Ophthalmology Commons^™

Reply To: "Microvascular Breakdown Due To Retinal Neurodegeneration In Ataxias", Christopher A. Turski, Gabrielle N. Turski, Jennifer Faber, Stefan J. Teipel, Frank G. Holz, Thomas Klockgether, Robert P. Finger

Ophthalmology and Visual Science Faculty Publications

No abstract provided.

Typical Sounding Atypical Diagnostic Conundrum -- A Rare Case Of Mycobacterium Avium Complex (Mac) Presenting With Multiple Cranial Nerve Involvement, Ashwini Kini, Karl Echiverri, Edward J. Escott, Padmaja Sudhakar

Neurology Faculty Publications

Background

MAC infections rarely cause symptomatic systemic infection in immunocompetent healthy individuals. This case brings to light a rare such presentation that gives us a learning point about keeping a strong pre-clinical suspicion for this condition in patients whom lung imaging reveals suspicious cavitary lesions. Starting empiric therapy while awaiting culture results may be considered after weighing risks and benefits in order to achieve the morbidity and mortality associated with the disease.

Case report

A 54 year-old white male presented for evaluation of progressively worsening vertigo, imbalance, vertical diplopia, facial diplegia, bilateral hyperacusis followed by hearing loss, dysphagia, and dysarthria …

Acute-Onset Central Serous Retinopathy After Immunization With Covid-19 Mrna Vaccine, Nicholas Fowler, Noe R. Mendez Martinez, Bernardo Velazquez Pallares, Ramiro S. Maldonado

Ophthalmology and Visual Science Faculty Publications

Purpose
We report the case of a 33-year-old male who presented with unilateral central serous retinopathy three days after the injection of a COVID-19 vaccine.

Observations
A 33-year-old healthy Hispanic male referred to the ophthalmology service due to blurry vision and metamorphopsia in the right eye without any flashes, floaters, eye redness or pain. The patient reported that 69 hours prior to presentation he received the first dose of the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine. He denied any past ocular history or pertinent medical history. He does not take any medicines and denies stressful factors in his life. The clinical …

Evaluation Of Multi-Level Barriers And Facilitators In A Large Diabetic Retinopathy Screening Program In Federally Qualified Health Centers: A Qualitative Study, Ana Bastos De Carvalho, S. Lee Ware, Tamara Belcher, Franceska Mehmeti, Eric B. Higgins, Robert Sprang, Cody Williams, Jamie L. Studts, Christina R. Studts

Ophthalmology and Visual Science Faculty Publications

BACKGROUND: Recommended annual diabetic retinopathy (DR) screening for people with diabetes has low rates in the USA, especially in underserved populations. Telemedicine DR screening (TDRS) in primary care clinics could expand access and increase adherence. Despite this potential, studies have observed high variability in TDRS rates among clinics and over time, highlighting the need for implementation supports. Previous studies of determinants of TDRS focus on patients' perspectives, with few studies targeting upstream multi-level barriers and facilitators. Addressing this gap, this qualitative study aimed to identify and evaluate multi-level perceived determinants of TDRS in Federally Qualified Health Centers (FQHCs), to inform …

Differential Leukocyte And Platelet Profiles In Distinct Models Of Traumatic Brain Injury, William Brad Hubbard, Meenakshi Banerjee, Hemendra J. Vekaria, Kanakanagavalli Shravani Prakhya, Smita Joshi, Qingjun Wang, Kathryn E. Saatman, Sidney W. Whiteheart, Patrick G. Sullivan

Spinal Cord and Brain Injury Research Center Faculty Publications

Traumatic brain injury (TBI) affects over 3 million individuals every year in the U.S. There is growing appreciation that TBI can produce systemic modifications, which are in part propagated through blood–brain barrier (BBB) dysfunction and blood–brain cell interactions. As such, platelets and leukocytes contribute to mechanisms of thromboinflammation after TBI. While these mechanisms have been investigated in experimental models of contusion brain injury, less is known regarding acute alterations following mild closed head injury. To investigate the role of platelet dynamics and bioenergetics after TBI, we employed two distinct, well-established models of TBI in mice: the controlled cortical impact (CCI) …

Compositions And Methods For Treating Retinal Degradation, Jayakrishna Ambati, Benjamin Fowler

Ophthalmology and Visual Science Faculty Patents

The present disclosure relates to compositions and methods for treating retinal damage and/or retinal degradation. More specifically, this disclosure relates to methods for treating degradation of the retinal pigment epithelium by administering compositions comprising a nucleoside and/or a nucleoside or nucleotide reverse transcriptase inhibitor.

