Laura E. Downie

AT1 receptor inhibition prevents astrocyte degeneration and restores vascular growth in oxygen-induced retinopathy

We investigated the effect of receptor blockade induced by an angiotensin II type‐1 receptor antagonist (AT1‐RB) on glial and vascular changes in oxygen‐induced retinopathy (OIR), a model of retinopathy of prematurity (ROP). OIR was induced in Sprague‐Dawley rats by exposure to 80% oxygen from postnatal (P) days 0–11, followed by 7 days in room air. Control animals were in room air for the entire duration. One cohort of OIR and control pups received the AT1‐RB valsartan (40 mg/kg/day intraperitoneal) from P11 to P18. The vascular response was examined immunocytochemically using retinal wholemounts and vertical sections labeled with endothelial (Isolectin‐B4) and pericyte (NG2, desmin) markers. Glial cell changes were assessed by measuring cell numbers and immunoreactivity (S100β, connexin‐26, and glial fibrillary acidic protein). OIR resulted in extensive intravitreal neovascularization and under‐development of the outer vascular plexus. Pericyte numbers were not significantly affected in OIR, although pericyte‐endothelial (desmin‐IB4) interactions were impaired. Peripheral astrocyte degeneration occurred between P11 and P13 with prominent Müller cell reactivity at P18. Valsartan imparted a protective effect on glia and blood vessels in OIR. At P18, valsartan‐treated OIR retinae showed significantly greater astrocyte survival, improved revascularization of the retina, and reduced preretinal neovascularization and Müller cell reactivity. This study identifies a glio‐vascular protective effect with AT1‐RB in OIR.

TFOS DEWS II Management and Therapy Report

The members of the Management and Therapy Subcommittee undertook an evidence-based review of current dry eye therapies and management options. Management options reviewed in detail included treatments for tear insufficiency and lid abnormalities, as well as anti-inflammatory medications, surgical approaches, dietary modifications, environmental considerations and complementary therapies. Following this extensive review it became clear that many of the treatments available for the management of dry eye disease lack the necessary Level 1 evidence to support their recommendation, often due to a lack of appropriate masking, randomization or controls and in some cases due to issues with selection bias or inadequate sample size. Reflecting on all available evidence, a staged management algorithm was derived that presents a step-wise approach to implementing the various management and therapeutic options according to disease severity. While this exercise indicated that differentiating between aqueous-deficient and evaporative dry eye disease was critical in selecting the most appropriate management strategy, it also highlighted challenges, based on the limited evidence currently available, in predicting relative benefits of specific management options, in managing the two dry eye disease subtypes. Further evidence is required to support the introduction, and continued use, of many of the treatment options currently available to manage dry eye disease, as well as to inform appropriate treatment starting points and understand treatment specificity in relation to dry eye disease subtype.

Neuronal and Glial Cell Changes Are Determined by Retinal Vascularization in Retinopathy of Prematurity

We have characterized the vascular, neuronal, and glial changes in oxygen‐induced retinopathy, a model of retinopathy of prematurity (ROP). Newborn Sprague‐Dawley rats were exposed to either 80% ± 2% oxygen to postnatal day P11 and then room air until P18 (ROP) or room air for the entire duration (controls). Retinal structure was examined under the light microscope and following postembedding immunocytochemistry in central, midperipheral, and peripheral regions. Müller cells were evaluated immunocytochemically with glial fibrillary acidic protein. The extent of vascularization was established histologically. ROP caused significant thinning of the inner cellular and plexiform layers, which became more pronounced in the peripheral inner nuclear layer of ROP animals (11.3% loss vs. 25.4% loss). Amacrine cell amino acid levels were particularly vulnerable in the peripheral retina; bipolar cells showed similar but less prominent changes. Müller cells had elevated glutamine levels and were most gliotic in the periphery. The vasculature extended to peripheral retinal regions at P18 in controls but not in ROP rats. The most striking pattern of change was evident in the midperipheral “transition zone” of ROP animals. Areas close to blood vessels showed neurochemical properties that were similar to those of the central retina, indicating a local protective effect of the inner retinal blood supply. We find that ROP produces complex vascular, neural, and glial changes that relate to the proximity of inner retinal blood vessels. J. Comp. Neurol. 504:404–417, 2007.

