Optometry and Vision Sciences - Research Publications
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ItemEndomembranes promote chromosome missegregation by ensheathing misaligned chromosomes(ROCKEFELLER UNIV PRESS, 2022-05-05)Errors in mitosis that cause chromosome missegregation lead to aneuploidy and micronucleus formation, which are associated with cancer. Accurate segregation requires the alignment of all chromosomes by the mitotic spindle at the metaphase plate, and any misalignment must be corrected before anaphase is triggered. The spindle is situated in a membrane-free "exclusion zone"; beyond this zone, endomembranes (mainly endoplasmic reticulum) are densely packed. We investigated what happens to misaligned chromosomes localized beyond the exclusion zone. Here we show that such chromosomes become ensheathed in multiple layers of endomembranes. Chromosome ensheathing delays mitosis and increases the frequency of chromosome missegregation and micronucleus formation. We use an induced organelle relocalization strategy in live cells to show that clearance of endomembranes allows for the rescue of chromosomes that were destined for missegregation. Our findings indicate that endomembranes promote the missegregation of misaligned chromosomes that are outside the exclusion zone and therefore constitute a risk factor for aneuploidy.
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ItemNeuroimmune crosstalk in the cornea: The role of immune cells in corneal nerve maintenance during homeostasis and inflammation(PERGAMON-ELSEVIER SCIENCE LTD, 2022-11)In the cornea, resident immune cells are in close proximity to sensory nerves, consistent with their important roles in the maintenance of nerves in both homeostasis and inflammation. Using in vivo confocal microscopy in humans, and ex vivo immunostaining and fluorescent reporter mice to visualize corneal sensory nerves and immune cells, remarkable progress has been made to advance our understanding of the physical and functional interactions between corneal nerves and immune cells. In this review, we summarize and discuss recent studies relating to corneal immune cells and sensory nerves, and their interactions in health and disease. In particular, we consider how disrupted corneal nerve axons can induce immune cell activity, including in dendritic cells, macrophages and other infiltrating cells, directly and/or indirectly by releasing neuropeptides such as substance P and calcitonin gene-related peptide. We summarize growing evidence that the role of corneal intraepithelial immune cells is likely different in corneal wound healing versus other inflammatory-dominated conditions. The role of different types of macrophages is also discussed, including how stromal macrophages with anti-inflammatory phenotypes communicate with corneal nerves to provide neuroprotection, while macrophages with pro-inflammatory phenotypes, along with other infiltrating cells including neutrophils and CD4+ T cells, can be inhibitory to corneal re-innervation. Finally, this review considers the bidirectional interactions between corneal immune cells and corneal nerves, and how leveraging this interaction could represent a potential therapeutic approach for corneal neuropathy.
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ItemNo Preview AvailableCorneal tissue-resident memory T cells form a unique immune compartment at the ocular surface(CELL PRESS, 2022-05-24)The eye is considered immune privileged such that immune responses are dampened to protect vision. As the most anterior compartment of the eye, the cornea is exposed to pathogens and can mount immune responses that recruit effector T cells. However, presence of immune memory in the cornea is not defined. Here, we use intravital 2-photon microscopy to examine T cell responses in the cornea in mice. We show that recruitment of CD8+ T cells in response to ocular virus infection results in the formation of tissue-resident memory T (TRM) cells. Motile corneal TRM cells patrol the cornea and rapidly respond in situ to antigen rechallenge. CD103+ TRM cell generation requires antigen and transforming growth factor β. In vivo imaging in humans also reveals highly motile cells that patrol the healthy cornea. Our study finds that TRM cells form in the cornea where they can provide local protective immunity.
