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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.
Wang L, Liu C, Lu W, Xu L, Kuang L, Hua D. ROS-sensitive Crocin-loaded chitosan microspheres for lung targeting and attenuation of radiation-induced lung injury. Carbohydr Polym 2023;307:120628.Abstract
Radiation-induced lung injury (RILI) is one of the major complications in patients exposed to accidental radiation and radiotherapy for thoracic malignancies. However, there is no reliable radioprotector for effective clinical treatment of RILI so far. Herein, a novel Crocin-loaded chitosan microsphere is developed for lung targeting and attenuation of RILI. The chitosan microspheres are modified with 4-carboxyphenylboronic acid and loaded with the natural antioxidant Crocin-I to give the drug-loaded microspheres (~10 μm). The microspheres possess good biocompatibility in vivo and in vitro. In a mouse model, they exhibit effective passive targeting performance and a long retention time in the lung after intravenous administration. Furthermore, they improve the radioprotective effect of Crocin-I for the treatment of RILI by reducing the level of inflammatory cytokines in bronchoalveolar lavage fluid and by regulating oxidative stress in lung tissues. The targeted agents significantly improved the bioavailability and radioprotection of Crocin-I by the outstanding passive targeting effect. This work may provide a promising strategy for efficient radioprotection on RILI using passive lung targeting microspheres.
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.
Maidana DE, Gonzalez-Buendia L, Miller JW, Vavvas DG. RIPK necrotic cell death pathway in both donor photoreceptor and host immune cells synergize to affect photoreceptor graft survival. FASEB J 2023;37(4):e22847.Abstract
Photoreceptor transplant has been put forward as a repair strategy to tackle degenerated retinas. Nonetheless, cell death and immune rejection seriously limit the success of this strategy, with only a small fraction of transplanted cells surviving. Improving the survival of transplanted cells is of critical importance. Recent evidence has identified receptor-interacting protein kinase 3 (RIPK3) as a molecular trigger controlling necroptotic cell death and inflammation. However, its role in photoreceptor transplantation and regenerative medicine has not been studied. We hypothesized that modulation of RIPK3 to address both cell death and immunity could have advantageous effects on photoreceptor survival. In a model of inherited retinal degeneration, deletion of RIPK3 in donor photoreceptor precursors significantly increases the survival of transplanted cells. Simultaneous RIPK3 deletion in donor photoreceptors and recipients maximizes graft survival. Lastly, to discern the role of RIPK3 in the host immune response, bone marrow transplant experiments demonstrated that peripheral immune cell RIPK3 deficiency is protective for both donor and host photoreceptor survival. Interestingly, this finding is independent of photoreceptor transplantation, as the peripheral protective effect is also observed in an additional retinal detachment photoreceptor degeneration model. Altogether, these results indicate that immunomodulatory and neuroprotective strategies targeting the RIPK3 pathway can aid regenerative therapies of photoreceptor transplantation.
Feng Q, Wong KA, Benowitz LI. Full-length optic nerve regeneration in the absence of genetic manipulations. JCI Insight 2023;8(7)Abstract
The inability of mature retinal ganglion cells (RGCs) to regenerate axons after optic nerve injury can be partially reversed by manipulating cell-autonomous and/or -nonautonomous factors. Although manipulations of cell-nonautonomous factors could have higher translational potential than genetic manipulations of RGCs, they have generally produced lower levels of optic nerve regeneration. Here, we report that preconditioning resulting from mild lens injury (conditioning LI, cLI) before optic nerve damage induced far greater regeneration than LI after nerve injury or the pro-inflammatory agent zymosan given either before or after nerve damage. Unlike zymosan-induced regeneration, cLI was unaltered by depleting mature neutrophils or T cells or blocking receptors for known inflammation-derived growth factors (oncomodulin, stromal cell-derived factor 1, CCL5) and was only partly diminished by suppressing CCR2+ monocyte recruitment. Repeated episodes of LI led to full-length optic nerve regeneration, and pharmacological removal of local resident macrophages with the colony stimulating factor 1 receptor inhibitor PLX5622 enabled some axons to reinnervate the brain in just 6 weeks, comparable to the results obtained with the most effective genetic manipulations of RGCs. Thus, cell-nonautonomous interventions can induce high levels of optic nerve regeneration, paving the way to uncovering potent, translatable therapeutic targets for CNS repair.
