Suzuki J, Yoshimura T, Simeonova M, Takeuchi K, Murakami Y, Morizane Y, Miller JW, Sobrin L, Vavvas DG. Aminoimidazole carboxamide ribonucleotide ameliorates experimental autoimmune uveitis. Invest Ophthalmol Vis Sci 2012;53(7):4158-69.Abstract
PURPOSE: To investigate the anti-inflammatory effect of an adenosine monophosphate (AMP) analog, aminoimidazole carboxamide ribonucleotide (AICAR), in experimental autoimmune uveoretinitis (EAU). METHODS: C57BL/6 mice were injected daily with AICAR (200 mg/kg, intraperitoneally [IP]) from day 0, the day of interphotoreceptor retinoid-binding protein (IRBP) immunization, until day 21. The severity of uveitis was assessed clinically and histopathologically. T-cell proliferation and cytokine production of IFN-γ, IL-17, and IL-10 in response to IRBP stimulation were determined. In addition, regulatory T-cell (Treg) populations were measured. Co-stimulatory molecule expression (CD40, 80, 86, and I-Ab) on dendritic cells (DCs) in EAU and on bone marrow-derived dendritic cells (BMDCs) treated with AICAR was measured. RESULTS: AICAR treatment significantly reduced clinical and histologic severity of EAU as well as ocular cytokine production. An anti-inflammatory effect associated with the inhibition of T-cell proliferation and Th1 and Th17 cytokine production was observed. Increases in the Th2 response and Treg population were not observed with AICAR treatment. AICAR did significantly inhibit BMDC maturation by reducing co-stimulatory molecule expression. CONCLUSIONS: AICAR attenuates EAU by preventing generation of Ag-specific Th1 and Th17 cells. Impaired DC maturation may be an underlying mechanism for this anti-inflammatory effect observed with AICAR.
Sobrin L, Ripke S, Yu Y, Fagerness J, Bhangale TR, Tan PL, Souied EH, Buitendijk GHS, Merriam JE, Richardson AJ, Raychaudhuri S, Reynolds R, Chin KA, Lee AY, Leveziel N, Zack DJ, Campochiaro P, Smith TR, Barile GR, Hogg RE, Chakravarthy U, Behrens TW, Uitterlinden AG, van Duijn CM, Vingerling JR, Brantley MA, Baird PN, Klaver CCW, Allikmets R, Katsanis N, Graham RR, Ioannidis JPA, Daly MJ, Seddon JM. Heritability and genome-wide association study to assess genetic differences between advanced age-related macular degeneration subtypes. Ophthalmology 2012;119(9):1874-85.Abstract
PURPOSE: To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes. DESIGN: Sibling correlation study and genome-wide association study (GWAS). PARTICIPANTS: For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls. METHODS: Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts. MAIN OUTCOME MEASURES: Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes. RESULTS: The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis). CONCLUSIONS: Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.
Shazly TA, Al-Hussaini AK. Pediatric ocular injuries from airsoft toy guns. J Pediatr Ophthalmol Strabismus 2012;49(1):54-7.Abstract
PURPOSE: To report ocular injuries caused by airsoft guns in children. METHODS: A retrospective chart review of pediatric patients who sustained ocular injuries related to airsoft guns between November 2005 and December 2007. Place of trauma, presenting symptoms and signs, surgical interventions performed, and final visual outcome were reviewed. RESULTS: Thirty-two patients with a mean age of 8.8 ± 4.0 years (range: 1.5 to 18 years) were examined; 28 were boys (87.5%). Presenting visual acuity ranged from hand motions to 20/20 and could not be assessed in 2 patients. Hyphema was a common finding that was present in 24 cases, corneal abrasions were present in 10 cases, and raised intraocular pressure was present in 7 cases. Seven patients presented with traumatic cataract, and two had iridodialysis. Immediate surgical intervention was performed in 7 patients and 7 patients were scheduled for elective surgery. The patients presented after an average of 1.9 ± 1.9 days (range: 4 hours to 6 days) after the injury. Average follow-up was 18 days (range: 7 days to 5 months). Final visual acuity was 20/200 or worse in 5 patients, 20/40 or better in 23 patients, and could not be assessed in 2 cases. CONCLUSION: Airsoft guns can cause a variety of serious injuries, sometimes necessitating operative intervention. The long-term morbidity from some of these injuries is significant. Airsoft guns are capable of inflicting serious and permanent ocular damage.
