Pasquale LR, Gong L, Wiggs JL, Pan L, Yang Z, Wu M, Yang Z, Chen DF, Zeng W. Development of Primary Open Angle Glaucoma-Like Features in a Rhesus Macaque Colony From Southern China. Transl Vis Sci Technol 2021;10(9):20.Abstract
Purpose: To describe the ocular phenotype of spontaneous glaucoma in a non-human primate colony. Methods: In total, 722 Rhesus macaque monkeys aged 10 to 25 years underwent optical coherence tomography (OCT), fundus photography (FP), and intraocular pressure (IOP) measurements. Monkeys with baseline cup-to-disc ratio (CDR) <0.5 were used to establish baseline ocular features. A subset was followed longitudinally for three years and compared to glaucoma suspects on the basis of OCT/FP criteria. Results: The average IOP under ketamine sedation and average CDR for the entire colony was 13.0 ± 4.3 mm Hg and 0.38 ± 0.07, respectively. The mean baseline conscious IOP of glaucoma suspects (N = 18) versus controls (N = 108) was 16.2 ± 3.5 mm Hg and 13.9 ± 2.3 mm Hg, respectively (P = 0.001). All glaucoma suspects had unremarkable slit lamp examinations and open angles based on anterior segment OCT. Baseline global circumpapillary retinal nerve fiber layer (RNFL) thickness was 91.5 ± 11.0 µM versus 102.7 ± 8.5 µM in suspects and controls, respectively (P < 0.0001). All sectors on the baseline circumpapillary OCT showed a significant reduction in RNFL thickness versus controls (P ≤ 0.0022) except for the temporal sector (P ≥ 0.07). In three-year longitudinal analysis, neither CDR nor OCT parameters changed in controls (N = 40; P ≥ 0.16), whereas significant increase in CDR (P = 0.018) and nominally significant decreases in two OCT sectors (nasal, P = 0.023 and nasal inferior, P = 0.046) were noted in suspects. Conclusions: Members of a nonhuman primate colony exhibit important ophthalmic features of human primary open-angle glaucoma. Translational Relevance: Identification of a spontaneous model of glaucoma in nonhuman primates represents an unprecedented opportunity to elucidate the natural history, pathogenesis and effective therapeutic strategies for the disease.
Rosenblatt TR, Vail D, Ludwig CA, Al-Moujahed A, Pasricha MV, Ji MH, Callaway NF, Moshfeghi DM. Fall risk in patients with pseudophakic monovision. Can J Ophthalmol 2021;Abstract
OBJECTIVE: Vision changes can precipitate falls in the elderly resulting in significant morbidity and mortality. We hypothesized that pseudophakic monovision and ensuing anisometropia and aniseikonia impact elderly fall risk. This study assessed fall risk in patients with pseudophakic monovision, pseudophakic single vision distance (classic cataract surgery), and cataracts with no surgery. DESIGN: Retrospective single-institution cohort study PARTICIPANTS: Patients with bilateral cataracts diagnosed at 60 years of age or older who underwent bilateral cataract surgery (monovision or single vision distance) or did not undergo any cataract surgery (n = 13 385). Patients with unilateral surgery or a fall prior to cataract diagnosis were excluded. METHODS: Data were obtained from the Stanford Research Repository. Time-to-fall analysis was performed across all 3 groups. Primary outcome was hazard ratio (HR) for fall after second eye cataract surgery or after bilateral cataract diagnosis. RESULTS: Of 13 385 patients (241 pseudophakic monovision, 2809 pseudophakic single vision, 10 335 no surgery), 850 fell after cataract diagnosis. Pseudophakic monovision was not associated with fall risk after controlling for age, sex, and myopia. Pseudophakic single-vision patients had a decreased time to fall compared with no-surgery patients (log rank, p < 0.001). Older age at cataract diagnosis (HR =1.05, 95% confidence interval [CI] 1.04-1.06, p < 0.001) or at time of surgery (HR = 1.05, 95% CI 1.03-1.07, p < 0.001) increased fall risk, as did female sex (HR = 1.29, 95% CI 1.10-1.51, p = 0.002) and preexisting myopia (HR = 1.31, 95% CI 1.01-1.71, p = 0.046) among nonsurgical patients. CONCLUSIONS: Pseudophakic monovision did not impact fall risk, but pseudophakic single vision may increase falls compared with patients without cataract surgery.
Jowett N, Pineda R. Corneal and Facial Sensory Neurotization in Trigeminal Anesthesia. Facial Plast Surg Clin North Am 2021;29(3):459-470.Abstract
Trigeminal anesthesia may yield blindness and facial disfigurement, secondary to neurotrophic keratopathy and trigeminal trophic syndrome. This article summarizes contemporary medical and emerging surgical approaches for the therapeutic management of this rare and devastating disease state.
