Intranasal Resveratrol Nanoparticles Enhance Neuroprotection in a Model of Multiple Sclerosis.

PURPOSE: Resveratrol is a natural polyphenol which has a very low bioavailability but whose antioxidant, anti-inflammatory and anti-apoptotic properties may have therapeutic potential for the treatment of neurodegenerative diseases such as multiple sclerosis (MS). Previously, we reported the oral administration of resveratrol nanoparticles (RNs) elicited a neuroprotective effect in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, at significantly lower doses than unconjugated resveratrol (RSV) due to enhanced bioavailability. Furthermore, we demonstrated that the intranasal administration of a cell-derived secretome-based therapy at low concentrations leads to the selective neuroprotection of the optic nerve in EAE mice. The current study sought to assess the potential selective efficacy of lower concentrations of intranasal RNs for attenuating optic nerve damage in EAE mice. METHODS: EAE mice received either a daily intranasal vehicle, RNs or unconjugated resveratrol (RSV) for a period of thirty days beginning on the day of EAE induction. Mice were assessed daily for limb paralysis and weekly for visual function using the optokinetic response (OKR) by observers masked to treatment regimes. After sacrifice at day 30, spinal cords and optic nerves were stained to assess inflammation and demyelination, and retinas were immunostained to quantify retinal ganglion cell (RGC) survival. RESULTS: Intranasal RNs significantly increased RGC survival at half the dose previously shown to be required when given orally, reducing the risk of systemic side effects associated with prolonged use. Both intranasal RSV and RN therapies enhanced RGC survival trends, however, only the effects of intranasal RNs were significant. RGC loss was prevented even in the presence of inflammatory and demyelinating changes induced by EAE in optic nerves. CONCLUSIONS: The intranasal administration of RNs is able to reduce RGC loss independent of the inflammatory and demyelinating effects on the optic nerve and the spinal cord. The concentration of RNs needed to achieve neuroprotection is lower than previously demonstrated with oral administration, suggesting intranasal drug delivery combined with nanoparticle conjugation warrants further exploration as a potential neuroprotective strategy for the treatment of optic neuritis, alone as well as in combination with glucocorticoids.

Ophthalmic sensing technologies for ocular disease diagnostics.

Point-of-care diagnosis and personalized treatments are critical in ocular physiology and disease. Continuous sampling of tear fluid for ocular diagnosis is a need for further exploration. Several techniques have been developed for possible ophthalmological applications, from traditional spectroscopies to wearable sensors. Contact lenses are commonly used devices for vision correction, as well as for other therapeutic and cosmetic purposes. They are increasingly being developed into ocular sensors, being used to sense and monitor biochemical analytes in tear fluid, ocular surface temperature, intraocular pressure, and pH value. These sensors have had success in detecting ocular conditions, optimizing pharmaceutical treatments, and tracking treatment efficacy in point-of-care settings. However, there is a paucity of new and effective instrumentation reported in ophthalmology. Hence, this review will summarize the applied ophthalmic technologies for ocular diagnostics and tear monitoring, including both conventional and biosensing technologies. Besides applications of smart readout devices for continuous monitoring, targeted biomarkers are also discussed for the convenience of diagnosis of various ocular diseases. A further discussion is also provided for future aspects and market requirements related to the commercialization of novel types of contact lens sensors.

Detecting Apoptosis as a Clinical Endpoint for Proof of a Clinical Principle.

The transparent eye media represent a window through which to observe changes occurring in the retina during pathological processes. In contrast to visualising the extent of neurodegenerative damage that has already occurred, imaging an active process such as apoptosis has the potential to report on disease progression and therefore the threat of irreversible functional loss in various eye and brain diseases. Early diagnosis in these conditions is an important unmet clinical need to avoid or delay irreversible sight loss. In this setting, apoptosis detection is a promising strategy with which to diagnose, provide prognosis and monitor therapeutic response. Additionally, monitoring apoptosis in vitro and in vivo has been shown to be valuable for drug development in order to assess the efficacy of novel therapeutic strategies both in the pre-clinical and clinical setting. Detection of Apoptosing Retinal Cells (DARC) technology is to date the only tool of its kind to have been tested in clinical trials, with other new imaging techniques under investigation in the fields of neuroscience, ophthalmology and drug development. We summarise the transitioning of techniques detecting apoptosis from bench to bedside, along with the future possibilities they encase.

