Putative Retina Metal/Metalloid-Binding Proteins: Molecular Functions, Biological Processes and Retina Disease Associations.

BACKGROUND: The mammalian retina contains high amounts of metals/metalloid-selenium. Their dyshomeostases are associated with certain retinal diseases. We carried out this bioinformatics study to identify the relationships between putative retinal metal/selenium binding proteins, their molecular functions and biological processes. METHODS: Identification of putative mouse metal/selenium binding proteins was based on known binding motifs, domains, patterns, and profiles. Annotations were obtained from Uniprot keyword "metal binding", "metal ion co-factors", "selenium proteins". Protein functions were estimated by associative frequency with key words in UniProt annotations. The raw data of 5 mouse proteomics PRIDE datasets (available to date) were downloaded and processed with Mascot against the mouse taxa of Uniprot (SwissProt/Trembl) and MaxQuant (version 1.6.10.43) for qualitative and quantitative datasets, respectively. Clinically relevant variants were evaluated using archive and aggregates information in ClinVar. RESULTS: The 438 proteins common to all the retina proteomics datasets were used to identify over-represented Gene Ontology categories. The putative mouse retinal metal/metalloid binding proteins identified are mainly involved in: 1) metabolic processes (enzymes), 2) homeostasis, 3) transport (vesicle mediated, transmembrane, along microtubules), 4) cellular localisation, 5) regulation of signalling and exocytosis, 6) organelle organisation, 7) (de)phosphorylation and 8) complex assembly. Twenty-one proteins were identified as involved in response to light stimulus and/or visual system development. An association of metal ion binding proteins rhodopsin, photoreceptor specific nuclear receptor, calcium binding protein 4 with disease-related mutations in inherited retinal conditions was identified, where the mutations affected an area within or in close proximity to the metal binding site or domain. CONCLUSION: These findings suggest a functional role for the putative metal/metalloid binding site in retinal proteins in certain retinal disorders.

Morning glory disc anomaly-associated maculopathy: multimodal imaging.

Morning glory disc anomaly (MGDA) is most commonly found in white females in childhood with reduced vision. One in two cases have been reported to develop maculopathy or posterior pole retinal detachment as they grow older. The pathophysiology of MGDA-associated maculopathy is not well understood.We describe a 31-year-old black woman, who presented with gradual reduction of vision in the right eye due to MGDA-associated maculopathy. We identified morphological characteristics of the optic disc and macula with multicolour and optical coherence tomography imaging.We speculate that the centripetal inner retina traction and cerebrospinal fluid pressure fluctuation play an important role in inner retinal fluid accumulation in the pathology of retinoschisis in MGDA. Further studies will shed some light of a potential cause-and-effect relationship between MGDA and retinoschisis.

Isolated juxtapapillary retinal capillary haemangioblastoma and exudative maculopathy in an elderly patient without von Hippel-Lindau syndrome: combined proton beam radiotherapy and intravitreal anti-VEGF.

A 71-year-old Caucasian man presented with an isolated juxtapapillary retinal capillary haemangioblastoma on the superior and temporal left optic disc with active exudation resulting in macular intraretinal and subretinal fluid, reduced vision, scotoma and distortion with progression over 6 weeks. He did not have von Hippel-Lindau syndrome. After proton beam radiotherapy (PBR), the tumour size remained unchanged, but did not stop the exudation. Three anti-vascular endothelial growth factor (VEGF) (ie, bevacizumab) injections at monthly intervals resulted in reduced macular oedema. Combined therapy with PBR and anti-VEGF injections sustained our patient's vision at 12 months follow-up.

Bilateral ocular toxoplasmosis in a returning traveller: age and route of infection as potential risk factors.

We report the case of a 69-year-old man, who presented in the UK with a short history of deteriorating vision and clinical features of bilateral atypical retinochoroiditis, after travelling to South America. Vitreous samples demonstrated Toxoplasma gondii DNA by PCR. Serology tests demonstrated recent acquired Toxoplasma gondii infection with IgM antibodies. He responded well to treatment with trimethoprim-sulfamethoxazole, azithromycin and oral steroids.This case is a reminder of the global importance of Toxoplasma related eye disease, and its uncommon bilateral severe presentation in a returning traveller, where the risk factors were age and the route of infection likely to be a virulent parasite oocyst from vegetables or water rather than undercooked meat or direct contact with cats.