Nakagawa H, Alemi H, Wang S, Kahale F, Blanco T, Liu C, Yin J, Dohlman TH, Dana R. Descemet Stripping Only Technique for Corneal Endothelial Damage in Mice. Cornea 2023;42(4):470-475.Abstract
PURPOSE: Descemet stripping only is an emerging surgical technique used to remove central Descemet membrane and corneal endothelial cells in patients with corneal endothelial disease. Here, we describe a murine model of this procedure to help facilitate basic science investigation and evaluation of postoperative outcomes using this surgical technique. METHODS: Slitlamp biomicroscopy, central corneal thickness assessment (by optical coherence tomography), and immunohistochemistry were used to assess the model through 7 weeks of follow-up. RESULTS: Complete removal of the endothelium and Descemet membrane was confirmed by slitlamp biomicroscopy and by histology. Central corneal thickness peaked at day 1 postinjury and then declined over the course of 2 weeks to a stable level of persistent edema. Seven weeks postinjury, immunohistochemical staining for ZO-1 showed the area of Descemet stripping was fully covered by enlarged and dysmorphic corneal endothelial cell. No significant ocular complications were appreciated through the end of the follow-up. CONCLUSIONS: We demonstrate the feasibility of and provide detailed instructions for a murine model of Descemet stripping only. This model provides a potential in vivo platform to investigate the mechanisms and biology of this emerging surgical procedure.
Douglas VP, Douglas KA, Torun N. Optical coherence tomography angiography in neuro-ophthalmology. Curr Opin Ophthalmol 2023;34(4):354-360.Abstract
PURPOSE OF REVIEW: Optical coherence tomography angiography (OCTA) is a novel, noninvasive imaging technique, which provides depth resolved visualization of microvasculature of the retina and choroid. Although OCTA has been widely used for the evaluation of a number of retinal diseases, its use in the field of neuro-ophthalmology has been less studied. In this review, we provide an update on the utility of OCTA in neuro-ophthalmic conditions. RECENT FINDINGS: Peripapillary and macular microvasculature analyses have indicated that OCTA can be a promising tool for early detection of a number of neuro-ophthalmic diseases, differential diagnosis, and monitoring of disease progression. Recent studies have demonstrated that structural and functional impairment can develop at early stages in some conditions such as in multiple sclerosis and Alzheimer's disease even in the absence of overt clinical symptoms. Furthermore, this dye-less technique can be a valuable adjunct tool in the detection of complications commonly seen in some congenital entities such optic disc drusen. SUMMARY: Since its introduction, OCTA has emerged as an important imaging approach shedding light on unrevealed pathophysiological mechanisms of several ocular diseases. The use of OCTA as a biomarker in the field of neuro-ophthalmology has recently gained considerable attention with studies supporting its role in clinical setting while larger studies are warranted for correlating these findings with traditional diagnostic procedures and clinical features and outcomes.
Chronopoulos P, Manicam C, Zadeh JK, Laspas P, Unkrig JC, Göbel ML, Musayeva A, Pfeiffer N, Oelze M, Daiber A, Li H, Xia N, Gericke A. Effects of Resveratrol on Vascular Function in Retinal Ischemia-Reperfusion Injury. Antioxidants (Basel) 2023;12(4)Abstract
Ischemia-reperfusion (I/R) events are involved in the development of various ocular pathologies, e.g., retinal artery or vein occlusion. We tested the hypothesis that resveratrol is protective against I/R injury in the murine retina. Intraocular pressure (IOP) was elevated in anaesthetized mice to 110 mm Hg for 45 min via a micropipette placed in the anterior chamber to induce ocular ischemia. In the fellow eye, which served as control, IOP was kept at a physiological level. One group received resveratrol (30 mg/kg/day p.o. once daily) starting one day before the I/R event, whereas the other group of mice received vehicle solution only. On day eight after the I/R event, mice were sacrificed and retinal wholemounts were prepared and immuno-stained using a Brn3a antibody to quantify retinal ganglion cells. Reactivity of retinal arterioles was measured in retinal vascular preparations using video microscopy. Reactive oxygen species (ROS) and nitrogen species (RNS) were quantified in ocular cryosections by dihydroethidium and anti-3-nitrotyrosine staining, respectively. Moreover, hypoxic, redox and nitric oxide synthase gene expression was quantified in retinal explants by PCR. I/R significantly diminished retinal ganglion cell number in vehicle-treated mice. Conversely, only a negligible reduction in retinal ganglion cell number was observed in resveratrol-treated mice following I/R. Endothelial function and autoregulation were markedly reduced, which was accompanied by increased ROS and RNS in retinal blood vessels of vehicle-exposed mice following I/R, whereas resveratrol preserved vascular endothelial function and autoregulation and blunted ROS and RNS formation. Moreover, resveratrol reduced I/R-induced mRNA expression for the prooxidant enzyme, nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2). Our data provide evidence that resveratrol protects from I/R-induced retinal ganglion cell loss and endothelial dysfunction in the murine retina by reducing nitro-oxidative stress possibly via suppression of NOX2 upregulation.