Han H, Yang Y, Liu B, Tian J, Dong L, Qi H, Zhu W, Wang J, Lei H. Chalcomoracin prevents vitreous-induced activation of AKT and migration of retinal pigment epithelial cells. J Cell Mol Med 2021;25(19):9102-9111.Abstract
Retinal pigment epithelial (RPE) cells are the major cell type in the epi- or sub-retinal membranes in the pathogenesis of proliferative vitreoretinopathy (PVR), which is a blinding fibrotic eye disease and still short of effective medicine. The purpose of this study is to demonstrate whether Chalocomoracin (CMR), a novel purified compound from fungus-infected mulberry leaves, is able to inhibit vitreous-induced signalling events and cellular responses intrinsic to PVR. Our studies have revealed that the CMR IC50 for ARPE-19 cells is 35.5 μmol/L at 72 hours, and that 5 μmol/L CMR inhibits vitreous-induced Akt activation and p53 suppression; in addition, we have discovered that this chemical effectively blocks vitreous-stimulated proliferation, migration and contraction of ARPE-19 cells, suggesting that CMR is a promising PVR prophylactic.
Zabaleta N, Dai W, Bhatt U, Hérate C, Maisonnasse P, Chichester JA, Sanmiguel J, Estelien R, Michalson KT, Diop C, Maciorowski D, Dereuddre-Bosquet N, Cavarelli M, Gallouët A-S, Naninck T, Kahlaoui N, Lemaitre J, Qi W, Hudspeth E, Cucalon A, Dyer CD, Pampena BM, Knox JJ, LaRocque RC, Charles RC, Li D, Kim M, Sheridan A, Storm N, Johnson RI, Feldman J, Hauser BM, Contreras V, Marlin R, Tsong Fang RH, Chapon C, van der Werf S, Zinn E, Ryan A, Kobayashi DT, Chauhan R, McGlynn M, Ryan ET, Schmidt AG, Price B, Honko A, Griffiths A, Yaghmour S, Hodge R, Betts MR, Freeman MW, Wilson JM, Le Grand R, Vandenberghe LH. An AAV-based, room-temperature-stable, single-dose COVID-19 vaccine provides durable immunogenicity and protection in non-human primates. Cell Host Microbe 2021;29(9):1437-1453.e8.Abstract
The SARS-CoV-2 pandemic has affected more than 185 million people worldwide resulting in over 4 million deaths. To contain the pandemic, there is a continued need for safe vaccines that provide durable protection at low and scalable doses and can be deployed easily. Here, AAVCOVID-1, an adeno-associated viral (AAV), spike-gene-based vaccine candidate demonstrates potent immunogenicity in mouse and non-human primates following a single injection and confers complete protection from SARS-CoV-2 challenge in macaques. Peak neutralizing antibody titers are sustained at 1 year and complemented by functional memory T cell responses. The AAVCOVID vector has no relevant pre-existing immunity in humans and does not elicit cross-reactivity to common AAVs used in gene therapy. Vector genome persistence and expression wanes following injection. The single low-dose requirement, high-yield manufacturability, and 1-month stability for storage at room temperature may make this technology well suited to support effective immunization campaigns for emerging pathogens on a global scale.
Nathan A, Rossin EJ, Kaseke C, Park RJ, Khatri A, Koundakjian D, Urbach JM, Singh NK, Bashirova A, Tano-Menka R, Senjobe F, Waring MT, Piechocka-Trocha A, Garcia-Beltran WF, Iafrate JA, Naranbhai V, Carrington M, Walker BD, Gaiha GD. Structure-guided T cell vaccine design for SARS-CoV-2 variants and sarbecoviruses. Cell 2021;184(17):4401-4413.e10.Abstract
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that escape convalescent and vaccine-induced antibody responses has renewed focus on the development of broadly protective T-cell-based vaccines. Here, we apply structure-based network analysis and assessments of HLA class I peptide stability to define mutationally constrained CD8+ T cell epitopes across the SARS-CoV-2 proteome. Highly networked residues are conserved temporally among circulating variants and sarbecoviruses and disproportionately impair spike pseudotyped lentivirus infectivity when mutated. Evaluation of HLA class I stabilizing activity for 18 globally prevalent alleles identifies CD8+ T cell epitopes within highly networked regions with limited mutational frequencies in circulating SARS-CoV-2 variants and deep-sequenced primary isolates. Moreover, these epitopes elicit demonstrable CD8+ T cell reactivity in convalescent individuals but reduced recognition in recipients of mRNA-based vaccines. These data thereby elucidate key mutationally constrained regions and immunogenic epitopes in the SARS-CoV-2 proteome for a global T-cell-based vaccine against emerging variants and SARS-like coronaviruses.