Retinal imaging in Alzheimer's and neurodegenerative diseases.

In the last 20 years, research focused on developing retinal imaging as a source of potential biomarkers for Alzheimer's disease and other neurodegenerative diseases, has increased significantly. The Alzheimer's Association and the Alzheimer's & Dementia: Diagnosis, Assessment, Disease Monitoring editorial team (companion journal to Alzheimer's & Dementia) convened an interdisciplinary discussion in 2019 to identify a path to expedite the development of retinal biomarkers capable of identifying biological changes associated with AD, and for tracking progression of disease severity over time. As different retinal imaging modalities provide different types of structural and/or functional information, the discussion reflected on these modalities and their respective strengths and weaknesses. Discussion further focused on the importance of defining the context of use to help guide the development of retinal biomarkers. Moving from research to context of use, and ultimately to clinical evaluation, this article outlines ongoing retinal imaging research today in Alzheimer's and other brain diseases, including a discussion of future directions for this area of study.

Ophthalmic Research Lecture 2018: DARC as a Potential Surrogate Marker.

Glaucoma is a progressive, neurodegenerative disease that is increasing in prevalence worldwide. There is a need to develop ways in which to diagnose the disease sooner and more reliably in order to prevent irreversible visual loss and meet the growing demands on healthcare services. Research into neuroprotective therapies in glaucoma is lacking a reliable surrogate marker in order to show treatment efficacy in a meaningful and cost-effective manner. The detection of apoptosing retinal cells (DARC) is a new technique that has promise in providing a solution to this unmet clinical need. Multiple animal studies have demonstrated its use as a biomarker in quantifying the effect of retinal neuroprotection methods, and it has recently been translated into humans in phase I and II trials, with phase I demonstrating the visualisation of individual apoptosing retinal cells in healthy and glaucomatous patients, with good safety and tolerability. The future for this technique will now be identifying disease-specific characteristics of human disease that can be used in order to provide us with a much-needed surrogate marker in the field of retinal neurodegeneration.

New Technologies for Outcome Measures in Glaucoma: Review by the European Vision Institute Special Interest Focus Group.

Glaucoma is the leading cause of irreversible blindness worldwide, with an increasing prevalence. The complexity of the disease has been a major challenge in moving the field forward with regard to both pathophysiological insight and treatment. In this context, discussing possible outcome measures in glaucoma trials is of utmost importance and clinical relevance. A recent meeting of the European Vision Institute (EVI) special interest focus group was held on "New Technologies for Outcome Measures in Retina and Glaucoma," addressing both functional and structural outcomes, as well as translational hot topics in glaucoma and retina research. In conjunction with the published literature, this review summarizes the meeting focusing on glaucoma.

Cellular Consequences of Coenzyme Q10 Deficiency in Neurodegeneration of the Retina and Brain.

Coenzyme Q10 (CoQ10) is a ubiquitous cofactor in the body, operating in the inner mitochondrial membrane, where it plays a vital role in the generation of adenosine triphosphate (ATP) through the electron transport chain (ETC). In addition to this, CoQ10 serves as an antioxidant, protecting the cell from oxidative stress by reactive oxygen species (ROS) as well as maintaining a proton (H+) gradient across lysosome membranes to facilitate the breakdown of cellular waste products. Through the process of ageing, the body becomes deficient in CoQ10, resulting in several systemic manifestations. On a cellular level, one of the consequences of CoQ10 deficiency is apoptosis, which can be visualised in tissues of the central nervous system (CNS). Diseases affecting the retina and brain such as age-related macular degeneration (AMD), glaucoma, Alzheimer's disease (AD) and Parkinson's disease (PD) have shown defects in cellular biochemical reactions attributed to reduced levels of CoQ10. Through further research into the pathogenesis of such conditions, the effects of CoQ10 deficiency can be counteracted through supplementation, early detection and intervention.

