Volume 7, Number 43
Monday, October 29, 2007



In this issue: (click heading to view article)
Effect of Cyclosporine A on Recovery of Visual Acuity Following LASIK
Cone- and Rod-Mediated Dark Adaptation Impairment in ARM
IOP Correlated with Arterial Blood Pressure
Cytogenetics of Uveal Melanoma: a Seven-Year Clinical Experience
Congenital Anterior Capsular Plaque in Pediatric Eyes with Cataract
Briefly










Effect of Cyclosporine A on Recovery of Visual Acuity Following LASIK

This study, by the Shiley Eye Center, University of California San Diego, and supported by a grant from Research to Prevent Blindness, Inc., compared the recovery of uncorrected visual acuity (UCVA) following LASIK in patients treated with topical cyclosporine A 0.05% with that of patients treated with a standard postoperative regimen.

The single-center, open-label, retrospective study included a standard refractive workup performed in 45 patients (85 eyes) who had undergone LASIK and did not have preexisting dry eye. In 36 eyes, a standard postoperative eye drop regimen was followed; in 49 eyes, cyclosporine A 0.05% was added to the standard regimen for 12 weeks. Uncorrected visual acuity was measured one week and one and three months postoperatively.

One week postoperatively, 22 eyes (44.9 percent) in the cyclosporine A group and 8 eyes (22.2 percent) in the standard treatment group had a UCVA of 20/15. Cumulatively, 36 eyes (73.5 percent) in the cyclosporine A group and 24 eyes (66.7 percent) in the standard treatment group had a UCVA of 20/20 or better. One month postoperatively, 37 eyes (75.5 percent) in the cyclosporine A group and 23 eyes (63.9 percent) in the standard treatment group had a UCVA of 20/20 or better. Three months postoperatively, 40 eyes (81.6 percent) in the cyclosporine A group and 25 eyes (69.4 percent) in the standard treatment group had a UCVA of 20/20 or better. Mean UCVA in the cyclosporine A group showed statistically significant improvements compared with the standard treatment group.

The results suggest that cyclosporine A 0.05%, in the form of Restasis, may be an effective treatment for reducing the time needed for visual recovery after LASIK. Use of cyclosporine A was associated with overall better and faster recovery of UCVA.


SOURCE: Ursea R, Purcell TL, Tan BU, et al. The effect of cyclosporine A (Restasis) on recovery of visual acuity following LASIK. J Refract Surg 2007; Oct 15 [Epub ahead of print]. 		Table of Contents





Cone- and Rod-Mediated Dark Adaptation Impairment in ARM

This cross-sectional study by University of Alabama ophthalmologists was aimed at examining impairment in cone- versus rod-mediated dark adaptation in the parafovea of people with age-related maculopathy (ARM).

Study participants included older adults with ARM at various severity levels, from early to advanced (83 participants) and in good retinal health (43 participants), as determined by stereo fundus photographs evaluated with the Age-Related Eye Disease Study (AREDS) severity scale. Researchers measured dark adaptation, both cone- and rod-mediated components, with a modified Humphrey Field Analyzer using a target located 12 degrees in the inferior visual field on the vertical meridian, after exposure to a 98 percent bleach. Information was collected on self-reported problems for activities at night or under dim illumination (Low Luminance Questionnaire [LLQ]) and for activities during daytime conditions (modified National Eye Institute Visual Function Questionnaire [NEI-VFQ]).

Compared with older adults with normal retinal health, ARM patients had significant impairments in rod-mediated parameters of dark adaptation (rod-cone break, rod slope and rod sensitivity), which were increasingly abnormal as disease severity increased. Cone-mediated parameters (cone time constant and cone sensitivity) were not impaired. LLQ scores and NEI-VFQ scores decreased with increased ARM severity; the percent decrease in LLQ scores as a function of disease severity was greater than the percent decrease in NEI VFQ scores.

Based on these results, the authors maintain that disturbances in rod-mediated but not cone-mediated dark adaptation in the parafovea at 12 degrees in the inferior field on the vertical meridian are characteristic of ARM even in its early phases.


SOURCE: Owsley C, McGwin G Jr, Jackson GR, et al. Cone- and rod-mediated dark adaptation impairment in age-related maculopathy. Ophthalmol 2007;114(9):1728-35.		 Table of Contents






IOP Correlated with Arterial Blood Pressure

Intraocular pressure (IOP) is associated significantly with systolic and diastolic blood pressure (BP), according to the Beijing Eye Study 2006, conducted by the Beijing Institute of Ophthalmology.

The population-based, cross-sectional cohort study included subjects aged 45 years or older (mean age 60.4 +/- 10.1 years). The goal was to assess the relation of arterial blood pressure (BP) and intraocular pressure (IOP) in an adult population in which members are not using glaucoma medications. Investigators measured seated BP and applanation tonometric IOP and determined their relationship using regression models. Patients with closed anterior chamber angles and an IOP of more than 21 mmHg or those who were receiving topical antiglaucomatous treatment were excluded; the final study included 2,981 subjects.

