2020

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Steinberg E, Fluksman A, Zemmour C, Tischenko K, Karsch-Bluman A, Brill-Karniely Y, Birsner AE, D'Amato RJ, Benny O. Low dose amiodarone reduces tumor growth and angiogenesis. Sci Rep 2020;10(1):18034.Abstract
Amiodarone is an anti-arrhythmic drug that was approved by the US Food and Drug Administration (FDA) in 1985. Pre-clinical studies suggest that Amiodarone induces cytotoxicity in several types of cancer cells, thus making it a potential candidate for use as an anti-cancer treatment. However, it is also known to cause a variety of severe side effects. We hypothesized that in addition to the cytotoxic effects observed in cancer cells Amiodarone also has an indirect effect on angiogensis, a key factor in the tumor microenvironment. In this study, we examined Amiodarone's effects on a murine tumor model comprised of U-87 MG glioblastoma multiforme (GBM) cells, known to form highly vascularized tumors. We performed several in vitro assays using tumor and endothelial cells, along with in vivo assays utilizing three murine models. Low dose Amiodarone markedly reduced the size of GBM xenograft tumors and displayed a strong anti-angiogenic effect, suggesting dual cancer fighting properties. Our findings lay the ground for further research of Amiodarone as a possible clinical agent that, used in safe doses, maintains its dual properties while averting the drug's harmful side effects.
Subburaman G-BB, Kempen JH, Durairaj S, Balakrishnan V, Valaguru V, Namperumalsamy VP, Thulasiraj RD, Gupta S. Making the decision to donate eyes: Perspectives from the families of the deceased in Madurai, India. Indian J Ophthalmol 2020;68(10):2094-2098.Abstract
Purpose: To identify factors affecting family members' decision whether to donate eye organs. Methods: A community-based case-control study based on in-home interviews with families of deceased individuals who had or had not donated eye organs, in Madurai district, Tamil Nadu, India. Data collected were knowledge and awareness of eye donations, whether the deceased individual had expressed or pledged willingness to donate, and family members' attitudes and willingness to donate their own eye organs. Results: Seventy-six families of donors and 256 families of non-donors completed the survey. Multivariable analysis showed that the following variables were significantly associated with a donation: age, whether the deceased had registered for eye donation, pre-expressed willingness of deceased to donate, whether family members personally know beneficiaries of eye donations, and higher score on a scale evaluating knowledge and awareness about eye donation. The majority of donors' families (71%) had been encouraged by someone to donate. Among non-donor families, a substantially larger fraction (52.8%) indicated they would have donated had someone reminded or encouraged them to do so, in comparison with those who indicated lack of awareness or knowledge (14.5%). Conclusion: Community programs are likely to be effective if they encourage individuals to pledge their eyes or express their willingness to donate their eyes to family members in advance of death; they increase public awareness of the value of eye donation. A friend, family member, neighbor or counselor approaching bereaved families and having a dialogue about eye donation would substantially increase the probability of a decision to donate.
Sudharshan S, Nair N, Curi A, Banker A, Kempen JH. Human immunodeficiency virus and intraocular inflammation in the era of highly active anti retroviral therapy - An update. Indian J Ophthalmol 2020;68(9):1787-1798.Abstract
Intraocular inflammation in patients with human immunodeficiency virus (HIV) infection is commonly due to infectious uveitis. Ocular lesions due to opportunistic infections (OI) are the most common and have been described extensively in the pre highly active antiretroviral therapy (HAART) era. Many eye lesions were classified as acquired immunodeficiency syndrome (AIDS) defining illnesses. HAART-associated improvement in immunity of the individual has changed the pattern of incidence of these hitherto reported known lesions leading to a marked reduction in the occurrence of ocular OI. Newer ocular lesions and newer ocular manifestations of known agents have been noted. Immune recovery uveitis (IRU), the new menace, which occurs as part of immune recovery inflammatory syndrome (IRIS) in the eye, can present with significant ocular inflammation and can pose a diagnostic and therapeutic challenge. Balancing the treatment of inflammation with the risk of reactivation of OI is a task by itself. Ocular involvement in the HAART era can be due to the adverse effects of some systemic drugs used in the management of HIV/AIDS. Drug-associated retinal toxicity and other ocular side effects are being increasingly reported. In this review, we discuss the ocular manifestations in HIV patients and its varied presentations following the introduction of HAART, drug-associated lesions, and the current treatment guidelines.
