Changes in relative peripheral refraction in children who switched from single-vision lenses to Defocus Incorporated Multiple Segments lenses.

PURPOSE: To investigate changes in relative peripheral refraction (RPR) associated with myopia progression in children who wore single-vision (SV) lenses for 2 years and switched to Defocus Incorporated Multiple Segments (DIMS) lenses in the third year versus children who wore DIMS lenses for 3 years. METHODS: In the first 2 years, children were allocated randomly to wear either DIMS or SV lenses. In the third year, children in the DIMS group continued to wear these lenses, while those in the SV group were switched to DIMS lenses (Control-to-DIMS group). Central and peripheral refraction and axial length were monitored every 6 months. RESULTS: Over 3 years, the DIMS group (n = 65) showed good myopia control and maintained a relatively constant and symmetrical RPR profile without significant changes. In the first 2 years, children who wore SV lenses (n = 55) showed asymmetrical RPR changes, with significant increases in hyperopic RPR at 20° nasal (N) (mean difference: 0.88 ± 1.06 D, p < 0.0001) and 30N (mean difference: 1.07 ± 1.09 D, p < 0.0001). The Control-to-DIMS group showed significant myopia retardation after wearing DIMS lenses in the third year. When compared with the RPR changes in the first 2 years, significant reductions in hyperopic RPR were observed at 20N (mean difference: -1.14 ± 1.93 D, p < 0.0001) and 30N (mean difference: -1.07 ± 1.17 D, p < 0.0001) in the third year. However, no significant difference between the RPR changes found in the nasal retina and temporal retina (p > 0.05) was noted in the third year. CONCLUSION: Symmetrical changes in RPR were found in children switching from SV to DIMS lenses, and a symmetrical pattern of RPR was noted in children who wore DIMS for 3 years. Myopia control using myopic defocus in the mid-periphery influenced the RPR changes and retarded myopia progression by altering the eye's growth pattern.

Central Role of Oxidative Stress in Age-Related Macular Degeneration: Evidence from a Review of the Molecular Mechanisms and Animal Models.

Age-related macular degeneration (AMD) is a common cause of visual impairment in the elderly. There are very limited therapeutic options for AMD with the predominant therapies targeting vascular endothelial growth factor (VEGF) in the retina of patients afflicted with wet AMD. Hence, it is important to remind readers, especially those interested in AMD, about current studies that may help to develop novel therapies for other stages of AMD. This study, therefore, provides a comprehensive review of studies on human specimens as well as rodent models of the disease, to identify and analyze the molecular mechanisms behind AMD development and progression. The evaluation of this information highlights the central role that oxidative damage in the retina plays in contributing to major pathways, including inflammation and angiogenesis, found in the AMD phenotype. Following on the debate of oxidative stress as the earliest injury in the AMD pathogenesis, we demonstrated how the targeting of oxidative stress-associated pathways, such as autophagy and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, might be the futuristic direction to explore in the search of an effective treatment for AMD, as the dysregulation of these mechanisms is crucial to oxidative injury in the retina. In addition, animal models of AMD have been discussed in great detail, with their strengths and pitfalls included, to assist inform in the selection of suitable models for investigating any of the molecular mechanisms.

Author Correction: Characterization of Retinal Ganglion Cell and Optic Nerve Phenotypes Caused by Sustained Intracranial Pressure Elevation in Mice.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The Interactions Between Bright Light and Competing Defocus During Emmetropization in Chicks.

