Sturge-Weber syndrome is a nonhereditary congenital neurocutaneous syndrome characterized by leptomeningeal angiomatosis, facial nevus flammeus, and diffuse choroidal hemangioma, which when complicated by total retinal detachment, portend a poor prognosis. Management is often limited to salvage external beam irradiation. We present a modified proton therapy technique for young children with total bullous retinal detachments that uses standard fractionation low-dose proton radiotherapy to decrease the risk of radiation complications. Treatment techniques for young children who cannot cooperate with conventional radiation protocols are also described.

UNLABELLED: The vascular beds supplying the retina may sustain injury as a result of underlying disease such as diabetes, and/or the interaction of genetic predisposition, environmental insults, and age. The vascular pathologic features observed in different intraocular vascular diseases can be categorized broadly as proliferation, exemplified by proliferative diabetic retinopathy, leakage such as macular edema secondary to retinal vein occlusion, or a combination of proliferation and leakage, as seen in neovascular age-related macular degeneration (AMD). The World Health Organization has identified diabetic retinopathy and AMD as priority eye diseases for the prevention of vision loss in developed countries. The pathologic transformations of the retinal vasculature seen in intraocular vascular disease are associated with increased expression of vascular endothelial growth factor A (VEGF), a potent endothelial-specific mitogen. Furthermore, in model systems, VEGF alone is sufficient to trigger intraocular neovascularization, and its inhibition is associated with functional and anatomic improvements in the affected eye. Therapeutic interventions with effect on VEGF include intraocular capture and neutralization by engineered antibodies or chimeric receptors, downregulation of its expression with steroids, or alleviation of retinal ischemia, a major stimulus for VEGF expression, with retinal ablation by laser treatment. Data from prospective randomized clinical trials indicate that VEGF inhibition is a potent therapeutic strategy for intraocular vascular disease. These findings are changing clinical practice and are stimuli for further study of the basic mechanisms controlling intraocular angiogenesis. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

PURPOSE: To present a case with bilateral choroidal neovascularization (CNV) secondary to acute disseminated encephalomyelitis-associated choroiditis requiring immunomodulatory therapy for prevention of recurrence. METHODS: The clinical course of a patient diagnosed with acute disseminated encephalomyelitis, who developed bilateral choroiditis at the time of his neurologic diagnosis and bilateral CNV 6 years later, is reviewed. PATIENT: A 57-year-old man developed CNV in both eyes, 6 years after the initial diagnosis of acute disseminated encephalomyelitis-associated choroiditis. The patient was initially treated successfully with intravitreal bevacizumab injections and oral prednisone, but CNV recurred with steroid tapering. Mycophenolate mofetil was initiated as steroid-sparing immunomodulatory therapy. RESULTS: There was no CNV recurrence for 1.5 years without the need for additional antiangiogenic therapy. CONCLUSION: To our best knowledge, this is the first report of choroiditis and secondary CNV associated with acute disseminated encephalomyelitis. In cases of recurrent CNV associated with choroiditis, systemic therapy should be strongly considered in conjunction with antiangiogenic therapy. The recurrence of CNV with tapering of oral steroids and the remission of CNV with steroid-sparing immunomodulatory therapy support the role of ongoing inflammation in the pathogenesis.

Fundus autofluorescence (FAF) is being increasingly employed in the evaluation of retinal diseases. We report the first description of FAF findings during the natural history of ampiginous choroiditis and correlate these findings to fundus photography, infrared imaging, and cross-sectional optical coherence tomography. In a patient with a 12-month recurring, relapsing course of ampiginous choroiditis, there was a predictable pattern of FAF findings. At the time of presentation with a whitish-yellow, creamy clinical lesion, FAF reveals a diffuse, subtle hyperautofluorescence at the site of activity. As the clinical lesion fades, the FAF takes on a more intense, discrete, coalesced hyperautofluorescence, which decreases and becomes stippled over time, eventually giving way to a patch of hypoautofluorescence at the site of inactivity. Examination over the patient's long course suggests that FAF evolves predictably during exacerbations and remissions, and the FAF findings reveal activity well after the clinical lesion resolves. FAF is a simple, noninvasive, and effective modality for following the evolution of ampiginous choroiditis.

