Journal articles on the topic 'Retina – Pathophysiology'
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1
Ola, Mohammad Shamsul. "Does Hyperglycemia Cause Oxidative Stress in the Diabetic Rat Retina?" Cells 10, no. 4 (April 2, 2021): 794. http://dx.doi.org/10.3390/cells10040794.
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Diabetes, being a metabolic disease dysregulates a large number of metabolites and factors. However, among those altered metabolites, hyperglycemia is considered as the major factor to cause an increase in oxidative stress that initiates the pathophysiology of retinal damage leading to diabetic retinopathy. Diabetes-induced oxidative stress in the diabetic retina and its damaging effects are well known, but still, the exact source and the mechanism of hyperglycemia-induced reactive oxygen species (ROS) generation especially through mitochondria remains uncertain. In this study, we analyzed precisely the generation of ROS and the antioxidant capacity of enzymes in a real-time situation under ex vivo and in vivo conditions in the control and streptozotocin-induced diabetic rat retinas. We also measured the rate of flux through the citric acid cycle by determining the oxidation of glucose to CO2 and glutamate, under ex vivo conditions in the control and diabetic retinas. Measurements of H2O2 clearance from the ex vivo control and diabetic retinas indicated that activities of mitochondrial antioxidant enzymes are intact in the diabetic retina. Short-term hyperglycemia seems to influence a decrease in ROS generation in the diabetic retina compared to controls, which is also correlated with a decreased oxidation rate of glucose in the diabetic retina. However, an increase in the formation of ROS was observed in the diabetic retinas compared to controls under in vivo conditions. Thus, our results suggest of diabetes/hyperglycemia-induced non-mitochondrial sources may serve as major sources of ROS generation in the diabetic retina as opposed to widely believed hyperglycemia-induced mitochondrial sources of excess ROS. Therefore, hyperglycemia per se may not cause an increase in oxidative stress, especially through mitochondria to damage the retina as in the case of diabetic retinopathy.
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Musayeva, Aytan, Johanna C. Unkrig, Mayagozel B. Zhutdieva, Caroline Manicam, Yue Ruan, Panagiotis Laspas, Panagiotis Chronopoulos, et al. "Betulinic Acid Protects from Ischemia-Reperfusion Injury in the Mouse Retina." Cells 10, no. 9 (September 16, 2021): 2440. http://dx.doi.org/10.3390/cells10092440.
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Ischemia/reperfusion (I/R) events are involved in the pathophysiology of numerous ocular diseases. The purpose of this study was to test the hypothesis that betulinic acid protects from I/R injury in the mouse retina. Ocular ischemia was induced in mice by increasing intraocular pressure (IOP) to 110 mm Hg for 45 min, while the fellow eye served as a control. One group of mice received betulinic acid (50 mg/kg/day p.o. once daily) and the other group received the vehicle solution only. Eight days after the I/R event, the animals were killed and the retinal wholemounts and optic nerve cross-sections were prepared and stained with cresyl blue or toluidine blue, respectively, to count cells in the ganglion cell layer (GCL) of the retina and axons in the optic nerve. Retinal arteriole responses were measured in isolated retinas by video microscopy. The levels of reactive oxygen species (ROS) were assessed in retinal cryosections and redox gene expression was determined in isolated retinas by quantitative PCR. I/R markedly reduced cell number in the GCL and axon number in the optic nerve of the vehicle-treated mice. In contrast, only a negligible reduction in cell and axon number was observed following I/R in the betulinic acid-treated mice. Endothelial function was markedly reduced and ROS levels were increased in retinal arterioles of vehicle-exposed eyes following I/R, whereas betulinic acid partially prevented vascular endothelial dysfunction and ROS formation. Moreover, betulinic acid boosted mRNA expression for the antioxidant enzymes SOD3 and HO-1 following I/R. Our data provide evidence that betulinic acid protects from I/R injury in the mouse retina. Improvement of vascular endothelial function and the reduction in ROS levels appear to contribute to the neuroprotective effect.
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Liu, Hanhan, and Verena Prokosch. "Energy Metabolism in the Inner Retina in Health and Glaucoma." International Journal of Molecular Sciences 22, no. 7 (April 1, 2021): 3689. http://dx.doi.org/10.3390/ijms22073689.
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Glaucoma, the leading cause of irreversible blindness, is a heterogeneous group of diseases characterized by progressive loss of retinal ganglion cells (RGCs) and their axons and leads to visual loss and blindness. Risk factors for the onset and progression of glaucoma include systemic and ocular factors such as older age, lower ocular perfusion pressure, and intraocular pressure (IOP). Early signs of RGC damage comprise impairment of axonal transport, downregulation of specific genes and metabolic changes. The brain is often cited to be the highest energy-demanding tissue of the human body. The retina is estimated to have equally high demands. RGCs are particularly active in metabolism and vulnerable to energy insufficiency. Understanding the energy metabolism of the inner retina, especially of the RGCs, is pivotal for understanding glaucoma’s pathophysiology. Here we review the key contributors to the high energy demands in the retina and the distinguishing features of energy metabolism of the inner retina. The major features of glaucoma include progressive cell death of retinal ganglions and optic nerve damage. Therefore, this review focuses on the energetic budget of the retinal ganglion cells, optic nerve and the relevant cells that surround them.
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Williams, J. Koudy, Gary L. Baumbach, Mark L. Armstrong, and Donald D. Heistad. "Hypothesis: Vasoconstriction Contributes to Amaurosis Fugax." Journal of Cerebral Blood Flow & Metabolism 9, no. 1 (February 1989): 111–16. http://dx.doi.org/10.1038/jcbfm.1989.15.
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Platelets play a critical role in the pathophysiology of amaurosis fugax. Emboli to retinal vessels apparently produce amaurosis but, in addition, we propose that augmented vasoconstrictor responses and vasospasm may contribute to amaurosis. In this study we tested the hypothesis that constrictor responses of retinal vessels to serotonin, which is released when platelets aggregate, are potentiated in experimental atherosclerosis. Blood flow to the retina was measured in normal and atherosclerotic cynomolgus monkeys. In normal monkeys, infusion of serotonin did not alter flow to the retina. In atherosclerotic monkeys, infusion of serotonin reduced retinal blood flow (in milliliters per minute per 100 g) from 66 ± 7 (mean ± SE) to 5 ±2. Infusion of serotonin in atherosclerotic monkeys abolished the retinal response to light. Thus, atherosclerosis greatly potentiates constrictor responses to serotonin in the retinal circulation and produces a profound but reversible impairment of retinal function. We propose that altered responses to vasoactive substances that are released by platelets may contribute to the pathogenesis of amaurosis fugax.
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Cabrera DeBuc, Delia, Gabor Mark Somfai, and Akos Koller. "Retinal microvascular network alterations: potential biomarkers of cerebrovascular and neural diseases." American Journal of Physiology-Heart and Circulatory Physiology 312, no. 2 (February 1, 2017): H201—H212. http://dx.doi.org/10.1152/ajpheart.00201.2016.
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Increasing evidence suggests that the conditions of retinal microvessels are indicators to a variety of cerebrovascular, neurodegenerative, psychiatric, and developmental diseases. Thus noninvasive visualization of the human retinal microcirculation offers an exceptional opportunity for the investigation of not only the retinal but also cerebral microvasculature. In this review, we show how the conditions of the retinal microvessels could be used to assess the conditions of brain microvessels because the microvascular network of the retina and brain share, in many aspects, standard features in development, morphology, function, and pathophysiology. Recent techniques and imaging modalities, such as optical coherence tomography (OCT), allow more precise visualization of various layers of the retina and its microcirculation, providing a “microscope” to brain microvessels. We also review the potential role of retinal microvessels in the risk identification of cerebrovascular and neurodegenerative diseases. The association between vision problems and cerebrovascular and neurodegenerative diseases, as well as the possible role of retinal microvascular imaging biomarkers in cerebrovascular and neurodegenerative screening, their potentials, and limitations, are also discussed.
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Maranhâo-Filho, PA, H. Martins-Ferreira, MB Vincent, LJC Ribeiro, and SAP Novis. "Sumatriptan Blocks Spreading Depression in Isolated Chick Retina." Cephalalgia 17, no. 8 (December 1997): 822–25. http://dx.doi.org/10.1046/j.1468-2982.1997.1708822.x.
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Spreading depression is a neurohumoral phenomenon that has been related to the pathophysiology of migraine. The recently introduced 5HTID agonist anti-migraine compound sumatriptan blocks neurogenic extravasation and induces cerebral vasoconstriction, but the actual mechanism of action against migraine remains obscure. Retinal spreading depression (RSD) velocity has been measured in isolated chick retinas in the presence of 0.05-2.00:nM sumatriptan. This drug reversibly blocks RSD in a concentration-dependent manner. Since the preparation is blood-vessel free, this effect must be related to the nervous tissue.
