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| September 2005 | Inside IOVS | Volume 46/9 |
Oncogenic BRAF Mutations in Conjunctival Melanocytic Lesions
Oncogenic BRAF mutations are frequent in cutaneous nevi and melanomas and were recently detected in conjunctival melanoma. Unlike cutaneous nevi and melanomas, the molecular events leading to the development of conjunctival melanocytic lesions and conjunctival melanoma are not yet understood. Goldenberg-Cohen et al. (p. 3027) analyzed the T1799A BRAF mutation in conjunctival nevi, primary acquired melanosis (PAM), and conjunctival melanomas. BRAF mutations were detected in high frequency in conjunctival nevi and conjunctival melanomas, but not in PAM. These results suggest that different molecular pathways are involved in the development of conjunctival melanoma.
Actions of Phosphodiesterase PDE5 Inhibitors on Photoreceptor PDE6
Drugs such as Viagra, Levitra, and Cialis selectively and potently target the phosphodiesterase (PDE5) that is abundant in smooth muscle cells and represent the first major application of isozyme-selective PDE inhibitors for treating human disease. The study by Zhang et al. (p. 3060) systematically examines the extent to which these and other drugs designed to inhibit a specific family of PDEs can also inhibit the photoreceptor PDE (PDE6). Many of the tested compounds inhibited PDE6 almost as well as the PDE family they were designed to target. However, intact rod outer segments were much less sensitive to the effects of PDE inhibitors. Several factors were identified that are likely to contribute to this diminished drug potency. The intrinsic properties of PDE6 and its unique cellular environment may lessen or prevent adverse drug effects on the visual transduction pathway during PDE inhibitor therapy.
Genes for Drusen Formation and for Age-Related Macular Degeneration
Despite extensive research on age-related macular degeneration (AMD), the effect of drusen formation on AMD pathogenesis remains unknown. Jun et al. (p. 3081) performed genome scans for drusen size and type in two populations. They found evidence of linkage on chromosomes 3, 5, 14, 16, 19, and 21. Their results demonstrate that common genetic determinants are shared between drusen formation and AMD, but some specialized genes for drusen formation are also likely to exist. Thus the results imply that different genes act at different stages of the disease, which contribute separately or together to the final AMD disease outcome.
Potentiation of Bacterial Lipopolysaccharide-Induced Responses in Corneal Fibroblasts
Corneal fibroblasts contribute to the innate immune response to bacterial infection in the cornea by releasing chemokines and expressing adhesion molecules on exposure to bacterial lipopolysaccharide (LPS). Fukuda et al. (p. 3095) now show that two serum-derived proteins, soluble CD14 (sCD14) and LPS-binding protein (LBP), enhance the LPS-induced upregulation both of intercellular adhesion molecule–1 and of the chemokines interleukin-8 and monocyte chemoattractant protein–1 in corneal fibroblasts. These effects appear to be mediated by activation of the transcription factor NF-kB in these cells. LBP and sCD14 thus likely play important roles in defense of the cornea against bacterial infection by facilitating the detection of LPS by corneal fibroblasts.
Association of Endothelial Nitric Oxide Synthase Gene in Glaucoma Subjects
It is believed that a faulty blood supply may play an important role in the disease process of glaucoma. This study by Logan et al. (p. 3221) investigated the genes whose products are responsible for controlling blood flow, two isoforms of nitric oxide synthase (NOS), NOS3 and NOS2A, and endothelin (ET)-1, in glaucoma subjects and ontrols. In particular, the authors were interested in glaucoma subjects who had symptoms of poor peripheral circulation, migraine, or cold extremities. They found evidence for an association between the NOS3 gene and glaucoma subjects who have a history of migraine. This may assist investigators researching the role of blood flow in the pathogenesis of glaucoma.
Roles of Toxins and Motility in Bacillus Endophthalmitis
Bacillus endophthalmitis is a highly explosive infection that commonly results in rapid inflammation and vision loss, if not loss of the eye itself, within a few days. Callegan et al. (p. 3233) studied the combined roles of toxins and bacterial motility in the eye during Bacillus endophthalmitis. Bacillus mutants that did not produce toxins and were unable to migrate throughout the eye during infection produced highly attenuated intraocular infections. Toxin production and motility may therefore represent possible targets for the development of therapies designed to attenuate the devastating effects of Bacillus in the eye during endophthalmitis.
Transfection of Photoreceptor Genes into Iris Cells
Akagi et al. (p. 3411) examined the effects of various genes related to photoreceptor development (Crx, Nrl, NeuroD, and some combinations, Crx-Nrl, Crx-NeuroD) on rodent and primate iris cells. The rat iris-derived cells transfected Crx and the monkey iris-derived cells transfected Crx-NeuroD expressed several photoreceptor-specific antigens and transcripts and were proved to have electrophysiological characteristics of rod-photoreceptors. Furthermore, the iris-derived cells were able to integrate in the developing host retina under coculture conditions. This report suggests that rodent- and primate-iris tissues have the potential to produce photoreceptor cells by modification of genes.
Retinal Cultures in a Mouse Model of GM2 Gangliosidosis
Light and electron microscopic studies by Sango et al. (p. 3420) revealed degenerative changes of neural retina in Sandhoff disease (SD) mice. Neurite outgrowth from the retinal tissue embedded in collagen gel was impaired in SD mice compared with age-matched normal mice. Brain-derived neurotrophic factor (BDNF) was effective at diminishing this impairment during an early stage of the disease. These findings suggest time- and storage-dependent degeneration and decrease in the neurite outgrowth capability of retinal ganglion cells in SD mice. This retinal culture system can be a useful tool for investigating the precise mechanism of neurodegeneration due to GM2 gangliosidosis and for developing effective therapies for the disease.
New Mouse Models of Retinitis Pigmentosa
Mutations in the gene phosphodiesterase 6b (Pde6b) are responsible for some forms of retinitis pigmentosa (RP) in man as well as mouse. Hart et al. (p. 3443) describe the identification of seven new mouse models with various mutations in Pde6b. A clear correlation with the type of mutation and the severity of the disease was observed. Three of the seven mutations showed a much slower onset of the disease, possibly resembling more closely retinitis pigmentosa syndromes in humans. Understanding the mechanism by which these Pde6b mutations cause a more slowly progressive retinal degeneration may lead to better understanding of some of the human syndromes and result in the development of therapies.
Cone Electroretinograms in Infants
Hansen and Fulton (p. 3458) assessed cone-mediated electroretinographic responses in infants. A model of the activation of cone phototransduction was fit to the a-waves. On average, the cone model parameters were 65% to 70% of the adult values. The infants' rod photoresponse parameters were considerably less mature. This suggests peripheral cone function is relatively more mature than rod function in young infants. The b-wave stimulus/response did not show the photopic hill that is characteristic of the adults’ photopic b-wave. The lack of a photopic hill is hypothesized to result from immaturity in the amplitude or timing of ON and OFF bipolar cell contributions to the b-wave.
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