Proliferative vitreoretinopathy (PVR) exemplifies a disease that is difficult to predict, lacks effective treatment options, and substantially reduces the quality of life of an individual. Surgery to correct a rhegmatogenous retinal detachment fails primarily because of PVR. Likely mediators of PVR are growth factors in vitreous, which stimulate cells within and behind the retina as an inevitable consequence of a breached retina. Three classes of growth factors [vascular endothelial growth factor A (VEGF-A), platelet-derived growth factors (PDGFs), and non-PDGFs (growth factors outside of the PDGF family)] are relevant to PVR pathogenesis because they act on PDGF receptor α, which is required for experimental PVR and is associated with this disease in humans. We discovered that ranibizumab (a clinically approved agent that neutralizes VEGF-A) reduced the bioactivity of vitreous from patients and experimental animals with PVR, and protected rabbits from developing disease. The apparent mechanism of ranibizumab action involved derepressing PDGFs, which, at the concentrations present in PVR vitreous, inhibited non-PDGF-mediated activation of PDGF receptor α. These preclinical findings suggest that available approaches to neutralize VEGF-A are prophylactic for PVR, and that anti-VEGF-based therapies may be effective for managing more than angiogenesis- and edema-driven pathological conditions.

PURPOSE: To investigate photoreceptor and postreceptor retinal function in patients with congenital stationary night blindness (CSNB). METHODS: Forty-one patients with CSNB (ages 0.19-32 years) were studied. ERG responses to a series of full-field stimuli were obtained under scotopic and photopic conditions and were used to categorize the CSNB patients as complete (cCSNB) or incomplete (iCSNB). Rod and cone photoreceptor (R(ROD), S(ROD), R(CONE), S(CONE)) and rod-driven postreceptor (V(MAX), log σ) response parameters were calculated from the a- and b-waves. Cone-driven responses to 30 Hz flicker and ON and OFF responses to a long duration (150 ms) flash were also obtained. Dark-adapted thresholds were measured. Analysis of variance was used to compare data from patients with cCSNB, patients with iCSNB, and controls. RESULTS: We found significant reduction in saturated photoreceptor amplitude (R(ROD), R(CONE)) but normal photoreceptor sensitivity (S(ROD), S(CONE)) in both CSNB groups. Rod-driven postreceptor response amplitude (V(MAX)) and sensitivity (log σ) were significantly reduced in CSNB. Log σ was significantly worse in cCSNB than in iCSNB; this was the only scotopic parameter that differed between the two CSNB groups. Photopic b-wave amplitude increased monotonically with stimulus strength in CSNB patients rather than showing a normal photopic hill. The amplitude of the 30-Hz flicker response was reduced compared with controls, more so in iCSNB than in cCSNB. The mean dark-adapted threshold was significantly elevated in CSNB, more so in cCSNB than in iCSNB. CONCLUSIONS: These results are evidence of normal photoreceptor function (despite the low saturated photoresponse amplitude) and anomalous postreceptor retinal circuitry.

PURPOSE: To characterize a unique cytomegalovirus (CMV)-associated retinopathy in patients with limited immune dysfunction. METHODS: Retrospective observational case series. CMV was confirmed as the pathogenic agent via polymerase chain reaction analysis of aqueous or vitreous humor samples or via immunohistochemical analysis of retinal biopsy specimens. RESULTS: Five non-HIV patients with granular necrotizing retinitis, vitritis, and severe occlusive vasculopathy were identified. Patient histories all suggested a basis for limited immune dysfunction including advanced age (n = 4), diabetes mellitus (n = 4), and noncytotoxic immunotherapy (n = 3). Diagnosis of CMV retinitis was delayed in all cases and patients received either no antiviral therapy (n = 2) or incorrect antiviral therapy (n = 3) for presumed herpes simplex/varicella zoster-related acute retinal necrosis. Retinitis subsequently regressed in all cases with introduction of systemic ganciclovir/valganciclovir (n = 5) and/or intravitreal foscarnet (n = 2). Four of five patients developed neovascularization because of extensive retinal ischemia. CONCLUSION: The clinical expression of CMV-associated retinopathy is strongly related to immune status. In patients with limited immune dysfunction, a mixed clinical picture of intraocular inflammation with panretinal occlusive vasculopathy, more characteristic of acute retinal necrosis, and peripheral slowly progressive granular retinitis, more characteristic of classic CMV retinitis, is observed. Recognition of this atypical clinical presentation, which the authors term chronic retinal necrosis, should prompt molecular testing for CMV to determine the appropriate antiviral therapy. Consideration should also be given to prophylactic panretinal photocoagulation in such eyes, given the high risk of neovascular complications.

