Volume 7, Number 22
Monday, June 4, 2007



In this issue: (click heading to view article)
VEGF Variants and Long-Term Complications in Type I Diabetes
Objective Methods for Measuring the Functional Optical Zone of the Cornea
Potential Role of Endothelin-1 in the Pathogenesis of PDR
Receptor Expressed by Uveal Melanoma Considered New Target for Diagnosis and Treatment
 
Briefly










VEGF Variants and Long-Term Complications in Type I Diabetes

Investigators at Toronto's Hospital of Sick Children Research Institute conducted a study aimed at determining whether any common variants in the gene for vascular endothelial growth factor (VEGF) are associated with long-term renal and retinal complications in Type I diabetes.

The study included 1,369 white subjects with Type I diabetes from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. Subjects had an average of 17 retinal photographs and 10 renal measures over 15 years. In the DCCT/EDIC, investigators studied 18 single nucleotide polymorphisms (SNPs) in VEGF that represent all linkage disequilibrium bins and tested them for association with time to development of severe retinopathy (SR), 3-step or greater progression of retinopathy, clinically significant macular edema, persistent microalbuminuria and severe nephropathy.

A global multi-SNP test showed a highly significant association of VEGF SNPs with SR; all other outcomes were non-significant. In survival analyses controlling for covariate risk factors, eight SNPs showed significant association with SR. The most significant single-SNP association was rs3025021. Family-based analyses of SR provided evidence of excess transmission of C at rs699947, T at rs3025021 and the C-T haplotype from both SNPs. Multi-SNP regression analysis including 15 SNPs and allowing for pairwise interactions independently selected six significant SNPs. The data demonstrates that multiple VEGF variants are associated with the development of SR in Type I diabetes.

SOURCE: Al-Kateb H, Mirea L, Xie X, et al. Multiple variants in vascular endothelial growth factor (VEGF) are risk factors for time to severe retinopathy in type 1 diabetes: The DCCT/EDIC genetics study. Diabetes 2007; May 18 [Epub ahead of print]. Table of Contents











Objective Methods for Measuring the Functional Optical Zone of the Cornea

When keratorefractive surgery is used to treat a central corneal diameter smaller than the resting pupil, visual symptoms of polyopia, ghosting, blur, haloes and glare may result. Although progress has been made to enlarge the area of surgical treatment to extend beyond the photopic pupil, geometric limitations can pose restrictions to extend the treatment beyond the mesopic pupil diameter and can lead to impediments in night vision. The size of the treated area that has achieved good optical performance has been defined as the functional optical zone (FOZ). This study by Spain's Universidad de Murcia describes three objective methods to measure the FOZ.

Researchers evaluated corneal topography examination results from one eye of 34 unoperated normal eyes and 32 myopic eyes corrected by laser in situ keratomileusis (LASIK) in three ways. First, a uniform axial power method, FOZ(A), assessed the area of the postoperative cornea within a +/- 0.5D window centered on the mathematical mode. Second, FOZ was determined based on the corneal wavefront true root mean squared (RMS) error as a function of the simulated pupil size, FOZ(R). Third, FOZ was determined from the radial modulation transfer function (MTF), established at the retinal plane as a function of pupil size, FOZ(M).

For normal eyes, mean for the FOZ(A) method was 7.6 mm, for the FOZ(R) method 9.1 mm and for the FOZ(M) method 7.7 mm. For LASIK-corrected eyes, mean for the FOZ(A) method was 6.0 mm, for the FOZ(R) method 6.9 mm and for the FOZ(M) method 6.0 mm. Overall, an average decrease of 1.8 mm in the FOZ was found after the LASIK procedure. Correlations between the FOZ methods after LASIK showed acceptable and statistically significant values.

The authors suggest that these methods will be useful in characterizing more fully corneal treatment profiles after keratorefractive surgery. Because of its ease of implementation, direct spatial correspondence to corneal topography and good correlation to the other more computationally intensive methods, the semiempiric uniform axial power method, FOZ(A), appears most practical in use. The authors believe that the ability to measure the size of the FOZ should permit further evolution of keratorefractive surgical lasers and their algorithms to reduce the night vision impediments that can arise from FOZs that do not encompass the entire mesopic pupil.

SOURCE: Tabernero J, Klyce SD, Sarver EJ, Artal P. Functional optical zone of the cornea. Invest Ophthalmol Vis Sci 2007;48(3):1053-60.
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Potential Role of Endothelin-1 in the Pathogenesis of PDR

Researchers at Spain's Universidad Complutense de Madrid investigated the potential role of endothelin-1 (ET-1), a potent vasoconstrictor with mitogenic properties, in the pathogenesis of proliferative diabetic retinopathy (PDR).

