PURPOSE: We examined the role of DNA copy number variants (CNVs) of known glaucoma genes in relation to primary open angle glaucoma (POAG). METHODS: Our study included DNA samples from two studies (NEIGHBOR and GLAUGEN). All the samples were genotyped with the Illumina Human660W_Quad_v1 BeadChip. After removing non-blood-derived and amplified DNA samples, we applied quality control steps based on the mean Log R Ratio and the mean B allele frequency. Subsequently, data from 3057 DNA samples (1599 cases and 1458 controls) were analyzed with PennCNV software. We defined CNVs as those ≥5 kilobases (kb) in size and interrogated by ≥5 consecutive probes. We further limited our investigation to CNVs in known POAG-related genes, including CDKN2B-AS1, TMCO1, SIX1/SIX6, CAV1/CAV2, the LRP12-ZFPM2 region, GAS7, ATOH7, FNDC3B, CYP1B1, MYOC, OPTN, WDR36, SRBD1, TBK1, and GALC. RESULTS: Genomic duplications of CDKN2B-AS1 and TMCO1 were each found in a single case. Two cases carried duplications in the GAS7 region. Genomic deletions of SIX6 and ATOH7 were each identified in one case. One case carried a TBK1 deletion and another case carried a TBK1 duplication. No controls had duplications or deletions in these six genes. A single control had a duplication in the MYOC region. Deletions of GALC were observed in five cases and two controls. CONCLUSIONS: The CNV analysis of a large set of cases and controls revealed the presence of rare CNVs in known POAG susceptibility genes. Our data suggest that these rare CNVs may contribute to POAG pathogenesis and merit functional evaluation.

Purpose: Patients with macular disease often report experiencing metamorphopsia (visual distortion). Although typically measured with Amsler charts, more objective and quantitative assessments of perceived distortion are desirable to effectively monitor the presence, progression and remediation of visual impairment. Methods: Participants with binocular (n = 33) and monocular (n= 50) maculopathy across seven disease groups, and control participants (n = 10) with no identifiable retinal disease completed a modified Amsler Grid assessment (presented on a computer screen with eye tracking to ensure fixation compliance) and two novel objective measures of metamorphopsia in the central five degrees of visual field. 81% (67/83) of participants completed a task requiring them to configure eight dots in the shape of a square, and 64% (32/50) of participants experiencing monocular distortion completed a spatial alignment task using dichoptic stimuli. 10 controls completed all tasks. Results: Horizontal and vertical distortion magnitudes were calculated for each of the three assessments. Distortion magnitudes were significantly higher in patients than controls in all assessments. There was no significant difference in magnitude of distortion across different macular diseases. Among patients, there were no significant correlations between overall magnitude of distortion among any of the three measures and no significant correlations in localized measures of distortion. Conclusions: Three alternative quantifications of monocular spatial distortion in the central visual field generated uncorrelated estimates of visual distortion. It is therefore unlikely that metamorphopsia is caused solely by displacement of photoreceptors in the retina, but instead involves additional top-down information, knowledge about the scene, and perhaps, cortical reorganization.

Only a small fraction of the mammalian genome codes for messenger RNAs destined to be translated into proteins, and it is generally assumed that a large portion of transcribed sequences--including introns and several classes of noncoding RNAs (ncRNAs)--do not give rise to peptide products. A systematic examination of translation and physiological regulation of ncRNAs has not been conducted. Here we use computational methods to identify the products of non-canonical translation in mouse neurons by analysing unannotated transcripts in combination with proteomic data. This study supports the existence of non-canonical translation products from both intragenic and extragenic genomic regions, including peptides derived from antisense transcripts and introns. Moreover, the studied novel translation products exhibit temporal regulation similar to that of proteins known to be involved in neuronal activity processes. These observations highlight a potentially large and complex set of biologically regulated translational events from transcripts formerly thought to lack coding potential.

Streptococcus pneumoniae, an inhabitant of the upper respiratory mucosa, causes respiratory and invasive infections as well as conjunctivitis. Strains that lack the capsule, a main virulence factor and the target of current vaccines, are often isolated from conjunctivitis cases. Here we perform a comparative genomic analysis of 271 strains of conjunctivitis-causing S. pneumoniae from 72 postal codes in the United States. We find that the vast majority of conjunctivitis strains are members of a distinct cluster of closely related unencapsulated strains. These strains possess divergent forms of pneumococcal virulence factors (such as CbpA and neuraminidases) that are not shared with other unencapsulated nasopharyngeal S. pneumoniae. They also possess putative adhesins that have not been described in encapsulated pneumococci. These findings suggest that the unencapsulated strains capable of causing conjunctivitis utilize a pathogenesis strategy substantially different from that described for S. pneumoniae at other infection sites.

