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    Emerging infectious uveitis: Chikungunya, dengue, Zika and Ebola: A review
    (Wiley, 2018-11-25) Oliver, Genevieve F ; Carr, Jill ; Smith, Justine R
    Recently recognized forms of uveitis include intraocular inflammations that occur during or following one of several emerging infectious diseases: chikungunya fever, dengue, Zika virus disease and Ebola virus disease. Anterior, intermediate, posterior and pan‐uveitis have been described in individuals infected with chikungunya virus. Persons who contract dengue or Zika viruses also may develop different types of uveitis in the course of the infection: maculopathy is a common manifestation of dengue eye disease, and Zika eye disease may cause hypertensive anterior uveitis or mimic a white dot syndrome. Up to one‐third of Ebola survivors develop aggressive uveitis, which is frequently associated with vision loss and complicated by cataract. There are no specific anti‐viral drugs for these forms of uveitis, and thus treatment is largely supportive. In this article, we summarize the systemic infectious diseases and virology, and describe the clinical presentations, outcomes and management of emerging viral forms of uveitis.
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    Use of Standardization of Uveitis Nomenclature for Reporting Clinical Data at 10 Years
    (Elsevier, 2017-03-31) Oliver, Genevieve F ; Stathis, Roy M ; Spurrier, Nicola Jane ; Smith, Justine R
    Uveitis is a heterogeneous group of infectious and noninfectious intraocular inflammatory diseases. Management of both subsets of uveitis is frequently challenging. Since 2000, advances in microbial diagnostics and introduction of biologic drugs, combined with the potential for electronic communication to facilitate research on diseases with low incidence, have provided uveitis specialists with unprecedented opportunities for clinical trials to establish evidence-based management algorithms. Hampering this effort, however, was lack of a common system for describing uveitis, including diagnosis, severity, and outcome. The Standardization of Uveitis Nomenclature (SUN) Project is an effort to develop “international consensus for the use of terms to report on uveitis at academic meetings and in the literature.”
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    Effect of NADPH oxidase 1 and 4 blockade in activated human retinal endothelial cells
    (Clinical and Experimental Ophthalmology, 2018-08) Appukuttan, Binoy ; Ma, Yuefang ; Stempel, Andrew ; Ashander, Liam M ; Deliyanti, Devy ; Wilkinson-Berka, Jennifer L ; Smith, Justine R
    Background Over‐production of reactive oxygen species (ROS) and resulting oxidative stress contribute to retinal damage in vascular diseases that include diabetic retinopathy, retinopathy of prematurity and major retinal vessel occlusions. NADPH oxidase (Nox) proteins are professional ROS‐generating enzymes, and therapeutic targeting in these diseases has strong appeal. Pharmacological inhibition of Nox4 reduces the severity of experimental retinal vasculopathy. We investigated the potential application of this drug approach in humans. Methods Differential Nox enzyme expression was studied by real‐time‐quantitative polymerase chain reaction in primary human retinal endothelial cell isolates and a characterized human retinal endothelial cell line. Oxidative stress was triggered chemically in endothelial cells, by treatment with dimethyloxalylglycine (DMOG; 100 μM); Nox4 and vascular endothelial growth factor (VEGFA) transcript were measured; and production of ROS was detected by 2′,7′‐dichlorofluorescein. DMOG‐stimulated endothelial cells were treated with two Nox1/Nox4 inhibitors, GKT136901 and GKT137831; cell growth was monitored by DNA quantification, in addition to VEGFA transcript and ROS production. Results Nox4 (isoform Nox4A) was the predominant Nox enzyme expressed by human retinal endothelial cells. Treatment with DMOG significantly increased endothelial cell expression of Nox4 over 72 h, accompanied by ROS production and increased VEGFA expression. Treatment with GKT136901 or GKT137831 significantly reduced DMOG‐induced ROS production and VEGFA expression by endothelial cells, and the inhibitory effect of DMOG on cell growth. Conclusions Our findings in experiments on activated human retinal endothelial cells provide translational corroboration of studies in experimental models of retinal vasculopathy and support the therapeutic application of Nox4 inhibition by GKT136901 and GKT137831 in patients with retinal vascular diseases.
