Author: jfg@linkoph.com

Ocular Toxoplasmosis Past, present and new aspects of an old disease

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Publication date: Available online 9 January 2014
Source:Progress in Retinal and Eye Research
Author(s): M. Maenz , D. Schlüter , O. Liesenfeld , G. Schares , U. Gross , U. Pleyer
Ocular toxoplasmosis (OT) is considered the most frequent form of infectious posterior uveitis and is caused by the protozoan parasite Toxoplasma gondii. The resulting vision loss frequently incapacitates patients and places a considerable socio-economic burden on societies in particular in developing countries. Although, toxoplasmic retinochoroiditis is a world-wide phenomenon stark regional differences with regard to prevalence and presumably route of infection exist. This review will discuss our current clinical understanding of OT including typical and atypical manifestations, patient characteristics which influence the course of disease and treatment options. Even though, congenital and acquired OT are not regarded as separate entities, certain differences exist, which will be assessed and evaluated in detail. A strong focus is laid on the disease causing parasite T. gondii, since solving the mystery of OT aetiology and the development of improved therapies will not be possibly with clinical science alone, but rather requires a precise understanding of parasitological and immunological pathomechanisms. Additionally, the biology and genetics of T. gondii form the foundation for novel and sophisticated diagnostic methods. Scientific advances in the recent years have shed some light on the different role of T. gondii strains with regard to OT manifestation and severity of disease. Genetic and environmental factors influencing OT will be presented and commonalities between OT and toxoplasmic encephalitis will be briefly discussed. Furthermore, the laboratory tools to study OT are crucial in our understanding of OT. In vivo and in vitro experimental approaches will be summarised and evaluated extensively. Finally, a brief outlook is given in which direction OT research should be headed in the future.

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Is neutralizing vitreal growth factors a viable strategy to prevent proliferative vitreoretinopathy?

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Publication date: Available online 9 January 2014
Source:Progress in Retinal and Eye Research
Author(s): Steven Pennock , Luis J. Haddock , Dean Eliott , Shizuo Mukai , Andrius Kazlauskas
Proliferative vitreoretinopathy (PVR) is a blinding disorder that occurs in eyes with rhegmatogenous retinal detachment and in eyes that have recently undergone retinal detachment surgery. There are presently no treatment strategies to reduce the risk of developing PVR in eyes with retinal detachment, and surgical intervention is the only option for eyes with retinal detachment and established PVR. Given the poor visual outcome associated with the surgical treatment of PVR, considerable work has been done to identify pharmacologic agents that could antagonize the PVR process. Intensive efforts to identify molecular determinants of PVR implicate vitreal growth factors. A surprise that emerged in the course of testing the ‘growth factor hypothesis’ of PVR was the existence of a functional relationship amongst growth factors that engage platelet-derived growth factor (PDGF) receptor α (PDGFRα), a receptor tyrosine kinase that is key to pathogenesis of experimental PVR. Vascular endothelial cell growth factor A (VEGF), which is best known for its ability to activate VEGF receptors (VEGFRs) and induce permeability and/or angiogenesis, enables activation of PDGFRα by a wide spectrum of vitreal growth factors outside of the PDGF family (non-PDGFs) in a way that triggers signaling events that potently enhance the viability of cells displaced into vitreous. Targeting these growth factors or signaling events effectively neutralizes the bioactivity of PVR vitreous and prevents PVR in a number of preclinical models. In this review, we discuss recent conceptual advances in understanding the role of growth factors in PVR, and consider the tangible treatment strategies for clinical application.

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Müller glia: stem cells for generation and regeneration of retinal neurons in teleost fish

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Publication date: Available online 8 January 2014
Source:Progress in Retinal and Eye Research
Author(s): Jenny R. Lenkowski , Pamela A. Raymond
Adult zebrafish generate new neurons in the brain and retina throughout life. Growth-related neurogenesis allows a vigorous regenerative response to damage, and fish can regenerate retinal neurons, including photoreceptors, and restore functional vision following photic, chemical, or mechanical destruction of the retina. Müller glial cells in fish function as radial-glial-like neural stem cells. During adult growth, Müller glial nuclei undergo sporadic, asymmetric, self-renewing mitotic divisions in the inner nuclear layer to generate a rod progenitor that migrates along the radial fiber of the Müller glia into the outer nuclear layer, proliferates, and differentiates exclusively into rod photoreceptors. When retinal neurons are destroyed, Müller glia in the immediate vicinity of the damage partially and transiently dedifferentiate, re-express retinal progenitor and stem cell markers, re-enter the cell cycle, undergo interkinetic nuclear migration (characteristic of neuroepithelial cells), and divide once in an asymmetric, self-renewing division to generate a retinal progenitor. This daughter cell proliferates rapidly to form a compact neurogenic cluster surrounding the Müller glia; these multipotent retinal progenitors then migrate along the radial fiber to the appropriate lamina to replace missing retinal neurons. Some aspects of the injury-response in fish Müller glia resemble gliosis as observed in mammals, and mammalian Müller glia exhibit some neurogenic properties, indicative of a latent ability to regenerate retinal neurons. Understanding the specific properties of fish Müller glia that facilitate their robust capacity to generate retinal neurons will inform and inspire new clinical approaches for treating blindness and visual loss with regenerative medicine.