A comparison of 23-gauge and 20-gauge vitrectomy for proliferative sickle cell retinopathy - clinical outcomes and surgical management.

AIMS: To report anatomical and functional outcomes in patients with proliferative sickle retinopathy (PSR) who underwent 23-gauge (23G) and 20-gauge (20G) vitrectomy. METHODS: Retrospective consecutive case series of patients who underwent vitreoretinal intervention for complications of PSR between April 2009 and February 2015. Operations were performed at a tertiary referral centre, Moorfields Eye Hospital. Visual acuity and anatomical success rates were evaluated for PSR complicated by retinal detachment, tractional vitreous haemorrhage and macular hole. Proliferative diabetic retinopathy cases were excluded. RESULTS: A total of 71 eyes (63 patients) underwent vitreoretinal surgery for PSR complications with 26 months mean follow-up. Primary indications were: tractional retinal detachment (TRD, n = 17), TRD with rhegmatogenous retinal detachment (n = 16), rhegmatogenous retinal detachment (n = 5, macula-on: 1, macula-off: 4), vitreous haemorrhage (n = 19), epiretinal membrane (n = 6), and full thickness macula hole (n = 8). Thirty-nine cases underwent 20G vitrectomy, and 23G surgery was performed in 32 eyes. Mean best corrected visual acuity (BCVA) improved from pre-operative 1.30 LogMAR to final BCVA of 0.74 LogMAR (p < 0.01, paired t-test). 23G vitrectomy yielded slightly better 32 vs. 25 ETDRS-letter improvement compared with 20G vitrectomy (p = 0.60, NS, unpaired t-test). 23G was associated with fewer per-operative complications (23G, 18% vs. 20G,13%). The subset of 38 eyes with retinal detachment demonstrated 79% primary reattachment rate, and a smaller BCVA improvement of 3 lines (p = 0.07, paired t-test). CONCLUSIONS: Surgical intervention for complicated PSR can preserve and/or improve vision although the degree of visual acuity stabilisation remains guarded in tractional/rhegmatogenous detachments. 23G vitrectomy may give a better functional outcome with lower per-operative complication rates.

Apraxia of lid opening.

We describe eyelid movement abnormalities in an 80-year-old man with apraxia of lid opening (ALO), resulting from involuntary levator palpebrae inhibition (ILPI) and pretarsal orbicularis oculi (OO) contraction. He was unable to open his lids at will following closure. Attempted eye opening resulted in forceful contraction of the frontalis muscle, backward thrusting of the head and lengthened lid closure. The inability to reopen the lids was not evident during spontaneous reflex blinking and he had no difficulty in keeping the lids open once they had been manually lifted up. There were no episodes of involuntary drooping of the eyelids or spasmodic contraction of the OO causing involuntary eyelid closure. Pursuit eye movements were not restricted, the vestibulo-ocular reflex was preserved and both horizontal and vertical saccades were normal. Despite the clinically visible persistence of pretarsal OO activity, treatment with botulinum toxin injections in the pretarsal and preseptal portions of the muscle did not reduce his difficulty in initiating lid elevation but he found some benefit using lid crutches. ALO is thought to be due to an abnormality in the supranuclear control of eyelid movement. ILPI can present either isolated or combined with blepharospasm. The excitatory levator palpebrae response necessary to lift the lids up is likely to be in very close connection with the OO antagonistic inhibitory response. Alterations in one or another pre-motor structure may result in inability to raise the lids due to inhibition of the levator palpebrae as well as persistence of the pretarsal OO.

Spontaneous wound dehiscence after removal of single continuous penetrating keratoplasty suture: conservative management.