Neuroimmunologic and systemic rheumatic diseases are frequently accompanied by inflammation of the eye, ocular adnexa, and orbital tissues. An understanding of the diverse forms of ophthalmic pathology in these conditions aids the clinician in making appropriate preventative, diagnostic, therapeutic, and prognostic decisions. In this review, the authors address ocular inflammation in neurorheumatic disease in three sections: first, they highlight current perspectives on immune mechanisms in the development of these disorders; next, they provide a framework for the recognition and evaluation of ophthalmologic inflammatory entities; finally, they discuss in detail several inflammatory conditions that affect the nervous system and the eye, emphasizing the features that should alert neurologists to initiate ophthalmologic evaluation. The conditions discussed include multiple sclerosis, neuromyelitis optica, chronic relapsing inflammatory optic neuropathy, Susac syndrome, Cogan syndrome, acute posterior multifocal placoid pigment epitheliopathy, Vogt-Koyanagi-Harada disease, Behçet disease, sarcoidosis, systemic lupus erythematosus, granulomatosis with polyangiitis (Wegener granulomatosis), polyarteritis nodosa, giant cell arteritis, IgG4-related disease, and Sjögren syndrome.

OBJECTIVE: To examine the clinical relevance and pathophysiology of Boston keratoprosthesis (B-KPro)-related corneal keratolysis (cornea melt) and to describe a novel method of preventing corneal melt using ex vivo crosslinked cornea tissue carrier. METHODS: A review of B-KPro literature was performed to highlight cases of corneal melt. Studies examining the effect of corneal collagen cross-linking (CXL) on the biomechanical properties of corneal tissue are summarized. The use of crosslinked corneal tissue as a carrier to the B-KPro is illustrated with a case. RESULTS: Corneal melting after B-KPro is a relatively rare event, occurring in 3% of eyes during the first 3 years of postoperative follow-up. The risk of post-KPro corneal melting is heightened in eyes with chronic ocular surface inflammation such as eyes with Stevens-Johnson syndrome and mucous membrane pemphigoid. This chronic inflammation results in high tear levels of matrix metalloproteinases, the enzymes responsible for collagenolysis and corneal melt. Crosslinked corneal tissue has been shown to have stiffer biomechanical properties and to be more resistant to degradation by collagenolytic enzymes. We have previously optimized the technique for ex vivo corneal CXL and are currently studying its impact on the prevention of corneal melting after B-KPro surgery in high-risk eyes. Crosslinked carrier tissue was used in a 52-year-old man with familial aniridia and severe post-KPro corneal melt. The patient maintained his visual acuity and showed no evidence of corneal thinning or melt in the first postoperative year. CONCLUSION: Collagen crosslinking was previously shown to halt the enzymatic degradation of corneal buttons ex vivo. This study demonstrates the safety and potential benefit of using crosslinked corneal grafts as carriers for the B-KPro, especially in eyes at higher risk of postoperative melt.

Partial persistence of the hyaloid artery unaccompanied by hyperplastic primary vitreous has not been previously reported in association with retinoblastoma. We describe an 18-month-old child with such a finding who had a retinoblastoma that was undifferentiated, extensively necrotic, heavily calcified, and completely filled the eyeball. The enucleated globe harbored a nonperfused, fossilized remnant of the hyaloid artery due to DNA/calcium deposition in the vascular wall. This structure inserted into a lenticular, extracapsular, fibrous plaque corresponding to a Mittendorf dot. The tumor had induced a placoid cataractous lens, obliterated the anterior and posterior chambers, caused glaucoma leading to buphthalmos, and extended into the optic nerve and extraocularly to involve the orbit. We conclude that the retinoblastoma arose early in ocular morphogenesis, at around 4 months gestation, when the programmed involution of the hyaloid artery begins. This process would typically end at 7-8 months gestation, but was aborted by the tumor. The patient died 6 weeks after surgery without receiving further treatment because of the parents' resistance.

FTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177 330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.