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Kelly, Melanie E. M., and Steven Barnes. "Physiology and Pathophysiology of Nitric Oxide in the Retina." Neuroscientist 3, no. 6 (November 1997): 357–60. http://dx.doi.org/10.1177/107385849700300607.
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Widomska, Justyna, John Paul SanGiovanni, and Witold K. Subczynski. "Why Is Zeaxanthin the Most Concentrated Xanthophyll in the Central Fovea?" Nutrients 12, no. 5 (May 7, 2020): 1333. http://dx.doi.org/10.3390/nu12051333.
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Diet-based xanthophylls (zeaxanthin and lutein) are conditionally essential polar carotenoids preferentially accreted in high concentrations (1 mM) to the central retina, where they have the capacity to impart unique physiologically significant biophysical biochemical properties implicated in cell function, rescue, and survival. Macular xanthophylls interact with membrane-bound proteins and lipids to absorb/attenuate light energy, modulate oxidative stress and redox balance, and influence signal transduction cascades implicated in the pathophysiology of age-related macular degeneration. There is exclusive transport, sequestration, and appreciable bioamplification of macular xanthophylls from the circulating carotenoid pool to the retina and within the retina to regions required for high-resolution sensory processing. The distribution of diet-based macular xanthophylls and the lutein metabolite meso-zeaxanthin varies considerably by retinal eccentricity. Zeaxanthin concentrations are 2.5-fold higher than lutein in the cone-dense central fovea. This is an ~20-fold increase in the molar ratio relative to eccentric retinal regions with biochemically detectable macular xanthophylls. In this review, we discuss how the differences in the specific properties of lutein and zeaxanthin could help explain the preferential accumulation of zeaxanthin in the most vulnerable region of the macula.
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Arjunan, Pachiappan, Radhika Swaminathan, Jessie Yuan, Mohamed Elashiry, Amany Tawfik, Mohamed Al-Shabrawey, Pamela M. Martin, Thangaraju Muthusamy, and Christopher W. Cutler. "Exacerbation of AMD Phenotype in Lasered CNV Murine Model by Dysbiotic Oral Pathogens." Antioxidants 10, no. 2 (February 18, 2021): 309. http://dx.doi.org/10.3390/antiox10020309.
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Emerging evidence underscores an association between age-related macular degeneration (AMD) and periodontal disease (PD), yet the biological basis of this linkage and the specific role of oral dysbiosis caused by PD in AMD pathophysiology remains unclear. Furthermore, a simple reproducible model that emulates characteristics of both AMD and PD has been lacking. Hence, we established a novel AMD+PD murine model to decipher the potential role of oral infection (ligature-enhanced) with the keystone periodontal pathogen Porphyromonas gingivalis, in the progression of neovasculogenesis in a laser-induced choroidal-neovascularization (Li-CNV) mouse retina. By a combination of fundus photography, optical coherence tomography, and fluorescein angiography, we documented inflammatory drusen-like lesions, reduced retinal thickness, and increased vascular leakage in AMD+PD mice retinae. H&E further confirmed a significant reduction of retinal thickness and subretinal drusen-like deposits. Immunofluorescence microscopy revealed significant induction of choroidal/retinal vasculogenesis in AMD+PD mice. qPCR identified increased expression of oxidative-stress, angiogenesis, pro-inflammatory mediators, whereas antioxidants and anti-inflammatory genes in AMD+PD mice retinae were notably decreased. Through qPCR, we detected Pg and its fimbrial 16s-RrNA gene expression in the AMD+PD mice retinae. To sum-up, this is the first in vivo study signifying a role of periodontal infection in augmentation of AMD phenotype, with the aid of a pioneering AMD+PD murine model established in our laboratory.
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Ola, Mohammad Shamsul, Dalia Al-Dosari, and Abdullah S. Alhomida. "Role of Oxidative Stress in Diabetic Retinopathy and the Beneficial Effects of Flavonoids." Current Pharmaceutical Design 24, no. 19 (September 24, 2018): 2180–87. http://dx.doi.org/10.2174/1381612824666180515151043.
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Diabetic Retinopathy (DR) is one of the leading causes of decreased vision and blindness in developed countries. Diabetes-induced metabolic disorder is believed to increase oxidative stress in the retina. This results in deleterious change through dysregulation of cellular physiology that damages both neuronal and vascular cells. In this review, we first highlight the evidence of potential metabolic sources and pathways which increase oxidative stress that contribute to retinal pathology in diabetes. As oxidative stress is a central factor in the pathophysiology of DR, antioxidants therapy would be beneficial towards preventing the retinal damage. A number of experimental studies by our group and others showed that dietary flavonoids cause reduction in increased oxidative stress and other beneficial effects in diabetic retina. We then discuss the beneficial effects of the six major flavonoid families, such as flavanones, flavanols, flavonols, isoflavones, flavones and anthocyanins, which have been studied to improve retinal damage. Flavanoids, being known antioxidants, may ameliorate the retinal degenerative factors including apoptosis, inflammation and neurodegeneration in diabetes. Therefore, intake of potential dietary flavonoids would limit oxidative stress and thereby prevent the retinal damage, and subsequently the development of DR.
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Jiang, Xiaotian, Rabab Rashwan, Valentina Voigt, Jeanne Nerbonne, David M. Hunt, and Livia S. Carvalho. "Molecular, Cellular and Functional Changes in the Retinas of Young Adult Mice Lacking the Voltage-Gated K+ Channel Subunits Kv8.2 and K2.1." International Journal of Molecular Sciences 22, no. 9 (May 5, 2021): 4877. http://dx.doi.org/10.3390/ijms22094877.
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Cone Dystrophy with Supernormal Rod Response (CDSRR) is a rare autosomal recessive disorder leading to severe visual impairment in humans, but little is known about its unique pathophysiology. We have previously shown that CDSRR is caused by mutations in the KCNV2 (Potassium Voltage-Gated Channel Modifier Subfamily V Member 2) gene encoding the Kv8.2 subunit, a modulatory subunit of voltage-gated potassium (Kv) channels. In a recent study, we validated a novel mouse model of Kv8.2 deficiency at a late stage of the disease and showed that it replicates the human electroretinogram (ERG) phenotype. In this current study, we focused our investigation on young adult retinas to look for early markers of disease and evaluate their effect on retinal morphology, electrophysiology and immune response in both the Kv8.2 knockout (KO) mouse and in the Kv2.1 KO mouse, the obligate partner of Kv8.2 in functional retinal Kv channels. By evaluating the severity of retinal dystrophy in these KO models, we demonstrated that retinas of Kv KO mice have significantly higher apoptotic cells, a thinner outer nuclear cell layer and increased activated microglia cells in the subretinal space. Our results indicate that in the murine retina, the loss of Kv8.2 subunits contributes to early cellular and physiological changes leading to retinal dysfunction. These results could have potential implications in the early management of CDSRR despite its relatively nonprogressive nature in humans.
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Low, Shermaine W. Y., Thomas B. Connor, Iris S. Kassem, Deborah M. Costakos, and Shyam S. Chaurasia. "Small Leucine-Rich Proteoglycans (SLRPs) in the Retina." International Journal of Molecular Sciences 22, no. 14 (July 7, 2021): 7293. http://dx.doi.org/10.3390/ijms22147293.
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Retinal diseases such as age-related macular degeneration (AMD), retinopathy of prematurity (ROP), and diabetic retinopathy (DR) are the leading causes of visual impairment worldwide. There is a critical need to understand the structural and cellular components that play a vital role in the pathophysiology of retinal diseases. One potential component is the family of structural proteins called small leucine-rich proteoglycans (SLRPs). SLRPs are crucial in many fundamental biological processes involved in the maintenance of retinal homeostasis. They are present within the extracellular matrix (ECM) of connective and vascular tissues and contribute to tissue organization and modulation of cell growth. They play a vital role in cell–matrix interactions in many upstream signaling pathways involved in fibrillogenesis and angiogenesis. In this comprehensive review, we describe the expression patterns and function of SLRPs in the retina, including Biglycan and Decorin from class I; Fibromodulin, Lumican, and a Proline/arginine-rich end leucine-rich repeat protein (PRELP) from class II; Opticin and Osteoglycin/Mimecan from class III; and Chondroadherin (CHAD), Tsukushi and Nyctalopin from class IV.
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Wang, Liang, and Xiaobo Mao. "Role of Retinal Amyloid-β in Neurodegenerative Diseases: Overlapping Mechanisms and Emerging Clinical Applications." International Journal of Molecular Sciences 22, no. 5 (February 26, 2021): 2360. http://dx.doi.org/10.3390/ijms22052360.
