The majority of visual recognition studies have focused on the neural responses to repeated presentations of static stimuli with abrupt and well-defined onset and offset times. In contrast, natural vision involves unique renderings of visual inputs that are continuously changing without explicitly defined temporal transitions. Here we considered commercial movies as a coarse proxy to natural vision. We recorded intracranial field potential signals from 1,284 electrodes implanted in 15 patients with epilepsy while the subjects passively viewed commercial movies. We could rapidly detect large changes in the visual inputs within approximately 100 ms of their occurrence, using exclusively field potential signals from ventral visual cortical areas including the inferior temporal gyrus and inferior occipital gyrus. Furthermore, we could decode the content of those visual changes even in a single movie presentation, generalizing across the wide range of transformations present in a movie. These results present a methodological framework for studying cognition during dynamic and natural vision.
Human adenoviruses (HAdVs) are uniquely important "model organisms" as they have been used to elucidate fundamental biological processes, are recognized as complex pathogens, and are used as remedies for human health. As pathogens, HAdVs may effect asymptomatic or mild and severe symptomatic disease upon their infection of respiratory, ocular, gastrointestinal, and genitourinary systems. High-resolution genomic data have enhanced the understanding of HAdV epidemiology, with recombination recognized as an important and major pathway in the molecular evolution and genesis of emergent HAdV pathogens. To support this view and to actualize an algorithm for identifying, characterizing, and typing novel HAdVs, we determined the DNA sequence of 95 isolates from archives containing historically important pathogens and collections housing currently circulating strains to be sequenced. Of the 85 samples that were completely sequenced, 18 novel recombinants within species HAdV-B and D were identified. Two HAdV-D genomes were found to contain novel penton base and fiber genes with significant divergence from known molecular types. In this data set, we found additional isolates of HAdV-D53 and HAdV-D58, two novel genotypes recognized recently using genomics. This supports the thesis that novel HAdV genotypes are not limited to "one-time" appearances of the prototype but are of importance in HAdV epidemiology. These data underscore the significance of lateral genomic transfer in HAdV evolution and reinforce the potential public health impact of novel genotypes of HAdVs emerging in the population.
Ocular adnexal smooth muscle masses/neoplasms are extremely rare. Such lesions are comparatively more common in the conjunctiva than in the orbit and are most unusual in the eyelid. A 58-year-old woman slowly developed over 4 months a firm, movable sausage-shaped lesion in the deep lateral half of the right lower eyelid. The lesion ran parallel to and above the orbital rim. At surgery, the lesion was located between the orbicularis muscle and the inferior orbital septum. The term ellipsoid is used descriptively and does not imply any particular biologic behavior. Immunohistochemical evaluation revealed smooth muscle actin and desmin positivity. Due to the ubiquity of small blood vessels and the absence of smooth muscle bundles in the potential space between the orbicularis striated muscle and the inferior orbital septum, venular smooth muscle emerges as a highly likely source for the lesion.
PURPOSE: To analyze 3 unusual mesenchymal transformations within the eye: adipose or osseous metaplasia of the lens and adipose tissue in the vitreous cavity. DESIGN: Observational case series. METHODS: Reevaluation of clinicopathologic diagnoses and histopathologic findings in sections stained with hematoxylin-eosin, periodic acid-Schiff (PAS) reaction, and Masson trichrome method. RESULTS: The 3 cases of mesenchymal transformation occurred in microphthalmic eyes with persistent hyperplastic primary vitreous (more recently termed persistent fetal vasculature). In 1 case there was total lens replacement with lamellar bone; in another, total replacement of the crystalline lens by adipose tissue; and in a third, an anomalous pocket of adipose tissue in the central vitreous. Multifocal remnants of the lens capsule were seen in the osseous case but were absent from the adipocytic cases. The vitreous adipose tissue was surrounded by an elaborate capillary plexus with an empty, collapsed PAS-positive lens capsule in the pupillary region. Anterior pigmented neuroectodermal disorganization, dysgenesis of angle structures, and a hypoplastic or disorganized iris were also observed in the 3 cases. CONCLUSIONS: After review of the literature, it appears that lenticular osseous replacement occurs more often than adipocytic. In addition to vascularization of the lens through a capsular dehiscence, other causes are explored, including direct epithelial-mesenchymal transformations of the lens epithelium or, less likely, of the disorganized adjacent neuroectoderm. The focus of vitreous adipose tissue may represent a transformed luxated lens extruded from its capsule, which was left behind in the pupillary zone.
