Fundus Tessellation and Parapapillary Atrophy, as Ocular Characteristics of Spontaneously High Myopia in Macaques: The Non-Human Primates Eye Study.

Purpose: This study aimed to evaluate the ocular characteristics associated with spontaneously high myopia in adult nonhuman primates (NHPs). Methods: A total of 537 eyes of 277 macaques with an average age of 18.53 ± 3.01 years (range = 5-26 years), raised in a controlled environment, were included. We measured ocular parameters, including spherical equivalent (SE), axial length (AXL), and intraocular pressure. The 45-degree fundus images centered on the macula and the disc assessed the fundus tessellation and parapapillary atrophy (PPA). Additionally, optical coherence tomography (OCT) was used to measure the thickness of the retinal nerve fiber layer (RNFL). Results: The mean SE was -1.58 ± 3.71 diopters (D). The mean AXL was 18.76 ± 0.86 mm. The prevalence rate of high myopia was 17.7%. As myopia aggravated, the AXL increased (r = -0.498, P < 0.001). Compared with non-high myopia, highly myopic eyes had a greater AXL (P < 0.001), less RNFL thickness (P = 0.004), a higher incidence of PPA (P < 0.001), and elevated grades of fundus tessellation (P < 0.001). The binary logistic regression was performed, which showed PPA (odds ratio [OR] = 4.924, 95% confidence interval [CI] = 2.375-10.207, P < 0.001) and higher grades of fundus tessellation (OR = 1.865, 95% CI = 1.474-2.361, P < 0.001) were independent risk characteristics for high myopia. Conclusions: In NHPs, a higher grade of fundus tessellation and PPA were significant biomarkers of high myopia. Translational Relevance: The study demonstrates adult NHPs raised in conditioned rooms have a similar prevalence and highly consistent fundus changes with human beings, which strengthens the foundation for utilizing macaques as an animal model in high myopic studies.

Quantifying refractive error in companion dogs with and without nuclear sclerosis: 229 eyes from 118 dogs.

OBJECTIVE: To evaluate the relationship between nuclear sclerosis (NS) and refractive error in companion dogs. ANIMALS STUDIED: One hundred and eighteen companion dogs. PROCEDURES: Dogs were examined and found to be free of significant ocular abnormalities aside from NS. NS was graded from 0 (absent) to 3 (severe) using a scale developed by the investigators. Manual refraction was performed. The effect of NS grade on refractive error was measured using a linear mixed effects analysis adjusted for age. The proportion of eyes with >1.5 D myopia in each NS grade was evaluated using a chi-square test. Visual impairment score (VIS) was obtained for a subset of dogs and compared against age, refractive error, and NS grade. RESULTS: Age was strongly correlated with NS grade (p < .0001). Age-adjusted analysis of NS grade relative to refraction showed a mild but not statistically significant increase in myopia with increasing NS grade, with eyes with grade 3 NS averaging 0.58-0.88 D greater myopia than eyes without NS. However, the myopia of >1.5 D was documented in 4/58 (6.9%) eyes with grade 0 NS, 12/91 (13.2%) eyes with grade 1 NS, 13/57 (22.8%) eyes with grade 2 NS, and 7/23 (30.4%) eyes with grade 3 NS. Risk of myopia >1.5 D was significantly associated with increasing NS grade (p = .02). VIS was associated weakly with refractive error, moderately with age, and significantly with NS grade. CONCLUSIONS: NS is associated with visual deficits in some dogs but is only weakly associated with myopia. More work is needed to characterize vision in aging dogs.

Corneal proteome and differentially expressed corneal proteins in highly myopic chicks using a label-free SWATH-MS quantification approach.

Myopia, or short-sightedness, is a highly prevalent refractive disorder in which the eye's focal length is too short for its axial dimension in its relaxed state. High myopia is associated with increased risks of blinding ocular complications and abnormal eye shape. In addition to consistent findings on posterior segment anomalies in high myopia (e.g., scleral remodeling), more recent biometric and biomechanical data in myopic humans and animal models also indicate anterior segment anomalies (e.g., corneal biomechanical properties). Because the cornea is the anterior-most ocular tissue, providing essential refractive power and physiological stability, it is important to understand the biochemical signaling pathway during myopia development. This study first aimed to establish the entire chicken corneal proteome. Then, using the classical form deprivation paradigm to induce high myopia in chicks, state-of-the-art bioinformatics technologies were applied to identify eight differentially expressed proteins in the highly myopic cornea. These results provide strong foundation for future corneal research, especially those using chicken as an animal model for myopia development.