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Amyloid-β (Aβ) accumulations have been identified in the retina for neurodegeneration-associated disorders like Alzheimer’s disease (AD), glaucoma, and age-related macular degeneration (AMD). Elevated retinal Aβ levels were associated with progressive retinal neurodegeneration, elevated cerebral Aβ accumulation, and increased disease severity with a decline in cognition and vision. Retinal Aβ accumulation and its pathological effects were demonstrated to occur prior to irreversible neurodegeneration, which highlights its potential in early disease detection and intervention. Using the retina as a model of the brain, recent studies have focused on characterizing retinal Aβ to determine its applicability for population-based screening of AD, which warrants a further understanding of how Aβ manifests between these disorders. While current treatments directly targeting Aβ accumulations have had limited results, continued exploration of Aβ-associated pathological pathways may yield new therapeutic targets for preserving cognition and vision. Here, we provide a review on the role of retinal Aβ manifestations in these distinct neurodegeneration-associated disorders. We also discuss the recent applications of retinal Aβ for AD screening and current clinical trial outcomes for Aβ-associated treatment approaches. Lastly, we explore potential future therapeutic targets based on overlapping mechanisms of pathophysiology in AD, glaucoma, and AMD.
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Lenin, Raji, Samuel M. Thomas, and Rajashekhar Gangaraju. "Endothelial Activation and Oxidative Stress in Neurovascular Defects of the Retina." Current Pharmaceutical Design 24, no. 40 (March 15, 2019): 4742–54. http://dx.doi.org/10.2174/1381612825666190115122622.
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Background: The eye is considered as a window of the disease, and a better understanding of neurodegenerative changes in the eye may help diagnose and manage neurodegenerative diseases including the diseases of brain, heart, kidney and liver. In the eye, the blood retinal barrier (BRB] is maintained by a combination of endothelial cells, pericytes, and glia. This BRB integrity is fundamental to the physiology of retinal cellular function and accurate vision. The role of endothelial dysfunction as a consequence of endothelial activation in the initiation and prolongation of neurovascular diseases of the retina is emerging. Methods: The observations made in this article are a result of our research over the years in the subject matter and also based on a literature search using PubMed with keywords including but not limited to endothelial, permeability, oxidative stress, ROS, TNF-α, retina, injury, and neurodegeneration. Several studies were identified that fulfilled the inclusion criteria. Overall, published studies support an association between endothelial activation, inflammation and oxidative stress in retinal diseases. Although the selection of specific endothelial activation biomarkers in the retina is less clear, there is an increased association between inflammation in the severity of diabetic retinopathy. Studies in other clinically relevant studies demonstrated a strong association of endothelial activation to alterations in mitochondrial respiratory chain complexes, pericyte integrity, microglial activation, neutrophil extracellular traps and elevated plasma concentrations of TNF-α. Conclusion: The compromise in BRB as a consequence of the neurovascular unit in the retinal tissue has gained a lot of attention and studies addressing these should result in a better understanding of the pathophysiology of retinal diseases. Although there are no specific retinal markers of endothelial activation and inflammation, future studies using specific models that display endothelial activation, inflammation and oxidative stress likely yield better understanding on the cause or effect relationship of endothelial activation in retinal diseases.
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Theriot, Corey A., Patricia Chevez-Barrios, Thomas Loughlin, Afshin Beheshti, Nathaniel D. Mercaldo, and Susana B. Zanello. "The Impact of Hindlimb Suspension on the Rat Eye: A Molecular and Histological Analysis of the Retina." Gravitational and Space Research 9, no. 1 (January 1, 2021): 86–103. http://dx.doi.org/10.2478/gsr-2021-0007.
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Abstract The Spaceflight Associated Neuro-ocular Syndrome (SANS) is hypothesized to be associated with microgravity-induced fluid shifts. There is a need for an animal model of SANS to investigate its pathophysiology. We used the rat hindlimb suspension (HS) model to examine the relationship between the assumed cephalad fluid shifts, intraocular (IOP) pressure and the molecular responses in the retina to the prolonged change in body posture. Long evans rats were subjected to HS up to 90 days. Animals completing 90-day suspension were further studied for recovery periods up to 90 additional days in normal posture. With respect to baseline, the average IOP increase in HS animals and the rate of change varied by cohort. Transcriptomics evidence supported a response to HS in the rat retina that was affected by age and sex. Several molecular networks suggested stress imposed by HS affected the retinal vasculature, oxidative and inflammation status, pigmented epithelium and glia. The CSNK1A1-TP53 pathway was implicated in the response in all cohorts. Sex-specific genes were involved in cytoprotection and may explain sex-dependent vulnerabilities to certain eye diseases. These results support the hypothesis that changes in the biology of the retina subjected to simulated microgravity involve both the neural and vascular retina.
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Guziewicz, Karina E., Artur V. Cideciyan, William A. Beltran, András M. Komáromy, Valerie L. Dufour, Malgorzata Swider, Simone Iwabe, et al. "BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure." Proceedings of the National Academy of Sciences 115, no. 12 (March 5, 2018): E2839—E2848. http://dx.doi.org/10.1073/pnas.1720662115.
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Mutations in the BEST1 gene cause detachment of the retina and degeneration of photoreceptor (PR) cells due to a primary channelopathy in the neighboring retinal pigment epithelium (RPE) cells. The pathophysiology of the interaction between RPE and PR cells preceding the formation of retinal detachment remains not well-understood. Our studies of molecular pathology in the canine BEST1 disease model revealed retina-wide abnormalities at the RPE-PR interface associated with defects in the RPE microvillar ensheathment and a cone PR-associated insoluble interphotoreceptor matrix. In vivo imaging demonstrated a retina-wide RPE–PR microdetachment, which contracted with dark adaptation and expanded upon exposure to a moderate intensity of light. Subretinal BEST1 gene augmentation therapy using adeno-associated virus 2 reversed not only clinically detectable subretinal lesions but also the diffuse microdetachments. Immunohistochemical analyses showed correction of the structural alterations at the RPE–PR interface in areas with BEST1 transgene expression. Successful treatment effects were demonstrated in three different canine BEST1 genotypes with vector titers in the 0.1-to-5E11 vector genomes per mL range. Patients with biallelic BEST1 mutations exhibited large regions of retinal lamination defects, severe PR sensitivity loss, and slowing of the retinoid cycle. Human translation of canine BEST1 gene therapy success in reversal of macro- and microdetachments through restoration of cytoarchitecture at the RPE–PR interface has promise to result in improved visual function and prevent disease progression in patients affected with bestrophinopathies.
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Cheung, Carol Y., Vincent Mok, Paul J. Foster, Emanuele Trucco, Christopher Chen, and Tien Yin Wong. "Retinal imaging in Alzheimer’s disease." Journal of Neurology, Neurosurgery & Psychiatry 92, no. 9 (June 9, 2021): 983–94. http://dx.doi.org/10.1136/jnnp-2020-325347.
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Identifying biomarkers of Alzheimer’s disease (AD) will accelerate the understanding of its pathophysiology, facilitate screening and risk stratification, and aid in developing new therapies. Developments in non-invasive retinal imaging technologies, including optical coherence tomography (OCT), OCT angiography and digital retinal photography, have provided a means to study neuronal and vascular structures in the retina in people with AD. Both qualitative and quantitative measurements from these retinal imaging technologies (eg, thinning of peripapillary retinal nerve fibre layer, inner retinal layer, and choroidal layer, reduced capillary density, abnormal vasodilatory response) have been shown to be associated with cognitive function impairment and risk of AD. The development of computer algorithms for respective retinal imaging methods has further enhanced the potential of retinal imaging as a viable tool for rapid, early detection and screening of AD. In this review, we present an update of current retinal imaging techniques and their potential applications in AD research. We also discuss the newer retinal imaging techniques and future directions in this expanding field.
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Saab, Sarah, Julie Mazzocco, Catherine P. Creuzot-Garcher, Alain M. Bron, Lionel Bretillon, and Niyazi Acar. "Plasmalogens in the retina: From occurrence in retinal cell membranes to potential involvement in pathophysiology of retinal diseases." Biochimie 107 (December 2014): 58–65. http://dx.doi.org/10.1016/j.biochi.2014.07.023.
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Nguyen, Van, and Yannis Paulus. "Photoacoustic Ophthalmoscopy: Principle, Application, and Future Directions." Journal of Imaging 4, no. 12 (December 12, 2018): 149. http://dx.doi.org/10.3390/jimaging4120149.
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Photoacoustic ophthalmoscopy (PAOM) is a novel, hybrid, non-ionizing, and non-invasive imaging technology that has been used to assess the retina. PAOM can provide both anatomic and functional retinal characterizations with high resolution, high sensitivity, high contrast, and a high depth of penetration. Thus, ocular diseases can be precisely detected and visualized at earlier stages, resulting in an improved understanding of pathophysiology, improved management, and the improved monitoring of retinal treatment to prevent vision loss. To better visualize ocular components such as retinal vessels, choroidal vessels, choroidal neovascularization, retinal neovascularization, and the retinal pigment epithelium, an advanced multimodal ocular imaging platform has been developed by a combination of PAOM with other optical imaging techniques such as optical coherence tomography (OCT), scanning laser ophthalmoscopy (SLO), and fluorescence microscopy. The multimodal images can be acquired from a single imaging system and co-registered on the same image plane, enabling an improved evaluation of disease. In this review, the potential application of photoacoustic ophthalmoscopy in both research and clinical diagnosis are discussed as a medical screening technique for the visualization of various ocular diseases. The basic principle and requirements of photoacoustic ocular imaging are introduced. Then, various photoacoustic microscopy imaging systems of the retina in animals are presented. Finally, the future development of PAOM and multimodal imaging is discussed.
