Volume 3, Number 13

Monday, March 31, 2003

In this issue: (click heading to view article)
		Tissue-Inhibitor Protein May Aid in Preventing Wet AMD and Diabetic Retinopathy
		Reduction in Retinotopic Processing in Late-Onset Myopes
		Oral Minocycline May Inhibit Lipase and Affect Ocular Flora
		Irrigating Contact Lenses and Epithelial Debridement in Vitrectomies
		Glucocorticoid Expression Related to Steroid Response in Uveitis Patients
		Briefly

Tissue-Inhibitor Protein May Aid in Preventing Wet AMD and Diabetic Retinopathy Tissue inhibitor of metalloproteinases-3 (TIMP-3), a protein that prevents the breakdown of specific cellular barriers, also helps prevent abnormal blood vessel growth that, if unchecked, can lead to wet age-related macular degeneration (AMD) or feed cancerous tumors, according to researchers at the Cleveland Clinic Cole Eye Institute. TIMP-3 is one of four members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases (MMP). TIMP-3, which encodes a potent angiogenesis inhibitor, is mutated in Sorsby fundus dystrophy, a macular degenerative disease with submacular choroidal neovascularization. In this study, researchers demonstrated the ability of TIMP-3 to inhibit vascular endothelial factor (VEGF)–mediated angiogenesis and identified the potential mechanism by which this occurs. TIMP-3 apparently blocks the binding of VEGF to VEGF receptor-2 and inhibits downstream signaling and angiogenesis. This property seems to be independent of its MMP-inhibitory activity, and thus indicates a previously unknown function for the molecule. Authors of the study believe that the finding may potentially lead to new treatments for wet AMD and diabetic retinopathy. They anticipate future research that incorporates this finding to develop drugs and gene therapies for the diseases. The TIMP-3 research project is funded by the National Institutes of Health, the Foundation Fighting Blindness and the Cleveland Clinic.

SOURCE: Qi JH, Ebrahem Q, Moore N, et al. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 24 March 2003 (online publication date);doi:10.1038/nm846.

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Reduction in Retinotopic Processing in Late-Onset Myopes A reduced sensitivity to retinal image blur has been reported in myopes. Diminished blur detection reduces the error signal to the retinotopic (blur-induced) accommodation system and results in impaired accommodation responses under retinotopic conditions. A study by the Department of Vision Sciences at Glasgow Caledonian University in Scotland investigated retinotopic accommodation responses in emmetropia and myopia under dynamic conditions, and found a reduction in retinotopic processing in late-onset myopics (LOMs). Clinicians measured static accommodation responses to a blur-only target with vergences of 0 to 4.5D using an optometer in 32 visually normal emmetropes (EMMs) and subjects with progressing myopia. They recorded microfluctuations of accommodation with the subject viewing the target at a vergence of 4D, and measured dynamic step responses for step stimuli from 2.5 to 3.5D and 2.0 to 4.0D, with the optometer in dynamic recording mode. Stimulus-response curves were not significantly different between the refractive groups. LOMs demonstrated significantly larger accommodation microfluctuations, compared with emmetropes and subjects with early-onset myopia (EOMs). Fourier analysis revealed that the increase in the magnitude of the fluctuations was mediated by the low-frequency components. Accommodation step responses revealed longer reaction times in LOMs. Further analysis showed that LOMs responded to accommodation step stimuli between 43 and 64 percent of the time, whereas subjects in the other groups showed a response rate of almost 100 percent. The experiments demonstrate a reduction in retinotopic processing in LOMs, which results in an increased variability in their dynamic accommodation response to stationary near targets and reduced performance for dynamic step tasks. Researchers believe that the reduced blur appreciation under dynamic conditions in these refractive groups may lead to periods of retinal image blur of varying magnitude during near work.

SOURCES: Seidel D, Gray LS, Heron G. Retinotopic accommodation responses in myopia. Invest Ophthalmol Vis Sci 2003;44(3):1035-41.