PURPOSE: To describe a case of spontaneous wound dehiscence (WD) following removal of single continuous penetrating keratoplasty (PKP) suture, who was treated conservatively with a bandage contact lens. METHODS: A 36 year-old man who had penetrating keratoplasty for keratoconus 15 months earlier and removal of the single continues suture the previous week underwent ocular examination. He was treated with topical dexamethasone 0.3%, chloramphenicol 0.5% and cyclopentolate 1% 3 times a day and had a bandage contact lens (BCL) inserted. RESULTS: On presentation, he was complaining of reduced vision, tearing and pain following an attack of rhinitis-induced sneezing. His visual acuity (VA) in the affected eye was counting fingers, the anterior chamber was formed, the intraocular pressure (IOP) was low and there was a 2-clock-hour WD with a positive Seidel test but no iris incarceration. Two months later, his corrected VA was 6/5, his IOP was normal and the graft-host junction was good with no uplift. CONCLUSIONS: A 2-clock-hour WD after single continuous PKP suture removal may be conservatively treated with a BCL.

Iron accumulates in the primate choroid of the eye with aging as revealed with synchrotron X-ray fluorescence microscopy.

Aging leads to an increase in iron-loaded cellular structures in the choroid of the eye. This study was carried out to determine the distribution and content of iron, zinc and copper in the macular retina, choroid and retrobulbar optic nerve of young (4-5 years, n = 3) and aged (15-16 years, n = 5) male non-human primates, Macaca fascicularis, whose ocular anatomy is similar to humans. Thirty µm-thick tissue sections were analysed with synchrotron X-ray fluorescence and stained histologically for iron deposition. Quantitative measurements showed high levels of iron, zinc and copper in the choroid and retinal pigment epithelium in the macular area and arachnoid layer in the retrobulbar optic nerve. In aged animals compared to young ones, there was an increase in iron in the choroid with larger deposits and iron-loaded cellular structures. Iron-accumulation within these cellular structures may contribute to choroidal function impairment in aging and age-related macular degeneration.

Waiting time reduction in intravitreal clinics by optimization of appointment scheduling: balancing demand and supply.

This study was designed guided by the Model for Improvement framework to reduce waiting times and visit duration in the intravitreal therapy clinic, while improving patient and staff experience. In our aim to provide good quality, patient-centred care and constantly improve, we optimised the appointment profile and patient flow. We involved a multidisciplinary team (one consultant, junior doctors, staff nurses, technicians, and receptionist), as well as patients and relatives, to try to understand the main delays in the clinic. Process mapping, a fishbone diagram, run charts, together with feedback from patients and staff, provided an insight on the possible roots of the delays experienced by our patients. The results of the inquiry led us to take actions focused on optimising appointment scheduling. After implementing the new scheduling profile (with a gap in the middle of the session), various cycles of plan-do-study-act and a comparative, qualitative study by interviewing 10 patients demonstrated that the waiting times decreased, and patients and staff experience improved.

Recent advances in the understanding of the role of zinc in ocular tissues.

Zinc levels are high in ocular tissues and the distribution is non-uniform. Zinc is particularly concentrated in the corneal epithelium and posterior stroma. Zinc is the most abundant trace metal in the retina. Bound-zinc is particularly located in the inner nuclear layer, (e.g. forming part of the structure of zinc finger transcription factors), while loosely-bound zinc is prominent in the retinal pigment epithelium and photoreceptor layers. Loosely-bound zinc ions in the photoreceptors might play a role in the phototransduction cascade and rhodopsin regeneration. Loosely-bound zinc is also found in presynaptic vesicles of photoreceptor cells in the outer plexiform and inner plexiform layers and can be synaptically released to affect both ionotropic and metabotropic receptors and also ion channels to modulate neurotransmission. The correct amount of loosely-bound zinc ions is maintained by regulating the function of zinc transporters, sensors and trafficking/storage proteins (i.e. metallothionein). The retinal homeostasis of zinc is dysregulated in systemic zinc depletion, aging and diseases such as age-related macular degeneration. Manipulation of retinal zinc metabolism in these situations might improve visual function.

Distribution of trace elements in the mammalian retina and cornea by use of particle-induced X-ray emission (PIXE): localisation of zinc does not correlate with that of metallothioneins.