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Liu, Yang, Junzo Kinoshita, Elena Ivanova, Duo Sun, Hong Li, Tara Liao, Jingtai Cao, et al. "Mouse models of X-linked juvenile retinoschisis have an early onset phenotype, the severity of which varies with genotype." Human Molecular Genetics 28, no. 18 (June 7, 2019): 3072–90. http://dx.doi.org/10.1093/hmg/ddz122.
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Abstract X-linked juvenile retinoschisis (XLRS) is an early-onset inherited condition that affects primarily males and is characterized by cystic lesions of the inner retina, decreased visual acuity and contrast sensitivity and a selective reduction of the electroretinogram (ERG) b-wave. Although XLRS is genetically heterogeneous, all mouse models developed to date involve engineered or spontaneous null mutations. In the present study, we have studied three new Rs1 mutant mouse models: (1) a knockout with inserted lacZ reporter gene; (2) a C59S point mutant substitution and (3) an R141C point mutant substitution. Mice were studied from postnatal day (P15) to 28 weeks by spectral domain optical coherence tomography and ERG. Retinas of P21–22 mice were examined using biochemistry, single cell electrophysiology of retinal ganglion cells (RGCs) and by immunohistochemistry. Each model developed intraretinal schisis and reductions in the ERG that were greater for the b-wave than the a-wave. The phenotype of the C59S mutant appeared less severe than the other mutants by ERG at adult ages. RGC electrophysiology demonstrated elevated activity in the absence of a visual stimulus and reduced signal-to-noise ratios in response to light stimuli. Immunohistochemical analysis documented early abnormalities in all cells of the outer retina. Together, these results provide significant insight into the early events of XLRS pathophysiology, from phenotype differences between disease-causing variants to common mechanistic events that may play critical roles in disease presentation and progression.
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Gnana-Prakasam, Jaya P., Ming Zhang, Pamela M. Martin, Sally S. Atherton, Sylvia B. Smith, and Vadivel Ganapathy. "Expression of the iron-regulatory protein haemojuvelin in retina and its regulation during cytomegalovirus infection." Biochemical Journal 419, no. 3 (April 14, 2009): 533–43. http://dx.doi.org/10.1042/bj20082240.
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Haemochromatosis is a genetic disorder of iron overload resulting from loss-of-function mutations in genes coding for the iron-regulatory proteins HFE [HLA-like protein involved in iron (Fe) homoeostasis], transferrin receptor 2, ferroportin, hepcidin and HJV (haemojuvelin). Expression of the first four genes coding for these proteins in retina has been established. Here we report on the expression of HJV. Since infection of retina with CMV (cytomegalovirus) causes blindness, we also investigated the expression of HJV and other iron-regulatory proteins in retina during CMV infection. HJV (HJV gene) mRNA was expressed in RPE (retinal pigment epithelium)/eyecup and neural retina in mouse. In situ hybridization and immunohistochemistry confirmed the presence of HJV mRNA and protein in RPE, outer and inner nuclear layers, and ganglion cell layer. Immunocytochemistry with cell lines and primary cell cultures showed HJV expression in RPE and Müller cells. In RPE, the expression was restricted to apical membrane. Infection of primary cultures of mouse RPE with CMV increased HJV mRNA and protein levels. Under similar conditions, HFE (HFE gene) mRNA levels were not altered, but HFE protein was decreased. Hepcidin expression was, however, not altered. These findings were demonstrable in vivo with CMV-infected mouse retina. The CMV-induced up-regulation of HJV in RPE was independent of changes in HFE because the phenomenon was also seen in HFE-null RPE cells. CMV-infected primary RPE cells showed evidence of iron accumulation and oxidative stress, as indicated by increased levels of ferritin and hydroxynonenal. The observed changes in HJV expression and iron status during CMV infection in retina may have significance in the pathophysiology of CMV retinitis
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Hwang, Inae, and Marta Ugarte. "Morning glory disc anomaly-associated maculopathy: multimodal imaging." BMJ Case Reports 14, no. 1 (January 2021): e237462. http://dx.doi.org/10.1136/bcr-2020-237462.
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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.
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Zadeh, Jenia Kouchek, Andreas Garcia-Bardon, Erik Kristoffer Hartmann, Norbert Pfeiffer, Wael Omran, Marion Ludwig, Andreas Patzak, Ning Xia, Huige Li, and Adrian Gericke. "Short-Time Ocular Ischemia Induces Vascular Endothelial Dysfunction and Ganglion Cell Loss in the Pig Retina." International Journal of Molecular Sciences 20, no. 19 (September 21, 2019): 4685. http://dx.doi.org/10.3390/ijms20194685.
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Visual impairment and blindness are often caused by retinal ischemia-reperfusion (I/R) injury. We aimed to characterize a new model of I/R in pigs, in which the intraocular pathways were not manipulated by invasive methods on the ocular system. After 12 min of ischemia followed by 20 h of reperfusion, reactivity of retinal arterioles was measured in vitro by video microscopy. Dihydroethidium (DHE) staining, qPCR, immunohistochemistry, quantification of neurons in the retinal ganglion cell layer, and histological examination was performed. Retinal arterioles of I/R-treated pigs displayed marked attenuation in response to the endothelium-dependent vasodilator, bradykinin, compared to sham-treated pigs. DHE staining intensity and messenger RNA levels for HIF-1α, VEGF-A, NOX2, and iNOS were elevated in retinal arterioles following I/R. Immunoreactivity to HIF-1α, VEGF-A, NOX2, and iNOS was enhanced in retinal arteriole endothelium after I/R. Moreover, I/R evoked a substantial decrease in Brn3a-positive retinal ganglion cells and noticeable retinal thickening. In conclusion, the results of the present study demonstrate that short-time ocular ischemia impairs endothelial function and integrity of retinal blood vessels and induces structural changes in the retina. HIF-1α, VEGF-A, iNOS, and NOX2-derived reactive oxygen species appear to be involved in the pathophysiology.
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Wiley, Luke A., Emily E. Kaalberg, Jessica A. Penticoff, Robert F. Mullins, Edwin M. Stone, and Budd A. Tucker. "Expression of the retina-specific flippase, ABCA4, in epidermal keratinocytes." F1000Research 5 (February 18, 2016): 193. http://dx.doi.org/10.12688/f1000research.8089.1.
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ATP-binding cassette, sub-family A, member 4 (ABCA4) is a photoreceptor transmembrane protein that is responsible for flipping N-retinylidene-phosphatidylethanolamine, a key intermediate in the visual cycle, from the lumen to the cytoplasmic leaflet of photoreceptor outer segment disks. Mutations in ABCA4 cause a build-up of toxic retinoids resulting in a variety of retinal degenerative phenotypes, including Stargardt disease, cone-rod dystrophy and retinitis pigmentosa. Since many of the ABCA4 variants are rare and non-exomic, their pathogenicity is often difficult to demonstrate statistically. Given that the neural retina is inaccessible to molecular analysis in living patients, we use patient-specific induced pluripotent stem cell (iPSC)-derived retinal neurons to identify and model disease-causing mutations. Here we demonstrate that a truncated version of the retinal-specific transmembrane enzyme ABCA4 is expressed in epidermal keratinocytes and is required for cellular proliferation and viability at late passage. This finding is of great importance for labs that wish to investigate the pathophysiology of novel ABCA4-variants, without having to incur the added expense and scientific expertise associated with iPSC generation, culture and differentiation. Likewise, this finding is also important for those intending to generate iPSCs from patient specific keratinocytes, which can prove difficult when ABCA4 mutations are present.
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Qian, Haohua, and Harris Ripps. "Neurovascular Interaction and the Pathophysiology of Diabetic Retinopathy." Experimental Diabetes Research 2011 (2011): 1–11. http://dx.doi.org/10.1155/2011/693426.
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Diabetic retinopathy (DR) is the most severe of the several ocular complications of diabetes, and in the United States it is the leading cause of blindness among adults 20 to 74 years of age. Despite recent advances in our understanding of the pathogenesis of DR, there is a pressing need to develop novel therapeutic treatments that are both safe and efficacious. In the present paper, we identify a key mechanism involved in the development of the disease, namely, the interaction between neuronal and vascular activities. Numerous pathological conditions in the CNS have been linked to abnormalities in the relationship between these systems. We suggest that a similar situation arises in the diabetic retina, and we propose a logical strategy aimed at therapeutic intervention.
