Cell types are the basic building blocks of multicellular organisms and are extensively diversified in animals. Despite recent advances in characterizing cell types, classification schemes remain ambiguous. We propose an evolutionary definition of a cell type that allows cell types to be delineated and compared within and between species. Key to cell type identity are evolutionary changes in the 'core regulatory complex' (CoRC) of transcription factors, that make emergent sister cell types distinct, enable their independent evolution and regulate cell type-specific traits termed apomeres. We discuss the distinction between developmental and evolutionary lineages, and present a roadmap for future research.
PURPOSE: To report strabismus surgery frequency and outcomes after monocular infantile cataract surgery with or without IOL implantation. METHODS: The Infant Aphakia Treatment Study (IATS) is a randomized, multicenter clinical trial comparing treatment of aphakia with a primary IOL or contact lens in 114 infants with a unilateral congenital cataract. This report is a secondary outcome analysis of ocular motor data from IATS patients who underwent strabismus surgery prior to age 5 years. RESULTS: Strabismus surgery was performed in 45 (39%) patients (contact lens group [CL], 37%; IOL group, 42% [P = 0.70]). The indications for strabismus surgery were esotropia (62%), exotropia (33%), and hypertropia (4%). Infants who underwent cataract surgery at a younger age were less likely to undergo strabismus surgery (28-48 days, 12/50 [24%]; 49-210 days, 33/64 [52%]; P = 0.0037). Of the 42 patients who underwent strabismus surgery, 14 (33%) had a postoperative distance alignment within 8(Δ) of orthotropia at age 5 years. The 5-year visual acuity of children with strabismus was the same whether or not strabismus surgery had been performed (1.10 logMAR with surgery vs 1.00 without [P = 0.71]). CONCLUSIONS: In this study cohort, cataract surgery performed in the first 6 weeks of life was associated with a reduced frequency of strabismus surgery. Strabismus surgery outcomes in this population are guarded. Surgical improvement of strabismus does not appear to influence long-term visual acuity.
OBJECTIVE: Nonarteritic anterior ischemic optic neuropathy (NAION) is a devastating ocular condition causing permanent vision loss. Little is known about risk factors for developing this disease. We assessed demographic, systemic, and ocular factors associated with NAION. DESIGN: Retrospective longitudinal cohort study. PARTICIPANTS: Beneficiaries between 40 and 75 years old without NAION at baseline enrolled in a large U.S. managed care network. METHODS: Enrollees were monitored continuously for ≥2 years between 2001 and 2014 to identify those newly diagnosed with NAION (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] code 377.41). All persons were under ophthalmic surveillance and all cases had ≥1 confirmatory ICD-9-CM code for NAION during follow-up. MAIN OUTCOME MEASURES: Multivariable Cox regression modeling was used to generate hazard ratios (HRs) with 95% confidence intervals (CIs) to describe the statistical relationship between selected demographic characteristics, systemic and ocular conditions, and the hazard of developing NAION. RESULTS: Of 1 381 477 eligible enrollees, 977 (0.1%) developed NAION during a mean ± standard deviation (SD) follow-up of 7.8±3.1 years. The mean ± SD age for NAION cases at the index date was 64.0±9.2 years vs. 58.4±9.4 years for the remainder of the beneficiaries. After adjustment for confounding factors, each additional year older was associated with a 2% increased hazard of NAION (HR = 1.02; 95% CI: 1.01-1.03). Female subjects had a 36% decreased hazard of developing NAION (HR = 0.64; 95% CI: 0.55-0.74) compared with male subjects. Compared with whites, Latinos had a 46% decreased hazard of developing NAION (HR = 0.54; 95% CI: 0.36-0.82), whereas African ancestry was not significantly associated with NAION (HR = 0.91; 95% CI: 0.72-1.15). Systemic diseases associated with NAION included hypertension (HR = 1.62; 95% CI: 1.26-2.07) and hypercoagulable states (HR = 2.46; 95% CI: 1.51-4.00). Although diabetes mellitus (DM) was not significantly associated with NAION compared with those without DM (P = 0.45), patients with end-organ involvement from DM had a 27% increased hazard of NAION relative to those with uncomplicated DM (HR = 1.27; 95% CI: 1.01-1.59). Ocular diseases associated with NAION were age-related macular degeneration (HR = 1.29; 95% CI: 1.08-1.54) and retinal vein occlusion (HR = 3.94; 95% CI: 3.11-4.99). CONCLUSIONS: Our study identified several modifiable risk factors that may be associated with NAION. Should future studies confirm these findings, they may offer opportunities to prevent or treat this debilitating condition.
