Glaucoma is a progressive optic neuropathy characterized by visual field defects that ultimately lead to irreversible blindness (Alward, 2000; Anderson et al., 2006). By the year 2020, an estimated 80 million people will have glaucoma, 11 million of which will be bilaterally blind. Primary open-angle glaucoma (POAG) is the most common type of glaucoma. Elevated intraocular pressure (IOP) is currently the only risk factor amenable to treatment. How IOP is regulated and can be modulated remains a topic of active investigation. Available therapies, mostly geared toward lowering IOP, offer incomplete protection, and POAG often goes undetected until irreparable damage has been done, highlighting the need for novel therapeutic approaches, drug targets, and biomarkers (Heijl et al., 2002; Quigley, 2011). In this review, the role of soluble (nitric oxide (NO)-activated) and membrane-bound, natriuretic peptide (NP)-activated guanylate cyclases that generate the secondary signaling molecule cyclic guanosine monophosphate (cGMP) in the regulation of IOP and in the pathophysiology of POAG will be discussed.
Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10(-11)). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10(-10)) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.
For profoundly blind individuals, navigating in an unfamiliar building can represent a significant challenge. We investigated the use of an audio-based, virtual environment called Audio-based Environment Simulator (AbES) that can be explored for the purposes of learning the layout of an unfamiliar, complex indoor environment. Furthermore, we compared two modes of interaction with AbES. In one group, blind participants implicitly learned the layout of a target environment while playing an exploratory, goal-directed video game. By comparison, a second group was explicitly taught the same layout following a standard route and instructions provided by a sighted facilitator. As a control, a third group interacted with AbES while playing an exploratory, goal-directed video game however, the explored environment did not correspond to the target layout. Following interaction with AbES, a series of route navigation tasks were carried out in the virtual and physical building represented in the training environment to assess the transfer of acquired spatial information. We found that participants from both modes of interaction were able to transfer the spatial knowledge gained as indexed by their successful route navigation performance. This transfer was not apparent in the control participants. Most notably, the game-based learning strategy was also associated with enhanced performance when participants were required to find alternate routes and short cuts within the target building suggesting that a ludic-based training approach may provide for a more flexible mental representation of the environment. Furthermore, outcome comparisons between early and late blind individuals suggested that greater prior visual experience did not have a significant effect on overall navigation performance following training. Finally, performance did not appear to be associated with other factors of interest such as age, gender, and verbal memory recall. We conclude that the highly interactive and immersive exploration of the virtual environment greatly engages a blind user to develop skills akin to positive near transfer of learning. Learning through a game play strategy appears to confer certain behavioral advantages with respect to how spatial information is acquired and ultimately manipulated for navigation.
IMPORTANCE: A phase 1 study has reported that dry eye disease is the most common adverse effect of human exposure to the antibody figitumumab, an anticancer drug that prevents insulin-like growth factor 1 (IGF-1) from binding to its receptor. We hypothesized that the mechanism underlying this effect is the inhibition of IGF-1 action in epithelial cells of the meibomian gland. OBJECTIVES: To test the hypothesis that IGF-1 stimulates meibomian gland function in vitro and to examine whether growth hormone, a closely related hormone of IGF-1, has the same effect. DESIGN, SETTING, AND MATERIAL: Immortalized human meibomian gland epithelial cells were cultured in the presence or the absence of IGF-1, growth hormone, and an IGF-1 receptor-blocking antibody. Signaling pathways, cell proliferation, neutral lipid staining, and a key protein involved in lipid biogenesis were evaluated. INTERVENTION: Application of IGF-1 and growth hormone to human meibomian gland epithelial cells. MAIN OUTCOMES AND MEASURES: Immunoblotting, cell counting, and neutral lipid staining. RESULTS Insulin-like growth factor 1 activated the phosphoinositol 3-kinase/Akt and forkhead box O1 pathways (showing a dose-dependent effect on immunoblotting), stimulated cellular proliferation (about 1.8-fold increase in cell number), increased sterol regulatory element-binding protein 1 expression (about 3-fold increase on immunoblotting), and promoted lipid accumulation in human meibomian gland epithelial cells (about 2-fold increase in lipid staining). These IGF-1 actions, which may be blocked by cotreatment with the anti-IGF-1 antibody, were accompanied by inconsistent effects on extracellular signal-regulated kinase phosphorylation. We were not able to demonstrate activation of Akt, forkhead box O1, extracellular signal-regulated kinase, Janus kinase 2, or signal transducers and activators of transcription 5, induced cell proliferation, or lipid accumulation in these cells by growth hormone application. CONCLUSIONS AND RELEVANCE: Our results support the hypothesis that IGF-1 acts on human meibomian gland epithelial cells and may explain why treatment with figitumumab, the IGF-1 inhibitor, causes dry eye disease. Ophthalmic care for dry eye disease may be needed when patients with cancer undergo treatment with drugs that inhibit IGF-1 action.
