169 results found
Yetisen AK, Jiang N, Castaneda Gonzalez CM, et al., 2019, Scleral lens sensor for ocular electrolyte analysis., Advanced Materials, Pages: e1906762-e1906762, ISSN: 0935-9648
The quantitative analysis of tear analytes in point-of-care settings can enable early diagnosis of ocular diseases. Here, a fluorescent scleral lens sensor is developed to quantitatively measure physiological levels of pH, Na+ , K+ , Ca2+ , Mg2+ , and Zn2+ ions. Benzenedicarboxylic acid, a pH probe, displays a sensitivity of 0.12 pH units within pH 7.0-8.0. Crown ether derivatives exhibit selectivity to Na+ and K+ ions within detection ranges of 0-100 and 0-50 mmol L-1 , and selectivities of 15.6 and 8.1 mmol L-1 , respectively. A 1,2 bis(o-aminophenoxy)ethane-N,N,-N',N'-tetraacetic-acid-based probe allows Ca2+ ion sensing with 0.02-0.05 mmol L-1 sensitivity within 0.50-1.25 mmol L-1 detection range. 5-Oxazolecarboxylic acid senses Mg2+ ions, exhibiting a sensitivity of 0.10-0.44 mmol L-1 within the range of 0.5-0.8 mmol L-1 . The N-(2-methoxyphenyl)iminodiacetate Zn2+ ion sensor has a sensitivity of 1 µmol L-1 within the range of 10-20 µmol L-1 . The fluorescent sensors are subsequently multiplexed in the concavities of an engraved scleral lens. A handheld ophthalmic readout device comprising light-emitting diodes (LEDs) and bandpass filters is fabricated to excite as well as read the scleral sensor. A smartphone camera application and an user interface are developed to deliver quantitative measurements with data deconvolution. The ophthalmic system enables the assessment of dry eye severity stages and the differentiation of its subtypes.
Considering the retina as an extension of the brain provides a platform from which to study diseases of the nervous system. Taking advantage of the clear optical media of the eye and ever-increasing resolution of modern imaging techniques, retinal morphology can now be visualized at a cellular level in vivo. This has provided a multitude of possible biomarkers and investigative surrogates that may be used to identify, monitor and study diseases until now limited to the brain. In many neurodegenerative conditions, early diagnosis is often very challenging due to the lack of tests with high sensitivity and specificity, but, once made, opens the door to patients accessing the correct treatment that can potentially improve functional outcomes. Using retinal biomarkers in vivo as an additional diagnostic tool may help overcome the need for invasive tests and histological specimens, and offers the opportunity to longitudinally monitor individuals over time. This review aims to summarise retinal biomarkers associated with a range of neurological conditions including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and prion diseases from a clinical perspective. By comparing their similarities and differences according to primary pathological processes, we hope to show how retinal correlates can aid clinical decisions, and accelerate the study of this rapidly developing area of research.
Walpert MJ, Normando EM, Annus T, et al., 2019, Age-related retinal thickness in Down's syndrome: A high-risk population for dementia, Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring, Vol: 11, Pages: 744-751
© 2019 Introduction: People with Down's syndrome (DS) have a high prevalence of early-onset Alzheimer's disease. Early markers of Alzheimer's disease pathology identifiable before clinical change are needed for the evaluation of preventative treatments. The retina, an extension of the brain, may provide a noninvasive imaging site. Methods: Forty-nine adults with DS and 36 age-matched controls completed retinal nerve fibre layer (RNFL) assessments using optical coherence tomography. RNFL thickness was analyzed in relation to cognitive status and age and previously acquired cortical thickness and cerebral amyloid β binding data in a subgroup. Results: RNFL thickness was greater in the DS group and did not show age-related thinning. RNFL correlated positively with cognitive scores and cortical thickness and was reduced in participants with positive cerebral amyloid β binding. Discussion: Increased RNFL in adults with DS may represent early Alzheimer's disease–related changes. Thinning was present in those with cerebral amyloid β binding, independent of age.
Blumenthal EZ, Cordeiro MF, Shmetterer L, et al., 2019, ISOPT Clinical Hot Topic Panel Discussion on Glaucoma., J Ocul Pharmacol Ther, Vol: 35, Pages: 441-446
As part of the 14th International Symposium on Ocular and Pharmacological Therapeutics, a unique panel was gathered to discuss two cardinal questions related to the treatment of glaucoma, peeking into the future: (1) What shape and form will glaucoma medical treatment have five and fifteen years from today, and (2) Will personalized medicine be commonly used five years from now. For each of the questions, we assigned an "optimist" and "pessimist" who provided the assigned point of view, for a total of 4 discussants, the authors of this panel discussion.
