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Abstract: Lyotropic liquid crystalline nanoparticles (cubosomes) have the potential to act as amphiphilic scaffolds for the presentation of lipids and subsequent application in, for example, bioseparations and therapeutic delivery. In this work we have formulated lyotropic liquid crystalline systems based on the synthetic amphiphile 1,2,3-trihydroxy-3,7,11,15-tetramethylhexadecane (phytantriol) and containing the lipid dipalmitoyl phosphatidylserine (DPPS). We have prepared a range of DPPS-containing phytantriol cubosome formulations and characterized them using Small Angle X-ray Scattering and Cryo-transmission electron microscopy. These techniques show that increased DPPS content induces marked changes in lyotropic liquid crystalline phase behaviour, characterized by changes in crystallographic dimensions and increases in vesicle content. Furthermore, in vitro cell culture studies indicate that these changes correlate with lipid/surfactant cellular uptake and cytotoxicity. A model cell membrane based on a surface supported phospholipid bilayer was used to gain insights into cubosome–bilayer interactions using Quartz Crystal Microgravimetry. The data show that mass uptake at the supported bilayer increased with DPPS content. We propose that the cytotoxicity of the DPPS-containing dispersions results from changes in lipid/surfactant phase behaviour and the preferential attachment and fusion of vesicles at the cell membrane. [Copyright &y& Elsevier]

Background: Intravitreal injection of bevacizumab (Avastin) in eyes with neovascular glaucoma (NVG) has recently been shown to induce rapid regression of anterior segment neovascularization and has promise as adjunct treatment to diode laser cyclophotocoagulation (CPC) to control intraocular pressure (IOP). This study presents the outcome of concomitant treatment with CPC and intravitreal bevacizumab in painful poor visual potential eyes in a case series of consecutively diagnosed NVG. Methods: Twelve patients (14 eyes) were treated with CPC and concurrent intravitreal bevacizumab 0.05 mL (1.25 mg) and study end-points were IOP lowering, regression of anterior segment neovascularization and resolution of pain. Results: The mean preoperative IOP was 42.1 ± 11.4 and was lowered to 16.6 ± 7.1 mmHg at 1-month postoperatively. Anterior segment neovascularization regressed dramatically within 1 week of intravitreal bevacizumab in 12 eyes. Thirteen eyes reported persistent relief of ocular pain at 6 months following treatment. Conclusions: Combined intravitreal bevacizumab and CPC treatment for NVG provides rapid control of anterior segment neovascularization and may lead to improved symptomatic relief and IOP control. [ABSTRACT FROM AUTHOR]

The author reflects on the retinal ganglion cell (RGC) death in glaucoma that takes place through apoptosis and mentions that the recovery of RGC can avoid loss of visual function in glaucoma patients. The author suggests that the reduction of intraocular pressure (OP) during the stage of neuroplasticity can help to recover RGCs from apoptosis. He states that specific measurement of RGC dysfunction and recovery can help to advance in glaucoma neurorecovery.

Objective: To examine the relationship between peripheral artery disease (PAD) and glaucoma. Methods: As part of a population-based study of 3280 persons of Malay descent (78.7% response) aged 40 to 80 years examined between August 1, 2004, and June 30, 2006, the ankle-brachial index (ABI) was assessed in all persons with known diabetes mellitus and every fifth systematically sampled participant without diabetes. Peripheral artery disease was deemed present if the ABI was 0.9 or less. Glaucoma was diagnosed using International Society of Geographical and Epidemiological Ophthalmology criteria. Results: Of the 922 participants who had ABI measured, 79 (8.6%) had PAD and 42 (4.6%) had glaucoma. Persons with PAD were more likely to have glaucoma (11.4% vs 3.9%; age- and sex-adjusted odds ratio [OR], 2.80; 95% confidence interval [CI], 1.26-6.24), higher intraocular pressure (age- and sex-adjusted mean, 16.4 vs 15.5; P=.05), and a larger vertical cup-disc ratio (ageand sex-adjusted mean, 0.45 vs 0.40; P=.02). The association of PAD with glaucoma persisted while controlling for hypertension, diabetes, body mass index, serum triglyceride levels, and β-blocker use (multivariableadjusted OR, 2.55; 95% CI, 1.09-5.98) and was stronger in people with diabetes (multivariable-adjusted OR, 2.91; 95% CI, 1.14-7.44). Conclusions: Peripheral artery disease was related to glaucoma, supporting an association between large-vessel atherosclerotic disease and glaucoma. However, because the study sample included a high proportion of persons with diabetes, further research is needed to determine the relevance of these results to the general population. [ABSTRACT FROM AUTHOR]

Background: We and others have demonstrated that in vivo retinal hyperspectral imaging may serve as a non‐invasive biomarker of brain amyloid beta (Aβ) levels (Hadoux, 2019; More, 2019). We next sought to determine whether individuals with a range of common eye diseases have imaging scores distinct from those of people known to have high Aβ burden on brain PET imaging. Method: Retinal hyperspectral imaging was performed on people presenting to ophthalmology outpatient clinics with visually significant cataracts (n=10), glaucoma (n=18) or diabetic retinopathy (n=14). Hyperspectral imaging scores were calculated for each participant using image processing methods described previously (Hadoux, 2019). Scores were compared with those of participants with high Aβ burden on brain PET imaging (n=15) and age‐matched PET‐negative controls (n = 20) (Hadoux, 2019). Result: Participants in each group were similar for gender and age. Significant differences in hyperspectral imaging scores were found between PET+ participants and all other groups (Figure 1). Post‐hoc analysis demonstrated that PET‐ control participants had lower hyperspectral imaging scores than PET+ participants with normal (≥24, n=7; p=0.01) or reduced (<24, n=8; p=0.035) MMSE scores. Conclusion: We have shown that individuals presenting to outpatient ophthalmology clinics with a range of eye diseases including cataract, diabetic retinopathy and glaucoma have retinal hyperspectral imaging scores that are distinct from those of individuals with high Aβ burden on brain PET imaging. Further studies are warranted to establish the influence these eye diseases on hyperspectral imaging scores in PET+ individuals. We also provide evidence that retinal hyperspectral scores may be elevated in PET+ individuals with normal MMSE scores, indicating that the method may have a role in identifying those with pre‐symptomatic Alzheimer's disease. Prospective studies are underway to test this hypothesis. References: Hadoux, X, et al. Nature Communications; 2019; More, SS, et al. ACS Chem Neurosci. 2019. [ABSTRACT FROM AUTHOR]

