Department of Ophthalmology Works

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    A narrative review on the association of high intraocular pressure and glaucoma in patients with retinal vein occlusion
    (AME Publishing Company, 2022) Jabbehdari, Sayena; Yazdanpanah, Ghasem; Cantor, Louis B.; Hajrasouliha, Amir Reza; Ophthalmology, School of Medicine
    Background and objective: Retinal vein occlusion (RVO) is a major cause of vision loss and elevated intraocular pressure (IOP), high ocular perfusion pressure, and glaucoma are known ophthalmic risk factors for RVO. The aim of this paper is to provide the update on the association and management of high IOP/glaucoma and RVO. Methods: A literature review was performed in PubMed and Medline until May 2022 utilizing specific keywords and cross-matched reference lists. Key content and findings: The association of RVO with high IOP/glaucoma may be attributed to retinal ganglion cell loss due to retinal ischemia in high IOP and glaucoma. As new modalities showed, decreased optic disc perfusion, reduced density of blood vessels in the optic nerve head of glaucoma patients, changes in the peripapillary microvascular parameters, and decreased retinal nerve fiber layer (RNFL) thickness of the optic nerve head of eyes with RVO suggest a common pathway between RVO and glaucoma. Literature suggests the close follow up for glaucoma development among patients with non-arteriovenous (AV) crossing (optic cup or optic nerve sited) RVO in fellow eye and management of elevated IOP among RVO cases treated with anti-vascular endothelial growth factor (VEGF) antibodies/corticosteroids and those with preexisting primary open angle glaucoma (POAG). Conclusions: Determining potential patient responses to treatment and considering therapeutic options are challenging among patients with RVO and glaucoma. However, IOP lowering managements in preventing IOP spikes in patients with preexisting glaucoma and early treatment of macular edema in eyes with RVO is recommended.
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    A Novel Technique Identifies Valve-Like Pathways Entering and Exiting Schlemm's Canal in Macaca nemestrina Primates With Similarities to Human Pathways
    (Frontiers Media, 2022-07-04) Martin, Elizabeth A.; Johnstone, Murray A.; Ophthalmology, School of Medicine
    Purpose: The aim of the study was 1) to describe a novel combination of techniques that permit immunohistochemistry imaging of Schlemm's canal inlet (SIV) and outlet (SOV) valve-like structures, 2) to identify tissue-level SIV adhesive relationships linking the trabecular meshwork (TM) to hinged collagen leaflets at the Schlemm's canal (SC) external wall, and 3) to determine whether the SIV lumen wall's adhesive vascular markers are similar to those of the SC inner wall endothelium. Materials and Methods: Anterior segments of 16 M. nemestrina primates underwent immunohistochemistry (IHC) labeling. We perfused fluorescent microspheres into 12 of the eyes. Limbal tissues were divided into quadrants, viscoelastic introduced into SC, tissues fixed, immunohistochemistry performed, radial segments cut, tissues clarified, and confocal microscopy performed. Finally, we generated ImageJ 3D projections encompassing the TM, SC, and distal pathways. Results: IHC imaging identified 3D relationships between SIV, collector channel ostia, collector channels (CC), SOV, and intrascleral channels. Imaging depth increased 176.9%, following clarification (p < 0.0001). Imaging demonstrated CD31, collagen type 1 and 4 in the walls of the SIV lumen and more distal pathways. In eight eyes, 384 segments were examined, 447 SIV identified, and 15.4% contained microspheres. Conclusion: Our technique's imaging depth permitted the identification of SIV linkage between the TM and SOV. We found comparable cell-cell adhesion molecules (CD31) and basement membrane components in the SC inner wall and SIV lumen walls. Recent OCT studies have suggested that SIV tensional relationships may control CC entrance dimensions that regulate distal resistance. Cellular adhesive properties sustain SIV tensional relationships. These SIV cell-cell and cell-basement membrane properties warrant further study because abnormalities could be a factor in the IOP elevation of glaucoma.
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    ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity
    (American Diabetes Association, 2016-01) Patel, Vaibhav B.; Mori, Jun; McLean, Brent A.; Basu, Ratnadeep; Das, Subhash K.; Ramprasath, Tharmarajan; Parajuli, Nirmal; Penninger, Josef M.; Grant, Maria B.; Lopaschuk, Gary D.; Oudit, Gavin Y.; Department of Ophthalmology, IU School of Medicine
    Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance.