Yap TE, Shamsher E, Guo L, et al., 2019, Ophthalmic Research Lecture 2018: DARC as a Potential Surrogate Marker., Ophthalmic Res, Pages: 1-7
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.
Normando EM, Davis BM, Yap TE, et al., 2019, Objective Assessment of Progressive Macular Changes in Glaucoma, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Davis BM, Tian K, Pahlitzsch M, et al., 2019, Topical Coenzyme Q10 demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular hypertension (vol 36, pg 114, 2017), MITOCHONDRION, Vol: 47, Pages: 330-330, ISSN: 1567-7249
Shamsher E, Davis BM, Yap TE, et al., Neuroprotection in glaucoma: old concepts, new ideas, EXPERT REVIEW OF OPHTHALMOLOGY, Vol: 14, Pages: 101-113, ISSN: 1746-9899
Arranz-Romera A, Davis BM, Bravo-Osuna I, et al., 2019, Simultaneous co-delivery of neuroprotective drugs from multi-loaded PLGA microspheres for the treatment of glaucoma, JOURNAL OF CONTROLLED RELEASE, Vol: 297, Pages: 26-38, ISSN: 0168-3659
D'Esposito F, Miodragovic S, Normando EM, et al., 2018, The 100 000 genomes project and the Western Eye Hospital experience, Publisher: WILEY, Pages: 28-28, ISSN: 1755-375X
Davis B, Guo L, Pahlitzsch M, et al., 2018, RGC cell size and susceptibility to loss in rodent glaucoma models, Publisher: WILEY, Pages: 30-31, ISSN: 1755-375X
Davis B, Pahlitzsch M, Balendra S, et al., 2018, Evaluation of topical curcumin nanoparticles in of rodent glaucoma models, Publisher: WILEY, Pages: 30-30, ISSN: 1755-375X
Guo L, Normando EM, Shah PA, et al., 2018, Oculo-Visual Abnormalities in Parkinson's Disease: Possible Value as Biomarkers, MOVEMENT DISORDERS, Vol: 33, Pages: 1390-1406, ISSN: 0885-3185
Davis BM, Pahlitzsch M, Guo L, et al., 2018, Topical curcumin nanocarriers are neuroprotective in eye disease, Scientific Reports, Vol: 8, ISSN: 2045-2322
Curcumin (1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5dione) is a polyphenol extracted from turmeric that has long been advocated for the treatment of a variety of conditions including neurodegenerative and inflammatory disorders. Despite this promise, the clinical use of curcumin has been limited by the poor solubility and low bioavailability of this molecule. In this article, we describe a novel nanocarrier formulation comprising Pluronic-F127 stabilised D-α-Tocopherol polyethene glycol 1000 succinate nanoparticles, which were used to successfully solubilize high concentrations (4.3 mg/mL) of curcumin. Characterisation with x-ray diffraction and in vitro release assays localise curcumin to the nanocarrier interior, with each particle measuring <20 nm diameter. Curcumin-loaded nanocarriers (CN) were found to significantly protect against cobalt chloride induced hypoxia and glutamate induced toxicity in vitro, with CN treatment significantly increasing R28 cell viability. Using established glaucoma-related in vivo models of ocular hypertension (OHT) and partial optic nerve transection (pONT), topical application of CN twice-daily for three weeks significantly reduced retinal ganglion cell loss compared to controls. Collectively, these results suggest that our novel topical CN formulation has potential as an effective neuroprotective therapy in glaucoma and other eye diseases with neuronal pathology.
