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Cai S, Smith ME, Redenti SM, Wnek GE, Young MJ. Mouse retinal progenitor cell dynamics on electrospun poly (ϵ-caprolactone). J Biomater Sci Polym Ed 2012;23(11):1451-65.Abstract
Age-related macular degeneration, retinitis pigmentosa and glaucoma are among the many retinal degenerative diseases where retinal cell death leads to irreversible vision loss and blindness. Working toward a cell-replacement-based therapy for such diseases, a number of research groups have recently evaluated the feasibility of using retinal progenitor cells (RPCs) cultured and transplanted on biodegradable polymer substrates to replace damaged retinal tissue. Appropriate polymer substrate design is essential to providing a three-dimensional environment that can facilitate cell adhesion, proliferation and post-transplantation migration into the host environment. In this study, we have designed and fabricated a novel, ultra-thin electrospun poly(ϵ-caprolactone) (PCL) scaffold with microscale fiber diameters, appropriate porosity for infiltration by RPCs, and biologically compatible mechanical characteristics. We have verified that our electrospun PCL scaffold supports robust mouse RPC proliferation, adhesion, and differentiation in vitro, as well as migration into mouse retinal explants. These promising results make PCL a strong candidate for further development as a cell transplantation substrate in retinal regenerative research.
Hemmati HD, Gologorsky D, Pineda R. Intraoperative wavefront aberrometry in cataract surgery. Semin Ophthalmol 2012;27(5-6):100-6.Abstract
Intraoperative wavefront aberrometry is a relatively new technology that aims to improve refractive outcomes following cataract surgery by optimizing the spherical power of the intraocular lens implant or calculating the appropriate axis and power of toric lenses during cataract surgery in an aphakic state. This article reviews the literature on intraoperative wavefront aberrometry and provides a critical assessment of the benefits and shortcomings of that technology.
Andreoli MT, Andreoli CM. Surgical rehabilitation of the open globe injury patient. Am J Ophthalmol 2012;153(5):856-60.Abstract
PURPOSE: To describe the long-term surgical course of patients with open globe injury. DESIGN: Retrospective case series. METHODS: Patients with open globe injuries (848 in total) treated surgically at the Massachusetts Eye and Ear Infirmary between 2000 and 2009 were retrospectively reviewed. Data from presentation, initial repair, and follow-up surgery were analyzed. RESULTS: Among 848 injuries, 1415 surgical procedures were performed. The mean follow-up time was 19.7 months, including 6017 visits. On average, patients required 1.7 surgeries and 7.1 follow-up visits. Factors predicting follow-up surgery included more severe ocular trauma score, worse prerepair visual acuity, retinal hemorrhage, anterior vitrectomy at primary repair, pars plana vitrectomy at primary repair, and lensectomy at primary repair. Patients with zone II injury, hemorrhagic choroidal detachment, and a history of previous ocular surgery tended to require follow-up surgery less frequently. Patients requiring a second surgery tended to have worse visual acuity at presentation and postrepair. Postoperative visual outcomes were worse for patients who underwent vitreoretinal follow-up surgery, likely because of mechanism of injury. Variables associated with inferior visual outcome were worse prerepair visual acuity, postoperative afferent pupillary defect (APD), old age, scleral laceration, and retinal detachment. CONCLUSION: Open globe injuries require significant surgical follow-up. Patients requiring multiple operations tended to have worse postoperative visual acuity. Patients who underwent vitreoretinal surgery had overall worse visual outcomes. While the first year of surveillance appears to be pivotal in the course of an open globe injury, these patients can expect long-term care from comprehensive and subspecialty ophthalmologists.
Gologorsky D, Thanos A, Vavvas D. Therapeutic interventions against inflammatory and angiogenic mediators in proliferative diabetic retinopathy. Mediators Inflamm 2012;2012:629452.Abstract
The global prevalence of diabetes is estimated to be 336 million people, with diabetic complications contributing to significant worldwide morbidity and mortality. Diabetic retinopathy results from cumulative microvascular damage to the retina and inflammation is recognized as a critical driver of this disease process. This paper outlines the pathophysiology leading to proliferative diabetic retinopathy and highlights many of the inflammatory, angiogenic, and cytokine mediators implicated in the development and progression of this disease. We focus a detailed discussion on the current targeted therapeutic interventions used to treat diabetic retinopathy.