The authors describe a 4-year-old girl presenting with a 2-year history of a superomedial eyelid "bump" that appeared cystic on MRI. The clinical diagnosis was dermoid cyst, possibly of conjunctival origin. Following excision, histology showed a cyst that contained keratin and lanugo hairs in its lumen with sebaceous glands and chronic inflammation in its fibrous wall. An unanticipated finding was the presence of a trichilemmal (pilar) variety of epithelial lining that stained positively for calretinin, an immunostain that identifies trichilemmal epithelium. To the authors' knowledge this is the first case of a dermoid cyst with trichilemmal lining. This study was conducted in compliance with the rules and regulations of the Health Insurance Portability and Accountability Act and in conformity with the Oslo declaration.
The cornea is the most commonly transplanted tissue in medicine. The main cause of corneal graft failure is allograft rejection. The incidence of graft rejection depends on the presence of high-risk characteristics, most notably corneal neovascularization. Although corneal grafting has a high success rates in the absence of these risk factors, high-risk keratoplasty is associated with low success rates because of a high incidence of immune-mediated graft rejection. To improve the survival of high-risk corneal transplantation, various preoperative, intraoperative, and postoperative measures can be considered.; however, the key step in the management of these grafts is the long-term use of local and/or systemic immunosuppressive agents. Although a number of immunosuppressive agents have been employed for this purpose, the results vary significantly across different studies. This is partly due to the lack of an optimized method for their use, as well as the lack of a precise stratification of the degree of risk in each individual patient. New targeted biologic treatments, as well as tolerance-inducing methods, show promising horizons in the management of high-risk corneal transplantation in near future.
Purpose: The purpose of this study was to evaluate the resistance to degradation by collagenase A of corneas that have been crosslinked with Rose Bengal and green light (RGX). Methods: The ex vivo crosslinking procedure was performed on enucleated rabbit corneas. Corneas were deepithelialized after applying 30% alcohol. Corneas were stained with Rose Bengal (RB, 0.1%) for 2 minutes and then exposed to green light (532 nm) at 0.25 W/cm2 for times to deliver doses of 50, 100, 150, or 200 J/cm2 (n = 5 per group). Five corneas were pretreated with riboflavin solution (0.1% riboflavin) for 15 minutes and irradiated with ultraviolet A (UVA) light (370 nm, 3 mW/cm2) for 30 minutes. Five corneas underwent only de-epithelialization and were otherwise untreated. Five corneas were stained with RB without light exposure. The central corneas of each group was removed with a 8.5-mm trephine and incubated at 37°C in 0.3% collagenase A solution. Time to dissolution of each cornea was compared across treatments. Results: Corneas treated with RGX were treated with light fluences of 50, 100, 150, and 200 J/cm2; these corneas dissolved completely at 8.3 ± 1.2, 11.1 ± 1.4, 12.4 ± 1.7, and 15.7 ± 1.8 hours, respectively. Corneas treated by riboflavin and UVA light dissolved at 15.7 ± 1.7 hours, and nontreated corneas dissolved at 6.1 ± 1.3 hours. Corneas treated with only RB (no green light) dissolved at 9.3 ± 1.7 hours. Compared with the untreated corneas, all of the RB groups and the riboflavin-UVA-treated group of corneas degraded statistically significantly slower than untreated corneas (P < 0.05). Conclusions: Crosslinking with RGX increased corneal resistance to digestion by collagenase comparable to that produced by riboflavin and UVA treatment.
