Ocular abnormalities in Whippets practicing lure coursing in Poland.

Coursing is a canine sport discipline invented for sighthounds. The dogs chase the mechanically operated lure on an open area at the track that consists of straight lines as well as turns. Thus, the dogs must rely mainly on their sight in order to chase the lure and to compete. Whippets are the most popular sighthound breed in Poland and more and more dogs practice lure coursing on professional level. Several ocular disorders are known or presumed to be inherited in Whippets, so we decided to check how often they occur amongst competing dogs and if they have any impact on the results during competitions. Forty-five regularly competing Whippets underwent complete ophthalmic examination, including evaluation of menace response, pupillary light reflex and dazzle reflex, biomicroscopic examination conducted before and after dilating pupils with topical tropicamide and fundus examination with indirect ophthalmoscopy. Refractive state of each eye was assessed via streak retinoscopy. Ocular abnormalities were identified in 24 dogs (53.3%). The most common finding was vitreous degeneration identified in 9 dogs (20%), five dogs presented multiple lesions. There were no statistically significant differences regarding sex, age, and ranking points between the dogs with and without lesions. However, some of the identified lesions are likely to progress, so we postulate that the ophthalmological examination should receive more attention in sport Whippets, to check if it has any impact on competing dogs at more advanced age.

Familial primary calcific band-shaped keratopathy with late onset systemic disease: a case series and review of the literature.

BACKGROUND: Familial calcific band-shaped keratopathy (BSK) is a very rare disease, with no underlying cause. There is no underlying disease in this form of the disease. This article introduces a family with seven children, three of whom were diagnosed with familial primary calcific BSK. One of them developed a systemic disease 38 years after ocular manifestation. CASE PRESENTATION: In this case report, three Iranian siblings from a family with familial calcific band-shaped keratopathy (BSK) are introduced. Systemic and ocular examinations performed on these patients indicated the occurrence of chronic kidney disease in the older child, a 41-year-old woman, 38 years after ocular manifestation. The examinations conducted on the other two siblings revealed no pathological findings. The 41-year-old sister and 37-year-old brother underwent unilateral deep anterior lamellar keratoplasty (DALK), while the 33-year-old sister underwent bilateral superficial keratectomy (SK). CONCLUSION: Considering the late onset of systemic disease in one of the siblings diagnosed with familial calcific band-shaped keratopathy (BSK), it is crucial to emphasize the necessity of long-term follow-up for these patients and their families.

[Current aspects of vernal and atopic keratoconjunctivitis]. / Aktuelles zur Keratoconjunctivitis vernalis und atopica.

BACKGROUND: Vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC) are complex and rare diseases. Thus, their diagnosis and treatment are often a challenge. OBJECTIVE: Discussion on the epidemiology, new pathogenetic concepts, interesting clinical findings, diagnostic possibilities and new treatment options and their side effects in severe ocular allergies. Analysis of the presentation of VKC in the internet. MATERIAL AND METHODS: Evaluation of recent review articles, original publications, and case reports on the topics of VKC and AKC over the past 5 years. RESULTS: Ocular allergies have significantly increased over the last decades. Recent concepts discussed in the pathogenesis of VKC and AKC are the role of the local and gut microbiome as well as the influence of neuroinflammation. Keratoconus is significantly more common in patients with VKC and AKC compared to the normal population. It is associated with faster progression and a more severe course of disease. A conjunctival provocation test is only rarely necessary in the diagnosis of allergic conjunctivitis. Treatment of atopic dermatitis with dupilumab, an interleukin 4 receptor alpha (IL-4Ra) antagonist, can cause ocular side effects. Unfortunately, information available on the internet for patients and parents on the topic of VKC is sometimes dangerously incorrect. CONCLUSION: From the abovementioned new pathogenetic concepts, preventive and personalized treatment options could be developed in the future. Keratoconus in AKC/VKC must be recognized and treated early. Official guidelines are now available for a standardized conjunctival provocation test in the diagnosis of allergic conjunctivitis. The unwanted ocular side effects of dupilumab are often difficult to discriminate from the actual underlying AKC and respond well to anti-inflammatory treatment. Patients with VKC must be informed about the incorrect information on the internet regarding their disease.