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    The acute and chronic effects of intravitreal anti-vascular endothelial growth factor injections on intraocular pressure: A review
    (Elsevier, 2017) Bracha, Peter; Moore, Nicholas A.; Ciulla, Thomas A.; WuDunn, Darrell; Cantor, Louis B.; Department of Ophthalmology, School of Medicine
    The acute and chronic effects of repeated intravitreal antivascular endothelial growth factor (VEGF) injections on intraocular pressure have not been fully characterized, and the development of sustained ocular hypertension could adversely affect patients who are at risk of glaucomatous optic neuropathy. As expected, volume-driven, acute ocular hypertension immediately follows intravitreal injection, but this pressure elevation is generally transient and well tolerated. Several medications have been investigated to limit acute ocular hypertension following anti-VEGF therapy, but the benefits of pretreatment are not conclusive. Chronic, sustained ocular hypertension, distinct from the short-term acute ocular hypertension after each injection, has also been associated with repeated intravitreal anti-VEGF injections. Risk factors for chronic ocular hypertension include the total number of injections, a greater frequency of injection, and preexisting glaucoma. Proposed mechanisms for chronic ocular hypertension include microparticle obstruction, toxic or inflammatory effects on trabecular meshwork, as well as alterations in outflow facility by anti-VEGF agents. Although limiting anti-VEGF therapy could minimize the risk of both acute and chronic ocular hypertension, foregoing anti-VEGF therapy risks progression of various macular diseases with resulting permanent central vision loss. While definitive evidence of damage to the retinal nerve fiber layer is lacking, patients receiving repeated injections should be monitored for ocular hypertension and patients in whom sustained ocular hypertension subsequently developed should be periodically monitored for glaucomatous changes with optic nerve optical coherence tomography and static visual fields.
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    Adeno-Associated Virus Overexpression of Angiotensin-Converting Enzyme-2 Reverses Diabetic Retinopathy in Type 1 Diabetes in Mice
    (Elsevier, 2016) Dominguez, James M., II; Hu, Ping; Caballero, Sergio; Moldovan, Leni; Verma, Amrisha; Oudit, Gavin Y.; Li, Qiuhong; Grant, Maria B.; Department of Ophthalmology, School of Medicine
    Angiotensin-converting enzyme (ACE)-2 is the primary enzyme of the vasoprotective axis of the renin angiotensin system that regulates the classic renin angiotensin system axis. We aimed to determine whether local retinal overexpression of adenoassociated virus (AAV)-ACE2 prevents or reverses diabetic retinopathy. Green fluorescent protein (GFP)-chimeric mice were generated to distinguish resident (retinal) from infiltrating bone marrow-derived inflammatory cells and were made diabetic using streptozotocin injections. Retinal digestion using trypsin was performed and acellular capillaries enumerated. Capillary occlusion by GFP(+) cells was used to measure leukostasis. Overexpression of ACE2 prevented (prevention cohort: untreated diabetic, 11.3 ± 1.4; ACE2 diabetic, 6.4 ± 0.9 per mm(2)) and partially reversed (reversal cohort: untreated diabetic, 15.7 ± 1.9; ACE2 diabetic, 6.5 ± 1.2 per mm(2)) the diabetes-associated increase of acellular capillaries and the increase of infiltrating inflammatory cells into the retina (F4/80(+)) (prevention cohort: untreated diabetic, 24.2 ± 6.7; ACE2 diabetic, 2.5 ± 1.6 per mm(2); reversal cohort: untreated diabetic, 56.8 ± 5.2; ACE2 diabetic, 5.6 ± 2.3 per mm(2)). In both study cohorts, intracapillary bone marrow-derived cells, indicative of leukostasis, were only observed in diabetic animals receiving control AAV injections. These results indicate that diabetic retinopathy, and possibly other diabetic microvascular complications, can be prevented and reversed by locally restoring the balance between the classic and vasoprotective renin angiotensin system.