BACKGROUND: Retinopathy of prematurity is one of the leading causes of childhood blindness worldwide, with vessel growth cessation and vessel loss in phase I followed by neovascularization in phase II. Ischemia contributes to its pathogenesis and lutein protects against ischemia-induced retinal damages. We aimed to investigate the effects of lutein on a murine model of oxygen-induced retinopathy. METHODS: Mouse pups were exposed to 75% oxygen for five days and returned to room air for another five days. Vascular obliteration, neovascularization and blood vessel leakage were examined. Immunohistochemistry for glial cells and microglia were performed. RESULTS: Compared with vehicle controls, mouse pups receiving lutein treatment displayed smaller central vaso-obliterated area and reduced blood vessel leakage. No significant difference in neovascular area was found between lutein and vehicle controls. Lutein promoted endothelial tip cell formation and maintained the astrocytic template in the avascular area in oxygen-induced retinopathy. No significant changes in Müller cell gliosis and microglial activation in the central avascular area were found in lutein-treated pups. CONCLUSIONS: Our observations indicated that lutein significantly promoted normal retinal vascular regrowth in the central avascular area, possibly through promoting endothelial tip cell formation and preserving astrocytic template. Our results indicated that lutein might be considered as a supplement for the treatment of proliferative retinopathy of prematurity due to its role in facilitating the revascularization of normal vasculature.
BACKGROUND: Pyogenic lacrimal gland abscesses are uncommon and thus may not be immediately clinically recognized without a high index of suspicion. FINDINGS: We present two patients with preseptal cellulitis and characteristic low-attenuation fluid collections in the lacrimal glands demonstrated on computed tomography (CT). CONCLUSIONS: Lacrimal gland abscesses should be considered when dacryoadenitis is refractory to medical treatment. Indeed, these cases highlight the value of prompt recognition of lacrimal abscess through ophthalmologic referral and the use of diagnostic imaging. Both patients were successfully treated via incision and drainage.
BACKGROUND: Allergic rhinitis is a common condition, with ragweed pollen one of the more prevalent aeroallergens. Environmental exposure units such as the Allergen BioCube(®) are valuable models for clinical allergy studies. A study was conducted to validate the Allergen BioCube for uniform ragweed pollen concentrations and clinically relevant sign and symptom responses to ragweed exposure. METHODS: Ragweed pollen concentrations were measured on 3 consecutive days in the Allergen BioCube and verified by Rotorod collection and continuous laser particle count measurements. Subjects (N=10) were exposed to ragweed pollen in the BioCube for 3 hours per day for 3 consecutive days. Subjects assessed their nasal itching, sneezing, rhinorrhea, and nasal congestion during each BioCube exposure; total nasal symptom score was computed. Peak nasal inspiratory flow was also assessed during BioCube exposure. RESULTS: Uniform ragweed pollen concentrations were obtained throughout each of the 3-hour testing periods in the Allergen BioCube, both spatially and temporally, at all subject positions, with a low mean standard deviation of 10%. Pronounced increases in mean total nasal symptom scores (6.7±0.94 to 7.6±0.86, last 90 minutes of exposure) occurred for all three BioCube ragweed pollen exposure visits. Mean peak nasal inspiratory flow decreased 24% at 3 hours of BioCube exposure on Day 3. No safety issues of concern occurred in this study. CONCLUSION: The Allergen BioCube achieved technical and clinical validation for ragweed allergen. Ragweed pollen concentration was uniform both temporally and spatially. Allergic rhinitis signs and symptoms were induced in subjects during exposure to ragweed in the BioCube at clinically meaningful levels for allergy studies.