Yonekawa Y, Kim IK. Pseudophakic cystoid macular edema. Curr Opin Ophthalmol 2012;23(1):26-32.Abstract
PURPOSE OF REVIEW: Pseudophakic cystoid macular edema (PCME) is a common cause of visual impairment after cataract surgery. This article systematically reviews and discusses the epidemiology, risk factors, diagnosis, and treatment of PCME, with a focus on advances in the past 1-2 years. RECENT FINDINGS: The incidence of PCME has declined with the advent of modern surgical techniques. Optical coherence tomography (OCT) has become an important adjunct to biomicroscopy and fluorescein angiography. PCME prophylaxis with topical nonsteroidal anti-inflammatory drugs remains unproven because long-term visual outcomes and comparative effectiveness studies are lacking. Chronic, refractory CME remains a therapeutic challenge, but investigational therapies with potential include corticosteroid intravitreal injections and implants, and intravitreal anti-vascular endothelial growth factor treatments. Few studies have assessed surgical options. SUMMARY: There is currently a lack of well designed randomized clinical trials to guide the treatment of PCME.
Woodward AM, Senchyna M, Williams R, Argüeso P. Characterization of the interaction between hydroxypropyl guar galactomannan and galectin-3. Biochem Biophys Res Commun 2012;424(1):12-7.Abstract
Multivalent galactose ligands have been proposed for selective targeting of carbohydrate-binding proteins on epithelial cell surfaces, both in normal and pathological conditions. One cellular partner is galectin-3, a β-galactoside-binding protein present on many epithelial linings, such as those of the ocular surface. In this study, we investigated the ability of hydroxypropyl guar galactomannan (HPGG) to bind recombinant galectin-3 and to target the apical surface of differentiated human corneal keratinocytes. Pull-down and slot-blot assays demonstrated that fluorescence-labeled HPGG bound recombinant galectin-3 through a galactose-dependent mechanism. In contrast, no binding of HPGG could be detected towards recombinant galectin-8 or -9. In a cell culture system, HPGG bound weakly to biotinylated cell surface corneal isolates containing endogenous galectin-3, and incubation of HPGG with corneal keratinocytes in culture resulted in discrete, galactose-independent, binding to the cell surface. Moreover, HPGG failed to elute the biological counter-receptor MUC16 from galectin-3 affinity columns. We conclude that HPGG binds galectin-3 through the conventional carbohydrate-recognition domain in vitro, but not in a biological system, suggesting that endogenous carbohydrate ligands on epithelial cell surface glycocalyces impair HPGG biorecognition.
Wiecek E, Pasquale LR, Fiser J, Dakin S, Bex PJ. Effects of peripheral visual field loss on eye movements during visual search. Front Psychol 2012;3:472.Abstract
Natural vision involves sequential eye movements that bring the fovea to locations selected by peripheral vision. How peripheral visual field loss (PVFL) affects this process is not well understood. We examine how the location and extent of PVFL affects eye movement behavior in a naturalistic visual search task. Ten patients with PVFL and 13 normally sighted subjects with full visual fields (FVF) completed 30 visual searches monocularly. Subjects located a 4° × 4° target, pseudo-randomly selected within a 26° × 11° natural image. Eye positions were recorded at 50 Hz. Search duration, fixation duration, saccade size, and number of saccades per trial were not significantly different between PVFL and FVF groups (p > 0.1). A χ(2) test showed that the distributions of saccade directions for PVFL and FVL subjects were significantly different in 8 out of 10 cases (p < 0.01). Humphrey Visual Field pattern deviations for each subject were compared with the spatial distribution of eye movement directions. There were no significant correlations between saccade directional bias and visual field sensitivity across the 10 patients. Visual search performance was not significantly affected by PVFL. An analysis of eye movement directions revealed patients with PVFL show a biased directional distribution that was not directly related to the locus of vision loss, challenging feed-forward models of eye movement control. Consequently, many patients do not optimally compensate for visual field loss during visual search.
