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Xue Y, Sun X, Wang SK, Collin GB, Kefalov VJ, Cepko CL. Chromophore supply modulates cone function and survival in retinitis pigmentosa mouse models. Proc Natl Acad Sci U S A 2023;120(23):e2217885120.Abstract
Retinitis pigmentosa (RP) is an ocular disease characterized by the loss of night vision, followed by the loss of daylight vision. Daylight vision is initiated in the retina by cone photoreceptors, which are gradually lost in RP, often as bystanders in a disease process that initiates in their neighboring rod photoreceptors. Using physiological assays, we investigated the timing of cone electroretinogram (ERG) decline in RP mouse models. A correlation between the time of loss of the cone ERG and the loss of rods was found. To investigate a potential role of the visual chromophore supply in this loss, mouse mutants with alterations in the regeneration of the retinal chromophore, 11-cis retinal, were examined. Reducing chromophore supply via mutations in Rlbp1 or Rpe65 resulted in greater cone function and survival in a RP mouse model. Conversely, overexpression of Rpe65 and Lrat, genes that can drive the regeneration of the chromophore, led to greater cone degeneration. These data suggest that abnormally high chromophore supply to cones upon the loss of rods is toxic to cones, and that a potential therapy in at least some forms of RP is to slow the turnover and/or reduce the level of visual chromophore in the retina.
Manley CE, Walter K, Micheletti S, Tietjen M, Cantillon E, Fazzi EM, Bex PJ, Merabet LB. Object identification in cerebral visual impairment characterized by gaze behavior and image saliency analysis. Brain Dev 2023;45(8):432-444.Abstract
Individuals with cerebral visual impairment (CVI) have difficulties identifying common objects, especially when presented as cartoons or abstract images. In this study, participants were shown a series of images of ten common objects, each from five possible categories ranging from abstract black & white line drawings to color photographs. Fifty individuals with CVI and 50 neurotypical controls verbally identified each object and success rates and reaction times were collected. Visual gaze behavior was recorded using an eye tracker to quantify the extent of visual search area explored and number of fixations. A receiver operating characteristic (ROC) analysis was also carried out to compare the degree of alignment between the distribution of individual eye gaze patterns and image saliency features computed by the graph-based visual saliency (GBVS) model. Compared to controls, CVI participants showed significantly lower success rates and longer reaction times when identifying objects. In the CVI group, success rate improved moving from abstract black & white images to color photographs, suggesting that object form (as defined by outlines and contours) and color are important cues for correct identification. Eye tracking data revealed that the CVI group showed significantly greater visual search areas and number of fixations per image, and the distribution of eye gaze patterns in the CVI group was less aligned with the high saliency features of the image compared to controls. These results have important implications in helping to understand the complex profile of visual perceptual difficulties associated with CVI.
Zhou Y, Zhou A, Philip AM, Margolis M, Babiker F, Chang PY, Anesi SD, Foster SC. Vision Outcomes of Long-Term Immunomodulatory and Steroid Therapy in Sympathetic Ophthalmia. Am J Ophthalmol 2023;253:152-159.Abstract
PURPOSE: To compare vision acuity outcomes of long-term steroid therapy compared with immunomodulatory therapy for treatment of sympathetic ophthalmia. DESIGN: Single-center, retrospective, comparative clinical study. METHODS: Patients with sympathetic ophthalmia treated from March 2005 to October 2022 with at least 1 year of follow-up were included. Visual acuity outcomes were compared by steroid and immunomodulatory treatment modality. RESULTS: Thirty-five patients with sympathetic ophthalmia were included in the study, with follow-up ranging from 1 to 17 years. Higher rates of vision loss correlated with longer periods of active uveitis and steroid treatment. Lower rates of vision loss correlated with longer periods of uveitis remission on immunomodulatory therapy alone and drug-free remission. Treatment with alkylating agents or combination therapy with an antimetabolite, a biologic-response modifier, and cyclosporine are more likely to result in sympathetic ophthalmia remission. CONCLUSION: Immunomodulatory therapy leads to superior vision outcomes in cases of steroid-resistant or recurrent sympathetic ophthalmia. Steroid therapy may be useful for acute or recalcitrant sympathetic uveitis but is insufficient for long-term inflammatory control. PRéCIS: This manuscript describes a retrospective analysis of vision outcomes in patients with sympathetic ophthalmia. Results indicate that long-term immunomodulatory therapy is associated with better vision outcomes than long-term steroid therapy for sympathetic ophthalmia treatment.
