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Ing E, Pagnoux C, Torun N. Advances in the diagnosis of giant cell arteritis. Curr Opin Ophthalmol 2019;30(6):407-411.Abstract
PURPOSE OF REVIEW: To summarize recent advances in the diagnosis of giant cell arteritis (GCA). RECENT FINDINGS: Less common manifestations of GCA include corneal edema, proptosis from lacrimal gland ischemia and sensorineuronal hearing loss. Histology studies have suggested that temporal artery biopsies (TAB) with fixed specimen lengths of 15 mm may be adequate to prevent false negative biopsies. In centers with appropriate radiologic expertise, a European rheumatology consensus guideline has proposed Doppler ultrasound as a first-line confirmatory test for GCA in lieu of temporal artery biopsy. Finding extracranial large vessel disease can help to diagnose GCA. Statistical prediction rules can help risk stratify patients with suspected GCA. Age and platelet level when maintained as continuous variables are the strongest predictors for GCA. SUMMARY: GCA can present with diverse ophthalmic and systemic presentations and expedient recognition of same can avoid diagnostic delay and possible vision loss, among other complications. TAB remains the conventional diagnostic standard test for GCA. The use of statistical prediction models and increased expertise in noninvasive imaging techniques such as ultrasound may decrease reliance on TAB, especially in patients determined to be at low risk for GCA.
Kumar V. Endoplasmic Reticulum-Mitochondrial Cross-Talk in Neurodegenerative and Eye Diseases. Neurology (ECronicon) 2019;11(9):864-873.Abstract
Neurodegenerative diseases demonstrate the progressive decline of brain functions resulting in a significant deterioration in the quality of patient's life. With increasing life expectancy, there has been a significant increase in the incidence of these diseases. Neurodegenerative diseases like Alzheimer's, Parkinson's, and Amyotrophic lateral sclerosis are devastating and afflicts a large world population. Eye, given the similar neural and vascular similarity to the brain, demonstrates many pathological hallmarks of some of these neurological diseases. Moreover, these diseases create an economic and social burden to society. Despite tremendous efforts made in the drug discovery, there is no cure for these fatal diseases. Thus, there is an unmet need to understand cellular and molecular pathophysiology of these diseases. All these diseases demonstrate damage to a large number of seemingly disparate cellular processes and functions such as Ca homeostasis, lipid metabolism, axonal transport, unfolded protein response, autophagy and inflammatory responses. Mitochondria are closely associated with Endoplasmic reticulum (ER) and ER-mitochondrial cross-talk regulates many of these cellular processes and functions damaged in neurodegenerative and eye diseases. Several studies have implicated the disruption of ER-mitochondria contacts in these diseases. This review is aimed at understanding and summarizing the role of ER-mitochondria interacting proteins in major neurodegenerative and eye diseases studied so far.
Pennington MR, Saha A, Painter DF, Gavazzi C, Ismail AM, Zhou X, Chodosh J, Rajaiya J. Disparate Entry of Adenoviruses Dictates Differential Innate Immune Responses on the Ocular Surface. Microorganisms 2019;7(9)Abstract
Human adenovirus infection of the ocular surface is associated with severe keratoconjunctivitis and the formation of subepithelial corneal infiltrates, which may persist and impair vision for months to years following infection. Long term pathology persists well beyond the resolution of viral replication, indicating that the prolonged immune response is not virus-mediated. However, it is not clear how these responses are sustained or even initiated following infection. This review discusses recent work from our laboratory and others which demonstrates different entry pathways specific to both adenovirus and cell type. These findings suggest that adenoviruses may stimulate specific pattern recognition receptors in an entry/trafficking-dependent manner, leading to distinct immune responses dependent on the virus/cell type combination. Additional work is needed to understand the specific connections between adenoviral entry and the stimulation of innate immune responses by the various cell types present on the ocular surface.
