Pennock S, Kim D, Mukai S, Kuhnle M, Chun DW, Matsubara J, Cui J, Ma P, Maberley D, Samad A, Van Geest RJ, Oberstein SL, Schlingemann RO, Kazlauskas A. Ranibizumab is a potential prophylaxis for proliferative vitreoretinopathy, a nonangiogenic blinding disease. Am J Pathol 2013;182(5):1659-70.Abstract
Proliferative vitreoretinopathy (PVR) exemplifies a disease that is difficult to predict, lacks effective treatment options, and substantially reduces the quality of life of an individual. Surgery to correct a rhegmatogenous retinal detachment fails primarily because of PVR. Likely mediators of PVR are growth factors in vitreous, which stimulate cells within and behind the retina as an inevitable consequence of a breached retina. Three classes of growth factors [vascular endothelial growth factor A (VEGF-A), platelet-derived growth factors (PDGFs), and non-PDGFs (growth factors outside of the PDGF family)] are relevant to PVR pathogenesis because they act on PDGF receptor α, which is required for experimental PVR and is associated with this disease in humans. We discovered that ranibizumab (a clinically approved agent that neutralizes VEGF-A) reduced the bioactivity of vitreous from patients and experimental animals with PVR, and protected rabbits from developing disease. The apparent mechanism of ranibizumab action involved derepressing PDGFs, which, at the concentrations present in PVR vitreous, inhibited non-PDGF-mediated activation of PDGF receptor α. These preclinical findings suggest that available approaches to neutralize VEGF-A are prophylactic for PVR, and that anti-VEGF-based therapies may be effective for managing more than angiogenesis- and edema-driven pathological conditions.
Pasquale LR, Loomis SJ, Weinreb RN, Kang JH, Yaspan BL, Bailey JC, Gaasterland D, Gaasterland T, Lee RK, Scott WK, Lichter PR, Budenz DL, Liu Y, Realini T, Friedman DS, McCarty CA, Moroi SE, Olson L, Schuman JS, Singh K, Vollrath D, Wollstein G, Zack DJ, Brilliant M, Sit AJ, Christen WG, Fingert J, Kraft P, Zhang K, Allingham RR, Pericak-Vance MA, Richards JE, Hauser MA, Haines JL, Wiggs JL. Estrogen pathway polymorphisms in relation to primary open angle glaucoma: an analysis accounting for gender from the United States. Mol Vis 2013;19:1471-81.Abstract
PURPOSE: Circulating estrogen levels are relevant in glaucoma phenotypic traits. We assessed the association between an estrogen metabolism single nucleotide polymorphism (SNP) panel in relation to primary open angle glaucoma (POAG), accounting for gender. METHODS: We included 3,108 POAG cases and 3,430 controls of both genders from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium genotyped on the Illumina 660W-Quad platform. We assessed the relation between the SNP panels representative of estrogen metabolism and POAG using pathway- and gene-based approaches with the Pathway Analysis by Randomization Incorporating Structure (PARIS) software. PARIS executes a permutation algorithm to assess statistical significance relative to the pathways and genes of comparable genetic architecture. These analyses were performed using the meta-analyzed results from the GLAUGEN and NEIGHBOR data sets. We evaluated POAG overall as well as two subtypes of POAG defined as intraocular pressure (IOP) ≥22 mmHg (high-pressure glaucoma [HPG]) or IOP <22 mmHg (normal pressure glaucoma [NPG]) at diagnosis. We conducted these analyses for each gender separately and then jointly in men and women. RESULTS: Among women, the estrogen SNP pathway was associated with POAG overall (permuted p=0.006) and HPG (permuted p<0.001) but not NPG (permuted p=0.09). Interestingly, there was no relation between the estrogen SNP pathway and POAG when men were considered alone (permuted p>0.99). Among women, gene-based analyses revealed that the catechol-O-methyltransferase gene showed strong associations with HTG (permuted gene p≤0.001) and NPG (permuted gene p=0.01). CONCLUSIONS: The estrogen SNP pathway was associated with POAG among women.