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Progress on Retinal Image Analysis for Age Related Macular Degeneration

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Publication date: Available online 7 November 2013
Source:Progress in Retinal and Eye Research
Author(s): Yogesan Kanagasingam , Alauddin Bhuiyan , Michael D. Abràmoff , R. Theodore Smith , Leonard Goldschmidt , Tien Y. Wong
Age-related macular degeneration (AMD) is the leading cause of vision loss in those over the age of 50 years in the developed countries. The number is expected to increase by ∼1.5 fold over the next ten years due to an increase in ageing population. One of the main measures of AMD severity is the analysis of drusen, pigmentary abnormalities, geographic atrophy (GA) and choroidal neovascularization (CNV) from imaging based on colour fundus photograph, optical coherence tomography (OCT) and other imaging modalities. Each of these imaging modalities has strengths and weaknesses for extracting individual AMD pathology and different imaging techniques are used in combination for capturing and/or quantification of different pathologies. Current dry AMD treatments cannot cure or reverse vision loss. However, the Age-Related Eye Disease Study (AREDS) showed that specific anti-oxidant vitamin supplementation reduces the risk of progression from intermediate stages (defined as the presence of either many medium-sized drusen or one or more large drusen) to late AMD which allows for preventative strategies in properly identified patients. Thus identification of people with early stage AMD is important to design and implement preventative strategies for late AMD, and determine their cost-effectiveness. A mass screening facility with teleophthalmology or telemedicine in combination with computer-aided analysis for large rural-based communities may identify more individuals suitable for early stage AMD prevention.In this review, we discuss different imaging modalities that are currently being considered or used for screening AMD. In addition, we look into various automated and semi-automated computer-aided grading systems and related retinal image analysis techniques for drusen, geographic atrophy and choroidal neovascularization detection and/or quantification for measurement of AMD severity using these imaging modalities. We also review the existing telemedicine studies which include diagnosis and management of AMD, and how automated disease grading could benefit telemedicine. As there is no treatment for dry AMD and only early intervention can prevent the late AMD, we emphasize mass screening through a telemedicine platform to enable early detection of AMD. We also provide a comparative study between the imaging modalities and identify potential study areas for further improvement and future research direction in automated AMD grading and screening.

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Grouped Retinae and Tapetal Cups in some Teleostian Fish: Occurrence, Structure, and Function

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Publication date: Available online 22 October 2013
Source:Progress in Retinal and Eye Research
Author(s): Mike Francke , Moritz Kreysing , Andreas Mack , Jacob Engelmann , Anett Karl , Felix Makarov , Jochen Guck , Mathias Kolle , Hartwig Wolburg , Roland Pusch , Gerhard von der Emde , Stefan Schuster , Hans-Joachim Wagner , Andreas Reichenbach
This article presents a summary and critical review of what is known about the ‘grouped retina’, a peculiar type of retinal organization in fish in which groups of photoreceptor cell inner and outer segments are arranged in spatially separated bundles. In most but not all cases, these bundles are embedded in light-reflective cups that are formed by the retinal pigment epithelial cells. These cups constitute a specialized type of retinal tapetum (i.e., they are biological ‘mirrors’ that cause eye shine) and appear to be optimized for different purposes in different fishes. Generally, the large retinal pigment epithelial cells are filled with light-reflecting photonic crystals that consist of guanine, uric acid, or pteridine depending on species, and which ensure that the incoming light becomes directed onto the photoreceptor outer segments. This structural specialization has so far been found in representatives of 17 fish families; of note, not all members of a given family must possess a grouped retina, and the 17 families are not all closely related to each other. In many cases (e.g., in Osteoglossomorpha and Aulopiformes) the inner surface of the cup is formed by three to four layers of strikingly regularly shaped and spaced guanine platelets acting as an optical multilayer. It has been estimated that this provides an up to 10fold increase of the incident light intensity. In certain deep-sea fish (many Aulopiformes and the Polymixidae), small groups of rods are embedded in such ‘parabolic mirrors’; most likely, this is an adaptation to the extremely low light intensities available in their habitat. Some of these fishes additionally possess similar tapetal cups that surround individual cones and, very likely, also serve as amplifiers of the weak incident light. In the Osteoglossomorpha, however, that inhabit the turbid water of rivers or streams, the structure of the cups is more complex and undergoes adaptation-dependent changes. At dim daylight, probably representing the usual environmental conditions of the fish, the outer segments of up to 30 cone cells are placed at the bottom of the cup where light intensity is maximized. Strikingly, however, a large number of rod receptor cells are positioned behind each mirroring cup. This peculiar arrangement (i) allows vision at deep red wavelenghts, (ii) matches the sensitivity of rod and cone photoreceptors, and (iii) facilitates the detection of low-contrast and color-mixed stimuli, within the dim, turbid habitat. Thus, for these fish the grouped retina appears to aid in reliable and quick detection of large, fast moving, biologically relevant stimuli such as predators. Overall, the grouped retina appears as a peculiar type of general retinal specialization in a variety of fish species that is adaptive in particular habitats such as turbid freshwater but also the deep-sea.The authors were prompted to write this review by working on the retina of Gnathonemus petersii; the data resulting from this work (Landsberg et al., 2008; Kreying et al., 2012) are included in the present review.