Pal-Ghosh S, Tadvalkar G, Lieberman VR, Guo X, Zieske JD, Hutcheon A, Stepp MA. Transient Mitomycin C-treatment of human corneal epithelial cells and fibroblasts alters cell migration, cytokine secretion, and matrix accumulation. Sci Rep 2019;9(1):13905.Abstract
A single application of Mitomycin C (MMC) is used clinically in ophthalmology to reduce scarring and enhance wound resolution after surgery. Here we show in vitro that a 3-hour MMC treatment of primary and telomerase immortalized human corneal limbal epithelial (HCLE) cells impacts their migration and adhesion. Transient MMC treatment induces HCLE expression of senescence associated secretory factors, cytokine secretion, and deposition of laminin 332 for several days. Transient MMC treatment also reduces migration and deposition of transforming growth factor-β1 (TGFβ1)-stimulated collagen by corneal fibroblasts. Using conditioned media from control and MMC treated cells, we demonstrate that factors secreted by MMC-treated corneal epithelial cells attenuate collagen deposition by HCFs whereas those secreted by MMC-treated HCFs do not. These studies are the first to probe the roles played by corneal epithelial cells in reducing collagen deposition by corneal fibroblasts in response to MMC.
Caron-Cantin M, Cestari DM, Fortin E. Clinical and radiologic approach to 'typical' versus antibody-related optic neuritis. Curr Opin Ophthalmol 2019;30(6):412-417.Abstract
PURPOSE OF REVIEW: Optic neuritis is an autoimmune optic neuropathy that has been associated with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and more recently antimyelin oligodendrocyte glycoprotein (anti-MOG)-positive disorder. At initial presentation, it is often difficult to differentiate these entities given their significant overlap in clinical presentation and MRI findings. This review summarizes the distinguishing clinical and radiological features of MS, NMOSD, and anti-MOG disorders to help clinicians accurately diagnose and manage patients affected by these conditions. RECENT FINDINGS: Antiaquaporin-4 (AQP4) and more recently anti-MOG antibodies are both associated with central nervous system demyelinating diseases that often initially present with optic neuritis. Serologic testing now allows for a new classification of these overlapping conditions that can help to differentiate 'typical' optic neuritis that is often associated with MS from 'atypical' optic neuritis associated with NMOSD and anti-MOG-positive disorder. SUMMARY: Optic neuritis associated with MS, NMOSD, and anti-MOG-positive disease can have a similar clinical presentation. However, some clinical and radiologic findings can help clinicians to differentiate these entities so that they can be properly managed to optimize visual prognosis.
Fini EM, Jeong S, Gong H, Martinez-Carrasco R, Laver NMV, Hijikata M, Keicho N, Argüeso P. Membrane-associated mucins of the ocular surface: New genes, new protein functions and new biological roles in human and mouse. Prog Retin Eye Res 2019;:100777.Abstract
The mucosal glycocalyx of the ocular surface constitutes the point of interaction between the tear film and the apical epithelial cells. Membrane-associated mucins (MAMs) are the defining molecules of the glycocalyx in all mucosal epithelia. Long recognized for their biophysical properties of hydration, lubrication, anti-adhesion and repulsion, MAMs maintain the wet ocular surface, lubricate the blink, stabilize the tear film and create a physical barrier to the outside world. However, it is increasingly appreciated that MAMs also function as cell surface receptors that transduce information from the outside to the inside of the cell. A number of excellent review articles have provided perspective on the field as it has progressed since 1987, when molecular cloning of the first MAM was reported. The current article provides an update for the ocular surface, placing it into the broad context of findings made in other organ systems, and including new genes, new protein functions and new biological roles. We discuss the epithelial tissue-equivalent with mucosal differentiation, the key model system making these advances possible. In addition, we make the first systematic comparison of MAMs in human and mouse, establishing the basis for using knockout mice for investigations with the complexity of an in vivo system. Lastly, we discuss findings from human genetics/genomics, which are providing clues to new MAM roles previously unimagined. Taken together, this information allows us to generate hypotheses for the next stage of investigation to expand our knowledge of MAM function in intracellular signaling and roles unique to the ocular surface.
Deng SX, Borderie V, Chan CC, Dana R, Figueiredo FC, Gomes JAP, Pellegrini G, Shimmura S, Kruse FE. Reply. Cornea 2019;38(12):e56-e57.