Ocular inflammatory myofibroblastic tumor in a pediatric patient.

Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm that rarely metastasizes and is more commonly seen in children, adolescents, and young adults than older adults. These tumors, composed of myofibroblasts and inflammatory cells, are often confused for a local infection due to the inflammatory cell infiltration, and they form in mucosal surfaces but rarely arise in the orbit. We present the case of a 6-year-old girl with excisional biopsy-confirmed conjunctival stromal IMT. There was no evidence of recurrence 2 years following resection with no subsequent medical therapy.

[Research advances in myopic children with dry eye].

Myopia is a global public health issue, particularly prevalent in China, with a rising trend in recent years. The increased use of computers, smartphones, and video display terminals has led to frequent dry eye symptoms, such as blinking, among myopic students. Studies have revealed a higher incidence of dry eye in myopic children compared to emmetropic children, significantly impacting their learning and quality of life. However, ophthalmologists have traditionally focused more on the prevention and control of myopia, often neglecting ocular surface health awareness in children. It is essential to understand the potential impact of myopia on dry eyes in children and whether there is a difference in dry eye prevalence. This article reviews the current state of research on childhood myopia-related dry eye, encompassing epidemiology, pathogenesis, and risk factors, aiming to provide clinical reference for intervention, prevention, and precise treatment of dry eyes in myopic children.

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.

B-scan measurements of intraocular tumor heights intraoperatively, before and after radioactive plaque application: A comparative prospective study.

PURPOSE: To assess the difference in intraocular tumors height measurements intraoperatively before and after radioactive plaque application. METHODOLOGY: Twenty-four eyes of 24 patients with intraocular tumors, candidates for radioactive therapy, were included. Each tumor was measured at the same setting before and after plaque application independently by 3 sonographers, using a 20-MHz B-scan transducer. Mean pre-plaque and post-plaque measurements were calculated and recorded. An A-scan vector aided in identification of the inner and outer tumor surfaces. RESULTS: Each patient was examined independently three times by three experienced ultrasonographers within the same setting to assess interobserver variability. There was no statistically significant difference between the 3 examiners' readings, with P-value 0.99 for pre-plaque height and 0.97 for post-plaque height. Mean pre-plaque height was 5.16±2.11mm, while post-plaque height was 5.51±2.1mm (P-value 0.001). The Spearman correlation test showed that initial tumor height was negatively correlated with the difference between both heights, but with no statistical significance. CONCLUSION: Intraocular tumor height measurement differs significantly before and after plaque application. Use of the pre-plaque height is advised until further studies are performed to assess the effect of this difference on treatment outcomes.

Oxidative stress in the eye and its role in the pathophysiology of ocular diseases.

Oxidative stress occurs through an imbalance between the generation of reactive oxygen species (ROS) and the antioxidant defense mechanisms of cells. The eye is particularly exposed to oxidative stress because of its permanent exposure to light and due to several structures having high metabolic activities. The anterior part of the eye is highly exposed to ultraviolet (UV) radiation and possesses a complex antioxidant defense system to protect the retina from UV radiation. The posterior part of the eye exhibits high metabolic rates and oxygen consumption leading subsequently to a high production rate of ROS. Furthermore, inflammation, aging, genetic factors, and environmental pollution, are all elements promoting ROS generation and impairing antioxidant defense mechanisms and thereby representing risk factors leading to oxidative stress. An abnormal redox status was shown to be involved in the pathophysiology of various ocular diseases in the anterior and posterior segment of the eye. In this review, we aim to summarize the mechanisms of oxidative stress in ocular diseases to provide an updated understanding on the pathogenesis of common diseases affecting the ocular surface, the lens, the retina, and the optic nerve. Moreover, we discuss potential therapeutic approaches aimed at reducing oxidative stress in this context.