Importance: Vitamin D plays an important role in both the innate and adaptive immune systems. It has been shown to contribute to the etiology of T-cell-mediated autoimmune diseases through the upregulation of type 2 anti-inflammatory T helper cells and the suppression of type 1 T helper cells. Noninfectious uveitis is postulated to be caused by immune dysfunction. Objective: To determine whether there is an association between vitamin D levels and noninfectious anterior uveitis. Design, Setting, and Participants: This was a case-control study. We identified patients with and without noninfectious uveitis using the Massachusetts Eye and Ear Infirmary Ocular Inflammation Database and electronic medical records from March 1, 2008, to December 12, 2015, at the Massachusetts Eye and Ear Infirmary Uveitis and Comprehensive Ophthalmology Clinics. One hundred patients with noninfectious anterior uveitis and 100 patients without uveitis were recruited. Patients with noninfectious uveitis were diagnosed by fellowship-trained uveitis specialists after exclusion of infectious causes and neoplastic masquerades of uveitis. All patients included had a total 25-hydroxyvitamin D level recorded. Multivariate regression models were constructed to determine the association between vitamin D levels and the presence of uveitis. Main Outcome and Measure: Presence of noninfectious anterior uveitis. Results: We identified 100 patients (64 white, 8 African American, 25 Asian, and 3 Hispanic) with a mean (SD) age of 51.8 (15.9) years (26 men) and 100 control individuals (58 white, 23 African American, 8 Asian, and 11 Hispanic) with a mean (SD) age of 53.6 (16.2) years (27 men). Hypovitaminosis D was associated with noninfectious uveitis in the univariate analysis (odds ratio, 2.53; 95% CI, 1.42-4.51; P = .002). The association in multivariate regression after adjusting for age, sex, and race/ethnicity was 2.96 (95% CI, 1.60-5.50; P = .001) The odds of developing uveitis were 4% lower for every 1-ng/mL increase in vitamin D level (odds ratio, 0.96; 95% CI, 0.93-0.99; P = .01) in the main multivariate analysis. Conclusions and Relevance: In this retrospective study, lower vitamin D levels were associated with an increased risk of noninfectious anterior uveitis. However, this does not confirm a causal effect.
PURPOSE: The qualities that applicants value in the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) fellowship programs have been studied, but the availability of this information on program websites has not yet been reviewed. The authors evaluated the availability of resident-valued ASOPRS fellowship program information on the Internet. METHODS: The authors performed an Internet search of the 53 ASOPRS fellowship program websites and evaluated websites for 20 characteristics of interest to ASOPRS fellowship applicants such as teaching faculty, program description, rotation schedule, operative cases, and interview information. RESULTS: Of the 53 ASOPRS fellowship programs, 43 (81.1%) had a fellowship program-dedicated website. The fellowship websites contained a mean 7.6 characteristics (38.1%, range 0-15). Faculty listing, program description, and case diversity were the most commonly included data (74.4%, 72.1%, and 69.8%, respectively). Fellow selection process, interview information, and graduate job placement were least commonly included (7.0%, 2.3%, and 0.0%, respectively). There was no significant difference in website inclusiveness based on fellowship region or faculty number. Programs affiliated with an ophthalmology residency were more complete than those that were not (40.3% vs. 20.0%, p = 0.0098). CONCLUSIONS: This review found that most programs had websites and contained a reasonable number of characteristics. However, applicant-valued information regarding surgical volume, procedure variety, application information, and postgraduate employment history were often missing. American Society of Ophthalmic Plastic and Reconstructive Surgery fellowship programs may improve match outcomes by providing and enhancing program websites with details that their applicants seek.
Diabetic retinopathy is a leading cause of new-onset vision loss worldwide. Treatments supported by large clinical trials are effective in preserving vision, but many persons do not receive timely diagnosis and treatment of diabetic retinopathy, which is typically asymptomatic when most treatable. Telemedicine evaluation to identify diabetic retinopathy has the potential to improve access to care and improve outcomes, but incomplete implementation of published standards creates a risk to program utility and sustainability. In a prior article, we reviewed the literature regarding the impact of imaging device, number and size of retinal images, pupil dilation, type of image grader, and diagnostic accuracy on telemedicine assessment for diabetic retinopathy. This article reviews the literature regarding the impact of automated image grading, cost effectiveness, program standards, and quality assurance (QA) on telemedicine assessment of diabetic retinopathy. Telemedicine assessment of diabetic retinopathy has the potential to preserve vision, but greater attention to development and implementation of standards is needed to better realize its potential.