The significance of neuronal and glial cell changes in the rat retina during oxygen-induced retinopathy.

Retinopathy of prematurity is a devastating vascular disease of premature infants. A number of studies indicate that retinal function is affected in this disease. Using the rat model of oxygen-induced retinopathy, it is possible to explore more fully the complex relationship between neuronal, glial and vascular pathology in this condition. This review examines the structural and functional changes that occur in the rat retina following oxygen-induced retinopathy. We highlight that vascular pathology in rats is characterized by aberrant growth of blood vessels into the vitreous at the expense of blood vessel growth into the body of the retina. Moreover, amino acid neurochemistry, a tool for examining neuronal changes in a spatially complete manner reveals widespread changes in amacrine and bipolar cells. In addition, neurochemical anomalies within inner retinal neurons are highly correlated with the absence of retinal vessels. The key cell types that link blood flow with neuronal function are macroglia. Macroglia cells, which in the retina include astrocytes and Müller cells, are affected by oxygen-induced retinopathy. Astrocyte loss occurs in the peripheral retina, while Müller cells show signs of reactive gliosis that is highly localized to regions that are devoid of intraretinal blood vessels. Finally, we propose that treatments, such as blockade of the renin–angiotensin system, that not only targets pathological angiogenesis, but that also promotes re-vascularization of the retina are likely to prove important in the treatment of those with retinopathy of prematurity.

Angiotensin type-1 receptor inhibition is neuroprotective to amacrine cells in a rat model of retinopathy of prematurity

Retinopathy of prematurity (ROP) is characterized by deficits in the scotopic pathway, although the cellular locus for these deficits is not clear. Here we examined neurochemical and cellular changes that develop during oxygen‐induced retinopathy, a model of ROP. In addition, we examined whether treatment with the angiotensin II type‐1 receptor inhibitor, valsartan, prevented these changes. Newborn Sprague–Dawley rats were exposed from postnatal day (P) 0 to 11 to 80%:20% O2 (22:2 hr/day) and then room air until P18. Valsartan (40 mg/kg/day) was administered from P12–P18. Pattern recognition analysis of overlapping amino acid profiles was used to provide a statistically robust and spatially complete classification of neural elements for each experimental condition. Classification yielded 12 neuronal theme classes in controls and nine classes following ROP. ROP was associated with a reduction in the number of amacrine and bipolar cell theme classes. The reduction in theme classes was confirmed as true neuronal loss by quantifying anatomical changes and using an apoptotic marker. ROP was associated with shifts in amino acid levels across all neuronal populations except for horizontal cells. A reduction in the density of glycine‐immunoreactive amacrine cells, and particularly parvalbumin‐immunoreactive AII amacrine cells, was observed following ROP. Valsartan treatment during ROP prevented loss of theme classes and loss of AII amacrine cells. This study suggests that deficits in scotopic vision during ROP may be associated with loss of AII amacrine cells. In addition, this study highlights the potential of AT1R blockade in preventing neuronal anomalies in this condition. J. Comp. Neurol. 518:41–63, 2010.

An Evidence-Based Analysis of Australian Optometrists' Dry Eye Practices

Purpose The aims of this study were to investigate the clinical practices of Australian optometrists as related to the diagnosis, quantification, and management of dry eye and to assess whether these are consistent with research evidence and current guidelines. Methods An online survey was distributed to registered optometrists (n = 654). Respondents provided information regarding their preferred diagnostic procedures and management strategies for dry eye, practice modality, year of commencing practice, and whether they possessed an interest in dry eye. Results Respondents (n = 144) used multiple procedures for diagnosis. Recording patient symptoms ranked as the most important, most valuable, and most commonly used technique. The main objective tests were fluorescein-assisted tear breakup time, corneal fluorescein staining, and meibomian gland evaluation. Optometrists with an interest in dry eye more frequently used lissamine green, phenol red test, interference fringes, and tear osmolarity than nonspecialist practitioners. Dry eye treatment varied with severity. The mainstay of therapy was nonpreserved lubricants and eyelid hygiene; more practitioners recommended topical corticosteroids, systemic omega-3 fatty acid supplementation and increased dietary intake of omega-3 fatty acids for moderate and severe disease, respectively. The primary sources of information used to guide practitioners’ management were derived from continuing education conferences. Conclusions This study indicates that although Australian optometrists use subjective and objective diagnostic tests and stratify treatment based on dry eye severity, there is a lack of uniformity regarding diagnostic testing, infrequent use of standardized grading scales, and significant variability in clinical care. These findings highlight the potential to improve the translation of dry eye research evidence and evidence-based guidelines into Australian optometric practice.