Wagley S, Yuan J, Hoffert DS, Arroyo JG. Postoperative choroidal hemorrhage shows elevated concentration of tissue plasminogen activator. Retin Cases Brief Rep 2012;6(3):261-2.Abstract
PURPOSE: The purpose of this study was to report the levels of tissue plasminogen activator in liquefied suprachoroidal hemorrhage. METHODS: An interventional case report of a 61-year-old woman who underwent drainage sclerotomy for choroidal hemorrhage. RESULTS: A 61-year-old pseudophakic woman underwent pars plana vitrectomy and fluid-gas exchange for retinal detachment in her right eye and developed postoperative serous choroidal detachments with large hemorrhages. Drainage sclerotomy was performed 18 days after the initial development of suprachoroidal hemorrhage. Sample of the liquefied hemorrhage and serum sample collected during sclerotomy were tested for tissue plasminogen activator levels using the antibody tissue plasminogen activator-enzyme immunoassay test. Hemorrhage tissue plasminogen activator levels were three times the levels present in the serum. CONCLUSION: Tissue plasminogen activator may be involved in the process of suprachoroidal hemorrhage liquefaction.
Thanos A, Morizane Y, Murakami Y, Giani A, Mantopoulos D, Kayama M, Roh M, Michaud N, Pawlyk B, Sandberg M, Young LH, Miller JW, Vavvas DG. Evidence for baseline retinal pigment epithelium pathology in the Trp1-Cre mouse. Am J Pathol 2012;180(5):1917-27.Abstract
The increasing popularity of the Cre/loxP recombination system has led to the generation of numerous transgenic mouse lines in which Cre recombinase is expressed under the control of organ- or cell-specific promoters. Alterations in retinal pigment epithelium (RPE), a multifunctional cell monolayer that separates the retinal photoreceptors from the choroid, are prevalent in the pathogenesis of a number of ocular disorders, including age-related macular degeneration. To date, six transgenic mouse lines have been developed that target Cre to the RPE under the control of various gene promoters. However, multiple lines of evidence indicate that high levels of Cre expression can be toxic to mammalian cells. In this study, we report that in the Trp1-Cre mouse, a commonly used transgenic Cre strain for RPE gene function studies, Cre recombinase expression alone leads to RPE dysfunction and concomitant disorganization of RPE layer morphology, large areas of RPE atrophy, retinal photoreceptor dysfunction, and microglial cell activation in the affected areas. The phenotype described herein is similar to previously published reports of conditional gene knockouts that used the Trp1-Cre mouse, suggesting that Cre toxicity alone could account for some of the reported phenotypes and highlighting the importance of the inclusion of Cre-expressing mice as controls in conditional gene targeting studies.
Stahl A, Joyal J-S, Chen J, Sapieha P, Juan AM, Hatton CJ, Pei DT, Hurst CG, Seaward MR, Krah NM, Dennison RJ, Greene ER, Boscolo E, Panigrahy D, Smith LEH. SOCS3 is an endogenous inhibitor of pathologic angiogenesis. Blood 2012;120(14):2925-9.Abstract
Inflammatory cytokines and growth factors drive angiogenesis independently; however, their integrated role in pathologic and physiologic angiogenesis is not fully understood. Suppressor of cytokine signaling-3 (SOCS3) is an inducible negative feedback regulator of inflammation and growth factor signaling. In the present study, we show that SOCS3 curbs pathologic angiogenesis. Using a Cre/Lox system, we deleted SOCS3 in vessels and studied developmental and pathologic angiogenesis in murine models of oxygen-induced retinopathy and cancer. Conditional loss of SOCS3 leads to increased pathologic neovascularization, resulting in pronounced retinopathy and increased tumor size. In contrast, physiologic vascularization is not regulated by SOCS3. In vitro, SOCS3 knockdown increases proliferation and sprouting of endothelial cells costimulated with IGF-1 and TNFα via reduced feedback inhibition of the STAT3 and mTOR pathways. These results identify SOCS3 as a pivotal endogenous feedback inhibitor of pathologic angiogenesis and a potential therapeutic target acting at the converging crossroads of growth factor- and cytokine-induced vessel growth.
Shukla AN, Cruzat A, Hamrah P. Confocal microscopy of corneal dystrophies. Semin Ophthalmol 2012;27(5-6):107-16.Abstract
In vivo confocal microscopy (IVCM) of the cornea is becoming an indispensable tool in the cellular study of corneal physiology and disease. This technique offers non-invasive imaging of the living cornea with images comparable to that of ex vivo histology. The ability to provide high-resolution images of all layers in the living cornea has resulted in new discoveries of corneal pathology at the cellular level. The IVCM analysis of corneal dystrophies is of importance to clinicians, as current methods of diagnosis involve slit-lamp characteristics, genetic analysis, and invasive biopsy. IVCM is helpful in evaluating the morphological characteristics of corneal dystrophies at the histological level and may be helpful in diagnosis, determination of progression, and understanding the pathophysiology of disease. The purpose of this review is to describe the principles, applications, and clinical correlation of IVCM in the study of corneal dystrophies.
