The mucin layer of the tear film is produced by goblet cells in the conjunctiva to protect the ocular surface and maintain homeostasis. The pro-resolving lipid mediator resolvin D2 (RvD2) biosynthesized from an omega 3 fatty acid actively terminates inflammation and regulates mucin secretion from conjunctival goblet cells. Our objective was to determine which Ca2+ -dependent signaling pathways RvD2 uses to stimulate conjunctival goblet cell function (CGC). We hypothesize that RvD2 activates multiple intracellular Ca2+ signaling pathways to stimulate CGC secretion. Rat and human CGCs were cultured from conjunctival explants. The amount of RvD2 receptor GPR18/DRV2 message and protein were determined. The intracellular concentration of Ca2+ ([Ca2+ ]i ) was measured in CGCs using a fluorescent Ca2+ dye and mucin secretion was determined by measuring protein secretion enzymatically with a lectin. Goblet cells were incubated with signaling pathway inhibitors before stimulation with RvD2 and [Ca2+ ]i or secretion was measured. In rat and human CGCs RvD2 receptor and in rat CGCs IP3 (a molecule that releases Ca2+ from intracellular organelles) receptors 1-3 were detected. In both species of CGC RvD2 increased [Ca2+ ]i similarly to RvD1. In rat CGCs, the increase in [Ca2+ ]i and secretion stimulated by RvD2 was significantly blocked by inhibitors to phospholipase (PL-) C and IP3 -receptor, but not protein kinase C. Increase in [Ca2+ ]i was blocked by the PLD inhibitor, but not the PLA2 inhibitor. Secretion was blocked by PLA2 inhibitor, but not the PLD inhibitor. An inhibitor of the epidermal growth factor receptor blocked the increase in [Ca2+ ]i by RvD2 in both species of CGCs. In CGCs RvD2 activates multiple intracellular signaling pathways that are Ca2+ -dependent, along with one Ca2+ -independent and one cAMP/protein kinase A-dependent pathway. Activation of these pathways stimulate mucin secretion from rat and human CGCs into the tear film contributing to ocular surface homeostasis and health.
PURPOSE: To evaluate the timing of ocular hypertension (OHT) after pediatric closed-globe injury (CGI) and traumatic hyphema. We hypothesize that OHT will occur at different times based on injury characteristics. DESIGN: Retrospective, cohort study. METHODS: Setting: Single-center, tertiary-care, pediatric hospital. PARTICIPANTS: Subjects included patients ≤18 years of age at the time of injury who suffered CGI and traumatic hyphema between 2002 and 2019. Observation Procedure(s): Intraocular pressure and injury demographics were abstracted for every visit after injury. OHT was defined as >21 mm Hg at presentation or after a reading of ≤21 mm Hg at a prior visit. MAIN OUTCOME MEASURES: The primary outcome measure was the timing of OHT categorized into 4 periods: presentation, acute (days 1-7), subacute (days 8-28), or late (day >28). Secondary outcome measures were identification of risks factors for OHT by multivariable logistic regression. RESULTS: OHT occurred in 119 of the 305 (39%) subject eyes. OHT occurred in 35 patients at presentation, 69 times acutely, 35 times subacutely, and 36 times late. Pupil damage predicted acute-period OHT (P = .004). OHT at presentation predicted subacute period OHT (P = .004). Iridodialysis and cataract predicted late-period OHT (P = .007 and P < .001, respectively). CONCLUSIONS: OHT after CGI and traumatic hyphema in pediatric patients is common. Injury demographics predict this complication. Integration of these risk factors with current literature allows proposal of a risk-stratification tool to guide efficient surveillance for OHT.
CONTEXT.—: Conjunctival melanocytic lesions consist of a variety of neoplastic and nonneoplastic conditions. These include benign processes such as primary intraepithelial hypermelanosis and melanocytic hyperplasia, secondary forms of intraepithelial hypermelanosis and melanocytic hyperplasia, melanocytic nevi, melanocytic proliferations with malignant potential, and melanoma. OBJECTIVE.—: To provide a concise yet comprehensive resource regarding the histopathologic diagnosis of conjunctival melanocytic lesions. We aim to detail and clarify the numerous classification schemes that exist for junctional melanocytic proliferations of the conjunctiva (known as primary acquired melanosis or PAM; also termed conjunctival melanocytic intraepithelial neoplasia or C-MIN). Although not uniformly adopted, C-MIN is classified by using a numeric system based on a defined set of criteria. A less complex scheme (conjunctival melanocytic intraepithelial lesion or CMIL) has recently been proposed by the World Health Organization. Additionally, we aim to update the reader regarding molecular features and prognostic indicators. DATA SOURCES.—: Peer-reviewed literature and archived cases for illustration. CONCLUSIONS.—: Accurate histologic classification is essential, as PAM/C-MIN/CMILs that have a significant potential to progress to invasive melanoma may be clinically indistinguishable from low-risk lesions. Conjunctival melanoma (CM) more closely resembles cutaneous melanoma in terms of its pathogenesis and molecular features, compared to melanoma arising at other mucosal sites or to uveal melanoma. Depth of invasion and ulceration status, among other factors, have emerged as important prognostic indicators in CM. Sentinel lymph node biopsy may provide further prognostic information. Lastly, integration of pathologic and clinical findings is essential at this anatomically sensitive location to determine appropriate clinical management.