Proton-induced X-ray emission (PIXE) in combination with 3D depth profiling with Rutherford backscattering spectrometry (RBS) was used to establish the distribution and concentration of trace elements within individual corneal and retinal areas in frozen sections from adult male Wistar rats (n = 6). The distribution of endogenous trace elements in the cornea and retina is non-homogenous. The most abundant metal in the cornea is calcium followed by zinc. Iron and copper are present in small amounts localised particularly to the epithelium. Iron is also identified in keratocytes. Relatively high levels of calcium occur in the corneal epithelial cell bodies. Zinc has a wide intense distribution across the corneal epithelium (with greater levels in the basal part) and posterior stroma. In the retina, zinc is the most common metal followed by iron and copper. Relatively high levels of zinc exist in the retinal pigment epithelium (RPE), photoreceptor inner segments (RIS) and inner nuclear layer (INL). Chelatable zinc was localised with fluorescent TSQ in the RPE, RIS and plexiform layers. It is interesting to note that the highest levels of total zinc and the greatest intensity of chelatable zinc staining do not coincide. In the RPE and corneal epithelium, zinc co-localised with the zinc-containing metallothioneins (MT). However, there was a clear mismatch between the localisation of the most intense levels of zinc in the neuroretina (i.e. INL) and corneal posterior stroma with that reported for MT. For example, the presence of zinc is not particularly associated with the retinal ganglion cells, retinal area that contains MTs in significant amounts. While high amounts of zinc are present in the INL and corneal posterior stroma, which are largely devoid of MTs. This probably represents pools of static, catalytic and structural zinc associated with substances other than the MTs.

Morphision: a method for subjective evaluation of metamorphopsia in patients with unilateral macular pathology (i.e., full thickness macular hole and epiretinal membrane).

BACKGROUND: Lack of clinical tests to quantify spatial components of distortion in patients with full thickness macular holes (FTMH) and epiretinal membranes (ERM). AIM: To develop a test for subjective evaluation of visual distortion in the central visual field around fixation in patients with unilateral FTMH or ERM. SETTINGS AND DESIGN: Prospective case-control study carried out at tertiary referral center. MATERIALS AND METHODS: Twenty-five patients with unilateral macular disease (13 macular epiretinal membranes, 12 full-thickness macular holes), and nine controls (without ocular pathology) underwent ophthalmological examination with logMAR ETDRS visual acuity, near vision and contrast sensitivity assessed. Macular optical coherence tomography and metamorphopsia assessment using Morphision test was also carried out. This test consists of a set of modified Amsler charts for detection, identification, and subjective quantification of visual distortion in the central visual field around fixation. Morphision test content and construct validity, and reliability (test-retest method) were evaluated. Sixteen patients completed an unstructured survey on test performance and preference. RESULTS: Every patient with unilateral FTMH or ERM identified a particular chart using Morphision test (content validity). None of the normal subjects without symptoms of metamorphopsia identified any distortion (construct validity). Test-retest showed a 100% consistency for frequency and 67% for amplitude. The mean amplitude difference between measurements was 0.02 degrees (SD = 0.038). The coefficient of repeatability was 0.075. There was a correlation between Morphision amplitude score and visual acuity and contrast sensitivity, individually. CONCLUSIONS: Morphision test allowed detection and subjective quantification of metamorphopsia in the clinical setting in our patients with unilateral macular epiretinal membranes and full thickness macular holes.

Iron, zinc, and copper in retinal physiology and disease.

The essential trace metals iron, zinc, and copper play important roles both in retinal physiology and disease. They are involved in various retinal functions such as phototransduction, the visual cycle, and the process of neurotransmission, being tightly bound to proteins and other molecules to regulate their structure and/or function or as unbound free metal ions. Elevated levels of "free" or loosely bound metal ions can exert toxic effects, and in order to maintain homeostatic levels to protect retinal cells from their toxicity, appropriate mechanisms exist such as metal transporters, chaperones, and the presence of certain storage molecules that tightly bind metals to form nontoxic products. The pathways to maintain homeostatic levels of metals are closely interlinked, with various metabolic pathways directly and/or indirectly affecting their concentrations, compartmentalization, and oxidation/reduction states. Retinal deficiency or excess of these metals can result from systemic depletion and/or overload or from mutations in genes involved in maintaining retinal metal homeostasis, and this is associated with retinal dysfunction and pathology. Iron accumulation in the retina, a characteristic of aging, may be involved in the pathogenesis of retinal diseases such as age-related macular degeneration (AMD). Zinc deficiency is associated with poor dark adaptation. Zinc levels in the human retina and RPE decrease with age in AMD. Copper deficiency is associated with optic neuropathy, but retinal function is maintained. The changes in iron and zinc homeostasis in AMD have led to the speculation that iron chelation and/or zinc supplements may help in its treatment.