Agreement between Lea Symbols and Patti Pics visual acuity in children and adults

Background Patti Pics (PP) and Lea Symbols (LS) are commonly used by eye care practitioners worldwide. Although the relationship between the two tests is fairly well understood, the availability of different chart designs (single optotypes, multiple optotypes, multiple optotypes with crowding box) merits futher understanding. The purpose of this study is to explore the agreement between the acuity measures obtained with Patti Pics and Lea Symbols in children and adults and compare their performance with the Sloan Letter (SL) chart in adults. Methods Monocular visual acuity was obtained from ninety-three 3 to 5-year-old children using Patti Pics and Lea Symbols. Acuities were also obtained from 113 adults using the same tests under identical conditions. Acuity results obtained with the pediatric tests were compared with the gold-standard Sloan Letter chart in adults. The Bland-Altman method was implemented to compare the level of agreement between tests. Results Patti Pics yielded worse visual acuity than the Lea Symbols by approximately half a logMAR line in both children (mean difference: -0.07 ± 0.07 logMAR, p <0.01) and adults (Mean difference: -0.05 ± 0.06 logMAR, p <0.01). The 95% limits of agreement between Lea Symbol acuity and Patti pics acuity in children was ± 0.14 logMAR. Mean difference between the Sloan Letter chart and Lea Symbols acuity was not statistically significant (p = 0.08) in adults but the difference was statistically significant between PP and SL (p<0.001). The 95% limits of agreement between LS and SL and between PP and SL was ± 0.19 logMAR and ± 0.22 logMAR, respectively. Conclusion Patti Pics consistently underestimated visual acuity as compared to Lea Symbols both in children and adults although the differences were not clinically significant. The LS and PP did not yield clinically significant differences in acuities when compared with Sloan letters in adults. (AU)

Cre-loxP System-Based Mouse Model for Investigating Graves' Disease and Associated Orbitopathy.

Background: Graves' disease (GD), one of the most common forms of autoimmune thyroid disorders, is characterized by hyperthyroidism caused by antibodies (Abs) against the extracellular A-subunit of the thyrotropin receptor (TSHR). Various approaches have been used to create mouse models of GD, including transfected fibroblasts and immunization with plasmids or adenoviruses expressing human TSHR A-subunit (hTSHR A-subunit). These models, however, require repeated immunization and produce inconsistent results. In this study, we established a novel Cre-loxP system-based mouse model that is able to generate the hTSHR A-subunit, mimicking human GD, and characterized the histological changes in Graves' orbitopathy (GO) progression after a single injection. Materials and Methods: A Cre-loxP system-based mouse model was constructed by inserting the CAG-loxP-STOP-loxP-hTSHR A-subunit cassette into the Rosa26 locus of the mouse genome. Conditional expression of the hTSHR A-subunit was successfully achieved by intramuscular injection of the transactivator of transcription-Cre recombinase (GD mice). Blood tests for anti-TSHR Abs and the total thyroxine (T4) level were performed. Magnetic resonance imaging (MRI) was used to monitor morphological changes in the eyes. A histological examination of the thyroid gland and retrobulbar tissues was performed to observe pathological changes. Results: Twenty-four (8 control and 16 GD) mice were investigated. All GD mice exhibited higher levels of TSHR Abs compared with the control group. Moreover, more than 80% of the mouse models showed elevated T4 levels accompanied by thyroid goiter. MRI analysis revealed an increased volume of retrobulbar tissue, while immunohistochemical staining of orbital tissues exhibited macrophage infiltration and muscle fibrosis in the GD mice, contrasting with the control group. Conclusions: Our novel mouse model for GD, which showed the histological features of GO, was successfully established using the Cre-loxP system. This animal model offers improved insights and contributes to advancing methodological developments for GD and GO.

Distribution of Axial Length in Australians of Different Age Groups, Ethnicities, and Refractive Errors.

