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| October 2004 | Inside IOVS | Volume 45/10 |
Vision-Induced Myopia in Adolescent Monkeys
Visual experience has a dramatic effect on refractive development during infancy; however, refractive errors in humans typically occur much later during adolescence. To determine if it is feasible that vision is involved in the genesis of common refractive errors, Zhong et al. (p. 3373) used an excimer laser to produce hyperopic anisometropia in adolescent monkeys and found clear evidence for compensating axial growth that eliminated the imposed optical errors. Thus, during adolescence, vision-dependent mechanisms normally maintain stable refractive errors in the two eyes, and optical defocus can produce axial myopia at ages when myopia usually emerges in children.
VEP Recovery in Amblyopic Eyes of Children after Patching
Patching the preferred eye is the mainstay of treatment for amblyopia in children. Weiss and Kelly (p. 3531) examined the cortical responses evoked by transient visual stimulation (VEPs) in amblyopic children before and after patching. Before patching, the amblyopic eye showed amplitude decreases with increasing spatial frequencies relative to the non-amblyopic eye. After patching, amplitudes in the amblyopic eye increased across all spatial frequencies. Spatial-frequency dependent changes were most robust for a late negative peak (N2) suggesting the cortical generator of this peak underlies the plasticity responsible for recovery of visual acuity.
Effects of Pirenzepine on Accommodation and Pupil Size in Rhesus Monkeys
Pirenzepine is an anti-muscarinic agent that is currently undergoing FDA clinical trials for the treatment of myopia in children. Ostrin et al. (p. 3620) evaluated the effects of subconjunctival injection of pirenzepine on pupil size and accommodation in Rhesus monkeys. 2% pirenzepine, a dosage similar to that used in the prevention of form deprivation myopia in animals, caused a significant increase in pupil size and nearly complete cycloplegia. Pirenzepine (0.02% or greater) significantly decreased centrally stimulated accommodation, and 0.2% or greater decreased pharmacologically stimulated accommodation. It is important to perform accommodation testing in children to understand side effects that may occur during myopia treatment.
Locus of Gene Expression Modulates Lens Gap Junctional Coupling
Martinez-Wittinghan et al. (p. 3629) studied the gap junctional conductance of lenses in which the Cx50 coding region was replaced by that of Cx46 (KI). The electrical properties of channels made from Cx46 were different when the protein was expressed by the Cx50 gene locus rather than the normal Cx46 gene. Indeed, some roles of gap junction coupling in the lens appear to depend on the locus of gene expression rather than the primary sequence of the protein, whereas other roles require a specific connexin regardless of its locus of expression. The Cx50 gene is expressed earlier in differentiation than Cx46, and this apparently leads to differences in posttranslational processing. In the lens, as in real estate, location matters.
A Possible Widespread Role for VMD2 Mutations in Ocular Disease
The developmental ocular disorder nanophthalmos has been mapped to chromosome 11q12. The demonstration by Yardley et al. (p. 3683) that nanophthalmos associated with retinal dystrophy results from highly specific VMD2 mutations illustrates areas of broad importance. First, the molecular mechanism is novel as the mutations do not solely alter the open reading frame to produce missense mutations, but in all cases, through splicing alterations, result in a second protein isoform containing an in-frame deletion. Second, VMD2 is mutated in Best disease, a monogenic macular dystrophy, and its functional role makes it an important candidate for AMD. This points to a unifying mechanism between disorders of development and late-onset.
Tubedown-1 Suppressed Mice Develop Proliferative Retinopathy
In this issue, Wall et al. (p. 3704) investigate the function of Tubedown-1, a novel protein that co-purifies with an acetyltransferase activity and that is suppressed in retinal endothelial cells in proliferative diabetic retinopathy. Using a conditional knockdown approach in vivo to block Tubedown-1 expression specifically in endothelial cells, the authors show that Tubedown-1-suppressed mice develop neovascularization and thickening of retinal and choroidal tissues similar to human neovascular proliferative retinopathies. These studies indicate that Tubedown-1 mediates a homeostatic influence which inhibits proliferative retinopathy and may offer a novel approach for developing improved therapies for the human retinopathies.
Neuroprotective and Anti-angiogenic Effects of Carboxyamido-triazole
Carboxyamido-triazole (CAI) is a small molecule that is relatively well tolerated in Phase II and III clinical trials for the treatment of advanced stage cancer. CAI is administered orally in humans and also possesses characteristics favorable for trans-scleral delivery. Franklin et al. (p. 3756) demonstrate that CAI exerts a potent anti-angiogenic effect to inhibit formation of retinal neovascularization and to hasten neovascular regression. Moreover, CAI protects the inner retina after ischemic damage. CAI is the first small molecule to demonstrate both neuroprotection and potent angiogenic inhibition for pathological retinal neovascularization. Thus, CAI should be considered as a clinical anti-angiogenic ophthalmic agent.
Optical Imaging of Retinal Function
Optical imaging is a well-established imaging technique for visualizing neuronal activity by measuring stimulus-evoked light reflectance changes from neural tissues. Tsunoda et al. (p. 3820) have applied this technique to the ocular fundus to measure cone- or rod-induced retinal responsiveness from macaque retina. The response topography in the retina, obtained by optical imaging, was consistent with psychophysical cone or rod sensitivity in humans and anatomical cone or rod distribution in humans and macaques. This functional measurement will have strong potential for a new diagnostic tool by which early and small retinal dysfunction can be non-invasively detected both in adults and infants.
Monkeys Recover from Form Deprivation Myopia
In contrast to many species, the available evidence indicates that primates cannot recover from form-deprivation myopia (FDM). To resolve this controversy, Qiao-Grider et al. (p. 3361) investigated refractive development in monkeys that had experimentally induced FDM and found that monkeys have a remarkable ability to recover from FDM. This recovery depends on when unrestricted vision is restored, the severity of the FDM, and possibly the method employed to produce FDM. However, the manner in which monkeys recover from FDM is very similar to that in other species, which indicates that the mechanisms responsible for emmetropization have been conserved across species.
cAMP and Aqueous Humor Secretion
cAMP has been the most intensively studied second messenger responsible for the regulation of aqueous humor secretion and thereby intraocular pressure. Little is known about the precise site(s) of their action. Using native bovine preparations, Do et al. (p. 3638) examined the effects of cAMP in the regulation of Cl- transport across the ciliary epithelium which plays the central role in aqueous humor formation. cAMP inhibited the net Cl- secretion by partially uncoupling the gap junctions between pigmented and non-pigmented ciliary epithelial cells, potentially decreasing the aqueous secretion. This study further indicates the crucial role of gap junctions in modulating aqueous humor secretion.
Adenosine Inhibits Glutamate-Induced Calcium Influx in Retinal Ganglion Cells
Using both purified retinal ganglion cell (RGC) cultures and whole-mounted retinal preparations, Hartwick et al. (p. 3740) found that adenosine, a neuromodulator in the central nervous system, inhibits the rise in RGC internal calcium levels that is induced by the excitatory neurotransmitter glutamate. These results indicate that adenosine could dampen the synaptic excitatory input to RGCs and supports the role of adenosine as a neuromodulator in the retina. In addition, this work suggests that adenosine could serve as an endogenous RGC neuroprotectant by inhibiting the lethal elevation in calcium levels that occurs following excessive glutamate receptor stimulation.
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