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| June 2007 | Inside IOVS | Volume 48/6 |
Antilymphangiogenic Effects of Bevacizumab Eye Drops
Bevacizumab (Avastin) is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF)-A and it is approved by the U.S. Food and Drug Administration as first line treatment in metastatic colorectal cancer. Bock et al. (p. 2545) demonstrated the ability of bevacizumab to inhibit heme- and also lymphangiogenesis in inflammatory corneal neovascularization by topical and systemic application, thus confirming the hypothesis that VEGF-A induces not only heme- but also lymphangiogenesis. These findings suggest that application of bevacizumab eye drops could improve graft survival after corneal transplantation by interrupting the afferent and efferent arms of the so-called immune reflex arc.
Desiccating Stress Stimulates Expression of Chemokines and Chemokine Receptors
Specific Th-1 and Th-2 immune responses are induced after desiccating stress in a strain-dependent fashion. Yoon et al. (p. 2561) showed that desiccating stress stimulates expression of Th-1 cell-attracting chemokines and chemokine receptors on the ocular surface of C57BL/6 mice. These findings suggest that certain human patients may develop a more robust cell-mediated response to dry eye based on their immunogenetic make-up. In addition, blocking production of certain chemokines or their receptors may modulate the ocular surface immune/inflammatory response in dry eye disease.
Muscles Not Malformed in Cross-eyed Monkeys
Strabismus (misalignment of the eyes) affects ~ 4% of normal children and a ten-fold greater percentage of children who have brain injuries in utero or in early infancy. Narasimhan and colleagues (p. 2576) used magnetic resonance imaging and histology to examine the extraocular muscles and nerves in monkeys with infantile strabismus, either naturally occurring or as a consequence of early abnormal sensory experience. The visuomotor behaviors of these monkeys were indistinguishable from those of strabismic human infants. The analysis showed that the monkeys' extraocular muscles, associated connective tissues, and motor nerves were normal. The findings strengthen a "top down" model of strabismus causality that has gained support over the last decade: infantile strabismus in both monkeys and humans is not due to muscular or peripheral nerve defects; rather, it is a consequence of damage to immature, cerebral binocular-alignment circuits.
G6PD Deficiency May Offer Protection against Retinal Vein Occlusion
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is one of the most common human genetic abnormalities, affecting an estimated 400 million people worldwide. Evidence indicates that G6PD-deficient patients are protected against ischemic heart and cerebrovascular disease. Pinna et al. (p. 2747) found that the frequency of G6PD deficiency in patients with retinal vein occlusion (RVO), a significant cause of ocular morbidity, was lower than expected. Logistic regression analysis revealed that G6PD deficiency was significantly associated with decreased risk for RVO. Overall, these data suggest that G6PD deficiency may offer protection against RVO.
Reactive Retinal Glia: An Adverse Role in Retinal Diseases
While virtually all forms of retinal injury trigger retinal glial responses, little is understood about the impact of such responses on retinal neurons. Using a retinal detachment model, Nakazawa et al. (p. 2760) showed that absence of two hallmark proteins of reactive astroglial cells leads to impaired glial responses to injury and increased photoreceptor cell survival. These results suggest a crucial role for reactive retinal glial cells in causing secondary neurodegeneration and collateral damage after injury. They support a new therapeutic concept for limiting photoreceptor and neuron damage in retinal detachment, age-related macular degeneration, and/or other retinal diseases.
The Role of Cones in Retinopathy-Associated Retinal Folding
In a variety of mammals, folds in the outer retina are produced by a subset of retinal disease gene mutations, toxic chemical exposure, or viral infection. Chen and Nathans (p. 2799) used transgenic mice in which diphtheria toxin was expressed in cone photoreceptors to examine the effect of cone ablation on the production of retinal folds in two mouse retinopathy models. Interestingly, cone ablation eliminated retinal folds in a genetic retinopathy model but did not affect retinal folds in a chemical retinopathy model. These experiments suggest that in some contexts cones play a critical role in generating or maintaining retinal folds.
Retinal Penetration of Bevacizumab after Intravitreal Injection in the Monkey
The increasing off-label use of intravitreally injected bevacizumab in neovascular eye diseases and the apparent success of this treatment raises the question whether the full-length antibody bevacizumab really would penetrate the retina after its intravitreal injection. Heiduschka et al. (p. 2814) therefore injected bevacizumab into the eyes of monkeys and analyzed their eyes at different time points. Bevacizumab immunoreactivity could clearly be detected within the retina, mainly in photoreceptor outer segments and in choroidal blood vessels. The findings prove retinal penetration of bevacizumab and encourage developing further treatments using big protein molecules exhibiting longer half-lives than small antibody fragments.