PURPOSE: To assess systemic vascular endothelial growth factor (VEGF)-A levels after treatment with intravitreous aflibercept, bevacizumab, or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab after a re-treatment algorithm. PARTICIPANTS: Participants with available plasma samples (N = 436). METHODS: Plasma samples were collected before injections at baseline and 4-week, 52-week, and 104-week visits. In a preplanned secondary analysis, systemic-free VEGF levels from an enzyme-linked immunosorbent assay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were -0.30±0.61 pg/ml, -0.31±0.54 pg/ml, and -0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted confidence interval [CI]; P value) were -0.01 (-0.12 to +0.10; P = 0.89), -0.31 (-0.44 to -0.18; P < 0.001), and -0.30 (-0.43 to -0.18; P < 0.001) for aflibercept-bevacizumab, aflibercept-ranibizumab, and bevacizumab-ranibizumab, respectively. At 52 weeks, a difference in mean VEGF changes between bevacizumab and ranibizumab persisted (-0.23 [-0.38 to -0.09]; P < 0.001); the difference between aflibercept and ranibizumab was -0.12 (P = 0.07) and between aflibercept and bevacizumab was +0.11 (P = 0.07). Treatment group differences at 2 years were similar to 1 year. No apparent treatment differences were detected at 52 or 104 weeks in the cohort of participants not receiving injections within 1 or 2 months before plasma collection. Participants with (N = 9) and without (N = 251) a heart attack or stroke had VEGF levels that appeared similar. CONCLUSIONS: These data suggest that decreases in plasma free-VEGF levels are greater after treatment with aflibercept or bevacizumab compared with ranibizumab at 4 weeks. At 52 and 104 weeks, a greater decrease was observed in bevacizumab versus ranibizumab. Results from 2 subgroups of participants who did not receive injections within at least 1 month and 2 months before collection suggest similar changes in VEGF levels after stopping injections. It is unknown whether VEGF levels return to normal as the drug is cleared from the system or whether the presence of the drug affects the assay's ability to accurately measure free VEGF. No significant associations between VEGF concentration and systemic factors were noted.
The emergence of Staphylococcus aureus strains resistant to 'last resort' antibiotics compels the development of new antimicrobials against this important human pathogen. We found that propyl 5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carbodithioate (HMPC) shows bacteriostatic activity against S. aureus (MIC = 4 μg/ml) and rescues Caenorhabditis elegans from S. aureus infection. Whole-genome sequencing of S. aureus mutants resistant to the compound, along with screening of a S. aureus promoter-lux reporter array, were used to explore possible mechanisms of action. All mutants resistant to HMPC acquired missense mutations at distinct codon positions in the global transcriptional regulator mgrA, followed by secondary mutations in the phosphatidylglycerol lysyltransferase fmtC/mprF. The S. aureus promoter-lux array treated with HMPC displayed a luminescence profile that was unique but showed similarity to DNA-damaging agents and/or DNA replication inhibitors. Overall, HMPC is a new anti-staphylococcal compound that appears to act via an unknown mechanism linked to the global transcriptional regulator MgrA.