Cordeiro MF, 2018, DARC and Glaucoma, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Normando EM, Blackwell C, Cordeiro MF, 2018, Effect of Topical Trehalose/Hyaluronic Acid on OCT Image Quality in Glaucoma Patients, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Arranz-Romera A, Shamsher E, Esteban-Perez S, et al., 2018, Co-delivery of Dexamethasone-Melatonin-CoQ10 from a microparticulate drug delivery system. Potential usefulness in neuroprotective therapy, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Guo L, Davis B, Ravindran N, et al., 2018, Topical rh-NGF is neuroprotective to retinal ganglion cells by targeting secondary degeneration, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Shamsher E, Davis B, Dev P, et al., 2018, Resveratrol nanoparticles are neuroprotective in vitro suggesting a potential to cure glaucoma and Alzheimer's disease, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
Yap TE, Donna P, Almonte MT, et al., 2018, Real-time imaging of retinal ganglion cell apoptosis, Cells, Vol: 7, ISSN: 2073-4409
Monitoring real-time apoptosis in-vivo is an unmet need of neurodegeneration science, both in clinical and research settings. For patients, earlier diagnosis before the onset of symptoms provides a window of time in which to instigate treatment. For researchers, being able to objectively monitor the rates of underlying degenerative processes at a cellular level provides a biomarker with which to test novel therapeutics. The DARC (Detection of Apoptosing Retinal Cells) project has developed a minimally invasive method using fluorescent annexin A5 to detect rates of apoptosis in retinal ganglion cells, the key pathological process in glaucoma. Numerous animal studies have used DARC to show efficacy of novel, pressure-independent treatment strategies in models of glaucoma and other conditions where retinal apoptosis is reported, including Alzheimer’s disease. This may forge exciting new links in the clinical science of treating both cognitive and visual decline. Human trials are now underway, successfully demonstrating the safety and efficacy of the technique to differentiate patients with progressive neurodegeneration from healthy individuals. We review the current perspectives on retinal ganglion cell apoptosis, the way in which this can be imaged, and the exciting advantages that these future methods hold in store.
Yang E, Al-Mugheiry TS, Normando EM, et al., 2018, Real-time imaging of retinal cell apoptosis by confocal scanning laser ophthalmoscopy and its role in glaucoma, Frontiers in Neurology, Vol: 9, ISSN: 1664-2295
Glaucoma is one of the leading causes of irreversible blindness in the world. It is characterized by the progressive loss of retinal ganglion cells (RGCs), mainly through the process of apoptosis. Glaucoma patients often come to clinical attention when irreversible loss of visual function has been already established; therefore, early recognition of RGC apoptosis is inordinately important in disease prevention. The novel technology called Detection of Apoptosing Retinal Cells (DARC) allows real-time in vivo quantification of apoptosing cells through the use of a fluorescent biomarker and a confocal scanning ophthalmoscope. A recent Phase I clinical trial has evaluated the safety of DARC and its ability to detect retinal apoptosis in glaucoma patients and healthy volunteers. Results suggest that DARC may have potential in the early detection of glaucoma, which could help alleviate the medical, social, and economic burden associated with this blinding condition.
Yap TE, Normando EM, Cordeiro MF, Redefining clinical outcomes and endpoints in glaucoma, Expert Review of Ophthalmology, ISSN: 1746-9899
Glaucoma is one of the leading causes of irreversible visual loss, which has been estimated to affect 3.5% of those over 40 years old and projected to affect a total of 112 million people by 2040. Such a dramatic increase in affected patients demonstrates the need for continual improvement in the way we diagnose and treat this condition. Annexin A5 is a 36 kDa protein that is ubiquitously expressed in humans and is studied as an indicator of apoptosis in several fields. This molecule has a high calcium-dependent affinity for phosphatidylserine, a cell membrane phospholipid externalized to the outer cell membrane in early apoptosis. The DARC (Detection of Apoptosing Retinal Cells) project uses fluorescently-labelled annexin A5 to assess glaucomatous degeneration, the inherent process of which is the apoptosis of retinal ganglion cells. Furthermore, this project has conducted investigation of the retinal apoptosis in the neurodegenerative conditions of the eye and brain. In this present study, we summarized the use of annexin A5 as a marker of apoptosis in the eye. We also relayed the progress of the DARC project, developing real-time imaging of retinal ganglion cell apoptosis in vivo from the experimental models of disease and identifying mechanisms underlying neurodegeneration and its treatments, which has been applied to the first human clinical trials. DARC has potential as a biomarker in neurodegeneration, especially in the research of novel treatments, and could be a useful tool for the diagnosis and monitoring of glaucoma.