Oral Minocycline May Inhibit Lipase and Affect Ocular Flora Oral minocycline may inhibit lipase and directly affect ocular flora, a finding that may aid in the treatment of blepharitis, according to researchers at the University of Texas. A study by the Department of Ophthalmology at the University of Texas, Southwestern Medical Center, suggests that oral minocycline may have lipase inhibition effect and/or a direct effect on ocular flora, which continues even after treatment is discontinued. The results give insight into disease mechanisms associated with chronic blepharitis. Researchers aimed to determine the effect of oral minocycline on the meibomian gland nonpolar and free fatty acid lipids of chronic blepharitis patients. Patients included had seborrheic blepharitis (SBBL), acne rosacea (AR) without ocular involvement, or acne rosacea with meibomianitis (AR-MKC). They were treated with 50 mg minocycline orally for 2 weeks, followed by 100 mg minocycline to the end of three months. This period was followed by three additional months with no treatment. Researchers collected meibomian gland secretions before treatment, at the end of the 3-month treatment period, and 3 months after stopping treatment. They separated and analyzed lipids for wax and sterol esters, triglycerides, diglycerides, free cholesterol and free fatty acids. Data were analyzed statistically by ANOVA. The treatment with oral minocycline resulted in decreased diglycerides and free fatty acids in the AR-MKC group, which was significant, and continued into the second 3 months (off treatment). Cholesterol decreased, but triglycerides initially decreased with treatment and then increased when treatment in the group was discontinued (second 3 months); these results, however, were not significant. Results showed that minocycline has its greatest effect on lipid types, which result from degradation (lipase) reactions. The fact that the minocycline effect continues after treatment is discontinued suggests a more lasting effect on ocular microflora. Minocycline may be most effective when the treatment period is longer than 3 months.

SOURCE: Shine WE, McCulley JP, Pandya AG. Minocycline effect on meibomian gland lipids in meibomianitis patients. Exp Eye Res 2003;76(4):417-20.

Irrigating Contact Lenses and Epithelial Debridement in Vitrectomies Irrigating contact lenses appear to increase the need for epithelial debridement during vitrectomy surgery for diabetic patients compared with other alternatives. Sew-on lenses with a viscoelastic cushion may provide the best corneal protection, according to a survey of active vitreoretinal surgeons by the Eye & Ear Institute of the University of Pittsburgh School of Medicine. Researchers asked 55 vitreoretinal surgeons to report retrospectively how many pars plana vitrectomies they performed in 1 year on diabetic eyes, and in what percent of the cases debridement of the cornea was necessary. In a second query, the surgeons were asked to note which specific type of surgical lens system (hand-held irrigating, Landers sew-on, or Oculus BIOM noncontact) they used for their surgical intervention. The total number of diabetic vitrectomies performed in 1 year by the respondents was 8,002. The frequency of epithelial debridement was 17.4 percent, with a range of 0 to 90 percent. The use of irrigating contact lenses was associated with a significantly higher rate of debridement compared with the use of sew-on or BIOM noncontact lenses (23.5 percent versus 12.1 percent). Forty-one surgeons indicated a specific type of lens used; among those surgeons, researchers found that the debridement rate for infusion lenses was 23.8 percent compared with 13.0 percent for sew-on lenses and 15.6 percent for noncontact BIOM lenses. The difference between these groups was statistically significant.

SOURCE: Friberg TR, Ohji M, Scherer JJ, Tano Y. Frequency of epithelial debridement during diabetic vitrectomy. Am J Ophthalmol 2003;135(4):553-4.

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Glucocorticoid Expression Related to Steroid Response in Uveitis Patients Glucocorticoids (GC) are widely used to treat uveitis, but their efficacy is known to vary substantially among patients. In a retrospective preliminary study by the Department of Ophthalmology at Tokyo’s Kosei Chuo Hospital, clinicians found that the level of GCR expression may relate to the response to steroids in the clinical course of inflammation. Researchers obtained iris samples from 13 patients during surgery for cataract associated with uveitis. From each sample, they extracted RNA and used it as template for construction of cDNA, a stronger, cloned copy of the otherwise fragile mRNA or "messenger" RNA, which aids in protein coding. They exposed the cDNA to GCR gene-detecting and TaqMan probes, and determined the level of GCR mRNA expression by real-time polymerase chain reaction (PCR). This level was compared to the frequency of postoperative ocular inflammation attacks that occurred despite daily and required subconjunctival glucocorticoid injection or other therapy. The ratio between the number of GCR and housekeeping gene 18SrRNA copies was calculated as the normalized ratio. The mean normalized ratio for the uveitis patients was 13.7; for uveitis-free control patients it was 7.3. The median normalized ratio in the uveitis patient group was 1.5. Mean frequency of inflammation attacks was 0.24/month in the uveitis patients with a normalized ratio of 1.5 or higher and 0.53/month in those with a normalized ratio of less than 1.5, a significant difference. The authors of the study conclude that further investigation is warranted.