Oculo-visual abnormalities in Parkinson's disease: Possible value as biomarkers.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders and the second leading cause of dementia worldwide. With an aging population, the prevalence of the disease has dramatically increased. Clinical management has advanced through recent developments in dopaminergic imaging and genetic risk profiling. However, early and accurate diagnosis of the disorder remains a challenge, largely because of the lack of noninvasive and inexpensive reliable diagnostic tests. Besides the well-studied cerebral neurodegeneration that underlies the cardinal symptoms of PD (ie, bradykinesia, tremor, rigidity, and postural instability), ocular changes have also been described in PD, including visual dysfunction, pupil abnormality, lens opacity, and retinal neuronal loss and dysfunction. These ocular pathological processes are related to α-synuclein deposition, and dopamine deficiency in the retina-mirroring the defining pathological features of PD in the brain. Together, these observations support the notion that the eye can serve as a window to the brain, providing clinicians with noninvasive methods to visualize disease. This review focuses on recent advances in the characterization of ocular changes in PD and their promising use as biomarkers in the eye, which can be potentially used for aiding in early diagnosis, tracking disease progression, and valuating novel therapeutic strategies. © 2018 International Parkinson and Movement Disorder Society.

Assessing anesthetic activity through modulation of the membrane dipole potential.

There is great individual variation in response to general anesthetics (GAs) leading to difficulties in optimal dosing and sometimes even accidental awareness during general anesthesia (AAGA). AAGA is a rare, but potentially devastating, complication affecting between 0.1% and 2% of patients undergoing surgery. The development of novel personalized screening techniques to accurately predict a patient's response to GAs and the risk of AAGA remains an unmet clinical need. In the present study, we demonstrate the principle of using a fluorescent reporter of the membrane dipole potential, di-8-ANEPPs, as a novel method to monitor anesthetic activity using a well-described inducer/noninducer pair. The membrane dipole potential has previously been suggested to contribute a novel mechanism of anesthetic action. We show that the fluorescence ratio of di-8-ANEPPs changed in response to physiological concentrations of the anesthetic, 1-chloro-1,2,2-trifluorocyclobutane (F3), but not the structurally similar noninducer, 1,2-dichlorohexafluorocyclobutane (F6), to artificial membranes and in vitro retinal cell systems. Modulation of the membrane dipole provides an explanation to overcome the limitations associated with the alternative membrane-mediated mechanisms of GA action. Furthermore, by combining this technique with noninvasive retinal imaging technologies, we propose that this technique could provide a novel and noninvasive technique to monitor GA susceptibility and identify patients at risk of AAGA.

Adenosine A3 receptor activation is neuroprotective against retinal neurodegeneration.

Death of retinal neural cells, namely retinal ganglion cells (RGCs), is a characteristic of several retinal neurodegenerative diseases. Although the role of adenosine A3 receptor (A3R) in neuroprotection is controversial, A3R activation has been reported to afford protection against several brain insults, with few studies in the retina. In vitro models (retinal neural and organotypic cultures) and animal models [ischemia-reperfusion (I-R) and partial optic nerve transection (pONT)] were used to study the neuroprotective properties of A3R activation against retinal neurodegeneration. The A3R selective agonist (2-Cl-IB-MECA, 1 µM) prevented apoptosis (TUNEL(+)-cells) induced by kainate and cyclothiazide (KA + CTZ) in retinal neural cultures (86.5 ± 7.4 and 37.2 ± 6.1 TUNEL(+)-cells/field, in KA + CTZ and KA + CTZ + 2-Cl-IB-MECA, respectively). In retinal organotypic cultures, 2-Cl-IB-MECA attenuated NMDA-induced cell death, assessed by TUNEL (17.3 ± 2.3 and 8.3 ± 1.2 TUNEL(+)-cells/mm(2) in NMDA and NMDA+2-Cl-IB-MECA, respectively) and PI incorporation (ratio DIV4/DIV2 3.3 ± 0.3 and 1.3 ± 0.1 in NMDA and NMDA+2-Cl-IB-MECA, respectively) assays. Intravitreal 2-Cl-IB-MECA administration afforded protection against I-R injury decreasing the number of TUNEL(+) cells by 72%, and increased RGC survival by 57%. Also, intravitreal administration of 2-Cl-IB-MECA inhibited apoptosis (from 449.4 ± 37.8 to 207.6 ± 48.9 annexin-V(+)-cells) and RGC loss (from 1.2 ± 0.6 to 8.1 ± 1.7 cells/mm) induced by pONT. This study demonstrates that 2-Cl-IB-MECA is neuroprotective to the retina, both in vitro and in vivo. Activation of A3R may have great potential in the management of retinal neurodegenerative diseases characterized by RGC death, as glaucoma and diabetic retinopathy, and ischemic diseases.