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ItemPoint-of-care tools to support optometric care provision to people with age-related macular degeneration: A randomised, placebo-controlled trial(WILEY, 2022-07)PURPOSE: Age-related macular degeneration (AMD) is a leading cause of vision impairment. This randomised placebo-controlled trial investigated whether point-of-care tools can improve optometrists' AMD knowledge and/or care provision. METHODS: Australian optometrists (n = 31) completed a demographics survey and theoretical AMD case study multiple-choice questions (MCQs) to assess their confidence in AMD care provision and AMD knowledge. Participants were then randomly assigned to one of three point-of-care tools (online 'Classification of Age-related macular degeneration and Risk Assessment Tool' (CARAT), paper CARAT, or 'placebo') to use when providing care to their subsequent 5-10 AMD patients. Participants self-audited the compliance of their AMD care to best practice for these patients, and a similar number of consecutive patients seen prior to enrolment. Post-intervention, participants retook the AMD knowledge MCQs and confidence survey. RESULTS: A total of 29 participants completed the study. At the study endpoint, clinical confidence relative to baseline improved with the paper CARAT, relative to placebo, for knowledge of AMD risk factors, asking patients about these factors and referring for medical retinal sub-specialist care. There were no between-group differences for the change in AMD knowledge scores. Considering record documentation for patients with any AMD severity, there were no significant between-group differences for documenting patient risk factors, AMD severity, clinical examination techniques or management. In a sub-analysis, the change from baseline in compliance for documenting discussions about patient smoking behaviours for early AMD patients was higher with use of the online CARAT relative to placebo (p = 0.04). For patients with intermediate AMD, the change from baseline in documenting the risk of progression to late AMD was greater among practitioners who used the paper CARAT, relative to placebo (p = 0.04). CONCLUSIONS: This study demonstrates that point-of-care clinical tools can improve practitioner confidence and aspects of the documentation of AMD clinical care by optometrists as assessed by self-audit.
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ItemTopographical Distribution and Phenotype of Resident Meibomian Gland Orifice Immune Cells (MOICs) in Mice and the Effects of Topical Benzalkonium Chloride (BAK)(MDPI, 2022-09)Meibomian gland orifices (MGOs) are located along the eyelid margin and secrete meibum into the tear film. The profile of resident innate immune cells (ICs) at this site is not well understood. The distribution and phenotype of resident ICs around MGOs in mice was investigated and herein defined as MGO-associated immune cells (MOICs). The effect of topical 0.1% benzalkonium chloride (BAK) on MOICs was also assessed. Eyelids from healthy CD11ceYFP and Cx3cr1gfp/gfp mice aged three or seven months were compared. ICs were identified as CD11c+, Cx3cr1+, and MHC-II+ using four-colour immunostaining and confocal microscopy. MOIC density was variable but clustered around MGOs. There were more CD11c+ MOICs in three-month-old compared with seven-month-old mice (three-month-old: 893 ± 449 cells/mm2 vs. seven-month-old: 593 ± 493 cells/mm2, p = 0.004). Along the eyelid margin, there was a decreasing gradient of CD11c+ MOIC density in three-month-old mice (nasal: 1003 ± 369 cells/mm2, vs. central: 946 ± 574 cells/mm2, vs. temporal: 731 ± 353 cells/mm2, p = 0.044). Cx3cr1-deficient mice had two-fold fewer MHC-II+ MOICs, suggesting a role for Cx3cr1 receptor signaling in meibomian gland surveillance. CD11c+ MOIC density was lower in BAK-exposed eyes compared to saline-treated controls, suggesting a change in homeostasis. This study provides novel insight into resident ICs located at MGOs, and their contribution to MG homeostasis.