Implementation And Sustainment Of A Statewide Telemedicine Diabetic Retinopathy Screening Network For Federally Designated Safety-Net Clinics, Ana Bastos De Carvalho, S. Lee Ware, Feitong Lei, Heather M. Bush, Robert Sprang, Eric B. Higgins

Ophthalmology and Visual Science Faculty Publications

CONTEXT: Diabetic retinopathy (DR) is the leading cause of incident blindness among working-age adults in the United States. Federally designated safety-net clinics (FDSC) often serve as point-of-contact for patients least likely to receive recommended DR screenings, creating opportunity for targeted interventions to increase screening access and compliance.

STUDY DESIGN AND METHODS: With such a goal, we implemented and assessed the longitudinal performance of an FDSC-based telemedicine DR screening (TDRS) network of 22 clinical sites providing nonmydriatic fundus photography with remote interpretation and reporting. Retrospective analysis of patient encounters between February 2014 and January 2019 was performed to assess rates of …

Imaging Data On Characterization Of Retinal Autofluorescent Lesions In A Mouse Model Of Juvenile Neuronal Ceroid Lipofuscinosis (Cln3 Disease), Qing Jun Wang, Kyung Sik Jung, Kabhilan Mohan, Mark E. Kleinman

Ophthalmology and Visual Science Faculty Publications

Juvenile neuronal ceroid lipofuscinosis (JNCL, aka. juvenile Batten disease or CLN3 disease), a lethal pediatric neurodegenerative disease without cure, often presents with vision impairment and characteristic ophthalmoscopic features including focal areas of hyper-autofluorescence. In the associated research article “Loss of CLN3, the gene mutated in juvenile neuronal ceroid lipofuscinosis, leads to metabolic impairment and autophagy induction in retinal pigment epithelium” (Zhong et al., 2020) [1], we reported ophthalmoscopic observations of focal autofluorescent lesions or puncta in the Cln3^Δex7/8 mouse retina at as young as 8 month old. In this data article, we performed differential interference contrast and …

Repurposing Anti-Inflammasome Nrtis For Improving Insulin Sensitivity And Reducing Type 2 Diabetes Development, Jayakrishna Ambati, Joseph Magagnoli, Hannah Leung, Shao-Bin Wang, Chris A. Andrews, Dongxu Fu, Akshat Pandey, Srabani Sahu, Siddharth Narendran, Shuichiro Hirahara, Shinichi Fukuda, Jian Sun, Lekha Pandya, Meenakshi Ambati, Felipe Pereira, Akhil Varshney, Tammy Cummings, James W. Hardin, Babatunde Edun, Charles L. Bennett, Kameshwari Ambati, Benjamin J. Fowler, Nagaraj Kerur, Christian Röver, Norbert Leitinger, Brian C. Werner, Joshua D. Stein, S. Scott Sutton, Bradley D. Gelfand

Ophthalmology and Visual Science Faculty Publications

Innate immune signaling through the NLRP3 inflammasome is activated by multiple diabetes-related stressors, but whether targeting the inflammasome is beneficial for diabetes is still unclear. Nucleoside reverse-transcriptase inhibitors (NRTI), drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation. Here, we show, by analyzing five health insurance databases, that the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure among 128,861 patients with HIV-1 or hepatitis B (adjusted hazard ratio for NRTI exposure, 0.673; 95% confidence interval, 0.638 to 0.710; P < 0.0001; 95% prediction interval, 0.618 to 0.734). Meanwhile, an NRTI, lamivudine, improves insulin sensitivity and reduces inflammasome activation in diabetic and insulin resistance-induced human cells, as well as in mice fed with high-fat chow; mechanistically, inflammasome-activating short interspersed nuclear element (SINE) transcripts are elevated, whereas SINE-catabolizing DICER1 is reduced, in diabetic cells and mice. These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes.

Glut1 Deficiency: Retinal Detrimental Effects Of Gliovascular Modulation, Matt Henry, John Kitchens, Juan M. Pascual, Ramiro S. Maldonado

Ophthalmology and Visual Science Faculty Publications

No abstract provided.

Methods Of Administering Igg1 Antibodies And Methods Of Suppressing Angiogenesis, Jayakrishna Ambati, Sandro De Falco

Ophthalmology and Visual Science Faculty Patents

A method of suppressing angiogenesis involves administering to a subject an isolated Fc fragment of an IgG1 antibody, or an IgG1 antibody.

Commentary: Recognizing Pupillary Dysfunction In Diabetic Autonomic Neuropathy, Padmaja Sudhakar

Ophthalmology and Visual Science Faculty Publications

No abstract provided.