Purpose: Treatments are available to slow myopic axial elongation. Understanding normal axial length (AL) distributions will assist clinicians in choosing appropriate treatment for myopia. We report the distribution of AL in Australians of different age groups and refractive errors. Methods: Retrospectively collected spherical equivalent refraction (SER) and AL data of 5938 individuals aged 5 to 89 years from 8 Australian studies were included. Based on the SER, participants were classified as emmetropes, myopes, and hyperopes. Two regression model parameterizations (piece-wise and restricted cubic splines [RCS]) were applied to the cross-sectional data to analyze the association between age and AL. These results were compared with longitudinal data from the Raine Study where the AL was measured at age 20 (baseline) and 28 years. Results: A piece-wise regression model (with 1 knot) showed that myopes had a greater increase in AL before 18 years by 0.119 mm/year (P < 0.001) and after 18 years by 0.011 mm/year (P < 0.001) compared to emmetropes and hyperopes, with the RCS model (with 3 knots) showing similar results. The longitudinal data from the Raine Study revealed that, when compared to emmetropes, only myopes showed a significant change in the AL in young adulthood (by 0.016 mm/year, P < 0.001). Conclusions: The AL of myopic eyes increases more rapidly in childhood and slightly in early adulthood. Further studies of longitudinal changes in AL, particularly in childhood, are required to guide myopia interventions. Translational Relevance: The axial length of myopic eyes increases rapidly in childhood, and there is a minimal increase in the axial length in non-myopic eyes after 18 years of age.

Ocular manifestations of mitochondrial neurogastrointestinal encephalomyopathy: A case report and literature review.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive multisystem disorder that often presents with gastrointestinal and neurological symptoms. Here we report a 33-year-old male who presented with a 16-year history of diarrhea with black stool and progressive weight loss. He complained of progressive bilateral blurred vision, upper eyelids heaviness, ocular motility impairment, and color blindness. Peripheral neuropathy, bilateral sensorineural deafness, hyperlactatemia, diabetes mellitus, hepatic steatosis, blood coagulation dysfunction, and diffuse leukoencephalopathy were detected in the systemic evaluation. Based on the novel homozygous pathogenic variant in the TYMP gene (c.1159+1G>A), he was diagnosed with MNGIE. On ophthalmic examinations, the thickness of the inner retina and ganglion cell complex significantly decreased. ERG showed diffusely decreased amplitudes. The electronegative electroretinogram, which was first reported in MNGIE, indicated a more severe inner retina impairment. The bilateral papillomacular bundle defect and central vision loss in MNGIE are consistent with classical mitochondrial optic neuropathies' features. According to the literature, pigmentary retinopathy, optic neuropathy, and abnormal pupillary reflexes are uncommon ocular features of MNGIE. This study contributes to a better understanding of ocular manifestations in MNGIE and demonstrates that MNGIE may have dyschromatopsia and an electronegative electroretinogram.

Assessment of Ocular Deformation in Pathologic Myopia Using 3-Dimensional Magnetic Resonance Imaging.