Dacryops of the lacrimal tissue can develop under diverse circumstances. Recent evidence suggests that scarring or obstruction of the lacrimal ducts may lead to their dilatation and formation of a cystic structure. Patients who undergo repeated orbital surgery may therefore be at greater risk of dacryops formation. In this report, a patient who underwent multiple corneal and glaucoma procedures including Boston type II keratoprosthesis, after acid burns to both eyes, is described. Over time, a fluid-filled collection developed in the lower orbit. On surgical exploration and incision, fluid was drained from a cystic lesion which abutted the lacrimal gland and spanned the upper and lower orbits. The lesion was removed and was proven by histopathology and immunohistochemistry to be dacryops. This is the first known case of dacryops associated with Boston type II keratoprosthesis.
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: To describe the diagnostic clinical findings and immunopathology of a fibrous histiocytoma of the upper eyelid tarsus of a 42-year-old man. METHODS: Analysis of clinical features and results of histopathologic and immunohistochemical evaluations using antibodies against the biomarkers smooth muscle actin, S100, CD1a, CD3, CD20, CD31, CD34, CD68, CD163, factor XIIIa, adipophilin, androgen receptor, and Ki-67. RESULTS: The skin moved over a firm lesion that was situated in the tarsus and protruded from the palpebral conjunctiva as a whitish flat-domed noninflamed mass that had caused an irritating corneal epitheliopathy. Histopathologically, there was a storiform or spiral nebular growth pattern, a moderate amount of intercellular collagen, and no nuclear atypia or mitotic activity. The main immunohistochemical findings were CD34 and smooth muscle actin negativity among the tumor cells and a scarcity of CD68/163 histiocytes. Androgen receptors were identified in the tumor cells. CONCLUSIONS: CD34 histiocytoma of the tarsus is a rare, benign, and separate entity from a CD34 solitary fibrous tumor. Conservative tarsectomy is curative.
PURPOSE: To evaluate the relation between time spent outdoors at various life periods and risk of exfoliation glaucoma or exfoliation glaucoma suspect. DESIGN: Retrospective cohort study in the United States. METHODS: Participants (49 033 women in the Nurses Health Study and 20 066 men in the Health Professionals Follow-up Study) were 60+ years old, were free of glaucoma and cataract, reported eye examinations, and completed questions about time spent outdoors in direct sunlight at midday at 3 life periods: high school to age 24 years, age 25-35 years, and age 36-59 years (asked in 2006 in women and 2008 in men). Participants were followed biennially with mailed questionnaires from 1980 women/1986 men to 2010. Incident cases (223 women and 38 men) were confirmed with medical records. Cohort-specific multivariable-adjusted rate ratios from Cox proportional hazards models were estimated and pooled with meta-analysis. RESULTS: Although no association was observed with greater time spent outdoors in the ages of 25-35 or ages 36-59 years, the pooled multivariable-adjusted rate ratios for ≥11 hours per week spent outdoors in high school to age 24 years compared with ≤5 hours per week was 2.00 (95% confidence interval = 1.30, 3.08; P for linear trend = .001). In women, this association was stronger in those who resided in the southern geographic tier in young adulthood (P for interaction = .07). CONCLUSIONS: Greater time spent outdoors in young adulthood was associated with risk of exfoliation glaucoma or exfoliation glaucoma suspect, supporting an etiologic role of early exposures to climatic factors.