Subramanian S, Maurer AC, Bator CM, Makhov AM, Conway JF, Turner KB, Marden JH, Vandenberghe LH, Hafenstein SL. Filling Adeno-Associated Virus Capsids: Estimating Success by Cryo-Electron Microscopy. Hum Gene Ther 2019;30(12):1449-1460.Abstract
Adeno-associated viruses (AAVs) have been employed successfully as gene therapy vectors in treating various genetic diseases for almost two decades. However, transgene packaging is usually imperfect, and developing a rapid and accurate method for measuring the proportion of DNA encapsidation is an important step for improving the downstream process of large scale vector production. In this study, we used two-dimensional class averages and three-dimensional classes, intermediate outputs in the single particle cryo-electron microscopy (cryo-EM) image reconstruction pipeline, to determine the proportion of DNA-packaged and empty capsid populations. Two different preparations of AAV3 were analyzed to estimate the minimum number of particles required to be sampled by cryo-EM in order for robust calculation of the proportion of the full versus empty capsids in any given sample. Cost analysis applied to the minimum amount of data required for a valid ratio suggests that cryo-EM is an effective approach to analyze vector preparations.
Heidary G, MacKinnon S, Elliott A, Barry BJ, Engle EC, Hunter DG. Outcomes of strabismus surgery in genetically confirmed congenital fibrosis of the extraocular muscles. J AAPOS 2019;Abstract
PURPOSE: To detail surgical strategy and strabismus outcomes in a genetically defined cohort of patients with congenital fibrosis of the extraocular muscles (CFEOM). METHODS: A total of 13 patients with genetically confirmed CFEOM (via genetic testing for mutations in KIF21A, PHOX2A, and TUBB3) were retrospectively identified after undergoing strabismus surgery at Boston Children's Hospital and surgical outcomes were compared. RESULTS: Age at first surgery ranged from 11 months to 63 years, with an average of 3 strabismus procedures per patient. Ten patients had CFEOM1, of whom 9 had the KIF21A R954W amino acid (AA) substitution and 1 had the M947T AA substitution. Of the 3 with CFEOM3, 2 had the TUBB3 E410K AA substitution, and 1 had a previously unreported E410V AA substitution. CFEOM1 patients all underwent at least 1 procedure to address chin-up posture. Chin-up posture improved from 24° ± 8° before surgery to 10.0° ± 8° postoperatively (P < 0.001). Three CFEOM1 patients developed exotropia after vertical muscle surgery alone; all had the R954W AA substitution. Postoperatively, 1 CFEOM1 patient developed a corneal ulcer. All CFEOM3 patients appeared to have underlying exposure keratopathy, successfully treated with prosthetic replacement of the ocular surface ecosystem (PROSE) lens in 2 patients. CONCLUSIONS: CFEOM is a complex strabismus disorder for which surgical management is difficult. Despite an aggressive surgical approach, multiple procedures may be necessary to achieve a desirable surgical effect. Knowledge of the underlying genetic diagnosis may help to inform surgical management.
Coco G, Kheirkhah A, Foulsham W, Dana R, Ciolino JB. Keratoconus progression associated with hormone replacement therapy. Am J Ophthalmol Case Rep 2019;15:100519.Abstract
Purpose: To report a postmenopausal patient with keratoconus who experienced significant progression after using hormone replacement therapy. Observations: A 51-year-old woman with previously stable keratoconus presented with acute disease progression following hormone replacement therapy in the context of prophylactic hysterectomy and bilateral ovariosalpingectomy. Over a 14-month period after starting hormone therapy, the steepest K increased from 63.7D to 71.5D in the right eye and from 65.8D to 78.1D in the left eye. Conclusions: Hormone replacement therapy may amplify progression of keratoconus.