Daniels AB, Lee J-E, MacConaill LE, Palescandolo E, van Hummelen P, Adams SM, Deangelis MM, Hahn WC, Gragoudas ES, Harbour WJ, Garraway LA, Kim IK. High throughput mass spectrometry-based mutation profiling of primary uveal melanoma. Invest Ophthalmol Vis Sci 2012;53(11):6991-6.Abstract
PURPOSE: We assessed for mutations in a large number of oncogenes and tumor suppressor genes in primary uveal melanomas using a high-throughput profiling system. METHODS: DNA was extracted and purified from 134 tissue samples from fresh-frozen tissues (n = 87) or formalin-fixed, paraffin-embedded tissues (n = 47) from 124 large uveal melanomas that underwent primary treatment by enucleation. DNA was subjected to whole genome amplification and MALDI-TOF mass spectrometry-based mutation profiling (>1000 mutations tested across 120 oncogenes and tumor suppressor genes) using the OncoMap3 platform. All candidate mutations, as well as commonly occurring mutations in GNAQ and GNA11, were validated using homogeneous mass extension (hME) technology. RESULTS: Of 123 samples, 97 (79%, representing 89 unique tumors) were amplified successfully, passed all quality control steps, and were assayed with the OncoMap platform. A total of 58 mutation calls was made for 49 different mutations across 26 different genes in 34/98 (35%) samples. Of 91 tumors that underwent hME validation, 83 (91%) harbored mutations in the GNAQ (47%) or GNA11 (44%) genes, while hME validation revealed two tumors with mutations in EGFR. These additional mutations occurred in tumors that also had mutations in GNAQ or GNA11. CONCLUSIONS: The vast majority of primary large uveal melanomas harbor mutually-exclusive mutations in GNAQ or GNA11, but very rarely have the oncogenic mutations that are reported commonly in other cancers. When present, these other mutations were found in conjunction with GNAQ/GNA11 mutations, suggesting that these other mutations likely are not the primary drivers of oncogenesis in uveal melanoma.
Chen J, Joyal J-S, Hatton CJ, Juan AM, Pei DT, Hurst CG, Xu D, Stahl A, Hellstrom A, Smith LEH. Propranolol inhibition of β-adrenergic receptor does not suppress pathologic neovascularization in oxygen-induced retinopathy. Invest Ophthalmol Vis Sci 2012;53(6):2968-77.Abstract
PURPOSE: Retinopathy of prematurity (ROP) is a leading cause of blindness in children and is, in its most severe form, characterized by uncontrolled growth of vision-threatening pathologic vessels. Propranolol, a nonselective β-adrenergic receptor blocker, was reported to protect against pathologic retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Based on this single animal study using nonstandard evaluation of retinopathy, clinical trials are currently ongoing to evaluate propranolol treatment in stage 2 ROP patients who tend to experience spontaneous disease regression and are at low risk of blindness. Because these ROP patients are vulnerable premature infants who are still in a fragile state of incomplete development, the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in preclinical animal models of retinopathy and potential benefits weighed against potential adverse effects. METHODS: Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to P12. Three routes of propranolol treatment were assessed from P12 to P16: oral gavage, intraperitoneal injection, or subcutaneous injection, with doses varying between 2 and 60 mg/kg/day. At P17, retinal flatmounts were stained with isolectin and quantified with a standard protocol to measure vasoobliteration and pathologic neovascularization. Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol-treated pups. RESULTS: None of the treatment approaches at any dose of propranolol (up to 60 mg/kg/day) were effective in preventing the development of retinopathy in a mouse model of OIR, evaluated using standard techniques. Propranolol treatment also did not change retinal expression of angiogenic factors including vascular endothelial growth factor. CONCLUSIONS: Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of β-adrenergic receptors is an appropriate therapeutic approach for treating ROP.
Kim LA, D'Amore PA. A brief history of anti-VEGF for the treatment of ocular angiogenesis. Am J Pathol 2012;181(2):376-9.Abstract
In 1994, The American Journal of Pathology published a key article reporting that hypoxic retina produces vascular endothelial growth factor (VEGF), suggesting a role for VEGF in ocular neovascularization. Subsequent developments in anti-VEGF treatment for neovascular eye disease have improved visual outcomes and changed the standard of care in retinal medicine and ophthalmology.