Purpose. We describe in detail a relatively simple technique of fundus photography in human and rabbit eyes using a smartphone, an inexpensive app for the smartphone, and instruments that are readily available in an ophthalmic practice. Methods. Fundus images were captured with a smartphone and a 20D lens with or without a Koeppe lens. By using the coaxial light source of the phone, this system works as an indirect ophthalmoscope that creates a digital image of the fundus. The application whose software allows for independent control of focus, exposure, and light intensity during video filming was used. With this app, we recorded high-definition videos of the fundus and subsequently extracted high-quality, still images from the video clip. Results. The described technique of smartphone fundus photography was able to capture excellent high-quality fundus images in both children under anesthesia and in awake adults. Excellent images were acquired with the 20D lens alone in the clinic, and the addition of the Koeppe lens in the operating room resulted in the best quality images. Successful photodocumentation of rabbit fundus was achieved in control and experimental eyes. Conclusion. The currently described system was able to take consistently high-quality fundus photographs in patients and in animals using readily available instruments that are portable with simple power sources. It is relatively simple to master, is relatively inexpensive, and can take advantage of the expanding mobile-telephone networks for telemedicine.

X-linked juvenile retinoschisis (XLRS) is one of the most common genetic causes of juvenile progressive retinal-vitreal degeneration in males. To date, more than 196 different mutations of the RS1 gene have been associated with XLRS. The mutation spectrum is large and the phenotype variable. This review will focus on the clinical features of XLRS and examine the relationship between phenotype and genotype.

The central region of the human retina, the fovea, provides high-acuity vision. The oculomotor system continually brings targets of interest into the fovea via ballistic eye movements (saccades). Thus, the fovea serves both as the locus for fixations and as the oculomotor reference for saccades. This highly automated process of foveation is functionally critical to vision and is observed from infancy. How would the oculomotor system adjust to a loss of foveal vision (central scotoma)? Clinical observations of patients with central vision loss suggest a lengthy adjustment period, but the nature and dynamics of this adjustment remain unclear. Here, we demonstrate that the oculomotor system can spontaneously and rapidly adopt a peripheral locus for fixation and can rereference saccades to this locus in normally sighted individuals whose central vision is blocked by an artificial scotoma. Once developed, the fixation locus is retained over weeks in the absence of the simulated scotoma. Our data reveal a basic guiding principle of the oculomotor system that prefers control simplicity over optimality. We demonstrate the importance of a visible scotoma on the speed of the adjustment and suggest a possible rehabilitation regimen for patients with central vision loss.

The popularization of ophthalmic endoscopy has been promoted by recent technological advancements that increase the number of indications for endoscopy. These advancements have improved the endoscope's capabilities in its two fundamental surgical advantages: (1) bypassing anterior segment opacities, and (2) visualizing anteriorly positioned structures such as the ciliary bodies and sub-iris space. In this article, the current state of the ophthalmic endoscope is reviewed alongside its growing number of applications in glaucoma, vitreoretinal, and ocular trauma surgery. We describe the role of endoscopy in endocyclophotocoagulation for glaucoma, cyclitic membrane peeling in hypotony, retinal detachment surgery, intraocular foreign body removal, severe endophthalmitis, and pediatric traumatic vitreoretinal surgery. This review examines both the pearls and limitations of the ophthalmic application of endoscopy. In doing so, we hope to provide guidelines for using the endoscope and also to highlight applications of endoscopy that merit further study.