Mutations in NMNAT1, a key enzyme involved in the synthesis of NAD+ in the nucleus, lead to an early onset severe inherited retinal degeneration (IRD). We aimed to understand the role of nuclear NAD+ in the retina and to identify the molecular mechanisms underlying NMNAT1-associated disease, using a mouse model that harbors the p.V9M mutation in Nmnat1 (Nmnat1V9M/V9M). We identified temporal transcriptional reprogramming in the retinas of Nmnat1V9M/V9M mice prior to retinal degeneration, which begins at 4 weeks of age, with no significant alterations in gene expression at 2 weeks of age and over 2600 differentially expressed genes by 3 weeks of age. Expression of the primary consumer of NAD+ in the nucleus, PARP1, an enzyme involved in DNA damage repair and transcriptional regulation, as well as 7 other PARP family enzymes, was elevated in the retinas of Nmnat1V9M/V9M. This was associated with elevated levels of DNA damage, PARP-mediated NAD+ consumption and migration of Iba1+/CD45+ microglia/macrophages to the subretinal space in the retinas of Nmnat1V9M/V9M mice. These findings suggest that photoreceptor cells are especially sensitive to perturbation of genome homeostasis, and that PARP-mediated cell death may play a role in other genetic forms of IRDs, and potentially other forms of neurodegeneration.
BACKGROUND: Supranuclear vertical gaze palsies and slowed vertical saccades are characteristic clinic features of progressive supranuclear palsy (PSP). The "hummingbird sign," reflective of midbrain atrophy, is a classic radiographic sign of PSP. Correlation between eye movement abnormalities and radiographic findings in PSP has been reported previously. However, due to the use of clinical criteria not commonly employed in neuro-ophthalmic practice and neuroimaging techniques that are not widely available, it remains unclear whether correlation between midbrain structure and characteristic ocular-motor disturbances can be helpful to neuro-ophthalmologists seeking to adjudicate difficult or unusual diagnostic cases. METHODS: Patients with a diagnosis of probable PSP according to Movement Disorders Society criteria were studied retrospectively. A neuroradiologist calculated brainstem volumes in enrolled participants and normal controls. Spearman correlations were used to correlate the extent of eye movement limitation as assessed by 2 neuro-ophthalmologists with brainstem volumes. RESULTS: Fourteen participants with PSP and 15 healthy controls with similar age and gender distribution were enrolled and evaluated retrospectively. All 14 participants with PSP had undergone MRIs. Midbrain atrophy significantly correlated with the PSP rating scale (P < 0.001). PSP patients had significantly reduced volumes in the midbrain (P -0.0026), tegmentum (0.0001), tectum (0.0001), and medulla (P = 0.0024) compared with normal controls. Notes documenting quantified ocular motor function were available in 7 of 14 participants with PSP. Midbrain atrophy significantly correlated with in the extent of upward gaze limitation (P = 0.03). CONCLUSIONS: The severity of upward gaze limitation correlates with the severity of midbrain atrophy in patients with PSP. Recognition of this correlation may help to adjudicate diagnostic dilemmas and guide further evaluation.
The state of the art therapy for treating corneal endothelial disease is transplantation. Advances in the reproducibility and accessibility of surgical techniques are increasing the number of corneal transplants, thereby causing a global deficit of donor corneas and leaving 12.7 million patients with addressable visual impairment. Approaches to regenerate the corneal endothelium offer a solution to the current tissue scarcity and a treatment to those in need. Methods for generating corneal endothelial cells into numbers that could address the current tissue shortage and the possible strategies used to deliver them have now become a therapeutic reality with clinical trials taking place in Japan, Singapore and Mexico. Nevertheless, there is still a long way before such therapies are approved by regulatory bodies and become clinical practice. Moreover, acellular corneal endothelial graft equivalents and certain drugs could provide a treatment option for specific disease conditions without the need of donor tissue or cells. Finally, with the emergence of gene modulation therapies to treat corneal endothelial disease, it would be possible to treat presymptomatic patients or those presenting early symptoms, drastically reducing the need for donor tissue. It is necessary to understand the most recent developments in this rapidly evolving field to know which conditions could be treated with which approach. This article provides an overview of the current and developing regenerative medicine therapies to treat corneal endothelial disease and provides the necessary guidance and understanding towards the treatment of corneal endothelial disease.
