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| January 2006 | Inside IOVS | Volume 47/1 |
New Orthotopic Human Choroidal Melanoma Xenograft Models
Patient survival has been linked to the presence of specific periodic acid-Schiff base (PAS)-positive patterns in choroidal melanomas. By implanting spheroids grown from three different human choroidal melanoma cell lines into the suprachoroidal space of nude rats, Braun and Abbas (p. 7) were able to grow tumors that predictably demonstrate the PAS-staining patterns associated with nonaggressive and aggressive tumors in human patients. In the future, these models can be used to study the nature of the PAS-positive patterns in vivo and to correlate differences in gene or protein expression to the presence of the different PAS-staining patterns.
Selective Mutation of ON-Bipolar Cell Function by a VSX1 Mutation
Vsx1 is a homeobox gene, closely related to Chx10, which are both essential for the differentiation and maintenance of vertebrate and invertebrate bipolar cells. Recent studies demonstrated that Vsx1 can function as a transcriptional repressor via its HD/CVC motifs, and thereby negatively regulates the generation of bipolar cells depending on the cones. Here, Valleix et al. (p. 48) report a family affected with a posterior polymorphous corneal dystrophy and a retinal macular dystrophy, both inherited as a dominant manner, which cosegregated with a mutation in the CVC-domain of VSX1. The authors show that this VSX1 mutation impairs cone ON-bipolar cell function, sparing both the rod and the cone OFF-bipolar cell visual pathways, giving therefore a rare example of such a selective heritable retinal defect in humans. Furthermore, this observation provides the first clinical support for a new alternative role of VSX1 in cone biology.
A Synthetic Tissue Equivalent with Potential Clinical Replacement Value
Ang et al. (p. 105) describe the use of an ultra-thin poly(e-caprolactone) membrane substrate for the development of a serum-free derived conjunctival epithelial equivalent. Ultra-thin PCL membranes 6 mm in thickness were prepared by solvent casting and biaxial stretching. These biocompatible membranes were highly flexible and mechanically strong to be handled. They supported the attachment and proliferation of conjunctival epithelial cells in culture as well as following transplantation. Surface modification with sodium hydroxide treatment enhanced epithelial cell proliferation. These findings may be an important step towards the development of safe and effective bioengineered tissue-equivalents for clinical use.
Visualization and Characterization of Inflammatory Responses in the Corneal Stroma
The infiltration of inflammatory cells into the cornea is a major determinant in the outcome of keratitis. In the study of Carlson et al. (p. 241), enhanced green fluorescent protein EGFP bone marrow chimeric (EGFP) mice were utilized to visualize and characterize the inflammatory cells that migrate into the corneal stroma during endotoxin-induced keratitis and to explore the mechanisms underlying this process. In vivo time-lapsed images, full thickness whole corneal mount confocal image analysis, and in vivo neutralization experiments showed a distinct pattern of migration of EGFP inflammatory cells through the anterior corneal stroma that in part is regulated by the production of the chemokine MIP-2. This unique way of visualizing and studying inflammation in the eye provides new insights into the understanding of ocular immune responses.
Effects of Sulfamethoxazole on Murine Ocular Toxoplasmosis
Norose et al. (p. 265) have developed a sensitive detection system that can provide effective and efficient measurement of the ability of antimicrobial therapy to provide protection against Toxoplasma gondii infection to the eye. They found that sulfamethoxazole (SMX) decreased the parasitic load in both wild type and interferon-g knockout (GKO) mice by using quantitative competitive polymerase chain reaction (QC-PCR) assay. SMX decreased the tachyzoite load but did not completely eliminate bradyzoites in GKO mice. The present study may represent a reliable starting point for the determination of therapeutic regimens in humans.
Repeat Adenovector Gene Delivery in the Eye
Adenovectors are currently undergoing clinical testing for the treatment of ocular diseases such as wet age-related macular degeneration and retinoblastoma. Repeat administration of adenovectors may be desirable to obtain optimal therapeutic benefit. Hamilton et al. (p. 299) show that repeat intravitreal or periocular administrations of adenovector to the eye are feasible and result in repeat transgene expression, even in the presence of a circulating immune response to vector. These studies support repeat administration of adenovectors to the eye for future clinical trial designs.
Neurovascular Dysfunction in Early Diabetic Retinopathy
The impact of pathology associated with diabetes, such as retinal edema and neurodegeneration, on retinal physiology is not well understood. Luan et al. (p. 320) demonstrate that early subnormal retinal oxygenation response to a hyperoxic provocation (DPO2), a parameter that is strongly associated with subsequent experimental diabetic retinopathy and that can be reversed by preventative drug treatment, is not a product of retinal edema and is only partially spatially linked with retinal thinning. These studies raise the possibility of dysfunctional neurovascular coupling early in diabetic retinopathy.
Inosine Monophosphate Dehydrogenase 1 (IMPDH1) Mutations and Inherited Retinal Degeneration
Bowne et al. (p. 34) analyzed DNA from a cohort of patients with inherited retinal degeneration and identified several novel IMPDH1 mutations. These mutations were not only associated with autosomal dominant retinitis pigmentosa as shown previously, but also with Leber congenital amaurosis. Mutant proteins showed no alteration in the IMPDH enzyme activity, suggesting that loss of enzyme activity is not the cause of photoreceptor degeneration. Additional analysis demonstrated that mutant IMPDH1 proteins lose their affinity for single stranded nucleic acids, suggesting that the photoreceptor disease mechanism is related to this new and ill-defined property of IMPDH1.
Evolution of CYP1B1 Haplotypes in Primary Congentital Glaucmoma
Common mutations in CYP1B1 associated with primary congenital glaucoma (PCG) occur on a uniform haplotype background among Indian patients, which is completely distinct from the most frequent haplotype found among unaffected Indian controls. Globally, there is a strong clustering of mutations by geographical and haplotype backgrounds. Together with data of chimpanzee and of normal controls from India and other global regions, it has been possible to reconstruct the evolution of these mutations on different haplotype backgrounds. These results, reported by Chakrabarti et al. (p. 43), are useful for predictive testing of PCG and call for similar studies on PCG mutations that are not associated with CYP1B1.
Mucins in the Protection of Corneal Epithelial Cells
Rose bengal-anionic dye has been clinically used for many decades to assess damage to ocular surface epithelial cells in ocular surface disease. Argüeso et al. (p. 113) show that differentiation of corneal epithelial cells, as measured by the capacity to produce O-glycosylated membrane-associated mucins, provides protection against rose bengal uptake in vitro. These data suggest that, on the ocular surface of patients with dry eye, rose bengal staining occurs in areas of cells either lacking or having an alteration (e.g., glycosylation) to these hydrophilic, membrane-tethered mucins.
Heritability of Macular Thickness in Normal Individuals
Chamberlain et al. (p. 336) examined whether genetic factors may influence macular thickness in healthy older populations without eye disease. By comparing the correlation of retinal thickness in both identical (monozygotic) and non-identical (dizygotic) twins, heritability estimates of over 80% were obtained for each region of the macula, suggesting that genetic factors may influence macular thickness in healthy older populations. With increasing use of optical coherence tomography (OCT) as a research tool, it should be recognized that both traditional biometric factors as well as genetic factors may influence macular thickness.
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