Osaki TH, Jakobiec FA, Mendoza PR, Lee Y, Fay AM. Immunohistochemical investigations of orbital infantile hemangiomas and adult encapsulated cavernous venous lesions (malformation versus hemangioma). Ophthalmic Plast Reconstr Surg 2013;29(3):183-95.Abstract
PURPOSE: Immunohistochemical studies have begun to advance knowledge regarding the pathogenesis of vascular anomalies in many anatomical regions. However, the immunohistochemical features of most orbital tumors have been overlooked. Therefore, a comparative immunohistochemical study of a series of the 2 most common orbital vascular lesions- infantile hemangioma (IH) and encapsulated cavernous venous lesion (ECVL), the latter also termed cavernous hemangioma or venous malformation-was undertaken. METHODS: Twenty surgically excised orbital tumors diagnosed clinically and histopathologically as IHs (10 cases) or "cavernous hemangioma" (10 cases) were evaluated pathologically and immunohistochemically using hematoxylin and eosin, Alcian blue, Masson trichrome, GLUT-1, CD31, CD34, D2-40, smooth muscle actin (SMA), desmin, and Ki-67 probes. RESULTS: All cases reacted strongly with the traditional blood vessel endothelial markers CD31 and CD34 and were negative for D2-40, a selective marker for lymphatic endothelium. All IH were positive for GLUT-1, and all ECVL were negative for GLUT-1. In IH, SMA (but not desmin) stained a monolayer of pericytes and in ECVL multilaminar smooth muscle vascular mural cells and intravascular (interstitial) stromal cells. Nuclear Ki-67 immunostaining was strongly positive in IH (average of 16.3%) and close to zero in ECVL. CONCLUSIONS: Immunophenotypic results for ECVL and IH demonstrated no overlapping staining patterns. Infantile hemangioma had the classical architecture of capillaries. Because of the constant presence of mural smooth muscle, it was concluded that ECVL is an accurate and descriptive term. However, desmin negativity in ECVL indicates myofibroblastic differentiation rather than full-fledged smooth muscle differentiation. Infantile hemangioma may display ectatic channels as the lesion ages but does not acquire multilaminar smooth muscle walls. Its pericytes lack cytoplasmic filaments and desmin reactivity but are SMA-positive because of the presence of poorly polymerized actin in the cytosol. In IH, Ki-67 positivity was observed in the endothelial cells of the solid and more ectatic regions. In contrast, the virtual absence of Ki-67 positivity in ECVL lends further support for the interpretation that it is more closely related to a malformation than a benign neoplasm.
Shah DN, Huang J, Ying G-S, Pietrobon R, O'Brien JM. Trends in female representation in published ophthalmology literature, 2000-2009. Digit J Ophthalmol 2013;19(4):50-5.Abstract
PURPOSE: To examine trends in female first and last authors in clinical ophthalmology literature published from January 2000 to December 2009. METHODS: A total of 3760 articles in American Journal of Ophthalmology (AJO), 2347 articles in Archives of Ophthalmology (Archives), and 3838 articles in Ophthalmology spanning 10 years of published ophthalmology peer-reviewed literature were examined. All original research articles and brief reports indexed online were included. Author gender was determined by an exhaustive Internet search. Articles were excluded if the sex of the author could not be determined or was not applicable (for example, articles by a study group rather than an individual author). RESULTS: Gender information was identified in 86.8% of articles for first authors and 86% for last authors. The number of female first authors (P < 0.0001) and last authors (P = 0.005) increased significantly in the study period in all journals examined, with a significant association between the sex of the first and last authors (OR = 2.19; 95% CI, 1.96-2.46; P < 0.0001), when examining all articles. Female representation increased for last authors significantly only in Ophthalmology. There was a significant correlation between gender of the first author and total number of authors that was not observed with last-author sex. CONCLUSIONS: Female first authorship has increased from 2000 to 2009 and is correlated with the gender of the last author; however, there were fewer female last authors compared to female first authors in the same period.