In multivariate regression analysis, IOP correlated significantly with systolic BP (95 percent confidence interval [CI], 0.011 to 0.022), diastolic BP (95 percent CI, 0.008 to 0.029), central corneal thickness (95 percent CI, 0.031 to 0.037) and myopic refractive error (95 percent CI, -0.103 to -0.015). Neither age nor body mass index were significantly associated with IOP.

SOURCE: Xu L, Wang H, Wang Y, Jonas JB. Intraocular pressure correlated with arterial blood pressure: The Beijing Eye Study. Am J Ophthalmol 2007;144(3):461-2.		 Table of Contents








Cytogenetics of Uveal Melanoma: a Seven-Year Clinical Experience

Chromosome 3 loss and chromosome 8 gains in uveal melanoma are associated with metastatic death. This nonrandomized case series study by investigators at the Ocular Oncology Service, Royal Liverpool University Hospital in Great Britain, correlated the results of the researchers" cytogenetic analysis of patients treated by local resection or enucleation with clinical and histologic predictors and disease-specific mortality.

The study included 356 patients (mean age 61.9 years) who had uveal melanoma with data on chromosome 3 and chromosome 8. Researchers measured tumor diameter using echography. They determined cell type, presence of closed connective tissue loops and mitotic rate histopathologically. Fluorescence in-situ hybridization was performed using centromeric probes for chromosomes 3 and 8 and for c-myc. Patients were flagged at Britain"s National Health Service Cancer Registry, which notified investigators of any deaths. Statistics included Cox multivariate analysis and Kaplan-Meier analysis. Main outcome measures included disease-specific mortality, according to clinical, histologic and cytogenetic features, as well as correlation between cytogenetic variables and other mortality predictors, including a predictive index.

In 42 percent of the patients, tumors showed no cytogenetic abnormalities of chromosomes 3 or 8. Tumors showed chromosome 8 gains in 11 percent, monosomy 3 in 21 percent and both abnormalities in 27 percent. These correlated with ciliary body involvement, extraocular spread, large basal tumor diameter, epithelioid cellularity, closed connective tissue loops and mitotic rate exceeding 4/40 high power fields. By the end of the study, 76 patients had died (67 from metastasis). Cox multivariate analysis showed the most significant factors to be basal tumor diameter, monosomy 3 and epithelioid cellularity. A predictive index (PI) was derived from these variables. Kaplan-Meier analysis showed that five-year metastatic death rates ranged from 0 percent in 84 patients with low-grade melanoma (PI less than 19) to 66 percent in 100 patients with high-grade tumor (PI greater than 26; 95 percent CI 53 to 80 percent).

The authors believe that cytogenetic analysis of chromosomes 3 and 8 enhances prediction of disease-specific mortality after treatment of uveal melanoma. However, they stress that the data must be interpreted in conjunction with tumor diameter and cell type.

SOURCE: Damato B, Duke C, Coupland SE, et al. Cytogenetics of uveal melanoma: a 7-year clinical experience. Ophthalmol 2007;114(10):1925-31.		 Table of Contents







Congenital Anterior Capsular Plaque in Pediatric Eyes with Cataract

This study by researchers in India aimed to determine the occurrence, morphology, immunofluorescence and ultrastructural features of congenital anterior capsular plaque (ACP) obtained from pediatric eyes undergoing cataract surgery.

The study included 260 consecutive pediatric eyes undergoing congenital cataract surgery. Researchers collected anterior lens epithelium from cataract without ACP and with ACP, and stained wholemounts of lens epithelium with hematoxylin-eosin. They subjected 5 micrometer-thick sections of large ACPs to immunofluorescence localization of collagen type I, collagen type IV, alpha-smooth muscle actin (alphaSMA) and alphaA-crystallin, and then studied ultrathin sections by transmission electron microscope.

The overall occurrence of ACP in pediatric eyes undergoing congenital cataract surgery was 11.5 percent. The occurrence of ACP was highest in mature cataract, followed by nuclear, lamellar and mixed cataract. The wholemount of anterior lens epithelium revealed non-plaque and plaque region or ACP. The extracellular matrix of ACP was fibrous, amorphous and rich in collagen type I. The cells of the ACP were surrounded by a network of collagen type IV and were positive for alphaSMA and alphaA-crystallin. The cells of the ACP were rich in rough endoplasmic reticulum and mitochondria.

The authors concluded that ACP is more closely associated with mature cataract than immature cataract, and that epithelial mesenchymal transdifferentiation of lens epithelial cells may be involved in the development of congenital ACP.