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Konenkov, Vladimir Iosifovich, Vadim Valerievich Klimontov, Svetlana Viktorovna Michurina, M. A. Prudnikova, and I. Ju Ishenko. "Melatonin and diabetes: from pathophysiology to the treatment perspectives." Diabetes mellitus 16, no. 2 (June 15, 2013): 11–16. http://dx.doi.org/10.14341/2072-0351-3751.
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Pineal hormone melatonin synchronizes insulin secretion and glucose homeostasis with solar periods. Misalliance between melatonin-mediated circadian rhythms and insulin secretion characterizes diabetes mellitus type 1 (T1DM) and type 2 (T2DM). Insulin deficiency in T1DM is accompanied by increased melatonin production. Conversely, T2DM is characterized by diminished melatonin secretion. In genome-wide association studies the variants of melatonin receptor MT2 gene (rs1387153 and rs10830963) were associated with fasting glucose, beta-cell function and T2DM. In experimental models of diabetes melatonin enhanced beta-cell proliferation and neogenesis, improved insulin resistance and alleviated oxidative stress in retina and kidneys. However, further investigation is required to assess the therapeutic value of melatonin in diabetic patients.
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Lobanova, Marina M., and Elena L. Golikova. "A clinical case of acute (middle) macular neuroretinopathy." Ophthalmology journal 9, no. 3 (September 15, 2016): 61–67. http://dx.doi.org/10.17816/ov9361-67.
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This study presents a case of acute (middle) macular neuroretinopathy. Acute onset of this disease corresponds with the appearance of paracentral scotomas and reddish brown lesions on the retina. The pathophysiology is unclear, but recent research suggests a microvascular etiology. Fluorescein and indocyanine green angiography usually reveal normal features. No specific treatment exists.
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Ewering, Carina, Nazmiye Haşal, Florian Alten, Christoph R. Clemens, Nicole Eter, Timm Oberwahrenbrock, Ella M. Kadas, et al. "Temporal retinal nerve fibre layer thinning in cluster headache patients detected by optical coherence tomography." Cephalalgia 35, no. 11 (February 5, 2015): 946–58. http://dx.doi.org/10.1177/0333102414560632.
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Background The exact pathophysiology of cluster headache (CH) is still not fully clarified. Various studies confirmed changes in ocular blood flow during CH attacks. Furthermore, vasoconstricting medication influences blood supply to the eye. We investigated the retina of CH patients for structural retinal alterations with optical coherence tomography (OCT), and how these changes correlate to headache characteristics, oxygen use and impaired visual function. Methods Spectral domain OCT of 107 CH patients – 67 episodic, 35 chronic, five former chronic sufferers – were compared to OCT from 65 healthy individuals. Visual function tests with Sloan charts and a substantial ophthalmologic examination were engaged. Results Reduction of temporal and temporal-inferior retinal nerve fibre layer (RNFL) thickness was found in both eyes for CH patients with a predominant thinning on the headache side in the temporal-inferior area. Chronic CH patients revealed thinning of the macula compared to episodic suffers and healthy individuals. Bilateral thinning of temporal RNFL was also found in users of 100% oxygen compared to non-users and healthy controls. Visual function did not differ between patients and controls. Discussion Our OCT findings show a systemic effect causing temporal retinal thinning in both eyes of CH patients possibly due to attack-inherent or medication-induced frequent bilateral vessel diameter changes. The temporal retina with its thinly myelinated parvo-cellular axons and its more susceptible vessels for the vasoconstricting influence of oxygen inhalation seems to be predisposed for tissue damage-causing processes related to CH.
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Mélik Parsadaniantz, Stéphane, Annabelle Réaux-le Goazigo, Anaïs Sapienza, Christophe Habas, and Christophe Baudouin. "Glaucoma: A Degenerative Optic Neuropathy Related to Neuroinflammation?" Cells 9, no. 3 (February 25, 2020): 535. http://dx.doi.org/10.3390/cells9030535.
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Glaucoma is one of the leading causes of irreversible blindness in the world and remains a major public health problem. To date, incomplete knowledge of this disease’s pathophysiology has resulted in current therapies (pharmaceutical or surgical) unfortunately having only a slowing effect on disease progression. Recent research suggests that glaucomatous optic neuropathy is a disease that shares common neuroinflammatory mechanisms with “classical” neurodegenerative pathologies. In addition to the death of retinal ganglion cells (RGCs), neuroinflammation appears to be a key element in the progression and spread of this disease. Indeed, early reactivity of glial cells has been observed in the retina, but also in the central visual pathways of glaucoma patients and in preclinical models of ocular hypertension. Moreover, neuronal lesions are not limited to retinal structure, but also occur in central visual pathways. This review summarizes and puts into perspective the experimental and clinical data obtained to date to highlight the need to develop neuroprotective and immunomodulatory therapies to prevent blindness in glaucoma patients.
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Tisi, Annamaria, Marco Feligioni, Maurizio Passacantando, Marco Ciancaglini, and Rita Maccarone. "The Impact of Oxidative Stress on Blood-Retinal Barrier Physiology in Age-Related Macular Degeneration." Cells 10, no. 1 (January 4, 2021): 64. http://dx.doi.org/10.3390/cells10010064.
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The blood retinal barrier (BRB) is a fundamental eye component, whose function is to select the flow of molecules from the blood to the retina and vice-versa, and its integrity allows the maintenance of a finely regulated microenvironment. The outer BRB, composed by the choriocapillaris, the Bruch’s membrane, and the retinal pigment epithelium, undergoes structural and functional changes in age-related macular degeneration (AMD), the leading cause of blindness worldwide. BRB alterations lead to retinal dysfunction and neurodegeneration. Several risk factors have been associated with AMD onset in the past decades and oxidative stress is widely recognized as a key factor, even if the exact AMD pathophysiology has not been exactly elucidated yet. The present review describes the BRB physiology, the BRB changes occurring in AMD, the role of oxidative stress in AMD with a focus on the outer BRB structures. Moreover, we propose the use of cerium oxide nanoparticles as a new powerful anti-oxidant agent to combat AMD, based on the relevant existing data which demonstrated their beneficial effects in protecting the outer BRB in animal models of AMD.
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Birkhoff, W. A. J., L. van Manen, J. Dijkstra, M. L. De Kam, J. C. van Meurs, and A. F. Cohen. "Retinal oximetry and fractal analysis of capillary maps in sickle cell disease patients and matched healthy volunteers." Graefe's Archive for Clinical and Experimental Ophthalmology 258, no. 1 (September 16, 2019): 9–15. http://dx.doi.org/10.1007/s00417-019-04458-0.
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Abstract Purpose Fractal analysis can be used to quantitatively analyze the retinal microvasculature and might be a suitable method to quantify retinal capillary changes in sickle cell disease (SCD) patients. Retinal oximetry measurements might function as a proxy for the pathophysiology of cerebrovascular diseases. Moreover, hypoxia has an important role in the pathophysiology of diabetic and other retinopathies. However, little is known about the oximetry around the macula in SCD patients. With this study, we explored the feasibility to perform these quantified measurements in SCD patients. Methods Retinal microvascular and oximetry measurements were performed in eight SCD patients and eight healthy matched controls. Oximetry pictures and non-invasive capillary perfusion maps (nCPM) were obtained by the retinal function imager. Measurements were conducted twice on two different study days. Measured variables included monofractal dimension (Dbox), relative saturation, deoxygenated hemoglobin (deoxyHb), and oxygenated hemoglobin (oxyHb) concentration. Results No statistically significant differences in vessel density were found in the different annular zones (large vessels, p = 0.66; small vessels, p = 0.66) and anatomical quadrants (large vessels, p = 0.74; small vessels, p = 0.72). Furthermore, no significant between-group differences were found in the other different anatomical quadrants and annular zones around the fovea for relative saturation levels and deoxygenated Hb. However, the oxyHb levels were significantly lower in SCD patients, compared with those in matched controls in the temporal quadrants (p = 0.04; p = 0.02) and the superior nasal quadrant (p = 0.05). Conclusions Our study demonstrated the feasibility of multispectral imaging to measure retinal changes in oxygenation in both SCD patients and matched volunteers. The results suggest that in SCD patients before any structural microvascular changes in the central retina are present, functional abnormalities can be observed with abnormal oximetry measurements.
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Wang, Heuy-Ching Hetty, Jae-Hyek Choi, Whitney A. Greene, Mark L. Plamper, Hector E. Cortez, Mikulas Chavko, Yansong Li, Jurandir J. Dalle Lucca, and Anthony J. Johnson. "Pathophysiology of Blast-Induced Ocular Trauma With Apoptosis in the Retina and Optic Nerve." Military Medicine 179, no. 8S (August 2014): 34–40. http://dx.doi.org/10.7205/milmed-d-13-00504.