Nassiri N, Eslani M, Panahi N, Mehravaran S, Ziaei A, Djalilian AR. Ocular graft versus host disease following allogeneic stem cell transplantation: a review of current knowledge and recommendations. J Ophthalmic Vis Res 2013;8(4):351-8.Abstract
Graft versus host disease (GVHD) is a common complication of allogeneic stem cell transplantation (allo-SCT). Ocular GVHD develops in approximately 40-60% of patients following allo-SCT and its most common clinical manifestations include keratoconjunctivitis sicca and cicatricial conjunctivitis. Ocular GVHD may lead to severe ocular surface disease, which can significantly diminish quality of life and restrict daily activities. It is thus important to monitor the condition closely since with timely diagnosis, irreversible damage can be avoided. The current review will focus on updated information regarding ocular GVHD.
Schaumberg DA, Uchino M, Christen WG, Semba RD, Buring JE, Li JZ. Patient reported differences in dry eye disease between men and women: impact, management, and patient satisfaction. PLoS One 2013;8(9):e76121.Abstract
PURPOSE: Dry eye disease affects women twice as often as men, but there is little information on whether dry eye treatments, treatment satisfaction, or the impact of dry eye disease on patients' lives and vision might differ by sex. DESIGN: Questionnaire survey of 4000 participants in the Women's Health Study and the Physicians' Health Studies I and II with a prior report of a diagnosis of DED. METHODS: Among participants who re-confirmed a diagnosis of dry eye disease, we assessed symptoms, treatments, patient satisfaction and impact of dry eye disease, and analyzed differences between men and women using regression models. RESULTS: The final study population consisted of 1,518 women (mean age 70.7 years) and 581 men (mean age 76.7 years), with a mean reported duration of dry eye disease of 10.5 years and 10.1 years, respectively. The frequency and severity of dry eye disease symptoms were higher among women (each P<0.0001), and women reported a greater impact on everyday activities (P<0.0001). Women were more likely to use artificial tears (P<0.0001) use them more often (P<0.0001), and to use Restasis® (P<0.0001), omega-3 fatty acids (P=0.0006), and have punctal occlusion (P=0.005). Women spent more money per month on dry eye treatments (P<0.0001), but reported greater dissatisfaction with treatment side effects (P=0.001), and the amount of time before treatments started working (P=0.03). CONCLUSIONS: These data show that dry eye disease is generally experienced as being more severe among women, having a greater impact on their self-assessed well-being.
Menon BB, Govindarajan B. Identification of an atypical zinc metalloproteinase, ZmpC, from an epidemic conjunctivitis-causing strain of Streptococcus pneumoniae. Microb Pathog 2013;56:40-6.Abstract
Streptococcus pneumoniae is a pathogen associated with a range of invasive and noninvasive infections. Despite the identification of the majority of virulence factors expressed by S. pneumoniae, knowledge of the strategies used by this bacterium to trigger infections, especially those originating at wet-surfaced epithelia, remains limited. In this regard, we recently reported a mechanism used by a nonencapsulated, epidemic conjunctivitis-causing strain of S. pneumoniae (strain SP168) to gain access into ocular surface epithelial cells. Mechanistically, strain SP168 secretes a zinc metalloproteinase, encoded by a truncated zmpC gene, to cleave off the ectodomain of a vital defense component - the membrane mucin MUC16 - from the apical glycocalyx barrier of ocular surface epithelial cells and, thereby invades underlying epithelial cells. Here, we compare the truncated SP168 ZmpC to its highly conserved archetype from S. pneumoniae serotype 4 (TIGR4), which has been linked to pneumococcal virulence in previous studies. Comparative nucleotide sequence analyses revealed that the zmpC gene corresponding to strain SP168 has two stretches of DNA deleted near its 5' end. A third 3 bp in-frame deletion, resulting in the elimination of an alanine residue, was found towards the middle segment of the SP168 zmpC. Closer examination of the primary structure revealed that the SP168 ZmpC lacks the canonical LPXTG motif - a signature typical of several surface proteins of gram-positive bacteria and of other pneumococcal zinc metalloproteinases. Surprisingly, in vitro assays performed using recombinant forms of ZmpC indicated that the truncated SP168 ZmpC induces more cleavage of the MUC16 ectodomain than its TIGR4 counterpart. This feature may help explain, in part, why S. pneumoniae strain SP168 is better equipped at abrogating the MUC16 glycocalyx barrier en route to causing epidemic conjunctivitis.