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ItemDefining an Optimal Sample Size for Corneal Epithelial Immune Cell Analysis Using in vivo Confocal Microscopy Images(FRONTIERS MEDIA SA, 2022-06-01)PURPOSE: In vivo confocal microscopy (IVCM) images are frequently used to quantify corneal epithelial immune cell (IC) density in clinical studies. There is currently limited evidence to inform the selection of a representative image sample size to yield a reliable IC density estimate, and arbitrary numbers of images are often used. The primary aim of this study was to determine the number of randomly selected, unique IVCM images required to achieve an acceptable level of accuracy when quantifying epithelial IC density, in both the central and peripheral cornea. The secondary aim was to evaluate the consistency and precision of an image selection approach where corneal epithelial IC density was quantified from "three representative images" selected independently by three experienced observers. METHODS: All combinations of two to 15 non-overlapping IVCM images were used for deriving IC density estimates, for both the central and peripheral cornea, in 20 healthy participants; the density value from averaging quantifications in the 16 images was defined as the "true mean". IC density estimates were compared with the true mean in each corneal region using a mean ratio. Intraclass correlation coefficients (ICCs) were used to evaluate the consistency of the mean ratios of IC density estimates derived from the method involving the manual selection of "three representative images" by the observers. The precision of the IC density estimates was compared to a scenario involving three randomly selected images. RESULTS: A total of 12 randomly selected, non-overlapping IVCM images were found to be required to produce a corneal epithelial IC density estimate that was within 30% of the true mean, 95% of the time, for the central cornea; seven such images produced an equivalent level of precision in the peripheral cornea. Mean ratios of corneal IC density estimates derived from "three representative images" methods had poor consistency between observers (ICC estimates <0.5) and similar levels of precision when compared with using three randomly selected images (p > 0.05 for all comparisons), in both the central and peripheral cornea. CONCLUSIONS: Data presented in this study can inform image selection methods, and the sample size required for a preferred level of accuracy, when quantifying IC densities in the central and peripheral corneal epithelium using IVCM images.
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ItemNo Preview AvailableStem Cell Therapies for Eye Conditions: A Survey of Australian Ophthalmologists(ASIA-PACIFIC ACAD OPHTHALMOLOGY-APAO, 2022-02)
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ItemNo Preview AvailableEvaluating the clinical translational relevance of animal models for limbal stem cell deficiency: A systematic review(ELSEVIER, 2022-01)PURPOSE: Animal models are pivotal for elucidating pathophysiological mechanisms and evaluating novel therapies. This systematic review identified studies that developed or adapted animal models of limbal stem cell deficiency (LSCD), assessed their reporting quality, summarized their key characteristics, and established their clinical translational relevance to human disease. METHODS: The protocol was prospectively registered (PROSPERO CRD42020203937). Searches were conducted in PubMed, Ovid EMBASE and Web of Science in August 2020. Two authors screened citations, extracted data, assessed the reporting quality of eligible studies using the ARRIVE guidelines, and judged the clinical translational relevance of each model using a custom matrix. RESULTS: 105 studies were included. Rabbits were the most common animal species. Overall, 97% of studies recapitulated LSCD to a clinical etiology, however 62% did not provide sufficient methodological detail to enable independent reproduction of the model. Adverse events and/or exclusion of animals were infrequently (20%) reported. Approximately one-quarter of studies did not produce the intended severity of LSCD; 34% provided insufficient information to assess the fidelity of disease induction. Adjunctive diagnostic confirmation of LSCD induction was performed in 13% of studies. CONCLUSIONS: This is the first systematic review to assess the reporting quality and clinical translational relevance of animal models of LSCD. Models of LSCD have evolved over time, resulting in variable reporting of the characteristics of animals, experimental procedures and adverse events. In most studies, validation of LSCD was made using clinical tests; newer adjunctive techniques would enhance diagnostic validation. As most studies sought to evaluate novel therapies for LSCD, animal models should ideally recapitulate all features of the condition that develop in patients.