Sun Y, Smith LEH. Notice of Withdrawal: Retinal Vasculature in Development and Diseases. Annu Rev Vis Sci 2020;Abstract
This article was withdrawn on October 15, 2020, at the request of the journal editors, with agreement from the authors, owing to a substantial amount of unattributed or improperly cited text overlap with other sources. In accordance with Annual Reviews' commitment to transparency, the original PDF of the article remains available for download at .
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Taketani Y, Marmalidou A, Dohlman TH, Singh RB, Amouzegar A, Chauhan SK, Chen Y, Dana R. Restoration of Regulatory T-Cell Function in Dry Eye Disease by Antagonizing Substance P/Neurokinin-1 Receptor. Am J Pathol 2020;190(9):1859-1866.Abstract
Substance P (SP) is a tachykinin neuropeptide, implicated in the pathogenesis of various inflammatory conditions and a critical mediator in pain transmission. Recently, the role of SP was described in the pathogenesis of dry eye disease (DED) through its role in the maturation of antigen-presenting cells at the ocular surface after exposure to desiccating stress. However, the effect of SP on regulatory T cells (Tregs), which are functionally impaired in DED, remains unclear. This study examined the phenotypic and functional changes in Tregs in response to SP in DED. The in vitro cultures of normal Tregs in the presence of SP led to a significant reduction in both Treg frequencies and their suppressive function, which was prevented by the addition of an SP receptor (neurokinin-1 receptor) antagonist. Furthermore, in vivo treatment with the neurokinin-1 receptor antagonist in DED mice effectively restored Treg function, suppressed pathogenic T helper 17 response, and significantly ameliorated the disease. Our results show that a significant increase in SP levels promotes Treg dysfunction in DED, and blockade of SP effectively restores Treg function and suppresses DED severity.
Tan NYQ, Friedman DS, Stalmans I, Ahmed IIK, Sng CCA. Glaucoma screening: where are we and where do we need to go?. Curr Opin Ophthalmol 2020;31(2):91-100.Abstract
PURPOSE OF REVIEW: Current recommendations for glaucoma screening are decidedly neutral. No studies have yet documented improved long-term outcomes for individuals who undergo glaucoma screening versus those who do not. Given the long duration that would be required to detect a benefit, future studies that may answer this question definitively are unlikely. Nevertheless, advances in artificial intelligence and telemedicine will lead to more effective screening at lower cost. With these new technologies, additional research is needed to determine the costs and benefits of screening for glaucoma. RECENT FINDINGS: Using optic disc photographs and/or optical coherence tomography, deep learning systems appear capable of diagnosing glaucoma more accurately than human graders. Eliminating the need for expert graders along with better technologies for remote imaging of the ocular fundus will allow for less expensive screening, which could enable screening of individuals with otherwise limited healthcare access. In India and China, where most glaucoma remains undiagnosed, glaucoma screening was recently found to be cost-effective. SUMMARY: Recent advances in artificial intelligence and telemedicine have the potential to increase the accuracy, reduce the costs, and extend the reach of screening. Further research into implementing these technologies in glaucoma screening is required.
Tao JP, Aakalu VK, Wladis EJ, Sobel RK, Freitag SK, Foster JA, Yen MT. Bioengineered Acellular Dermal Matrix Spacer Grafts for Lower Eyelid Retraction Repair: A Report by the American Academy of Ophthalmology. Ophthalmology 2020;127(5):689-695.Abstract
PURPOSE: To review the literature on the efficacy and safety of bioengineered acellular dermal matrix (BADM) grafts for lower eyelid retraction repair. METHODS: A literature search was conducted in the PubMed database initially in January 2018 and updated in July 2019 to identify all studies in the English language literature on the use of BADM grafts in eyelid reconstruction. The searches yielded 193 citations, and 15 of the 34 articles selected for full review met all inclusion criteria for this assessment. A panel methodologist then assigned a level of evidence rating for each study. Two of the 15 studies included were rated level II and 13 were rated level III. RESULTS: The definition of success varied, but lower eyelid position improvement using lower lid margin-to-pupillary reflex distance was the most common outcome measure. Other end points were the amount of lagophthalmos, cosmesis, exposure, reoperation, or complications, as well as prosthesis retention in anophthalmic socket cases. The surgeon-reported success rate of these outcomes ranged from 75% to 100%. Minor complications included cyst formation, infection, chemosis, pyogenic granuloma, and corneal abrasion. No serious complications such as blindness, anaphylactic reaction, or terminal disease transmission occurred. Of the 526 implants included for assessment in these disparate studies, 27 cases (5%) required reoperation. CONCLUSIONS: No level I evidence was available, and the existing level II and level III studies have variable primary end points, study design limitations, and only short-term follow-up data. The current literature suggests that BADM grafts represent an implantation option for lower eyelid retraction repair. Short-term results are favorable, and the materials used may fill an important gap in care for patients for whom no acceptable alternatives exist, but long-term safety and efficacy remain unknown.