The ophthalmic health and refractive state of working dogs in South Brazil.

Background: Working dogs, such as police dogs and guide dogs, have important roles in the contemporary society by performing specific and demanding jobs. Ocular health and the maintenance of good visual acuity are imperative to strong work performance and thus human safety. Aim: The aim of this study was to assess ophthalmic abnormalities and refractive errors in police and guide dogs in Brazil. Methods: A total of 71 dogs (141 eyes) were evaluated. Ten were guide dogs and 61 were police dogs. The work performance was assessed by a questionnaire to each dog's handler/owner. All the dogs underwent a complete ocular examination, and abnormalities were classified by condition, if they were active or inactive and if they were located within the visual axis. In addition, 62 dogs were evaluated by streak retinoscopy for refractive errors. Results: Ophthalmic abnormalities were detected in 38 (54%) dogs, of which 23 were considered inherited, 25 were considered active, and 10 were located within the visual axis. Incipient cataracts were the most prevalent abnormality. No guide dog had an abnormality within the visual axis. The most common refractive error was myopia with the median and interquartile range of -0.75 ± 0.75 diopters; among these, police dogs had -1.0 ± 0.5 diopters, whereas guide dogs +0.38 ± 0.75 diopters. Police dogs tended to be slightly myopic and guide dogs were emmetropic. Conclusion: Despite finding a considerable number of ophthalmic abnormalities and refractive error, work performance was good with no signs of visual impairment in any dog. Regular ophthalmic examinations are advised for working dogs, and an exclusion of severely affected dogs from breeding programs is recommended.

Genome-wide association study and whole-genome sequencing identify a deletion in LRIT3 associated with canine congenital stationary night blindness.

Congenital stationary night blindness (CSNB), in the complete form, is caused by dysfunctions in ON-bipolar cells (ON-BCs) which are secondary neurons of the retina. We describe the first disease causative variant associated with CSNB in the dog. A genome-wide association study using 12 cases and 11 controls from a research colony determined a 4.6 Mb locus on canine chromosome 32. Subsequent whole-genome sequencing identified a 1 bp deletion in LRIT3 segregating with CSNB. The canine mutant LRIT3 gives rise to a truncated protein with unaltered subcellular expression in vitro. Genetic variants in LRIT3 have been associated with CSNB in patients although there is limited evidence regarding its apparently critical function in the mGluR6 pathway in ON-BCs. We determine that in the canine CSNB retina, the mutant LRIT3 is correctly localized to the region correlating with the ON-BC dendritic tips, albeit with reduced immunolabelling. The LRIT3-CSNB canine model has direct translational potential enabling studies to help understand the CSNB pathogenesis as well as to develop new therapies targeting the secondary neurons of the retina.

Isotope-coded protein label based quantitative proteomic analysis reveals significant up-regulation of apolipoprotein A1 and ovotransferrin in the myopic chick vitreous.

This study used isotope-coded protein label (ICPL) quantitative proteomics and bioinformatics analysis to examine changes in vitreous protein content and associated pathways during lens-induced eye growth. First, the vitreous protein profile of normal 7-day old chicks was characterized by nano-liquid chromatography electrospray ionization tandem mass spectrometry. A total of 341 unique proteins were identified. Next, myopia and hyperopia were induced in the same chick by attaching -10D lenses to the right eye and +10D lenses to the left eye, for 3 and 7 days. Protein expression in lens-induced ametropic eyes was analyzed using the ICPL approach coupled to LCMS. Four proteins (cystatin, apolipoprotein A1, ovotransferrin, and purpurin) were significantly up-regulated in the vitreous after 3 days of wearing -10D lenses relative to +10D lens contralateral eyes. The differences in protein expression were less pronounced after 7 days when the eyes approached full compensation. In a different group of chicks, western blot confirmed the up-regulation of apolipoprotein A1 and ovotransferrin in the myopic vitreous relative to both contralateral lens-free eyes and hyperopic eyes in separate animals wearing +10D lenses. Bioinformatics analysis suggested oxidative stress and lipid metabolism as pathways involved in compensated ocular elongation.

