PURPOSE: Retinitis pigmentosa is a Mendelian disease with a very elevated genetic heterogeneity. Most mutations are responsible for less than 1% of cases, making molecular diagnosis a multigene screening procedure. In this study, we assessed whether direct testing of specific alleles could be a valuable screening approach in cases characterized by prevalent founder mutations. METHODS: We screened 275 North American patients with recessive/isolate retinitis pigmentosa for two mutations: an Alu insertion in the MAK gene and the p.Lys42Glu missense in the DHDDS gene. All patients were unrelated; 35 reported Jewish ancestry and the remainder reported mixed ethnicity. RESULTS: We identified the MAK and DHDDS mutations homozygously in only 2.1% and 0.8%, respectively, of patients of mixed ethnicity, but in 25.7% and 8.6%, respectively, of cases reporting Jewish ancestry. Haplotype analyses revealed that inheritance of the MAK mutation was attributable to a founder effect. CONCLUSION: In contrast to most mutations associated with retinitis pigmentosa-which are, in general, extremely rare-the two alleles investigated here cause disease in approximately one-third of North American patients reporting Jewish ancestry. Therefore, their screening constitutes an alternative procedure to large-scale tests for patients belonging to this ethnic group, especially in time-sensitive situations.Genet Med 17 4, 285-290.

BACKGROUND: Graft failure because of immune rejection remains a significant problem in organ transplantation, and lymphatic and blood vessels are important components of the afferent and efferent arms of the host alloimmune response, respectively. We compare the effect of antihemangiogenic and antilymphangiogenic therapies on alloimmunity and graft survival in a murine model of high-risk corneal transplantation. METHODS: Orthotopic corneal transplantation was performed in hemevascularized and lymph-vascularized high-risk host beds, and graft recipients received subconjunctival vascular endothelial growth factor (VEGF)-trap, anti-VEGF-C, sVEGFR-3, or no treatment, beginning at the time of surgery. Fourteen days after transplantation, graft hemeangiogenesis and lymphangiogenesis were evaluated by immunohistochemistry. The frequencies of Th1 cells in regional lymphoid tissue and graft-infiltrating immune cells were evaluated by flow cytometry. Long-term allograft survival was compared using Kaplan-Meier curves. RESULTS: VEGF-trap significantly decreased graft hemangiogenesis as compared to the control group and was most effective in reducing the frequency of graft-infiltrating immune cells. Anti-VEGF-C and sVEGFR3 significantly decreased graft lymphangiogenesis and lymphoid Th1 cell frequencies as compared to control. VEGF-trap (72%), anti-VEGF-C (25%), and sVEGFR-3 (11%) all significantly improved in the 8-week graft survival compared to control (0%), although VEGF-trap was significantly more effective than both anti-VEGF-C (P < 0.05) and sVEGFR-3 (P < 0.05). CONCLUSION: In a clinically relevant model of high-risk corneal transplantation in which blood and lymphatic vessels are present and treatment begins at the time of transplantation, VEGF-trap is significantly more effective in improving long-term graft survival as compared to anti-VEGF-C and sVEGFR-3, but all approaches improve survival when compared to untreated control.

An unprecedented pigmented caruncular apocrine hidrocystoma with the additional feature of an oncocytic transformation of the cyst's lining cells is reported. Over a year, a 79-year-old woman developed a centrally pigmented lesion of her right caruncle with translucent borders. Because of concern about a melanoma, a carunculectomy with adjunctive cryotherapy and placement of an amniotic membrane graft were performed, and the excised specimen was evaluated microscopically. A large cyst dominated the caruncle and was lined by an inner layer of columnar eosinophilic and granular cells with an outer, interrupted layer of flattened myoepithelial cells. Phosphotungstic acid hematoxylin staining disclosed myriad cytoplasmic, dot-like mitochondria signifying an oncocytic change. Immunohistochemistry revealed gross cystic fluid disease protein-15 and cytokeratin 7-positivity indicative of apocrine differentiation. Oncocytic change is characteristically encountered in lacrimal ductal cysts and tumors.