Unexpected low-dose toxicity of the universal solvent DMSO.

Dimethyl sulfoxide (DMSO) is an important aprotic solvent that can solubilize a wide variety of otherwise poorly soluble polar and nonpolar molecules. This, coupled with its apparent low toxicity at concentrations <10%, has led to its ubiquitous use and widespread application. Here, we demonstrate that DMSO induces retinal apoptosis in vivo at low concentrations (5 µl intravitreally dosed DMSO in rat from a stock concentration of 1, 2, 4, and 8% v/v). Toxicity was confirmed in vitro in a retinal neuronal cell line, at DMSO concentrations >1% (v/v), using annexin V, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and AlamarBlue cell viability assays. DMSO concentrations >10% (v/v) have recently been reported to cause cellular toxicity through plasma membrane pore formation. Here, we show the mechanism by which low concentrations (2-4% DMSO) induce caspase-3 independent neuronal death that involves apoptosis-inducing factor (AIF) translocation from mitochondria to the nucleus and poly-(ADP-ribose)-polymerase (PARP) activation. These results highlight safety concerns of using low concentrations of DMSO as a solvent for in vivo administration and in biological assays. We recommend that methods other than DMSO are employed for solubilizing drugs but, where no alternative exists, researchers compute absolute DMSO final concentrations and include an untreated control group in addition to DMSO vehicle control to check for solvent toxicity.

A semi-automated technique for labeling and counting of apoptosing retinal cells.

BACKGROUND: Retinal ganglion cell (RGC) loss is one of the earliest and most important cellular changes in glaucoma. The DARC (Detection of Apoptosing Retinal Cells) technology enables in vivo real-time non-invasive imaging of single apoptosing retinal cells in animal models of glaucoma and Alzheimer's disease. To date, apoptosing RGCs imaged using DARC have been counted manually. This is time-consuming, labour-intensive, vulnerable to bias, and has considerable inter- and intra-operator variability. RESULTS: A semi-automated algorithm was developed which enabled automated identification of apoptosing RGCs labeled with fluorescent Annexin-5 on DARC images. Automated analysis included a pre-processing stage involving local-luminance and local-contrast "gain control", a "blob analysis" step to differentiate between cells, vessels and noise, and a method to exclude non-cell structures using specific combined 'size' and 'aspect' ratio criteria. Apoptosing retinal cells were counted by 3 masked operators, generating 'Gold-standard' mean manual cell counts, and were also counted using the newly developed automated algorithm. Comparison between automated cell counts and the mean manual cell counts on 66 DARC images showed significant correlation between the two methods (Pearson's correlation coefficient 0.978 (p < 0.001), R Squared = 0.956. The Intraclass correlation coefficient was 0.986 (95% CI 0.977-0.991, p < 0.001), and Cronbach's alpha measure of consistency = 0.986, confirming excellent correlation and consistency. No significant difference (p = 0.922, 95% CI: -5.53 to 6.10) was detected between the cell counts of the two methods. CONCLUSIONS: The novel automated algorithm enabled accurate quantification of apoptosing RGCs that is highly comparable to manual counting, and appears to minimise operator-bias, whilst being both fast and reproducible. This may prove to be a valuable method of quantifying apoptosing retinal cells, with particular relevance to translation in the clinic, where a Phase I clinical trial of DARC in glaucoma patients is due to start shortly.