Leinonen HO, Bull E, Fu Z. Neural and Müller glial adaptation of the retina to photoreceptor degeneration. Neural Regen Res 2023;18(4):701-707.Abstract
The majority of inherited retinal degenerative diseases and dry age-related macular degeneration are characterized by decay of the outer retina and photoreceptors, which leads to progressive loss of vision. The inner retina, including second- and third-order retinal neurons, also shows aberrant structural changes at all stages of degeneration. Müller glia, the major glial cells maintain retinal homeostasis, activating and rearranging immediately in response to photoreceptor stress. These phenomena are collectively known as retinal remodeling and are anatomically well described, but their impact on visual function is less well characterized. Retinal remodeling has traditionally been considered a detrimental chain of events that decreases visual function. However, emerging evidence from functional assays suggests that remodeling could also be a part of a survival mechanism wherein the inner retina responds plastically to outer retinal degeneration. The visual system´s first synapses between the photoreceptors and bipolar cells undergo rewiring and functionally compensate to maintain normal signal output to the brain. Distinct classes of retinal ganglion cells remain even after the massive loss of photoreceptors. Müller glia possess the regenerative potential for retinal recovery and possibly exert adaptive transcriptional changes in response to neuronal loss. These types of homeostatic changes could potentially explain the well-maintained visual function observed in patients with inherited retinal degenerative diseases who display prominent anatomic retinal pathology. This review will focus on our current understanding of retinal neuronal and Müller glial adaptation for the potential preservation of retinal activity during photoreceptor degeneration. Targeting retinal self-compensatory responses could help generate universal strategies to delay sensory disease progression.
Apivatthakakul A, Liu R, Sobrin L. Successful treatment of idiopathic retinal vasculitis with rituximab in two patients. Am J Ophthalmol Case Rep 2023;30:101844.Abstract
PURPOSE: To describe results of treatment of idiopathic retinal vasculitis with intravenous rituximab. OBSERVATIONS: We present two patients with idiopathic retinal vasculitis who required steroid-sparing therapy and achieved steroid-free remission with intravenous rituximab. Rituximab was used as a first-line steroid-sparing agent after steroids in one patient and as a second-line steroid-sparing agent in the other patient. Both patients achieved steroid-free remission of disease with follow up of at least one year after rituximab initiation. CONCLUSIONS AND IMPORTANCE: Rituximab achieved steroid-free remission in two patients with idiopathic retinal vasculitis. It should be considered as a treatment option in these patients.
Nagino K, Inomata T, Nakamura M, Sung J, Midorikawa-Inomata A, Iwagami M, Fujio K, Akasaki Y, Okumura Y, Huang T, Fujimoto K, Eguchi A, Miura M, Hurramhon S, Zhu J, Ohno M, Hirosawa K, Morooka Y, Dana R, Murakami A, Kobayashi H. Symptom-based stratification algorithm for heterogeneous symptoms of dry eye disease: a feasibility study. Eye (Lond) 2023;37(16):3484-3491.Abstract
BACKGROUND/OBJECTIVE: To test the feasibility of a dry eye disease (DED) symptom stratification algorithm previously established for the general population among patients visiting ophthalmologists. SUBJECT/METHODS: This retrospective cross-sectional study was conducted between December 2015 and October 2021 at a university hospital in Japan; participants who underwent a comprehensive DED examination and completed the Japanese version of the Ocular Surface Disease Index (J-OSDI) were included. Patients diagnosed with DED were stratified into seven clusters using a previously established symptom-based stratification algorithm for DED. Characteristics of the patients in stratified clusters were compared. RESULTS: In total, 426 participants were included (median age [interquartile range]; 63 [48-72] years; 357 (83.8%) women). Among them, 291 (68.3%) participants were diagnosed with DED and successfully stratified into seven clusters. The J-OSDI total score was highest in cluster 1 (61.4 [52.2-75.0]), followed by cluster 5 (44.1 [38.8-47.9]). The tear film breakup time was the shortest in cluster 1 (1.5 [1.1-2.1]), followed by cluster 3 (1.6 [1.0-2.5]). The J-OSDI total scores from the stratified clusters in this study and those from the clusters identified in the previous study showed a significant correlation (r = 0.991, P < 0.001). CONCLUSIONS: The patients with DED who visited ophthalmologists were successfully stratified by the previously established algorithm for the general population, uncovering patterns for their seemingly heterogeneous and variable clinical characteristics of DED. The results have important implications for promoting treatment interventions tailored to individual patients and implementing smartphone-based clinical data collection in the future.
