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Yamaguchi T, Turhan A, Harris DL, Hu K, Prüss H, von Andrian U, Hamrah P. Bilateral nerve alterations in a unilateral experimental neurotrophic keratopathy model: a lateral conjunctival approach for trigeminal axotomy. PLoS One 2013;8(8):e70908.Abstract
To study bilateral nerve changes in a newly developed novel mouse model for neurotrophic keratopathy by approaching the trigeminal nerve from the lateral fornix. Surgical axotomy of the ciliary nerve of the trigeminal nerve was performed in adult BALB/c mice at the posterior sclera. Axotomized, contralateral, and sham-treated corneas were excised on post-operative days 1, 3, 5, 7 and 14 and immunofluorescence histochemistry was performed with anti-β-tubulin antibody to evaluate corneal nerve density. Blink reflex was evaluated using a nylon thread. The survival rate was 100% with minimal bleeding during axotomy and a surgical time of 8±0.5 minutes. The blink reflex was diminished at day 1 after axotomy, but remained intact in the contralateral eyes in all mice. The central and peripheral subbasal nerves were not detectable in the axotomized cornea at day 1 (p<0.001), compared to normal eyes (101.3±14.8 and 69.7±12.0 mm/mm² centrally and peripherally). Interestingly, the subbasal nerve density in the contralateral non-surgical eyes also decreased significantly to 62.4±2.8 mm/mm² in the center from day 1 (p<0.001), but did not change in the periphery (77.3±11.7 mm/mm², P = 0.819). Our novel trigeminal axotomy mouse model is highly effective, less invasive, rapid, and has a high survival rate, demonstrating immediate loss of subbasal nerves in axotomized eyes and decreased subbasal nerves in contralateral eyes after unilateral axotomy. This model will allow investigating the effects of corneal nerve damage and serves as a new model for neurotrophic keratopathy.
Werdich XQ, Jakobiec FA, Singh AD, Kim IK. A review of advanced genetic testing for clinical prognostication in uveal melanoma. Semin Ophthalmol 2013;28(5-6):361-71.Abstract
Uveal melanoma (UM) has a strong propensity to metastasize and the prognosis for metastatic disease is very poor. It has been suggested that occult micrometastases are already present, but undetectable, in many patients at the time when the primary ocular tumor is diagnosed and treated. To identify high-risk patients for close monitoring and early intervention with prophylactic adjuvant systemic therapy, an accurate predictive system is necessary for stratifying those patients at risk of developing metastatic disease. To date, many clinical and histopathological features, molecular pathway characteristics, and genetic fingerprints of UM have been suggested for disease prognostication. Among the newest of them, tumor genetics has received the most attention in demonstrating promise as a prognostic tool. Because of the plethora of recent developments, we summarize and compare in this review the important standard and more advanced cytogenetic prognostic markers. We further describe the variety of genetic tests available for prognostication of UM, and provide a critical assessment of the respective advantages and disadvantages of these tools.
VanderVeen DK, Martin CR, Mehendale R, Allred EN, Dammann O, Leviton A, Leviton A. Early nutrition and weight gain in preterm newborns and the risk of retinopathy of prematurity. PLoS One 2013;8(5):e64325.Abstract
OBJECTIVE: To identify nutritional and weight gain limitations associated with retinopathy of prematurity (ROP) severity among very preterm newborns. PATIENTS AND METHODS: 1180 infants <28 weeks GA at birth with ROP examination results were grouped and analyzed by quartile of weekly total calorie, carbohydrate, protein, and lipid intake, as well as growth velocity between postnatal days 7 and 28 (adjusted for GA and birth weight Z-score). ROP was categorized by development of no, mild (
Sánchez J, Espinoza M, de Borba Campos M, Merabet LB. Enhancing Orientation and Mobility Skills in Learners who are Blind through Video gaming. Creat Cognit 2013;2013:353-356.Abstract
In this work we present the results of the cognitive impact evaluation regarding the use of Audiopolis, an audio and/or haptic-based videogame. The software has been designed, developed and evaluated for the purpose of developing orientation and mobility (O&M) skills in blind users. The videogame was evaluated through cognitive tasks performed by a sample of 12 learners. The results demonstrated that the use of Audiopolis had a positive impact on the development and use of O&M skills in school-aged blind learners.