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ItemInterventions for the Management of Computer Vision Syndrome A Systematic Review and Meta-analysis(ELSEVIER SCIENCE INC, 2022-10)TOPIC: To evaluate the efficacy and safety of interventions for treating eye strain related to computer use relative to placebo or no treatment. CLINICAL RELEVANCE: Computer use is pervasive and often associated with eye strain, referred to as computer vision syndrome (CVS). Currently, no clinical guidelines exist to help practitioners provide evidence-based advice about CVS treatments, many of which are marketed directly to patients. This systematic review and meta-analysis was designed to help inform best practice for eye care providers. METHODS: Eligible randomized controlled trials (RCTs) were identified in Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and trial registries, searched from inception through November 23, 2021. Eligible studies were appraised for risk of bias and were synthesized. The certainty of the body of evidence was judged using the Grading of Recommendations, Assessment, Development, and Evaluation system. Standardized mean differences (SMDs) were used when differently scaled measures were combined. RESULTS: Forty-five RCTs, involving 4497 participants, were included. Multifocal lenses did not improve visual fatigue scores compared with single-vision lenses (3 RCTs; SMD, 0.11; 95% confidence interval [CI], -0.14 to 0.37; P = 0.38). Visual fatigue symptoms were not reduced by blue-blocking spectacles (3 RCTs), with evidence judged of low certainty. Relative to placebo, oral berry extract supplementation did not improve visual fatigue (7 RCTs; SMD, -0.27; 95% CI, -0.70 to 0.16; P = 0.22) or dry eye symptoms (4 RCTs; SMD, -0.10; 95% CI, -0.54 to 0.33; P = 0.65). Likewise, berry extract supplementation had no significant effects on critical flicker-fusion frequency (CFF) or accommodative amplitude. Oral omega-3 supplementation for 45 days to 3 months improved dry eye symptoms (2 RCTs; mean difference [MD], -3.36; 95% CI, -3.63 to -3.10 on an 18 unit scale; P < 0.00001) relative to placebo. Oral carotenoid supplementation improved CFF (2 RCTs; MD, 1.55 Hz; 95% CI, 0.42 to 2.67 Hz; P = 0.007) relative to placebo, although the clinical significance of this finding is unclear. DISCUSSION: We did not identify high-certainty evidence supporting the use of any of the therapies analyzed. Low-certainty evidence suggested that oral omega-3 supplementation reduces dry eye symptoms in symptomatic computer users.
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ItemThe effect of topical decorin on temporal changes to corneal immune cells after epithelial abrasion(BMC, 2022-04-12)BACKGROUND: Corneal immune cells interact with corneal sensory nerves during both homeostasis and inflammation. This study sought to evaluate temporal changes to corneal immune cell density in a mouse model of epithelial abrasion and nerve injury, and to investigate the immunomodulatory effects of topical decorin, which we have shown previously to promote corneal nerve regeneration. METHODS: Bilateral corneal epithelial abrasions (2 mm) were performed on C57BL/6J mice. Topical decorin or saline eye drops were applied three times daily for 12 h, 24 h, 3 days or 5 days. Optical coherence tomography imaging was performed to measure the abrasion area. The densities of corneal sensory nerves (β-tubulin III) and immune cells, including dendritic cells (DCs; CD11c+), macrophages (Iba-1+) and neutrophils (NIMP-R14+) were measured. Cx3cr1gfp/gfp mice that spontaneously lack resident corneal intraepithelial DCs were used to investigate the specific contribution of epithelial DCs. Neuropeptide and cytokine gene expression was evaluated using qRT-PCR at 12 h post-injury. RESULTS: In decorin-treated corneas, higher intraepithelial DC densities and lower neutrophil densities were observed at 24 h after injury, compared to saline controls. At 12 h post-injury, topical decorin application was associated with greater re-epithelialisation. At 5 days post-injury, corneal stromal macrophage density in the decorin-treated and contralateral eyes was lower, and nerve density was higher, compared to eyes treated with saline only. Lower expression of transforming growth factor beta (TGF-β) and higher expression of CSPG4 mRNA was detected in corneas treated with topical decorin. There was no difference in corneal neutrophil density in Cx3cr1gfp/gfp mice treated with or without decorin at 12 h. CONCLUSIONS: Topical decorin regulates immune cell dynamics after corneal injury, by inhibiting neutrophils and recruiting intraepithelial DCs during the acute phase (< 24 h), and inhibiting macrophage density at the study endpoint (5 days). These immunomodulatory effects were associated with faster re-epithelialisation and likely contribute to promoting sensory nerve regeneration. The findings suggest a potential interaction between DCs and neutrophils with topical decorin treatment, as the decorin-induced neutrophil inhibition was absent in Cx3cr1gfp/gfp mice that lack corneal epithelial DCs. TGF-β and CSPG4 proteoglycan likely regulate decorin-mediated innate immune cell responses and nerve regeneration after injury.