Purpose: The environment comprises multiple optical signals that affect eye growth. We aimed to determine if the inhibitory effects of myopic defocus and bright light (BL) against myopia are additive in the presence of the myopia-genic hyperopic defocus. Methods: In experiment 1, three groups of 24 chicks each were fitted with the following multizone dual-power lenses (pl): pl/-10 D (50:50 area), +10/-10 D (50:50 area), and +10/-10 D (33:67 area) monocularly for 6 days. Half of each group were raised under normal illumination of 500 lux, 12/12-hour light/dark cycle, whereas the remainder were exposed to 6-hour BL of 40 klx and 6-hour 500 lux during the light cycle. In experiment 2, 38 chicks wore +10/-10 D (33:67 area) lenses monocularly for 8 days and were exposed to one of four light intensities for 6 hours per day-500 lux, 10 klx, 20 klx, or 40 klx-and received 500 lux for the remainder of the light cycle. Results: In experiment 1, interocular difference in refractions after 6 days for the three groups were -3.6 D, +2.0 D, and -4.2 D, respectively, under normal light and were -0.9 D, +4.2 D, and +0.67 D under BL, manifesting as a shorter anterior segment and vitreous chamber. In experiment 2, the effect of BL increased with light intensity in the +10/-10 D (33:67) group, with a significant difference in refraction between the 10 klx and 20 klx groups (interocular difference -2.75 ± 2.76 D vs. 1.70 ± 2.40 D, P < 0.01), but plateaued between 20 klx and 40 klx (1.70 ± 2.40 D vs. 1.70 ± 0.35 D, P > 0.05). Conclusions: The protective effects of myopic defocus and BL against experimental myopia were additive. The inhibitory effect of BL against myopia was dose dependent at 10 klx and above but plateaued at 20 klx.

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency.

The accumulation of undegraded molecular material leads to progressive neurodegeneration in a number of lysosomal storage disorders (LSDs) that are caused by functional deficiencies of lysosomal hydrolases. To determine whether inducing macroautophagy/autophagy via small-molecule therapy would be effective for neuropathic LSDs due to enzyme deficiency, we treated a mouse model of mucopolysaccharidosis IIIB (MPS IIIB), a storage disorder caused by deficiency of the enzyme NAGLU (alpha-N-acetylglucosaminidase [Sanfilippo disease IIIB]), with the autophagy-inducing compound trehalose. Treated naglu-/ - mice lived longer, displayed less hyperactivity and anxiety, retained their vision (and retinal photoreceptors), and showed reduced inflammation in the brain and retina. Treated mice also showed improved clearance of autophagic vacuoles in neuronal and glial cells, accompanied by activation of the TFEB transcriptional network that controls lysosomal biogenesis and autophagic flux. Therefore, small-molecule-induced autophagy enhancement can improve the neurological symptoms associated with a lysosomal enzyme deficiency and could provide a viable therapeutic approach to neuropathic LSDs. ABBREVIATIONS: ANOVA: analysis of variance; Atg7: autophagy related 7; AV: autophagic vacuoles; CD68: cd68 antigen; ERG: electroretinogram; ERT: enzyme replacement therapy; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFAP: glial fibrillary acidic protein; GNAT2: guanine nucleotide binding protein, alpha transducing 2; HSCT: hematopoietic stem cell transplantation; INL: inner nuclear layer; LC3: microtubule-associated protein 1 light chain 3 alpha; MPS: mucopolysaccharidoses; NAGLU: alpha-N-acetylglucosaminidase (Sanfilippo disease IIIB); ONL: outer nuclear layer; PBS: phosphate-buffered saline; PRKCA/PKCα: protein kinase C, alpha; S1BF: somatosensory cortex; SQSTM1: sequestosome 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; VMP/VPL: ventral posterior nuclei of the thalamus.

Characterization of Retinal Ganglion Cell and Optic Nerve Phenotypes Caused by Sustained Intracranial Pressure Elevation in Mice.

Elevated intracranial pressure (ICP) can result in multiple neurologic sequelae including vision loss. Inducible models of ICP elevation are lacking in model organisms, which limits our understanding of the mechanism by which increased ICP impacts the visual system. We adapted a mouse model for the sustained elevation of ICP and tested the hypothesis that elevated ICP impacts the optic nerve and retinal ganglion cells (RGCs). ICP was elevated and maintained for 2 weeks, and resulted in multiple anatomic changes that are consistent with human disease including papilledema, loss of physiologic cupping, and engorgement of the optic nerve head. Elevated ICP caused a loss of RGC somas in the retina and RGC axons within the optic nerve, as well as a reduction in both RGC electrical function and contrast sensitivity. Elevated ICP also caused increased hypoxia-inducible factor (HIF)-1 alpha expression in the ganglion cell layer. These experiments confirm that sustained ICP elevation can be achieved in mice and causes phenotypes that preferentially impact RGCs and are similar to those seen in human disease. With this model, it is possible to model human diseases of elevated ICP such as Idiopathic Intracranial Hypertension and Spaceflight Associated Neuro-ocular Syndrome.