Aminkhani A, Sharifi R, Dorosti R. Chemical Composition and Antimicrobial Activity of Achillea tenuifolia Lam. Essential Oil at Different Phenological Stages from Khoy. Chem Biodivers 2019;16(12):e1900289.Abstract
Achillea species and in particular Achillea tenuifolia Lam. is generally used as a food flavor and traditional remedies, especially in the initial developmental stage for medical conditions in the Mediterranean part of Iran. In this report, we extracted the essential oil from the aerial parts of A. tenuifolia (collected from Khoy), at various developmental stages (i. e., vegetative, flowering and fruiting), characterized them and studied their antibacterial activities. Of 46, 51 and 38 components found in the vegetative, flowering, and fruiting stages, respectively, 35 were present in all three stages, including oxygenated terpenes such as carvacrol (30.85-34.11), germacrene C (16.21-17.87), spathulenol (7.26-8.96), β-sesquiphellandrene (4.11-4.25), τ-muurolol (2.27-3.25) and α-cadinol (2.01-3.29). We witnessed that the composition of the essential oils varies with phenological stages and geographic regions. The essential oil demonstrated substantial antibacterial properties against both Gram-positive and Gram-negative bacteria, indicated by disk method, Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) assays. Except Pseudomonas aeruginosa, the essential oils of various phenological stages showed higher antibacterial activity against tested bacteria, with Bacillus anthracis as the most sensitive strain. Moreover, although antibacterial characteristics of the essential oil from the vegetative and flowering stages were similar (p=0.91), they were significantly different from those of fruiting stage (p<0.005 in both MIC and MBC tests). This emphasizes the importance of the developmental stage of the plant in the biological properties of its essential oil and justifies the widespread application of this plant in the vegetative stage.
You C, Lasave AF, Kubaisi B, Syeda S, Ma L, Wai KCK, Diaz MH, Walsh M, Stephenson A, Montieth A, Foster SC. Long-term outcomes of systemic corticosteroid-sparing immunomodulatory therapy for Birdshot Retinochoroidopathy. Ocul Immunol Inflamm 2019;:1-9.Abstract
: To report the visual prognosis, electroretinography (ERG) and perimetry outcomes of systemic corticosteroid-sparing immunomodulatory treatment (IMT) for birdshot retinochoroidopathy (BSRC). : Retrospective non-comparative case series of 132 patients (264 eyes) with BSRC treated with IMT from Massachusetts Eye Research and Surgery Institution. : The average follow-up time was 60.1 months. After one year on IMT, 39.4% showed no clinically active inflammation. After 5 years of IMT, 78.0% had no signs of clinical inflammation. No significant differences were observed on best-corrected visual acuity (BCVA), ERG parameters, and perimetry parameters between baseline and subsequent visits on IMT. : Long-term systemic corticosteroid-sparing IMT was associated with a low rate of BSRC disease exacerbation. While differences were seen on testing parameters, they were not consistent trends and difference were attributed to variability of testing or fluctuation of inflammation that may be expected in the course of the disease.
Stanwyck LK, Place EM, Comander J, Huckfeldt RM, Sobrin L. Predictive value of genetic testing for inherited retinal diseases in patients with suspected atypical autoimmune retinopathy. Am J Ophthalmol Case Rep 2019;15:100461.Abstract
Purpose: The clinical features of autoimmune retinopathy (AIR) can resemble and be difficult to differentiate from inherited retinal degenerations (IRDs). Misdiagnosis of an IRD as AIR causes unnecessary treatment with immunosuppressive agents. The purpose of this study is to calculate the predictive value of genetic testing for IRDs in patients with suspected AIR and provide clinical examples where genetic testing has been useful. Methods: We identified patients seen at MEEI between April 2013 and January 2017 for whom the differentiation of AIR vs. IRDs was difficult based on clinical assessment alone. All patients had some atypical features for AIR, but tested positive for anti-retinal antibodies. Within this group, we identified six patients who had genetic testing for IRDs with the Genetic Eye Disease panel for retinal genes (GEDi-R). We calculated the positive predictive value (PPV) and negative predictive value (NPV) of genetic testing in a population with approximately equal numbers of IRD and AIR patients. Results: Six patients had clinical features that made distinguishing between IRDs and AIR on a clinical basis difficult and were sent for genetic testing: four women and two men with a mean age of 59.5 years. In two of these six patients, genetic diagnoses were made based upon the identification of known pathogenic variants in the common IRD genes and . Two patients had variants of unknown significance within genes associated with IRDs, and the other two had no relevant genetic findings. Given the 60% sensitivity and 3% false positive rate for GEDi-R testing and assuming a 50% pre-test probability of having an IRD, the PPV for GEDi-R for detecting IRD is 95.2% and the NPV is 70.8%. Conclusions and Importance: In patients for whom the differential diagnosis of AIR and IRDs is unclear based on clinical information, genetic testing can be a valuable tool when it identifies an IRD, sparing the patient unnecessary immunosuppressive treatment. However, the test has a low NPV so a negative genetic testing result does not confidently exclude IRD as the true diagnosis.

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