Tashbayev B, Utheim TP, Utheim ØA, Ræder S, Jensen JL, Yazdani M, Lagali N, Vitelli V, Dartt DA, Chen X. Utility of Tear Osmolarity Measurement in Diagnosis of Dry Eye Disease. Sci Rep 2020;10(1):5542.Abstract
The prevalence of dry eye disease is high worldwide and poses a great burden on patients' daily lives. Accurate diagnosis of the disease is important, and it requires application of various methods. Hyperosmolarity is believed to be the disease marker and thus measuring it provides useful information. In this study we investigated utility of tear osmolarity measured with TearLab osmometer, along with other diagnostic tests (Ocular Surface Disease Index questionnaire, Tear film break-up time, Ocular Protection Index, Ocular Surface Staining, Schirmer I test, Meibomian gland functionality in 757 patients (1514 eyes) with dry eye disease and 29 healthy controls (58 eyes). Statistical differences between the patient group and the control group were observed for all the tests apart from tear osmolarity, regardless of cut-off value (>308 mOsm/L, >316 mOsm/L, and inter-eye difference >8 mOsm/L). Moreover, in the receiver operating characteristics curve analyses tear osmolarity measurement could not discriminate dry eye disease pathological scores. Therefore, our study suggests that tear osmolarity measured with TearLab osmometer cannot be used as a key indicator of DED.
Tayebi B, Sharif F, Han J-H. Smart filtering of phase residues in noisy wrapped holograms. Sci Rep 2020;10(1):16965.Abstract
Phase unwrapping is one of the major challenges in multiple branches of science that extract three-dimensional information of objects from wrapped signals. In several applications, it is important to extract the unwrapped information with minimal signal resolution degradation. However, most of the denoising techniques for unwrapping are designed to operate on the entire phase map to remove a limited number of phase residues, and therefore they significantly degrade critical information contained in the image. In this paper, we present a novel, smart, and automatic filtering technique for locally minimizing the number of phase residues in noisy wrapped holograms, based on the phasor average filtering (PAF) of patches around each residue point. Both patch sizes and PAF filters are increased in an iterative algorithm to minimize the number of residues and locally restrict the artifacts caused by filtering to the pixels around the residue pixels. Then, the improved wrapped phase can be unwrapped using a simple phase unwrapping technique. The feasibility of our method is confirmed by filtering, unwrapping, and enhancing the quality of a noisy hologram of neurons; the intensity distribution of the spatial frequencies demonstrates a 40-fold improvement, with respect to previous techniques, in preserving the higher frequencies.
Tecilazich F, Phan TA, Simeoni F, Scotti GM, Dagher Z, Lorenzi M. Patrolling Monocytes Are Recruited and Activated by Diabetes to Protect Retinal Microvessels. Diabetes 2020;69(12):2709-2719.Abstract
In diabetes there is a long latency between the onset of hyperglycemia and the appearance of structural microangiopathy. Because Ly6C patrolling monocytes (PMo) behave as housekeepers of the vasculature, we tested whether PMo protect microvessels against diabetes. We found that in wild-type mice, diabetes reduced PMo in the general circulation but increased by fourfold the absolute number of PMo adherent to retinal vessels (leukostasis). Conversely, in diabetic NR4A1 mice, a model of absence of PMo, there was no increase in leukostasis, and at 6 months of diabetes, the number of retinal acellular capillaries almost doubled compared with diabetic wild-type mice. Circulating PMo showed gene expression changes indicative of enhanced migratory, vasculoprotective, and housekeeping activities, as well as profound suppression of genes related to inflammation and apoptosis. Promigratory CXCR4 was no longer upregulated at longer duration when retinal acellular capillaries begin to increase. Thus, after a short diabetes duration, PMo are the cells preferentially recruited to the retinal vessels and protect vessels from diabetic damage. These observations support the need for reinterpretation of the functional meaning of leukostasis in diabetes and document within the natural history of diabetic retinopathy processes of protection and repair that can provide novel paradigms for prevention.