BACKGROUND: Hydroxychloroquine (HCQ) retinopathy may be more common than previously recognized; recent ophthalmology guidelines have revised recommendations from ideal body weight (IBW)-based dosing to actual body weight (ABW)-based dosing. However, contemporary HCQ prescribing trends in the UK remain unknown. METHODS: We examined a UK general population database to investigate HCQ dosing between 2007 and 2016. We studied trends of excess HCQ dosing per ophthalmology guidelines (defined by exceeding 6.5 mg/kg of IBW and 5.0 mg/kg of ABW) and determined their independent predictors using multivariable logistic regression analyses. RESULTS: Among 20,933 new HCQ users (78% female), the proportions of initial HCQ excess dosing declined from 40% to 36% using IBW and 38% to 30% using ABW, between 2007 and 2016. Among these, 47% of women were excess-dosed (multivariable OR 12.52; 95% CI 10.99-14.26) using IBW and 38% (multivariable OR 1.98; 95% CI,1.81-2.15) using ABW. Applying IBW, 37% of normal and 44% of obese patients were excess-dosed; however, applying ABW, 53% of normal and 10% of obese patients were excess-dosed (multivariable ORs = 1.61 and 0.1 (reference = normal); both p < 0.01). Long-term HCQ users showed similar excess dosing. CONCLUSION: A substantial proportion of HCQ users in the UK, particularly women, may have excess HCQ dosing per the previous or recent weight-based guidelines despite a modest decline in recent years. Over half of normal-BMI individuals were excess-dosed per the latest guidelines. This implies the potential need to reduce dosing for many patients but also calls for further research to establish unifying evidence-based safe and effective dosing strategies.
Despite advances in therapy for rheumatic diseases, hydroxychloroquine remains almost universally recommended for the treatment of systemic lupus erythematosus (SLE), and is often used in the management of other rheumatic diseases such as rheumatoid arthritis (RA). However, the major dose-limiting toxicity of hydroxychloroquine is retinopathy that can lead to loss of vision. New highly sensitive screening methods can identify early stages of retinopathy, and studies that include these modalities have indicated a substantially higher prevalence of hydroxychloroquine retinopathy than was previously recognized, resulting in revisions to ophthalmology guidelines and the recommendation of a low dose of hydroxychloroquine for many patients. However, the efficacy of low-dose hydroxychloroquine for treating SLE and other rheumatic diseases is unknown. Further studies are required to establish the effectiveness and retinal safety of the latest hydroxychloroquine treatment recommendations.
SIGNIFICANCE: Acquired monocular vision (AMV) is a common visual field loss. Patients report mobility difficulties in walking due to collisions with objects or other pedestrians on the blind side. PURPOSE: The visual field of people with AMV extends more than 90° temporally on the side of the seeing eye but is restricted to approximately 55° nasally. We developed a novel field expansion device using a multiplexing prism (MxP) that superimposes the see-through and shifted views for true field expansion without apical scotoma. We present various designs of the device that enable customized fitting and improved cosmetics. METHODS: A partial MxP segment is attached (base-in) near the nose bridge. To avoid total internal reflection due to the high angle of incidence at nasal field end (55°), we fit the MxP with serrations facing the eye and tilt the prism base toward the nose. We calculated the width of the MxP (the apex location) needed to prevent apical scotoma and monocular diplopia. We also consider the effect of spectacle prescriptions on these settings. The results are verified perimetrically. RESULTS: We documented the effectivity of various prototype glasses designs with perimetric measurements. With the prototypes, all patients with AMV had field-of-view expansions up to 90° nasally without any loss of seeing field. CONCLUSIONS: The novel and properly mounted MxP in glasses has the potential for meaningful field-of-view expansion up to the size of normal binocular vision in cosmetically acceptable form.