Qazi Y, Hamrah P. Gene therapy in corneal transplantation. Semin Ophthalmol 2013;28(5-6):287-300.Abstract
Corneal transplantation is the most commonly performed organ transplantation. Immune privilege of the cornea is widely recognized, partly because of the relatively favorable outcome of corneal grafts. The first-time recipient of corneal allografts in an avascular, low-risk setting can expect a 90% success rate without systemic immunosuppressive agents and histocompatibility matching. However, immunologic rejection remains the major cause of graft failure, particularly in patients with a high risk for rejection. Corticosteroids remain the first-line therapy for the prevention and treatment of immune rejection. However, current pharmacological measures are limited in their side-effect profiles, repeated application, lack of targeted response, and short duration of action. Experimental ocular gene therapy may thus present new horizons in immunomodulation. From efficient viral vectors to sustainable alternative splicing, we discuss the progress of gene therapy in promoting graft survival and postulate further avenues for gene-mediated prevention of allogeneic graft rejection.
Patel MM, Jakobiec FA, Zakka FR, Du R, Annino DJ, Borboli-Gerogiannis S, Daniels AB. Intraorbital metastasis from solitary fibrous tumor. Ophthalmic Plast Reconstr Surg 2013;29(3):e76-9.Abstract
Solitary fibrous tumor (SFT) is a rare spindle cell tumor of mesenchymal origin that usually arises from pleura or pericardium but can also arise from many extraserosal sites. Although more than 50 cases of primary SFT of the orbit have been reported, there are no reports to date of a malignant nonophthalmic SFT metastasizing in the orbital soft tissues (although sphenoid wing bony involvement has been reported). The authors report here the first case of a patient with intraorbital metastasis of a CD34-positive malignant SFT. The patient was a 57-year-old man with a history of malignant pleural SFT and a prior kidney metastasis. He presented with the rapid appearance of proptosis and massive conjunctival chemosis preventing eyelid closure, and he was found to have a well-circumscribed metastasis to his lateral rectus muscle. Surgical excision cured his ocular symptoms, although he died 3 months later from brain and widespread metastases.
Palioura S, Chodosh J, Pineda R. A novel approach to the management of a progressive Descemet membrane tear in a patient with keratoglobus and acute hydrops. Cornea 2013;32(3):355-8.Abstract
PURPOSE: To report a case of corneal hydrops in a patient with keratoglobus that was managed with endothelial keratoplasty to achieve corneal stability and prevent a limbus-to-limbus tear in Descemet membrane. METHODS: A 30-year-old man with keratoglobus presented with corneal hydrops in his left eye resulting from a central vertical tear in Descemet membrane. His other eye had been previously treated with penetrating keratoplasty using a large graft (an 11-mm donor graft to a 10-mm recipient bed) because of a limbus-to-limbus tear in Descemet membrane without resolution of his edema. An attempt to approximate the edges of the Descemet tear in the left eye by an intracameral air injection failed, and the tear continued to progress peripherally. An endothelial keratoplasty button with anchoring sutures was placed over the Descemet tear because of excessive localized edema. RESULTS: One month after insertion of the sutured endothelial keratoplasty button, the edema had resolved, and 1 year later, the tear remains sealed. The patient's visual acuity improved from counting fingers at 1 foot to 20/100. CONCLUSIONS: Reconstitution of the posterior corneal surface in keratoglobus-induced hydrops can be achieved with endothelial keratoplasty over the Descemet tear. Preventing progression of a central Descemet tear is essential to bypass the need for a large-diameter penetrating keratoplasty graft and its complications in a young patient with a history of bilateral corneal hydrops.
