Category: Peer-reviewed

The complex interactions of retinal, optical and environmental factors in myopia aetiology

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Publication date: November 2012
Source:Progress in Retinal and Eye Research, Volume 31, Issue 6
Author(s): D.I. Flitcroft
Myopia is the commonest ocular abnormality but as a research topic remains at the margins of mainstream ophthalmology. The concept that most myopes fall into the category of ‘physiological myopia’ undoubtedly contributes to this position. Yet detailed analysis of epidemiological data linking myopia with a range of ocular pathologies from glaucoma to retinal detachment demonstrates statistically significant disease association in the 0 to −6 D range of ‘physiological myopia’. The calculated risks from myopia are comparable to those between hypertension, smoking and cardiovascular disease. In the case of myopic maculopathy and retinal detachment the risks are an order of magnitude greater. This finding highlights the potential benefits of interventions that can limit or prevent myopia progression.Our understanding of the regulatory processes that guide an eye to emmetropia and, conversely how the failure of such mechanisms can lead to refractive errors, is certainly incomplete but has grown enormously in the last few decades. Animal studies, observational clinical studies and more recently randomized clinical trials have demonstrated that the retinal image can influence the eye’s growth. To date human intervention trials in myopia progression using optical means have had limited success but have been designed on the basis of simple hypotheses regarding the amount of defocus at the fovea.Recent animal studies, backed by observational clinical studies, have revealed that the mechanisms of optically guided eye growth are influenced by the retinal image across a wide area of the retina and not solely the fovea. Such results necessitate a fundamental shift in how refractive errors are defined. In the context of understanding eye growth a single sphero-cylindrical definition of foveal refraction is insufficient. Instead refractive error must be considered across the curved surface of the retina. This carries the consequence that local retinal image defocus can only be determined once the 3D structure of the viewed scene, off axis performance of the eye and eye shape has been accurately defined. This, in turn, introduces an under-appreciated level of complexity and interaction between the environment, ocular optics and eye shape that needs to be considered when planning and interpreting the results of clinical trials on myopia prevention.

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A proteomics view of the molecular mechanisms and biomarkers of glaucomatous neurodegeneration

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Publication date: Available online 5 February 2013
Source:Progress in Retinal and Eye Research
Author(s): Gülgün Tezel
Despite improving understanding of glaucoma, key molecular players of neurodegeneration that can be targeted for treatment of glaucoma, or molecular biomarkers that can be useful for clinical testing, remain unclear. Proteomics technology offers a powerful toolbox to accomplish these important goals of the glaucoma research and is increasingly being applied to identify molecular mechanisms and biomarkers of glaucoma. Recent studies of glaucoma using proteomics analysis techniques have resulted in the lists of differentially expressed proteins in human glaucoma and animal models. The global analysis of protein expression in glaucoma has been followed by cell-specific proteome analysis of retinal ganglion cells and astrocytes. The proteomics data have also guided targeted studies to identify post-translational modifications and protein–protein interactions during glaucomatous neurodegeneration. In addition, recent applications of proteomics have provided a number of potential biomarker candidates. Proteomics technology holds great promise to move glaucoma research forward toward new treatment strategies and biomarker discovery. By reviewing the major proteomics approaches and their applications in the field of glaucoma, this article highlights the power of proteomics in translational and clinical research related to glaucoma and also provides a framework for future research to functionally test the importance of specific molecular pathways and validate candidate biomarkers.

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Gap junctional coupling in the vertebrate retina: Variations on one theme?

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Publication date: May 2013
Source:Progress in Retinal and Eye Research, Volume 34
Author(s): Béla Völgyi , Tamás Kovács-Öller , Tamás Atlasz , Márta Wilhelm , Róbert Gábriel
Gap junctions connect cells in the bodies of all multicellular organisms, forming either homologous or heterologous (i.e. established between identical or different cell types, respectively) cell-to-cell contacts by utilizing identical (homotypic) or different (heterotypic) connexin protein subunits. Gap junctions in the nervous system serve electrical signaling between neurons, thus they are also called electrical synapses. Such electrical synapses are particularly abundant in the vertebrate retina where they are specialized to form links between neurons as well as glial cells. In this article, we summarize recent findings on retinal cell-to-cell coupling in different vertebrates and identify general features in the light of the evergrowing body of data. In particular, we describe and discuss tracer coupling patterns, connexin proteins, junctional conductances and modulatory processes. This multispecies comparison serves to point out that most features are remarkably conserved across the vertebrate classes, including (i) the cell types connected via electrical synapses; (ii) the connexin makeup and the conductance of each cell-to-cell contact; (iii) the probable function of each gap junction in retinal circuitry; (iv) the fact that gap junctions underlie both electrical and/or tracer coupling between glial cells. These pan-vertebrate features thus demonstrate that retinal gap junctions have changed little during the over 500 million years of vertebrate evolution. Therefore, the fundamental architecture of electrically coupled retinal circuits seems as old as the retina itself, indicating that gap junctions deeply incorporated in retinal wiring from the very beginning of the eye formation of vertebrates. In addition to hard wiring provided by fast synaptic transmitter-releasing neurons and soft wiring contributed by peptidergic, aminergic and purinergic systems, electrical coupling may serve as the ‘skeleton’ of lateral processing, enabling important functions such as signal averaging and synchronization.

