Suzuki T, Campbell J, Kim Y, Swoboda JG, Mylonakis E, Walker S, Gilmore MS. Wall teichoic acid protects Staphylococcus aureus from inhibition by Congo red and other dyes. J Antimicrob Chemother 2012;67(9):2143-51.Abstract
OBJECTIVES: Polyanionic polymers, including lipoteichoic acid and wall teichoic acid, are important determinants of the charged character of the staphylococcal cell wall. This study was designed to investigate the extent to which teichoic acid contributes to protection from anionic azo dyes and to identify barriers to drug penetration for development of new antibiotics for multidrug-resistant Staphylococcus aureus infection. METHODS: We studied antimicrobial activity of azo dyes against S. aureus strains with or without inhibition of teichoic acid in vitro and in vivo. RESULTS: We observed that inhibition of wall teichoic acid expression resulted in an ∼1000-fold increase in susceptibility to azo dyes such as Congo red, reducing its MIC from >1024 to <4 mg/L. Sensitization occurred when the first step in the wall teichoic acid pathway, catalysed by TarO, was inhibited either by mutation or by chemical inhibition. In contrast, genetic blockade of lipoteichoic acid biosynthesis did not confer Congo red susceptibility. Based on this finding, combination therapy was tested using the highly synergistic combination of Congo red plus tunicamycin at sub-MIC concentrations (to inhibit wall teichoic acid biosynthesis). The combination rescued Caenorhabditis elegans from a lethal challenge of S. aureus. CONCLUSIONS: Our studies show that wall teichoic acid confers protection to S. aureus from anionic azo dyes and related compounds, and its inhibition raises the prospect of development of new combination therapies based on this inhibition.
Shazly TA, Latina MA, Dagianis JJ, Chitturi S. Effect of central corneal thickness on the long-term outcome of selective laser trabeculoplasty as primary treatment for ocular hypertension and primary open-angle glaucoma. Cornea 2012;31(8):883-6.Abstract
PURPOSE: To determine if central corneal thickness (CCT) impacts the intraocular pressure (IOP)-lowering effect of selective laser trabeculoplasty (SLT) in patients with ocular hypertension (OHT) and primary open-angle glaucoma (POAG). METHODS: A retrospective chart review of consecutive patients, who underwent SLT as primary treatment for OHT and POAG, between 2002 and 2005, was performed. Partial correlation analysis was performed to correlate the CCT to the percentage of IOP reduction at 3 to 30 months after SLT. Independent samples t test was performed to compare mean percentage of IOP reduction in eyes with CCT less than 555 μm versus CCT 555 μm or greater. RESULTS: Eighty eyes of 47 patients were identified. The partial correlation coefficient value between the CCT and percentage of IOP reduction after SLT at 3 months was -0.253 (P = 0.025), at 12 months it was -0.22 (P = 0.049), and at 30 months it was 0.301 (P = 0.007). Independent samples t test showed that the mean percentage of IOP reduction in eyes with thinner corneas (CCT < 555 μm) was greater than that in thicker corneas (CCT ≥ 555 μm) at 3-, 6-, 9-, 12-, and 30-month post-SLT (P < 0.05). CONCLUSIONS: In patients with POAG and OHT, percentage of IOP reduction after SLT was significantly greater in eyes with thinner corneas (CCT < 555 μm). These findings indicate that patients treated with SLT as primary therapy who had thinner corneas demonstrated better IOP control for at least 30 months after SLT.
Yonekawa Y, Kim IK. Epidemiology and management of uveal melanoma. Hematol Oncol Clin North Am 2012;26(6):1169-84.Abstract
Uveal melanoma is the most common primary intraocular malignancy in adults. The disease overwhelmingly affects white populations. Other risk factors include fair skin, light iris color, ancestry from northern latitudes, and ocular/oculodermal melanocytosis. Historically, enucleation was the definitive treatment of uveal melanoma, but brachytherapy and proton beam irradiation are now the most commonly used treatment methods. However, there are still no effective therapies against metastatic uveal melanoma, which is almost always fatal. Continued advances in understanding of the molecular mechanisms of uveal melanoma will facilitate the identification of prognostic markers and therapeutic targets.