SIGNIFICANCE: Full-field prisms that fill the entire spectacle eye wire have been considered as field expansion devices for homonymous hemianopia (HH) and acquired monocular vision (AMV). Although the full-field prism is used for addressing binocular dysfunction and for prism adaptation training after brain injury as treatment for spatial hemineglect, we show that the full-field prism for field expansion does not effectively expand the visual field in either HH or AMV. PURPOSE: Full-field prisms may shift a portion of the blind side to the residual seeing side. However, foveal fixation on an object of interest through a full-field prism requires head and/or eye rotation away from the blind side, thus negating the shift of the field toward the blind side. METHODS: We fit meniscus and flat full-field 7Δ and 12Δ yoked prisms and conducted Goldmann perimetry in HH and AMV. We compared the perimetry results with ray tracing calculations. RESULTS: The rated prism power was in effect at the primary position of gaze for all prisms, and the meniscus prisms maintained almost constant power at all eccentricities. To fixate on the perimetry target, the subjects needed to turn their head and/or eyes away from the blind side, which negated the field shift into the blind side. In HH, there was no difference in the perimetry results on the blind side with any of the prisms. In AMV, the lower nasal field of view was slightly shifted into the blind side with the flat prisms, but not with the meniscus prisms. CONCLUSIONS: Full-field prisms are not an effective field expansion device owing to the inevitable fixation shift. There is potential for a small field shift with the flat full-field prism in AMV, but such lenses cannot incorporate refractive correction. Furthermore, in considering the apical scotoma, the shift provides a mere field substitution at best.
The corneal endothelium (CE) is vital for maintaining the water balance and clarity of the cornea. The CE is a cell layer that is particularly susceptible to aging because of its postmitotic arrest, high metabolic activity involving pumping of ions, and lifelong exposure to ultraviolet light. Despite gradual age-related cell loss, a sufficient number of CE cells are preserved during the lifespan of an individual. However, in conditions such as Fuchs endothelial corneal dystrophy (FECD), permanent loss of CE cells leads to corneal edema and loss of vision requiring corneal transplantation. FECD is a genetic and oxidative stress disorder manifested by abnormal cell-matrix interactions and expedited cellular aging culminating in cellular death. Because the endothelium has minimal replicative capacity in vivo and an inability to replace its genome, it is particularly prone to cumulative DNA damage acquired throughout life. In FECD, the underlying genetic defects make the CE genome even more vulnerable to this damage, to the point of causing mitochondrial dysfunction, mitochondrial membrane potential loss, and excessive mitophagy activation. Endogenous and exogenous intracellular stressors alter the synthetic footprint of CE cells, leading to endothelial-mesenchymal transition and secretion of aberrant extracellular matrix (in the form of guttae), resembling scar formation in other organs. In turn, the guttae or endothelial scars contribute to a vicious cycle of FECD pathogenesis and, by further inducing endothelial-mesenchymal transition and oxidant-antioxidant imbalance, perpetuate the molecular changes of the degenerating endothelium.
OBJECTIVE: We evaluated the relation of prediagnostic sex hormone levels in postmenopausal women with primary open-angle glaucoma (POAG) and intraocular pressure (IOP). METHODS: Among postmenopausal participants of the Nurses' Health Study, POAG cases (n = 189; diagnosed 1990-2008) and controls (n = 189) were matched on age, fasting status, and postmenopausal hormone use at blood draw (1989-1990). Plasma concentrations of estrone sulfate, estradiol, testosterone, sex hormone binding globulin, and dehydroepiandrosterone sulfate were assessed. The primary outcome was POAG; in secondary analyses, among cases only, we evaluated maximum untreated IOP at diagnosis. Multivariable-adjusted logistic/multiple linear regression models were used to evaluate tertiles (Ts) of biomarker levels and the two outcomes, adjusting for various potential confounders. RESULTS: We observed no significant associations of estrone, estradiol, sex hormone binding globulin, or dehydroepiandrosterone sulfate with POAG risk or with maximum IOP at glaucoma diagnosis among cases. Suggestive significant associations were observed with highest testosterone and POAG risk (T3 vs T1 multivariable-adjusted odds ratio 1.84; 95% confidence interval 1.02, 3.33; P trend 0.10). Similarly, for maximum IOP at diagnosis among cases only (mean 8 years after blood draw), higher testosterone was significantly associated with higher IOP (multivariable-adjusted difference in IOP T3 vs T1 2.17 mm Hg; 95% confidence interval 0.34, 3.99; P trend 0.02). CONCLUSIONS: Overall, plasma sex hormone levels in postmenopausal women were not associated with POAG risk; however, a trend of higher testosterone levels being associated with higher POAG risk and higher IOP at diagnosis was observed and needs confirmation.