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Corneal endothelial regeneration and tissue engineering

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Publication date: Available online 23 January 2013
Source:Progress in Retinal and Eye Research
Author(s): Tatsuya Mimura , Satoru Yamagami , Shiro Amano
Human corneal endothelial cells (HCECs) have a limited proliferative capacity. Descemet stripping with automated endothelial keratoplasty (DSAEK) has become the preferred method for the treatment of corneal endothelial deficiency, but it requires a donor cornea. To overcome the shortage of donor corneas, transplantation of cultured HCEC sheets has been attempted in experimental studies. This review summarizes current knowledge about the mechanisms of corneal endothelial wound healing and about tissue engineering for the corneal endothelium. We also discuss recent work on tissue engineering for DSAEK grafts using cultured HCECs and HCEC precursor cell isolation method (the sphere-forming assay). DSAEK grafts (HCEC sheets) were constructed by seeding cultured HCECs on human amniotic membrane, thin human corneal stroma, and collagen sheets. The pump function of the HCEC sheets thus obtained was approximately 75%–95% of that for human donor corneas. HCEC sheets were transplanted onto rabbit corneas after DSAEK. While the untransplanted control group displayed severe stromal edema, the transplanted group had clear corneas throughout the observation period. The sphere-forming assay using donor human corneal endothelium or cultured HCECs can achieved mass production of human corneal endothelial precursors. These findings indicate that cultured HCECs transplanted after DSAEK can perform effective corneal dehydration in vivo and suggest the feasibility of employing the transplantation of cultured HCECs to treat endothelial dysfunction. Additionally, corneal endothelial precursors may be an effective strategy for corneal endothelial regeneration.

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Macular telangiectasia type 2

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Publication date: May 2013
Source:Progress in Retinal and Eye Research, Volume 34
Author(s): Peter Charbel Issa , Mark C. Gillies , Emily Y. Chew , Alan C. Bird , Tjebo F.C. Heeren , Tunde Peto , Frank G. Holz , Hendrik P.N. Scholl
Macular telangiectasia type 2 is a bilateral disease of unknown cause with characteristic alterations of the macular capillary network and neurosensory atrophy. Its prevalence may be underestimated and has recently been shown to be as high as 0.1% in persons 40 years and older. Biomicroscopy may show reduced retinal transparency, crystalline deposits, mildly ectatic capillaries, blunted venules, retinal pigment plaques, foveal atrophy, and neovascular complexes. Fluorescein angiography shows telangiectatic capillaries predominantly temporal to the foveola in the early phase and a diffuse hyperfluorescence in the late phase. High-resolution optical coherence tomography (OCT) may reveal disruption of the photoreceptor inner segment–outer segment border, hyporeflective cavities at the level of the inner or outer retina, and atrophy of the retina in later stages. Macular telangiectasia type 2 shows a unique depletion of the macular pigment in the central retina and recent therapeutic trials showed that such depleted areas cannot re-accumulate lutein and zeaxanthin after oral supplementation. There have been various therapeutic approaches with limited or no efficacy. Recent clinical trials with compounds that block vascular endothelial growth factor (VEGF) have established the role of VEGF in the pathophysiology of the disease, but have not shown significant efficacy, at least for the non-neovascular disease stages. Recent progress in structure–function correlation may help to develop surrogate outcome measures for future clinical trials.In this review article, we summarize the current knowledge on macular telangiectasia type 2, including the epidemiology, the genetics, the clinical findings, the staging and the differential diagnosis of the disease. Findings using retinal imaging are discussed, including fluorescein angiography, OCT, adaptive optics imaging, confocal scanning laser ophthalmoscopy, and fundus autofluorescence, as are the findings using visual function testing including visual acuity and fundus-controlled microperimetry. We provide an overview of the therapeutic approaches for both non-neovascular and neovascular disease stages and provide a perspective of future directions including animal models and potential therapeutic approaches.

Highlights

► Macular telangiectasia (MacTel) type 2 is a neurodegenerative disease affecting the central retina. ► Its prevalence has long been underestimated and may be as high as 0.1%. ► There is central depletion of macular pigment and hyporeflective retinal cavities on OCT imaging. ► Vascular endothelial growth factor (VEGF) appears to play a significant role in the pathophysiology. ► Anti-VEGF therapy may show efficacy in neovascular disease only.