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The Vast Complexity of Primary Open Angle Glaucoma: Disease Genes, Risks, Molecular Mechanisms and Pathobiology

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Publication date: Available online 19 September 2013
Source:Progress in Retinal and Eye Research
Author(s): Sarah F. Janssen , Theo G.M.F. Gorgels , Wishal D. Ramdas , Caroline C.W. Klaver , Cornelia M. van Duijn , Nomdo M. Jansonius , Arthur A.B. Bergen
Primary open angle glaucoma (POAG) is a complex progressive optic nerve neuropathy triggered by both environmental and genetic risk factors. Several ocular tissues, including the ciliary body, trabecular meshwork and optic nerve head, and perhaps even brain tissues, are involved in a chain of pathological events leading to POAG.Genetic risk evidence for POAG came from family linkage-studies implicating a small number of disease genes (MYOC, OPTN, WDR36). Recent Genome Wide Association Studies (GWAS) identified a large number of new POAG loci and disease genes, such as CAV1, CDKN2B and GAS7. In the current study, we reviewed over 120 family and GWA studies. We selected in total 65 (candidate) POAG disease genes and proceeded to assess their function, mRNA expression in POAG relevant eye tissues and possible changes in disease state. We found that the proteins corresponding to these 65 (candidate) POAG disease genes take part in as few as four common functional molecular networks. Functions attributed to these 4 networks were developmental (dys)function, lipid metabolism, and inflammatory processes. For the 65 POAG disease genes, we reviewed the available (transgenic) mouse models of POAG, which may be useful for future functional studies. Finally, we showed that the 65 (candidate) POAG genes substantially increased the specificity and sensitivity of a discriminative POAG risk test. This suggests that personal risk assessment and personalized medicine for POAG are on the horizon. Taken together, the data presented are essential to comprehend the role of genetic variation in POAG, and may provide leads to understand the pathophysiology of POAG as well as other neurodegenerative disorders, such as Alzheimer’s disease.

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A molecular mechanism of optic nerve regeneration in fish: the retinoid signaling pathway

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Publication date: Available online 28 August 2013
Source:Progress in Retinal and Eye Research
Author(s): Satoru Kato , Toru Matsukawa , Yoshiki Koriyama , Kayo Sugitani , Kazuhiro Ogai
The fish optic nerve regeneration process takes more than 100 days after axotomy and comprises four stages: neurite sprouting (1–4 days), axonal elongation (5–30 days), synaptic refinement (35–80 days) and functional recovery (100–120 days). We screened genes specifically upregulated in each stage from axotomized fish retina. The mRNAs for heat shock protein 70 and insulin-like growth factor-1 rapidly increased in the retinal ganglion cells soon after axotomy and function as cell-survival factors. Purpurin mRNA rapidly and transiently increased in the photoreceptors and purpurin protein diffusely increased in all nuclear layers at 1–4 days after injury. The purpurin gene has an active retinol-binding site and a signal peptide. Purpurin with retinol functions as a sprouting factor for thin neurites. This neurite-sprouting effect was closely mimicked by retinoic acid and blocked by its inhibitor. We propose that purpurin works as a retinol transporter to supply retinoic acid to damaged RGCs which in turn activates target genes. We also searched for genes involved in the second stage of regeneration. The mRNA of retinoid-signaling molecules increased in retinal ganglion cells at 7–14 days after injury and tissue transglutaminase and neuronal nitric oxide synthase mRNAs, RA-target genes, increased in retinal ganglion cells at 10–30 days after injury. They function as factors for the outgrowth of thick, long neurites. Here we present a retinoid-signaling hypothesis to explain molecular events during the early stages of optic nerve regeneration in fish.

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