Jakobiec FA, Zakka FR, Papakostas TD, Fay A. Angiomyofibroma of the orbit: a hybrid of vascular leiomyoma and cavernous hemangioma. Ophthalmic Plast Reconstr Surg 2012;28(6):438-45.Abstract
PURPOSE: The aim of this study was to describe a novel primary orbital vascular tumor combining elements of a vascular leiomyoma (angioleiomyoma) and a cavernous hemangioma. METHODS: A critical review of clinical records, diagnostic tests, and radiographic studies combined with histopathologic evaluation with standard and special histochemical staining and immunohistochemical investigations was conducted. RESULTS: A 44-year-old man slowly developed 5 mm of well-tolerated relative right proptosis with minimal motility disturbance and no visual decline. Computed tomography and magnetic resonance imaging demonstrated a medial and intraconal rounded mass that perfused slowly and whose anterior surface was well circumscribed. At surgery, the tumor was solid and pink with intersecting white bands and densely attached to surrounding normal tissues. The most adherent apical portion of the mass was left behind after subtotal excision. Histopathologically, only a partial pseudocapsule was discovered. The tumor was composed of cavernous channels, capillary zones, compressed lumens with linear strands of endothelium, and collections of muscular veins devoid of an elastica. Striking smooth muscle actin positivity was identified in disorganized masses of smooth muscle cells in the intervascular spaces and around the cavernous vascular units; these myocytes were intermixed with bundles of interstitial keloidal collagen. The endothelium was CD31 and CD34 positive for vascular endothelium and D2-40 negative for lymphatic endothelium. CONCLUSIONS: The authors have classified this hybrid tumor an angiomyofibroma with low neoplastic potential and features of a malformation. It is a composite variant of cavernous hemangioma associated with a conspicuous proliferation of anomalous disorganized smooth muscle cells (leiomyoma). Most of the lesion lacked a pseudocapsule, which impeded surgical delivery. Incomplete excision is recommended in such cases as preferable to the complications that could ensue from overly aggressive efforts at complete removal, particularly at the orbital apex. Supporting this position is the observation that incompletely excised cavernous hemangioma generally does not recur.
Callahan AB, Yoon MK. Infantile hemangiomas: A review. Saudi J Ophthalmol 2012;26(3):283-91.Abstract
Infantile hemangiomas (IH) are the most common eyelid and orbital tumors of childhood. Although they are considered benign lesions that have a generally self-limited course, in the periocular region, they have the potential to cause amblyopia, strabismus, and severe disfigurement. The decision for treatment can be a source of anxiety for patients, parents, and physicians alike. There are numerous treatment modalities, including emerging therapies that may make treatment safer and more effective than ever before. This review discusses our current understanding of this disease, its management, and future therapies.
Hodges RR, Bair JA, Carozza RB, Li D, Shatos MA, Dartt DA. Signaling pathways used by EGF to stimulate conjunctival goblet cell secretion. Exp Eye Res 2012;103:99-113.Abstract
The purpose of this study was to identify the signaling pathways that epidermal growth factor (EGF) uses to stimulate mucin secretion from cultured rat conjunctival goblet cells and to compare the pathways used by EGF with those used by the known secretagogue muscarinic, cholinergic agonists. To this end, goblet cells from rat conjunctiva were grown in culture using RPMI media. For immunofluorescence experiments, antibodies against EGF receptor (EGFR) and ERK 2 as well as muscarinic receptors (M(1)AchR, M(2)AchR, and M(3)AchR) were used, and the cells viewed by fluorescence microscopy. Intracellular [Ca(2+)] ([Ca(2+)](i)) was measured using fura 2/AM. Glycoconjugate secretion was determined after cultured goblet cells were preincubated with inhibitors, and then stimulated with EGF or the cholinergic agonist carbachol (Cch). Goblet cell secretion was measured using an enzyme-linked lectin assay with UEA-I or ELISA for MUC5AC. In cultured goblet cells EGF stimulated an increase in [Ca(2+)](i) in a concentration-dependent manner. EGF-stimulated increase in [Ca(2+)](i) was blocked by inhibitors of the EGF receptor and removal of extracellular Ca(2+). Inhibitors against the EGFR and ERK 1/2 blocked EGF-stimulated mucin secretion. In addition, cultured goblet cells expressed M(1)AchR, M(2)AchR, and M(3)AchRs. Cch-stimulated increase in [Ca(2+)](i) was blocked by inhibitors for the M(1)AchRs, matrix metalloproteinases, and EGF receptors. Inhibitors against the EGF receptor and ERK 1/2 also blocked Cch-stimulated mucin secretion. We conclude that in conjunctival goblet cells, EGF itself increases [Ca(2+)](i) and activates ERK 1/2 to stimulate mucin secretion. EGF-stimulated secretion is dependent on extracellular Ca(2+). This mechanism of action is similar to cholinergic agonists that use muscarinic receptors to transactivate the EGF receptor, increase [Ca(2+)](i), and activate ERK 1/2 leading to an increase in mucin secretion.