Metabolomic analysis of rat serum in streptozotocin-induced diabetes and after treatment with oral triethylenetetramine (TETA).

BACKGROUND: The prevalence, and associated healthcare burden, of diabetes mellitus is increasing worldwide. Mortality and morbidity are associated with diabetic complications in multiple organs and tissues, including the eye, kidney and cardiovascular system, and new therapeutics to treat these complications are required urgently. Triethylenetetramine (TETA) is one such experimental therapeutic that acts to chelate excess copper (II) in diabetic tissues and reduce oxidative stress and cellular damage. METHODS: Here we have performed two independent metabolomic studies of serum to assess the suitability of the streptozotocin (STZ)-induced rat model for studying diabetes and to define metabolite-related changes associated with TETA treatment. Ultraperformance liquid chromatography-mass spectrometry studies of serum from non-diabetic/untreated, non-diabetic/TETA-treated, STZ-induced diabetic/untreated and STZ-induced diabetic/TETA-treated rats were performed followed by univariate and multivariate analysis of data. RESULTS: Multiple metabolic changes related to STZ-induced diabetes, some of which have been reported previously in other animal and human studies, were observed, including changes in amino acid, fatty acid, glycerophospholipid and bile acid metabolism. Correlation analysis suggested that treatment with TETA led to a reversal of diabetes-associated changes in bile acid, fatty acid, steroid, sphingolipid and glycerophospholipid metabolism and proteolysis. CONCLUSIONS: Metabolomic studies have shown that the STZ-induced rat model of diabetes is an appropriate model system to undertake research into diabetes and potential therapies as several metabolic changes observed in humans and other animal models were also observed in this study. Metabolomics has also identified several biological processes and metabolic pathways implicated in diabetic complications and reversed following treatment with the experimental therapeutic TETA.

The vitreous glycoprotein opticin inhibits preretinal neovascularization.

PURPOSE: Opticin is an extracellular matrix glycoprotein that the authors discovered in the vitreous humor of the eye. It is synthesized by the nonpigmented ciliary epithelium and secreted into the vitreous cavity and, unusually for an extracellular matrix molecule, high-level synthesis is maintained into adult life. Here the authors investigated the hypothesis that opticin influences vascular development in the posterior segment of the eye and pathologic angiogenesis into the normally avascular, mature (secondary) vitreous. METHODS: Opticin was localized in murine eyes by immunohistochemistry. An opticin knockout mouse was established and vascular development was compared between knockout and wild-type mice. Wild-type and opticin null mice were compared in the oxygen-induced retinopathy model, a model of pathologic angiogenesis, and this model was also used to assess the effects of intravitreal injection of recombinant opticin into eyes of wild-type mice. RESULTS: Opticin colocalizes with the collagen type II-rich fibrillar network of the vitreous, the inner limiting lamina, the lens capsule, the trabecular meshwork, and the iris. Analyses of the hyaloid and retinal vasculature showed that opticin has no effect on hyaloid vascular regression or developmental retinal vascularization. However, using the oxygen-induced retinopathy model, the authors demonstrated that opticin knockout mice produce significantly more preretinal neovascularization than wild-type mice, and the intravitreal delivery of excess opticin inhibited the formation of neovessels in wild-type mice. CONCLUSIONS: A lack of opticin does not influence vascular development, but opticin is antiangiogenic and inhibits preretinal neovascularization.

Concentration of various trace elements in the rat retina and their distribution in different structures.