Subretinal injection of sodium hyaluronate is a widely accepted method of inducing retinal detachment (RD). However, the height and duration of RD or the occurrence of subretinal hemorrhage can affect photoreceptor cell death in the detached retina. Hence, it is advantageous to create reproducible RDs without subretinal hemorrhage for evaluating photoreceptor cell death. We modified a previously reported method to create bullous and persistent RDs in a reproducible location with rare occurrence of subretinal hemorrhage. The critical step of this modified method is the creation of a self-sealing scleral incision, which can prevent leakage of sodium hyaluronate after injection into the subretinal space. To make the self-sealing scleral incision, a scleral tunnel is created, followed by scleral penetration into the choroid with a 30 G needle. Although choroidal hemorrhage may occur during this step, astriction with a surgical spear reduces the rate of choroidal hemorrhage. This method allows a more reproducible and reliable model of photoreceptor death in diseases that involve RD such as rhegmatogenous RD, retinopathy of prematurity, diabetic retinopathy, central serous chorioretinopathy, and age-related macular degeneration (AMD). [corrected].

Previous studies have demonstrated that ocular injury can lead to prompt infiltration of bone-marrow-derived peripheral monocytes into the retina. However, the ability of these cells to integrate into the tissue and become microglia has not been investigated. Here we show that such peripheral monocytes that infiltrate into the retina after ocular injury engraft permanently, migrate to the three distinct microglia strata, and adopt a microglia-like morphology. In the absence of ocular injury, peripheral monocytes that repopulate the retina after depletion with colony-stimulating factor 1 receptor (CSF1R) inhibitor remain sensitive to CSF1R inhibition and can be redepleted. Strikingly, consequent to ocular injury, the engrafted peripheral monocytes are resistant to depletion by CSF1R inhibitor and likely express low CSF1R. Moreover, these engrafted monocytes remain proinflammatory, expressing high levels of MHC-II, IL-1β, and TNF-α over the long term. The observed permanent neuroglia remodeling after injury constitutes a major immunological change that may contribute to progressive retinal degeneration. These findings may also be relevant to other degenerative conditions of the retina and the central nervous system.

BACKGROUND: To evaluate changes in image sharpness across ultrawide field (UWF) images and the effect of phase-plate adjustment on image contrast and extent of visible retinal area (VRA). METHODS: This was a single site evaluation of 200° UWF images acquired with phase-plate adjustment (California, Optos, plc) and without (200TX, Optos, plc). Images were acquired using standardized protocol. VRA was manually outlined on each image and quantified using customized software. Mean image sharpness was evaluated using an automated method within the full VRA of each image and within the peripheral region of the VRA. The VRA and image sharpness were evaluated and compared between the two devices. RESULTS: Twenty eyes of 10 healthy volunteers were evaluated. Devices with and without phase-plate adjustment produced a similar extent of VRA. Eye steering increased VRA in devices with and without phase-plate adjustment by 39.3% and 34.3%, respectively. Regardless of gaze direction, mean sharpness of the full VRA was reduced in peripheral area with or without phase-plate adjustment. Compared to images without phase-plate adjustment, use of phase-plate adjustment reduced the loss of peripheral image sharpness in all fields (-4.2 to -26.0%; p < 0.001 all fields). The sharpness of the peripheral area for on-axis images was 61.5% higher with phase-plate adjustment. CONCLUSIONS: The use of phase-plate adjustment does not alter the extent of VRA. However, for on-axis images the loss of sharpness in the periphery is 4.5-fold less with phase-plate adjustment, potentially reducing the need to steer images and improving lesion detection in these areas.

Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a clinically heterogeneous maculopathy that may mimic other conditions and be difficult to diagnose. It is characterized by late onset, slow progression and high variability in morphologic and functional alterations. Diagnostic evaluation should include careful ophthalmoscopy and imaging studies. The typical ophthalmoscopic findings are bilateral, asymmetric, foveal or perifoveal, yellow, solitary, round to oval elevated subretinal lesions, often with central pigmentation. The lesions characteristically demonstrate increased autofluorescence and hypofluorescent lesions surrounded by irregular annular hyperfluorescence on fluorescein angiography. Optical coherence tomography studies demonstrate homogenous or heterogeneous hyperreflective material between the retinal pigment epithelium and the neurosensory retina. The visual prognosis is generally favorable, but visual loss can occur from chorioretinal atrophy and choroidal neovascularization.

The receptive fields of early visual neurons are anchored in retinotopic coordinates (Hubel and Wiesel, 1962). Eye movements shift these receptive fields and therefore require that different populations of neurons encode an object's constituent features across saccades. Whether feature groupings are preserved across successive fixations or processing starts anew with each fixation has been hotly debated (Melcher and Morrone, 2003; Melcher, 2005, 2010; Knapen et al., 2009; Cavanagh et al., 2010a,b; Morris et al., 2010). Here we show that feature integration initially occurs within retinotopic coordinates, but is then conserved within a spatiotopic coordinate frame independent of where the features fall on the retinas. With human observers, we first found that the relative timing of visual features plays a critical role in determining the spatial area over which features are grouped. We exploited this temporal dependence of feature integration to show that features co-occurring within 45 ms remain grouped across eye movements. Our results thus challenge purely feedforward models of feature integration (Pelli, 2008; Freeman and Simoncelli, 2011) that begin de novo after every eye movement, and implicate the involvement of brain areas beyond early visual cortex. The strong temporal dependence we quantify and its link with trans-saccadic object perception instead suggest that feature integration depends, at least in part, on feedback from higher brain areas (Mumford, 1992; Rao and Ballard, 1999; Di Lollo et al., 2000; Moore and Armstrong, 2003; Stanford et al., 2010).

PURPOSE: The purpose of this study is to evaluate the functional and morphological changes in subretinal xenografts of human retinal progenitor cells (hRPCs) in B6 mice treated with Cyclosporin A (CsA; 210 mg/l in drinking water). METHODS: The hRPCs from human fetal eyes were isolated and expanded for transplantation. These cells, with green fluorescent protein (GFP) at 11 passages, were transplanted into the subretinal space in B6 mice. A combination of invasive and noninvasive approaches was used to analyze the structural and functional consequences of the subretinal injection of the hRPCs. The process of change was monitored using spectral domain optical coherence tomography (SDOCT), histology, and electroretinography (ERG) at 3 days, 1 week, and 3 weeks after transplantation. Cell counts were used to evaluate the survival rate with a confocal microscope. ERGs were performed to evaluate the physiologic changes, and the structural changes were evaluated using SDOCT and histological examination. RESULTS: The results of the histological examination showed that the hRPCs gained a better survival rate in the mice treated with CsA. The SDOCT showed that the bleb size of the retinal detachment was significantly decreased, and the retinal reattachment was nearly complete by 3 weeks. The ERG response amplitudes in the CsA group were less decreased after the injection, when compared with the control group, in the dark-adapted and light-adapted conditions. However, the cone-mediated function in both groups was less affected by the transplantation after 3 weeks than the rod-mediated function. CONCLUSIONS: Although significant functional and structural recovery was observed after the subretinal injection of the hRPCs, the effectiveness of CsA in xenotransplantation may be a novel and potential approach for increasing retinal progenitor cell survival.