The ocular toxicity and pharmacokinetics of simvastatin following intravitreal injection in mice.

AIM: To investigate the retinal toxicity and pharmacokinetics of simvastatin intravitreally injected into mice. METHODS: Forty-eight 6-8-week-old C57BL/6J mice were used in this study. Simvastatin was intravitreally injected into the right eye of each mouse; the left eye was injected with vehicle and was used as a control. Bilateral dark-adapted electroretinography (ERG) was performed 1 and 7d following injection. Histology was examined using a combination of light, fluorescence and electron microscopy. High-performance liquid chromatography (HPLC) was used to determine the decay in the retinal simvastatin concentration. RESULTS: ERG revealed no significant changes in the simvastatin-injected eyes compared to control. Histologic studies showed normal retinal morphology in eyes injected with simvastatin up to a final vitreal concentration of 200 µmol/L. No significant changes in the number of photoreceptors, bipolar cells or ganglion cells were found. The retinal simvastatin concentration decayed exponentially, with a half-life of 1.92-2.41h. CONCLUSION: Intravitreal injection of up to 200 µmol/L simvastatin produced no signs of adverse effects in the mouse retina. Simvastatin reaches the retina shortly after intravitreal injectionand has a short half-life.

Corrigendum: mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases.

This corrects the article DOI: 10.1038/ncomms14338.

mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases.

Neurodegenerative diseases characterized by aberrant accumulation of undigested cellular components represent unmet medical conditions for which the identification of actionable targets is urgently needed. Here we identify a pharmacologically actionable pathway that controls cellular clearance via Akt modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathways. We show that Akt phosphorylates TFEB at Ser467 and represses TFEB nuclear translocation independently of mechanistic target of rapamycin complex 1 (mTORC1), a known TFEB inhibitor. The autophagy enhancer trehalose activates TFEB by diminishing Akt activity. Administration of trehalose to a mouse model of Batten disease, a prototypical neurodegenerative disease presenting with intralysosomal storage, enhances clearance of proteolipid aggregates, reduces neuropathology and prolongs survival of diseased mice. Pharmacological inhibition of Akt promotes cellular clearance in cells from patients with a variety of lysosomal diseases, thus suggesting broad applicability of this approach. These findings open new perspectives for the clinical translation of TFEB-mediated enhancement of cellular clearance in neurodegenerative storage diseases.

Phosphatidylinositol-3-phosphate is light-regulated and essential for survival in retinal rods.

Phosphoinositides play important roles in numerous intracellular membrane pathways. Little is known about the regulation or function of these lipids in rod photoreceptor cells, which have highly active membrane dynamics. Using new assays with femtomole sensitivity, we determined that whereas levels of phosphatidylinositol-3,4-bisphosphate and phosphatidylinositol-3,4,5-trisphosphate were below detection limits, phosphatidylinositol-3-phosphate (PI(3)P) levels in rod inner/outer segments increased more than 30-fold after light exposure. This increase was blocked in a rod-specific knockout of the PI-3 kinase Vps34, resulting in failure of endosomal and autophagy-related membranes to fuse with lysosomes, and accumulation of abnormal membrane structures. At early ages, rods displayed normal morphology, rhodopsin trafficking, and light responses, but underwent progressive neurodegeneration with eventual loss of both rods and cones by twelve weeks. The degeneration is considerably faster than in rod knockouts of autophagy genes, indicating defects in endosome recycling or other PI(3)P-dependent membrane trafficking pathways are also essential for rod survival.