Redundant contribution of a Transient Receptor Potential cation channel Member 1 exon 11 single nucleotide polymorphism to equine congenital stationary night blindness.

BACKGROUND: Congenital stationary night-blindness (CSNB) is a recessive autosomal defect in low-light vision in Appaloosa and other horse breeds. This condition has been mapped by linkage analysis to a gene coding for the Transient Receptor Potential cation channel Member 1 (TRPM1). TRPM1 is normally expressed in the ON-bipolar cells of the inner nuclear layer of the retina. Down-regulation of TRPM1 expression in CSNB results from a transposon-like insertion in intron 1 of the TRPM1 gene. Stop transcription signals in this transposon significantly reduce TRPM1 primary transcript levels in CSNB horses. This study describes additional contributions by a second mutation of the TRPM1 gene, the ECA1 108,249,293 C > T SNP, to down-regulation of transcription of the TRPM1 gene in night-blind horses. This TRPM1 SNP introduces a consensus binding site for neuro-oncological ventral antigen 1 (Nova-1) protein in the primary transcript. Nova-1 binding disrupts normal splicing signals, producing unstable, non-functional mRNA transcripts. RESULTS: Retinal bipolar cells express both TRPM1 and Nova-1 proteins. In vitro addition of Nova-1 protein retards electrophoretic migration of TRPM1 RNA containing the ECA1 108,249,293 C > T SNP. Up-regulating Nova-1 expression in primary cultures of choroidal melanocytes carrying the intron 11 SNP caused an average log 2-fold reduction of ~6 (64-fold) of TRPM1 mRNA expression. CONCLUSIONS: These finding suggest that the equine TRPM1 SNP can act independently to reduce survival of TRPM1 mRNA escaping the intron 1 transcriptional stop signals in CSNB horses. Coexistence and co-inheritance of two independent TRPM1 mutations across 1000 equine generations suggests a selective advantage for the apparently deleterious CSNB trait.

Aging Dogs Manifest Myopia as Measured by Autorefractor.

OBJECTIVE: Dogs, like humans, experience eye changes with aging: hardening and clouding of the lens and accumulated oxidative damage from UV sunlight. It has been debated whether such changes could be affecting the visual function of dogs. The objective of this study was to determine if autorefractometry could be used to measure visual function in dogs. ANIMALS AND METHODS: Nine Beagle dogs (ages 1 to 14 years) were examined by a veterinary ophthalmologist and their eyes determined to be free of cataracts. Spherical equivalent refractive error was measured by handheld autorefractor (Welch Allyn SureSight) under both indirect and direct lighting conditions with five measurements per condition, per eye. Measures were repeated on three different days for each dog within six weeks. Nonparametric statistics were used to detect differences among lighting conditions and test days, and between eyes. Spearmen correlation assessed the visual measurement outcomes' association with age. RESULTS: There was no difference for day-to-day or between-eye measurements. Significantly, the Beagles showed a myopic shift with aging (average spherical equivalent ranged from plano to -3.00 diopters), suggesting that dogs become more near-sighted as they age (r = -0.48 and -0.73 under direct and indirect lights; p<0.05 both). Younger dogs were able to make larger accommodation changes from indirect light to direct light conditions, indicating a more flexible lens (r = -0.50, p<0.05). CONCLUSIONS: Although designed for humans, the hand-held autorefractor technique is applicable to dogs and sensitive to light conditions. The age-associated myopic shift could be expected to compromise dogs' visual functions.

Twenty-five thousand years of fluctuating selection on leopard complex spotting and congenital night blindness in horses.