PURPOSE: To explore the function of natural killer (NK) cells in inflammatory angiogenesis in mice. METHODS: To study ocular angiogenic responses we used the cornea BFGF micropellet and the laser-induced choroidal neovascularization (CNV) mouse models (C57BL/6). To deplete NK cells in these models, we injected an anti-NK1.1 antibody or an isotype antibody as a control. Corneas or choroids were immunohistochemically stained for blood vessels (CD31), macrophages (F4/80), or CNV (isolectin-IB4). Vascular endothelial growth factors (VEGF), IFN-γ, or TNF-α levels were measured by real-time quantitative PCR (qPCR) or flow cytometry. A coculture assay of macrophages, NK cells, and human umbilical vein endothelial cells (HUVECs) was analyzed morphometrically to examine the ability of NK cells to induce angiogenesis in vitro. RESULTS: Our data demonstrate that in vivo depletion of NK cells leads to a significant reduction of corneal angiogenesis and CNV. Furthermore, NK cell depletion reduces macrophage infiltration into the cornea and mRNA expression levels of VEGF-A, VEGF-C, and VEGFR3 at day 7 after micropellet insertion. In the laser-induced CNV model, our data show that NK cell depletion leads to decreased areas of CNV and significantly reduced mRNA expression of VEGFs and IFN-γ in the choroid. An in vitro coculture assay shows an IFN-γ-dependent increase in VEGF expression levels, thereby increasing endothelial cell proliferation. CONCLUSIONS: Our findings demonstrate a novel pro-angiogenic function for NK cells, indicating that IFN-γ-secreting NK cells can induce angiogenesis by promoting enhanced VEGF expression by macrophages.
PURPOSE: To evaluate the potential for mouse genetic background to effect photoreceptor cell death in response to experimental retinal detachment (RD). METHODS: Retinal detachment was induced in three inbred mouse strains (C57BL/6, BALB/c, and B6129SF2) by subretinal injection of sodium hyaluronate. A time course of photoreceptor cell death was assessed by TUNEL assay. Total photoreceptor cell death was analyzed through comparing the outer nuclear layer (ONL)/inner nuclear layer (INL) ratio 7 days post RD. Western blot analysis or quantitative real-time PCR (qPCR) were performed to assess cell death signaling, expression of endogenous neurotrophin, and levels of apoptosis inhibitors 24 hours after RD. Inflammatory cytokine secretion and inflammatory cell infiltration were quantified by ELISA and immunostaining, respectively. RESULTS: The peak of photoreceptor cell death after RD was at 24 hours in all strains. Photoreceptor cell death as well as monocyte chemoattractant protein 1 and interleukin 6 secretion at 24 hours after RD was the highest in BALB/c, followed in order of magnitude by C57BL/6 and B6129SF2. Conversely, nerve growth factor expression and ONL/INL ratio were the lowest in BALB/c. Apoptosis signaling was higher in C57BL/6, whereas necroptosis signaling was higher in C57BL/6 and BALB/c. Autophagic signaling was higher in BALB/c. X-linked inhibitor of apoptosis (XIAP) and survivin protein levels were lower in C57BL/6 and BALB/c, respectively. Macrophage/microglia infiltration was higher in C57BL/6 and BALB/c at 24 hours after RD. CONCLUSIONS: Photoreceptor cell death after RD was significantly different among the three strains, suggesting the presence of genetic factors that affect photoreceptor cell death after RD.
