TNF-α and NF-κB Signaling Play a Critical Role in Cigarette Smoke-induced Epithelial-mesenchymal Transition of Retinal Pigment Epithelial Cells in Proliferative Vitreoretinopathy

Proliferative vitreoretinopathy (PVR) is characterized by the growth and contraction of cellular membranes within the vitreous cavity and on both surfaces of the retina, resulting in recurrent retinal detachments and poor visual outcomes. Proinflammatory cytokines like tumor necrosis factor alpha (TNFα) have been associated with PVR and the epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells. Cigarette smoke is the only known modifiable risk factor for PVR, but the mechanisms are unclear. The purpose of this study was to examine the impact of cigarette smoke on the proinflammatory TNFα/NF-κB/Snail pathway in RPE cells to better understand the mechanisms through which cigarette smoke increases the risk of PVR. Human ARPE-19 cells were exposed to cigarette smoke extract (CSE), for 4 to 24-hours and TNFα, Snail, IL-6, IL-8, and α-SMA levels were analyzed by qPCR and/or Western blot. The severity of PVR formation was assessed in a murine model of PVR after intravitreal injection of ARPE-19 cells pre-treated with CSE or not. Fundus imaging, OCT imaging, and histologic analysis 4 weeks after injection were used to examine PVR severity. ARPE-19 cells exposed to CSE expressed higher levels of TNFα, SNAIL, IL6 and IL8 mRNA as well as SNAIL, Vimentin and α-SMA protein. Inhibition of TNFα and NF-κB pathways blocked the effect of CSE. In vivo, intravitreal injection of ARPE-19 cells treated with CSE resulted in more severe PVR compared to mice injected with untreated RPE cells. These studies suggest that the TNFα pathway is involved in the mechanism whereby cigarette smoke increases PVR. Further investigation into the role of TNFα/NF-κB/Snail in driving PVR and pharmacological targeting of these pathways in disease are warranted

Development and validation of a computerized expert system for evaluation of automated visual fields from the Ischemic Optic Neuropathy Decompression Trial

BACKGROUND: The objective of this report is to describe the methods used to develop and validate a computerized system to analyze Humphrey visual fields obtained from patients with non-arteritic anterior ischemic optic neuropathy (NAION) and enrolled in the Ischemic Optic Neuropathy Decompression Trial (IONDT). The IONDT was a multicenter study that included randomized and non-randomized patients with newly diagnosed NAION in the study eye. At baseline, randomized eyes had visual acuity of 20/64 or worse and non-randomized eyes had visual acuity of better than 20/64 or were associated with patients refusing randomization. Visual fields were measured before treatment using the Humphrey Field Analyzer with the 24-2 program, foveal threshold, and size III stimulus. METHODS: We used visual fields from 189 non-IONDT eyes with NAION to develop the computerized classification system. Six neuro-ophthalmologists ("expert panel") described definitions for visual field patterns defects using 19 visual fields representing a range of pattern defect types. The expert panel then used 120 visual fields, classified using these definitions, to refine the rules, generating revised definitions for 13 visual field pattern defects and 3 levels of severity. These definitions were incorporated into a rule-based computerized classification system run on Excel(® )software. The computerized classification system was used to categorize visual field defects for an additional 95 NAION visual fields, and the expert panel was asked to independently classify the new fields and subsequently whether they agreed with the computer classification. To account for test variability over time, we derived an adjustment factor from the pooled short term fluctuation. We examined change in defects with and without adjustment in visual fields of study participants who demonstrated a visual acuity decrease within 30 days of NAION onset (progressive NAION). RESULTS: Despite an agreed upon set of rules, there was not good agreement among the expert panel when their independent visual classifications were compared. A majority did concur with the computer classification for 91 of 95 visual fields. Remaining classification discrepancies could not be resolved without modifying existing definitions. Without using the adjustment factor, visual fields of 63.6% (14/22) patients with progressive NAION and no central defect, and all (7/7) patients with a paracentral defect, worsened within 30 days of NAION onset. After applying the adjustment factor, the visual fields of the same patients with no initial central defect and 5/7 of the patients with a paracentral defect were seen to worsen. CONCLUSION: The IONDT developed a rule-based computerized system that consistently defines pattern and severity of visual fields of NAION patients for use in a research setting

The Potential Use of Mannitol in Treating Optic Nerve Diseases

High dose (1 to 2 gr/day) IV methylprednisolone (MP) has been used to treat various optic neuropathies. Recently, IV mannitol (MN) was successfully substituted for high dose MP to treat papillitis in two patients on the assumption that the "anti-edematous" action of steroids could be mimicked using IV MN. To test this hypothesis, serum osmolalities were measured for 3 days in 21 patients receiving IV MP (250 mg q 6 hours) to treat various optic neuropathies, and compared to values from 1 0 control patients

Intraocular Vascular Complications Of Orbital Masses

Orbital masses cause visual loss by numerous mechanisms. Pressure on the posterior pole of the globe shortens axial length, Inducing hyperopia. Such pressure may also Induce retinal and choroidal striae with metamorphopsia and misalignment of retinal receptors

Immunology of Thyroid Eye Disease

Thyroid Eye Disease (TED) is the most common orbital disease, affecting 50%-60% of patients with Graves' hyperthyroidism.1 Although clinical symptoms and signs are usually mild, consisting of mild ocular irritation, periorbital swelling, and lid retraction without visual compromise, the disease can be severe in approximately 15% of cases, resulting in exposure keratopathy, diplopia, and optic neuropathy. To date, there is no ability to predict which patients will develop the severe form of the disease, although age over 50, male gender, smoking, and microvascular disease are known risk factors

Orbital Venous Stasis: A New Animal Model of Graves' Ophthalmology

Graves' ophthalmopathy is generally considered to have an autoimmune etiology. Recently, however, it has been hypothesized that venous obstruction may produce the clinical manifestations. To determine whether such obstruction could induce the findings characteristic of Graves'ophthalmopathy, we developed an animal model of orbital venous obstruction by ligating the superior and inferior ophthalmic veins of the right eye of each of four cats

Infrared Oculography of Duane's Retraction Syndrome Type I

Duane's retraction syndrome (DRS) Type I, is a congenital eye movement disorder characterized by decreased abduction past midline in the affected eye, slow abduction velocities and palpebral fissure narrowing on attempted adduction. Pathologic examination of patients with Duane's syndrome have shown an absence of the abducens nuclei and peripheral nerves on the affected side. The lateral rectus muscle is aberrantly innervated by branches of the inferior division of the oculomotor nerve (4,5)

Histiocytosis and Other Oddballs of the Orbit

The vast majority of orbital inflammations are related to thyroid eye disease or idiopathic orbital inflammation. However, the differential diagnosis includes a number of relatively rare systemic diseases that may manifest primarily or solely in the orbit with unique or characteristic imaging and histopathology. The purpose of this review is to point out the systemic, ocular, and orbital manifestations that aid in the differential diagnosis. Based upon these observations, appropriate diagnostic testing and treatment options can be defined.VBorbitalpathologyorbitalinflammatio