The researchers collected plasma and vitreous samples from 25 normal patients, 25 diabetic patients with PDR and 25 diabetic patients with non-PDR. The patients had to have epiretinal membranes (ERMs) or other ocular conditions that made them candidates for vitrectomy. Immunoreactive ET-1 (IR-ET-1) was assayed in plasma and vitreous samples by radioimmunoassay. IR-ET-1 was immunohistochemically localized in ERMs. Expression of endothelin receptors A (ETA) and B (ETB) was confirmed by reverse transcription-polymerase chain reaction analysis.

IR-ET-1 levels in plasma and vitreous samples from diabetic patients were higher than those in samples from the control group. The levels for patients with PDR were even higher than those for patients with non-PDR. Eyes with ERMs in the PDR group had the highest vitreous IR-ET-1 levels (14.67 +/- 0.67 pg/mL). IR-ET-1 was localized in the cellular and stromal components of ERMs in diabetic and nondiabetic patients. Furthermore, the ETA and ETB receptors were expressed in both diabetic and nondiabetic ERMs. The authors believe that these results suggest that ET-1 is involved in diabetic vitreoretinal disease.

SOURCE: Roldan-Pallares M, Rollin R, Martinez-Montero JC, et al. Immunoreactive endothelin-1 in the vitreous humor and epiretinal membranes of patients with proliferative diabetic retinopathy. Retina 2007;27(2):222-35.
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http://www.jobsonresearch.com/Publ.htm






Receptor Expressed by Uveal Melanoma Considered New Target for Diagnosis and Treatment

Uveal melanoma is the most common primary malignant ocular cancer in adults and has a distinct expression pattern of markers compared with that of cutaneous melanoma. In this study, researchers in Chile prove that the receptor MC1R is present in uveal melanoma and may provide a new therapeutic target for treatment of this type of melanoma.

Investigators used two novel monoclonal antibodies, MP1.1C11 and MP1.1B7, to examine the expression of MC1R in uveal melanomas. They analyzed tissue samples obtained from 17 patients for expression of MC1R by immunohistochemistry. Additionally, they treated uveal melanoma cell lines with proinflammatory cytokines, after which they analyzed MC1R cell surface expression by flow cytometry.

Results demonstrated that MC1R is expressed by uveal melanoma to a significantly greater extent than other melanoma markers. With the use of MP1.1C11 or MP1.1B7, MC1R was detected in 95 percent of the tested melanoma tissues, including one liver metastasis. In contrast, MART-1 was expressed by 66 percent of the analyzed samples, S100-specific protein by 33 percent and gp-100 by 67 percent of the analyzed samples. Results also showed that even though MC1R is mainly located intracellularly, its cell surface expression can be promoted by cytokines such as IFN-gamma, TNF-alpha, IL-4 and IL-10.

The study authors believe that these results support the inclusion of MC1R in the panel of markers for diagnosing uveal melanoma. Therapeutic use of MC1R-specific antibodies targeting cytokine-induced MC1R potentially requires expression of the target molecule on the surfaces of tumor cells.

SOURCE: Lopez MN, Pereda C, Ramirez M, et al. Melanocortin 1 receptor is expressed by uveal malignant melanoma and can be considered a new target for diagnosis and immunotherapy. Invest Ophthalmol Vis Sci 2007;48(3):1219-27.
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BRIEFLY
  • ADULT BONE MARROW STEM CELLS MAY HELP CURE CERTAIN GENETIC EYE DISEASES. Bone marrow stem cells of mice can switch roles and produce keratocan, a natural protein involved in the growth of the cornea. This ability to differentiate into keratocan-producing cells may provide a means to treat abnormal corneal cell growth in humans, according to University of Cincinnati researchers Winston Whei-Yang Kao, PhD, and Hongshan Liu, PhD. The findings were presented at the recent annual meeting of ARVO. In the laboratory, the researchers induced corneal abnormalities that mimicked genetic eye mutations, then injected bone marrow stem cells into the corneas of mice to see whether they altered the mutations. After one week, the abnormal corneas of animal models injected with bone marrow stem cells began to change shape and heal. The researchers believe that the procedure could one day help prevent blindness in patients suffering from genetic corneal diseases.

  • NOVAGALI RECEIVES FDA ORPHAN DRUG DESIGNATION FOR VKC TREATMENT. The FDA has granted orphan drug designation to Vekacia, Novagali Pharma's patented cationic emulsion for treating vernal keratoconjunctivitis (VKC). Drugs receiving this designation obtain seven years of marketing exclusivity from the date of drug approval; the manufacturer also receives tax credits for clinical trial costs, marketing application filing fee waivers and assistance from the FDA in the drug development process. In March 2006, the Committee for Orphan Medical Products (COMP), a division of the European Medicines Agency (EMEA), granted orphan drug designation in the European Union to Vekacia; positive results from a U.S. Phase III pivotal clinical study in children were announced in April 2007. The study showed that both symptoms and signs of disease improved in patients receiving Vekacia, and that the product was safe and well tolerated. Novagali plans to file European Marketing Authorization in mid-2007.

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