Purpose: Uveal melanoma (UM) is uniformly refractory to all available systemic chemotherapies, thus creating an urgent need for novel therapeutics. In this study, we investigated the sensitivity of UM cells to ICG-001, a small molecule reported to suppress the Wnt/β-catenin-mediated transcriptional program. Methods: We used a panel of UM cell lines to examine the effects of ICG-001 on cellular proliferation, migration, and gene expression. In vivo efficacy of ICG-001 was evaluated in a UM xenograft model. Results: ICG-001 exerted strong antiproliferative activity against UM cells, leading to cell cycle arrest, apoptosis, and inhibition of migration. Global gene expression profiling revealed strong suppression of genes associated with cell cycle proliferation, DNA replication, and G1/S transition. Gene set enrichment analysis revealed that ICG-001 suppressed Wnt, mTOR, and MAPK signaling. Strikingly, ICG-001 suppressed the expression of genes associated with UM aggressiveness, including CDH1, CITED1, EMP1, EMP3, SDCBP, and SPARC. Notably, the transcriptomic footprint of ICG-001, when applied to a UM patient dataset, was associated with better clinical outcome. Lastly, ICG-001 exerted anticancer activity against a UM tumor xenograft in mice. Conclusions: Using in vitro and in vivo experiments, we demonstrate that ICG-001 has strong anticancer activity against UM cells and suppresses transcriptional programs critical for the cancer cell. Our results suggest that ICG-001 holds promise and should be examined further as a novel therapeutic agent for UM.
Fuchs endothelial corneal dystrophy (FECD) is a genetic and oxidative stress disorder of post-mitotic human corneal endothelial cells (HCEnCs), which normally exhibit hexagonal shape and form a compact monolayer compatible with normal corneal functioning and clear vision. FECD is associated with increased DNA damage, which in turn leads to HCEnC loss, resulting in the formation rosettes and aberrant extracellular matrix (ECM) deposition in the form of pro-fibrotic guttae. Since the mechanism of ECM deposition in FECD is currently unknown, we aimed to investigate the role of endothelial-mesenchymal transition (EMT) in FECD using a previously established cellular in vitro model that recapitulates the characteristic rosette formation, by employing menadione (MN)-induced oxidative stress. We demonstrate that MN treatment alone, or a combination of MN and TGF-β1 induces reactive oxygen species (ROS), cell death, and EMT in HCEnCs during rosette formation, resulting in upregulation of EMT- and FECD-associated markers such as Snail1, N-cadherin, ZEB1, and transforming growth factor-beta-induced (TGFβI), respectively. Additionally, FECD ex vivo specimens displayed a loss of organized junctional staining of plasma membrane-bound N-cadherin, with corresponding increase in fibronectin and Snail1 compared to ex vivo controls. Addition of N-acetylcysteine (NAC) downregulated all EMT markers and abolished rosette formation. Loss of NQO1, a metabolizing enzyme of MN, led to greater increase in intracellular ROS levels as well as a significant upregulation of Snail1, fibronectin, and N-cadherin compared to normal cells, indicating that NQO1 regulates Snail1-mediated EMT. This study provides first line evidence that MN-induced oxidative stress leads to EMT in corneal endothelial cells, and the effect of which is further potentiated when redox cycling activity of MN is enhanced by the absence of NQO1. Given that NAC inhibits Snail-mediated EMT, this may be a potential therapeutic intervention for FECD.