Photoreceptor cell death is the definitive cause of vision loss in retinal detachment (RD). Mammalian STE20-like kinase (MST) is a master regulator of both cell death and proliferation and a critical factor in development and tumorigenesis. However, to date the role of MST in neurodegeneration has not been fully explored. Utilizing MST1(-/-) and MST2(-/-) mice we identified MST2, but not MST1, as a regulator of photoreceptor cell death in a mouse model of RD. MST2(-/-) mice demonstrated significantly decreased photoreceptor cell death and outer nuclear layer (ONL) thinning after RD. Additionally, caspase-3 activation was attenuated in MST2(-/-) mice compared to control mice after RD. The transcription of p53 upregulated modulator of apoptosis (PUMA) and Fas was also reduced in MST2(-/-) mice post-RD. Retinas of MST2(-/-) mice displayed suppressed nuclear relocalization of phosphorylated YAP after RD. Consistent with the reduction of photoreceptor cell death, MST2(-/-) mice showed decreased levels of proinflammatory cytokines such as monocyte chemoattractant protein 1 and interleukin 6 as well as attenuated inflammatory CD11b cell infiltration during the early phase of RD. These results identify MST2, not MST1, as a critical regulator of caspase-mediated photoreceptor cell death in the detached retina and indicate its potential as a future neuroprotection target.
I shall discuss the work of researchers at Harvard Medical School who came together in the early 1990s. Scattered across various Harvard-affiliated hospitals and research centers, these individuals were unified by their interest in ocular neovascularization. Together and separately, they investigated models of ocular neovascularization, exploring tumor angiogenesis in eye development and disease.
Normalization has been proposed as a canonical computation operating across different brain regions, sensory modalities, and species. It provides a good phenomenological description of non-linear response properties in primary visual cortex (V1), including the contrast response function and surround suppression. Despite its widespread application throughout the visual system, the underlying neural mechanisms remain largely unknown. We recently observed that corticocortical feedback contributes to surround suppression in V1, raising the possibility that feedback acts through normalization. To test this idea, we characterized area summation and contrast response properties in V1 with and without feedback from V2 and V3 in alert macaques and applied a standard normalization model to the data. Area summation properties were well explained by a form of divisive normalization, which computes the ratio between a neuron's driving input and the spatially integrated activity of a "normalization pool." Feedback inactivation reduced surround suppression by shrinking the spatial extent of the normalization pool. This effect was independent of the gain modulation thought to mediate the influence of contrast on area summation, which remained intact during feedback inactivation. Contrast sensitivity within the receptive field center was also unaffected by feedback inactivation, providing further evidence that feedback participates in normalization independent of the circuit mechanisms involved in modulating contrast gain and saturation. These results suggest that corticocortical feedback contributes to surround suppression by increasing the visuotopic extent of normalization and, via this mechanism, feedback can play a critical role in contextual information processing.
PURPOSE: Stereotactic navigation systems have been used in neurosurgery and otolaryngology with great success. The current investigation illustrates the novel use of a microdebrider with built-in stereotactic guidance in a series of thyroid orbitopathy patients who underwent deep lateral orbital wall decompression surgery. METHODS: A noncomparative, interventional, retrospective case series of patients who underwent deep lateral deep orbital wall decompression from 2006 to 2013 was conducted in accordance with Institutional Review Board policy and the Declaration of Helsinki. Patient demographics, indications for surgery, pre-, intra-, and postoperative findings along with complications were recorded. RESULTS: One hundred eight deep lateral orbital decompression surgeries were performed in 69 patients using the Straightshot M4 Microdebrider with built-in stereotactic guidance (Medtronics). Seventy-eight cases were in women and 30 cases were in men. The average age was 50.4 years (SD = 11.9 years). Indications for surgery included proptosis, exposure keratopathy, or compressive optic neuropathy. No patient experienced intraoperative complications. Specifically, cerebrospinal fluid leak, visual loss, infection, or unanticipated inflammation were not encountered. The average postoperative follow-up time was 5.35 months. Mean reduction in proptosis was 3.72 mm (SD = 2.1). Visual acuity improved in 32.4% (35/108) of cases. CONCLUSIONS: This surgical instrument combines a single handpiece locator, microdebrider, irrigator, retractor, and suction device into one. It enhances anatomical localization during orbital decompression and, with an integrated tissue guard, may decrease the risk of injury to orbital soft tissues. Stereotactic navigation enhances the surgeon's ability to determine the maximal limits of decompression in real time by confirming depth of bone removal and may potentially increase surgeons' confidence in orbital decompression surgery.
