin O-glycosylation could be an effective approach to treating dry eye diseases.
Corneal Expression of Fas Ligand Regulates Neovascularization
Results of several studies have shown that Fas ligand (FasL) expression on the cornea is involved in maintaining the immune privileged status of the eye. The authors have extended those studies by demonstrating that FasL also is involved in maintaining the avascular state of the cornea. Stuart et al. (p. 93) demonstrate that corneas that do not express functional FasL develop significantly more neovascularization than do corneas that express normal FasL. Furthermore, corneas treated with anti-Fas antibody have much less neovascularization than do corneas not treated with this antibody. These data suggest that FasL plays a very important role in maintaining the clarity of the cornea and that treatments designed to augment FasL function might be an important tool in preventing unwanted corneal vessel growth.
Suppressing Corneal Conjunctivalization
Corneal conjunctivalization leads to corneal opacity and graft failure in Stevens Johnson syndrome and ocular cicatricial pemphigoid. The process is complex and involves both the adoption of a conjunctival epithelial phenotype, complete with goblet cells, and neovascularization. Using a mouse model of limbal deficiency, Joussen et al. (p. 117) demonstrate that the inhibition of endogenous vascular endothelial growth factor bioactivity suppresses not only corneal neovascularization, but also the appearance of corneal goblet cells. The high affinity VEGF receptor Flt-1 is implicated as it is expressed on the surface of conjunctivalized cornea. An anti-VEGF approach may prove useful in the treatment of ocular surface diseases characterized by corneal conjunctivalization.
Graft-Host Integration
Integration of subretinally placed neural retinal grafts with the host retina occurs but is found to be limited. Using different specific neuronal cell markers, Zhang et al. (p. 324) have now shown that bridging of neuronal fibers between a subretinal transplant and the host retina occurs only through discontinuities in the host photoreceptor cell layer or at a time point when photoreceptor cells of the host are absent. These observations indicate that structures and/or molecules associated with the host photoreceptor cell layer limit graft-host integration and suggest that subretinal grafts should be placed in areas where most or all host photoreceptors have been lost at the time of transplantation.
Lithium and Optic Nerve Regeneration
The optic nerve regenerates poorly following injury in mammals. Most often, injured retinal ganglion cells die by apoptosis. Huang et al. (p. 347) found that lithium, a widely used mood-stabilizing drug, at its established therapeutic concentrations promotes the survival of retinal ganglion cells and the regeneration of their axons via induction of Bcl-2 expression. These results suggest that lithium may be used to treat optic nerve degeneration, occurring, for example, in glaucoma and optic nerve neuritis. They also offer new clues toward a better understanding of the regulation of nerve regeneration in the mammalian retina and the brain.
Nepafenac, a Topical COX Inhibitor, Suppresses Ocular Neovascularization
Recent observations suggest that cyclooxygenase-2 (COX-2) is upregulated in colon cancers, that prostaglandins (PGs) may act as tumor promoters, at least in part through stimulating angiogenesis, and that COX inhibitors may be chemoprotective by inhibiting tumor angiogenesis. Takahashi et al. (p. 409) have demonstrated that COX inhibition also suppresses ocular neovascularization (NV). Nepafenac, a potent nonspecific COX inhibitor, significantly reduces retinal NV and choroidal NV by decreasing expression of vascular endothelial growth factor (VEGF). Direct inhibitors of VEGF are currently being tested in patients with age-related macular degeneration and choroidal NV, but are delivered by intravitreous injection. Nepafenac exhibited its therapeutic effects in 3 mouse models of ocular NV after topical administration to the cornea. If Nepafenac has similar effects in human eyes with retinal and choroidal NV, it will provide a major noninvasive addition to treatment options for several blinding eye diseases.
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