IMPORTANCE: Biomarkers that predict future visual acuity (VA) in eyes with baseline diabetic macular edema (DME) would substantively improve risk assessment, management decisions, and selection of eyes for clinical studies targeting DME. OBJECTIVE: To determine whether baseline or early change in the novel spectral domain-optical coherence tomography (SD-OCT) parameter disorganization of the retinal inner layers (DRIL) is predictive of VA in eyes with center-involved DME. DESIGN, SETTING, AND PARTICIPANTS: At a tertiary care referral center for diabetic eye disease, a retrospective, longitudinal cohort study obtained demographics, VA, and SD-OCT images from baseline, 4-month, and 8-month visits in 96 participants (120 eyes) with diabetes mellitus and baseline center-involved DME (SD-OCT central subfield thickness, ≥ 320 µm for men and ≥ 305 µm for women). Exclusion criteria included substantial media opacity, cataract surgery within 6 months, and nondiabetic retinal pathology affecting VA. On SD-OCT, the 1-mm-wide retinal area centered on the fovea was evaluated by masked graders for DRIL extent, cysts, hyperreflective foci, microaneurysms, cone outer segment tip visibility, and external limiting membrane or photoreceptor disruption and reflectivity. MAIN OUTCOMES AND MEASURES: Visual acuity and SD-OCT-derived retinal morphology. RESULTS: Greater DRIL extent at baseline correlated with worse baseline VA (point estimate, 0.04; 95% CI, 0.02-0.05 per 100 µm; P < .001). An increase in DRIL during 4 months was associated with VA worsening at 8 months (point estimate, 0.03; 95% CI, 0.02-0.05 per 100 µm; P < .001). A multivariate model that included a 4-month change in VA, DRIL, and external limiting membrane disruption was predictive of an 8-month VA change (r = 0.80). Each approximately 300-µm DRIL increase during 4 months predicted a 1-line, 8-month VA decline. When DRIL increased at least 250 µm at 4 months, no eyes had VA improvement of at least 1 line at 8 months. When DRIL decreased at least 250 µm at 4 months, no eyes had VA decline of at least 1 line at 8 months, and 77.7% had VA improvement of at least 1 line. CONCLUSIONS AND RELEVANCE: Disorganization of the retinal inner layers in the 1-mm foveal area is associated with VA, and change in DRIL predicts future change in VA. Early change in DRIL prospectively identifies eyes with a high likelihood of subsequent VA improvement or decline. Therefore, DRIL warrants further study as a robust, readily obtained, and noninvasive biomarker of future VA response in eyes with DME.

We describe 2 patients who developed postoperative orbital cerebrospinal fluid (CSF) collection after orbitozygomatic pterional craniotomy. An 18-year-old woman underwent exploratory pterional-orbitozygomatic craniotomy. Five days postoperatively, after removal of a lumbar drain, proptosis and a compressive optic neuropathy developed. Computed tomography demonstrated a CSF collection contiguous with the craniotomy site. Resolution followed percutaneous aspiration and replacement of the lumbar drain. A 57-year-old woman underwent a pterional-orbitozygomatic craniotomy for removal of a left anterior clinoid meningioma, complicated by a large left hemorrhagic stroke requiring decompressive hemicraniectomy. Extracranial CSF collections accumulated in both the orbit and subgaleal spaces. Resolution followed placement of an external ventricular drain. Based on these cases, the mechanism seems to be the combination of iatrogenic formation of a communication with the subarachnoid space and elevated intracranial pressure. Resolution was achieved by normalizing intracranial pressure.

In this report, we describe the development of a modified adeno-associated virus (AAV) capsid and promoter for transduction of retinal ON-bipolar cells. The bipolar cells, which are post-synaptic to the photoreceptors, are important retinal targets for both basic and preclinical research. In particular, a therapeutic strategy under investigation for advanced forms of blindness involves using optogenetic molecules to render ON-bipolar cells light-sensitive. Currently, delivery of adequate levels of gene expression is a limiting step for this approach. The synthetic AAV capsid and promoter described here achieves high level of optogenetic transgene expression in ON-bipolar cells. This evokes high-frequency (~100 Hz) spiking responses in ganglion cells of previously blind, rd1, mice. Our vector is a promising vehicle for further development toward potential clinical use.