Jowett N, Pineda R. Seeing through the evidence for corneal neurotization. Curr Opin Otolaryngol Head Neck Surg 2021;29(4):252-258.Abstract
PURPOSE OF REVIEW: Trigeminal anesthesia causes neurotrophic keratopathy, which may yield facial disfigurement and corneal blindness. RECENT FINDINGS: We summarize approaches and evidence for corneal neurotization. SUMMARY: Regional sensory nerve transfer appears safe and effective for therapeutic management of neurotrophic keratopathy. Prospective randomized clinical trials are necessary to confirm the utility of corneal neurotization.
Douglas VP, Douglas KA, Reinshagen KL, Chwalisz BK. Case 292: Lyme Neuroborreliosis. Radiology 2021;300(2):484-488.Abstract
History A 24-year-old right-handed woman presented to a neuro-ophthalmology clinic in Massachusetts in the summer with acute binocular diplopia when looking down and to the left, which started about 1 month earlier. Her medical history was notable for Raynaud syndrome, recurrent streptococcal pharyngitis, and an allergy to amoxicillin. Three days prior to developing diplopia, she presented to an outside emergency department due to fever, chills, and back pain. She received ciprofloxacin for presumed urinary tract infection based on urinalysis, which demonstrated few bacteria and was negative for leukocyte esterase, nitrites, and white blood cells. She then presented again to an outside emergency department for diplopia evaluation. Initial MRI and MR angiography of the brain at that time did not demonstrate any relevant findings, and the patient was referred to our department for neuro-ophthalmic evaluation, where she was seen 4 weeks later. Neuro-ophthalmic examination revealed 20/20 visual acuity in both eyes, and a right hypertropia in left gaze, downgaze and right head tilt, with right eye excyclotorsion. There were no ocular signs of myasthenia gravis or thyroid eye disease, nor did the patient report ocular or systemic symptoms. She denied recent travel. High-spatial-resolution MRI of the brain and orbit were performed.
Pamir Z, Bauer CM, Bennett CR, Kran BS, Merabet LB. Visual perception supported by verbal mediation in an individual with cerebral visual impairment (CVI). Neuropsychologia 2021;160:107982.Abstract
Cerebral visual impairment (CVI) often presents with deficits associated with higher order visual processing. We report a case of an individual with CVI who uses a verbal mediation strategy to perceive and interact with his visual surroundings. Visual perceptual performance was assessed using a virtual reality based visual search task combined with eye tracking. Functional magnetic resonance imaging (fMRI) was employed to identify the neural correlates associated with this strategy. We found that when using verbal mediation, the individual could readily detect and track the target within the visual scene which was associated with robust activation within a network of occipito-parieto-temporal visual cortical areas. In contrast, when not using verbal mediation, the individual was completely unable to perform the task, and this was associated with dramatically reduced visual cortical activation. This unique compensatory strategy may be related to the individual's use of verbal working memory for the purposes of understanding complex visual information.
Wagner A, Wang C, Fessler J, DeTomaso D, Avila-Pacheco J, Kaminski J, Zaghouani S, Christian E, Thakore P, Schellhaass B, Akama-Garren E, Pierce K, Singh V, Ron-Harel N, Douglas VP, Bod L, Schnell A, Puleston D, Sobel RA, Haigis M, Pearce EL, Soleimani M, Clish C, Regev A, Kuchroo VK, Yosef N. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell 2021;184(16):4168-4185.e21.Abstract
Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.
Huang X, Sun J, Majoor J, Vermeer KA, Lemij H, Elze T, Wang M, Boland MV, Pasquale LR, Mohammadzadeh V, Nouri-Mahdavi K, Johnson C, Yousefi S. Estimating the Severity of Visual Field Damage From Retinal Nerve Fiber Layer Thickness Measurements With Artificial Intelligence. Transl Vis Sci Technol 2021;10(9):16.Abstract
Purpose: The purpose of this study was to assess the accuracy of artificial neural networks (ANN) in estimating the severity of mean deviation (MD) from peripapillary retinal nerve fiber layer (RNFL) thickness measurements derived from optical coherence tomography (OCT). Methods: Models were trained using 1796 pairs of visual field and OCT measurements from 1796 eyes to estimate visual field MD from RNFL data. Multivariable linear regression, random forest regressor, support vector regressor, and 1D convolutional neural network (CNN) models with sectoral RNFL thickness measurements were examined. Three independent subsets consisting of 698, 256, and 691 pairs of visual field and OCT measurements were used to validate the models. Estimation errors were visualized to assess model performance subjectively. Mean absolute error (MAE), root mean square error (RMSE), median absolute error, Pearson correlation, and R-squared metrics were used to assess model performance objectively. Results: The MAE and RMSE of the ANN model based on the testing dataset were 4.0 dB (95% confidence interval = 3.8-4.2) and 5.2 dB (95% confidence interval = 5.1-5.4), respectively. The ranges of MAE and RMSE of the ANN model on independent datasets were 3.3-5.9 dB and 4.4-8.4 dB, respectively. Conclusions: The proposed ANN model estimated MD from RNFL measurements better than multivariable linear regression model, random forest, support vector regressor, and 1-D CNN models. The model was generalizable to independent data from different centers and varying races. Translational Relevance: Successful development of ANN models may assist clinicians in assessing visual function in glaucoma based on objective OCT measures with less dependence on subjective visual field tests.