Abstract: Assessment of the accuracy of non-invasive rebound tonometry, and comparison with invasive cannulation tonometry. An in vivo calibration technique was devised to improve the accuracy of the rebound tonometer. IOP was then measured in SW mice using both rebound and cannulation tonometry. The ability of the rebound tonometer to accurately measure small IOP reductions after instillation of a topical prostaglandin was also determined. With the rebound method, mid-afternoon IOP in two groups of similar aged SW mice was 15.9±3.9mmHg (mean±s.d., n=25) compared to 16.3±1.2mmHg (n=32) using the cannulation technique. This difference was not statistically significant (p=0.6). For serial measurements using both techniques in the same eyes of a third group of SW mice (n=14), mean IOP was 15.0±3.9mmHg for rebound tonometry but only 13.4±2.3mmHg for subsequent cannulation tonometry. This effect was subsequently shown to be a consequence of the rebound tonometry, as multiple rebound measurements induced a statistically significant reduction in IOP. The average IOP reduction observed 2hr after a single application of topical latanoprost (200ng) was 2.8±1.3mmHg (p<0.001) and 2.4±4.7mmHg (p=0.03) with cannulation and rebound tonometers, respectively. These differences were not significantly different (p=0.8). In vivo calibration of the rebound tonometer increased measurement accuracy and provided IOP values within the physiological range that agreed closely with the IOP measured by cannulation tonometry. However, IOP measurement with the rebound tonometer had larger variability compared with the cannulation method. Repeat IOP measurements with the rebound tonometer led to a reduction in IOP. The rebound tonometer was sufficiently sensitive to detect a 2–3mmHg reduction in IOP following application of topical latanoprost. Despite these limitations, the rebound tonometer has a significant advantage over cannulation tonometry in that it permits longitudinal IOP measurement in conscious mice. [Copyright &y& Elsevier]

Objectives To develop and validate a predictive model to estimate the risk of conversion from ocular hypertension to glaucoma. Methods Predictive models for the 5-year risk of conversion to glaucoma were derived from the results of the Ocular Hypertension Treatment Study (OHTS). The performance of these models was assessed in an independent population of 126 subjects with ocular hypertension from a longitudinal study (Diagnostic Innovations in Glaucoma Study [DIGS]). The performance of the OHTS-derived models was assessed in the DIGS cohort according to equality of regression coefficients, discrimination (c-index), and calibration. Results Thirty-one patients (25%) developed glaucoma during follow-up. Hazard ratios for DIGS- and OHTS-derived predictive models were similar for age, intraocular pressure, central corneal thickness, vertical cup-disc ratio, and pattern standard deviation but were significantly different for the presence of diabetes mellitus. When applied to the DIGS population, the OHTS-derived predictive models had reasonably good discrimination (c-indexes of 0.68 [full model] and 0.73 [reduced model]) and calibration. Conclusions The OHTS-derived predictive models performed well in assessing the risk of glaucoma development in an independent population of untreated subjects with ocular hypertension. A risk scoring system was developed that allows calculation of the 5-year risk of glaucoma development for an individual patient. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of distilled deionized water (DDW) on lens epithelial cells (LECs) attached to the lens capsule.Setting: Wound Healing Research Laboratory, Center for Vision Research, Westmead Hospital, Sydney, NSW, Australia.Methods: Anterior capsulotomy specimens taken during routine cataract surgery were divided in half. One half was immersed in DDW and the other half in culture medium (control) for 1 to 5 minutes and photographed at intervals by phase-contrast microscopy. In further experiments, the capsules were exposed to DDW for 1 or 2 minutes and placed in culture for 1 week to determine whether LECs survive treatment and are capable of repopulating the lens capsule.Results: Distilled-deionized water induced marked swelling of the cytoplasm within 60 seconds of treatment. At 120 seconds, there was disruption of the plasma membranes, with few intact cells remaining. In the control capsules, confluent monolayers of LECs covered the entire capsule surface with a halo of LECs growing on the surrounding plastic well. Viable LECs were observed in 1 of 3 capsules treated for 1 minute with DDW. These did not reach confluence or grow off the capsule onto the surrounding well. No viable LECs were seen on capsules exposed to DDW for 2 minutes.Conclusions: Short exposure of LECs to DDW induced extensive and rapid cell lysis. Distilled-deonized water may be a useful agent for instillation in the capsular bag during sealed-capsule irrigation to prevent posterior capsule opacification. [Copyright &y& Elsevier]

Glaucoma is a leading cause of blindness worldwide. In glaucoma, a progressive dysfunction and death of retinal ganglion cells occurs, eliminating transfer of visual information to the brain. Currently, the only available therapies target the lowering of intraocular pressure, but many patients continue to lose vision. Emerging pre-clinical and clinical evidence suggests that metabolic deficiencies and defects may play an important role in glaucoma pathophysiology. While pre-clinical studies in animal models have begun to mechanistically uncover these metabolic changes, some existing clinical evidence already points to potential benefits in maintaining metabolic fitness. Modifying diet and exercise can be implemented by patients as an adjunct to intraocular pressure lowering, which may be of therapeutic benefit to retinal ganglion cells in glaucoma. [ABSTRACT FROM AUTHOR]