Diabetic retinopathy is a leading cause of new-onset vision loss worldwide. Treatments supported by large clinical trials are effective in preserving vision, but many persons do not receive timely diagnosis and treatment of diabetic retinopathy, which is typically asymptomatic when most treatable. Telemedicine evaluation to identify diabetic retinopathy has the potential to improve access to care, but there are no universal standards regarding camera choice or protocol for ocular telemedicine. We review the literature regarding the impact of imaging device, number and size of retinal images, pupil dilation, type of image grader, and diagnostic accuracy on telemedicine assessment for diabetic retinopathy. Telemedicine assessment of diabetic retinopathy has the potential to preserve vision, but further development of telemedicine specific technology and standardization of operations are needed to better realize its potential.
Regulatory T cells (Tregs) are crucial for allograft survival. Tregs can be divided into thymus-derived natural Tregs (tTregs) and peripherally-derived induced Tregs (pTregs). Here, we determine whether the suppressive function of Treg subsets is hampered in hosts who are at high risk for rejecting their graft. To induce graft beds that promote high risk of transplant rejection, intrastromal corneal sutures were placed two weeks prior to the transplant procedure in mice. We demonstrate that in high-risk recipients the frequencies and function of pTregs (but not tTregs) are suppressed. Reduced function of pTregs correlated with decreased expression of CTLA-4, interleukin-10, and transforming growth factor-β. Adoptive transfer of pTregs from mice at low risk of subsequent graft rejection is able to rescue graft survival in recipients that are at high risk of rejecting their grafts. Our data suggest that impaired function of pTregs, but not tTregs, mediates the loss of immune tolerance and promotes allograft rejection.
Dermatofibromas are most frequently encountered in women on the lower extremities, often after minor trauma. A 64-year-old woman developed a recurrent lesion of the right lower eyelid. It harbored "monster cells" that were large, with either multiple nuclei or a single, large, convoluted and hyperchromatic nucleus. The presence of these cells does not signify a malignant transformation. The background cells were either histiocytoid (many were adipophilin-positive), spindled cells, or dendritiform cells without mitoses. Factor XIIIa, CD68 and CD163 immunostaining was positive and a subpopulation of CD1a(+) Langerhans cells were intermixed. Facial and eyelid dermatofibromas are more likely to recur and deserve wider, tumor-free surgical margins. Their microscopic differential diagnosis includes a cellular scar, peripheral nerve tumor, atypical fibrous xanthoma and dermatofibrosarcoma protuberans.
Glaucoma is a multifactorial disease resulting in the death of retinal ganglion cells (RGCs) and irreversible blindness. Glaucoma-associated RGC death depends on the proapoptotic and proinflammatory activity of membrane-bound Fas ligand (mFasL). In contrast to mFasL, the natural cleavage product, soluble Fas ligand (sFasL) inhibits mFasL-mediated apoptosis and inflammation and, therefore, is an mFasL antagonist. DBA/2J mice spontaneously develop glaucoma and, predictably, RGC destruction is exacerbated by expression of a mutated membrane-only FasL gene that lacks the extracellular cleavage site. Remarkably, one-time intraocular adeno-associated virus-mediated gene delivery of sFasL provides complete and sustained neuroprotection in the chronic DBA/2J and acute microbead-induced models of glaucoma, even in the presence of elevated intraocular pressure. This protection correlated with inhibition of glial activation, reduced production of TNF-α, and decreased apoptosis of RGCs and loss of axons. These data indicate that cleavage of FasL under homeostatic conditions, and the ensuing release of sFasL, normally limits the neurodestructive activity of FasL. The data further support the notion that sFasL, and not mFasL, contributes to the immune-privileged status of the eye.