Zhang Q, Liu Q, Austin C, Drummond I, Pierce EA. Knockdown of ttc26 disrupts ciliogenesis of the photoreceptor cells and the pronephros in zebrafish. Mol Biol Cell 2012;23(16):3069-78.Abstract
In our effort to understand genetic disorders of the photoreceptor cells of the retina, we have focused on intraflagellar transport in photoreceptor sensory cilia. From previous mouse proteomic data we identified a cilia protein Ttc26, orthologue of dyf-13 in Caenorhabditis elegans, as a target. We localized Ttc26 to the transition zone of photoreceptor and to the transition zone of cilia in cultured murine inner medullary collecting duct 3 (mIMCD3) renal cells. Knockdown of Ttc26 in mIMCD3 cells produced shortened and defective primary cilia, as revealed by immunofluorescence and scanning electron microscopy. To study Ttc26 function in sensory cilia in vivo, we utilized a zebrafish vertebrate model system. Morpholino knockdown of ttc26 in zebrafish embryos caused ciliary defects in the pronephric kidney at 27 h postfertilization and distension/dilation of pronephros at 5 d postfertilization (dpf). In the eyes, the outer segments of photoreceptor cells appeared shortened or absent, whereas cellular lamination appeared normal in retinas at 5 dpf. This suggests that loss of ttc26 function prevents normal ciliogenesis and differentiation in the photoreceptor cells, and that ttc26 is required for normal development and differentiation in retina and pronephros. Our studies support the importance of Ttc26 function in ciliogenesis and suggest that screening for TTC26 mutations in human ciliopathies is justified.
Wu H, de Boer JF, Chen TC. Diagnostic capability of spectral-domain optical coherence tomography for glaucoma. Am J Ophthalmol 2012;153(5):815-826.e2.Abstract
PURPOSE: To determine the diagnostic capability of spectral-domain optical coherence tomography in glaucoma patients with visual field defects. DESIGN: Prospective, cross-sectional study. METHODS: SETTINGS: Participants were recruited from a university hospital clinic. STUDY POPULATION: One eye of 85 normal subjects and 61 glaucoma patients with average visual field mean deviation of -9.61 ± 8.76 dB was selected randomly for the study. A subgroup of the glaucoma patients with early visual field defects was calculated separately. OBSERVATION PROCEDURES: Spectralis optical coherence tomography (Heidelberg Engineering, Inc) circular scans were performed to obtain peripapillary retinal nerve fiber layer (RNFL) thicknesses. The RNFL diagnostic parameters based on the normative database were used alone or in combination for identifying glaucomatous RNFL thinning. MAIN OUTCOME MEASURES: To evaluate diagnostic performance, calculations included areas under the receiver operating characteristic curve, sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio. RESULTS: Overall RNFL thickness had the highest area under the receiver operating characteristic curve values: 0.952 for all patients and 0.895 for the early glaucoma subgroup. For all patients, the highest sensitivity (98.4%; 95% confidence interval, 96.3% to 100%) was achieved by using 2 criteria: ≥ 1 RNFL sectors being abnormal at the < 5% level and overall classification of borderline or outside normal limits, with specificities of 88.9% (95% confidence interval, 84.0% to 94.0%) and 87.1% (95% confidence interval, 81.6% to 92.5%), respectively, for these 2 criteria. CONCLUSIONS: Statistical parameters for evaluating the diagnostic performance of the Spectralis spectral-domain optical coherence tomography were good for early perimetric glaucoma and were excellent for moderately advanced perimetric glaucoma.