Topical delivery of Avastin to the posterior segment of the eye in vivo using annexin A5-associated liposomes.

Effective delivery to the retina is presently one of the most challenging areas in drug development in ophthalmology, due to anatomical barriers preventing entry of therapeutic substances. Intraocular injection is presently the only route of administration for large protein therapeutics, including the anti-Vascular Endothelial Growth Factors Lucentis (ranibizumab) and Avastin (bevacizumab). Anti-VEGFs have revolutionised the management of age-related macular degeneration and have increasing indications for use as sight-saving therapies in diabetes and retinal vascular disease. Considerable resources have been allocated to develop non-invasive ocular drug delivery systems. It has been suggested that the anionic phospholipid binding protein annexin A5, may have a role in drug delivery. In the present study we demonstrate, using a combination of in vitro and in vivo assays, that the presence of annexin A5 can significantly enhance uptake and transcytosis of liposomal drug carrier systems across corneal epithelial barriers. This system is employed to deliver physiologically significant concentrations of Avastin to the posterior of the rat eye (127 ng/g) and rabbit retina (18 ng/g) after topical application. Our observations provide evidence to suggest annexin A5 mediated endocytosis can enhance the delivery of associated lipidic drug delivery vehicles across biological barriers, which may have therapeutic implications.

Prevalence of comorbidities with the potential to increase the risk of nonadherence to topical ocular hypotensive medication in patients with open-angle glaucoma.

OBJECTIVE: To evaluate the prevalence of comorbidities that may limit or prevent adherence to topical ocular hypotensive therapy in patients with open-angle glaucoma (OAG). METHODS: The UK Clinical Practice Research Datalink (CPRD) database of primary and secondary care and prescription records was analyzed to identify patients with a first (index) diagnosis of OAG during 2016-2020. The primary care records of these patients were screened for diagnostic terms linked to prespecified (qualifying) comorbidities considered to have the potential to impact patients' ability to instill eye drops. The prevalence of each of 10 categories of qualifying comorbidity recorded within the period from 5 years before to 2 years after the index OAG diagnosis was analyzed. RESULTS: A total of 100,968 patients with OAG were included in the analysis. Among the patients in the OAG cohort, 13,962 (13.8%) were aged 40-54 years, 32,145 (31.8%) were aged 55-69 years, 42,042 (41.6%) were aged 70-84 years, and 12,819 (12.7%) were aged 85+ years. Within the OAG population, 82.7%, 14.6%, and 2.7% of patients had no category, one category, and two or more categories of qualifying comorbidity, respectively. Qualifying comorbidities were most common in older patients. The most prevalent qualifying comorbidities were categorized as degenerative, traumatic, or pathological central nervous system disorder disrupting cognitive function (5.2%), movement disorder (4.4%), and low vision (4.1%). The prevalence of arthropathies and injuries affecting upper limbs (including arthritis in the hands) was 2.4%. CONCLUSIONS: The presence of comorbidities should be considered when determining whether eye drops are suitable treatment for glaucoma. Neurodegenerative disease affecting cognition and memory, motor disease, and low vision are common comorbidities that may impact adherence to eye drops, and affected patients may benefit from non-drop treatment modalities.

Effects of COVID-19 pandemic on glaucoma appointment scheduling in a tertiary hospital in London, UK.