Leopard complex spotting is inherited by the incompletely dominant locus, LP, which also causes congenital stationary night blindness in homozygous horses. We investigated an associated single nucleotide polymorphism in the TRPM1 gene in 96 archaeological bones from 31 localities from Late Pleistocene (approx. 17 000 YBP) to medieval times. The first genetic evidence of LP spotting in Europe dates back to the Pleistocene. We tested for temporal changes in the LP associated allele frequency and estimated coefficients of selection by means of approximate Bayesian computation analyses. Our results show that at least some of the observed frequency changes are congruent with shifts in artificial selection pressure for the leopard complex spotting phenotype. In early domestic horses from Kirklareli-Kanligecit (Turkey) dating to 2700-2200 BC, a remarkably high number of leopard spotted horses (six of 10 individuals) was detected including one adult homozygote. However, LP seems to have largely disappeared during the late Bronze Age, suggesting selection against this phenotype in early domestic horses. During the Iron Age, LP reappeared, probably by reintroduction into the domestic gene pool from wild animals. This picture of alternating selective regimes might explain how genetic diversity was maintained in domestic animals despite selection for specific traits at different times.

Correction of refractive errors in rhesus macaques (Macaca mulatta) involved in visual research.

Macaques are the most common animal model for studies in vision research, and due to their high value as research subjects, often continue to participate in studies well into old age. As is true in humans, visual acuity in macaques is susceptible to refractive errors. Here we report a case study in which an aged macaque demonstrated clear impairment in visual acuity according to performance on a demanding behavioral task. Refraction demonstrated bilateral myopia that significantly affected behavioral and visual tasks. Using corrective lenses, we were able to restore visual acuity. After correction of myopia, the macaque's performance on behavioral tasks was comparable to that of a healthy control. We screened 20 other male macaques to assess the incidence of refractive errors and ocular pathologies in a larger population. Hyperopia was the most frequent ametropia but was mild in all cases. A second macaque had mild myopia and astigmatism in one eye. There were no other pathologies observed on ocular examination. We developed a simple behavioral task that visual research laboratories could use to test visual acuity in macaques. The test was reliable and easily learned by the animals in 1 d. This case study stresses the importance of screening macaques involved in visual science for refractive errors and ocular pathologies to ensure the quality of research; we also provide simple methodology for screening visual acuity in these animals.

A retinoscopic survey of 333 horses and ponies in the UK.

INTRODUCTION: Ophthalmic examination in the horse is generally limited to crude assessment of vision and screening for ocular lesions. The refractive state of equine eyes and the potential impact on vision and performance requires further investigation. OBJECTIVE: To assess the refractive state of a large, mixed-breed sample of horses and ponies in the United Kingdom (UK). PROCEDURE: The refractive state of both eyes of 333 horses and ponies was determined by streak retinoscopy, and the effect of age, height, gender, breed and management regime on the refractive state assessed. RESULTS: Emmetropia was found in 557 of 666 (83.63%) of eyes; 228/333 (68.5%) of the horses/ponies were emmetropic in both eyes. Refractive errors of greater than 1.50 D (in either direction) were found in 2.7% of the eyes tested. Ametropic eyes included hyperopia (54%) and myopia (46%). Anisometropia was found in 30.3% of horses and ponies. Breed of horse/pony was the only factor that affected refractive state (in the left eye only, P < 0.05) with Thoroughbred crosses having a tendency toward myopia and Warmbloods/Shires toward hyperopia. DISCUSSION AND CONCLUSION: The retinoscopic survey found emmetropia to be the predominant refractive state of the equine eye with no evidence of an overall trend toward myopia or hyperopia. However, individual and breed-related differences were found. Such factors should be considered in the selection of horses for sport and leisure, and when evaluating their performance potential. More comprehensive visual testing would be valuable in identifying underlying causes of behavioral problems.

Heritability of lenticular myopia in English Springer spaniels.