De Groef L, Cordeiro MF, 2018, Is the Eye an Extension of the Brain in Central Nervous System Disease?, JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS, Vol: 34, Pages: 129-133, ISSN: 1080-7683
Fayers T, Loh GK, Cordeiro MF, et al., 2018, Overprescribing of antibiotics by UK ophthalmologists., Eye, Vol: 32, Pages: 240-242, ISSN: 0950-222X
D'Esposito F, Cennamo G, de Crecchio G, et al., 2018, Multimodal Imaging in Autosomal Dominant Cone-Rod Dystrophy Caused by Novel CRX Variant., Ophthalmic Res, Vol: 60, Pages: 169-175
AIM: To characterize by multimodal approach the phenotype of patients from a 3 generations pedigree, affected by autosomal dominant cone-rod dystrophy (CRD), found to carry a novel pathogenic variant in the cone-rod homeobox-containing (CRX) gene. METHODS: Examination of the adult patients included the following tests: visual acuity, multicolour imaging, spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF) and OCT angiography (OCT-A) recordings. In a 2.5-year-old child, cycloplegic refraction, fundoscopy, ocular motility evaluation and electrophysiological exams were performed. Next Generation Sequencing of patients' DNA has been carried out. RESULTS: A novel CRX pathogenic variant has been identified in our patients. The 2.5-year-old child in the third generation was found to have inherited the variant, with no clinical signs of the condition, but electroretinographic abnormalities in the scotopic component. In the adult patients, diffuse atrophy of the retinal pigment epithelium/photoreceptor complex in the macular region was evident at the OCT and FAF, while OCT-A showed choriocapillaris density reduction. CONCLUSIONS: Multimodal study allowed the characterization of a peculiar form of CRD. The novel pathogenic variant seems to have a different effect on the phenotype if compared with a previously described similar one, giving an insight into the pathogenic mechanism of CRX-related retinal dystrophies and offering valuable information that could lead to the development of possible future therapies.
Sanchez-Lopez E, Antonia Egea M, Davis BM, et al., 2017, Memantine-Loaded PEGylated Biodegradable Nanoparticles for the Treatment of Glaucoma, SMALL, Vol: 14, ISSN: 1613-6810
Glaucoma is a multifactorial neurodegenerative disease associated with retinal ganglion cells (RGC) loss. Increasing reports of similarities in glaucoma and other neurodegenerative conditions have led to speculation that therapies for brain neurodegenerative disorders may also have potential as glaucoma therapies. Memantine is an N-methyl-d-aspartate (NMDA) antagonist approved for Alzheimer's disease treatment. Glutamate-induced excitotoxicity is implicated in glaucoma and NMDA receptor antagonism is advocated as a potential strategy for RGC preservation. This study describes the development of a topical formulation of memantine-loaded PLGA-PEG nanoparticles (MEM-NP) and investigates the efficacy of this formulation using a well-established glaucoma model. MEM-NPs <200 nm in diameter and incorporating 4 mg mL−1 of memantine were prepared with 0.35 mg mL−1 localized to the aqueous interior. In vitro assessment indicated sustained release from MEM-NPs and ex vivo ocular permeation studies demonstrated enhanced delivery. MEM-NPs were additionally found to be well tolerated in vitro (human retinoblastoma cells) and in vivo (Draize test). Finally, when applied topically in a rodent model of ocular hypertension for three weeks, MEM-NP eye drops were found to significantly (p < 0.0001) reduce RGC loss. These results suggest that topical MEM-NP is safe, well tolerated, and, most promisingly, neuroprotective in an experimental glaucoma model.
Davis BM, Brenton J, Davis S, et al., 2017, Assessing anesthetic activity through modulation of the membrane dipole potential, Journal of Lipid Research, Vol: 58, Pages: 1962-1976, ISSN: 0022-2275
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.
Davis BM, Tian K, Pahlitzsch M, et al., 2017, Topical coenzyme Q10 demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular hypertension, Mitochondrion, Vol: 36, Pages: 114-123, ISSN: 1567-7249
Coenzyme Q10 (CoQ10) is a mitochondrial-targeted antioxidant with known neuroprotective activity. Its ocular effects when co-solubilised with α–tocopherol polyethylene glycol succinate (TPGS) were evaluated. In vitro studies confirmed that CoQ10 was significantly protective in different retinal ganglion cell (RGC) models. In vivo studies in Adult Dark Agouti (DA) rats with unilateral surgically-induced ocular hypertension (OHT) treated with either CoQ10/TPGS micelles or TPGS vehicle twice daily for three weeks were performed, following which retinal cell health was assessed in vivo using DARC (Detection of Apoptotic Retinal Cells) and post-mortem with Brn3a histological assessment on whole retinal mounts. CoQ10/TPGS showed a significant neuroprotective effect compared to control with DARC (p < 0.05) and Brn3 (p < 0.01). Topical CoQ10 appears an effective therapy preventing RGC apoptosis and loss in glaucoma-related models.
Normando EM, Bono V, Davis B, et al., 2017, Prospective Comparison of Global and Cluster Visual Field Progression Criteria in Glaucoma and Their Relationship to Structural Changes, Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology (ARVO), Publisher: ASSOC RESEARCH VISION OPHTHALMOLOGY INC, ISSN: 0146-0404
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