Electrophysiological and Histological Characterization of Rod-Cone Retinal Degeneration and Microglia Activation in a Mouse Model of Mucopolysaccharidosis Type IIIB.

Sanfilippo syndrome Type B or Mucopolysaccharidosis IIIB (MPS IIIB) is a neurodegenerative autosomal recessive lysosomal storage disorder in which patients suffer severe vision loss from associated retinopathy. Here we sought to study the underlying retinal functional and morphological changes associated with MPS IIIB disease progression using the established model of MPS IIIB, the B6.129S6-Naglu(tm1Efn)/J mouse line. Electroretinogram (ERG) was recorded from MPS IIIB and wild-type (WT) mice at the age of 28 and 46 weeks, and retinal tissues were subsequently collected for immunohistochemistry analysis. At the 28th week, rod a- and b-wave amplitudes were significantly diminished in MPS IIIB compared to WT mice. The cone a- and b-waves of MPS IIIB mice were not significantly different from those of the control at the 28th week but were significantly diminished at the 46 th week, when MPS IIIB mice showed a major loss of rods and rod bipolar cells in both central and peripheral regions and a minor loss of cones in the periphery. Activation of microglia and neovascularization were also detected in the MPS IIIB retina. The new findings that cones and rod bipolar cells also undergo degeneration, and that retinal microglia are activated, will inform future development of therapeutic strategies.

[Study of guinea pig refractive status and ocular length during the early recovery from lens-induced myopia].

OBJECTIVE: To investigate changes in refractive status and ocular length in guinea pigs during the early time of myopic recovery for the causes of recovery. METHODS: Exp guinea pigs wore a -5.00 D lens on one eye from 4-18 days, which was then removed for 48 hours. At 18 and 20 days of age, each eye was evaluated for refractive status and ocular length of the eye. RESULTS: The right eyes treated with -5 D lenses for 12 days developed (-2.00 ± 1.50) D (P = 0.04) of myopia and had an increase in axial length of (0.033 ± 0.025) mm compared to the left eyes (P = 0.04). After 48 hours of recovery, the difference between the two eyes was reduced to (-0.72 ± 0.86) D (P = 0.13), but the ocular length still had significant difference (0.031 ± 0.022) mm (P = 0.04). During the myopia recovery early period, the refractive status and ocular length changed in the same direction in the left eyes but in the opposite way in the right eyes. CONCLUSIONS: Guinea pigs treated with -5.00 D lenses for 12 days developed explicit relative axial myopia. After removal of the lens for 48 hours, myopia significantly recovery can be due to the thickening of choroid and the reduction in ocular growth.

Prolonged elevation of intraocular pressure results in retinal ganglion cell loss and abnormal retinal function in mice.

The purpose of this study was to assess the impact of prolonged intraocular pressure (IOP) elevation on retinal anatomy and function in a mouse model of experimental glaucoma. IOP was elevated by anterior chamber injection of a fixed combination of polystyrene beads and sodium hyaluronate, and maintained via re-injection after 24 weeks. IOP was measured weekly with a rebound tonometer for 48 weeks. Histology was assessed with a combination of retrograde labeling and antibody staining. Retinal physiology and function was assessed with dark-adapted electroretinograms (ERGs). Comparisons between bead-injected animals and various controls were conducted at both 24 and 48 weeks after bead injection. IOP was elevated throughout the study. IOP elevation resulted in a reduction of retinal ganglion cell (RGCs) and an increase in axial length at both 24 and 48 weeks after bead injection. The b-wave amplitude of the ERG was increased to the same degree in bead-injected eyes at both time points, similar to previous studies. The positive scotopic threshold response (pSTR) amplitude, a measure of RGC electrical function, was diminished at both 24 and 48 weeks when normalized to the increased b-wave amplitude. At 48 weeks, the pSTR amplitude was reduced even without normalization, suggesting more profound RGC dysfunction. We conclude that injection of polystyrene beads and sodium hyaluronate causes chronic IOP elevation which results in phenotypes of stable b-wave amplitude increase and progressive pSTR amplitude reduction, as well as RGC loss and axial length elongation.