Curran A-LK, Stukin J, Ambrosio L, Mantagos IS, Wu C, VanderVeen DK, Hansen RM, Akula JD, Fulton AB. Electroretinographic Responses in Retinopathy of Prematurity Treated Using Intravitreal Bevacizumab or Laser. Am J Ophthalmol 2023;252:275-285.Abstract
PURPOSE: Intravitreal injection of bevacizumab (IVB) offers advantages over laser photoablation for treatment of type 1 retinopathy of prematurity (ROP). However, retinal function has not, to date, been quantitatively compared following these interventions. Therefore, electroretinography (ERG) was used compare retinal function among eyes treated using IVB or laser, and control eyes. In addition, among the IVB-treated eyes, ERG was used to compare function in individuals in whom subsequent laser was and was not required. DESIGN: Prospective clinical cohort study. METHODS: ERG was used to record dark- and light-adapted stimulus/response functions in 21 children treated using IVB (12 of whom required subsequent laser in at least 1 eye for persistent avascular retina [PAR]). Sensitivity and amplitude parameters were derived from the a-wave, b-wave, and oscillatory potentials (OPs), representing activity in photoreceptor, postreceptor, and inner retinal cells, respectively. These parameters were then referenced to those of 76 healthy, term-born controls and compared to those of 10 children treated using laser only. RESULTS: In children with treated ROP, every ERG parameter was significantly below the mean in controls. However, these significant ERG deficits did not differ between IVB- and laser-treated eyes. Among children treated using IVB, no ERG parameter was significantly associated with dose or need for subsequent laser. CONCLUSION: Retinal function was significantly impaired in treated ROP eyes. Function in IVB-treated eyes did not differ from that in laser-treated eyes. Functional differences also did not distinguish those IVB-treated eyes that would subsequently need laser for PAR.
Lu JE, Wolkow N, Lee GN, Lefebvre DR, Freitag SK, Yoon MK. Perceived change in age after functional upper blepharoplasty. Orbit 2023;:1-3.Abstract
PURPOSE: To evaluate the perceived age of patients before and after functional upper blepharoplasty. METHODS: Retrospective chart review of patients who underwent upper blepharoplasty by a single surgeon at an academic center. The inclusion criterion was having external photographs before and after blepharoplasty. Exclusion criteria included any other concurrent eyelid or facial surgery. Primary endpoint: perceived change in age after surgery as judged by the American Society of Ophthalmic Plastic & Reconstructive Surgery (ASOPRS) surgeons. RESULTS: Sixty-seven patients (14 men, 53 women) were included. Mean pre-operative age was 66.9 years (range 37.8-89.4) and mean post-operative age was 67.4 years (range 38.6-89). The mean perceived age pre-operatively was 68.9 years, and the mean perceived age post-operatively was 67.1 years, a change of 1.8 years (p = 0.0001 by two-tailed paired T-test). Inter-rater reliability of the observers was measured by intraclass correlation coefficient of 0.77 for pre-operative and 0.75 for post-operative photos. The decreased perceived age was 1.9 years for women, 1.4 years for men, 0.3 years for Asians, 1.2 years for Hispanics, and 2.1 years for whites. DISCUSSION: Functional upper blepharoplasty by an experienced ASOPRS surgeon was shown to reduce the perceived age of a patient by an average of 1.8 years.
Rothfield L, Falcone MM, Gaier ED, Heidary G, Gise R. Neuro-ophthalmic Complications in Pediatric Leukemia. J Neuroophthalmol 2023;43(4):520-524.Abstract
BACKGROUND: Optic neuropathy in childhood leukemia occurs through multiple direct and indirect mechanisms, including leukemic infiltration of the optic nerve, infection, blood dyscrasias, or adverse effects of treatment. We aimed to characterize visual outcomes in pediatric patients with leukemia-associated neuro-ophthalmic manifestations. METHODS: We retrospectively identified patients with leukemia and optic nerve pathology over 13 years by diagnostic billing codes. We collected information on demographics, presentation, treatment course, and visual outcomes directly from medical records. RESULTS: Of the 19 patients who met inclusion criteria, 17 (89.5%) had pseudotumor cerebri and 2 had direct optic nerve infiltration. Causes of increased intracranial pressure included central nervous system infiltration (6 of 17), hyperviscosity/leukemia (2 of 17), venous sinus thrombosis (3 of 17), medication induced (5 of 17), and bacterial meningitis (1 of 17). 47.1% (8 of 17) had papilledema at the time of leukemia diagnosis, and 94.1% (16 of 17) of patients with pseudotumor cerebri were treated with acetazolamide. At presentation, 3 patients had decreased vision secondary to macular ischemia, subhyaloid vitreous hemorrhage, or steroid induced glaucoma. Following treatment of pseudotumor cerebri, binocular visual acuity was ≥20/25 in all patients. One patient with optic nerve infiltration had a final visual acuity of count fingers in the affected eye. CONCLUSIONS: In our chart review, the most common mechanism of neuro-ophthalmic involvement in pediatric leukemia was elevated intracranial pressure from a myriad of causes. Visual outcomes from patients with elevated intracranial pressure were excellent. Understanding the mechanisms by which leukemia can cause optic nerve disease in pediatric patients can facilitate earlier diagnosis and treatment and potentially improve visual outcomes.