PURPOSE: To investigate the impact of the delay in patient appointments caused by the COVID-19 pandemic and the triage system on the glaucomatous disease of patients in a London tertiary hospital. METHODS: Observational retrospective study that randomly selected 200 glaucoma patients with more than 3 months of unintended delay for their post-COVID visit and other inclusion and exclusion criteria. Demographic information, clinical data, number of drugs, best-corrected visual acuity (BCVA), intraocular pressure (IOP), visual field (VF) mean deviation (MD), and global peripapillary retinal nerve fibre layer (pRNFL) thickness were obtained from the pre- and post-COVID visit. At the post-COVID visit, the clinical outcomes subjective clinical concern and change of treatment or need for surgery were also annotated. The variables were stratified by glaucoma severity (according to the MD into early, moderate and advanced) and by delay time (more and less than 12 months) and analysed using SPSS. RESULTS: We included 121 eyes (from 71 patients). The median patient age was 74 years (interquartile range -IQR- 15), 54% were males and 52% Caucasians. Different glaucoma types and all glaucoma severities were included. When data was stratified for glaucoma severity, at the pre-COVID visit, significant differences in BCVA, CCT and IOP were observed and there were significantly higher values in the early glaucoma group. The median follow-up delay was 11 months (IQR 8), did not differ between the glaucoma severity groups and did not correlate to the glaucoma severity. At the post-COVID visit, significant differences in BCVA, IOP, and Global pRNFL thickness were observed between the glaucoma severity groups, as lower BCVA and higher IOP and pRNFL thickness were observed in the early glaucoma group. At the post-COVID visit there was cause for concern in 40 eyes: 5 were followed more closely, 22 had a change of treatment and 13 were booked for surgery (3 for cataract and 10 for glaucoma surgery). However, the number of eyes with causes for concern were similar between the glaucoma severity groups and there was no correlation between these clinical outcomes and the delay of the post-COVID visit. The number of topical hypotensive medications increased significantly after the post-COVID visit, higher number of medications were observed in the advanced glaucoma group. When differences of IOP, MD and pRNFL thickness between the pre and post-COVID visit, only the MD difference was significantly different between the glaucoma severity groups because it was higher in the severe group. When data was stratified for delay longer or shorter than 12 months, no differences were observed between the groups except at the pre-COVID visit, when the numbers of patients with MD deviation >-6 dB had longer delay time. When differences in IOP, MD and RNFL thickness were calculated, only the pRNFL thickness showed significant differences between the delay groups, because it was higher in the longer delay group. Finally, when paired analysis of the variables at the pre- and post-COVID visits, stratified by glaucoma severity and delay were conducted, although there were no significant differences in IOP in any group, the BCVA decreased significantly in the overall group and in the longer delay groups, the number of hypotensive drugs increased significantly overall and in the moderate and advanced glaucoma, the MD of the VF worsened significantly in the overall group and in the early glaucoma and longer delay groups and the pRNFL thickness decreased significantly in all groups. CONCLUSIONS: We document that delayed care impacts negatively on the glaucomatous disease of our patients because at the post-COVID visit there were reasons for clinical concern in a third of eyes that resulted in change of treatment or surgery. However, these clinical consequences were not related to IOP, glaucoma severity or delay time and reflect that the triage methods implemented worked adequately. The most sensitive parameter to indicate progression in our sample was the pRNFL thickness.

The potential of annexin-labelling for the diagnosis and follow-up of glaucoma.

Glaucoma is one of the leading causes of blindness in developed countries and is mainly attributable to the apoptosis of retinal ganglion cells (RGCs). Although several diagnostic tools have been developed to detect and monitor this disease, none has the requisite sensitivity to identify it at a preclinical stage or to perceive small changes in retinal health over short periods. Specifically, irreversible visual changes occur before neuronal damage is discovered. The most widely accepted in vitro assay for apoptotic cells involves the use of fluorescent annexin A5. The radiolabelling of this marker makes it possible to assess, in vivo and non-invasively, various diseases in which the apoptotic process is pivotal, such as myocardial infarction or tumour response to chemotherapy. Recently, a new technique has been developed to visualise directly individual RGCs undergoing apoptosis in the living eye. This DARC (detection of apoptosing retinal cells) technology uses fluorescently labelled annexin A5 to bind apoptosing retinal neurons and confocal scanning laser ophthalmoscopy to detect the marked dying cells. Based on experimental models, DARC has been suggested to offer a direct and quantitative assessment of the retinal condition of patients. A Phase I clinical trial in glaucoma patients is scheduled to start shortly. This technology has the potential to pre-empt the diagnosis of glaucoma prior to visual deterioration, to provide an accurate numeric evaluation highlighting even small retinal changes and to allow the rapid judgement of the efficacy of both current and new therapeutic strategies.