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    Advanced glycation end (AGE) product modification of laminin downregulates Kir4.1 in retinal Müller cells
    (PLOS, 2018-02-23) Thompson, Kayla; Chen, Jonathan; Luo, Qianyi; Xiao, Yucheng; Cummins, Theodore R.; Bhatwadekar, Ashay D.; Ophthalmology, School of Medicine
    Diabetic retinopathy (DR) is a major cause of adult blindness. Retinal Müller cells maintain water homeostasis and potassium concentration via inwardly rectifying Kir4.1 channels. Accumulation of advanced glycation end products (AGEs) is a major pathologic event in DR. While diabetes leads to a decrease in the Kir4.1 channels, it remains unknown whether AGEs-linked to the basement membrane (BM) affect normal Kir4.1 channels. For this study, we hypothesized that AGE-modification of laminin is detrimental to Kir4.1 channels, therefore, disrupting Müller cell function. The AGE-modified laminin-coated substrates were prepared by incubating Petri-dishes with laminin and methylglyoxal for seven days. The rat Müller cells (rMC-1) were propagated on AGE-modified laminin, and Kir4.1 expression and function were evaluated. Quantification of AGEs using ELISA revealed a dose-dependent increase in methylglyoxal-hydro-imidazolone adducts. The rMC-1 propagated on AGE-modified laminin demonstrated a decrease in Kir4.1 levels in immunofluorescence and western blot studies and a decrease in the Kir4.1 channel function. Kir4.1 decrease on AGE-modified laminin resulted in a disorganization of an actin cytoskeleton and disruption of α-dystroglycan-syntrophin-dystrophin complexes. Our studies suggest that AGE-modification of laminin is detrimental to Kir4.1 channels. By studying the role of AGEs in Kir4.1 channels we have identified a novel mechanism of Müller cell dysfunction and its subsequent involvement in DR.
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    Advancing Nerve Regeneration: Translational Perspectives of Tacrolimus (FK506)
    (MDPI, 2023-08-14) Daeschler, Simeon C.; Feinberg, Konstantin; Harhaus, Leila; Kneser, Ulrich; Gordon, Tessa; Borschel, Gregory H.; Ophthalmology, School of Medicine
    Peripheral nerve injuries have far-reaching implications for individuals and society, leading to functional impairments, prolonged rehabilitation, and substantial socioeconomic burdens. Tacrolimus, a potent immunosuppressive drug known for its neuroregenerative properties, has emerged in experimental studies as a promising candidate to accelerate nerve fiber regeneration. This review investigates the therapeutic potential of tacrolimus by exploring the postulated mechanisms of action in relation to biological barriers to nerve injury recovery. By mapping both the preclinical and clinical evidence, the benefits and drawbacks of systemic tacrolimus administration and novel delivery systems for localized tacrolimus delivery after nerve injury are elucidated. Through synthesizing the current evidence, identifying practical barriers for clinical translation, and discussing potential strategies to overcome the translational gap, this review provides insights into the translational perspectives of tacrolimus as an adjunct therapy for nerve regeneration.
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    Age and sex affect TGFβ2-induced ocular hypertension in C57BL/6J mice
    (Elsevier, 2022) Sugali, Chenna Kesavulu; Rayana, Naga Pradeep; Dai, Jiannong; Peng, Michael; Mao, Weiming; Ophthalmology, School of Medicine
    Glaucoma is a leading cause of blindness worldwide. The loss of vision in glaucoma patients is due to optic nerve damage. The most important risk factor of glaucoma is elevated intraocular pressure (IOP) which is due to glaucomatous changes in the trabecular meshwork. Animal models, especially mouse models for ocular hypertension (OHT), are important for studying glaucoma. Published studies showed that 2.5X107 PFU adenoviral vectors expressing the biologically active form of human TGFβ2 elevate IOP in female C57BL/6J mice when they are intravitreally delivered. In this study, we found that 2.5X107 PFU adenoviral TGFβ2 vector did not elevate IOP in 3- or 5-month old male C57BL/6J mice. In contrast, 5X107 PFU of the same viral vectors elevated IOP in both 3- and 5-month old male C57BL/6J mice. Also, 5-month old mice showed earlier OHT and higher IOP compared to 3-month old mice. In summary, our data showed that age and sex play roles in adenoviral vector-mediated TGFβ2-induced OHT in C57BL/6J mice.
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    Alzheimer's disease and primary open‐angle glaucoma associated with vascular health in patients of African descent
    (Wiley, 2018-12) Hutchins, Katherine; Harris, Alon; Thomas, Joseph; Alkhairy, Sameerah; Vercellin, Alice Chandra Verticchio; Shah, Aaditya; Siesky, Brent; Ophthalmology, School of Medicine
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    Amblyopia Preferred Practice Pattern
    (Elsevier, 2023) Cruz, Oscar A.; Repka, Michael X.; Hercinovic, Amra; Cotter, Susan A.; Lambert, Scott R.; Hutchinson, Amy K.; Sprunger, Derek T.; Morse, Christie L.; Wallace, David K.; American Academy of Ophthalmology Preferred Practice Pattern Pediatric Ophthalmology/Strabismus Panel; Ophthalmology, School of Medicine