Wu C, Löfqvist C, Smith LEH, VanderVeen DK, Hellström A, Hellström A. Importance of early postnatal weight gain for normal retinal angiogenesis in very preterm infants: a multicenter study analyzing weight velocity deviations for the prediction of retinopathy of prematurity. Arch Ophthalmol 2012;130(8):992-9.Abstract
OBJECTIVE: To assess WINROP (, an algorithm using postnatal weight measurements, as a tool for the prediction of retinopathy of prematurity (ROP) in a large geographically and racially diverse study population. METHODS: WINROP analysis was performed retrospectively on conventionally at-risk infants from 10 neonatal intensive careunits.Weight measurements were entered into WINROP, which signals an alarm for an abnormal weight gain rate. Infants were classified into categories of no alarm (unlikely to develop type 1ROP)and alarm (at risk for developing type 1ROP).Use of WINROP requires that an infant has (1) gestational age less than 32 weeks at birth, (2) weekly weight measurements,(3) physiologic weight gain,and(4)absence of other pathologic retinal vascular disease. RESULTS: A total of 1706 infants with a median gestational age of 28 weeks (range, 22-31 weeks) and median birth weight of 1016 g (range, 378-2240 g) were included in the study analysis. An alarm occurred in 1101 infants (64.5%), with a median time from birth to alarm of 3 weeks (range, 0-12 weeks) and from alarm to treatment of 8 weeks (range, 1 day to 22 weeks). The sensitivity of WINROP was 98.6% and the negative predictive value was 99.7%. Two infants with type 1 ROP requiring treatment after 40 weeks' postmenstrual age did not receive an alarm. CONCLUSION: The WINROP system is a useful adjunct for ROP screening that identifies high-risk infants early to optimize care and potentially reduce the overall number of diagnostic ROP examinations.
Wallis TSA, Bex PJ. Image correlates of crowding in natural scenes. J Vis 2012;12(7)Abstract
Visual crowding is the inability to identify visible features when they are surrounded by other structure in the peripheral field. Since natural environments are replete with structure and most of our visual field is peripheral, crowding represents the primary limit on vision in the real world. However, little is known about the characteristics of crowding under natural conditions. Here we examine where crowding occurs in natural images. Observers were required to identify which of four locations contained a patch of "dead leaves'' (synthetic, naturalistic contour structure) embedded into natural images. Threshold size for the dead leaves patch scaled with eccentricity in a manner consistent with crowding. Reverse correlation at multiple scales was used to determine local image statistics that correlated with task performance. Stepwise model selection revealed that local RMS contrast and edge density at the site of the dead leaves patch were of primary importance in predicting the occurrence of crowding once patch size and eccentricity had been considered. The absolute magnitudes of the regression weights for RMS contrast at different spatial scales varied in a manner consistent with receptive field sizes measured in striate cortex of primate brains. Our results are consistent with crowding models that are based on spatial averaging of features in the early stages of the visual system, and allow the prediction of where crowding is likely to occur in natural images.
Trese M, Regatieri CV, Young MJ. Advances in Retinal Tissue Engineering. Materials (Basel) 2012;5(1):108-120.Abstract
Retinal degenerations cause permanent visual loss and affect millions world-wide. Current treatment strategies, such as gene therapy and anti-angiogenic drugs, merely delay disease progression. Research is underway which aims to regenerate the diseased retina by transplanting a variety of cell types, including embryonic stem cells, fetal cells, progenitor cells and induced pluripotent stem cells. Initial retinal transplantation studies injected stem and progenitor cells into the vitreous or subretinal space with the hope that these donor cells would migrate to the site of retinal degeneration, integrate within the host retina and restore functional vision. Despite promising outcomes, these studies showed that the bolus injection technique gave rise to poorly localized tissue grafts. Subsequently, retinal tissue engineers have drawn upon the success of bone, cartilage and vasculature tissue engineering by employing a polymeric tissue engineering approach. This review will describe the evolution of retinal tissue engineering to date, with particular emphasis on the types of polymers that have routinely been used in recent investigations. Further, this review will show that the field of retinal tissue engineering will require new types of materials and fabrication techniques that optimize the survival, differentiation and delivery of retinal transplant cells.
Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune-mediated ocular surface disorder. Arch Ophthalmol 2012;130(1):90-100.Abstract
Dry eye disease is a multifactorial disorder of the tears and ocular surface characterized by symptoms of dryness and irritation. Although the pathogenesis of dry eye disease is not fully understood, it is recognized that inflammation has a prominent role in the development and propagation of this debilitating condition. Factors that adversely affect tear film stability and osmolarity can induce ocular surface damage and initiate an inflammatory cascade that generates innate and adaptive immune responses. These immunoinflammatory responses lead to further ocular surface damage and the development of a self-perpetuating inflammatory cycle. Herein, we review the fundamental links between inflammation and dry eye disease and discuss the clinical implications of inflammation in disease management.