Lopera F, Marino C, Chandrahas AS, O'Hare M, Villalba-Moreno ND, Aguillon D, Baena A, Sanchez JS, Vila-Castelar C, Ramirez Gomez L, Chmielewska N, Oliveira GM, Littau JL, Hartmann K, Park K, Krasemann S, Glatzel M, Schoemaker D, Gonzalez-Buendia L, Delgado-Tirado S, Arevalo-Alquichire S, Saez-Torres KL, Amarnani D, Kim LA, Mazzarino RC, Gordon H, Bocanegra Y, Villegas A, Gai X, Bootwalla M, Ji J, Shen L, Kosik KS, Su Y, Chen Y, Schultz A, Sperling RA, Johnson K, Reiman EM, Sepulveda-Falla D, Arboleda-Velasquez JF, Quiroz YT. Resilience to autosomal dominant Alzheimer's disease in a Reelin-COLBOS heterozygous man. Nat Med 2023;29(5):1243-1252.Abstract
We characterized the world's second case with ascertained extreme resilience to autosomal dominant Alzheimer's disease (ADAD). Side-by-side comparisons of this male case and the previously reported female case with ADAD homozygote for the APOE3 Christchurch (APOECh) variant allowed us to discern common features. The male remained cognitively intact until 67 years of age despite carrying a PSEN1-E280A mutation. Like the APOECh carrier, he had extremely elevated amyloid plaque burden and limited entorhinal Tau tangle burden. He did not carry the APOECh variant but was heterozygous for a rare variant in RELN (H3447R, termed COLBOS after the Colombia-Boston biomarker research study), a ligand that like apolipoprotein E binds to the VLDLr and APOEr2 receptors. RELN-COLBOS is a gain-of-function variant showing stronger ability to activate its canonical protein target Dab1 and reduce human Tau phosphorylation in a knockin mouse. A genetic variant in a case protected from ADAD suggests a role for RELN signaling in resilience to dementia.
Pramanik B, Islam MM, Patra HK. Rational design of peptide-based implants for corneal bioengineering. Curr Opin Biotechnol 2023;81:102947.Abstract
Regeneration of damaged cornea can save vision for millions of patients. Most of these patients are waiting for transplantation of a donor cornea or suitable substitute to restore vision. Although donor cornea transplantation is the most clinically accepted treatment, shortage of donor cornea results in almost 69 out of every 70 patients untreated with the waiting list for transplantation drastically increasing every year according to a prepandemic estimation. Therefore, corneal replacements are coming up as a cutting-edge alternative strategy. In view of the peptides, especially collagen-like peptides and peptide amphiphiles with bioactive functional motifs demonstrate promising avenue for the corneal tissue engineering and promoting regeneration, by their hierarchical self-assembling propensity to acquire desired nano- to macroscale 3D architecture. Here, we analyze rational peptide designing, self-assembly, and strategies of peptide/peptide-based nanoscale building blocks to create the extracellular matrix mimetic implants for functional regeneration of the cornea.
Falahati M, Kurukuti NM, Vargas-Martin F, Peli E, Jung J-H. Oblique multi-periscopic prism for field expansion of homonymous hemianopia. Biomed Opt Express 2023;14(5):2352-2364.Abstract
Oblique Fresnel peripheral prisms have been used for field expansion in homonymous hemianopia mobility such as walking and driving. However, limited field expansion, low image quality, and small eye scanning range limit their effectiveness. We developed a new oblique multi-periscopic prism using a cascade of rotated half-penta prisms, which provides 42° horizontal field expansion along with 18° vertical shift, high image quality, and wider eye scanning range. Feasibility and performance of a prototype using 3D-printed module are demonstrated by raytracing, photographic depiction, and Goldmann perimetry with patients with homonymous hemianopia.