Wiggs JL, Hewitt AW, Fan BJ, Wang DY, Figueiredo Sena DR, O'Brien C, Realini A, Craig JE, Dimasi DP, Mackey DA, Haines JL, Pasquale LR. The p53 codon 72 PRO/PRO genotype may be associated with initial central visual field defects in caucasians with primary open angle glaucoma. PLoS One 2012;7(9):e45613.Abstract
BACKGROUND: Loss of vision in glaucoma is due to apoptotic retinal ganglion cell loss. While p53 modulates apoptosis, gene association studies between p53 variants and glaucoma have been inconsistent. In this study we evaluate the association between a p53 variant functionally known to influence apoptosis (codon 72 Pro/Arg) and the subset of primary open angle glaucoma (POAG) patients with early loss of central visual field. METHODS: Genotypes for the p53 codon 72 polymorphism (Pro/Arg) were obtained for 264 POAG patients and 400 controls from the U.S. and in replication studies for 308 POAG patients and 178 controls from Australia (GIST). The glaucoma patients were divided into two groups according to location of initial visual field defect (either paracentral or peripheral). All cases and controls were Caucasian with European ancestry. RESULTS: The p53-PRO/PRO genotype was more frequent in the U.S. POAG patients with early visual field defects in the paracentral regions compared with those in the peripheral regions or control group (p=2.7 × 10(-5)). We replicated this finding in the GIST cohort (p  =7.3 × 10(-3), and in the pooled sample (p=6.6 × 10(-7)) and in a meta-analysis of both the US and GIST datasets (1.3 × 10(-6), OR 2.17 (1.58-2.98 for the PRO allele). CONCLUSIONS: These results suggest that the p53 codon 72 PRO/PRO genotype is potentially associated with early paracentral visual field defects in primary open-angle glaucoma patients.
Weinberger AD, Wolf YI, Lobkovsky AE, Gilmore MS, Koonin EV. Viral diversity threshold for adaptive immunity in prokaryotes. MBio 2012;3(6):e00456-12.Abstract
UNLABELLED: Bacteria and archaea face continual onslaughts of rapidly diversifying viruses and plasmids. Many prokaryotes maintain adaptive immune systems known as clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated genes (Cas). CRISPR-Cas systems are genomic sensors that serially acquire viral and plasmid DNA fragments (spacers) that are utilized to target and cleave matching viral and plasmid DNA in subsequent genomic invasions, offering critical immunological memory. Only 50% of sequenced bacteria possess CRISPR-Cas immunity, in contrast to over 90% of sequenced archaea. To probe why half of bacteria lack CRISPR-Cas immunity, we combined comparative genomics and mathematical modeling. Analysis of hundreds of diverse prokaryotic genomes shows that CRISPR-Cas systems are substantially more prevalent in thermophiles than in mesophiles. With sequenced bacteria disproportionately mesophilic and sequenced archaea mostly thermophilic, the presence of CRISPR-Cas appears to depend more on environmental temperature than on bacterial-archaeal taxonomy. Mutation rates are typically severalfold higher in mesophilic prokaryotes than in thermophilic prokaryotes. To quantitatively test whether accelerated viral mutation leads microbes to lose CRISPR-Cas systems, we developed a stochastic model of virus-CRISPR coevolution. The model competes CRISPR-Cas-positive (CRISPR-Cas+) prokaryotes against CRISPR-Cas-negative (CRISPR-Cas-) prokaryotes, continually weighing the antiviral benefits conferred by CRISPR-Cas immunity against its fitness costs. Tracking this cost-benefit analysis across parameter space reveals viral mutation rate thresholds beyond which CRISPR-Cas cannot provide sufficient immunity and is purged from host populations. These results offer a simple, testable viral diversity hypothesis to explain why mesophilic bacteria disproportionately lack CRISPR-Cas immunity. More generally, fundamental limits on the adaptability of biological sensors (Lamarckian evolution) are predicted. IMPORTANCE: A remarkable recent discovery in microbiology is that bacteria and archaea possess systems conferring immunological memory and adaptive immunity. Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated genes (CRISPR-Cas) are genomic sensors that allow prokaryotes to acquire DNA fragments from invading viruses and plasmids. Providing immunological memory, these stored fragments destroy matching DNA in future viral and plasmid invasions. CRISPR-Cas systems also provide adaptive immunity, keeping up with mutating viruses and plasmids by continually acquiring new DNA fragments. Surprisingly, less than 50% of mesophilic bacteria, in contrast to almost 90% of thermophilic bacteria and Archaea, maintain CRISPR-Cas immunity. Using mathematical modeling, we probe this dichotomy, showing how increased viral mutation rates can explain the reduced prevalence of CRISPR-Cas systems in mesophiles. Rapidly mutating viruses outrun CRISPR-Cas immune systems, likely decreasing their prevalence in bacterial populations. Thus, viral adaptability may select against, rather than for, immune adaptability in prokaryotes.