Ccr3 Inhibition For Ocular Angiogenesis And Macular Degeneration, Jayakrishna Ambati

Ophthalmology and Visual Science Faculty Patents

Provided are methods and compositions for the treatment or prevention of ocular angiogenesis and neovascularization. Administration of inhibitors of the CCR3 receptor or its ligands eotaxin (CCL11), eotaxin-2 (CCL24) or eotaxin-3 (CCL26) inhibits ocular angiogenesis.

Commentary: Ganglion Cell Complex Of Retinal Layer Thickness By Optical Coherence Tomography In Cases Of Multiple Sclerosis Without Optic Neuritis Compared To Healthy Eyes, Padmaja Sudhakar

Neurology Faculty Publications

No abstract provided.

Latent Sensitization In A Mouse Model Of Ocular Neuropathic Pain, Jooyoung Cho, Nicholas Bell, Gregory Botzet, Paras Vora, Benjamin J. Fowler, Renee R. Donahue, Heather M. Bush, Bradley K. Taylor, Romulo J. C. Albuquerque

Ophthalmology and Visual Science Faculty Publications

Purpose: Chronic ocular pain is poorly understood and difficult to manage. We developed a murine model of corneal surface injury (CSI)–induced chronic ocular neuropathic pain. The study focuses on changes in corneal nerve morphology and associated short- and long-term pain-like behavior after CSI.

Methods: CSI was induced in mice by local application of an alkali solution (0.75 N NaOH). Corneal nerve architecture, morphology, density, and length were studied. Eye-wiping was evaluated before and after CSI in response to hypertonic saline (2 M NaCl). Naltrexone (NTX) or Naloxone-methiodide (NLX-me), opioid receptor antagonists, were given subcutaneously (s.c., 3 mg/kg) or …

The Relative Financial Cost And Benefit Of An Ophthalmology Resident Compared To An Advanced Practice Provider, Optometrist, Or Faculty Ophthalmologist, Daniel B. Moore, William Barr

Ophthalmology and Visual Science Faculty Publications

Objective The main objective of the article is to determine the relative direct financial cost and benefit of an advanced practice provider (APP), optometrist, and faculty ophthalmologist compared with an ophthalmology resident.

Design Single center cost–benefit financial analysis.

Methods The direct total expenses, including mean salary and benefits; the cost/week, based upon calculated hours worked; and net revenue, based upon technical collections subtracted from total expenses were collected for all APPs, optometrists, faculty ophthalmologists, and ophthalmology residents at the University of Kentucky for the 2016 to 2017 academic year. Optometry and ophthalmology faculty collections were adjusted for clinical full-time equivalents. …

Cgas Drives Noncanonical-Inflammasome Activation In Age-Related Macular Degeneration, Nagaraj Kerur, Shinichi Fukuda, Daipayan Banerjee, Younghee Kim, Dongxu Fu, Ivana Apicella, Akhil Varshney, Reo Yasuma, Benjamin J. Fowler, Elmira Baghdasaryan, Kenneth M. Marion, Xiwen Huang, Tetsuhiro Yasuma, Yoshio Hirano, Vlad Serbulea, Meenakshi Ambati, Vidya L. Ambati, Yuji Kajiwara, Kameshwari Ambati, Shuichiro Hirahara, Ana Bastos-Carvalho, Yuichiro Ogura, Hiroko Terasaki, Tetsuro Oshika, Kyung Bo Kim, David R. Hinton, Norbert Leitinger, John C. Cambier, Joseph D. Buxbaum, M. Cristina Kenney, Bradley D. Gelfand, Jayakrishna Ambati

Ophthalmology and Visual Science Faculty Publications

Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits DICER1 deficiency, resultant accumulation of endogenous Alu-retroelement RNA, and NLRP3-inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human-cell-culture and mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon-β production and gasdermin D-dependent interleukin-18 secretion. Decreased DICER1 levels or Alu-RNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin …

Protection Of Cells From Degeneration And Treatment Of Geographic Atrophy, Jayakrishna Ambati

Ophthalmology and Visual Science Faculty Patents

Therapeutic uses P2X₇ inhibition and inhibition of IRAK1 and/or IRAK4, methods protecting a cell, and screening methods for identifying inhibitors are described herein.

An Objective Assessment Of The Variability In Number Of Drops Per Bottle Of Glaucoma Medication, Daniel B. Moore, Judy Beck, Richard J. Kryscio

Ophthalmology and Visual Science Faculty Publications

Background: The purpose of this study is to evaluate the number of eyedrops available per bottle of a variety of commonly prescribed glaucoma medications.