BACKGROUND/AIMS: To evaluate ex vivo biomechanical and enzymatic digestion resistance differences between standard myopic laser in-situ keratomileusis (LASIK) compared with LASIK+CXL, in which high-irradiance cross-linking (CXL) is added. METHODS: Eight human donor corneas were subjected to femtosecond-assisted myopic LASIK. Group A (n=4) served as a control group (no CXL). The corneas in LASIK+CXL group B were subjected to concurrent prophylactic high-irradiance CXL (n=4). Saline-diluted (0.10%) riboflavin was instilled on the stroma, subsequently irradiated with UV-A through the repositioned flap. The cornea stroma and flap specimens were separately subjected to transverse biaxial resistance measurements; biomechanical differences were assessed via stress and Young's shear modulus. Subsequently, the specimens were subjected to enzymatic degradation. RESULTS: For the corneal stroma specimen, stress at 10% strain was 128±11 kPa for control group A versus 293±20 kPa for the LASIK+CXL group B (relative difference Δ=+129%, p<0.05). The stress in group B was also increased at 20% strain by +68% (p<0.05). Shear modulus in group B was increased at 10% strain by +79%, and at 20% strain by +48% (both statistically significant, p<0.05). The enzymatic degradation time to dissolution was 157.5±15.0 min in group A versus 186.25±7.5 min in group B (Δ=+18%, p=0.014). For the flaps, both biomechanical, as well as enzymatic degradation tests showed no significant differences. CONCLUSIONS: LASIK+CXL appears to provide significant increase in underlying corneal stromal rigidity, up to +130%. Additionally, there is significant relevant enzymatic digestion resistance confirmatory to the above. LASIK flaps appear unaffected biomechanically by the LASIK+CXL procedure, suggesting effective CXL just under the flap.

PURPOSE: We explored whether risk factor associations differed by primary open-angle glaucoma (POAG) subtypes defined by visual field (VF) loss pattern (i.e., paracentral or peripheral). METHODS: We included 77,157 women in the Nurses Health Study and 42,773 men in the Health Professionals Follow-up Study (1986-2010) and incident medical-record confirmed cases of paracentral (n=440) and peripheral (n=865) POAG subtypes. We evaluated African-heritage, glaucoma family history, body mass index (BMI), mean arterial blood pressure, diabetes mellitus, physical activity, smoking, caffeine and alcohol intakes. We used competing risk Cox regression analyses modeling age as the metameter and stratified by age, cohort and event type. We sequentially identified factors with the least significant differences in associations with POAG subtypes ("stepwise down" approach with P for heterogeneity [P-het]<0.10 as threshold). RESULTS: BMI was more inversely associated with the POAG paracentral VF loss subtype than the peripheral VF loss subtype (per 10 kg/m2; hazard ratio [HR]=0.67 [95% Confidence Interval [CI]: 0.52, 0.86] vs. HR=0.93 [95% CI: 0.78, 1.10]; P-het=0.03) as was smoking (per 10 pack-years; HR=0.92 [95% CI: 0.87, 0.98] vs. HR=0.98 [95% CI: 0.94, 1.01]; P-het=0.09). These findings were robust in sensitivity analyses using a "stepwise up" approach (identify factors that showed the most significant differences). Non-heterogeneous (p-het>0.10) adverse associations with both POAG subtypes were observed with glaucoma family history, diabetes, African-heritage, greater caffeine intake and higher mean arterial pressure. CONCLUSIONS: These data indicate that POAG with early paracentral VF loss has distinct as well as common determinants compared to POAG with peripheral VF loss.

PURPOSE: To evaluate corneal endothelial cell density (ECD) in patients with dry eye disease (DED) compared to an age-matched control group. DESIGN: Cross-sectional, controlled study. METHODS: This study included 90 eyes of 45 patients with moderate to severe DED (aged 53.7 ± 9.8 years) and 30 eyes of 15 normal controls (aged 50.7 ± 9.8 years). All subjects had a complete ophthalmic evaluation including symptom assessment using the Ocular Surface Disease Index (OSDI) and corneal fluorescein staining. In addition, laser scanning in vivo confocal microscopy was performed to measure the density of the following parameters in the central cornea: endothelial cells, subbasal nerves, and subbasal immune dendritic cells. RESULTS: Corneal ECD was significantly lower in the DED group (2595.8 ± 356.1 cells/mm(2)) than in the control group (2812.7 ± 395.2 cells/mm(2), P = .046). The DED group showed significantly lower corneal subbasal nerve density (17.1 ± 6.9 mm/mm(2)) compared to the control group (24.7 ± 4.4 mm/mm(2), P < .001). Dendritic cell density was significantly higher in the DED group than in the controls (111.7 ± 137.3 vs 32.0 ± 24.4 cells/mm(2), respectively, P = .002). There were statistically significant correlations between corneal ECD and dry eye severity parameters including the OSDI score (rs = -0.26, P = .03), and corneal fluorescein staining (rs = -0.28, P = .008). CONCLUSIONS: There is a significant reduction in corneal ECD in DED that correlates with clinical severity of the disease.