Tellefsen S, Badian RA, Utheim TP, Utheim ØA, Stojanovic A, Tashbayev B, Raeder S, Dartt DA, Chen X. Sex and age differences in symptoms and signs of dry eye disease in a Norwegian cohort of patients. Ocul Surf 2020;Abstract
PURPOSE: To investigate sex and age differences in symptoms and signs in a Norwegian clinic-based cohort of patients with dry eye disease (DED). METHODS: Visitors at the Norwegian Dry Eye Clinic were examined using Ocular Surface Disease Index (OSDI) questionnaire score, tear osmolarity, tear break-up time (TFBUT), ocular surface staining, corneal sensitivity, Schirmer I test, and meibum expressibility (ME) and quality (MQ). A diagnosis of DED was made by an ophthalmologist based on symptoms and signs, and only DED patients were enrolled in the study: 1823 patients (338 males; mean age 51.2 ± 16.2 years; 1485 females; mean age 52.5 ± 16.0 years). The patients were divided into age subgroups: 20-39 years, 40-59 years and ≥60 years. Sex differences in the aforementioned tests were analyzed. Values were reported as mean ± standard deviation (SD), and intergroup comparisons were performed using Mann-Whitney U test. Multiple regression was used to analyze sex and age influences on symptoms and signs. RESULTS: When patients of all ages were analyzed, females had increased osmolarity, shorter TFBUT, reduced MQ and ME and higher corneal sensitivity. OSDI, Schirmer I test, ocular surface staining and corneal staining were not significantly different between the sexes. Only with TFBUT and ME were the sex difference present in all age subgroups. Multiple regression showed that all parameters were influenced by either sex or age, but only TFBUT and ME were influenced by both sex and age. (all p < 0.05). CONCLUSIONS: Sex and age differences in dry eye were most consistent in TFBUT and ME, that indicate differences in meibomian gland functionality. Sex and age subgroup stratification is important in future studies investigating DED in other populations.
Teran E, Yee-Rendon C-M, Ortega-Salazar J, De Gracia P, Garcia-Romo E, Woods RL. Evaluation of Two Strategies for Alleviating the Impact on the Circadian Cycle of Smartphone Screens. Optom Vis Sci 2020;97(3):207-217.Abstract
SIGNIFICANCE: Electronic display devices used before bed may negatively affect sleep quality through the effects of short-wavelength (blue) light on melatonin production and the circadian cycle. We quantified the efficacy of night-mode functions and blue-light-reducing lenses in ameliorating this problem. PURPOSE: The purpose of this study was to compare the radiation produced by smartphones that reaches the eye when using night-mode functions or blue-light-reducing spectacle lenses. METHODS: Radiant flux of 64 smartphones was measured with an integrating sphere. The retinal illuminance was calculated from the radiant flux of the smartphones. For the night-mode functions, the spectra produced by the smartphones were measured. The transmittance of four blue-light-reducing spectacle lenses, which filter light with either antireflective coatings or tints, was measured using a spectrometer. To determine the impact of blue-light-reducing spectacles, the radiant flux of the smartphone was weighted by the transmission spectrum of these glasses. Visual and nonvisual (circadian) parameters were calculated to compute the melatonin suppression values (MSVs) through a logistic fitting of previously published data. The MSV was used as the figure of merit to evaluate the performance of blue-light spectacles and smartphone night-mode functions. RESULTS: Night-mode functions in smartphones reduced MSVs by up to 93%. The warmest mode produced the least suppression. Blue-light-reducing spectacles reduced melatonin suppression by 33%, the coated lenses being more efficient than tinted lenses. CONCLUSIONS: All smartphones in this study emit radiant power in the short-wavelength region of the visible spectrum. Such smartphones may impair the regulation of circadian cycles at nighttime. The activation of night-mode functions was more efficient than the commercially available blue-light-reducing spectacle lenses in reducing the amount of short-wavelength light (up to 2.25 times). These results can be extrapolated to most electronic devices because they share the same type of white radiant sources with smartphones.