BACKGROUND: Variants in RCBTB1 were recently described to cause a retinal dystrophy with only eight families described to date and a predominant phenotype of macular atrophy and peripheral reticular degeneration. Here, we further evaluate the genotypic and phenotypic characteristics of biallelic RCBTB1-associated retinal dystrophy in a North American clinic population. METHODS: A retrospective analysis of genetic and clinical features was performed in individuals with biallelic variants in RCBTB1. RESULTS: Three unrelated individuals of French-Canadian descent with rare biallelic RCBTB1 variants were identified. All individuals shared a novel p.(Ser342Leu) missense variant; one patient was homozygous whereas the other two each possessed a second unique novel variant p.(Gln120*) and p.(Pro224Leu). All three had macula-predominant disease with symptom onset in the fifth decade of life. CONCLUSION: This report adds to the genetic diversity of RCBTB1-associated disease. These cases confirm the later-onset, relative to many other retinal dystrophies, and macular focus of disease described in most cases to-date. They are thus a reminder of considering hereditary disease in the differential for later-onset macular atrophy.
PURPOSE: To review the published literature assessing the safety and effectiveness of laser refractive surgery to treat anisometropic amblyogenic refractive error in children aged ≤ 18 years. METHODS: A literature search of the PubMed database was conducted in October 2021 with no date limitations and restricted to publications in English. The search yielded 137 articles, 69 of which were reviewed in full text. Eleven articles met the criteria for inclusion and were assigned a level of evidence rating. RESULTS: The 11 included articles were all level III evidence and consisted of 1 case-control study and 10 case series. Six studies used laser-assisted in situ keratomileusis (LASIK), 1 used photorefractive keratectomy (PRK), 1 used refractive lenticule extraction/small incision lenticule extraction, and the rest used a combination of LASIK, PRK, laser epithelial keratomileusis (LASEK), or refractive lenticule extraction/small incision lenticule extraction. Five studies enrolled patients with anisometropic myopia, 2 studies enrolled patients with anisometropic hyperopia, and the remainder were mixed. Although all studies demonstrated an improvement in best-corrected visual acuity (BCVA), the magnitude of improvement varied widely. As study parameters varied, a successful outcome was defined as residual refractive error of 1 diopter (D) or less of the target refraction because this was the most commonly used metric. Successful outcomes ranged between 38% and 87%, with a mean follow-up ranging from 4 months to 7 years. Despite this wide range, all studies demonstrated an improvement in the magnitude of anisometropia. Regression in refractive error occurred more frequently and to a greater degree in myopic eyes and eyes with longer follow-up, and in younger patients. Although one study reported 2 free flaps, most studies reported no serious adverse events. The most common complications were corneal haze and striae. CONCLUSIONS: Findings from included studies suggest that laser refractive surgery may address amblyogenic refractive error in children and that it appears to decrease anisometropia. However, the evidence for improvement in amblyopia is unclear and long-term safety data are lacking. Long-term data and well-designed clinical studies that use newer refractive technologies in standardized patient populations would help address the role of refractive surgery in children and its potential impact on amblyopia.
The increasing morbidity and mortality of patients due to post-surgery complications of coronary artery bypass grafts (CABPG) are related to blood-material interactions. Thus, the characterization of the thrombogenicity of the biomaterial for cardiovascular devices is of particular interest. This research evaluated the anti-thrombogenic activity of polyurethanes-starch composites. We previously synthesized polyurethane matrices that were obtained from polycaprolactone diol (PCL), polyethylene glycol (PEG), pentaerythritol (PE), and isophorone diisocyanate (IPDI). In addition, potato starch (AL-N) and zwitterionic starch (AL-Z) were added as fillers. The anti-thrombogenic property was characterized by the clot formation time, platelet adhesion, protein absorption, TAT complex levels, and hemolysis. Additionally, we evaluated the cell viability of the endothelial and smooth muscle cells. Statically significant differences among the polyurethane matrices (P1, P2, and P3) were found for protein absorption and the blood clotting time without fillers. The polyurethanes composites with AL-Z presented an improvement in the anti-thrombogenic property. On the other hand, the composites with AL-Z reduced the viability of the endothelial cells and did not significantly affect the AoSCM (except for P1, which increased). These results classify these biomaterials as inert; therefore, they can be used for cardiovascular applications.