Reorganization of Retinal Neurons during Normal Aging
The literature on the neurobiology of aging is dominated by descriptions of cell loss and degeneration. Eliasieh et al. (p. 2824) demonstrate dendritic elongation of retinal interneurons during normal human aging. Bipolar and horizontal cells in the retinas of aged individuals extend beyond the normal boundary of the OPL into the ONL, normally a fiber- and synapse-free zone. While it is unclear exactly what triggers retinal reorganization, this extension of dendritic processes appears not to be instigated by photoreceptor loss as has been demonstrated in a variety of disease states. The capability for new growth suggests the possibility of future therapies involving the rewiring of neuronal connections in the aging nervous system.
Impact of Ethnicity and Parental Myopia on Childhood Refraction
Previous research has suggested that the link between parental myopia and childhood refraction may be mediated by the inheritance of axial length (AL). Ip et al. (p. 2520) evaluated this hypothesis by examining the refractive error and AL in Australian school children with none, one, or two myopic parents. We found a marked increase in childhood refractive error and AL with the number of myopic parents after adjusting for demographic and environmental factors. Stronger effects from parental myopia on measures of childhood refraction in Asian children compared to European children provide evidence in support of significant ethnic interactions for childhood myopia.
Dose-Response Characteristics of Occlusion for Childhood Amblyopia
Based upon outcome data from the Monitored Occlusion Treatment for Amblyopia Study (MOTAS), Stewart et al. (p. 2589) describe an empirically derived mathematical model of the treatment dose-response of occlusion therapy. The majority of children achieved their best visual acuity after 150 to 250 hours' cumulative dose. Specific patient characteristics (especially age) modified the dose-response function. For example, a 0.20 logMAR (2-line) gain in visual acuity required, on average, a cumulative dose of 170 hours for children aged 4 years but 236 hours at the age of 6. Mathematical modeling of treatment dose-response is a novel approach that elucidates the kinetics of the visual sensitive period and provides evidence of reduced plasticity towards the end of the sensitive period for recovery. In practical terms, it permits the development of child-specific evidence-based treatment plans that avoid unnecessarily prolonging treatment while optimizing outcome.
Eye Movement Deficits in Preterm Children
Despite an increased risk of eye movement deficits in preterm children, from a variety of cerebral lesions, Newsham et al. (p. 2595) found the control of saccades and smooth pursuit to be similar to that of full-term children. Preterm subjects were, however, found to have significant deficits in the voluntary control of saccades. These impairments are indicative of dysfunction in the area of the frontal cortex, particularly in the dorsolateral prefrontal region. This is also consistent with behavioral disorders such as attention deficit and executive dysfunction that have been reported in preterm children. Eye movement testing may therefore assist with the early diagnosis of these disorders.
Caspase and Retinal Degeneration
Perche et al. (p. 2753) evaluated the potential role of caspases in photoreceptor cell apoptosis during light-induced retinal degeneration. Rats were intravitreally injected with caspase inhibitors before light exposure. A broad spectrum caspase inhibitor as well as a caspase-3 specific inhibitor reduced photoreceptor cell apoptosis and protected retinal function and structure against light damage. These results suggest that caspases, and specifically caspase-3, play a major role in photoreceptor cell apoptosis during light-induced retinal degeneration. A better understanding of the mechanism involved in the apoptotic process of the photoreceptor could lead to new potential therapeutics targets.
Choosing the Route for Differentiation of Retinal Precursor Cells
Schwechter and colleagues (p. 2845) compare two mechanisms for differentiation of a retinal neuronal precursor cell line, RGC-5. One mechanism, histone deacetylase (HDAC) inhibition, is transcription-dependent and results in a neurotrophin-dependent retinal ganglion cell-like cell. In contrast, differentiation with the broad spectrum kinase inhibitor staurosporine results in a cell that is morphologically highly differentiated, but is not dependent on neurotrophins for survival. HDAC inhibition could potentially be employed to differentiate RGC progenitors for use in repopulating the retina in optic neuropathies, resulting in RGCs that are physiologically neurotrophic factor-dependent.
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