SOURCE: Johar K, Vasavada AR, Tatsumi K, et al. Anterior capsular plaque in congenital cataract: Occurrence, morphology, immunofluorescence, and ultrastructure. Invest Ophthalmol Vis Sci 2007;48(9):4209-14.		 Table of Contents







BRIEFLY
  • CELL THAT CAUSES RETINOBLASTOMA IDENTIFIED; DISPROVES PRINCIPLE OF NERVE GROWTH AND DEVELOPMENT. Investigators at St. Jude Children"s Research Hospital have identified the cell that causes retinoblastoma, disproving a longstanding principle of nerve growth and development. The finding suggests for the first time that it may be possible for scientists to induce fully developed neurons to multiply and coax the injured brain to repair itself. The study appears in the October 19 issue of Cell. The discovery occurred after the investigators developed different populations of mice whose retinas lacked one or more members of the Rb family of genes that include Rb, p107 and p130. These genes are critical to the ability of an immature cell to stop dividing and begin to differentiate. In the study, when the mouse retina had reduced Rb family function, fully differentiated horizontal neurons could multiply while retaining all of the differentiated features of normal horizontal neurons. The researchers showed that as the horizontal interneurons multiplied their numbers up to 50-fold, they maintained their normal position in the retina AND their normal connections to other cells. When they allowed the horizontal interneuron cell division to proceed unchecked, highly differentiated tumors resembling normal horizontal neurons formed. Unexpectedly, these tumors were aggressive and spread rapidly. The investigators concluded that the Rb family"s only task is to prevent mature horizontal interneurons from multiplying as they did when they were immature cells. The findings surprisingly showed that retinoblastoma can arise from fully matured nerves in the retina called horizontal interneurons--disproving the scientific principle that such nerves cannot multiply the way young, immature cells can. The discovery that the horizontal interneurons can multiply to form retinoblastoma also challenges the established scientific belief that cancer cells are most aggressive when they are undifferentiated. If researchers are able to alter the activity of certain genes in fully developed neurons, they might be able to trigger them to multiply temporarily and replace neighboring neurons lost as a result of neurodegenerative diseases such as Alzheimer"s. Having nerves duplicate themselves might be more efficient than trying to stimulate nerve replacement by inserting stem cells into the brain, since the existing nerves would already be in the proper place to restore missing brain cells, according to the study"s authors.
    SOURCE: Ajioka I, Martins RAP, Bayazitov IT. Differentiated horizontal interneurons clonally expand to form metastatic retinoblastoma in mice. Cell 2007;131(2):378-90.

  • ELEVATED HOMOCYSTEINE LEVELS MAY HAVE AN IMPACT ON VISION. Homocysteine, an amino acid believed to contribute to heart attack, stroke and dementia, may also play a role in retinal damage and vision loss, according to a study conducted by Dr. Sylvia Smith, cell biologist at Medical College of Georgia (MCG), and Dr. Vadivel Ganapathy, chair of the MCG Department of Biochemistry and Molecular Biology. Folate and vitamin B12 convert homocysteine to methionine, an amino acid essential to protein synthesis. While studying how folate reaches the retina and how diseases such as diabetes interfere with the process, Drs. Smith and Ganapathy discovered that without the conversion, rising homocysteine levels interfere with folding and structure of collagen. People with a genetic defect that results in a homocysteine level 40 times higher than normal are tall, thin, have osteoporosis and a markedly increased risk of clotting, according to Dr. Ganapathy. Very small clots can cause small and frequent strokes and cumulative tissue damage. Such thrombotic attacks in the retina affect visual function. The researchers studied the effects of homocysteine in a mouse model with a slightly elevated homocysteine level that simulates a low-folate diet in humans; in a version of the mouse that also has diabetes; and in a second model of the rare genetic defect that results in extraordinarily high homocysteine levels. They hypothesize that sustained elevation will compromise retinal function and degrade the once well-stratified tissue; in pilot studies, the researchers have shown that diabetes exacerbates this problem.
  • OPTHERION LICENSES WORLDWIDE RIGHTS TO DEVELOP AMD DIAGNOSTICS BASED ON GENETIC VARIATIONS. Optherion, Inc. has licensed from the University of Pittsburgh the worldwide rights to develop diagnostic products for age-related macular degeneration (AMD) associated with specific variations in genes on Chromosome 10. Scientists at the University of Pittsburgh published in 2005 their findings of a link between Chromosome 10 (specifically the LOC387715 and HTRA1 genes) and AMD. Genetic tests that can identify people at risk of developing AMD or predict the likely rate of progression and end-stage outcome of patients already diagnosed may enable physicians to intervene more aggressively at an earlier stage of the disease with lifestyle changes and available therapies. Three gene loci have been strongly linked to AMD: CFH, CFB, and specific variations on Chromosome 10. About one-half of patients with AMD suffer from variations in the CFH gene; 74 percent of AMD occurrences can be explained by variations in the CFH and CFB genes combined. Variations associated with specific gene loci on Chromosome 10 in combination with CFH are associated with about 79 percent of cases. Studies conducted after the 2005 University of Pittsburgh study found that people with homozygous risk profiles for CFH, CFB and LOC387715/HTRA1 have as much as 250 times the increased risk of developing AMD. For more information, go to www.optherion.com.
    REFERENCE: Jakobsdottir j, Conley YP, Weeks DE, et al. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 2005:77:389-407.


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