WFDC1 is a key modulator of inflammatory and wound repair responses.

WFDC1/ps20 is a whey acidic protein four-disulfide core member that exhibits diverse growth and immune-associated functions in vitro. In vivo functions are unknown, although WFDC1 is lower in reactive stroma. A Wfdc1-null mouse was generated to assess core functions. Wfdc1-null mice exhibited normal developmental and adult phenotypes. However, homeostasis challenges affected inflammatory and repair processes. Wfdc1-null mice infected with influenza A exhibited 2.75-log-fold lower viral titer relative to control mice. Wfdc1-null infected lungs exhibited elevated macrophages and deposition of osteopontin, a potent macrophage chemokine. In wounding studies, Wfdc1-null mice exhibited an elevated rate of skin closure, and this too was associated with elevated deposition of osteopontin and macrophage recruitment. Wfdc1-null fibroblasts exhibited impaired spheroid formation, elevated adhesion to fibronectin, and an increased rate of wound closure in vitro. This was reversed by neutralizing antibody to osteopontin. Osteopontin mRNA and cleaved protein was up-regulated in Wfdc1-null cells treated with lipopolysaccharide or polyinosinic-polycytidylic acid coordinate with constitutively active matrix metallopeptidase-9 (MMP-9), a protease that cleaves osteopontin. These data suggest that WFDC1/ps20 modulates core host response mechanisms, in part, via regulation of osteopontin and MMP-9 activity. Release from WFDC1 regulation is likely a key component of inflammatory and repair response mechanisms, and involves the processing of elevated osteopontin by activated MMP-9, and subsequent macrophage recruitment.

Pharmacological inhibitions of glutamate transporters EAAT1 and EAAT2 compromise glutamate transport in photoreceptor to ON-bipolar cell synapses.

To maintain reliable signal transmission across a synapse, free synaptic neurotransmitters must be removed from the cleft in a timely manner. In the first visual synapse, this critical task is mainly undertaken by glutamate transporters (EAATs). Here we study the differential roles of the EAAT1, EAAT2 and EAAT5 subtypes in glutamate (GLU) uptake at the photoreceptor-to-depolarizing bipolar cell synapse in intact dark-adapted retina. Various doses of EAAT blockers and/or GLU were injected into the eye before the electroretinogram (ERG) was measured. Their effectiveness and potency in inhibiting the ERG b-wave were studied to determine their relative contributions to the GLU clearing activity at the synapse. The results showed that EAAT1 and EAAT2 plays different roles. Selectively blocking glial EAAT1 alone using UCPH101 inhibited the b-wave 2-24h following injection, suggesting a dominating role of EAAT1 in the overall GLU clearing capacity in the synaptic cleft. Selectively blocking EAAT2 on photoreceptor terminals had no significant effect on the b-wave, but increased the potency of exogenous GLU in inhibiting the b-wave. These suggest that EAAT2 play a secondary yet significant role in the GLU reuptake activity at the rod and the cone output synapses. Additionally, we have verified our electrophysiological findings with double-label immunohistochemistry, and extend the literature on the spatial distribution of EAAT2 splice variants in the mouse retina.

Egr-1 mRNA expression is a marker for the direction of mammalian ocular growth.

