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Retinal development was studied by explant culture of retinas from embryonic and neonatal rats in response to medium conditioned (CM) by a transformed neonatal rat retinal pigment epithelial (tnrRPE) cell line. Retinal explants from embryonic days 16 and 18 and postnatal day 2 Long-Evans rats were cultured for over 3 weeks on a poly-D,L-ornithine-coated surface in RPE-CM only, 10% serum or a serum-free defined medium. By 2 days in vitro, round cells were seen emerging from both embryonic and neonatal retinal explants grown in tnrRPE-CM. With extended time in culture, these round cells had increased in number and were seen in large confluent clusters adjacent to the explants. After 2 weeks in culture, some of these cells had undergone a morphological differentiation as shown by process formation. Insignificant numbers of these same cells were seen in explant cultures grown in 10% serum or serum-free defined medium. When isolated and subcultured, approx. 80% of the round cells from embryonic and neonatal rat retinal explants were densely immunolabeled for opsin and arrestin, both photoreceptor cell markers and neuron-specific enolase, a marker for mature neurons. Cellular retinaldehyde-binding protein, a Müller cell marker, immunolabeled approx. 30% of the cells from embryonic and neonatal rat retinal explants. In addition, nestin, an intermediate filament protein found only in neuroepithelial cells, was present in approx. 70% of the embryonic cells, but in only less than 1% of the neonatal cells. Based on this immunocytochemical characterization, these round cells are termed retinal progenitor cells and because of their mitogenic capacity under these in vitro conditions, these cells appear to possess stem cell characteristics. Moreover, in a 3-day bioassay, tnrRPE-CM caused a twofold and greater increase in harvested progenitor cells from both neonatal and embryonic explants, while cell numbers in control and growth factor-supplemented cultures showed no increase above the initial plating density. In these studies, CM from cultures of transformed neonatal rat RPE cells promoted the production, survival, proliferation and maturation of retinal progenitor cells from neonatal and embryonic rat retinal explants.
PURPOSE: Tissue plasminogen activator (tPA) is an efficient thrombolytic agent, but the dose-dependent retinal toxicity of intravitreal injection of commercial tPA (containing L-arginine) has been reported. Here, we sought to investigate the mechanism of tPA-induced cell death in mouse retinal cell cultures and the role of nitric oxide (NO). METHODS: Primary retinal cell cultures were maintained using glial conditioned medium (GCM) solution. Mouse retinal cell death was observed by using Hoechst-propidium iodide staining. Mouse retinal cell death was also measured by lactate dehydrogenase (LDH) assay. The formation of NO was measured using Griess reagent. RESULTS: tPA-induced cell death was detected in mouse retinal cell cultures by Hoechst-propidium iodide staining or LDH assay. L-arginine seems to be the major factor in retinal toxicity of commercial tPA (containing L-arginine). The formation of NO was markedly increased in mouse retinal cell cultures treated with tPA (containing L-arginine) or L-arginine. NO inhibitor reduced the cell death induced by commercially available tPA or L-arginine. CONCLUSIONS: This study suggests that l-arginine from commercial tPA (containing L-arginine) induces the majority of cell death in mouse retinal cell cultures and that its cytotoxicity may depend on the induction of NO.
PURPOSE: To assess retinal thickness at the posterior pole in healthy Chinese subjects with the retinal thickness analyzer (RTA). METHODS: Retinal thicknesses at the posterior pole and fovea were measured by the RTA in 331 eyes of 178 healthy Chinese subjects. Retinal thicknesses as a function of sex, age, refractive errors, and axial length were also evaluated. RESULTS: The average thickness of the foveal area +/- SD was 158.6 +/- 24.8 microm, the average thickness of the perifoveal region (600-2,500 microm from fovea) +/- SD was 174 +/- 25.2 microm, and the average thickness of the posterior pole region (600-6,000 microm from fovea) +/- SD was 171.9 +/- 25.3 microm. There was no significant difference in retinal thicknesses of the foveal, perifoveal, and posterior pole regions in either right or left eyes or as a function of different spherical equivalents. Moreover, there was no significant difference of foveal thickness between males and females. Greater retinal thicknesses of the foveal, perifoveal, and posterior pole regions were associated with age of older than 40 years and axial length of < 24 mm, and greater perifoveal and posterior pole thicknesses were found for females. Furthermore, there were no significant correlations between age, refractive errors, and axial lengths with retinal thicknesses. CONCLUSION: Retinal thicknesses of the posterior pole region differed by age, axial length, and sex, but there was no effect of laterality or different spherical equivalents. The RTA is a fast and noninvasive technology to assess retinal conditions with thickening or thinning in the fovea and posterior pole.