PURPOSE: To evaluate lesbian, gay, bisexual, transgender, questioning and other sexual/gender minority (LGBTQ+) orientation as a burnout risk factor among an international ophthalmologist cohort. METHODS: An anonymous, cross-sectional electronic survey was distributed via an internet platform to characterize the relationship between demographic factors, including LGBTQ+ orientation, and burnout as measured by the Copenhagen Burnout Inventory (CBI). Univariable data analysis (linear) by sexual orientation was performed and variables with association with p-value < 0.15 in univariable analysis were included in the multiple linear regression modeling. RESULTS: A total of 403 ophthalmologists participated in the survey, the majority self-identified as "White" (69.2%), were from North America (72.0% United States, 18.6% Canada), and were evenly distributed between age of 30 and 65 years. Overall, 13.2% of participants identified as LGBTQ+, 98.2% as cisgender. Approximately 12% had witnessed or experienced LGBTQ+-related workplace discrimination or harassment. The personal and work-related burnout scores and confidence limits of those identified as LGBTQ+ were higher and non-overlapping than those reported as non-LGBTQ+. Multivariable analysis identified significant risk factors for higher personal and work-related burnout scores: LGBTQ+ (11.8 and 11.1, P = .0005 and .0023), female gender (5.36 and 4.83, P = .0153 and .0434), older age (19.1 and 19.2, P = .0173 and .0273) and caretaker stress (6.42 and 5.97, P = .0085 and .0239). CONCLUSIONS: LGBTQ+ orientation is a burnout risk factor among ophthalmologists, and LGBTQ+ workplace discrimination may be a contributing factor. Support from ophthalmology organization to address LGBTQ+-, gender- and age-related work-place discrimination may decrease burnout.
PRCIS: Glaucoma cascade screening in first-degree relatives (FDRs) of young Haitian glaucoma patients had high yield for diagnosing manifest and suspected glaucoma in 30.8% of those screened despite modest participation. PURPOSE: To evaluate the outcomes of glaucoma cascade screening in FDRs (parents, siblings, and offspring) of Haitian juvenile open-angle glaucoma (JOAG) patients. PATIENTS AND METHODS: Consecutive index patients (Haitians with JOAG) were identified, and the number/type of FDRs residing in South Florida were recorded. These FDRs were invited for free glaucoma screening, which included a comprehensive ophthalmic exam, gonioscopy, automated visual field testing and optical coherence tomographic analysis of the retinal nerve fiber layers. FDR characteristics and clinical findings from screening are reported. RESULTS: A total of 77 FDRs were invited, 26 (33.8%) agreed to undergo screening (18 females, 9 males), which revealed 2 (7.7%) with manifest glaucoma (mean age 77.5 y; one of whom was previously unaware of his glaucoma diagnosis), 6 (23.1%) with suspected glaucoma (mean age 29.8±18.3 y), and 18 (69.2%) without manifest or suspected glaucoma (mean age 37.2±21.8 y). Siblings of index patients were least likely to participate in cascade glaucoma screening when compared with index patients' parents or offspring. FDR eyes with manifest glaucoma had significantly worse best-corrected visual acuities, higher intraocular pressures, thinner central corneal thicknesses, and thinner circumferential papillary retinal nerve fiber layer thicknesses than those without glaucoma. CONCLUSION: Glaucoma cascade screening of Haitian JOAG patients' FDRs revealed that 30.8% had suspected or manifest glaucoma. Future efforts centered on provider-initiated recruitment and improving public glaucoma awareness and education may increase screening participation.