PURPOSE: The immediate early gene Egr-1 is thought to form part of the pathway that mediates abnormal ocular growth. This study investigated whether the mRNA expression levels of Egr-1 in a mammalian retina are modulated differentially, depending on the direction of ocular growth. METHODS: To induce accelerated growth and myopia, guinea pigs wore a -5 diopter (D) lens over one eye from 4 to 11 days of age. To induce inhibited growth, the lens was removed after 7 days of -5 D lens wear, and the eye allowed to recover from myopia for 3 days. Ocular parameters and Egr-1 mRNA levels were subsequently assessed, and compared to untreated fellow eyes and eyes from untreated littermates. Possible circadian changes in Egr-1 mRNA levels were also determined in 18 additional animals by taking measures every 4 hours during a 24-hour cycle. RESULTS: Ocular compensation to a -5 D lens occurred after 7 days (Δ -4.8 D, Δ +147 µm growth, N = 20). In 5 highly myopic eyes (Δ -7.4 D), Egr-1 mRNA levels in the retina were significantly downregulated relative to contralateral control (51%) and age-matched untreated (47%) eyes. Three days after the -5 D lens was removed, eyes had recovered from the myopia (Δ -0.5 D, relative change of +2.9 D, N = 4) and Egr-1 mRNA levels were significantly elevated relative to contralateral (212%) and untreated (234%) eyes, respectively. Normal Egr-1 mRNA expression was higher in the middle of the day than in the middle of the night. Immunolabeling showed strong Egr-1 reactivity in cell bodies in the inner nuclear and ganglion cell layers. CONCLUSIONS: Egr-1 mRNA levels in a mammalian retina show a bi-directional persistent response to opposing ocular growth stimuli. This suggests retinal Egr-1 might act as a signal for the direction of ocular growth in different species.

Possible roles of glutamate transporter EAAT5 in mouse cone depolarizing bipolar cell light responses.

A remarkable feature of neuronal glutamate transporters (EAATs) is their dual functions of classical carriers and ligand-gated chloride (Cl(-)) channels. Cl(-) conductance is rapidly activated by glutamate in subtype EAAT5, which mediates light responses in depolarizing bipolar cells (DBC) in retinae of lower vertebrates. In this study, we examine whether EAAT5 also mediates the DBC light response in mouse. We took advantage of an infrared illuminated micro-injection system, and studied the effects of the EAAT blocker (TBOA) and a glutamate receptor agonist (LAP4) on the mouse electroretinogram (ERG) b-wave responses. Our results showed that TBOA and LAP4 shared similar temporal patterns of inhibition: both inhibited the ERG b-wave shortly after injection and recovered with similar time courses. TBOA inhibited the b-wave completely at mesopic light intensity with an IC50 value about 1 log unit higher than that of LAP4. The inhibitory effects of TBOA and LAP4 were found to be additive in the photopic range. Furthermore, TBOA alone inhibited the b-wave in the cone operative range in knockout mice lacking DBCRs at a low concentration that did not alter synaptic glutamate clearance activity. It also produced a stronger inhibition than that of LAP4 on the cone-driven b-wave measured with a double flash method in wildtype mice. These electrophysiological data suggest a significant role for EAAT5 in mediating cone-driven DBC light responses. Our immunohistochemistry data indicated the presence of postsynaptic EAAT5 on some DBCCs and some DBCRs, providing an anatomical basis for EAAT5's role in DBC light responses.

Integration of defocus by dual power Fresnel lenses inhibits myopia in the mammalian eye.

PURPOSE: Eye growth compensates in opposite directions to single vision (SV) negative and positive lenses. We evaluated the response of the guinea pig eye to Fresnel-type lenses incorporating two different powers. METHODS: A total of 114 guinea pigs (10 groups with 9-14 in each) wore a lens over one eye and interocular differences in refractive error and ocular dimensions were measured in each of three experiments. First, the effects of three Fresnel designs with various diopter (D) combinations (-5D/0D; +5D/0D or -5D/+5D dual power) were compared to three SV lenses (-5D, +5D, or 0D). Second, the ratio of -5D and +5D power in a Fresnel lens was varied (50:50 compared with 60:40). Third, myopia was induced by 4 days of exposure to a SV -5D lens, which was then exchanged for a Fresnel lens (-5D/+5D) or one of two SV lenses (+5D or -5D) and ocular parameters tracked for a further 3 weeks. RESULTS: Dual power lenses induced an intermediate response between that to the two constituent powers (lenses +5D, +5D/0D, 0D, -5D/+5D, -5D/0D and -5D induced +2.1 D, +0.7 D, +0.1 D, -0.3 D, -1.6 D and -5.1 D in mean intraocular differences in refractive error, respectively), and changing the ratio of powers induced responses equal to their weighted average. In already myopic animals, continued treatment with SV negative lenses increased their myopia (from -3.3 D to -4.2 D), while switching to SV positive lenses or -5D/+5D Fresnel lenses reduced their myopia (by 2.9 D and 2.3 D, respectively). CONCLUSIONS: The mammalian eye integrates competing defocus to guide its refractive development and eye growth. Fresnel lenses, incorporating positive or plano power with negative power, can slow ocular growth, suggesting that such designs may control myopia progression in humans.