1. Na+ and HCO3- transport across the retinal membrane of the frog retinal pigment epithelium was studied by means of double-barrelled Na(+)- and pH-selective microelectrodes. Transient changes in the intracellular pH and in the intracellular Na+ activity were monitored in response to abrupt changes in the Na+ concentration and in the HCO3- concentration on the retinal side of the epithelium, and in response to transepithelial currents. 2. Removal of Na+ from the retinal side of the epithelium caused a depolarization of the membrane potential across the retinal membrane, a decrease in the intracellular Na+ activity and a decrease in the intracellular pH. 3. An increase in the HCO3- concentration on the retinal side of the epithelium from 27.5 to 50 mM caused a hyperpolarization of the membrane potential across the retinal membrane, an increase in the intracellular Na+ activity and an increase in the intracellular pH. 4. Passage of a transepithelial current of 30 microA in the choroid-to-retina direction caused an increase in the intracellular Na+ activity and an increase in the intracellular pH. 5. The data are interpreted as evidence for rheogenic co-transport of Na+, HCO3- across the retinal membrane of the frog retinal pigment epithelium. 6. The transient changes described under 2, 3 and 4 above were blocked by 0.5 mM-4-acetamido-4'-isothiocyanostilbene-2.2'-disulphonic acid (SITS). The Na(+)- HCO3- co-transport was not inhibited by 1 mM-amiloride.
Illumination of different areas of the human retina elicits differences in acute light-induced suppression of melatonin. The aim of this study was to compare changes in plasma melatonin levels when light exposures of equal illuminance and equal photon dose were administered to superior, inferior, and full retinal fields. Nine healthy subjects participated in the study. Plexiglass eye shields were modified to permit selective exposure of the superior and inferior halves of the retinas of each subject. The Humphrey Visual Field Analyzer was used both to confirm intact full visual fields and to quantify exposure of upper and lower visual fields. On study nights, eyes were dilated, and subjects were exposed to patternless white light for 90 min between 0200 and 0330 under five conditions: (1) full retinal exposure at 200 lux, (2) full retinal exposure at 100 lux, (3) inferior retinal exposure at 200 lux, (4) superior retinal exposure at 200 lux, and (5) a dark-exposed control. Plasma melatonin levels were determined by radioimmunoassay. ANOVA demonstrated a significant effect of exposure condition (F = 5.91, p < 0.005). Post hoc Fisher PLSD tests showed significant (p < 0.05) melatonin suppression of both full retinal exposures as well as the inferior retinal exposure; however, superior retinal exposure was significantly less effective in suppressing melatonin. Furthermore, suppression with superior retinal exposure was not significantly different from that of the dark control condition. The results indicate that the inferior retina contributes more to the light-induced suppression of melatonin than the superior retina at the photon dosages tested in this study. Findings suggest a greater sensitivity or denser distribution of photoreceptors in the inferior retina are involved in light detection for the retinohypothalamic tract of humans.
One of the earliest events in vertebrate eye development is the establishment of the pigmented epithelium and neural retina. These fundamentally different tissues derive from the invaginated optic vesicle, or optic cup. Even after achieving a fairly advanced state of differentiation, the pigmented epithelium exhibits the same potential as the optic cup in that it can "transdifferentiate" into neural retina. C. M. Park and M. J. Hollenberg (Dev. Biol. 134, 201-205, 1989) discovered that administration of basic fibroblast growth factor, coupled with retinal removal, could trigger this transformation in vivo. We have developed a quantitative in vitro assay to study the role(s) of the fibroblast growth factor (FGF) family in this phenomenon and more generally in early retinal development. We found that several aspects of the process, including inhibition of pigmented epithelium differentiation, proliferation, and conversion to a retinal fate, were not strictly correlated. Both acidic and basic FGFs were found to potentiate all aspects of the process, with acidic FGF being 4 to 20 times more potent than basic FGF for inhibition of pigmentation and induction of retinal antigens. Depending upon its concentration, acidic FGF induced from 40% to 80% of the cells in the explants to produce antigens normally expressed by retinal ganglion cells, the first cell type to be generated in retinal development. Expression of such a ganglion cell marker could be directly stimulated in non-dividing cells as well as in dividing cells, indicating that conversion from the pigmented epithelial to retinal fate did not require cell division. These data suggest that acidic FGF, or a related molecule, may function in establishment of retinal fate from the optic cup. This effect may be directly or indirectly mediated by induction of retinal ganglion cell fate among multipotent progenitor cells.