Spurr-Michaud SJ, Gipson IK. Methods for culture of human corneal and conjunctival epithelia. Methods Mol Biol 2013;945:31-43.Abstract
The surface of the eye is exposed to the outside world and is, thus, subject to surface abrasion, infections, and drying, cicatrizing diseases. Availability of in vitro methods for culture of the human corneal and conjunctival epithelia, which cover the ocular surface, is therefore important in understanding the biology of these epithelia and their response to disease/infections, as well as for providing human-relevant models for preclinical testing of potential therapeutic agents. The ensuing chapter describes several methods for primary culture of both corneal and conjunctival epithelia and culture of immortalized cell lines, and methods employed to induce differentiation in the cultured epithelia.
Yoon MK, McCulley TJ. Secondary tarsoconjunctival graft: a modification to the Cutler-Beard procedure. Ophthalmic Plast Reconstr Surg 2013;29(3):227-30.Abstract
PURPOSE: The Cutler-Beard procedure is a commonly used technique to reconstruct large upper eyelid defects. Eyelid retraction and entropion are common complications. To prevent these problems, the authors modified the traditional Cutler-Beard procedure with secondary placement of an autologous tarsoconjunctival graft. METHODS: This is a retrospective review of 2 patients with large upper eyelid defects necessitating upper eyelid reconstruction. The initial stage is unaltered. At the time of flap division, a tarsoconjunctival graft from the contralateral upper eyelid is sutured to the posterior surface of the newly constructed upper eyelid. Two patients underwent this procedure, and follow up was 4 and 23 months, respectively. Patients developed no postoperative complications, including entropion or retraction. CONCLUSIONS: This modification to the Cutler-Beard operation is a technically simple procedure that can restore a more anatomically correct eyelid and can prevent subsequent entropion or retraction. This technique is unique, offering 3 major advances: first, placing the graft at the second surgical stage; second, replacing the tarsus and conjunctiva with like tissue; and third, preserving a lip of conjunctiva to cover the edge of the newly reconstructed upper eyelid.
Yonekawa Y, Miller JB, Turalba AV, Eliott D. Traumatic macular hole from intentional basketball overinflation. Ophthalmic Surg Lasers Imaging Retina 2013;44(3):303-5.Abstract
We report a new mechanism of ocular trauma. A basketball was intentionally overinflated until it exploded, resulting in corneal edema, hyphema, iritis, vitreous hemorrhage, commotio retinae, and a macular hole. The macular hole did not close after observation and subsequent pars plana vitrectomy with posterior hyaloid removal, but a repeat vitrectomy with internal limiting membrane peeling resulted in hole closure. Basketball overinflation to the point of explosion is a potentially blinding practice of which the public and manufacturers should be made aware.
Wiggs JL, Howell GR, Linkroum K, Abdrabou W, Hodges E, Braine CE, Pasquale LR, Hannon GJ, Haines JL, John SWM. Variations in COL15A1 and COL18A1 influence age of onset of primary open angle glaucoma. Clin Genet 2013;84(2):167-74.Abstract
Primary open angle glaucoma (POAG) is a genetically and phenotypically complex disease that is a leading cause of blindness worldwide. Previously we completed a genome-wide scan for early-onset POAG that identified a locus on 9q22 (GLC1J). To identify potential causative variants underlying GLC1J, we used targeted DNA capture followed by high throughput sequencing of individuals from four GLC1J pedigrees, followed by Sanger sequencing to screen candidate variants in additional pedigrees. A mutation likely to cause early-onset glaucoma was not identified, however COL15A1 variants were found in the youngest affected members of 7 of 15 pedigrees with variable disease onset. In addition, the most common COL15A1 variant, R163H, influenced the age of onset in adult POAG cases. RNA in situ hybridization of mouse eyes shows that Col15a1 is expressed in the multiple ocular structures including ciliary body, astrocytes of the optic nerve and cells in the ganglion cell layer. Sanger sequencing of COL18A1, a related multiplexin collagen, identified a rare variant, A1381T, in members of three additional pedigrees with early-onset disease. These results suggest genetic variation in COL15A1 and COL18A1 can modify the age of onset of both early and late onset POAG.