Bitar MS, Liu C, Ziaei A, Chen Y, Schmedt T, Jurkunas UV. Decline in DJ-1 and decreased nuclear translocation of Nrf2 in Fuchs endothelial corneal dystrophy. Invest Ophthalmol Vis Sci 2012;53(9):5806-13.Abstract
PURPOSE: This study sought to determine factors involved in nuclear factor erythroid 2-related factor 2 (Nrf2) regulation and their response to oxidative stress in Fuchs endothelial corneal dystrophy (FECD) and normal corneal endothelial cells (CECs). METHODS: FECD corneal buttons were obtained from transplantations and normal human corneas from tissue banks. Oxidative stress was induced by tert-butyl hydroperoxide (tBHP). Protein and mRNA levels of Nrf2, DJ-1, p53, and Kelch-like ECH-associated protein1 (Keap1) were investigated using Western blotting and real-time PCR. Immunoprecipitation was used to detect levels of oxidized DJ-1 protein and Cullin 3- (Cul3)-regulated degradation of DJ-1 in immortalized FECD (FECDi) and normal CEC (HCECi) cell lines. Nrf2 subcellular localization was assessed by immunocytochemistry. RESULTS: Nrf2 protein stabilizer, DJ-1, decreased significantly in FECD CECs compared with normal, whereas Nrf2 protein repressor, Keap1, was unchanged at baseline but increased under oxidative stress. Under oxidative stress, normal CECs upregulated DJ-1 protein synthesis, whereas FECD CECs did not. DJ-1 decline correlated with increased DJ-1 oxidative modification and carbonylation in FECDi as compared with HCECi. Increased labeling of immunoprecipitated DJ-1 protein with anti-Cul3 antibody indicated enhanced DJ-1 degradation in FECDi as compared with HCECi. Following tBHP treatment, Nrf2 translocated from cytoplasm to nuclei in normal CECs, whereas Nrf2 nuclear localization was not observed in FECD. CONCLUSIONS: Decreased levels of DJ-1 in FECD at baseline and under oxidative stress correlate with impaired Nrf2 nuclear translocation and heightened cell susceptibility to apoptosis. Targeting the DJ-1/Nrf2 axis could yield a mechanism to slow CEC degeneration in FECD.
Haddadin RI, Oh D-J, Kang MH, Villarreal G, Kang J-heon, Jin R, Gong H, Rhee DJ. Thrombospondin-1 (TSP1)-null and TSP2-null mice exhibit lower intraocular pressures. Invest Ophthalmol Vis Sci 2012;53(10):6708-17.Abstract
PURPOSE: Thrombospondin-1 (TSP1) and TSP2 are matricellular proteins that have been shown to regulate cytoskeleton, cell adhesion, and extracellular matrix remodeling. Both TSP1 and TSP2 are found in the trabecular meshwork (TM). In cadaver eyes with primary open-angle glaucoma (POAG), TSP1 is increased in one third of patients. We hypothesized that TSP1 and TSP2 participate in the regulation of intraocular pressure (IOP). Methods. IOPs of TSP1-null, TSP2-null mice, and their corresponding wild-type (WT) mice were measured using a commercial rebound tonometer. Fluorophotometric measurements assessed aqueous turnover. Central corneal thickness (CCT) was measured by optical coherence tomography. Iridocorneal angles were examined using light microscopy (LM), immunofluorescence (IF), and transmission electron microscopy (TEM). RESULTS: Average IOPs of TSP1-null and TSP2-null mice were 10% and 7% less than that of the corresponding WT mice, respectively. CCTs were 6.5% less in TSP1-null mice (P < 0.05) and 1.1% less in TSP2-null mice (P > 0.05). Fluorophotometric measurements suggest that aqueous turnover rates in TSP1-null and TSP2-null mice are greater than those of WT mice. LM of the TSP1-null and TSP2-null iridocorneal angles reveals morphology, which is indistinguishable from that of their corresponding WTs. IF revealed possible concurrent underexpression of TSP2 in TSP1-null mice and of TSP1 in TSP2-null mice. TEM revealed larger collagen fibril diameters in TSP1-null and TSP2-null mice compared with WTs. CONCLUSIONS: TSP1-null and TSP2-null mice have lower IOPs than their WT counterparts. The rate of aqueous turnover suggests that the mechanism is enhanced outflow facility. An alteration in the extracellular matrix may contribute to this finding.

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