Silva PS, Cavallerano JD, Sun JK, Noble J, Aiello LM, Aiello LP. Nonmydriatic ultrawide field retinal imaging compared with dilated standard 7-field 35-mm photography and retinal specialist examination for evaluation of diabetic retinopathy. Am J Ophthalmol 2012;154(3):549-559.e2.Abstract
PURPOSE: To compare nonmydriatic stereoscopic Optomap ultrawide field images with dilated stereoscopic Early Treatment Diabetic Retinopathy Study 7-standard field 35-mm color 30-degree fundus photographs (ETDRS photography) and clinical examination for determining diabetic retinopathy (DR) and diabetic macular edema (DME) severity. DESIGN: Single-site, prospective, comparative, instrument validation study. METHODS: One hundred three diabetic patients (206 eyes) representing the full spectrum of DR severity underwent nonmydriatic ultrawide field 100-degree and 200-degree imaging, dilated ETDRS photography, and dilated fundus examination by a retina specialist. Two independent readers graded images to determine DR and DME severity. A third masked retina specialist adjudicated discrepancies. RESULTS: Based on ETDRS photography (n = 200), the results were as follows: no DR (n = 25 eyes [12.5%]), mild nonproliferative DR (NPDR; 47 [23.5%]), moderate NPDR (61 [30.5%]), severe NPDR (11 [5.5%]), very severe NPDR (3 [1.5%]), and proliferative DR (52 [2.5%]). One (0.5%) eye was ungradable and 6 eyes did not complete ETDRS photography. No DME was found in 114 eyes (57.0%), DME was found in 28 eyes (14.0%), and clinically significant DME was found in 47 eyes (23.5%), and 11 (5.5%) eyes were ungradable. Exact DR severity agreement between ultrawide field 100-degree imaging and ETDRS photography occurred in 84%, with agreement within 1 level in 91% (K(W) = 0.85; K = 0.79). Nonmydriatic ultrawide field images exactly matched clinical examination results for DR in 70% and were within 1 level in 93% (K(W) = 0.71; K = 0.61). Nonmydriatic ultrawide field imaging acquisition time was less than half that of dilated ETDRS photography (P < .0001). CONCLUSIONS: Nonmydriatic ultrawide field images compare favorably with dilated ETDRS photography and dilated fundus examination in determining DR and DME severity; however, they are acquired more rapidly. If confirmed in broader diabetic populations, nonmydriatic ultrawide field imaging may prove to be beneficial in DR evaluation in research and clinical settings.
Zhou X, Robinson CM, Rajaiya J, Dehghan S, Seto D, Jones MS, Dyer DW, Chodosh J. Analysis of human adenovirus type 19 associated with epidemic keratoconjunctivitis and its reclassification as adenovirus type 64. Invest Ophthalmol Vis Sci 2012;53(6):2804-11.Abstract
PURPOSE: Human adenovirus species D type 19 (HAdV-D19) has been associated with epidemic keratoconjunctivitis (EKC), a highly inflammatory infection of the ocular surface. Confusion exists regarding the origins of HAdV-D19. The prototype virus (HAdV-D19p) does not cause EKC, while a virus identified later with the identical serologic determinant is a significant ocular pathogen. METHODS: High throughput genome sequencing and bioinformatics analysis were performed on HAdV-D19p and three HAdV-D19 EKC strains, and compared to the previously sequenced clinical isolate, HAdV-D19 (C) and HAdV-D37. Corneas of C57BL/6J mice were injected with HAdV-D19p, HAdV-D19 (C), or virus-free buffer, and inflammation assessed by clinical examination, flow cytometry, and cytokine ELISA. Confocal microscopy and real-time PCR of infected corneal cell cultures were used to test viral entry. RESULTS: HAdV-D19 (C) and the other clinical EKC isolates showed nearly 100% sequence identity. EKC strains diverged from HAdV-D19p in the penton base, E3, and fiber transcription units. Simplot analysis showed recombination between EKC-associated HAdV-D19 with HAdV-D37, HAdV-D22, and HAdV-D19p, the latter contributing only the hexon gene, the principal serum neutralization determinant. HAdV-D19p induced stromal keratitis in the C57BL/6J mouse, but failed to infect productively human corneal epithelial cells. These data led to retyping of the clinical EKC isolates with a HAdV-D19 hexon gene as HAdV-D64. CONCLUSIONS: HAdV-D19 associated with EKC (HAdV-D64) originated from a recombination between HAdV-D19p, HAdV-D37, and HAdV-D22, and was mischaracterized because of a shared hexon gene. HAdV-D19p is not infectious for corneal epithelial cells, thus explaining the lack of any association with keratitis.