PURPOSE: We determined whether naturally-occurring lenticular myopia in English Springer spaniels (ESS) has a genetic component. METHODS: Streak retinoscopy was performed on 226 related ESS 30 minutes after the onset of pharmacologic mydriasis and cycloplegia. A pedigree was constructed to determine relationships between affected offspring and parents. Estimation of heritability was done in a Bayesian analysis (facilitated by the MCMCglmm package of R) of refractive error in a model, including terms for sex and coat color. Myopia was defined as ≤-0.5 diopters (D) spherical equivalent. RESULTS: The median refractive error for ESS was 0.25 D (range, -3.5 to +4.5 D). Median age was 0.2 years (range, 0.1-15 years). The prevalence of myopia in related ESS was 19% (42/226). The ESS had a strong correlation (r = 0.95) for refractive error between the two eyes. Moderate heritability was present for refractive error with a mean value of 0.29 (95% highest probability density, 0.07-0.50). CONCLUSIONS: The distribution of refractive error, and subsequently lenticular myopia, has a moderate genetic component in ESS. Further investigation of genes responsible for regulation of the development of refractive ocular components in canines is warranted.

Refractive state of the Spanish Thoroughbred horse: a comparison with the Crossbred horse.

OBJECTIVE: To assess the refractive state of the equine eye utilizing retinoscopy. To compare the refractive state of Spanish Thoroughbred horses with the refractive state of Crossbred horses. PROCEDURES: The refractive state of 135 horses (264 eyes) was assessed utilizing streak retinoscopy. Two perpendicular meridians were examined in order to assess astigmatism at a working distance of approximately 67 cm. A group of 81 Spanish Thoroughbred horses was compared with a group of 54 Crossbred horses. Cyclopentolate ophthalmic solution was instilled in the eyes of a group of 18 horses to determine if accommodation has any influence on the assessment of the refractive state. RESULTS: Mean ± SE refractive state of all horses examined was -0.17 ± 0.04 D. The mean refractive state of the Spanish Thoroughbred was -0.28 ± 0.06 D while that of the Crossbred was -0.01 ± 0.05 D. The refractive state of the Spanish Thoroughbred was found to be statistically different to that of the Crossbred. The most prevalent refractive state was emmetropia in all cases, followed by hyperopia for the Crossbred, and myopia for the Spanish Thoroughbred. Astigmatism ≥0.50 D present in both eyes from the same individual was found in 21.7% of all horses examined. Anisometropia ≥1.00 D was diagnosed in 4 out of 129 horses with both visual eyes. Cycloplegia did not statistically affect the refractive state of the evaluated eyes. CONCLUSIONS: The equine eye has a refractive state close to emmetropia. Myopia is higher among Spanish Thoroughbred horses than among Crossbred horses.

Congenital stationary night blindness is associated with the leopard complex in the Miniature Horse.

OBJECTIVE: To determine if congenital stationary night blindness (CSNB) exists in the Miniature Horse in association with leopard complex spotting patterns (LP), and to investigate if CSNB in the Miniature Horse is associated with three single nucleotide polymorphisms (SNPs) in the region of TRPM1 that are highly associated with CSNB and LP in Appaloosas. ANIMALS STUDIED: Three groups of Miniature Horses were studied based on coat patterns suggestive of LP/LP (n=3), LP/lp (n=4), and lp/lp genotype (n=4). PROCEDURES: Horses were categorized based on phenotype as well as pedigree analysis as LP/LP, LP/lp, and lp/lp. Neurophthalmic examination, slit-lamp biomicroscopy, indirect ophthalmoscopy, and scotopic flash electroretinography were performed on all horses. Hair samples were processed for DNA analysis. Three SNPs identified and associated with LP and CSNB in the Appaloosa were investigated for association with LP and CSNB in these Miniature Horses. RESULTS: All horses in the LP/LP group were affected by CSNB, while none in the LP/lp or lp/lp groups were affected. All three SNPs were completely associated with LP genotype (χ(2) = 22, P << 0.0005) and CSNB status (χ(2) =11, P<0.0005). CONCLUSIONS: The Miniature Horse breed is affected by CSNB and it appears to be associated with LP as in the Appaloosa breed. The SNPs tested could be used as a DNA test for CSNB until the causative mutation is determined.

A canine model of inherited myopia: familial aggregation of refractive error in labrador retrievers.