Collagen accumulation in sub-conjunctival tissue at the surgical wound is one of the major complications associated with glaucoma filtration surgery (GFS). This process often leads to unwanted fibrotic scar formation at the lesion site and dysfunction of tissues. Previously, we demonstrated that NADPH oxidase 4 (Nox4) is implicated in transforming growth factor-beta (TGFβ)-induced collagen production in ocular fibroblasts and scarring responses in a mouse model of corneal injury. Here, we propose that Nox4 is an important facilitator of TGFβ-induced responses. We tested this hypothesis in human Tenon's fibroblasts (HTF) and also assessed a role of Nox4 in an experimental mouse model of GFS. TGFβ1 induced Nox4 mRNA expression but downregulated Nox5 in HTF. Targeting Nox4 gene expression with an adenovirus carrying a Nox4 small interfering RNA (siRNA) (Ad-Nox4i) or removal of hydrogen peroxide (H2O2) with EUK-134 (25 μM) in HTFs significantly reduced TGFβ1-induced Nox4 expression, H2O2 production, and collagen synthesis (p < 0.05, n = 3–6). SIS3 (5 μM) that prevents Smad3 phosphorylation is found to suppress TGFβ1-induced collagen production in HTFs. Furthermore, Ad-Nox4i and EUK-134 both abolished TGFβ1-stimulated proliferation of HTFs. We also compared collagen deposition at the wound arising from GFS between wildtype (WT) and Nox4 knockout (KO) mice. Both collagen deposition and fibrovascularization at the wound were significantly decreased in Nox4 KO mice at 14 days after GFS. Our results provide comprehensive evidence that Nox4 is an important mediator for TGFβ1-induced responses in HTFs and collagen deposition in surgical wound following GFS in mice. As such, pharmacological inhibition of Nox4 would be a viable therapeutic strategy for the control of scarring after glaucoma surgery. [ABSTRACT FROM AUTHOR]

Presents a case of elevated intraocular pressure (IOP), a major side effect of intravitreal steroid injection. Identification of risk factors for steroid IOP-responsiveness; Control of IOP with topical anti-glaucoma medications; Development of glaucomatous optic neuropathy.

The peak expiratory flow rate (PEFR) was studied in 20 matched pairs of children with homozygous sickle cell disease with either no episodes or six or more episodes of acute chest syndrome. The pairs were carefully matched for height and a highly significant reduction in PEFR was observed in children with multiple episodes of acute chest syndrome. Lateral and anteroposterior chest diameters and chest circumference correlated with PEFR but did not differ between index and control cases. The most likely cause of the reduced PEFR in children with multiple episodes of acute chest syndrome is an accumulating pulmonary fibrosis that decreases lung compliance. [ABSTRACT FROM AUTHOR]

The original version of this article unfortunately contained a mistake in the author name. The family name of Dr. Vanessa A. Johannsen should be written as "Johanssen." [ABSTRACT FROM AUTHOR]

A letter to the editor is presented on the lack of data on the publication output of academic ophthalmologists in Australia and New Zealand to enable comparison between them while performing professional development reviews.

A letter to the editor is presented which discusses the requirement of filtration surgery in patient who undergone bilateral toric Artisan phakic intraocular lens (p-IOL) surgery.

A response to a letter to the editor that comments on the trabeculectomy failure rates that are increasing is presented.

The article discusses a report published within the issue on the long term outcomes of trabeculectomies performed in Otago, New Zealand.

Background Ocular surface disease ( OSD) is relatively common in glaucoma patients. OSD symptoms could be linked to prolonged exposure to preservatives in anti-glaucoma medications, especially benzalkonium chloride ( BAK). The OBSERVE clinical audit was designed to track the impact of intraocular pressure lowering medications in patients with evidence of OSD to test the hypothesis that BAK-free anti-glaucoma preparations offer clinical advantages over BAK-containing products. Design Prospective clinical audit from March 2012 to April 2013, open to ophthalmologists practising in Australia. Participants There were 375 patients enrolled, with a completion rate of 64%. The cohort was predominantly female (68%) with an average age of 71 years. Methods Patients were screened for inclusion during a routine consultation. If eligible, they were enrolled. At the ophthalmologist's discretion, some patients were switched to BAK-free anti-glaucoma products. Data were collected via an online survey completed by the ophthalmologist during three appointments over a 16- to 30-week period for all patients. Main Outcome Measures Intraocular pressure, tear-film breakup time, Mc Monnies Dry Eye Questionnaire score and reported lubricant use. Results Patients who switched to BAK-free preparations reported a significant fall in the use of lubricants ( P = <0.001). Patients in both groups experienced a significant improvement in Mc Monnies Dry Eye Questionnaire score ( P = <0.0001). The percentage of patients with low tear-film breakup time decreased significantly in both groups ( P = 0.0001). There was no significant change in intraocular pressure from pre-study levels for either group ( P = 0.105). Conclusions BAK-free anti-glaucoma preparations were associated with a change in lubricant use, suggesting reduction in some OSD symptoms, but more research is needed. [ABSTRACT FROM AUTHOR]

Abstract: Mitochondrial oxidative phosphorylation (OXPHOS) dysfunction is implicated in a growing spectrum of diseases, from neurodegeneration to cancer. Where tissues or transformed cells are available, respirometry and enzymology allow a sophisticated analysis of OXPHOS with modest-cost equipment. The isolation of organelle fractions is also invaluable for determining association of proteins of interest. Here we revisit and consolidate methods to measure whole cell mitochondrial ATP synthesis, respiration, isolation of mitochondria from cultured cells and tissues, and OXPHOS enzymology. We also explain common pitfalls, guide optimisation of the methods for new users, and provide full laboratory protocols in Supplementary materials. [Copyright &y& Elsevier]