In vertebrate rods and cones, photon capture by rhodopsin leads to the destruction of cyclic GMP (cGMP) and the subsequent closure of cyclic nucleotide gated ion channels in the outer segment plasma membrane. Replenishment of cGMP and reopening of the channels limit the growth of the photon response and are requisite for its recovery. In different vertebrate retinas, there may be as many as four types of membrane guanylyl cyclases (GCs) for cGMP synthesis. Ten neuronal Ca(2+) sensor proteins could potentially modulate their activities. The mouse is proving to be an effective model for characterizing the roles of individual components because its relative simplicity can be reduced further by genetic engineering. There are two types of GC activating proteins (GCAPs) and two types of GCs in mouse rods, whereas cones express one type of GCAP and one type of GC. Mutant mouse rods and cones bereft of both GCAPs have large, long lasting photon responses. Thus, GCAPs normally mediate negative feedback tied to the light-induced decline in intracellular Ca(2+) that accelerates GC activity to curtail the growth and duration of the photon response. Rods from other mutant mice that express a single GCAP type reveal how the two GCAPs normally work together as a team. Because of its lower Ca(2+) affinity, GCAP1 is the first responder that senses the initial decrease in Ca(2+) following photon absorption and acts to limit response amplitude. GCAP2, with a higher Ca(2+) affinity, is recruited later during the course of the photon response as Ca(2+) levels continue to decline further. The main role of GCAP2 is to provide for a timely response recovery and it is particularly important after exposure to very bright light. The multiplicity of GC isozymes and GCAP homologs in the retinas of other vertebrates confers greater flexibility in shaping the photon responses in order to tune visual sensitivity, dynamic range and frequency response.

PURPOSE: To describe a favorable outcome after the surgical repair of a very large macular hole with a neurosensory operculum. METHODS: Case report. A 42-year-old man with a history of decreased vision for 3 months was found to have vision of 20/400, a very large macular hole (1159 μm in diameter), and an operculum suspended on the posterior hyaloid above the hole. RESULTS: Vitrectomy and internal limiting membrane peel were performed. The operculum was processed for histology and found to contain neurons and glial cells. Fourteen months later, the patient's vision improved to 20/60. CONCLUSION: Very large macular holes have traditionally been considered to have a poor prognosis. Here, we demonstrate that such large holes can be repaired with good visual outcome, even in the setting of an operculum consisting of avulsed neural retina.

Irreversible vision loss is most often caused by the loss of function and subsequent death of retinal neurons, such as photoreceptor cells-the cells that initiate vision by capturing and transducing signals of light. One reason why retinal degenerative diseases are devastating is that, once retinal neurons are lost, they don't grow back. Stem cell-based cell replacement strategy for retinal degenerative diseases are leading the way in clinical trials of transplantation therapy, and the exciting findings in both human and animal models point to the possibility of restoring vision through a cell replacement regenerative approach. A less invasive method of retinal regeneration by mobilizing endogenous stem cells is, thus, highly desirable and promising for restoring vision. Although many obstacles remain to be overcome, the field of endogenous retinal repair is progressing at a rapid pace, with encouraging results in recent years.

Retinopathy of prematurity (ROP) is a leading cause of blindness in children worldwide due to increasing survival rates of premature infants. Initial suppression, followed by increased production of the retinal vascular endothelial growth factor-A (VEGF) expression are key events that trigger the pathological neovascularization in ROP. Fatty acid binding protein 4 (FABP4) is an intracellular lipid chaperone that is induced by VEGF in a subset of endothelial cells. FABP4 exhibits a pro-angiogenic function in cultured endothelial cells and in airway microvasculature, but whether it plays a role in modulation of retinal angiogenesis is not known. We hypothesized that FABP4 deficiency could ameliorate pathological retinal vascularization and investigated this hypothesis using a well-characterized mouse model of oxygen-induced retinopathy (OIR). We found that FABP4 was not expressed in retinal vessels, but was present in resident macrophages/microglial cells and endothelial cells of the hyaloid vasculature in the immature retina. While FABP4 expression was not required for normal development of retinal vessels, FABP4 expression was upregulated and localized to neovascular tufts in OIR. FABP4-/- mice demonstrated a significant decrease in neovessel formation as well as a significant improvement in physiological revascularization of the avascular retinal tissues. These alterations in retinal vasculature were accompanied by reduced endothelial cell proliferation, but no effect on apoptosis or macrophage/microglia recruitment. FABP4-/- OIR samples demonstrated decreased expression of genes involved in angiogenesis, such as Placental Growth Factor, and angiopoietin 2. Collectively, our findings suggest FABP4 as a potential target of pathologic retinal angiogenesis in proliferative retinopathies.