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Surve, Abhidnya, Akshaya Balaji, Shorya Vardhan Azad, Vinod Kumar, Rajpal Vohra, and Pradeep Venkatesh. "Role of red free imaging, retinal reflectance and fundus autofluorescence in Bietti crystalline dystrophy: case report." Therapeutic Advances in Rare Disease 1 (January 2020): 263300402095801. http://dx.doi.org/10.1177/2633004020958013.
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Bietti crystalline dystrophy (BCD), a rare autosomal recessive hereditary disorder, is identified by its clinical features. It is characterised by crystalline deposits and hence called crystalline retinopathy. The retinopathy progresses with age, showing a decrease in the number of crystalline deposits and increase in the area of chorioretinal degeneration, which spreads in a centrifugal pattern. Thus, BCD can be confused with other disorders with crystalline-like deposits and chorioretinal degenerations. The red-free and near-infrared reflectance allows prominent visualisation of crystalline deposits that may be missed. The non-inferiority of red-free imaging and its wider availability could allow its use as a screening tool. The enhanced depth imaging optical coherence tomography shows crystalline deposits throughout the retina and outer retinal tubulation. Thus, multimodality imaging can act as an adjunct in diagnosis, monitoring and follow up in these cases, acting not only as a teaching tool but also giving an insight into the underlying pathophysiology of the disorder. Plain language summary Use of imaging in diagnosis of Bietti crystalline dystrophy Bietti crystalline dystrophy is a rare familial disorder but is not shown in all family members and may skip generations, as it has an autosomal recessive pattern of inheritance. It shows refractile yellow-white crystalline deposits and degenerative changes in the retina. These crystalline deposits disappear with age while degenerative changes increase and spread from centre to the periphery. This may cause difficulty in early detection, and confusion with similar degenerative diseases of the retina. The use of various imaging modalities can help in diagnosis and follow up of these cases. These modalities also provide understanding of the basic disease process.
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Canning, Paul, Josephine V. Glenn, Daniel K. Hsu, Fu-Tong Liu, Tom A. Gardiner, and Alan W. Stitt. "Inhibition of Advanced Glycation and Absence of Galectin-3 Prevent Blood-Retinal Barrier Dysfunction during Short-Term Diabetes." Experimental Diabetes Research 2007 (2007): 1–10. http://dx.doi.org/10.1155/2007/51837.
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Breakdown of the inner blood-retinal barrier (iBRB) occurs early in diabetes and is central to the development of sight-threatening diabetic macular edema (DME) as retinopathy progresses. In the current study, we examined how advanced glycation end products (AGEs) forming early in diabetes could modulate vasopermeability factor expression in the diabetic retina and alter inter-endothelial cell tight junction (TJ) integrity leading to iBRB dysfunction. We also investigated the potential for an AGE inhibitor to prevent this acute pathology and examined a role of the AGE-binding protein galectin-3 (Gal-3) in AGE-mediated cell retinal pathophysiology. Diabetes was induced in C57/BL6 wild-type (WT) mice and in Gal-3−/−transgenic mice. Blood glucose was monitored and AGE levels were quantified by ELISA and immunohistochemistry. The diabetic groups were subdivided, and one group was treated with the AGE-inhibitor pyridoxamine (PM) while separate groups of WT and Gal-3−/−mice were maintained as nondiabetic controls. iBRB integrity was assessed by Evans blue assay alongside visualisation of TJ protein complexes via occludin-1 immunolocalization in retinal flat mounts. Retinal expression levels of the vasopermeability factor VEGF were quantified using real-time RT-PCR and ELISA. WT diabetic mice showed significant AGE -immunoreactivity in the retinal microvasculature and also showed significant iBRB breakdown (P<.005). These diabetics had higher VEGF mRNA and protein expression in comparison to controls (P<.01). PM-treated diabetics had normal iBRB function and significantly reduced diabetes-mediated VEGF expression. Diabetic retinal vessels showed disrupted TJ integrity when compared to controls, while PM-treated diabetics demonstrated near-normal configuration. Gal-3−/−mice showed significantly less diabetes-mediated iBRB dysfunction, junctional disruption, and VEGF expression changes than their WT counterparts. The data suggests an AGE-mediated disruption of iBRB via upregulation of VEGF in the diabetic retina, possibly modulating disruption of TJ integrity, even after acute diabetes. Prevention of AGE formation or genetic deletion of Gal-3 can effectively prevent these acute diabetic retinopathy changes.
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Tolone, Arianna, Soumaya Belhadj, Andreas Rentsch, Frank Schwede, and François Paquet-Durand. "The cGMP Pathway and Inherited Photoreceptor Degeneration: Targets, Compounds, and Biomarkers." Genes 10, no. 6 (June 14, 2019): 453. http://dx.doi.org/10.3390/genes10060453.
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Photoreceptor physiology and pathophysiology is intricately linked to guanosine-3’,5’-cyclic monophosphate (cGMP)-signaling. Here, we discuss the importance of cGMP-signaling for the pathogenesis of hereditary retinal degeneration. Excessive accumulation of cGMP in photoreceptors is a common denominator in cell death caused by a variety of different gene mutations. The cGMP-dependent cell death pathway may be targeted for the treatment of inherited photoreceptor degeneration, using specifically designed and formulated inhibitory cGMP analogues. Moreover, cGMP-signaling and its down-stream targets may be exploited for the development of novel biomarkers that could facilitate monitoring of disease progression and reveal the response to treatment in future clinical trials. We then briefly present the importance of appropriate formulations for delivery to the retina, both for drug and biomarker applications. Finally, the review touches on important aspects of future clinical translation, highlighting the need for interdisciplinary cooperation of researchers from a diverse range of fields.
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Salman, Ahmed, Samuel B. Hutton, Tutte Newall, Jennifer A. Scott, Helen L. Griffiths, Helena Lee, Diego Gomez-Nicola, Andrew J. Lotery, and Jay E. Self. "Characterization of the Frmd7 Knock-Out Mice Generated by the EUCOMM/COMP Repository as a Model for Idiopathic Infantile Nystagmus (IIN)." Genes 11, no. 10 (September 30, 2020): 1157. http://dx.doi.org/10.3390/genes11101157.
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In this study, we seek to exclude other pathophysiological mechanisms by which Frmd7 knock-down may cause Idiopathic Infantile Nystagmus (IIN) using the Frmd7.tm1a and Frmd7.tm1b murine models. We used a combination of genetic, histological and visual function techniques to characterize the role of Frmd7 gene in IIN using a novel murine model for the disease. We demonstrate that the Frmd7.tm1b allele represents a more robust model of Frmd7 knock-out at the mRNA level. The expression of Frmd7 was investigated using both antibody staining and X-gal staining confirming previous reports that Frmd7 expression in the retina is restricted to starburst amacrine cells and demonstrating that X-gal staining recapitulates the expression pattern in this model. Thus, it offers a useful tool for further expression studies. We also show that gross retinal morphology and electrophysiology are unchanged in these Frmd7 mutant models when compared with wild-type mice. High-speed eye-tracking recordings of Frmd7 mutant mice confirm a specific horizontal optokinetic reflex defect. In summary, our study confirms the likely role for Frmd7 in the optokinetic reflex in mice mediated by starburst amacrine cells. We show that the Frmd7.tm1b model provides a more robust knock-out than the Frmd7.tm1a model at the mRNA level, although the functional consequence is unchanged. Finally, we establish a robust eye-tracking technique in mice that can be used in a variety of future studies using this model and others. Although our data highlight a deficit in the optiokinetic reflex as a result of the starburst amacrine cells in the retina, this does not rule out the involvement of other cells, in the brain or the retina where Frmd7 is expressed, in the pathophysiology of IIN.
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Koschak, Alexandra, Monica L. Fernandez-Quintero, Thomas Heigl, Marco Ruzza, Hartwig Seitter, and Lucia Zanetti. "Cav1.4 dysfunction and congenital stationary night blindness type 2." Pflügers Archiv - European Journal of Physiology 473, no. 9 (July 1, 2021): 1437–54. http://dx.doi.org/10.1007/s00424-021-02570-x.
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AbstractCav1.4 L-type Ca2+ channels are predominantly expressed in retinal neurons, particularly at the photoreceptor terminals where they mediate sustained Ca2+ entry needed for continuous neurotransmitter release at their ribbon synapses. Cav1.4 channel gating properties are controlled by accessory subunits, associated regulatory proteins, and also alternative splicing. In humans, mutations in the CACNA1F gene encoding for Cav1.4 channels are associated with X-linked retinal disorders such as congenital stationary night blindness type 2. Mutations in the Cav1.4 protein result in a spectrum of altered functional channel activity. Several mouse models broadened our understanding of the role of Cav1.4 channels not only as Ca2+ source at retinal synapses but also as synaptic organizers. In this review, we highlight different structural and functional phenotypes of Cav1.4 mutations that might also occur in patients with congenital stationary night blindness type 2. A further important yet mostly neglected aspect that we discuss is the influence of alternative splicing on channel dysfunction. We conclude that currently available functional phenotyping strategies should be refined and summarize potential specific therapeutic options for patients carrying Cav1.4 mutations. Importantly, the development of new therapeutic approaches will permit a deeper understanding of not only the disease pathophysiology but also the physiological function of Cav1.4 channels in the retina.