Methods: Six bottles of each glaucoma medication were tested: three each in the vertical and horizontal orientations. Bottles were housed in a customized force gauge apparatus designed to mimic ballpoint fingertip contact with a bottle. At a standard rate, all drops were expressed from each bottle and counted with an automated drop counter. Simultaneously, bottle volume was measured and drop size and number were also estimated. The main outcome measures were: total number of drops, volume …

GabaB Receptor Attenuation Of GabaA Currents In Neurons Of The Mammalian Central Nervous System, Wen Shen, Changlong Nan, Peter T. Nelson, Harris Ripps, Malcolm M. Slaughter

Pathology and Laboratory Medicine Faculty Publications

Ionotropic receptors are tightly regulated by second messenger systems and are often present along with their metabotropic counterparts on a neuron's plasma membrane. This leads to the hypothesis that the two receptor subtypes can interact, and indeed this has been observed in excitatory glutamate and inhibitory GABA receptors. In both systems the metabotropic pathway augments the ionotropic receptor response. However, we have found that the metabotropic GABA_B receptor can suppress the ionotropic GABA_A receptor current, in both the in vitro mouse retina and in human amygdala membrane fractions. Expression of amygdala membrane microdomains in Xenopus oocytes by microtransplantation …

Methods Of Inhibiting Alu Rna And Therapeutic Uses Thereof, Jayakrishna Ambati

Ophthalmology and Visual Science Faculty Patents

The presently-disclosed subject matter includes methods of identifying an Alu RNA inhibitor, and methods and compositions for inhibiting Alu RNA. Methods and compositions can be used for the treatment of geographic atrophy and other conditions of interest.

Protection Of Cells From Alu-Rna-Induced Degeneration And Inhibitors For Protecting Cells, Jayakrishna Ambati, Valeria Tarallo

Ophthalmology and Visual Science Faculty Patents

A method of protecting a cell includes inhibiting an inflammasome, MyD88, IL-18, VDAC1, VDAC2, caspase-8, and/or NFκB of the cell. Administering an inhibitor of MyD88, IL-18, VDAC1, VDAC2, caspase-8, and/or NFκB can protect the cell from Alu-RNA-induced degeneration. Protecting a cell, such as an retinal pigment epithelium (RPE), can be therapeutically useful in the context of age-related macular degeneration and geographic atrophy.

Compositions And Methods For Treating Retinal Degradation, Jayakrishna Ambati, Benjamin J. Fowler

Ophthalmology and Visual Science Faculty Patents

The present disclosure relates to compositions and methods for treating retinal damage and/or retinal degradation. More specifically, this disclosure relates to methods for treating degradation of the retinal pigment epithelium by administering compositions comprising a nucleoside and/or a nucleoside or nucleotide reverse transcriptase inhibitor.

Human Igg1 Antibodies Suppress Angiogenesis In A Target-Independent Manner, Sasha Bogdanovich, Younghee Kim, Takeshi Mizutani, Reo Yasuma, Laura Tudisco, Valeria Cicatiello, Ana Bastos-Carvalho, Nagaraj Kerur, Yoshio Hirano, Judit Z. Baffi, Valeria Tarallo, Shengjian Li, Tetsuhiro Yasuma, Parthasarathy Arpitha, Benjamin James Fowler, Charles B. Wright, Ivana Apicella, Adelaide Greco, Arturo Brunetti, Menotti Ruvo, Annamaria Sandomenico, Miho Nozaki, Ryo Ijima, Hiroki Kaneko, Yuichiro Ogura, Hiroko Terasaki, Balamurali K. Ambati, Jeanette H. W. Leusen, Wallace Y. Langdon, Michael R. Clark, Bradley D. Gelfand, Jayakrishna Ambati

Ophthalmology and Visual Science Faculty Publications

Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world’s population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in mice. Here we show bevacizumab suppressed angiogenesis in three mouse models not via Vegfa blockade but rather Fc-mediated signaling through FcγRI (CD64) and c-Cbl, impairing macrophage migration. Other approved humanized or human IgG1 antibodies without mouse targets (adalimumab, alemtuzumab, ofatumumab, omalizumab, palivizumab and tocilizumab), mouse IgG2a, and overexpression of human IgG1-Fc or mouse IgG2a-Fc, also inhibited angiogenesis in wild-type …

Modulation Of Angiogenesis, Balamurali Krishna Ambati, Jayakrishna Ambati, Nirbhai Singh

Ophthalmology and Visual Science Faculty Patents

This invention relates to compounds, composJtwns, and methods for the treatment of traits, diseases and conditions that respond to the modulation of angiogenic growth factor bioavailability or biological activity.