Aim To determine the incidence and predictors of glaucoma following surgery for congenital and infantile cataract in an Australian population. Design Retrospective cohort study. Participants Infants (<12 months) having had lens extraction between January 1992 and May 2006, from two tertiary referral centres. Methods Children with uveitis, anterior segment dysgenesis, aniridia, retinopathy of prematurity, and lens subluxation were excluded. Potential predictors of incident glaucoma were examined using Cox proportional hazards regression with adjustment for clustering between eyes. Main Outcome Measures Incidence and predictors of secondary glaucoma. Results One hundred and forty-seven eyes of 101 patients (46 bilateral cataract; 55 unilateral cataract) were included, with median follow-up of 9.9 years (range 1.2-18.9 years). Cumulative incidence of glaucoma was 32.0% for eyes ( n = 47) and 30.7% ( n = 31) for subjects. Incidence was higher in children with bilateral cataract (38.9 vs. 17.1%, p = 0.004). There were 3.9 cases of glaucoma per 100 person years of follow-up, the incidence rate being highest for surgery performed in the first month of life. Children with glaucoma had longer median follow-up (11.8 vs. 9.3 years, p = 0.005). Risk of glaucoma decreased with increasing months of age at operation: hazard ratio 0.79, 95% confidence interval 0.69-0.91, p = 0.001. Median visual acuity was worse in children with unilateral cataract ( p < 0.001). Conclusions We identified an increased risk of glaucoma when cataract surgery was performed in younger infants, and in those with bilateral cataract. As glaucoma may develop over a decade following lens extraction, life-long surveillance is needed to prevent glaucoma-associated vision loss. [ABSTRACT FROM AUTHOR]

Objective: To determine the rate of intentional and unintentional nonadherence in glaucoma patients and to identify associations between adherence behavior and patients'' beliefs. Design: Cross-sectional study. Participants: One hundred thirty-one glaucoma patients using topical eye drops for at least 6 months. Methods: Interviewer-administered surveys. Main Outcome Measures: Self-reported adherence and beliefs about glaucoma and its treatment were assessed using the Reported Adherence to Medication scale, the Brief Illness Perception Questionnaire, and the Beliefs about Medicines–Specific Questionnaire. Results: Overall, 59 (45%) participants reported some degree of nonadherence, among whom 39 (66.1%) reported unintentional nonadherence (e.g., forgetting), 10 (16.9%) reported intentional nonadherence (deliberate nonadherence), and 10 (16.9%) reported both forms of nonadherence. Compared with adherers, nonadherers were significantly younger, were less likely to have other nonocular health conditions or to use medicines other than their eye drops, and reported lower belief in the necessity of eye drops for glaucoma (P<0.05). Degree of unintentional nonadherence was associated with lower belief in necessity of eye drops, whereas degree of intentional nonadherence was associated with concerns about eye drops. Conclusions: Strategies aimed at improving adherence in glaucoma patients need to address both intentional and unintentional dimensions. Interventions focused on eliciting and addressing patients'' beliefs and concerns about their eye drops require evaluation. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. [Copyright &y& Elsevier]

Abstract: Assessment of optic disk size is an important, but often overlooked, component of the diagnostic evaluation for glaucoma. Measured values of optic disk size vary with the measurement technique utilized. Available methods for disk size measurement and their respective strengths and limitations will be discussed. Further, actual disk size varies with race and possibly other demographic characteristics. Disk size is also associated with variation of specific anatomical structures of the optic nerve head and the retinal nerve fiber layer. These disk size- dependent variations may influence the susceptibility to glaucoma or the likelihood of glaucoma diagnosis. This manuscript reviews the published evidence relating to disk size and glaucoma. [Copyright &y& Elsevier]

Energy metabolism refers to the processes by which life transfers energy to do cellular work. The retina's relatively large energy demands make it vulnerable to energy insufficiency. In addition, evolutionary pressures to optimize human vision have been traded against retinal ganglion cell bioenergetic fragility. Details of the metabolic profiles of the different retinal cells remain poorly understood and are challenging to resolve. Detailed immunohistochemical mapping of the energy pathway enzymes and substrate transporters has provided some insights and highlighted interspecies differences. The different spatial metabolic patterns between the vascular and avascular retinas can account for some inconsistent data in the literature. There is a consilience of evidence that at least some individuals with glaucoma have impaired RGC energy metabolism, either due to impaired nutrient supply or intrinsic metabolic perturbations. Bioenergetic-based therapy for glaucoma has a compelling pathophysiological foundation and is supported by recent successes in animal models. Recent demonstrations of visual and electrophysiological neurorecovery in humans with glaucoma is highly encouraging and motivates longer duration trials investigating bioenergetic neuroprotection. [ABSTRACT FROM AUTHOR]

Mitochondrial OXPHOS generates most of the energy required for cellular function. OXPHOS biogenesis requires the coordinated expression of the nuclear and mitochondrial genomes. This represents a unique challenge that highlights the importance of nuclear-mitochondrial genetic communication to cellular function. Here we investigated the transcriptomic and functional consequences of nuclear-mitochondrial genetic divergence in vitro and in vivo. We utilized xenomitochondrial cybrid cell lines containing nuclear DNA from the common laboratory mouse Mus musculus domesticus and mitochondrial DNA (mtDNA) from Mus musculus domesticus, or exogenous mtDNA from progressively divergent mouse species Mus spretus, Mus terricolor, Mus caroli and Mus pahari. These cybrids model a wide range of nuclear-mitochondrial genetic divergence that cannot be achieved with other research models. Furthermore, we used a xenomitochondrial mouse model generated in our laboratory that harbors wild-type, C57BL/6J Mus musculus domesticus nuclear DNA and homoplasmic mtDNA from Mus terricolor. RNA sequencing analysis of xenomitochondrial cybrids revealed an activation of interferon signaling pathways even in the absence of OXPHOS dysfunction or immune challenge. In contrast, xenomitochondrial mice displayed lower baseline interferon gene expression and an impairment in the interferon-dependent innate immune response upon immune challenge with herpes simplex virus, which resulted in decreased viral control. Our work demonstrates that nuclear-mitochondrial genetic divergence caused by the introduction of exogenous mtDNA can modulate the interferon immune response both in vitro and in vivo, even when OXPHOS function is not compromised. This work may lead to future insights into the role of mitochondrial genetic variation and the immune function in humans, as patients affected by mitochondrial disease are known to be more susceptible to immune challenges. [ABSTRACT FROM AUTHOR]