Peters K, McDonald T, Muhammad F, Walsh M, Drenen K, Montieth A, Stephen Foster C, Lee DJ. A2Ar-dependent PD-1+ and TIGIT+ Treg cells have distinct homing requirements to suppress autoimmune uveitis in mice. Mucosal Immunol 2023;16(4):422-431.Abstract
The proper function of regulatory T cells (Tregs) to suppress inflammation requires homing to the correct tissue site. Resolution of autoimmune uveitis generates distinct programmed death receptor 1 (PD-1+) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT+) Tregs in an adenosine 2A receptor (A2Ar)-dependent manner found in the spleen. Where and how these Tregs migrate from the spleen to prevent uveitis is not known. In this work, we show that A2Ar-dependent Tregs migrated to the eye and secondary lymphoid tissue and expressed chemokine receptor (CCR)6 and CCR7. Suppression of autoimmune uveitis required CCR6 and CCR7 expression for TIGIT+ Tregs but not PD-1+ Tregs. Moreover, stimulation of A2Ar on T cells from patients showed a decreased capacity to induce TIGIT+ Tregs that expressed CCR6 or CCR7, and PD-1+ Treg that expressed CCR6. This work provides a mechanistic understanding of the homing requirements of each of these Treg populations. Importantly, this work is clinically relevant because patients with chronic autoimmune uveitis are unable to induce the Treg populations identified in mice that home to the target tissue.
Jones L, Efron N, Bandamwar K, Barnett M, Jacobs DS, Jalbert I, Pult H, Rhee MK, Sheardown H, Shovlin JP, Stahl U, Stanila A, Tan J, Tavazzi S, Ucakhan OO, Willcox MDP, Downie LE. TFOS lifestyle: Impact of contact lenses on the ocular surface. Ocul Surf 2023;Abstract
Several lifestyle choices made by contact lens wearers can have adverse consequences on ocular health. These include being non-adherent to contact lens care, sleeping in lenses, ill-advised purchasing options, not seeing an eyecare professional for regular aftercare visits, wearing lenses when feeling unwell, wearing lenses too soon after various forms of ophthalmic surgery, and wearing lenses when engaged in risky behaviours (e.g., using tobacco, alcohol or recreational drugs). Those with a pre-existing compromised ocular surface may find that contact lens wear exacerbates ocular disease morbidity. Conversely, contact lenses may have various therapeutic benefits. The coronavirus disease-2019 (COVID-19) pandemic has impinged upon the lifestyle of contact lens wearers, introducing challenges such as mask-associated dry eye, contact lens discomfort with increased use of digital devices, inadvertent exposure to hand sanitizers, and reduced use of lenses. Wearing contact lenses in challenging environments, such as in the presence of dust and noxious chemicals, or where there is the possibility of ocular trauma (e.g., sport or working with tools) can be problematic, although in some instances lenses can be protective. Contact lenses can be worn for sport, theatre, at high altitude, driving at night, in the military and in space, and special considerations are required when prescribing in such situations to ensure successful outcomes. A systematic review and meta-analysis, incorporated within the review, identified that the influence of lifestyle factors on soft contact lens dropout remains poorly understood, and is an area in need of further research. Overall, this report investigated lifestyle-related choices made by clinicians and contact lens wearers and discovered that when appropriate lifestyle choices are made, contact lens wear can enhance the quality of life of wearers.
Aboobakar IF, Collantes ERA, Hauser MA, Stamer DW, Wiggs JL. Rare protective variants and glaucoma-relevant cell stressors modulate Angiopoietin-like 7 expression. Hum Mol Genet 2023;32(15):2523-2531.Abstract
Rare missense and nonsense variants in the Angiopoietin-like 7 (ANGPTL7) gene confer protection from primary open-angle glaucoma (POAG), though the functional mechanism remains uncharacterized. Interestingly, a larger variant effect size strongly correlates with in silico predictions of increased protein instability (r = -0.98), suggesting that protective variants lower ANGPTL7 protein levels. Here, we show that missense and nonsense variants cause aggregation of mutant ANGPTL7 protein in the endoplasmic reticulum (ER) and decreased levels of secreted protein in human trabecular meshwork (TM) cells; a lower secreted:intracellular protein ratio strongly correlates with variant effects on intraocular pressure (r = 0.81). Importantly, accumulation of mutant protein in the ER does not increase expression of ER stress proteins in TM cells (P > 0.05 for all variants tested). Cyclic mechanical stress, a glaucoma-relevant physiologic stressor, also significantly lowers ANGPTL7 expression in primary cultures of human Schlemm's canal (SC) cells (-2.4-fold-change, P = 0.01). Collectively, these data suggest that the protective effects of ANGPTL7 variants in POAG stem from lower levels of secreted protein, which may modulate responses to physiologic and pathologic ocular cell stressors. Downregulation of ANGPTL7 expression may therefore serve as a viable preventative and therapeutic strategy for this common, blinding disease.

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