Iron Toxicity In The Retina Requires Alu Rna And The Nlrp3 Inflammasome, Bradley D. Gelfand, Charles B. Wright, Younghee Kim, Tetsuhiro Yasuma, Reo Yasuma, Shengjian Li, Benjamin J. Fowler, Ana Bastos-Carvalho, Nagaraj Kerur, Annette Uittenbogaard, Youn Seon Han, Dingyuan Lou, Mark E. Kleinman, W. Hayes Mcdonald, Gabriel Núñez, Philippe Georgel, Joshua L. Dunaief, Jayakrishna Ambati

Ophthalmology and Visual Science Faculty Publications

Excess iron induces tissue damage and is implicated in age-related macular degeneration (AMD). Iron toxicity is widely attributed to hydroxyl radical formation through Fenton's reaction. We report that excess iron, but not other Fenton catalytic metals, induces activation of the NLRP3 inflammasome, a pathway also implicated in AMD. Additionally, iron-induced degeneration of the retinal pigmented epithelium (RPE) is suppressed in mice lacking inflammasome components caspase-1/11 or Nlrp3 or by inhibition of caspase-1. Iron overload increases abundance of RNAs transcribed from short interspersed nuclear elements (SINEs): Alu RNAs and the rodent equivalent B1 and B2 RNAs, which are inflammasome agonists. Targeting …

Powerful Anti-Tumor And Anti-Angiogenic Activity Of A New Anti-Vascular Endothelial Growth Factor Receptor 1 Peptide In Colorectal Cancer Models, Valeria Cicatiello, Ivana Apicella, Laura Tudisco, Valeria Tarallo, Luigi Formisano, Annamaria Sandomenico, Younghee Kim, Ana Bastos-Carvalho, Augusto Orlandi, Jayakrishna Ambati, Menotti Ruvo, Roberto Bianco, Sandro De Falco

Ophthalmology and Visual Science Faculty Publications

To assess the therapeutic outcome of selective block of VEGFR1, we have evaluated the activity of a new specific antagonist of VEGFR1, named iVR1 (inhibitor of VEGFR1), in syngenic and xenograft colorectal cancer models, in an artificial model of metastatization, and in laser-induced choroid neovascularization. iVR1 inhibited tumor growth and neoangiogenesis in both models of colorectal cancer, with an extent similar to that of bevacizumab, a monoclonal antibody anti-VEGF-A. It potently inhibited VEGFR1 phosphorylation in vivo, determining a strong inhibition of the recruitment of monocyte-macrophages and of mural cells as confirmed, in vitro, by the ability to inhibit …

Toll Like Receptor (Tlr) Stimulation For Ocular Angiogenesis And Macular Degeneration, Jayakrishna Ambati

Ophthalmology and Visual Science Faculty Patents

Provided are methods and compositions for the treatment or prevention of ocular angiogenesis and neovascularization. Administration of stimulators of the TLR3 and TLR7 receptors, Trif or of IL-10 and IL-12 inhibits ocular angiogenesis. Furthermore, all siRNAs (both targeted and non-targeted) can inhibit ocular angiogenesis.

Svegfr-2 And Its Role In Lymphangiogenesis Modulation, Jayakrishna Ambati, Romulo J. Albuquerque

Ophthalmology and Visual Science Faculty Patents

Disclosed herein are nucleic acid molecules comprising a nucleotide sequence of sVEGF-2, proteins encoded by those sequences and antibodies that bind to the protein. Also disclosed are methods for inhibiting or enhancing expression or activity of sVEGFR-2 and methods for inhibiting graft rejection, particularly cornea graph rejection. Also described are methods for inhibiting lymphangiogenesis and lymphatic endothelial cell proliferation by administering an effective amount of sVEGFR-2 and methods for treating lymphedema by inhibiting the activity of sVEGFR-2.

Method Of Using Ccr3 Binding Agents To Detect Choroidal Neovascularization, Jayakrishna Ambati, Mark E. Kleinman

Ophthalmology and Visual Science Faculty Patents

The results presented herein demonstrate the specific expression of CCR3 in CNV endothelial cells in humans with AMD, and despite the expression of its ligands, eotaxin-1, -2, and -3, neither eosinophils nor mast cells are present in human CNV. The genetic or pharmacological targeting of CCR3 or eotaxins as disclosed herein inhibited injury-induced CNV in mice. CNV suppression by CCR3 blockade was due to direct inhibition of endothelial cell proliferation, and was uncoupled from inflammation as it occurred in mice lacking eosinophils or mast cells and was independent of macrophage and neutrophil recruitment. CCR3 blockade was more effective at reducing …