PURPOSE: To examine retinal changes induced by scleral imbrication during retinal translocation surgery in dog eyes. METHODS: Fifteen dogs were anesthetized and underwent retinal translocation surgery. After lensectomy and vitrectomy, an intentional retinal detachment was created, and the upper temporal sclera around the equator was imbricated with five mattress sutures. Translocated distances were calculated by pre- and postoperative photographs. At 1, 2, and 4 weeks after the surgery, the retina was studied by TdT-dNTP terminal nick-end labeling (TUNEL) and immunohistochemistry of peanut agglutinin (PNA) lectin and glial fibrillary acidic protein (GFAP). RESULTS: The retina was translocated by a mean distance of 0.53 +/- 0.30 disc diameters or 959 +/- 543 micrometer. Retinal folds were created around the optic disc in all eyes. Histologic examination of the retinal folds 1 week after the surgery showed many TUNEL-positive cells in the outer nuclear layer, loss of photoreceptor cells, and shortening of the outer and inner segments. A strong immunoreactivity to GFAP was detected in the folds of the retina. CONCLUSIONS: . The results demonstrated that retinal translocation surgery by scleral imbrication inevitably caused retinal folds as a postoperative complication, and the retina within the folds showed extensive loss of photoreceptor cells. It is recommended that the foveal translocation surgery be planned to avoid involving the fovea in the retinal folds.
Pathological changes in retinas of diabetics include specific morphological, biochemical, and functional abnormalities. As biochemical manifestations of the disease, increased sorbitol and decreased myo-inositol were found in retinas of experimentally diabetic animals. Similar alterations in polyol metabolism have been associated in nerves of diabetics with a reduction of Na+-K+-ATPase activity. To determine whether this association extends to the retinas of diabetic animals, we applied quantitative histochemical techniques to measure ATPase activities and the amounts of sodium and potassium in samples from nine individual layers of cryostat sections of rabbit retina. ATPase activities were determined fluorimetrically, and the ions were measured by atomic absorption with a carbon rod atomizer. The activity of Na+-K+-ATPase was reduced in the retinal pigmented epithelium (retinal pigment epithelium) and in selected layers of the neural retina, and total sodium in the retinal pigment epithelium layer was elevated in diabetes. The retinal pigment epithelium forms the outer component of the blood-retinal barrier and partly determines the composition of the retinal interstitial fluid. Changes in retinal pigment epithelium biochemistry and function might alter the intraretinal environment, predisposing neural retina or retinal blood vessels to disease. The morphologically and functionally well defined retinal pigment epithelium may provide a useful model for studying the pathogenesis of diabetic complications.
Experimental occlusion of both major temporal retinal veins simultaneously (in six eyes of cynomolgus monkeys) and of the central retinal vein (in one rhesus monkey) produced a fall in intraocular pressure (hypotensive effect) and neovascularization (NV) of the iris and, less frequently, of the optic disc (vasogenic effect). The retinal changes (severity and extent of retinopathy, retinal capillary leakage, and onset and extent of retinal capillary obliteration) were correlated with the pattern of ocular NV and hypotony. No direct correlation was seen between the retinal capillary obliteration and the hypotensive or vasogenic effect. However, a correlation was found between the retinal vascular leakage and the development of ocular NV and hypotony. The pathogeneses of ocular NV and hypotony in retinal vein occlusion are discussed in light of the findings of this study.
We describe five eyes of five patients that developed an exudative retinal detachment following a central retinal vein occlusion (including one eye with a hemicentral [hemispheric] retinal vein occlusion). The time interval between the occurrence of the vein occlusion and the appearance of the retinal detachment ranged from 7 to 36 weeks in the four cases seen in the acute period. Each detachment involved the posterior retina and was associated with the development of marked retinal ischemia. Neovascular glaucoma occurred in two cases. The subretinal fluid completely or partially resorbed in the four eyes that were treated with retinal photocoagulation, but the final visual acuity was poor in all cases. Exudative retinal detachment is a potential complication of central retinal vein occlusion and in this series was associated with a poor visual prognosis.
