Manuel Sánchez-Salorio

Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10−75), ARMS2 (P < 10−59), C2/CFB (P < 10−20), C3 (P < 10−9), and CFI (P < 10−6). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10−11), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 × 10−7; CETP, P = 7.4 × 10−7) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles near LPL (P = 3.0 × 10−3) and ABCA1 (P = 5.6 × 10−4). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

Comparative study of incomplete posterior vitreous detachment as a risk factor for proliferative vitreoretinopathy

Abstract · Background: Abnormal vitreoretinal relationships have recently been implicated in many vitreoretinal disorders. Sites of abnormal vitreoretinal adherences are likely to exist in eyes predisposed to rhegmatogenous retinal detachment (RD), causing either retinal tears or incomplete posterior vitreous detachment (PVD). The present study was designed in two parts to identify the risk for preoperative and postoperative proliferative vitreoretinopathy (PVR) due to incomplete PVD. · Methods: We prospectively evaluated the vitreoretinal relationships using high-resolution kinetic echography in 102 consecutive eyes of 100 patients with rhegmatogenous RD. In the first part, a case-control study was conducted to compare the vitreous status in patients with preoperative PVR (cases) with that in patients with non-PVR-complicated RD (controls). During the second part, patients with noncomplicated RD (65 eyes) who were operated on by a simple retinal attachment procedure were followed up for a mean period of 6.6 months to compare the recurrence of RD due to postoperative PVR according to their vitreous status. · Results: Patients with PVR on study entry had a higher prevalence of partial PVD (28 of 32 eyes, 87%) than did controls (25 of 70 eyes, 35%). The statistical significance of this difference was independent of all other variables studied. After a mean follow-up period of 6.6 months, the incidence of recurrence of RD associated with postoperative PVR was 33% in the eyes with incomplete PVD, compared with 4.9% in the eyes without incomplete PVD. · Conclusions: Our results support the notion that the occurrence of incomplete PVD in RD is a significant risk factor for preoperative and postoperative PVR.

A Comparison of the Long-Term Effects of Dorzolamide 2% and Brinzolamide 1%, Each Added to Timolol 0.5%, on Retrobulbar Hemodynamics and Intraocular Pressure in Open-Angle Glaucoma Patients

PURPOSE To compare the effect on the retrobulbar hemodynamics and intraocular pressure (IOP) of dorzolamide 2% and brinzolamide 1%, each added to timolol 0.5% in patients with primary open-angle glaucoma (POAG). METHODS 146 POAG patients were prospectively randomized to receive either dorzolamide 2% or brinzolamide 1% BID, each added to timolol 0.5%, during a 60-month evaluator-masked study. At baseline and every 6 months for 60 months, we measured the retrobulbar hemodynamic parameters in the ophthalmic artery (OA), central retinal artery (CRA), and short posterior ciliary arteries (SPCA) using color Doppler imaging (CDI), intraocular pressure (IOP), and blood pressure measurements. RESULTS Dorzolamide significantly increased the end-diastolic velocity (EDV) in the OA in 1.22 cm/s, 95% confidence interval (95% CI) 0.90-1.56 cm/s, P < 0.001 and reduced the resistivity index (RI) in the OA in 0.04 units, 95% CI 0.03-0.05, P < 0.001. None of the retrobulbar parameters changed significantly on therapy with brinzolamide when the results were analyzed at month 60. Both dorzolamide and brinzolamide significantly decreased IOP (-4.3, 95% CI -4.5 to -4.2 mmHg and -4.3, 95% CI -4.4 to -4.2 mmHg, respectively). Dorzolamide significantly reduced the RI in the OA from 0.74 (0.02) to 0.70 (0.02), CRA from 0.66 (0.02) to 0.62 (0.02), and SPCA from 0.66 (0.02) to 0.62 (0.02), P < 0.001, respectively. CONCLUSIONS Our results suggest augmented retrobulbar blood flow after 5 years of treatment with dorzolamide but not with brinzolamide, each added to timolol, in POAG patients.

Genetic association study of age-related macular degeneration in the Spanish population

Acta Ophthalmol. 2011: 89: e12–e22

Efficacy of subconjunctival cyclosporin-containing microspheres on keratoplasty rejection in the rabbit.

Abstract · Background: The purpose of this study was to evaluate microspheres of PLGA containing cyclosporin (CsA) as a subconjunctival drug delivery system and to test their efficacy in the prevention of corneal allograft rejection in the rabbit. · Methods: Rabbits were injected subconjunctivally with a solution of CsA (CsA-AR) (20 animals) or a microsphere suspension of CsA (CsA-MP) (20 animals), with equivalent drug concentrations (15 mg/ml). The concentration of CsA in the aqueous, cornea and blood was measured by radioimmunoassay at different times thereafter. In other rabbits, 40 allogeneic grafts were performed. Animals were divided into four groups that received the following subconjunctival treatments: group 1: AR solution (solvents of CsA-AR solution); group 2: CsA-AR solution; group 3: MP suspension (empty microspheres); group 4: CsA-MP suspension. · Results: Mean corneal levels of CsA were 1174±830, 918±179, 972±580, 268±182 and 243±162 ng/ml at 12, 24 and 48 h and 7 and 14 days after the injection of CsA-AR. For the CsA-MP suspension, corneal concentrations were 1195±321, 234±147 and 88±77 ng/ml at 12, 24 and 48 h but subsequently dropped to undetectable levels. Blood and aqueous levels were undetectable. Treatment with CsA significantly improved the survival time and survival rate of grafts in the CsA-treated groups (2, 4) over grafts in non-CsA-treated groups (1, 3). There was no significant difference in the graft survival curve between groups 2 and 4. · Conclusion: CsA-containing microspheres might be a promising formulation in the prevention of corneal graft rejection. Since the levels of CsA in blood were undetectable, this treatment might avoid the problems associated with systemic side effects.