Testi I, Agrawal R, Mahajan S, Agarwal A, Gunasekeran DV, Raje D, Aggarwal K, Murthy SI, Westcott M, Chee S-P, McCluskey P, Ho SL, Teoh S, Cimino L, Biswas J, Narain S, Agarwal M, Mahendradas P, Khairallah M, Jones N, Tugal-Tutkun I, Babu K, Basu S, Carreño E, Lee R, Al-Dhibi H, Bodaghi B, Invernizzi A, Goldstein DA, Herbort CP, Barisani-Asenbauer T, González-López JJ, Androudi S, Bansal R, Moharana B, Esposti SD, Tasiopoulou A, Nadarajah S, Agarwal M, Abraham S, Vala R, Singh R, Sharma A, Sharma K, Zierhut M, Kon OM, Cunningham ET, Kempen JH, Nguyen QD, Pavesio C, Gupta V. The Collaborative Ocular Tuberculosis Study (COTS)-1: A Multinational Descriptive Review of Tubercular Uveitis in Paediatric Population. Ocul Immunol Inflamm 2020;:1-7.Abstract
PURPOSE: To examine disease profile of tubercular uveitis (TBU) in Paediatric population. METHODS: Among 945 patients of the retrospective multinational study by the Collaborative Ocular Tuberculosis Study (COTS)-1, 29 Paediatric patients diagnosed with TBU were analyzed. RESULTS: Mean age of disease presentation was 12.8 (range 4-18 years), with predominance of males (n = 14/20; 70.0%) and Asian ethnicity (n = 25/29; 86.2%). Posterior uveitis (n = 14/28; 50%) was the most frequent uveitis phenotype, with choroidal involvement occurring in 64.7% (n = 11/17). Incidence of optic disc edema and macular edema was higher in children (n = 8/18; 44.4% and n = 5/18; 27.8%, respectively) than in adults (n = 160/942; 16.9% and n = 135/942; 14.3%, respectively). Comparison of optic disc edema between subgroups showed a significant difference (). All patients received oral corticosteroids, most of them with antitubercular therapy. Treatment failure developed in 4.8% (n = 1/21). CONCLUSIONS: Children have a more severe inflammatory response to the disease, and an intensive anti-inflammatory therapeutic regimen is required to achieve a positive treatment outcome.
Thomas MG, Maconachie GDE, Constantinescu CS, Chan W-M, Barry B, Hisaund M, Sheth V, Kuht HJ, Dineen RA, Harieaswar S, Engle EC, Gottlob I. Congenital monocular elevation deficiency associated with a novel gene variant. Br J Ophthalmol 2020;104(4):547-550.Abstract
BACKGROUND: The genetic basis of monocular elevation deficiency (MED) is unclear. It has previously been considered to arise due to a supranuclear abnormality. METHODS: Two brothers with MED were referred to Leicester Royal Infirmary, UK from the local opticians. Their father had bilateral ptosis and was unable to elevate both eyes, consistent with the diagnosis of congenital fibrosis of extraocular muscles (CFEOM). Candidate sequencing was performed in all family members. RESULTS: Both affected siblings (aged 7 and 12 years) were unable to elevate the right eye. Their father had bilateral ptosis, left esotropia and bilateral limitation of elevation. Chin up head posture was present in the older sibling and the father. Bell's phenomenon and vertical rotational vestibulo-ocular reflex were absent in the right eye for both children. Mild bilateral facial nerve palsy was present in the older sibling and the father. Both siblings had slight difficulty with tandem gait. MRI revealed hypoplastic oculomotor nerve. Left anterior insular focal cortical dysplasia was seen in the older sibling. Sequencing of revealed a novel heterozygous variant (c.1263G>C, p.E421D) segregating with the phenotype. This residue is in the C-terminal H12 α-helix of β-tubulin and is one of three putative kinesin binding sites. CONCLUSION: We show that familial MED can arise from a variant and could be considered a limited form of CFEOM. Neurological features such as mild facial palsy and cortical malformations can be present in patients with MED. Thus, in individuals with congenital MED, consideration may be made for mutation screening.