OBJECTIVES: To examine clinical outcomes of oversized titanium back plates in type I Boston keratoprosthesis (KPro) implantation. METHODS: Retrospective study of 22 sequential eyes (20 patients) undergoing type I KPro implantation with an oversized titanium back plate (larger than trephined wound diameter by 1.0 mm or more), performed by a single surgeon (K.A.C.) from June 2010 to November 2014. Data were collected regarding preoperative eye characteristics, surgical details, and postoperative clinical outcomes. RESULTS: Mean follow-up time per eye was 24.1±14.9 months. All eyes had improved vision after surgery; 13 eyes (59.1%) maintained visual acuity improvement at last follow-up. Initial KPro's were retained in 19 eyes (86.4%); one eye required KPro replacement. Primary retroprosthetic membrane (RPM) developed in three eyes (13.6%), with similar occurrence in aniridic (14.3%) and nonaniridic eyes (13.3%). Secondary RPM's developed in two eyes (9.1%) after vitritis (one eye) and retinal and choroidal detachment (one eye). Glaucoma was a common comorbidity: 2 of 14 eyes (14.3%) with preoperative glaucoma had glaucoma progression, and 4 of 8 eyes (50.0%) without preoperative glaucoma developed glaucoma postoperatively. Other postoperative complications included retinal detachment (5 eyes, 22.7%) and idiopathic vitritis (3 eyes, 13.6%). CONCLUSIONS: Oversized titanium KPro back plates are associated with a low rate of primary RPM formation and may have particular utility in reducing primary RPM formation in aniridic eyes. Glaucoma remains a challenge in postoperative KPro management. Complex eyes, at increased risk of postoperative complications, require careful management.
Natural products have served as an inspiration to scientists both for their complex three-dimensional architecture and exquisite biological activity. Promysalin is one such Pseudomonad secondary metabolite that exhibits narrow-spectrum antibacterial activity, originally isolated from the rhizosphere. We herein utilize affinity-based protein profiling (AfBPP) to identify succinate dehydrogenase (Sdh) as the biological target of the natural product. The target was further validated in silico, in vitro, in vivo, and through the selection, and sequencing, of a resistant mutant. Succinate dehydrogenase plays an essential role in primary metabolism of Pseudomonas aeruginosa as the only enzyme that is involved both in the tricarboxylic acid cycle (TCA) and in respiration via the electron transport chain. These findings add credence to other studies that suggest that the TCA cycle is an understudied target in the development of novel therapeutics to combat P. aeruginosa, a significant pathogen in clinical settings.
Glaucoma is the leading cause of irreversible blindness globally . Despite its gravity, the disease is frequently undiagnosed in the community . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG). Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.
PURPOSE: To determine the factors that influence the sensitivity and specificity of laser-scanning in vivo confocal microscopy (IVCM) for diagnosing Acanthamoeba keratitis (AK). METHODS: This retrospective, controlled study included 28 eyes of 27 patients with AK and 34 eyes of 34 patients with bacterial keratitis (as the control group). All patients had undergone corneal imaging with a laser-scanning IVCM (Heidelberg Retina Tomograph 3 with the Rostock Cornea Module). The IVCM images were independently evaluated by 2 experienced and 2 inexperienced masked observers. Sensitivity and specificity of IVCM for diagnosing AK and the effects of various clinical and imaging parameters on the sensitivity were then investigated. RESULTS: Overall, IVCM had average sensitivity and specificity of 69.7% ± 2.5% and 97.1% ± 4.2% for experienced observers and 59.0% ± 7.6% and 92.7% ± 10.4% for inexperienced observers, respectively. However, the sensitivity did not show any significant association with the duration of disease, size of ulcer, depth of involvement, culture results, or cyst morphology. Although interobserver agreement was good (κ = 0.60, P < 0.001) for the experienced observers, it was only at a moderate level (κ = 0.48, P < 0.001) for the inexperienced observers. CONCLUSIONS: IVCM has a moderate sensitivity and a high specificity for diagnosis of AK. Although clinical parameters do not affect this diagnostic accuracy, a higher sensitivity is seen when images are interpreted by experienced observers.