OBJECTIVE: We characterized and correlated endothelial progenitor cells (EPCs) and circulating progenitor cells (CPCs) with lack of vascular complications in the Joslin Medalist Study in patients with type 1 diabetes for 50 years or longer. RESEARCH DESIGN AND METHODS: EPC and CPC levels were ascertained by flow cytometry and compared among Medalists (n = 172) with or without diabetic retinopathy (DR; n = 84 of 162), neuropathy (n = 94 of 165), diabetic nephropathy (DN; n = 18 of 172), cardiovascular disease (CVD; n = 63 of 168), age-matched controls (n = 83), type 2 diabetic patients (n = 36), and younger type 1 diabetic patients (n = 31). Mitogens, inflammatory cytokines, and oxidative markers were measured in blood or urine. Migration of cultured peripheral blood mononuclear cells (PBMCs) from Medalists and age-matched controls were compared. RESULTS: Medalists' EPC and CPC levels equaled those of their nondiabetic age-matched controls, were 10% higher than those in younger type 1 diabetic patients, and were 20% higher than those in age-matched type 2 diabetic patients. CPC levels were 15% higher in Medalists without CVD and nephropathy than in those affected, whereas EPC levels were significantly higher in those without peripheral vascular disease (PVD) than those with PVD. Stromal-derived factor 1 (SDF-1) levels were higher in Medalists with CVD, DN, and DR than in those not affected and their controls. IGF-I levels were lower in Medalists and correlated inversely with CPC levels. Additionally, cultured PBMCs from Medalists migrated more than those from nondiabetic controls. CONCLUSIONS: Normal levels of EPC and CPC in the Medalists, unlike other groups with diabetes, especially those without CVD, support the idea that endogenous factors exist to neutralize the adverse effects of metabolic abnormalities of diabetes on vascular tissues.

PURPOSE: We characterized antigen-presenting cell (APC)-relevant chemokine receptor expression in dry eye disease (DED), and investigated the effect of topical CC chemokine receptor (CCR)-7 blockade specifically on Th17 cell immunity and dry eye disease severity. METHODS: We induced DED in female C57BL/6 mice. Chemokine receptor expression by corneal APCs was characterized using immunohistochemistry. To determine the functional role of CCR7 in DED, mice were treated topically with either anti-CCR7, a control isotype antibody, or left untreated, and clinical disease severity, Th17 responses, and molecular markers of DED were quantified. RESULTS: Frequencies of CD11b(+) cells and their chemokine expression were increased in the cornea of DED mice. Mice treated topically with anti-CCR7 antibody displayed a significant reduction in clinical disease severity and Th17 response compared to the isotype and untreated groups. Topical CCR7 blockade was effective in ameliorating DED in its acute and chronic stages. CONCLUSIONS: Our findings suggest that CCR7-mediated trafficking of APCs drives the induction and maintenance of Th17 immunity in DED and that CCR7 blockade is effective in suppressing the immunopathogenic mechanisms in DED.

In the so-called McGurk illusion, when the synchronized presentation of the visual stimulus /ga/ is paired with the auditory stimulus /ba/, people in general hear it as /da/. Multisensory integration processing underlying this illusion seems to occur within the Superior Temporal Sulcus (STS). Herein, we present evidence demonstrating that bilateral cathodal transcranial direct current stimulation (tDCS) of this area can decrease the McGurk illusion-type responses. Additionally, we show that the manipulation of this audio-visual integrated output occurs irrespective of the number of eye-fixations on the mouth of the speaker. Bilateral anodal tDCS of the Parietal Cortex also modulates the illusion, but in the opposite manner, inducing more illusion-type responses. This is the first demonstration of using non-invasive brain stimulation to modulate multisensory speech perception in an illusory context (i.e., both increasing and decreasing illusion-type responses to a verbal audio-visual integration task). These findings provide clear evidence that both the superior temporal and parietal areas contribute to multisensory integration processing related to speech perception. Specifically, STS seems fundamental for the temporal synchronization and integration of auditory and visual inputs. For its part, posterior parietal cortex (PPC) may adjust the arrival of incoming audio and visual information to STS thereby enhancing their interaction in this latter area.

Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor (VEGF). A soluble isoform of Nrp1 (sNrp1) has not been described in the mouse. Our goal was to examine the expression of mouse sNrp1 during liver development and regeneration.sNrp1 was cloned from mouse liver. The expression of sNrp1 and VEGF was examined in mouse liver during post-natal development and regeneration using northern blot, western blot, in situ hybridisation, and immunohistochemical analyses. HGF/NRP1 binding was examined in vitro.A novel 588-amino acid sNrp1 isoform was found to contain the ligand binding regions of Nrp1. The adult liver expressed more sNrp1 than full-length Nrp1. In vivo, hepatocytes constitutively expressed VEGF and sNrp1 in the quiescent state. sNrp1 was highly up-regulated at P20, a time point coinciding with a plateau in liver and body weights. Following hepatectomy, endogenous levels of sNrp1 decreased during the rapid growth phase, and VEGF levels were highest just prior to and during the angiogenic phase. sNrp1 levels again rose 5-10 days post-hepatectomy, presumably to control regeneration. HGF protein bound NRP1 and binding was competed with sNRP1.We cloned a novel mouse sNrp1 isoform from liver and provide evidence that this endogenous angiogenesis inhibitor may regulate VEGF or HGF bioavailability during normal physiological growth and development as well as during liver regeneration.