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| February 2005 | Inside IOVS | Volume 46/2 |
Familial Clustering of Refractive Errors in a Population
Refractive errors, myopia and hyperopia are common conditions requiring corrective lenses. The familial clustering of myopia has been well established. Klein et al. (p. 442) examined the familial aggregation and pattern of inheritance of ocular refraction in an adult population using data from the Beaver Dam Eye Study. They found substantial positive correlation between family members. Their results suggest that several genes, each having a modest effect, may influence refractive error, possibly in conjunction with environmental factors.
Mass Gene Suppression in Mouse Lacrimal Gland following Acute Corneal Injury
The integrity of the corneal-lacrimal gland functional unit is essential in maintaining the health of the ocular surface and the normal function of the lacrimal gland. Fang et al. (p. 461) found that acute corneal chemical injury induced a widespread suppression of gene expression in the mouse lacrimal gland using a spotted cDNA microarray. The gene families that were suppressed involved almost all major functional groups including housekeeping, energy metabolism, protein degradation, DNA and protein synthesis, and apoptosis-associated genes. Strikingly, heat shock genes were upregulated, indicating a stress response. The results from this study may generate opportunities to identify potential target genes that are critical to the stress-response process and are important in controlling lacrimal gland tear production and secretion.
Toll-Like Receptor (TLR)-Induced Keratitis
TLRs are important in the host innate response to microbial pathogens. Using TLR-/- and MyD88-/- mice, Johnson et al. (p. 589) showed that abraded corneas exposed to TLR2, TLR4, or TLR9 agonists induced MyD88-dependent chemokine production, neutrophil recruitment to the corneal stroma, and development of corneal thickness and haze. These findings demonstrate that corneal epithelium activated by bacterial products can induce keratitis, and indicate that TLRs are potential targets for immune-based therapy.
Dominant Rhegmatogenous Retinal Detachment
In contrast to many blinding retinal disorders, blindness through retinal detachment is potentially avoidable if patients at high risk could be more accurately identified. Stickler syndrome (hereditary arthrophthalmopathy) is the most common inherited cause of rhegmatogenous retinal detachment, but the diagnosis is frequently missed in patients with minimal systemic involvement. Four years ago, Richards et al. first reported a sub-group of patients with Type 1 Stickler syndrome with ocular involvement only, due to mutations in exon 2 of the COL2A1 gene. They now report (p. 663) a mutation of COL2A1 resulting in dominantly inherited retinal detachment. This has important implications for the investigation of patients with a family history of retinal detachment, even in the absence the typical vitreous phenotype and systemic features more usually associated with the various Stickler syndromes.
Synergic Effect of Trophic Factors on Retinal Neurons
Neurotrophins regulate neural cell survival and apoptosis during retinal development and degeneration. Harada et al. (p. 669) demonstrate that loss of neurotrophin-4/5 (NT-4/5) increases ischemia-induced retinal cell death, but has no effect on retinal development. However, loss of both brain-derived neurotrophic factor (BDNF) and NT-4/5 leads to delayed retinal development. These results suggest that functions of neurotrophins may differ according to the developmental stage. Thus, treatment of ischemic retinal diseases, such as retinal vein occlusion and glaucoma, by NT-4/5 in combination with other trophic factors may stimulate multiple cellular targets and activate separate mechanisms, thereby enhancing retinal cell survival.
Ranibizumab Ocular Pharmacokinetics in Primates
Gaudreault et al. (p. 726) characterized the ocular and systemic pharmacokinetics of ranibizumab, a monoclonal antibody fragment targeting vascular endothelial growth factor (VEGF), in cynomolgus monkeys after intravitreal and intravenous administration. After intravitreal administration, ranibizumab distributed rapidly into the retina and subsequently cleared in parallel from the vitreous, the retina and the anterior chamber, with a terminal half-life of 3 days. Ocular ranibizumab concentrations were approximately 3000 times larger than VEGF concentrations. These results suggest that monthly administration of ranibizumab will result in significant VEGF inhibition and may therefore inhibit growth of choroidal neovascularization in patients with age-related macular degeneration.
Telomerase-Immortalized Human Corneal Epithelial Cells
Previous corneal epithelial cell lines developed for studies on epithelial cell biology have been hampered by genomic instability and an inability to differentiate normally. Robertson et al. (p. 470) report the development of a human corneal epithelial cell line by infection with hTERT (hTCEpi) that demonstrated normal cell cycle kinetics and chromosomal stability at greater than 200 population doublings. In organotypic culture, hTCEpi cells appeared to differentiate and undergo apoptotic cell shedding similar to normal human corneal epithelium in vivo. These findings suggest that hTCEpi cells may provide a valuable model for studying the molecular mechanism(s) regulating epithelial differentiation, desquamation, and general biology in a three-dimensional cell culture model.
Drug Diffusion through Retinal Pigment Epithelium
Retinal pigment epithelium (RPE) restricts the diffusion of drugs from the choroid to neural retina after systemic or transscleral drug delivery. Pitkänen et al. (p. 641) determined the effects of solute molecular weight and lipophilicity on the permeability of fresh bovine RPE-choroid preparations in vitro. The data indicate that the RPE is the rate-limiting barrier in the retinal delivery of hydrophilic drugs and macromolecules via the transscleral route. For lipophilic drugs, RPE-choroid and sclera are equally important barriers. These results provide useful background information for improving the drug delivery to the posterior segment after local drug administration.
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