Elevated intraocular pressure causes inner retinal dysfunction before cell loss in a mouse model of experimental glaucoma.

PURPOSE: We assessed the relationship among intraocular pressure (IOP), histology, and retinal function changes in a mouse model of induced, chronic, mild ocular hypertension. METHODS: IOP was elevated experimentally via anterior chamber injection of polystyrene beads and measured twice weekly with a rebound tonometer. Histology was assessed with a combination of neurobiotin (NB) retrograde labeling of retinal ganglion cells (RGCs) and TO-PRO3 staining. Retinal function was assessed with serial dark-adapted electroretinograms (ERGs) optimized for detection of the a-wave, b-wave, and positive and negative scotopic threshold responses (pSTR, nSTR). Comparisons between bead-injected and saline-injected (control) eyes were conducted. RESULTS: IOP remained elevated for at least 3 months following a single injection of polystyrene beads. Elevated IOP resulted in a mild, progressive reduction of RGCs, and a mild increase in axial length at 6 and 12 weeks after bead injection. The raw b-wave amplitude was increased shortly after IOP elevation, but the raw a-wave, pSTR, and nSTR amplitudes were unchanged. pSTR and nSTR amplitudes were normalized to the increased b-wave. With this normalization, the pSTR amplitude was decreased shortly after IOP elevation. CONCLUSIONS: Polystyrene bead injection results in a mild, chronic elevation of IOP that recapitulates several critical aspects of human ocular hypertension and glaucoma, and results in early changes in retinal electrical function that precede histologic changes. It is possible that glaucoma associated with elevated IOP involves the early disruption of a complex combination of retinal synapses.

Graded competing regional myopic and hyperopic defocus produce summated emmetropization set points in chick.

PURPOSE: Chicks emmetropize accurately to experimentally induced myopic and hyperopic defocus. The authors investigated the emmetropization response when a specific proportion of the retina was exposed to myopic defocus while the remainder was exposed to (competing) hyperopic defocus. METHODS: Normal chicks (14-15 days old) were fitted monocularly with a "lens-cone" device that exposed a specific proportion of the available visual field to a high-contrast grating under 10 diopters (D) of myopic defocus (with accommodation relaxed) in a series of patches. The remainder of the visual field (adjacent patches) viewed a grating under 10 D of hyperopic defocus. Groups of chicks wore a lens-cone device designed to provide a "spatial ratio" (relative proportion of visual field area) of 100:0, 50:50, 40:60, 33:67, 25:75, or 0:100 myopic versus hyperopic defocus. On-axis ocular refraction and axial ocular component dimensions were assessed after 3 and 6 days of cone wear. RESULTS: Interocular differences in refraction (mean ± SD) at day 6 were as follows: +10.4 ± 2.5 D, +7.6 ± 3.6 D, +5.9 ± 3.7 D, +1.6 ± 2.6 D, -2.4 ± 2.7 D, and -8.9 ± 2.6 D for spatial ratios of 100:0, 50:50, 40:60. 33:67, 25:75, and 0:100 respectively. The corresponding interocular vitreous chamber depths were as follows: -515 ± 135 µm, -447 ± 137 µm, -253 ± 220 µm, -105 ± 252 µm, 230 ± 218 µm, and 592 ± 161 µm. The refraction and biometry results for the 33:67 and 25:75 groups were significantly different from those of the single defocus control groups. CONCLUSIONS: In chicks, the on-axis emmetropization response was weighted according to the spatial ratio. Thus, as the proportion of retinal area receiving myopic defocus increased relative to that receiving hyperopic defocus, the degree of myopic eye growth was reduced.