IMPORTANCE: Ocular deformation in pathologic myopia can affect the entire globe. However, few studies have investigated the equatorial pattern of ocular shape. In addition, the correlation between equatorial and posterior morphology needs to be further explored. OBJECTIVE: To assess global ocular deformation in pathologic myopia. DESIGN, SETTING, AND PARTICIPANTS: This hospital-based, cross-sectional study included 180 pathologic myopic eyes with atrophic maculopathy grading C2 (diffuse chorioretinal atrophy) or more from 180 participants who underwent comprehensive ophthalmic examination, including high-resolution 3-dimensional magnetic resonance imaging. In addition, 10 nonpathologic myopic eyes of 10 participants were set as the control group. Main Outcomes and Measures: According to the cross-sectional view of equator, equatorial shape was classified as round, rectangular, pyriform (noncircular and more protruded in 1 direction), vertical-elliptical, or horizontal-elliptical; according to the nasal and inferior views, the posterior shape was categorized as spheroidal, conical, bulb-shaped, ellipsoidal, multidistorted, and barrel-shaped. Equatorial circularity and ocular sphericity were used to quantitatively assess the morphological variability of the equatorial and posterior regions, respectively. The association between ocular morphology and ocular parameters and myopic maculopathy was also investigated. Results: The mean (SD) age of 180 participants with pathologic myopia was 55.14 (10.74) years, 127 were female (70.6%), and the mean (SD) axial length of studied eyes was 30.22 (2.25) mm. The predominant equatorial shape was pyriform (66 eyes [36.7%]), followed by round (45 eyes [25.0%]). The predominant posterior shape was bulb-shaped (97 eyes [52.2%]), followed by multidistorted (46 eyes [24.7%]). Equatorial circularity and equatorial shapes were correlated (r = -0.469; 95% CI, -0.584 to -0.346; P < .001) and ocular sphericity was correlated with posterior shapes (r = -0.533; 95% CI, -0.627 to -0.427; P < .001). In eyes with a vertical-elliptical equator, equatorial circularity and ocular sphericity were positively linearly correlated (R2 = 0.246; 95% CI, 0.050-0.496; P = .002) and the prevalence of inferior staphyloma was higher (27.8%; P = .04). Eyes with a horizontal-elliptical equator have the most horizontally oriented axis of corneal flat keratometry (median, 43.55 [interquartile range, 43.84] degrees; P = .01) and tended to present with multidistorted posterior shape (21.7%; P = .04). Conclusions and Relevance: These findings suggest ocular deformation is common in pathologic myopia and can affect the entire eye, including the equatorial and posterior regions. The morphological classification may enhance the understanding of the diverse patterns of ocular shape in pathologic myopia.

Disease parameters following ocular herpes simplex virus type 1 infection are similar in male and female BALB/C mice.

Sex related differences in the incidence or severity of infection have been described for multiple viruses. With herpes simplex viruses, the best example is HSV-2 genital infection where women have a higher incidence of infection and can have more severe infections than men. HSV-1 causes several types of infections including skin and mucosal ulcers, keratitis, and encephalitis in humans that do not appear to have a strong biological sex component. Given that mouse strains differ in their MHC loci it is important to determine if sex differences occur in multiple strains of mice. Our goal was to answer two questions: Are virus related sex differences present in BALB/C mice and does virulence of the viral strain have an effect? We generated a panel of recombinant HSV-1 viruses with differing virulence phenotypes and characterized multiple clinical correlates of ocular infection in BALB/c mice. We found no sex-specific differences in blepharitis, corneal clouding, neurovirulence, and viral titers in eye washes. Sex differences in neovascularization, weight loss and eyewash titers were observed for some recombinants, but these were not consistent across the phenotypes tested for any recombinant virus. Considering these findings, we conclude that there are no significant sex specific ocular pathologies in the parameters measured, regardless of the virulence phenotype following ocular infection in BALB/c mice, suggesting that the use of both sexes is not necessary for the bulk of ocular infection studies.

Mechanistic insight into the adverse outcome of tire wear and road particle leachate exposure in zebrafish (Danio rerio) larvae.

Tire wear particles (TWP) have become the major microplastic pollution in China. Road runoff containing TWP leachate can decrease the eye size and even induced mortality in the aquatic organisms. However, the toxic mechanism of TWP and road particles (RP) leachate on aquatic organisms is still unclear. In this study, the zebrafish embryos were exposed to TWP or RP leachate for 5 days at both environmental relevant and high concentrations. The adverse outcome pathways (AOPs) were screened from individual to molecular levels. The morphological and behavioral analysis demonstrated that the leachate exposure mainly impaired the eye development of zebrafish larvae and inhibited the larval swim behavior and phototactic response, which are the adverse outcomes. The phototransduction modulated by zebrafish retina was significantly down-regulated through transcriptomics and metabolomics analysis. The eye histopathological analysis showed that the decreased thickness of the retinal outer nuclear layer (ONL) and retinal pigmented epithelium (RPE) after leachate exposure were caused by the decreased photoreceptor cells. Moreover, the expression of NR2E3 and TPO genes showed concentration-dependent down-regulation after leachate exposure. The inhibition of photoreceptor cell proliferation was identified as the main reason for photoreceptor cell decrease in zebrafish larval eye. This study, for the first time, uncovered the underlying toxic mechanism of TWP and RP on zebrafish larval eyes.