Tisdale AK, Chwalisz BK. Neuro-ophthalmic manifestations of coronavirus disease 19. Curr Opin Ophthalmol 2020;31(6):489-494.Abstract
PURPOSE OF REVIEW: To provide a summary of the neuro-ophthalmic manifestations of coronavirus disease 19 (COVID-19), documented in the literature thus far. RECENT FINDINGS: A small but growing literature documents cases of new onset neuro-ophthalmic disease, in the setting of COVID-19 infection. Patients with COVID-19 have experienced acute onset vision loss, optic neuritis, cranial neuropathies, and Miller Fisher syndrome. In addition, COVID-19 increases the risk of cerebrovascular diseases that can impact the visual system. SUMMARY: The literature on COVID-19 continues to evolve. Although COVID-19 primarily impacts the respiratory system, there are several reports of new onset neuro-ophthalmic conditions in COVID-infected patients. When patients present with new onset neuro-ophthalmic issues, COVID-19 should be kept on the differential. Testing for COVID-19 should be considered, especially when fever or respiratory symptoms are also present. When screening general patients for COVID-19-associated symptoms, frontline physicians can consider including questions about diplopia, eye pain, pain with extraocular movements, decreased vision, gait issues, and other neurologic symptoms. The presence of these symptoms may increase the overall probability of viral infection, especially when fever or respiratory symptoms are present. More research is needed to establish a causal relationship between COVID-19 and neuro-ophthalmic disease, and better understand pathogenesis.
Tolesa K, Abateneh A, Kempen JH, Gelaw Y. Patterns of Uveitis among Patients Attending Jimma University Department of Ophthalmology, Jimma, Ethiopia. Ocul Immunol Inflamm 2020;28(7):1109-1115.Abstract
: Uveitis is an important cause of blindness and ocular morbidity in the world. The patterns of uveitis have not been well characterized in sub-Saharan Africa. : To describe the characteristics of uveitis among patients presenting to Jimma University Department of Ophthalmology (JUDO) from July 2013 to December 2014. : This hospital-based prospective cross-sectional study included all new uveitis patients visiting JUDO outpatient department during the study period. : Among 98 patients diagnosed with uveitis, anterior uveitis was found in 74.5% of patients. Majority of the patients, 83.7%, had unilateral uveitis. A uveitis syndrome was identified in 22.5% of cases; of these 15 (68.2%) were infectious. Herpes simplex uveitis was the commonest infectious cause (53.3%) while Toxoplasmosis was the most common cause of posterior uveitis (60%). : Anterior uveitis was the most common pattern found among uveitis patients. Herpes simplex and toxoplasmic chorioretinitis were the most common-identified infectious causes.
Tomita Y, Fu Z, Wang Z, Cakir B, Cho SS, Britton W, Sun Y, Hellström A, Talukdar S, Smith LEH. Long-Acting FGF21 Inhibits Retinal Vascular Leakage in In Vivo and In Vitro Models. Int J Mol Sci 2020;21(4)Abstract
The aim of the current study was to investigate the impact of long-acting fibroblast growth factor 21 (FGF21) on retinal vascular leakage utilizing machine learning and to clarify the mechanism underlying the protection. To assess the effect on retinal vascular leakage, C57BL/6J mice were pre-treated with long-acting FGF21 analog or vehicle (Phosphate Buffered Saline; PBS) intraperitoneally (i.p.) before induction of retinal vascular leakage with intravitreal injection of mouse (m) vascular endothelial growth factor 164 (VEGF164) or PBS control. Five hours after mVEGF164 injection, we retro-orbitally injected Fluorescein isothiocyanate (FITC) -dextran and quantified fluorescence intensity as a readout of vascular leakage, using the Image Analysis Module with a machine learning algorithm. In FGF21- or vehicle-treated primary human retinal microvascular endothelial cells (HRMECs), cell permeability was induced with human (h) VEGF165 and evaluated using FITC-dextran and trans-endothelial electrical resistance (TEER). Western blots for tight junction markers were performed. Retinal vascular leakage in vivo was reduced in the FGF21 versus vehicle- treated mice. In HRMECs in vitro, FGF21 versus vehicle prevented hVEGF-induced increase in cell permeability, identified with FITC-dextran. FGF21 significantly preserved TEER compared to hVEGF. Taken together, FGF21 regulates permeability through tight junctions; in particular, FGF21 increases Claudin-1 protein levels in hVEGF-induced HRMECs. Long-acting FGF21 may help reduce retinal vascular leakage in retinal disorders and machine learning assessment can help to standardize vascular leakage quantification.