PURPOSE: To report a case of ocular ischemic syndrome presenting as retinal vasculitis in a patient with Moyamoya syndrome. METHODS: A retrospective chart review was conducted to record clinical data including fluorescein angiography, optical coherence tomography, and serologic testing. A review of the literature from 1969 to 2014 of ocular involvement in Moyamoya syndrome was performed. RESULTS: A 51-year-old woman with long history of bilateral retinal vasculitis and refractory cystoid macular edema was eventually diagnosed with Moyamoya syndrome after sustaining a perioperative cerebrovascular accident. Moyamoya syndrome has been associated in the literature with ocular ischemic syndrome, presenting with narrowed retinal arteries, dilated veins, and midperipheral retinal hemorrhages, but retinal vasculitis with cystoid macular edema has not been reported. CONCLUSION: Moyamoya-related ocular ischemic syndrome can present as retinal vascular leakage and macular edema. Ophthalmologists should be cognizant that signs of the disease may be first observed in the eye before manifestations in the cerebrovascular system.

PURPOSE: To report the prevalence and risk factors for retinopathy in African Americans with impaired fasting glucose (IFG) and type 2 diabetes in the Jackson Heart Study and to determine if P-selectin plasma levels are independently associated with retinopathy in this population. DESIGN: Prospective, cross-sectional observational study. METHODS: setting: Community-based epidemiologic study. STUDY POPULATION: Total of 629 patients with type 2 diabetes and 266 participants with impaired fasting glucose. OBSERVATION PROCEDURES: Bilateral, 7-field fundus photographs were scored by masked readers for diabetic retinopathy (DR) level. Covariate data including P-selectin plasma levels and genotypes were collected in a standardized fashion. MAIN OUTCOME MEASURES: Association between risk factors, including P-selectin plasma levels and genotypes, and retinopathy. RESULTS: The prevalences of any retinopathy among participants with IFG and type 2 diabetes were 9.4% and 32.4%, respectively. Among those with type 2 diabetes, in multivariate models adjusted for age, sex, and other traditional risk factors, higher P-selectin levels were associated with any DR (odds ratio = 1.11, 95% confidence interval = 1.02-1.21, P = .02) and proliferative DR (odds ratio = 1.23, 95% confidence interval = 1.03-1.46, P = .02). To further investigate the relationship between P-selectin and DR, we examined the association between P-selectin genotype and DR. Minor allele homozygotes for the variant rs6128 were less likely to develop DR (P after Bonferroni correction = 0.03). CONCLUSIONS: Both serologic and genetic data show an association between P-selectin and DR in the Jackson Heart Study. If confirmed in other studies, this association may provide insight into the pathogenesis of retinopathy.

PURPOSE: A pocket-sized collision warning device equipped with a video camera was developed to predict impending collisions based on time to collision rather than proximity. A study was conducted in a high density obstacle course to evaluate the effect of the device on collision avoidance in people with peripheral field loss (PFL). METHODS: The 41 meter long loop-shaped obstacle course consisted of 46 stationary obstacles from floor to head level, and oncoming pedestrians. Twenty five patients with tunnel vision (n = 13) or hemianopia (n = 12) completed 4 consecutive loops with and without the device, while not using any other habitual mobility aid. Walking direction and device usage order were counterbalanced. Number of collisions and preferred percentage of walking speed (PPWS) were compared within subjects. RESULTS: Collisions were reduced significantly by about 37% (p < 0.001) with the device (Floor-level obstacles were excluded because the device was not designed for them). No patient had more collisions when using the device. While the PPWS also reduced with the device from 52% to 49% (p = 0.053), this did not account for the lower number of collisions, as the changes in collisions and PPWS were not correlated (p = 0.516). CONCLUSIONS: The device may help patients with a wide range of PFL avoid collisions with high-level obstacles and barely affect their walking speed.