Experimental evidence to understand mechanical causes of retinal detachment following blunt trauma.

PURPOSE: This study aimed to perform an in vitro experiment to simulate retinal detachment caused by blunt impact, and provide experimental evidence to understand mechanical causes of traumatic retinal detachment. METHODS: The experiment was conducted on twenty-two fresh porcine eyes using a bespoke pendulum testing device at two energy levels (0.1J for low energy and 1.0J for high energy). We examined dynamic forces and mechanical responses to the impact, including global deformations, intraocular pressure changes and the energy absorption. Another set of twenty-two eyes underwent pathological examination immediately after being subjected to blunt impact. Twelve additional intact eyes were examined as controls. All pathological sections were scored to indicate whether retinal detachment had occurred. RESULTS: A dynamic variation in intraocular pressure was detected following impact and exhibited an approximate sinusoidal oscillation-attenuation profile. The peaks of impact force were 12.9 ± 1.9 N at low-energy level and 34.8 ± 9.8 N at high-energy level, showing a significant difference (p < 0.001). The positive and negative peaks of intraocular pressure were 149.4 ± 18.9 kPa and -10.9 ± 7.2 kPa at low-energy level, and 274.5 ± 55.2 kPa and -35.7 ± 23.7 kPa at high-energy level, showing significant differences (p < 0.001 for both levels). Retinal detachments were observed in damaged eyes while few detachments were found in control eyes. The occurrence rate of retinal detachment differed significantly (p < 0.05) between the high- and low-energy impact groups. CONCLUSIONS: This study provided experimental evidence that shockwaves produced by blunt trauma break the force equilibrium and lead to the oscillation and negative pressure, which mainly contribute to traumatic retinal detachment.

Establishment and Comparison of Two Different Animal Models of Graves' Orbitopathy.

Purpose: The purpose of this study was to construct an animal model of Graves' ophthalmopathy (GO) by comparing recombinant adenovirus expressing human thyrotropin receptor A subunit (Ad-TSHR A) gene immunization and dendritic cell (DC) immunization. We evaluated the animal models that are closer to the pathology of human GO, and laid the foundation for the study of GO. Materials and Methods: Ad-TSHR A was injected intramuscularly into female BALB/c mice to induce the GO animal model. A GO animal model was constructed using TSHR combined with IFN-γ-modified primary DC immunized female BALB/c. The animal models constructed by the above two methods were evaluated in terms of ocular appearance, serology, pathology, and imaging to assess the modeling rate of the animal models, respectively. Results: Both modeled mice exhibited increased serological indexes of free thyroxine (FT4) and TSH receptor antibodies (TRAbs) levels and decreased TSH (P < 0.01). Thyroid pathology analysis revealed the number of thyroid follicles increases, the size varies, and the follicular epithelial cells proliferate to varying degrees in a cuboidal or tall columnar pattern, with a small amount of lymphocytic infiltration visible. Adipose tissue behind the eyeball was accumulated, the muscle outside the eyeball was broken and fibrotic, and hyaluronic acid (HA) behind the eyeball was increased. The animal model of GO constructed by immunization of TSHR with IFN-γ-modified DC had a modeling rate of 60%, whereas that of Ad-TSHR A gene immunization was 72%. Conclusions: Both gene immunization and cellular immunization can be used to construct GO models, and the modeling rate of gene immunization is higher than that of cellular immunization. Translational Relevance: In this study, two innovative methods, cellular immunity and gene immunity, were used to establish GO animal models, which improved the success rate to a certain extent. To our knowledge, this study presents the first cellular immunity modeling idea of TSHR combined with IFN-γ for the GO animal model, which provides an animal model basis for understanding the pathogenesis of GO and developing new treatment methods.