Shatos MA, Haugaard-Kedstrom L, Hodges RR, Dartt DA. Isolation and characterization of progenitor cells in uninjured, adult rat lacrimal gland. Invest Ophthalmol Vis Sci 2012;53(6):2749-59.Abstract
PURPOSE: The purpose of this study was to investigate the presence of progenitor cells in the uninjured, adult rat lacrimal gland (LG). METHODS: The presence of progenitor cells was examined in LG sections from male rats using antibodies against selected stem cell markers and α-smooth muscle actin (SMA), which marks myoepithelial cells (MECs), by immunofluorescence microscopy (IF). Small, immature cells were isolated after digestion of LG with collagenase and culture in RPMI 1640 for 2 weeks. Immature cells were examined for expression of stem cell markers by IF. Immature cell were grown in neuronal, epithelial, and myoepithelial cell media, and examined by light morphology and IF using antibodies to markers of different cell lineages. RESULTS: In the intact LGs, MECs expressed the stem cell markers nestin, Musashi 1, ABCG2, Pax6, Chx 10, ΔN p63, and Sox 2. All markers colocalized with SMA. Isolated immature cells contained Ki-67, nestin, Musashi 1, Pax 6, and CHX 10. In neuronal media, immature cells differentiated and assumed a neuronal cell morphology expressing neurofilament 200. In media for human corneal endothelial cells, immature cells differentiated, assumed cobblestone morphology, and labeled with the epithelial marker AE1/AE3. In RPMI media immature cells differentiated into cells with MEC-like morphology, and expressed the MEC markers SMA, α-actinin, adenylate cyclase II, and vimentin. CONCLUSIONS: We conclude that uninjured, adult LG contains progenitor cells that may be MECs, which can be isolated and differentiated into multiple lineages.
Yanai R, Thanos A, Connor KM. Complement involvement in neovascular ocular diseases. Adv Exp Med Biol 2012;946:161-83.Abstract
Pathological neovascularization (NV) is a hallmark of late stage neovascular age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinopathy of prematurity (ROP). There is accumulating evidence that alterations in inflammatory and immune system pathways that arise from genetic differences, injury, and disease can predispose individuals to retinal neovascular eye diseases. Yet the mechanism of disease progression with respect to the complement system in these maladies is not fully understood. Recent studies have implicated the complement system as an emerging player in the etiology of several retinal diseases. We will summarize herein several of the complement system pathways known to be involved in ocular neovascular pathologies. Current treatment for many neovascular eye diseases focuses on suppression of NV with laser ablation, photodynamic therapy, or anti-VEGF angiogenic inhibitors. However, these treatments do not address the underlying cause of many of these diseases. A clear understanding of the cellular and molecular mechanisms could bring a major shift in our approach to disease treatment and prevention.
Wiggs JL, Yaspan BL, Hauser MA, Kang JH, Allingham RR, Olson LM, Abdrabou W, Fan BJ, Wang DY, Brodeur W, Budenz DL, Caprioli J, Crenshaw A, Crooks K, Delbono E, Doheny KF, Friedman DS, Gaasterland D, Gaasterland T, Laurie C, Lee RK, Lichter PR, Loomis S, Liu Y, Medeiros FA, McCarty C, Mirel D, Moroi SE, Musch DC, Realini A, Rozsa FW, Schuman JS, Scott K, Singh K, Stein JD, Trager EH, Vanveldhuisen P, Vollrath D, Wollstein G, Yoneyama S, Zhang K, Weinreb RN, Ernst J, Kellis M, Masuda T, Zack D, Richards JE, Pericak-Vance M, Pasquale LR, Haines JL. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet 2012;8(4):e1002654.Abstract
Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63-0.75], p = 1.86×10⁻¹⁸), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21-1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50-0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53-0.72], p = 8.88×10⁻¹⁰). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41-0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54-1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.
Weinberger AD, Gilmore MS. CRISPR-Cas: to take up DNA or not-that is the question. Cell Host Microbe 2012;12(2):125-6.Abstract
Landmark experiments in the 1920s showed that capsule switching is critical for Streptococcus pneumonia survival. Further studies demonstrated that capsule "transformation" occurs via DNA uptake. In this issue of Cell Host and Microbe, Bikard et al. (2012) show that CRISPR-Cas systems inhibit DNA uptake, selecting for the outgrowth of CRISPR-defective pneumococci.