BACKGROUND/AIMS: Prophylactic laser peripheral iridotomy (LPI) is performed in primary angle-closure suspect (PACS) eyes to prevent acute angle-closure attacks. However, accelerated cataractogenesis is a potential risk of the procedure that may result in decreased visual acuity. We aimed to assess the long-term impact of LPI on cataract formation in Chinese PACS. METHODS: In the Zhongshan Angle Closure Prevention Trial, eligible bilateral PACS participants received LPI in one randomly selected eye, while the fellow eye remained untreated. Cataract was graded using the Lens Opacity Classification System III, and progression was defined as an increase in grade by at least two units in any category or cataract surgery. RESULTS: In total, 889 participants were randomly assigned to LPI in one eye only (mean age 59±5 years, 83% female). At 72 months, treated eyes had slightly higher average nuclear grades (p<0.001). However, there were no differences between eyes for predefined cataract progression (cumulative probability at 72 months: 21.2% in LPI vs 19.4% in control, p=0.401) or cataract surgery (1% for both). While LPI-treated eyes had a 10% higher risk of progression over 6 years (HR=1.10 (95% CI 0.88 to 1.36)), this was not statistically significant. Visual acuity at 72 months was similar in treated and untreated eyes (p=0.43). CONCLUSION: Although lenses were graded on average as slightly more opaque in laser-treated eyes, prophylactic neodymium:yttrium-aluminum-garnet LPI did not cause significant cataract progression. Our results suggest that LPI treatment of asymptomatic narrow angles does not increase the risk of developing clinically meaningful cataract worsening over time. TRIAL REGISTRATION NUMBER: ISRCTN45213099.
PURPOSE: To review the literature on the efficacy of surgical procedures to improve visual acuity (VA) in patients with infantile nystagmus syndrome (INS). METHODS: Literature searches were last conducted in January 2022 in the PubMed database for English-language studies with no date restrictions. The combined searches yielded 354 abstracts, of which 46 were reviewed in full text. Twenty-three of these were considered appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. RESULTS: One included study was a randomized trial; the remaining 22 were case series. The 23 studies included children and adults with INS and a variable proportion with anomalous head position (AHP), strabismus, and sensory diagnoses. The surgical interventions evaluated included large recessions, tenotomy and reattachment (TAR), myectomy with or without pulley fixation, and anterior extirpation of the 4 horizontal rectus muscles, as well as various procedures to correct an AHP in which VA was reported as a secondary outcome. The data were mixed, with improvements in binocular best-corrected visual acuity (BCVA) ranging from no improvement to 0.3 logarithm of the minimum angle of resolution (logMAR), or 3 lines. (Most studies were in the range of 0.05-0.2 logMAR.) Statistically significant improvement in VA was noted in 12 of 16 studies (75%) that performed statistical analyses, with no clear advantage of any single procedure. Complications and reoperations were lowest in patients who underwent TAR and highest in those who underwent myectomy or anterior extirpation. CONCLUSIONS: The best available evidence suggests that eye muscle surgery in patients with INS results in a modest improvement in VA. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.
PURPOSE OF REVIEW: The purpose of this review is to provide an overview of the ophthalmic findings associated with peripapillary hyperreflective ovoid mass-like structures (PHOMS) in both adult and pediatric patients. RECENT FINDINGS: PHOMS have recently been identified in a number of different ophthalmic disease entities ranging from nonpathologic to pathologic, including but not limited to anatomic abnormalities (tilting in myopia), optic nerve head drusen, optic disc edema from inflammation (optic neuritis, white dot syndromes), vascular insults (ischemic optic neuropathy, retinal vascular occlusion), and papilledema. The mechanism underlying the formation of PHOMS has not been fully elucidated although it has been hypothesized that PHOMS occur secondary to axoplasmic stasis from crowding at the optic nerve head. SUMMARY: Although the clinical significance of the presence of PHOMS remains unclear, PHOMS are associated with several disease processes. Understanding the mechanism behind their formation and their impact on optic nerve head structure and visual function may be relevant in patients with optic nerve head pathology. The presence of PHOMS may also correlate with disease severity and duration. Future studies to evaluate whether the formation of PHOMS may be useful as an early indicator of disease or a prognostic tool are warranted.
Chen SP, Azad AD, Pershing S. Reply. Ophthalmology 2022;129(2):e33-e35.
Despite constant exposure to various environmental stimuli, the ocular surface remains intact and uninflamed while maintaining the transparency of the cornea and its visual function. This 'immune privilege' of the ocular surface is not simply a result of the physical barrier function of the mucosal lining but, more importantly, is actively maintained through a variety of immunoregulatory mechanisms that prevent the disruption of immune homeostasis. In this review, we focus on essential molecular and cellular players that promote immune quiescence in steady-state conditions and suppress inflammation in disease-states. Specifically, we examine the interactions between the ocular surface and its local draining lymphoid compartment, by encompassing the corneal epithelium, corneal nerves and cornea-resident myeloid cells, conjunctival goblet cells, and regulatory T cells (Treg) in the context of ocular surface autoimmune inflammation (dry eye disease) and alloimmunity (corneal transplantation). A better understanding of the immunoregulatory mechanisms will facilitate the development of novel, targeted immunomodulatory strategies for a broad range of ocular surface inflammatory disorders.