The high-affinity 67-kd laminin receptor (67LR) is expressed by proliferating endothelial cells during retinal neovascularization. The role of 67LR has been further examined experimentally by administration of selective 67LR agonists and antagonists in a murine model of proliferative retinopathy. These synthetic 67LR ligands have been previously shown to stimulate or inhibit endothelial cell motility in vitro without any direct effect on proliferation. In the present study, a fluorescently labeled 67LR antagonist (EGF(33-42)) was injected intraperitoneally into mice and its distribution in the retina was assessed by confocal scanning laser microscopy. Within 2 hours this peptide was localized to the retinal vasculature, including preretinal neovascular complexes, and a significant amount had crossed the blood retinal barrier. For up to 24 hours postinjection, the peptide was still present in the retinal vascular walls and, to a lesser extent, in the neural retina. Non-labeled EGF(33-42) significantly inhibited pre-retinal neovascularization in comparison to controls treated with phosphate-buffered saline or scrambled peptide (P < 0.0001). The agonist peptide (Lam beta 1(925-933)) also significantly inhibited proliferative retinopathy; however, it caused a concomitant reduction in retinal ischemia in this model by promoting significant revascularization of the central retina (P < 0.001). Thus, 67LR appears to be an important target receptor for the modulation of retinal neovascularization. Agonism of this receptor may be valuable in reducing the hypoxia-stimulated release of angiogenic growth factors which drives retinal angiogenesis.
The authors performed retinal reattachment surgery in 29 eyes of 24 patients with acquired immune deficiency syndrome virus with retinal detachment associated with cytomegalovirus (CMV) retinitis and documented the course of eight additional untreated eyes. Retinal detachment repair using vitrectomy, posterior hyaloid removal, and intraocular tamponade with silicone oil or SF-6 gas resulted in a total retinal reattachment rate of 76% and a macular attachment rate of 90% in one operation. The mean postoperative visual acuity (best corrected) was 20/60, but, in some patients, the visual acuity decreased because of progressive retinitis. Prophylactic laser photocoagulation of fellow eyes to surround CMV lesions did not appear to prevent retinal detachment. The mean postoperative survival was 37 weeks (range, 8 to 127 weeks). The surgical techniques used and pathophysiology of these retinal detachments are discussed.
PURPOSE: The authors have further developed their method of retinal thickness analysis to rapidly generate multiple optical cross sections of the retina and provide thickness maps at the posterior pole. The potential use of this method was evaluated in a number of macular disorders. METHODS: A commercial prototype of the scanning retinal thickness analyzer was used to examine patients with a variety of macular diseases. A laser slit beam was projected on the retina and scanned across a 2- X 2-mm retinal area in 200 to 400 msec. The images of the intersection of the laser slit beam with the retina were recorded digitally and used for visualization of disease. Nine scans were combined, and an operator-free algorithm generated a three-dimensional thickness map at the posterior pole. RESULTS: Cysts could be visualized in macular edema associated with diabetes mellitus and with retinal vein occlusion. The retinal thickness map quantitated the location, extent, and height of the edema. In serous detachment, the extent and the height of the retinal pigment epithelial elevation could be documented. In cases of suspected macular holes and pseudoholes, the diagnosis was considered more reliable than with conventional biomicroscopy. The extent of epiretinal membranes, the sites of adherence, and associated intraretinal cystic changes were identified. In glaucoma, the anatomic course of localized loss of neuronal retinal tissue could be traced. CONCLUSIONS: Scanning retinal thickness analysis provided multiple optical cross sections of the retina and yielded information useful in the diagnosis and monitoring of macular diseases. The three-dimensional thickness map provided quantitative information that may be useful for clinical management.
Retinitis reminiscent of the acute retinal necrosis syndrome was recognized in a patient with AIDS-related complex after he had experienced several episodes of a sacral, dermatomic zosteriform eruption. Varicella-zoster virus (VZV) was subsequently recovered from cell culture of retinal tissue. The literature on VZV retinitis, including that on acute retinal necrosis, is reviewed. Dissemination of VZV infection in AIDS is also reviewed. Features that differentiate the findings and course of VZV retinitis in patients with AIDS from those in otherwise healthy adults are noted and related to potentially different pathogenic mechanisms. This unusual and recently recognized complication of herpesvirus infection may be promoted by AIDS-related immunosuppression. Acute retinal necrosis and other more-recently described forms of VZV retinitis, which have primarily been subjects of the ophthalmologic literature, merit the attention of clinicians and investigators of infectious diseases.