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Puro, Donald G., Ryohsuke Kohmoto, Yasushi Fujita, Thomas W. Gardner, and Dolly A. Padovani-Claudio. "Bioelectric impact of pathological angiogenesis on vascular function." Proceedings of the National Academy of Sciences 113, no. 35 (August 22, 2016): 9934–39. http://dx.doi.org/10.1073/pnas.1604757113.
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Pathological angiogenesis, as seen in many inflammatory, immune, malignant, and ischemic disorders, remains an immense health burden despite new molecular therapies. It is likely that further therapeutic progress requires a better understanding of neovascular pathophysiology. Surprisingly, even though transmembrane voltage is well known to regulate vascular function, no previous bioelectric analysis of pathological angiogenesis has been reported. Using the perforated-patch technique to measure vascular voltages in human retinal neovascular specimens and rodent models of retinal neovascularization, we discovered that pathological neovessels generate extraordinarily high voltage. Electrophysiological experiments demonstrated that voltage from aberrantly located preretinal neovascular complexes is transmitted into the intraretinal vascular network. With extensive neovascularization, this voltage input is substantial and boosts the membrane potential of intraretinal blood vessels to a suprahyperpolarized level. Coincident with this suprahyperpolarization, the vasomotor response to hypoxia is fundamentally altered. Instead of the compensatory dilation observed in the normal retina, arterioles constrict in response to an oxygen deficiency. This anomalous vasoconstriction, which would potentiate hypoxia, raises the possibility that the bioelectric impact of neovascularization on vascular function is a previously unappreciated pathophysiological mechanism to sustain hypoxia-driven angiogenesis.
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Kleerekooper, Iris, Axel Petzold, and S. Anand Trip. "Anterior visual system imaging to investigate energy failure in multiple sclerosis." Brain 143, no. 7 (March 12, 2020): 1999–2008. http://dx.doi.org/10.1093/brain/awaa049.
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Abstract Mitochondrial failure and hypoxia are key contributors to multiple sclerosis pathophysiology. Importantly, improving mitochondrial function holds promise as a new therapeutic strategy in multiple sclerosis. Currently, studying mitochondrial changes in multiple sclerosis is hampered by a paucity of non-invasive techniques to investigate mitochondrial function of the CNS in vivo. It is against this backdrop that the anterior visual system provides new avenues for monitoring of mitochondrial changes. The retina and optic nerve are among the metabolically most active structures in the human body and are almost always affected to some degree in multiple sclerosis. Here, we provide an update on emerging technologies that have the potential to indirectly monitor changes of metabolism and mitochondrial function. We report on the promising work with optical coherence tomography, showing structural changes in outer retinal mitochondrial signal bands, and with optical coherence angiography, quantifying retinal perfusion at the microcapillary level. We show that adaptive optics scanning laser ophthalmoscopy can visualize live perfusion through microcapillaries and structural changes at the level of single photoreceptors and neurons. Advantages and limitations of these techniques are summarized with regard to future research into the pathology of the disease and as trial outcome measures.
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Matsumoto, Hidetaka, Ryo Mukai, Junki Hoshino, Mai Oda, Toshiyuki Matsuzaki, Yasuki Ishizaki, Koji Shibasaki, and Hideo Akiyama. "Choroidal congestion mouse model: Could it serve as a pachychoroid model?" PLOS ONE 16, no. 1 (January 28, 2021): e0246115. http://dx.doi.org/10.1371/journal.pone.0246115.
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Pachychoroid spectrum diseases have been described as a new clinical entity within the spectrum of macular disorders. “Pachychoroid” is defined as choroidal thickening associated with dilated outer choroidal vessels often showing retinal pigment epithelium (RPE) degeneration. Although various clinical studies on the pachychoroid spectrum diseases have been conducted, the pathophysiology of pachychoroid has yet to be fully elucidated. In this study, we attempted to establish a mouse model of pachychoroid. We sutured vortex veins in eyes of wild type mice to imitate the vortex vein congestion in pachychoroid spectrum diseases. Fundus photography and ultra-widefield indocyanine green angiography showed dilated vortex veins from the posterior pole to the ampulla in eyes after induction of choroidal congestion. Optical coherence tomography and tissue sections presented choroidal thickening with dilatation of choroidal vessels. The RPE-choroid/retina thickness ratios on the tissue sections in the treated day 1 and day 7 groups were significantly greater than that in the control group (0.19±0.03 and 0.16±0.01 vs. 0.12±0.02, P<0.05 each). Moreover, immunohistochemistry using RPE flatmount revealed focal RPE degeneration in the treated eyes. Furthermore, inflammatory response-related genes were upregulated in eyes with choroidal congestion induction, and macrophages migrated into the thickened choroid. These results indicated that vortex vein congestion triggered some pachychoroid features. Thus, we have established a choroidal congestion mouse model by suturing vortex veins, which would potentially be useful for investigating the pathophysiology of pachychoroid spectrum diseases.
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Pollan, Charlene. "Retinopathy of Prematurity: An Eye Toward Better Outcomes." Neonatal Network 28, no. 2 (March 2009): 93–101. http://dx.doi.org/10.1891/0730-0832.28.2.93.
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Retinopathy of prematurity (ROP) results from the abnormal growth of blood vessels in the vascular bed supporting the developing retina. Estimated to cause up to 500 new cases of blindness in the U.S. each year, ROP affects primarily infants born at less than 1,500 g. Although its etiology is not well understood, ROP is thought to occur as a result of a complex interaction between oxygen and vascular growth factors. This article briefly reviews the history of ROP, discusses its pathophysiology, and addresses the risk factors and strategies for prevention.
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Gologorsky, Daniel, Aristomenis Thanos, and Demetrios Vavvas. "Therapeutic Interventions against Inflammatory and Angiogenic Mediators in Proliferative Diabetic Retinopathy." Mediators of Inflammation 2012 (2012): 1–10. http://dx.doi.org/10.1155/2012/629452.
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The global prevalence of diabetes is estimated to be 336 million people, with diabetic complications contributing to significant worldwide morbidity and mortality. Diabetic retinopathy results from cumulative microvascular damage to the retina and inflammation is recognized as a critical driver of this disease process. This paper outlines the pathophysiology leading to proliferative diabetic retinopathy and highlights many of the inflammatory, angiogenic, and cytokine mediators implicated in the development and progression of this disease. We focus a detailed discussion on the current targeted therapeutic interventions used to treat diabetic retinopathy.
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Andrews, James C., Larry A. Hoover, Regina S. Lee, and Vicente Honrubia. "Vertigo in the Hyperviscosity Syndrome." Otolaryngology–Head and Neck Surgery 98, no. 2 (February 1988): 144–49. http://dx.doi.org/10.1177/019459988809800208.
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Diseases that cause hyperviscosity of the blood can result in otologic symptoms—especially vertigo. These symptoms are predominantly produced by peripheral vestibular involvement. The pathophysiology probably involves vascular obstruction in the venules. Specific changes in the microvasculature are presumed to be comparable to those that occur with hyperviscosity disorders in the retina. Maintenance of a normal blood viscosity will prevent damage to the ear, as well as other organs. Additionally, reduction of the blood viscosity can greatly improve otologic symptoms. Case studies and a review of the pertinent literature are included.
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Lu, Renhao, Paul Soden, and Esak Lee. "Tissue-Engineered Models for Glaucoma Research." Micromachines 11, no. 6 (June 24, 2020): 612. http://dx.doi.org/10.3390/mi11060612.
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Glaucoma is a group of optic neuropathies characterized by the progressive degeneration of retinal ganglion cells (RGCs). Patients with glaucoma generally experience elevations in intraocular pressure (IOP), followed by RGC death, peripheral vision loss and eventually blindness. However, despite the substantial economic and health-related impact of glaucoma-related morbidity worldwide, the surgical and pharmacological management of glaucoma is still limited to maintaining IOP within a normal range. This is in large part because the underlying molecular and biophysical mechanisms by which glaucomatous changes occur are still unclear. In the present review article, we describe current tissue-engineered models of the intraocular space that aim to advance the state of glaucoma research. Specifically, we critically evaluate and compare both 2D and 3D-culture models of the trabecular meshwork and nerve fiber layer, both of which are key players in glaucoma pathophysiology. Finally, we point out the need for novel organ-on-a-chip models of glaucoma that functionally integrate currently available 3D models of the retina and the trabecular outflow pathway.
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Massa, Rita, Carolina Vale, Mafalda Macedo, Maria João Furtado, Miguel Gomes, Miguel Lume, and Angelina Meireles. "Purtscher-Like Retinopathy." Case Reports in Ophthalmological Medicine 2015 (2015): 1–5. http://dx.doi.org/10.1155/2015/421329.