Contact lens management of keratoconus

Contact lenses are the primary form of visual correction for patients with keratoconus. Contemporary advances in contact lens designs and materials have significantly expanded the available fitting options for patients with corneal ectasia. Furthermore, imaging technology, such as corneal topography and anterior segment optical coherence tomography, can be applied to both gain insight into corneal microstructural changes and to guide contact lens fitting. This paper provides a comprehensive review of the range of contact lens modalities, including soft lenses, hybrid designs, rigid lenses, piggyback configurations, corneo‐scleral, mini‐scleral and scleral lenses that are currently available for the optical management of keratoconus. The review also discusses the importance of monitoring for disease progression in patients with keratoconus, in particular children, who tend to undergo more rapid progressive changes, so as to facilitate appropriate modification to contact lens fitting and/or potential referral for corneal collagen cross‐linking treatment, as appropriate.

A review of the role of glial cells in understanding retinal disease

Retinal vascular diseases such as diabetic retinopathy and retinopathy of prematurity are major causes of visual loss. Although the focus of a great deal of research has been on the aetiology of vascular growth, it is now emerging that anomalies in other retinal cell types, especially glial cells, occur very early in the course of the disease. Glial cells have major roles in every stage of disease, from the earliest subtle variations in neural function, to the development of epi‐retinal membranes and tractional detachment. Therefore, having a firm understanding of the function of retinal glia is important in our understanding of retinal disease and is crucial for the development of new treatment strategies.

Nutrition and Age-Related Macular Degeneration: Research Evidence in Practice

Age-related macular degeneration (AMD) is the leading cause of irreversible visual impairment in developed countries. In the absence of effective treatments to slow AMD progression, it is predicted that the prevalence of AMD will double over the next 20 years. One area of significant interest is the potential role that nutrition may play in preventing and/or delaying the progression of AMD. Specifically, is there any benefit in oral antioxidant and/or mineral supplementation? This review critically evaluates the currently available evidence relating to nutrition and AMD, with particular reference to the key findings of two large National Eye Institute-sponsored clinical studies, namely, the Age-Related Eye Disease Study (AREDS) and AREDS2. Topical controversies relating to nutrition and AMD are considered and analyzed in the context of the published literature to guide practitioners through assessing the merit, or otherwise, of common claims. This article provides a foundation for clinicians to provide informed advice to AMD patients based on available research evidence.

Tear Interferon-Gamma as a Biomarker for Evaporative Dry Eye Disease.

Purpose To assess whether tear hyperosmolarity, being diagnostic of dry eye disease (DED), is associated with specific alterations to the cytokine content of human tears that may provide a biomarker for DED. Methods In this prospective, cross-sectional, clinical study, participants (n = 77) were recruited from a single clinical site and categorized into groups based upon tear osmolarity status (n = 62 hyperosmolar, n = 15 normo-osmolar). Comprehensive anterior eye clinical assessments were undertaken. Concentrations of seven cytokines (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, and TNF-α) in basal tears were assayed using multiplex cytometric bead array. The main outcome measure was difference in cytokine concentration between groups. Group comparisons were undertaken using 2-tailed t-tests. Cohens effect size was calculated for each finding. Spearman correlations between cytokine concentrations, clinical symptoms, and clinical parameters of DED were calculated. Results Tear hyperosmolarity was specifically associated with increased tear IFN-γ levels (13.3 ± 2.0 vs. 4.4 ± 1.4 pg/mL, P = 0.03). Cohens effect size was large (0.8) for changes to tear IFN-γ levels. Significant correlations were observed between IFN-γ concentration and each of: tear osmolarity (r = 0.34; P = 0.007), total ocular surface staining (r = 0.56, P < 0.0001), and Schirmer test score (r = -0.33, P = 0.003). Conclusions Tear hyperosmolarity is specifically associated with higher levels of the proinflammatory cytokine IFN-γ, which correlate with key clinical parameters of DED. The calculated effect size (0.8) suggests that this assay has diagnostic power as a biomarker for evaporative DED.