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Optical plasticity in fish lenses

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Publication date: May 2013
Source:Progress in Retinal and Eye Research, Volume 34
Author(s): Ronald H.H. Kröger
In a typical fish eye, the crystalline lens is the only refractive element. It is spherical in shape and has high refractive power. Most fish species have elaborate color vision and spectral sensitivity may range from the near-infrared to the near-ultraviolet. Longitudinal chromatic aberration exceeds depth of focus and chromatic blur is compensated for by species-specific multifocality of the lens. The complex optical properties of fish lenses are subject to accurate regulation, including circadian reversible adjustments and irreversible developmental tuning. The mechanisms optimize the transfer of visual information to the retina in diverse and variable environments, and allow for rapid evolutionary changes in color vision. Active optical tuning of the lens is achieved by changes in the refractive index gradient and involves layers of mature, denucleated lens fiber cells. First steps have been taken toward unraveling the signaling systems controlling lens optical plasticity. Multifocal lenses compensating for chromatic blur are common in all major groups of vertebrates, including birds and mammals. Furthermore, the optical quality of a monofocal lens, such as in the human eye, is equally sensitive to the exact shape of the refractive index profile. Optical plasticity in the crystalline lens may thus be present in vertebrates in general.

Highlights

► Multifocal crystalline lenses compensate for chromatic defocus. ► Different types of optical plasticity optimize information transfer to the retina. ► Denucleated lens fiber cells participate in the regulation. ► Active optical tuning of the lens explains rapid evolution of color vision. ► Similar mechanisms may be present in vertebrates in general.

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Bone marrow-CNS connections: Implications in the pathogenesis of diabetic retinopathy

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Publication date: September 2012
Source:Progress in Retinal and Eye Research, Volume 31, Issue 5
Author(s): Jane Yellowlees Douglas , Ashay D. Bhatwadekar , Sergio Li Calzi , Lynn C. Shaw , Debra Carnegie , Sergio Caballero , Quihong Li , Alan W. Stitt , Mohan K. Raizada , Maria B. Grant
Diabetic retinopathy is the fourth most common cause of blindness in adults. Current therapies, including anti-VEGF therapy, have partial efficacy in arresting the progression of proliferative diabetic retinopathy and diabetic macular edema. This review provides an overview of a novel, innovative approach to viewing diabetic retinopathy as the result of an inflammatory cycle that affects the bone marrow (BM) and the central and sympathetic nervous systems. Diabetes associated inflammation may be the result of BM neuropathy which skews haematopoiesis towards generation of increased inflammatory cells but also reduces production of endothelial progenitor cells responsible for maintaining healthy endothelial function and renewal. The resulting systemic inflammation further impacts the hypothalamus, promoting insulin resistance and diabetes, and initiates an inflammatory cascade that adversely impacts both macrovascular and microvascular complications, including diabetic retinopathy (DR). This review examines the idea of using anti-inflammatory agents that cross not only the blood–retinal barrier to enter the retina but also have the capability to target the central nervous system and cross the blood–brain barrier to reduce neuroinflammation. This neuroinflammation in key sympathetic centers serves to not only perpetuate BM pathology but promote insulin resistance which is characteristic of type 2 diabetic patients (T2D) but is also seen in T1D. A case series of morbidly obese T2D patients with retinopathy and neuropathy treated with minocycline, a well-tolerated antibiotic that crosses both the blood–retina and blood–brain barrier is presented. Our results indicates that minocycine shows promise for improving visual acuity, reducing pain from peripheral neuropathy, promoting weight loss and improving blood pressure control and we postulate that these observed beneficial effects are due to a reduction of chronic inflammation.

Highlights

► Blocking systemic inflammation may prove an effective means of treating DR. ► High-fat diets promote inflammation in the hypothalamus. ► High-fat diets may play a direct role in the development of DR. ► Anti-inflammatory therapies also address other complications of Type 2 diabetes.

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Glaucomatous damage of the macula

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Publication date: January 2013
Source:Progress in Retinal and Eye Research, Volume 32
Author(s): Donald C. Hood , Ali S. Raza , Carlos Gustavo V. de Moraes , Jeffrey M. Liebmann , Robert Ritch
There is a growing body of evidence that early glaucomatous damage involves the macula. The anatomical basis of this damage can be studied using frequency domain optical coherence tomography (fdOCT), by which the local thickness of the retinal nerve fiber layer (RNFL) and local retinal ganglion cell plus inner plexiform (RGC+) layer can be measured. Based upon averaged fdOCT results from healthy controls and patients, we show that: 1. For healthy controls, the average RGC+ layer thickness closely matches human histological data; 2. For glaucoma patients and suspects, the average RGC+ layer shows greater glaucomatous thinning in the inferior retina (superior visual field (VF)); and 3. The central test points of the 6° VF grid (24-2 test pattern) miss the region of greatest RGC+ thinning. Based upon fdOCT results from individual patients, we have learned that: 1. Local RGC+ loss is associated with local VF sensitivity loss as long as the displacement of RGCs from the foveal center is taken into consideration; and 2. Macular damage is typically arcuate in nature and often associated with local RNFL thinning in a narrow region of the disc, which we call the macular vulnerability zone (MVZ). According to our schematic model of macular damage, most of the inferior region of the macula projects to the MVZ, which is located largely in the inferior quadrant of the disc, a region that is particularly susceptible to glaucomatous damage. A small (cecocentral) region of the inferior macula, and all of the superior macula (inferior VF), project to the temporal quadrant, a region that is less susceptible to damage. The overall message is clear; clinicians need to be aware that glaucomatous damage to the macula is common, can occur early in the disease, and can be missed and/or underestimated with standard VF tests that use a 6° grid, such as the 24-2 VF test.

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