Peterson SL, Li Y, Sun CJ, Wong KA, Leung KS, de Lima S, Hanovice NJ, Yuki K, Stevens B, Benowitz LI. Retinal Ganglion Cell Axon Regeneration Requires Complement and Myeloid Cell Activity within the Optic Nerve. J Neurosci 2021;41(41):8508-8531.Abstract
Axon regenerative failure in the mature CNS contributes to functional deficits following many traumatic injuries, ischemic injuries, and neurodegenerative diseases. The complement cascade of the innate immune system responds to pathogen threat through inflammatory cell activation, pathogen opsonization, and pathogen lysis, and complement is also involved in CNS development, neuroplasticity, injury, and disease. Here, we investigated the involvement of the classical complement cascade and microglia/monocytes in CNS repair using the mouse optic nerve injury (ONI) model, in which axons arising from retinal ganglion cells (RGCs) are disrupted. We report that central complement C3 protein and mRNA, classical complement C1q protein and mRNA, and microglia/monocyte phagocytic complement receptor CR3 all increase in response to ONI, especially within the optic nerve itself. Importantly, genetic deletion of C1q, C3, or CR3 attenuates RGC axon regeneration induced by several distinct methods, with minimal effects on RGC survival. Local injections of C1q function-blocking antibody revealed that complement acts primarily within the optic nerve, not retina, to support regeneration. Moreover, C1q opsonizes and CR3+ microglia/monocytes phagocytose growth-inhibitory myelin debris after ONI, a likely mechanism through which complement and myeloid cells support axon regeneration. Collectively, these results indicate that local optic nerve complement-myeloid phagocytic signaling is required for CNS axon regrowth, emphasizing the axonal compartment and highlighting a beneficial neuroimmune role for complement and microglia/monocytes in CNS repair.SIGNIFICANCE STATEMENT Despite the importance of achieving axon regeneration after CNS injury and the inevitability of inflammation after such injury, the contributions of complement and microglia to CNS axon regeneration are largely unknown. Whereas inflammation is commonly thought to exacerbate the effects of CNS injury, we find that complement proteins C1q and C3 and microglia/monocyte phagocytic complement receptor CR3 are each required for retinal ganglion cell axon regeneration through the injured mouse optic nerve. Also, whereas studies of optic nerve regeneration generally focus on the retina, we show that the regeneration-relevant role of complement and microglia/monocytes likely involves myelin phagocytosis within the optic nerve. Thus, our results point to the importance of the innate immune response for CNS repair.
Avraham D, Jung J-H, Yitzhaky Y, Peli E. Retinal prosthetic vision simulation: temporal aspects. J Neural Eng 2021;18(4)Abstract
Objective. The perception of individuals fitted with retinal prostheses is not fully understood, although several retinal implants have been tested and commercialized. Realistic simulations of perception with retinal implants would be useful for future development and evaluation of such systems.Approach.We implemented a retinal prosthetic vision simulation, including temporal features, which have not been previously simulated. In particular, the simulation included temporal aspects such as persistence and perceptual fading of phosphenes and the electrode activation rate.Main results.The simulated phosphene persistence showed an effective reduction in flickering at low electrode activation rates. Although persistence has a positive effect on static scenes, it smears dynamic scenes. Perceptual fading following continuous stimulation affects prosthetic vision of both static and dynamic scenes by making them disappear completely or partially. However, we showed that perceptual fading of a static stimulus might be countered by head-scanning motions, which together with the persistence revealed the contours of the faded object. We also showed that changing the image polarity may improve simulated prosthetic vision in the presence of persistence and perceptual fading.Significance.Temporal aspects have important roles in prosthetic vision, as illustrated by the simulations. Considering these aspects may improve the future design, the training with, and evaluation of retinal prostheses.