Inductively coupled plasma mass spectrometry (ICP-MS) was used to quantify the total amount of trace elements in retina from adult male Sprague-Dawley rats (n = 6). Concentration of trace elements within individual retinal areas in frozen sections of the fellow eye was established with the use of two methodologies: (1) particle-induced X-ray emission (PIXE) in combination with 3D depth profiling with Rutherford backscattering spectrometry (RBS) and (2) synchrotron X-ray fluorescence (SXRF) microscopy. The most abundant metal in the retina was zinc, followed by iron and copper. Nickel, manganese, chromium, cobalt, selenium and cadmium were present in very small amounts. The PIXE and SXRF analysis yielded a non-homogenous pattern distribution of metals in the retina. Relatively high levels of zinc were found in the inner part of the photoreceptor inner segments (RIS)/outer limiting membrane (OLM), inner nuclear layer and plexiform layers. Iron was found to accumulate in the retinal pigment epithelium/choroid layer and RIS/OLM. Copper in turn, was localised primarily in the RIS/OLM and plexiform layers. The trace elements iron, copper, and zinc exist in different amounts and locations in the rat retina.

Ophthalmoplegia secondary to herpes zoster ophthalmicus.

An 80-year-old Caucasian woman had been diagnosed with right herpes zoster ophthalmicus 2 ½ weeks before presentation to our department. Ten days after stopping oral aciclovir, she presented with periorbital pain, visual loss, ptosis and complete ophthalmoplegia. On examination, visual acuity in her right eye was hand movements, with a relative afferent pupillary defect and 2 mm proptosis. MRI demonstrated contrast enhancement within the orbit extending into the apex, suggestive of an inflammatory process. Oral treatment was started with oral aciclovir and corticosteroids for 2 months, when she had resolution of the optic neuropathy and ophthalmoplegia. Vision recovered to 6/9 and repeat neuroimaging revealed regression of the inflammatory process.

Chronic intraocular copper foreign body and candida: a unique combination.

PURPOSE: To describe a case of unilateral intermediate uveitis, retained copper intraocular foreign body (IOFB) and fungus. METHODS: Interventional case report. RESULTS: Brown-orange discoloration of the iris, lens and opacified vitreous was observed. Computed tomography revealed a retained IOFB, which was composed of copper. IOFB was removed during vitrectomy and cataract surgery. Copper deposition was demonstrated on the anterior capsule. Incidentally, dimorphic fungus were found in the vitreous. CONCLUSIONS: The presence of intraocular copper might have reduced the virulence of the fungus preventing endophthalmitis.

Horizontal and vertical micropsia following macula-off rhegmatogenous retinal-detachment surgical repair.

BACKGROUND: Dysmetropsia or distorted image size perception (smaller: micropsia; larger: macropsia) is known to occur after successful surgical re-attachment for macula-off rhegmatogenous retinal detachment. However, the vertical and horizontal components of size distortion have not been previously quantified separately. The purpose of this article is to describe horizontal and vertical dysmetropsia occurring in patients following pars plana vitrectomy and gas treatment (octafluoropropane, C(3)F(8) or sulfur hexafluoride, SF(6)) for macula-off rhegmatogenous retinal detachment. MATERIAL AND METHODS: Four patients (mean+/-SD, 59+/-8 years; three women and one man) who had had pars plana vitrectomy and gas treatment for macula-off rhegmatogenous retinal detachment 6-7 months earlier underwent ocular examination, best corrected visual acuity test, threshold horizontal and vertical dysmetropsia measurement using a computerised version of the New Aniseikonia Test, slit-lamp examination and optical coherence tomography of the macula. RESULTS: All patients had binocular visual complaints including difficulty judging distances or reading, rivalry or asthenopia. The logMAR visual acuity (mean+/-SD) in the operated eye was 0.52+/-0.199 and 0.02+/-0.171 in the unaffected eye. All patients perceived the image as smaller (micropsia) with the affected eye, with differences ranging from -9 to 0%. Four patients showed 3% or more size difference between horizontal and vertical meridians. CONCLUSIONS: Dysmetropsia does occur in symptomatic patients following successful surgical repair of macula-off rhegmatogenous retinal detachment by pars plana vitrectomy and gas treatment. The effect on image size is heterogenous across the retinal area affected.