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    Expression of microRNA in human retinal pigment epithelial cells following infection with Zaire ebolavirus
    (BMC Research Notes, 2019) Oliver, Genevieve F ; Orang, Ayla V ; Appukuttan, Binoy ; Marri, Shashikanth ; Michael, Michael Zenon ; Marsh, Glenn A ; Smith, Justine R
    Objective: Survivors of Ebola virus disease (EVD) are at risk of developing blinding intraocular inflammation—or uveitis—which is associated with retinal pigment epithelial (RPE) scarring and persistence of live Zaire ebolavirus (EBOV) within the eye. As part of a large research project aimed at defining the human RPE cell response to being infected with EBOV, this work focused on the microRNAs (miRNAs) associated with the infection. Results: Using RNA-sequencing, we detected 13 highly induced and 2 highly repressed human miRNAs in human ARPE-19 RPE cells infected with EBOV, including hsa-miR-1307-5p, hsa-miR-29b-3p and hsa-miR-33a-5p (up-regulated), and hsa-miR-3074-3p and hsa-miR-27b-5p (down-regulated). EBOV-miR-1-5p was also found in infected RPE cells. Through computational identification of putative miRNA targets, we predicted a broad range of regulatory activities, including effects on innate and adaptive immune responses, cellular metabolism, cell cycle progression, apoptosis and autophagy. The most highly-connected molecule in the miR-target network was leucine-rich repeat kinase 2, which is involved in neuroinflammation and lysosomal processing. Our findings should stimulate new studies on the impact of miRNA changes in EBOV-infected RPE cells to further understanding of intraocular viral persistence and the pathogenesis of uveitis in EVD survivors.
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    Current ophthalmology practice patterns for syphilitic uveitis
    (British Journal of Opthalmology, 2019) Oliver, Genevieve F ; Stathis, Roy M ; Furtado, João M ; Arantes, Tiago E ; McCluskey, Peter Joseph ; Matthews, Janet M ; Smith, Justine R
    Background Syphilitic uveitis is re-emerging alongside the systemic infection. In July 2017, an international group of uveitis-specialised ophthalmologists formed the International Ocular Syphilis Study Group to define current practice patterns. Methods 103 Study Group members based in 35 countries completed a 25-item questionnaire focused on case load, clinical presentations, use and interpretation of investigations, treatment and clinical indicators of poor prognosis. Results Members managed a mean of 6.1 patients with syphilitic uveitis in clinics that averaged 707 annual cases of uveitis (0.9%); 53.2% reported increasing numbers over the past decade. Patients presented to more members (40.2%) during secondary syphilis. Uveitis was usually posterior (60.8%) or pan (22.5%); complications included optic neuropathy, macular oedema and posterior synechiae. All members diagnosed syphilitic uveitis using serological tests (simultaneous or sequential testing algorithms), and 97.0% routinely checked for HIV co-infection. Cerebrospinal fluid (CSF) analysis was ordered by 90.2% of members, and 92.7% took uveitis plus Venereal Disease Research Laboratory test (VDRL) or fluorescent treponemal antibody absorption test (FTA-ABS) to indicate neurosyphilis. Patients were commonly co-managed with infectious disease physicians, and treated with penicillin for at least 10–14 days, plus corticosteroid. Features predicting poor outcome included optic neuropathy (86.3%) and initial misdiagnosis (63.7%). Reasons for delayed diagnosis were often practitioner-related. 82.5% of members tested every patient they managed with uveitis for syphilis. Conclusion This comprehensive report by an international group of uveitis-specialised ophthalmologists provides a current approach for the management of syphilitic uveitis.