Importance Retinal ganglion cells endure significant metabolic stress in glaucoma but maintain capacity to recover function. Nicotinamide, a precursor of NAD+, is low in serum of glaucoma patients and its supplementation provides robust protection of retinal ganglion cells in preclinical models. However, the potential of nicotinamide in human glaucoma is unknown. Background: To examine the effects of nicotinamide on inner retinal function in glaucoma, in participants receiving concurrent glaucoma therapy. Design Crossover, double‐masked, randomized clinical trial. Participants recruited from two tertiary care centres. Participants: Fifty‐seven participants, diagnosed and treated for glaucoma. Methods: Participants received oral placebo or nicotinamide and reviewed six‐weekly. Participants commenced 6 weeks of 1.5 g/day then 6 weeks of 3.0 g/day followed by crossover without washout. Visual function measured using electroretinography and perimetry. Main outcome measures: Change in inner retinal function, determined by photopic negative response (PhNR) parameters: saturated PhNR amplitude (Vmax), ratio of PhNR/b‐wave amplitude (Vmax ratio). Results: PhNR Vmax improved beyond 95% coefficient of repeatability in 23% of participants following nicotinamide vs 9% on placebo. Overall, Vmax improved by 14.8% [95% CI: 2.8%, 26.9%], (P =.02) on nicotinamide and 5.2% [−4.2%, 14.6%], (P =.27) on placebo. Vmax ratio improved by 12.6% [5.0%, 20.2%], (P =.002) following nicotinamide, 3.6% [−3.4%, 10.5%], (P =.30) on placebo. A trend for improved visual field mean deviation was observed with 27% improving ≥1 dB on nicotinamide and fewer deteriorating (4%) compared to placebo (P =.02). Conclusions: Nicotinamide supplementation can improve inner retinal function in glaucoma. Further studies underway to elucidate the effects of long‐term nicotinamide supplementation. [ABSTRACT FROM AUTHOR]

We characterize a new experimental model for inducing retinal ganglion cell (RGC) dysfunction and degeneration in mice. C57BL/6J mice were subjected to two acute periods of intraocular pressure (IOP) elevation (50 mmHg for 30 min) by cannulation of the anterior chamber. We used full-field electroretinography and visual evoked potentials (VEPs) to measure subsequent changes in retina and optic nerve function, and histochemical techniques to assess RGC survival and optic nerve structure. In 12 month old mice, a single IOP challenge caused loss and subsequent recovery of RGC function over the following 28 days with minimal cell death and no observed axonal damage. A second identical IOP challenge resulted in persistent RGC dysfunction and significant (36%) loss of RGC somas. This was accompanied by a 16.7% delay in the latency and a 27.6% decrease in the amplitude of the VEP. Severe axonal damage was seen histologically with enlargement of axons, myelin disruption, reduced axon density, and the presence of glial scarring. In contrast, younger 3 month old mice when exposed to a single or repeat IOP challenge showed quicker RGC functional recovery after a single challenge and full functional recovery after a repeat challenge with no detectable optic nerve dysfunction. These data demonstrate a highly reproducible and minimally invasive method for inducing RGC degeneration and axonal damage in mice. Resilience of the optic nerve to damage is highly dependent on animal age. The time-defined nature of functional versus structural loss seen in this model stands to facilitate investigation of neuroglial responses in the retina after IOP injury and the associated evaluation of neuroprotective treatment strategies. Further, the model may be used to investigate the impact of aging and the cellular switch between neurorecovery and neurodegeneration. • Repeat intraocular pressure challenge causes axonal degeneration in older mice. • An initial neurorecovery phase is followed by a neurodegeneration phase. • Younger mice are resilient to the effects of a repeat intraocular pressure challenge. • This model may be used to investigate glaucoma pathogenesis and treatment strategies. [ABSTRACT FROM AUTHOR]

Importance Bleb‐associated endophthalmitis is a potentially vision‐threatening complication of trabeculectomy. With improvements in surgical technique and changing patterns of intraoperative antimetabolite use, a re‐evaluation of the incidence of bleb‐associated endophthalmitis is warranted. Background: To investigate changes in the incidence, presentation, management and outcomes of bleb‐associated endophthalmitis between 1997 and 2015 in Victoria, Australia. Design A retrospective cohort analysis. Participants: Consecutive cases of bleb‐associated endophthalmitis managed at the Royal Victorian Eye and Ear Hospital (RVEEH) between 1997 and 2015. Methods: Medical record review of consecutive cases of bleb‐associated endophthalmitis and statistical analysis were performed. Main Outcome Measures: Visual acuity, including loss of light perception, intraocular pressure, and need for further surgery. Results: Sixty‐seven eyes with bleb‐associated endophthalmitis (BAE) were identified. Of these, 41 had trabeculectomy performed in Victoria during the study period, over which time 11 129 trabeculectomies were performed. The proportion of BAE was stable over time (0.4%). The mean age at presentation was 73.7 ± 12.1 years old and the majority of patients were Caucasian (79.1%). The mean duration between glaucoma filtration surgery and the development of bleb‐associated endophthalmitis was 3 years (Interquartile Range = 0.4‐6.0 years). The cultures were positive in 71.6% of cases. Approximately 1 in 8 patients required enucleation. The final visual acuity was poor with a Snellen Visual Acuity (VA) of 6/60 or worse in two‐thirds of patients. Conclusions and Relevance: Bleb‐associated endophthalmitis is an uncommon complication following glaucoma filtration surgery. The proportion has remained stable over time. Visual outcomes remain poor. [ABSTRACT FROM AUTHOR]