PURPOSE: To classify blinks in dry eye and normal subjects into six subtypes, and to define the blink rate and duration within each type of blink, as well as the total lid-contact time/minute. MATERIALS AND METHODS: This was a single-centered, prospective, double-blind study of eleven dry-eye and ten normal subjects. Predefined subjects watched a video while blinks were recorded for 10 minutes. Partial blinks were classified by percentage closure of maximal palpebral fissure opening: 25%, 50%, 75%. Complete blinks were characterized as full (>0 seconds), extended (>0.1 seconds), or superextended (>0.5 seconds). The mean duration of each type of blink was determined and standardized per minute as total lid-contact time. RESULTS: Total blinks observed were 4,990 (1,414 normal, 3,756 dry eye): 1,809 (50.59%) partial and 1,767 (49.41%) complete blinks among dry-eye subjects versus 741 (52.90%) partial and 673 (47.60%) complete blinks among normal subjects. Only superextended blinks of ≥0.5-second duration were significantly more frequent in dry-eye subjects than normals (2.3% versus 0.2%, respectively; P=0.023). Total contact time was seven times higher in dry-eye subjects than normals (0.565 versus 0.080 seconds, respectively; P<0.001). Isolating only extended blinks (>0.1 second), the average contact time (seconds) was four times longer in dry-eye versus normal subjects (2.459 in dry eye, 0.575 in normals; P=0.003). Isolating only superextended blinks (>0.5 seconds), average contact time was also significantly different (7.134 in dry eye, 1.589 in normals; P<0.001). The contact rate for all full closures was 6.4 times longer in dry-eye (0.045 versus 0.007, P<0.001) than normal subjects. CONCLUSION: Dry-eye subjects spent 4.5% of a minute with their eyes closed, while normal subjects spent 0.7% of a minute with their eyes closed. Contact time might play a role in the visual function decay associated with increased blink rates.
PURPOSE: Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway. METHODS: Using a tagSNP, direct sequencing and meta-analysis approach within four ethnically diverse cohorts, we identified genetic risk present in FLT1, though not within other VEGF pathway genes KDR, VEGFA, or VASH1. We used ChIP and ELISA in functional analysis. RESULTS: The FLT1 SNPs rs9943922, rs9508034, rs2281827, rs7324510, and rs9513115 were significantly associated with increased risk of neovascular AMD. Each association was more significant after meta-analysis than in any one of the four cohorts. All associations were novel, within noncoding regions of FLT1 that do not tag for coding variants in linkage disequilibrium. Analysis of soluble FLT1 demonstrated higher expression in unaffected individuals homozygous for the FLT1 risk alleles rs9943922 (P = 0.0086) and rs7324510 (P = 0.0057). In silico analysis suggests that these variants change predicted splice sites and RNA secondary structure, and have been identified in other neovascular pathologies. These data were supported further by murine chromatin immunoprecipitation demonstrating that FLT1 is a target of Nr2e3, a nuclear receptor gene implicated in regulating an AMD pathway. CONCLUSIONS: Although exact variant functions are not known, these data demonstrate relevancy across ethnically diverse genetic backgrounds within our study and, therefore, hold potential for global efficacy.
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.
Humans can recognize objects and scenes in a small fraction of a second. The cascade of signals underlying rapid recognition might be disrupted by temporally jittering different parts of complex objects. Here we investigated the time course over which shape information can be integrated to allow for recognition of complex objects. We presented fragments of object images in an asynchronous fashion and behaviorally evaluated categorization performance. We observed that visual recognition was significantly disrupted by asynchronies of approximately 30 ms, suggesting that spatiotemporal integration begins to break down with even small deviations from simultaneity. However, moderate temporal asynchrony did not completely obliterate recognition; in fact, integration of visual shape information persisted even with an asynchrony of 100 ms. We describe the data with a concise model based on the dynamic reduction of uncertainty about what image was presented. These results emphasize the importance of timing in visual processing and provide strong constraints for the development of dynamical models of visual shape recognition.