Walshe TE, Dela Paz NG, D'Amore PA. The role of shear-induced transforming growth factor-β signaling in the endothelium. Arterioscler Thromb Vasc Biol 2013;33(11):2608-17.Abstract
OBJECTIVE: Vascular endothelial cells (ECs) are continuously exposed to blood flow that contributes to the maintenance of vessel structure and function; however, the effect of hemodynamic forces on transforming growth factor-β (TGF-β) signaling in the endothelium is poorly described. We examined the potential role of TGF-β signaling in mediating the protective effects of shear stress on ECs. APPROACH AND RESULTS: Human umbilical vein ECs (HUVECs) exposed to shear stress were compared with cells grown under static conditions. Signaling through the TGF-β receptor ALK5 was inhibited with SB525334. Cells were examined for morphological changes and harvested for analysis by real-time polymerase chain reaction, Western blot analysis, apoptosis, proliferation, and immunocytochemistry. Shear stress resulted in ALK5-dependent alignment of HUVECs as well as attenuation of apoptosis and proliferation compared with static controls. Shear stress led to an ALK5-dependent increase in TGF-β3 and Krüppel-like factor 2, phosphorylation of endothelial NO synthase, and NO release. Addition of the NO donor S-nitroso-N-acetylpenicillamine rescued the cells from apoptosis attributable to ALK5 inhibition under shear stress. Knockdown of TGF-β3, but not TGF-β1, disrupted the HUVEC monolayer and prevented the induction of Krüppel-like factor 2 by shear. CONCLUSIONS: Shear stress of HUVECs induces TGF-β3 signaling and subsequent activation of Krüppel-like factor 2 and NO, and represents a novel role for TGF-β3 in the maintenance of HUVEC homeostasis in a hemodynamic environment.
Theodoropoulou S, Brodowska K, Kayama M, Morizane Y, Miller JW, Gragoudas ES, Vavvas DG. Aminoimidazole carboxamide ribonucleotide (AICAR) inhibits the growth of retinoblastoma in vivo by decreasing angiogenesis and inducing apoptosis. PLoS One 2013;8(1):e52852.Abstract
5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), an analog of AMP is widely used as an activator of AMP-kinase (AMPK), a protein that regulates the responses of the cell to energy change. Recently, we showed that AICAR-induced AMPK activation inhibits the growth of retinoblastoma cells in vitro by decreasing cyclins and by inducing apoptosis and S-phase arrest. In this study, we investigated the effects of AMPK activator AICAR on the growth of retinoblastoma in vivo. Intraperitoneal injection of AICAR resulted in 48% growth inhibition of Y79 retinoblastoma cell tumors in mice. Tumors isolated from mice treated with AICAR had decreased expression of Ki67 and increased apoptotic cells (TUNEL positive) compared with the control. In addition, AICAR treatment suppressed significantly tumor vessel density and macrophage infiltration. We also showed that AICAR administration resulted in AMPK activation and mTOR pathway inhibition. Paradoxically observed down-regulation of p21, which indicates that p21 may have a novel function of an oncogene in retinoblastoma tumor. Our results indicate that AICAR treatment inhibited the growth of retinoblastoma tumor in vivo via AMPK/mTORC1 pathway and by apoptogenic, anti-proliferative, anti-angiogenesis mechanism. AICAR is a promising novel non-chemotherapeutic drug that may be effective as an adjuvant in treating Retinoblastoma.