Oke I, Nihalani BR, VanderVeen DK. Axial length and corneal curvature of normal eyes in the first decade of life. Eur J Ophthalmol 2023;33(6):2217-2221.Abstract
BACKGROUND/AIMS: To establish normative curves for axial length and corneal curvature in the first decade of life. METHODS: This is a cross-sectional study from a single institution in the United States. Children from 0- to 10-years of age with no underlying ocular pathology were prospectively enrolled to obtain ultrasound biometry and hand-held keratometry while under anaesthesia for an unrelated procedure. Older cooperative children had optical biometry obtained in-office. Logarithmic quantile regression models were used to determine the change in axial length and average keratometry as a function of age. RESULTS: Single-eye measurements from 100 children were included. 75% of children were White and 49% female. Median axial length ranged from 20.6 mm (IQR, 20.2 to 21.1 mm) at age one year to 23.1 mm (IQR, 22.5 to 23.8 mm) at age ten years. Median average keratometry ranged from 44.1 D (IQR, 42.6 to 45.4 D) at age one year to 43.5 (IQR, 42.2 to 44.0 D) at age ten years. As age increased, there was a significant increase in axial length (0.74 mm per doubling of age; 95% CI, 0.62 to 0.82 mm), and a non-significant trend towards lower average keratometry (-0.21 D per doubling of age; 95% CI, -0.62 to 0.08 D). CONCLUSIONS: We provide a set of normative charts for axial length and corneal curvature which may facilitate the identification of eyes outside the normal range and assist in the management of ocular conditions such as glaucoma or cataract.
Patel H, Pavlichenko I, Grinthal A, Zhang CT, Alvarenga J, Kreder MJ, Weaver JC, Ji Q, Ling CWF, Choy J, Li Z, Black NL, Bispo PJM, Lewis JA, Kozin ED, Aizenberg J, Remenschneider AK. Design of medical tympanostomy conduits with selective fluid transport properties. Sci Transl Med 2023;15(690):eadd9779.Abstract
Implantable tubes, shunts, and other medical conduits are crucial for treating a wide range of conditions from ears and eyes to brain and liver but often impose serious risks of device infection, obstruction, migration, unreliable function, and tissue damage. Efforts to alleviate these complications remain at an impasse because of fundamentally conflicting design requirements: Millimeter-scale size is required to minimize invasiveness but exacerbates occlusion and malfunction. Here, we present a rational design strategy that reconciles these trade-offs in an implantable tube that is even smaller than the current standard of care. Using tympanostomy tubes (ear tubes) as an exemplary case, we developed an iterative screening algorithm and show how unique curved lumen geometries of the liquid-infused conduit can be designed to co-optimize drug delivery, effusion drainage, water resistance, and biocontamination/ingrowth prevention in a single subcapillary-length-scale device. Through extensive in vitro studies, we demonstrate that the engineered tubes enabled selective uni- and bidirectional fluid transport; nearly eliminated adhesion and growth of common pathogenic bacteria, blood, and cells; and prevented tissue ingrowth. The engineered tubes also enabled complete eardrum healing and hearing preservation and exhibited more efficient and rapid antibiotic delivery to the middle ear in healthy chinchillas compared with current tympanostomy tubes, without resulting in ototoxicity at up to 24 weeks. The design principle and optimization algorithm presented here may enable tubes to be customized for a wide range of patient needs.
Romano D, Aiello F, Parekh M, Levis HJ, Gadhvi KA, Moramarco A, Viola P, Fontana L, Semeraro F, Romano V. Incidence and management of early postoperative complications in lamellar corneal transplantation. Graefes Arch Clin Exp Ophthalmol 2023;261(11):3097-3111.Abstract
PURPOSE: To provide a comprehensive review of the incidence, risk factors, and management of early complications after deep anterior lamellar keratoplasty (DALK), Descemet stripping automated keratoplasty (DSAEK), and Descemet membrane endothelial keratoplasty (DMEK). METHODS: A literature review of complications, that can occur from the time of the transplant up to 1 month after the transplant procedure, was conducted. Case reports and case series were included in the review. RESULTS: Complications in the earliest postoperative days following anterior and posterior lamellar keratoplasty have shown to affect graft survival. These complications include, but are not limited to, double anterior chamber, sclerokeratitis endothelial graft detachment, acute glaucoma, fluid misdirection syndrome, donor-transmitted and recurrent infection, and Uretts-Zavalia syndrome. CONCLUSION: It is essential for surgeons and clinicians to not only be aware of these complications but also know how to manage them to minimize their impact on long-term transplant survival and visual outcomes.

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