Tomita Y, Cakir B, Liu C-H, Fu Z, Huang S, Cho SS, Britton WR, Sun Y, Puder M, Hellström A, Talukdar S, Smith LEH. Free fatty acid receptor 4 activation protects against choroidal neovascularization in mice. Angiogenesis 2020;23(3):385-394.Abstract
To examine whether free fatty acid receptor 4 (FFAR4) activation can protect against choroidal neovascularization (CNV), which is a common cause of blindness, and to elucidate the mechanism underlying the inhibition, we used the mouse model of laser-induced CNV to mimic angiogenic aspects of age-related macular degeneration (AMD). Laser-induced CNV was compared between groups treated with an FFAR4 agonist or vehicle, and between FFAR4 wild-type (Ffar4) and knock out (Ffar4) mice on a C57BL/6J/6N background. The ex vivo choroid-sprouting assay, including primary retinal pigment epithelium (RPE) and choroid, without retina was used to investigate whether FFAR4 affects choroidal angiogenesis. Western blotting for pNF-ĸB/NF-ĸB and qRT-PCR for Il-6, Il-1β, Tnf-α, Vegf, and Nf-ĸb were used to examine the influence of FFAR4 on inflammation, known to influence CNV. RPE isolated from Ffar4 and Ffar4 mice were used to assess RPE contribution to inflammation. The FFAR4 agonist suppressed laser-induced CNV in C57BL/6J mice, and CNV increased in Ffar4 compared to Ffar4 mice. We showed that the FFAR4 agonist acted through the FFAR4 receptor. The FFAR4 agonist suppressed mRNA expression of inflammation markers (Il-6, Il-1β) via the NF-ĸB pathway in the retina, choroid, RPE complex. The FFAR4 agonist suppressed neovascularization in the choroid-sprouting ex vivo assay and FFAR4 deficiency exacerbated sprouting. Inflammation markers were increased in primary RPE cells of Ffar4 mice compared with Ffar4 RPE. In this mouse model, the FFAR4 agonist suppressed CNV, suggesting FFAR4 to be a new molecular target to reduce pathological angiogenesis in CNV.
Tomita Y, Shao Z, Cakir B, Kotoda Y, Fu Z, Smith LEH. An Ex Vivo Choroid Sprouting Assay of Ocular Microvascular Angiogenesis. J Vis Exp 2020;(162)Abstract
Pathological choroidal angiogenesis, a salient feature of age-related macular degeneration, leads to vision impairment and blindness. Endothelial cell (EC) proliferation assays using human retinal microvascular endothelial cells (HRMECs) or isolated primary retinal ECs are widely used in vitro models to study retinal angiogenesis. However, isolating pure murine retinal endothelial cells is technically challenging and retinal ECs may have different proliferation responses than choroidal endothelial cells and different cell/cell interactions. A highly reproducible ex vivo choroidal sprouting assay as a model of choroidal microvascular proliferation was developed. This model includes the interaction between choroid vasculature (EC, macrophages, pericytes) and retinal pigment epithelium (RPE). Mouse RPE/choroid/scleral explants are isolated and incubated in growth-factor-reduced basal membrane extract (BME) (day 0). Medium is changed every other day and choroid sprouting is quantified at day 6. The images of individual choroid explant are taken with an inverted phase microscope and the sprouting area is quantified using a semi-automated macro plug-in to the ImageJ software developed in this lab. This reproducible ex vivo choroidal sprouting assay can be used to assess compounds for potential treatment and for microvascular disease research to assess pathways involved in choroidal micro vessel proliferation using wild type and genetically modified mouse tissue.
Tomita Y, Lee D, Tsubota K, Kurihara T. PPARα Agonist Oral Therapy in Diabetic Retinopathy. Biomedicines 2020;8(10)Abstract
Diabetic retinopathy (DR) is an eye condition that develops after chronically poorly-managed diabetes, and is presently the main cause for blindness on a global scale. Current treatments for DR such as laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents and vitreoretinal surgery are only applicable at the late stages of DR and there are possibilities of significant adverse effects. Moreover, the forms of treatment available for DR are highly invasive to the eyes. Safer and more effective pharmacological treatments are required for DR treatment, in particular at an early stage. In this review, we cover recently investigated promising oral pharmacotherapies, the methods of which are safer, easier to use, patient-friendly and pain-free, in clinical studies. We especially focus on peroxisome proliferator-activator receptor alpha (PPARα) agonists in which experimental evidence suggests PPARα activation may be closely related to the attenuation of vascular damages, including lipid-induced toxicity, inflammation, an excess of free radical generation, endothelial dysfunction and angiogenesis. Furthermore, oral administration of selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) agonists may induce hepatic fibroblast growth factor 21 expression, indirectly resulting in retinal protection in animal studies. Our review will enable more comprehensive approaches for understanding protective roles of PPARα for the prevention of DR development.

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