Oh D-J, Kang MH, Ooi YH, Choi KR, Sage HE, Rhee DJ. Overexpression of SPARC in human trabecular meshwork increases intraocular pressure and alters extracellular matrix. Invest Ophthalmol Vis Sci 2013;54(5):3309-19.Abstract
PURPOSE: Intraocular pressure (IOP) regulation is largely unknown. SPARC-null mice demonstrate a lower IOP resulting from increased outflow. SPARC is a matricellular protein often associated with fibrosis. We hypothesized that SPARC overexpression would alter IOP by affecting extracellular matrix (ECM) synthesis and/or turnover in the trabecular meshwork (TM). METHODS: An adenoviral vector containing human SPARC was used to increase SPARC expression in human TM endothelial cells and perfused human anterior segments using multiplicities of infection (MOIs) 25 or 50. Total RNA from TM was used for quantitative PCR, while protein from cell lysates and conditioned media were used for immunoblot analyses and zymography. After completion of perfusion, the anterior segments were fixed, sectioned, and examined by light and confocal microscopy. RESULTS: SPARC overexpression increased the IOP of perfused human anterior segments. Fibronectin and collagens IV and I protein levels were elevated in both TM cell cultures and within the juxtacanalicular (JCT) region of perfused anterior segments. Collagen VI and laminin protein levels were increased in TM cell cultures but not in perfused anterior segments. The protein levels of pro-MMP-9 decreased while the kinetic inhibitors of metalloproteinases, TIMP-1 and PAI-1 protein levels, increased at MOI 25. At MOI 50, the protein levels of pro-MMP-1, -3, and -9 also decreased while PAI-1 and TIMP-1 and -3 increased. Only MMP-9 activity was decreased on zymography. mRNA levels of the collagens, fibronectin, and laminin were not affected by SPARC overexpression. CONCLUSIONS: SPARC overexpression increases IOP in perfused cadaveric human anterior segments resulting from a qualitative change the JCT ECM. Selective decrease of MMP-9 activity is likely part of the mechanism. SPARC is a regulatory node for IOP.
Schneier AJ, Fulton AB. The hermansky-pudlak syndrome: clinical features and imperatives from an ophthalmic perspective. Semin Ophthalmol 2013;28(5-6):387-91.Abstract
The Hermansky-Pudlak Syndrome (HPS) is a rare, autosomal recessive condition comprising nine genetically heterogeneous entities that feature oculocutaneous albinism (OCA) and bleeding tendency as their principal clinical manifestations. The pathogenesis of HPS involves disturbances in the biogenesis and trafficking of lysosome-related organelles. While the ophthalmologist is trained to address the ocular manifestations of OCA, it is critical for the provider to consider HPS when examining OCA patients as its systemic sequelae may be associated with morbidity and mortality. If there is suspicion of HPS in a patient with albinism, the ophthalmologist should enlist the aid of consultants to confirm the diagnosis and monitor for systemic features. As the nine HPS subtypes explored in this article vary widely in the character and severity of their associated systemic manifestations, some authors advocate determining the specific gene defect in each HPS patient in order to optimize care and provide anticipatory guidance.
Miller JW, Le Couter J, Strauss EC, Ferrara N. Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology 2013;120(1):106-14.Abstract
UNLABELLED: The vascular beds supplying the retina may sustain injury as a result of underlying disease such as diabetes, and/or the interaction of genetic predisposition, environmental insults, and age. The vascular pathologic features observed in different intraocular vascular diseases can be categorized broadly as proliferation, exemplified by proliferative diabetic retinopathy, leakage such as macular edema secondary to retinal vein occlusion, or a combination of proliferation and leakage, as seen in neovascular age-related macular degeneration (AMD). The World Health Organization has identified diabetic retinopathy and AMD as priority eye diseases for the prevention of vision loss in developed countries. The pathologic transformations of the retinal vasculature seen in intraocular vascular disease are associated with increased expression of vascular endothelial growth factor A (VEGF), a potent endothelial-specific mitogen. Furthermore, in model systems, VEGF alone is sufficient to trigger intraocular neovascularization, and its inhibition is associated with functional and anatomic improvements in the affected eye. Therapeutic interventions with effect on VEGF include intraocular capture and neutralization by engineered antibodies or chimeric receptors, downregulation of its expression with steroids, or alleviation of retinal ischemia, a major stimulus for VEGF expression, with retinal ablation by laser treatment. Data from prospective randomized clinical trials indicate that VEGF inhibition is a potent therapeutic strategy for intraocular vascular disease. These findings are changing clinical practice and are stimuli for further study of the basic mechanisms controlling intraocular angiogenesis. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.