Retinal ganglion cell (RGC) degeneration causes vision loss in patients with glaucoma, and this has been generally considered to be irreversible due to RGC death. We question this assertion and summarise accumulating evidence that points to visual function improving in glaucoma patients with treatment, particularly in the early stages of disease. We propose that prior to death, RGCs enter periods of dysfunction but can recover with relief of RGC stress. We first summarise the clinical evidence for vision improvement in glaucoma and then detail our experimental work that points to the underlying processes that underpin clinical improvement. We show that functional recovery can occur following a prolonged course of RGC dysfunction and demonstrate how the capacity for recovery can be modified. Detecting RGC dysfunction and augmenting recovery of such 'comatosed' RGCs holds clinical potential to improve early detection of glaucoma and improve visual function. [ABSTRACT FROM AUTHOR]

The aim of the current work was to test whether increased intake of dietary fat and sucrose in mice modifies the response of retinal ganglion cells (RGCs) of the optic nerve to injury, and whether any effects of diet are influenced by physical activity levels. C57BL/6J mice were given a high-fat high-sucrose (HFS) diet for 7 weeks, with or without exposure to regular exercise by swimming (60 min/day, 5 days/week). Injury to RGCs was subsequently induced by acute elevation of intraocular pressure (IOP) and retinas were assessed for function and structure. We report that mice on a HFS diet had similar body mass and blood glucose levels compared to mice on a control diet but suffered a 30% greater loss of RGC function following injury, as measured in vivo with the electroretinogram. RGC dysfunction in retinas from mice on the HFS diet was accompanied by activation of retinal macroglia but was not associated with neuronal cell loss. Exercising mice by swimming did not prevent HFS-induced RGC dysfunction in response to injury. This study shows for the first time that a short term increase in dietary fat and sucrose enhances the vulnerability of RGCs to dysfunction and cell stress after an acute injury, and that this is independent of obesity or hyperglycemia. Furthermore, our results suggest that detrimental effects of diet predominate over protective effects of exercise. [ABSTRACT FROM AUTHOR]

Background To assess the impact of cataract on quality of life ( QoL) for patients with glaucoma. Design Cross-sectional study. Participants Two hundred forty-two patients with mild ( n = 67), moderate ( n = 80) or severe ( n = 45) glaucoma and 50 controls (glaucoma suspects). Patients with cataract of any severity were included. Methods The following data were collected: sociodemographic information, phakic/pseudophakic status, cataract grade according to the Lens Opacities Classification System ( LOCS) III, visual acuity and visual field test parameters. Glaucoma severity was stratified according to binocular visual field loss. Visually significant cataract was defined as: LOCS III criteria nuclear cataract ≥3/6.9, cortical cataract ≥3/5.9 or posterior subcapsular cataract ≥2/5.9. Main Outcome Measures Patients' QoL was measured using Rasch-transformed scores from the Glaucoma Activity Limitation-9 ( GAL-9) questionnaire. Multiple linear regression models were used to determine the association between cataract and GAL-9 (logit) score. Results Fifty-six (23.1%) patients had at least one visually significant cataract. At least one visually significant cataract (standardized coefficient [β] 1.19, 95% confidence interval 1.04-1.34, P = 0.011) and poor visual field index (better eye) (β 1.47, 95% confidence interval 1.36-1.88, P < 0.001) were independently associated with worse GAL-9 score. Conclusions Cataract influences glaucoma-related QoL among glaucoma patients of all severity levels and is an important cause of potentially reversible visual impairment among glaucoma patients. The Rasch-analysed GAL-9 questionnaire is a useful metric to quantify visual disability related to cataract in glaucoma patients. [ABSTRACT FROM AUTHOR]

Background: Steroid-induced ocular hypertension is currently treated in the same way as primary open-angle glaucoma. However, the treatment is often suboptimal and is associated with adverse effects. We evaluated the oculohypotensive effects of topical trans-resveratrol in rats with steroid-induced ocular hypertension and involvement of adenosine receptors (AR) in intraocular pressure (IOP) lowering effect of trans-resveratrol. Methods: The oculohypotensive effect of unilateral single-drop application of various concentrations of trans-resveratrol was first studied in oculonormotensive rats. Concentration with maximum effect was similarly studied in rats with steroid-induced ocular hypertension. Involvement of AR was studied by observing the alterations of IOP in response to trans-resveratrol after pretreating animals with AR subtype-specific antagonists. Additionally, we used computational methods, including 3D modelling, 3D structure generation and protein-ligand interaction, to determine the AR-trans-resveratrol interaction. Results: All concentrations of trans-resveratrol produced significant IOP reduction in normotensive rat eyes. Maximum mean IOP reduction of 15.1% was achieved with trans-resveratrol 0.2%. In oculohypertensive rats, trans-resveratrol 0.2% produced peak IOP reduction of 25.2%. Pretreatment with A1 antagonist abolished the oculohypotensive effect of trans-resveratrol. Pretreatment with A3 and A2A AR antagonists produced significant IOP reduction in both treated and control eyes, which was further augmented by transresveratrol application in treated eyes. Computational studies showed that trans-resveratrol has highest affinity for A2B and A1, followed by A2A and A3 AR. Conclusion: Topically applied trans-resveratrol reduces IOP in rats with steroid-induced ocular hypertension. Trans-resveratrol-induced oculohypotension involves its agonistic activity at the A1 AR. [ABSTRACT FROM AUTHOR]