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Purtscher-like retinopathy is associated with retinal hemorrhages and ischaemia probably due to the complement-mediated leukoembolization. It is a rare and severe angiopathy found in conditions such as acute pancreatitis.Case. We present a case of a 53-year-old man who presented with a Purtscher-like retinopathy associated with the development of acute pancreatitis in the context of a Klatskin tumour (a hilar cholangiocarcinoma). The ophthalmologic evaluation revealed the best corrected visual acuity (BCVA) of 20/32 in the right eye (RE) and of 20/40 in the left eye (LE); biomicroscopy of anterior segment showed scleral icterus and fundoscopy revealed peripapillary cotton-wool spots, optic disc edema, and RPE hypo- and hyperpigmentation in the middle peripheral retina in both eyes with an intraretinal hemorrhage in the LE. 15 months after the initial presentation, without ophthalmological treatment, there was an improvement of BCVA to 20/20 in both eyes and optical coherence tomography (OCT) revealed areas of reduction of retinal nerve fiber layer thickness corresponding to the previous cotton-wool spots.Conclusion. Purtscher-like retinopathy should not be neglected in complex clinical contexts. Its unclear pathophysiology determines an uncertain treatment strategy, but a meticulous follow-up is compulsory in order to avoid its severe complications.
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Polosa, Anna, Shasha Lv, Wassila Ait Igrine, Laura-Alexie Chevrolat, Hyba Bessaklia, and Pierre Lachapelle. "Evidences Suggesting that Distinct Immunological and Cellular Responses to Light Damage Distinguishes Juvenile and Adult Rat Retinas." International Journal of Molecular Sciences 20, no. 11 (June 4, 2019): 2744. http://dx.doi.org/10.3390/ijms20112744.
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To unravel the mechanisms behind the higher resistance to light damage of juvenile (JR) versus adult (AR) rats, Sprague Dawley rats were exposed to a bright luminous environment of 10, 000 lux. The light-induced retinopathy (LIR) was assessed with histology, electroretinography and immunohistochemistry (IHC). In JR, 2 days of exposure induced the typical LIR, while >3 days added little LIR. IHC revealed a subtle migration of microglia (Iba1 marker) from the inner to the outer retina after 3 days of exposure in JR contrasting with the stronger reaction seen after 1 day in AR. Similarly, in JR, the Müller cells expressed less intense GFAP, CNTF and FGF2 staining compared to AR. Our results suggest that in JR the degree of retinal damage is not proportional to the duration of light exposure (i.e., dose-independent retinopathy), contrasting with the dose-dependent LIR reported in AR. The immature immune system in JR may explain the delayed and/or weaker inflammatory response compared to AR, a finding that would also point to the devastating contribution of the immune system in generating the LIR phenotype, a claim also advanced to explain the pathophysiology of other retinal degenerative disorders such as Age-related Macular Degeneration, Diabetic Retinopathy and Retinitis Pigmentosa.
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Salter, AR, A. Conger, TC Frohman, R. Zivadinov, E. Eggenberger, P. Calabresi, G. Cutter, L. Balcer, and EM Frohman. "Retinal architecture predicts pupillary reflex metrics in MS." Multiple Sclerosis Journal 15, no. 4 (December 17, 2008): 479–86. http://dx.doi.org/10.1177/1352458508100503.
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Objective To study the relation of retinal nerve fiber layer thinning to clinical and physiologic measures of visual function in patients with MS or neuromyelitis optica and unilateral optic neuropathy. Methods We studied a cohort of control subjects ( n = 64) and patients ( n = 24) with evidence of unilateral thinning of their average retinal nerve fiber layer as measured by optical coherence tomography in order to characterize the relationship between ganglion cell axonal degeneration and its impact upon vision and pupillary light reflex metrics using infrared pupillometry. Results When compared to the normal fellow eye, and with respect to normal subjects’ eyes, we confirmed significant abnormalities in retinal nerve fiber layer thickness, total macular volume, low-contrast letter acuity, and pupillary reflex metrics in the eye with the thinner retinal nerve fiber layer. For each −5% change in pupil diameter, there was a corresponding 7.1 µm reduction in the average retinal nerve fiber layer thickness. There was a significant difference between the pupillary metric of percent change in diameter and a decrease in low-contrast letter acuity ( P < 0.001). Each −5% change in pupil diameter was associated with a substantial 3.4 line loss of low-contrast letter acuity ( P < 0.001). Each −5% change in pupil diameter was associated with a 0.2 mm2 decrease in total macular volume ( P < 0.001). Conclusion These findings further corroborate the hypothesis that the retina can be utilized as a model to advance our understanding of the mechanisms of axonal and neurodegeneration, and the corresponding impact of these processes upon the pathophysiology of MS and related disorders.
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Gericke, Adrian, Carolina Mann, Jenia Kouchek Zadeh, Aytan Musayeva, Ismael Wolff, Maoren Wang, Norbert Pfeiffer, et al. "Elevated Intraocular Pressure Causes Abnormal Reactivity of Mouse Retinal Arterioles." Oxidative Medicine and Cellular Longevity 2019 (December 30, 2019): 1–12. http://dx.doi.org/10.1155/2019/9736047.
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Objective. Glaucoma is a leading cause of severe visual impairment and blindness. Although high intraocular pressure (IOP) is an established risk factor for the disease, the role of abnormal ocular vessel function in the pathophysiology of glaucoma gains more and more attention. We tested the hypothesis that elevated intraocular pressure (IOP) causes vascular dysfunction in the retina. Methods. High IOP was induced in one group of mice by unilateral cauterization of three episcleral veins. The other group received sham surgery only. Two weeks later, retinal vascular preparations were studied by video microscopy in vitro. Reactive oxygen species (ROS) levels and expression of hypoxia markers and of prooxidant and antioxidant redox genes as well as of inflammatory cytokines were determined. Results. Strikingly, responses of retinal arterioles to stepwise elevation of perfusion pressure were impaired in the high-IOP group. Moreover, vasodilation responses to the endothelium-dependent vasodilator, acetylcholine, were markedly reduced in mice with elevated IOP, while no differences were seen in response to the endothelium-independent nitric oxide donor, sodium nitroprusside. Remarkably, ROS levels were increased in the retinal ganglion cell layer including blood vessels. Expression of the NADPH oxidase isoform, NOX2, and of the inflammatory cytokine, TNF-α, was increased at the mRNA level in retinal explants. Expression of NOX2, but not of the hypoxic markers, HIF-1α and VEGF-A, was increased in the retinal ganglion cell layer and in retinal blood vessels at the protein level. Conclusion. Our data provide first-time evidence that IOP elevation impairs autoregulation and induces endothelial dysfunction in mouse retinal arterioles. Oxidative stress and inflammation, but not hypoxia, appear to be involved in this process.
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Liu, Hanhan, Natarajan Perumal, Caroline Manicam, Karl Mercieca, and Verena Prokosch. "Proteomics Reveals the Potential Protective Mechanism of Hydrogen Sulfide on Retinal Ganglion Cells in an Ischemia/Reperfusion Injury Animal Model." Pharmaceuticals 13, no. 9 (August 27, 2020): 213. http://dx.doi.org/10.3390/ph13090213.
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Glaucoma is the leading cause of irreversible blindness and is characterized by progressive retinal ganglion cell (RGC) degeneration. Hydrogen sulfide (H2S) is a potent neurotransmitter and has been proven to protect RGCs against glaucomatous injury in vitro and in vivo. This study is to provide an overall insight of H2S’s role in glaucoma pathophysiology. Ischemia-reperfusion injury (I/R) was induced in Sprague-Dawley rats (n = 12) by elevating intraocular pressure to 55 mmHg for 60 min. Six of the animals received intravitreal injection of H2S precursor prior to the procedure and the retina was harvested 24 h later. Contralateral eyes were assigned as control. RGCs were quantified and compared within the groups. Retinal proteins were analyzed via label-free mass spectrometry based quantitative proteomics approach. The pathways of the differentially expressed proteins were identified by ingenuity pathway analysis (IPA). H2S significantly improved RGC survival against I/R in vivo (p < 0.001). In total 1115 proteins were identified, 18 key proteins were significantly differentially expressed due to I/R and restored by H2S. Another 11 proteins were differentially expressed following H2S. IPA revealed a significant H2S-mediated activation of pathways related to mitochondrial function, iron homeostasis and vasodilation. This study provides first evidence of the complex role that H2S plays in protecting RGC against I/R.
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Fourgeux, Cynthia, Alain Bron, Niyazi Acar, Catherine Creuzot-Garcher, and Lionel Bretillon. "24S-hydroxycholesterol and cholesterol-24S-hydroxylase (CYP46A1) in the retina: from cholesterol homeostasis to pathophysiology of glaucoma." Chemistry and Physics of Lipids 164, no. 6 (September 2011): 496–99. http://dx.doi.org/10.1016/j.chemphyslip.2011.04.006.
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