New trends in glaucoma risk, diagnosis & management.

Recent advances have seen a surge of new ideas and technologies to aid in the detection, treatment and further understanding of glaucoma. These technologies and advances are discussed to provide information on risk-factors, diagnosis and treatment. Glaucoma has never before seen such an advance in research and therapies coming forward in to the clinical workplace. It is an exciting time for physicians and researchers alike and over the next decade will certainly see advances in early detection, efficacious treatments and neuroprotection.

Combining phacoemulsification with endoscopic cyclophotocoagulation to manage cataract and glaucoma.

BACKGROUND: To examine the outcome and complications of combined phacoemulsification and endoscopic cyclophotocoagulation as surgical management of cataract and glaucoma. DESIGN: Retrospective uncontrolled case series from the glaucoma unit, Western Eye Hospital, London, UK. PARTICIPANTS: Sixty-three eyes from 59 patients with coexisting cataract and glaucoma. METHODS: Patients underwent routine phacoemulsification followed by 270-360 degree endoscopic cyclophotocoagulation as a single procedure. MAIN OUTCOME MEASURES: Intraocular pressure, number of intraocular pressure-lowering medications, logMAR visual acuity, recorded complications. RESULTS: Baseline characteristics included mean age (77.3 ± 11.1 years), mean logMAR visual acuity (1.01 ± 0.98), mean intraocular pressure (21.13 ± 6.21 mmHg) and mean number of intraocular pressure-lowering medications, (2.71 ± 1.06). Twelve months after phacoemulsification and endoscopic cyclophotocoagulation, mean intraocular pressure had reduced to 16.09 ± 5.27 mmHg (P < 0.01), number of intraocular pressure-lowering medications reduced to 1.47 ± 1.30 (P < 0.01) and mean logMAR acuity improved to 0.33 ± 0.22 (P < 0.01). Success, defined as an intraocular pressure reduction > 20% with intraocular pressure 6-21 mmHg, was achieved in 55.5% of eyes at 12 months. Complications included fibrinous uveitis, elevated intraocular pressure, posterior vitreous detachment and induced astigmatism. CONCLUSION: Phacoemulsification and endoscopic cyclophotocoagulation is both safe and effective as surgical management for cataract and glaucoma. Larger intraocular pressure reductions can be achieved in older patients and those with higher baseline intraocular pressure.

Nanoparticles Enhance Solubility and Neuroprotective Effects of Resveratrol in Demyelinating Disease.

Resveratrol is a natural polyphenol which may be useful for treating neurodegenerative diseases such as multiple sclerosis (MS). To date, current immunomodulatory treatments for MS aim to reduce inflammation with limited effects on the neurodegenerative component of this disease. The purpose of the current study is to develop a novel nanoparticle formulation of resveratrol to increase its solubility, and to assess its ability to prevent optic nerve and spinal cord degeneration in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Resveratrol nanoparticles (RNs) were made using a thin rehydration technique. EAE mice received a daily oral administration of vehicle, RNs or unconjugated resveratrol for one month. They were assessed daily for clinical signs of paralysis and weekly for their visual acuity with optokinetic responses (OKR). After one month, their spinal cords and optic nerves were stained for inflammation and demyelination and retinal ganglion cells immunostained for Brn3a. RNs were stable for three months. The administration of RNs did not have any effect on clinical manifestation of EAE and did not preserve OKR scores but reduced the intensity of the disease. It did not reduce inflammation and demyelination in the spinal cord and the optic nerve. However, RNs were able to decrease RGC loss compared to the vehicle. Results demonstrate that resveratrol is neuroprotective by reducing RGC loss. Interestingly, neuroprotective effects and decreased disease severity occurred without reduction of inflammation or demyelination, suggesting this therapy may fill an unmet need to limit the neurodegenerative component of MS.