Anti-Vascular Endothelial Growth Factors (Anti-VEGF) agents have received recent interest as potential anti-fibrotic agents for their concurrent use with trabeculectomy. Preliminary cohort studies have revealed improved bleb morphology following trabeculectomy augmented with ranibizumab. The effects of this humanized monoclonal antibody on human Tenon's fibroblast (HTF), the key player of post trabeculectomy scar formation, are not fully understood. This study was conducted to understand the effects of ranibizumab on extracellular matrix production by HTF. The effect of ranibizumab on HTF proliferation and cell viability was determined using MTT assay (3-(4,5-dimethylthiazone-2-yl)-2,5-diphenyl tetrazolium). Ranibizumab at concentrations ranging from 0.01 to 0.5 mg/mL were administered for 24, 48 and 72 h in serum and serum free conditions. Supernatants and cell lysates from samples were assessed for collagen type 1 alpha 1 and fibronectin mRNA and protein level using quantitative real time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). After 48-h, ranibizumab at 0.5 mg/mL, significantly induced cell death under serum-free culture conditions ( p < 0.05). Ranibizumab caused significant reduction of collagen type 1 alpha 1 (COL1A1) mRNA, but not for fibronectin (FN). Meanwhile, COL1A1 and FN protein levels were found upregulated in treated monolayers compared to control monolayers. Ranibizumab at 0.5 mg/mL significantly reduced cell viability in cultured HTF. From this study, we found that single application of ranibizumab is inadequate to induce the anti-fibrotic effects on HTF, suggesting the importance of adjunctive therapy. Further studies are underway to understand mechanism of actions of ranibizumab on HTF. [ABSTRACT FROM AUTHOR]

Background To evaluate the effect of phacoemulsification on trabeculectomy function. Design Retrospective case-control study. Participants Forty-eight patients who underwent trabeculectomy surgery and had at least 2 years of follow up. Methods Patients were classified into two groups: patients who had phacoemulsification subsequent to trabeculectomy ( Trab_phaco, n = 18) and patients who were pseudophakic for greater than 6 months preceding their trabeculectomy ( Phaco_trab, n = 30). Groups were matched for length of follow up of 2 years from time of trabeculectomy. Main Outcome Measures The primary outcome measures were target intraocular pressure of criteria A, ≤12 mm Hg; B, ≤15 mm Hg; C, ≤18 mm Hg with or without additional topical treatment. A separate measure for bleb function failure was also used; with failure defined as the need for additional topical antiglaucoma therapy or surgical intervention to achieve control of intraocular pressure. Results There was no significant difference in achieving each intraocular pressure criterion between groups (12 months, P = 1.0; 24 months, P = 0.330). In the first 12 months, significantly more trabeculectomies in the Trab_phaco group failed, requiring additional intervention to control the IOP (39%) compared with the Phaco_trab (10%) group ( P = 0.028). Although this trend continued at 24 months, there were no significant differences in failure rates ( P = 0.522). Conclusions Phacoemulsification performed after trabeculectomy significantly increased rates of bleb failure in the following 12 months but not at 24 months. [ABSTRACT FROM AUTHOR]

PURPOSE: To determine whether monoscopic vs stereoscopic viewing impacts evaluation of optic disc photographs for glaucoma diagnosis in an expert population. DESIGN: Prospective observational study. METHODS: Twenty pairs of high-quality monoscopic and stereoscopic photographs of similar size and magnification (ie, 40 images), were selected to demonstrate a range of optic disc features from a total of 197 eyes of 197 patients with glaucoma and normal subjects recruited from a tertiary clinic. These were presented in randomized order via an interactive platform (http://stereo. gone-project.com/). Participants assessed 9 topographic features and estimated glaucoma likelihood for each photograph. Main outcome measures were intra- and inter-observer agreement. RESULTS: There was good intra-observer agreement between monoscopic and stereoscopic assessments of glaucoma likelihood (κw =0.56). There was also good to substantial agreement for peripapillary atrophy (κw = 0.65), cup shape (κw = 0.65), retinal nerve fiber layer loss (κw = 0.69), vertical cup-to-disc ratio (κw = 0.58), and disc shape (κw = 0.57). However, intra-observer agreement was only fair to moderate for disc tilt, cup depth, and disc size (κw =0.46-0.49). Inter-observer agreement for glaucoma likelihood in monoscopic photographs (κw = 0.61, 95% confidence interval [CI] = 0.55-0.67) was substantial and not lower than in stereoscopic photographs (κw =0.59, CI=0.54-0.65). Monoscopic photographs did not lead to lower levels of inter-observer agreement compared to stereoscopic photographs in the assessment of any optic disc characteristics, for example disc size (mono κw = 0.65, stereo κw = 0.52) and cupto-disc ratio (mono κw =0.72, stereo κw =0.62). CONCLUSIONS: For expert observers in the evaluation of optic disc photographs for glaucoma likelihood, monoscopic optic disc photographs did not appear to represent a significant disadvantage compared to stereoscopic photographs [ABSTRACT FROM AUTHOR]

Rabbits play a growing role in research into glaucoma surgical models and ocular drug delivery models. However, the lack of an accurate method for measuring intraocular pressure (IOP) in this animal has been a significant deficit. In this study we validated the use of the TonoVet rebound tonometer and provide conversion tables for its use in rabbits. Experiments were performed on 18 adult New Zealand White rabbits. The TonoVet measurements were obtained and compared to manometric readings by anterior chamber (AC) cannulation. The TonoVet position and ‘d’ (dog or cat) and ‘p’ (other species) modes were compared. The sensitivity of the TonoVet tonometer in assessing IOP changes was also tested. There was a strong linear correlation for both the ‘d’ mode (mean slope = 0.84 ± 0.03, r(2) = 0.99 ± 0.03) and the ‘p’ mode (mean slope = 0.64 ± 0.02, r(2) = 0.97 ± 0.01) of the TonoVet with manometric IOP. However, the TonoVet had a tendency to underestimate IOP compared to manometry and conversion formulae were possible to calculate for both modes. The orientation of the TonoVet handle had no effect on IOP reading, as long as the groove was horizontal. No significant differences were observed when comparing right and left eyes (P > 0.05). IOP recovered four days after cannulation. Younger rabbits had lower IOP compared with older rabbits (P < 0.01). Timolol produced a 2.5 mmHg reduction in IOP 2 h later as detected by the TonoVet. Using the conversion table presented, the TonoVet is a reliable and precise tool for the measurement of IOP in rabbits. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction increases reactive oxygen species (ROS) production and when this overwhelms the cellular antioxidant defences, oxidative stress ensues. Oxidative stress is recognized as a common pathologic pathway in many neurodegenerative diseases. Recent reports have also demonstrated oxidative stress in ocular tissues derived from experimental glaucoma models and clinical samples. There is also accumulating evidence pointing to mitochondrial dysfunction being present in some glaucoma patients. Thus oxidative stress from mitochondrial dysfunction may also play a causal role in glaucoma. The mechanisms by which oxidative stress may induce retinal ganglion cell loss in glaucoma are not fully understood but could include direct neurotoxic effects from ROS or indirect damage from oxidative stress-induced dysfunction of glial cells. This review will consider the evidence for the presence of oxidative stress in glaucoma; the mechanisms by which oxidative stress may contribute to disease pathogenesis; and also consider therapeutic approaches that target oxidative stress as a means of protecting against optic nerve degeneration. [ABSTRACT FROM AUTHOR]