Photoreceptor rod outer segment membrane guanylate cyclase (ROS-GC) is central to visual transduction; it generates cyclic GMP, the second messenger of the photon signal. Photoexcited rhodopsin initiates a biochemical cascade that leads to a drop in the intracellular level of cyclic GMP and closure of cyclic nucleotide gated ion channels. Recovery of the photoresponse requires resynthesis of cyclic GMP, typically by a pair of ROS-GCs, 1 and 2. In rods, ROS-GCs exist as complexes with guanylate cyclase activating proteins (GCAPs), which are Ca(2+)-sensing elements. There is a light-induced fall in intracellular Ca(2+). As Ca(2+) dissociates from GCAPs in the 20-200 nM range, ROS-GC activity rises to quicken the photoresponse recovery. GCAPs then progressively turn down ROS-GC activity as Ca(2+) and cyclic GMP levels return to baseline. To date, GCAPs mediate the only known mechanism of ROS-GC regulation in the photoreceptors. However, in mammalian cone outer segments, cone synapses and ON bipolar cells, another Ca(2+) sensor protein, S100B, complexes with ROS-GC1 and senses the Ca(2+) signal with a K1/2 of 400 nM. Unlike GCAPs, S100B stimulates ROS-GC activity when Ca(2+) is bound. Thus, the ROS-GC system in cones functions as a Ca(2+) bimodal switch; with rising intracellular Ca(2+), its activity is first turned down by GCAPs and then turned up by S100B. This presentation provides a historical perspective on the role of S100B in the photoreceptors, offers a pictorial model for the "bimodal" operation of the ROS-GC switch and projects future tasks that are needed to understand its operation. Some accounts of this review have been adopted from the original publications of these authors.

PURPOSE: The clinical phenotype of advanced stage retinopathy of prematurity (ROP, stages 4 and 5) cannot be replicated in an animal model. To dissect the molecular events that can lead up to advanced ROP, we examined subretinal fluid (SRF) and surgically dissected retrolental membranes from patients with advanced ROP to evaluate its influences on cell proliferation, angiogenic properties, and macrophage polarity. METHODS: We compared our findings to SRF collected from patients with uncomplicated rhegmatogenous retinal detachment (RD) without proliferative vitreoretinopathy and surgically dissected epiretinal membrane from eyes with macular pucker. All subretinal fluid samples were equalized for protein. The angiogenic potential of SRF from ROP eyes was measured using a combination of capillary cord formation in a fibrin clot assay, and its proliferative effect was tested with a DNA synthesis of human retinal microvascular endothelial cells. Findings were compared with SRF collected from participants with uncomplicated rhegmatogenous RD without proliferative vitreoretinopathy. The ability of SRF to induce nitric oxide production was measured in vitro using murine J774A.1 macrophages. Cytokine profiles of SRF from ROP and RD eyes were measured using a multienzyme-linked immunosorbent assay (ELISA). Fluorescent immunohistochemistry of retrolental membranes from ROP was performed to detect the presence of leukocytes and the composition of tissue macrophages using markers for M1 and M2 differentiation. RESULTS: The cytokine composition in SRF revealed that in ROP, not only were several proangiogenic factors were preferentially elevated but also the profile of proinflammatory factors was also increased compared to the RD eyes. SRF from ROP eyes supported cell proliferation and endothelial cord formation while SRF from RD eyes had inhibitory effects. SRF from eyes with ROP but not RD robustly induced nitric oxide production in macrophages. Furthermore, fluorescent immunostaining revealed a preponderance of M1 over M2 macrophages in retrolental fibrous membranes from ROP eyes. The cytokine profile and biologic properties of SRF in ROP promote a proangiogenic environment, which supports the maintenance and proliferation of fibrous membranes associated with advanced stages of ROP. In contrast, SRF from RD eyes exhibits a suppressive environment for endothelial cell proliferation and angiogenesis. CONCLUSIONS: Our investigation demonstrates that the microenvironment in advanced ROP eyes is proangiogenic and proinflammatory. These findings suggest that management of advanced ROP should not be limited to the surgical removal of the fibrovascular membranes and antiangiogenic therapy but also directed to anti-inflammatory therapy and to promote M2 activation over M1 activity.