PURPOSE: To determine whether the distribution of naturally occurring myopia in Labrador Retrievers has a genetic component. METHODS: Pedigree records of a large canine family were analyzed. Pure Labrador Retrievers, 1 to 8 years of age, free of ocular disease, and available for testing were studied. Refractive error was measured by cycloplegic retinoscopy in both eyes. The family included mating loops, and so an expectation maximization (EM) algorithm (multivar program, MORGAN software; University of Washington, Seattle) was used to calculate log likelihoods of refractive error with environmental and additive genetic models. The fixed effects of coat color, sex, and litter size were also tested. RESULTS: In our sample of 116 dogs from this one family, the average spherical equivalent refraction (SER) was -0.41 D (range, -5.38 to +1.65 D, mean of both eyes, n = 116): 31% were myopic (SER or= +1.00 D). The significance of fixed and genetic effects was tested by comparing the full model (including genetic and all fixed effects) to models with one effect removed. Litter size and additive genetic effects were significant (P = 0.0013 and P = 0.000093, respectively), whereas sex and coat color were not. The overall variance in SER was accounted for approximately equally by additive genetic variance and residual/environmental variance. Narrow sense heritability of SER was 0.506. CONCLUSIONS: The distribution of refractive error within this family of Labrador Retrievers had a significant genetic component, but was also influenced by other factors (litter size, and undefined residual/environmental effects). The dog represents a unique model for the study of naturally occurring, heritable, high-prevalence, low-degree myopia.

Naturally occurring vitreous chamber-based myopia in the Labrador retriever.

PURPOSE: To investigate whether myopia is present in a breed of domestic dog, the Labrador retriever, and how the ocular components are related to refractive error in this breed. METHODS: Cycloplegic refractive error was measured in 75 Labrador retrievers by retinoscopy. Corneal and crystalline lens radii of curvature were measured in the right eyes of 57 of these dogs using a video-based keratophakometer, with axial ocular dimensions measured using A-scan ultrasonography. RESULTS: Of the 75 dogs tested, 11 (14.7%) were myopic by at least -0.50 D in one eye, and 6 (8.0%) were myopic in both eyes (full range of refractive errors, +3.50 D to -5.00 D). Of the 57 dogs with ocular component measurements, seven (12.3%) were myopic by at least -0.50 D in the right eye. There was a significant negative correlation between refractive error and vitreous chamber depth (Spearman r = -0.42; P < 0.001). Myopic eyes had an elongated vitreous chamber depth (10.87+/-0.34 mm for myopic dogs, 10.02+/-0.40 mm for nonmyopic dogs; P < 0.0001, Kruskal-Wallis test). There was also a significant quadratic association between lens thickness and vitreous chamber depth (P < 0.005; R2 = 0. 11), indicating that thinner lenses occurred at both shorter and longer vitreous chamber depths. CONCLUSIONS: Myopia in the Labrador retriever is analogous to human myopia in that it is caused by an elongated vitreous chamber. Thinner crystalline lenses found at longer vitreous chamber depths may be analogous to lens thinning documented in human ocular development. The Labrador retriever warrants investigation as a potential model of myopia that is naturally occurring rather than experimentally induced.

Rhegmatogenous retinal detachment in Labrador retrievers. I. Development of retinal tears and detachment.

We used clinical and pathologic methods to examine ten Labrador retrievers with ocular and skeletal abnormalities. The major ocular findings were axial myopia; cataract; vitreous abnormalities, including liquefaction, detachment, and vitreoretinal traction; retinal tears; rhegmatogenous retinal detachment; and proliferative vitreoretinopathy. The appendicular skeleton showed retarded bone growth, bone dysplasia, and degenerative arthropathy. Vitreoretinal traction appeared to be the cause of the retinal tears because (1) formed vitreous was always attached near the anterior edge of the tear, and (2) vitreous traction caused a retinal ridge adjacent to a retinal tear in a dog that had not yet developed retinal detachment. The pathogenetic sequence of spontaneous vitreous abnormalities, retinal tears, and retinal detachment observed in these dogs has not previously been described in animals, to the best of our knowledge, and mimicked human rhegmatogenous retinal detachment, particularly those associated with giant retinal tears.