SOURCE: Tanaka T, Yamakawa N, Usui M. Level of glucocorticoid receptor mRNA expression in iris tissue and postoperative ocular inflammation in patients with uveitis. Graefes Arch Clin Exp Ophthalmol 2003;241(2):81-4.

BRIEFLY NEW HOPE FOR DRUG-DISPENSING CONTACT LENSES. Chemical engineers from the University of Florida (Gainesville) have successfully created soft contact lenses containing a time-release drug delivery system. Anuj Chauhan, Ph.D., assistant professor of chemical engineering, and graduate student Derya Gulsen, presented their research at the 225th national meeting of the American Chemical Society in New Orleans, La., on March 23. Previous attempts at contact lens drug delivery involved soaking the lenses in a drug solution or placing the drug in a cavity between two pieces of lens material; the authors say they have found a more effective method in which they encapsulate a drug in nanoparticles that can be added to contact lens matrices during manufacture. Theoretically, the lenses could be worn for up to two weeks to deliver a steady supply of a drug directly to the eye. The lenses can also provide vision correction, depending on the needs of the patient. Thus far, no in vitro or animal testing has been conducted. FDA ON EFFECTIVENESS OF VITRASE. An FDA panel voted 7 to 5 that the benefits of Vitrase (Ista Pharmaceuticals) outweigh its risks; however, the panel also voted 8 to 4 that the company had not provided sufficient evidence to support the drug’s claims. Vitrase, according to the FDA panel members, did not persuasively improve vision by clearing vitreous hemorrhage, which hampers vision in diabetics. Ista had presented study results that suggested the drug helps liquefy the vitreous, thus softening it and helping blood filter. The panel stated that the company must provide additional studies of Vitrase to warrant its approval; the FDA itself will study its panel’s recommendations and is expected to respond by April 9. OCULAR SIDE EFFECTS FOR OSTEOPOROSIS AND CANCER DRUGS IDENTIFIED. Researchers at the Oregon Health & Science University’s Casey Eye Institute have released a study showing that drugs commonly prescribed for osteoporosis and cancer patients may also cause serious ocular side effects. The study of 314 patients, funded by Research to Prevent Blindness and outlined in letter form in the March 20 New England Journal of Medicine, shows that two medications in a class of drugs called bisphosphonates may cause inflammation in several regions of the eye. Lung, breast and prostate cancer that metastasizes to the bones can reduce bone density; bisphosphonates help increase bone density and are commonly provided in conjunction with chemotherapy and other cancer treatments. Of the 314 patients in the study, as many as 100 reported blurred vision while taking the bisphosphonates. Other complaints included ocular pain and swelling. The results, say the study’s authors, should alert physicians to monitor cancer patients for eye problems not previously associated with a prescribed drug. They believe it may not only help physicians identify ocular problems early and therefore prevent long-term vision damage, but it might also prompt drug manufacturers to update their product labeling.

	Women in Ophthalmology Spring Lecture Sunday April 13th, Hotel Argent, Olympic Rm. 50 Third St. (at Market), San Francisco Featured Speaker: Brad Wong, MD, AAO Executive Director of EyeCare America. "The Academy's Commitment to Education and Public Service." Please RSVP Women in Ophthalmology (WIO): Phone: 415-561-8523; Fax: 415-561-8531; e-mail: jgubelman@aao.org Admission is $50 for member; $60 for non-member; and $25 for WIO member-in-training. Registration forms are also available at Review of Ophthalmology's booth #3146 at ASCRS on Saturday and Sunday before the luncheon. Advanced Medical Optics, Inc. sponsors the luncheon.

	It's only been up and running a few short weeks. Yet, it's already clear that the Check Yearly. See Clearly.(SM) marketing campaign is opening consumers' eyes to the benefits of regular eye exams. Call the Vision Council of America at 800-424-8422 today or visit checkyearly.com for your free promotional materials.

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