Purpose: To determine whether cone density, spacing, or regularity in eyes with and without diabetes (DM) as assessed by high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) correlates with presence of diabetes, diabetic retinopathy (DR) severity, or presence of diabetic macular edema (DME). Methods: Participants with type 1 or 2 DM and healthy controls underwent AOSLO imaging of four macular regions. Cone assessment was performed by independent graders for cone density, packing factor (PF), nearest neighbor distance (NND), and Voronoi tile area (VTA). Regularity indices (mean/SD) of NND (RI-NND) and VTA (RI-VTA) were calculated. Results: Fifty-three eyes (53 subjects) were assessed. Mean ± SD age was 44 ± 12 years; 81% had DM (duration: 22 ± 13 years; glycated hemoglobin [HbA1c]: 8.0 ± 1.7%; DM type 1: 72%). No significant relationship was found between DM, HbA1c, or DR severity and cone density or spacing parameters. However, decreased regularity of cone arrangement in the macular quadrants was correlated with presence of DM (RI-NND: P = 0.04; RI-VTA: P = 0.04), increasing DR severity (RI-NND: P = 0.04), and presence of DME (RI-VTA: P = 0.04). Eyes with DME were associated with decreased density (P = 0.04), PF (P = 0.03), and RI-VTA (0.04). Conclusions: Although absolute cone density and spacing don't appear to change substantially in DM, decreased regularity of the cone arrangement is consistently associated with the presence of DM, increasing DR severity, and DME. Future AOSLO evaluation of cone regularity is warranted to determine whether these changes are correlated with, or predict, anatomic or functional deficits in patients with DM.
PURPOSE: To study resident compliance with the American Academy of Ophthalmology (AAO) Preferred Practice Patterns (PPPs) for primary open-angle glaucoma suspect (POAGS) in a resident ophthalmology clinic. PATIENTS AND METHODS: Two hundred charts were selected for analysis of adult patients with the International Classification of Diseases diagnosis code for POAGS during their initial visit between November 2, 2010 and May 6, 2014 at the Kresge Eye Institute resident clinic. Electronic medical records of clinic visits for POAGS patients were evaluated for documentation and compliance with 17 elements of AAO PPPs. RESULTS: The overall mean compliance was 73.8% for all charts (n=200), 74.4% for first-year residents (n=53), 74.5% for second-year residents (n=38), and 73.3% for third-year residents (n=109). Documentation rates were high (>90%) for 9 elements, which included most elements of physical examination and history. Documentation of ocular history, central corneal thickness, gonioscopy, optic nerve head and retinal nerve fiber layer analysis, and visual field ranged from 40% to 80%. Documentation was lowest for patient education elements which ranged from 0% to 10%. Compliance was not significantly different (P>0.05) between residents or between different resident years for any element. CONCLUSIONS: Residents' compliance was high for most elements of the PPPs for POAGS. We identified elements with poor compliance especially regarding patient education. Adherence to AAO PPPs can be a helpful method of assessing resident performance.
PURPOSE: Large relaxing retinectomies have become increasingly used in the repair of retinal detachment related to proliferative vitreoretinopathy (PVR). Retinectomies expose the retinal pigment epithelium (RPE) to the vitreous cavity; the direct effects of silicone oil on the RPE are only beginning to be understood. DESIGN: Retrospective case series. PARTICIPANTS: Twelve patients noted to develop pigmented epiretinal deposits at regularly scheduled follow-up visits after repair of complex retinal detachments using silicone oil tamponade and retinectomy. METHODS: Epiretinal pigment deposits were characterized clinically by wide-field color photography, fundus autofluorescence imaging, and spectral-domain optical coherence tomography (SD OCT). At the time of silicone oil removal, the pigmented membranes were preserved in fixative and analyzed by light microscopy/immunostaining or electron microscopy for histologic characterization. MAIN OUTCOME MEASURES: Not applicable. RESULTS: We describe the development of diffuse preretinal pigmentary deposits in 12 eyes after surgery for complicated PVR detachments using retinectomies with oil, with an average onset of 3.2 months postoperatively. These pigment clumps produced a striking leopard-spot pattern on fundus autofluorescence imaging. Histopathologic and ultrastructural analysis of these epiretinal proliferations peeled at the time of silicone oil removal revealed RPE cells with intracellular silicone oil droplets, singly dispersed membrane-bound melanin granules, glial tissue (1 case), and a fibrous stroma. CONCLUSIONS: Although in vitro studies have suggested that RPE cells can phagocytose emulsified oil droplets, this report represents the first in vivo documentation by electron microscopy of this phenomenon in patients. These findings underscore that direct contact with silicone oil may affect the behavior of the RPE, which may be clinically relevant in patients who have undergone large relaxing retinectomies with silicone oil tamponade for PVR-related retinal detachments.