A bstract Background: The aim of this study is to examine the relationship between sociodemographic factors and utilization of eye care services in patients presenting in acute angle-closure (AAC). Design: A hospital-based retrospective, case-control study. Participants: Fifty-five patients consecutively presenting to the emergency department of the Royal Victorian Eye and Ear Hospital with AAC (cases), and 43 patients consecutively referred to the outpatient department for prophylactic laser peripheral iridotomy (controls) over a 3-year period. Methods: Standardized telephone questionnaires. Main Outcome Measures: Comparisons were made for sociodemographic factors, utilization of eye care services and provision of information on glaucoma and premonitory symptoms of AAC. Results: No significant differences across a range of socioeconomic and demographic factors were found. Fewer cases reported having attended an eye care professional ever ( P = 0.02), or in the 12 months preceding their acute hospital attendance ( P = 0.002), and had less awareness of angle closure glaucoma ( P = 0.001). Logistic regression modelling demonstrated premonitory symptoms of AAC (odds ratio 3.96, [95% confidence interval 1.52-10.32], P < 0.001) and a period of greater than 12 months since the last eye examination (odds ratio 3.89, [95% confidence interval 1.64-9.21]) were significantly associated with the risk of AAC. Conclusions: No significant differences in socioeconomic or demographic parameters between cases and controls were identified. Control subjects had a history of more frequent and recent access to eye care services than cases. The finding that more than one-third of patients presenting with AAC had consulted an eye care provider in the preceding year suggests that a significant proportion of individuals at risk of AAC remain undetected. [ABSTRACT FROM AUTHOR]

A bstract Background: To determine whether postoperative subconjunctival bevacizumab significantly alters bleb vascularity. Design: A randomized, prospective interventional study. Participants: Forty-three eyes from 39 patients were recruited, with 21 eyes randomized to subconjunctival injections of 5-fluorouracil, and 22 eyes to combined 5-fluorouracil/bevacizumab. Methods: All patients who underwent uncomplicated primary antimetabolite augmented trabeculectomy who subsequently required postoperative subconjunctival 5-fluorouracil injection within 4 weeks of surgery were eligible. Patients were randomized to receive subconjunctival 5-fluorouracil only (7.5 mg/0.15 mL) or 5-fluorouracil plus bevacizumab (1.25 mg/0.05 mL). Main Outcome Measures: Primary outcome was bleb vascularity with secondary endpoints including visual acuity, intraocular pressure, bleb morphology, complications and total numbers of 5-fluorouracil injections were recorded at baseline, week 12 and 18 months. Results: At week 12, there was no significant difference between groups for visual acuity, intraocular pressure, bleb vascularity and morphology, or total number of 5-fluorouracil injections. By 18 months, 47.4% of the 5-fluorouracil/bevacizumab group exhibited central bleb avascularity compared with 21.1% of the 5-fluorouracil group (Fisher's exact test, P = 0.17). Two bleb complications (one blebitis; one suture abscess) recorded in the 5-fluorouracil/bevacizumab group. Conclusions: After a single combined injection, a trend for increased central bleb avascularity was observed, although this effect was not sufficient to reach statistical significance. This, in addition to the occurrence of two bleb-related complications in the bevacizumab group, suggests the need for a larger clinical trial to further evaluate the safety and efficacy of bevacizumab as a modulating agent in glaucoma filtration surgery. [ABSTRACT FROM AUTHOR]

A bstract Background: To determine the prevalence of signs and symptoms of ocular surface disease in two hospital-based cohorts; glaucoma patients and non-glaucoma patients. Design: A cross-sectional, comparative case series. Participants: Glaucoma patients ( n = 300) prescribed topical glaucoma medications for ≥6 months were compared with control patients ( n = 100) who were not applying prescribed topical medications. Methods: A validated self-report questionnaire was used to elicit the extent of ocular symptoms. Signs of ocular surface and eyelid disease were assessed along with medication history. Main Outcome Measures: Signs and symptoms of ocular surface pathology were determined including the tear film break-up time, fluorescein staining of the cornea and conjunctiva, meibomian gland dysfunction and Schirmer's test. Results: A significant increase in the prevalence of ocular surface disease signs was observed in the glaucoma population, 70.3%, compared with controls, 33% ( P < 0.001). The overall prevalence of clinically significant ocular surface disease symptoms was not significantly different between cohorts, 30.7% versus 24.0%, respectively ( P = 0.252). Logistic regression analysis showed that the number of anti-glaucoma medications and duration of therapy were key predictors of significant ocular surface disease signs in the glaucoma group. There was no significant correlation between signs and symptoms of ocular surface disease in either group after adjusting for age and gender. Conclusions: Signs and symptoms of ocular surface disease are relatively common in older patients, but signs of ocular surface disease are significantly higher in individuals who instil topical glaucoma therapy. [ABSTRACT FROM AUTHOR]