Predictors for visual field progression and the effects of treatment with dorzolamide 2% or brinzolamide 1% each added to timolol 0.5% in primary open‐angle glaucoma

Purpose:  This study aims to identify progression factors in patients with primary open‐angle glaucoma (POAG), including the effects of treatment with dorzolamide 2% or brinzolamide 1%, each added to timolol 0.5%.

Abnormal cell cycle regulation in primary human uveal melanoma cultures

Uveal malignant melanoma is the most frequent primary intraocular tumor in adult humans. The cellular events leading to neoplasic transformation of normal uveal melanocytes are not well known when compared to other cancers. In this study, we investigated the role of G1 and G1/S regulatory proteins of the cell cycle in human uveal melanoma (UM) primary cell cultures, since these proteins are common targets in tumor development. Further, freshly established and characterized tumor cells are a better model for in vitro studies when compared to cell lines established long ago. Human primary cell cultures from eight different UM were established, as well as one primary culture from rhesus uveal normal melanocytes (UNM). Primary human UM cultures were characterized by a low establishment and growing rate. From four successful cultures, three showed a high expression of cyclin D1, cyclin E, p16INK4A, and p27KIP1 with no variations in cyclin A, cyclin‐dependent kinase 2 (CDK2), and CDK4. Interestingly, in one of the cultured tumors, tumor suppressor protein retinoblastoma (Rb) did not bind E2F despite the fact that Rb was found in its hypophosphorylated form. No mutations in either RB1 or the Rb‐binding pocket of E2F‐1 were detected. Furthermore, we identified seven proteins co‐immunoprecipitating with Rb in this tumor, including Lamin A/C and six proteins not previously reported to bind Rb: Hsc70, high mobility group protein 1 (HMG‐1), hnRPN, glyceraldehyde 3 phosphate dehydrogenase (G3PDH), EF‐1, and EF‐2. Our results indicate that the overexpression of cyclins D1/E and CDKIs p16 and p27, together with a deregulation of the Rb/E2F pathway, may be implicated in the development of human UM.

Ultrasound biomicroscopy in the diagnosis of supraciliochoroidal fluid after trabeculectomy

PURPOSE To report supraciliochoroidal effusion after trabeculectomy with the use of ultrasound biomicroscopy. METHODS In a prospective study, 28 eyes of 19 patients with primary open-angle glaucoma that underwent trabeculectomy were evaluated preoperatively and postoperatively by ultrasound biomicroscopy. RESULTS Four eyes showed a hypoechogenic suprachoroidal space that remained stable for 6 months postoperatively. These four eyes had intraocular pressures of 11 mm Hg or less on no antiglaucoma medications and without signs of choroidal detachment. CONCLUSION Ultrasound biomicroscopy proved to be a useful method of detecting, after trabeculectomy, supraciliochoroidal fluid without clinically detectable choroidal detachment. This fluid may signify an iatrogenic cyclodialysis during surgery or, less likely, subclinical ciliochoroidal detachment.

Iris Metastasis From Endometrial Carcinoma

PURPOSE To report a case of metastasis to the iris from endometrial carcinoma. METHOD Case report. A 67-year-old woman with a history of endometrial carcinoma and local recurrence after surgery presented 11 months later with two yellow-pink nodules on the iris of the right eye. RESULTS Systemic medical evaluation demonstrated no other metastases. The iris tumors were removed surgically, and histology demonstrated adenocarcinoma consistent with endometrial carcinoma. CONCLUSIONS Endometrial carcinoma can metastasize to the iris. This possibility should be considered because the frequency of endometrial carcinoma is increasing.

changes in Anterior Chamber Depth and Angle Width After Filtration Surgery: A Quantitative Study Using Ultrasound Biomicroscopy

Purpose: To evaluate the anterior chamber configuration by means of ultrasound biomicroscopy in patients with glaucoma and control subjects, and to determine quantitative changes in this configuration after glaucoma filtration surgery (trabeculectomy) and combined cataract and filtration surgery. Methods: The study included 33 eyes of 33 patients with glaucoma (diagnosed with primary open‐angle or exfoliative glaucoma) in which filtration surgery (n = 17) or combined cataract and filtration surgery (n = 16) was performed, and 25 eyes of 25 age‐matched control subjects. Ultrasound biomicroscopy was used to measure anterior chamber depth and the angle width at 500 &mgr;m from the scleral spur in all eyes. The patients with glaucoma were examined 2 days before surgery and 3 and 6 months after surgery. Results: There were no significant differences in anterior chamber depth and angle width between patients with glaucoma before surgery and control subjects. Postoperative values for anterior chamber depth were significantly greater in patients with glaucoma who underwent combined surgery, but no significant changes were observed in those who underwent filtration surgery alone. In contrast, angle width was significantly greater after surgery both in patients who underwent combined surgery and in those who underwent filtration surgery alone. Conclusion: On ultrasound biomicroscopic evaluation, there were no differences in anterior chamber depth and angle width between patients with glaucoma and control subjects. Trabeculectomy alone widens the angle but does not affect the anterior chamber depth; however, combined surgery both deepens the anterior chamber depth and widens the angle.