Yousuf MA, Zhou X, Mukherjee S, Chintakuntlawar AV, Lee JY, Ramke M, Chodosh J, Rajaiya J. Caveolin-1 associated adenovirus entry into human corneal cells. PLoS One 2013;8(10):e77462.Abstract
The cellular entry of viruses represents a critical area of study, not only for viral tropism, but also because viral entry dictates the nature of the immune response elicited upon infection. Epidemic keratoconjunctivitis (EKC), caused by viruses within human adenovirus species D (HAdV-D), is a severe, ocular surface infection associated with corneal inflammation. Clathrin-mediated endocytosis has previously been shown to play a critical role in entry of other HAdV species into many host cell types. However, HAdV-D endocytosis into corneal cells has not been extensively studied. Herein, we show an essential role for cholesterol rich, lipid raft microdomains and caveolin-1, in the entry of HAdV-D37 into primary human corneal fibroblasts. Cholesterol depletion using methyl-β-cyclodextrin (MβCD) profoundly reduced viral infection. When replenished with soluble cholesterol, the effect of MβCD was reversed, allowing productive viral infection. HAdV-D37 DNA was identified in caveolin-1 rich endosomal fractions after infection. Src kinase activity was also increased in caveolin-1 rich endosomal fractions after infection, and Src phosphorylation and CXCL1 induction were both decreased in caveolin-1-/- mice corneas compared to wild type mice. siRNA knock down of caveolin-1 in corneal cells reduced chemokine induction upon viral infection, and caveolin-1-/- mouse corneas showed reduced cellular entry of HAdV-D37. As a control, HAdV-C2, a non-corneal pathogen, appeared to utilize the caveolar pathway for entry into A549 cells, but failed to infect corneal cells entirely, indicating virus and cell specific tropism. Immuno-electron microscopy confirmed the presence of caveolin-1 in HAdV-D37-containing vesicles during the earliest stages of viral entry. Collectively, these experiments indicate for the first time that HAdV-D37 uses a lipid raft mediated caveolin-1 associated pathway for entry into corneal cells, and connects the processes of viral entry with downstream proinflammatory cell signaling.
Silva PS, Cavallerano JD, Sun JK, Soliman AZ, Aiello LM, Aiello LP. Peripheral lesions identified by mydriatic ultrawide field imaging: distribution and potential impact on diabetic retinopathy severity. Ophthalmology 2013;120(12):2587-2595.Abstract
OBJECTIVE: To assess diabetic retinopathy (DR) as determined by lesions identified using mydriatic ultrawide field imaging (DiSLO200; Optos plc, Scotland, UK) compared with Early Treatment Diabetic Retinopathy Study (ETDRS) 7-standard field film photography. DESIGN: Prospective comparative study of DiSLO200, ETDRS 7-standard field film photographs, and dilated fundus examination (DFE). PARTICIPANTS: A total of 206 eyes of 103 diabetic patients selected to represent all levels of DR. METHODS: Subjects had DiSLO200, ETDRS 7-standard field film photographs, and DFE. Images were graded for severity and distribution of DR lesions. Discrepancies were adjudicated, and images were compared side by side. MAIN OUTCOME MEASURES: Distribution of hemorrhage and/or microaneurysm (H/Ma), venous beading (VB), intraretinal microvascular abnormality (IRMA), and new vessels elsewhere (NVE). Kappa (κ) and weighted κ statistics for agreement. RESULTS: The distribution of DR severity by ETDRS 7-standard field film photographs was no DR 12.5%; nonproliferative DR mild 22.5%, moderate 30%, and severe/very severe 8%; and proliferative DR 27%. Diabetic retinopathy severity between DiSLO200 and ETDRS film photographs matched in 80% of eyes (weighted κ = 0.74,κ = 0.84) and was within 1 level in 94.5% of eyes. DiSLO200 and DFE matched in 58.8% of eyes (weighted κ = 0.69,κ = 0.47) and were within 1 level in 91.2% of eyes. Forty eyes (20%) had DR severity discrepancies between DiSLO200 and ETDRS film photographs. The retinal lesions causing discrepancies were H/Ma 52%, IRMA 26%, NVE 17%, and VB 4%. Approximately one-third of H/Ma, IRMA, and NVE were predominantly outside ETDRS fields. Lesions identified on DiSLO200 but not ETDRS film photographs suggested a more severe DR level in 10% of eyes. Distribution in the temporal, superotemporal, inferotemporal, superonasal, and inferonasal fields was 77%, 72%, 61%, 65%, and 59% for H/Ma, respectively (P<0.0001); 22%, 24%, 21%, 28%, and 22% for VB, respectively (P = 0.009); 52%, 40%, 29%, 47%, and 36% for IRMA, respectively (P<0.0001), and 8%, 4%, 4%, 8%, and 5% for NVE, respectively (P = 0.03). All lesions were more frequent in the temporal fields compared with the nasal fields (P<0.0001). CONCLUSIONS: DiSLO200 images had substantial agreement with ETDRS film photographs and DFE in determining DR severity. On the basis of DiSLO200 images, significant nonuniform distribution of DR lesions was evident across the retina. The additional peripheral lesions identified by DiSLO200 in this cohort suggested a more severe assessment of DR in 10% of eyes than was suggested by the lesions within the ETDRS fields. However, the implications of peripheral lesions on DR progression within a specific ETDRS severity level over time are unknown and need to be evaluated prospectively.
Yonekawa Y, MacDonald SM, Shildkrot Y, Mukai S. Standard fractionation low-dose proton radiotherapy for diffuse choroidal hemangiomas in pediatric Sturge-Weber syndrome. J AAPOS 2013;17(3):318-22.Abstract
Sturge-Weber syndrome is a nonhereditary congenital neurocutaneous syndrome characterized by leptomeningeal angiomatosis, facial nevus flammeus, and diffuse choroidal hemangioma, which when complicated by total retinal detachment, portend a poor prognosis. Management is often limited to salvage external beam irradiation. We present a modified proton therapy technique for young children with total bullous retinal detachments that uses standard fractionation low-dose proton radiotherapy to decrease the risk of radiation complications. Treatment techniques for young children who cannot cooperate with conventional radiation protocols are also described.
Yadav P, De Castro DK, Waner M, Meyer L, Fay A. Vascular anomalies of the head and neck: a review of genetics. Semin Ophthalmol 2013;28(5-6):257-66.Abstract
PURPOSE: Vascular anomalies comprise malformations, hemangiomas, and rare tumors. The commonality among these lesions is their origin in vascular endothelia. Most occur sporadically, but occasional inheritance is observed and thus allows genetic research and insight into etiology. This review highlights those vascular anomalies in which genetic inheritance has been demonstrated. METHODS: A comprehensive literature search was performed on PubMed. Fifty-five full-length articles were reviewed. RESULTS: Five categories of vascular anomalies with patterned inheritance were identified: arteriovenous malformation (AVM), capillary malformation (CM), lymphatic malformation (LM), venous malformation (VM), and infantile hemangioma (IH). Capillary and arteriovenous malformation subtypes are associated with a RASA-1 gene mutation and show autosomal dominant inheritance. VEGFR3 mutations have been associated with generalized forms of LM and lymphedema. Mutations in TIE2/TEK genes cause inherited forms of venous malformations also with autosomal dominant inheritance. Familial clustering and atopic disease are associated with infantile hemangioma, and gene expression varies with the developmental stage of these lesions. CONCLUSION: Most vascular anomalies occur sporadically, but several genes and genetic disorders have been associated with them. Specific forms of capillary malformation appear to be most convincingly associated with genomic errors. Further research promises new insights into the development of this diverse group of disorders.

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