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2014

Lefebvre D, Robinson-Bostom L, Migliori M. Cellular neurothekeoma of the eyelid: a unique internal palpebral presentation. Ophthalmic Plast Reconstr Surg. 2014;30(4):e91–2.
A 50-year-old woman presented with a mass lesion of the inferolateral palpebral conjunctiva similar in appearance to a chalazion, but unusual enough in presentation that excisional biopsy was initially performed. Histopathologic analysis revealed a dermal fibrohistiocytic neoplasm consistent with cellular neurothekeoma. Neurothekeoma is a benign tumor; the cellular variant is rare and of unclear histogenesis. Completely internal eyelid location is particularly rare, with other identifiable case reports of cellular neurothekeoma palpebrae referring to external or unspecified eyelid location. This case provides an example of the chalazion as masquerader and re-emphasizes the importance of maintaining a broad differential diagnosis and high index of suspicion regarding atypically appearing chalazia.
Yadav P, Jakobiec F, De Castro D, Mendoza P, Fay A. Extruded, partially disintegrated, poly-HEMA orbital implant (AlphaSphere). Ophthalmic Plast Reconstr Surg. 2014;30(4):e86–91.
A 54-year-old diabetic man underwent enucleation for endophthalmitis. Secondary implantation of a 2-hydroxyethyl methacrylate (HEMA) sphere (AlphaSphere, Addition Technology) was performed 2 weeks later. Six weeks after insertion, noninfectious disintegration of sutured tissue planes represented by Tenon's capsule, rectus muscle, and conjunctiva occurred, requiring removal of the fragmenting implant before uncontrolled extrusion occurred. Histopathologic analysis revealed an absence of infectious pathogens and no tissue necrosis, but rather breakup of the implant material that elicited a granulomatous response with sparse T-lymphocytes and almost no polymorphonuclear leukocytes. This distinctively designed poly-HEMA orbital implant incited a dramatic and irreversible host tissue response. Investigation of other cases will be necessary to determine the frequency of such a complication and should include rigorous histopathologic techniques.
Zhu R, Cho KS, Chen DF, Yang L. Ephrin-A2 and -A3 are negative regulators of the regenerative potential of Möller cells. Chin Med J (Engl). 2014;127(19):3438–42.
BACKGROUND: In a previous study, we demonstrated that ephrin-A2 and -A3 negatively regulate the growth of neural progenitor cells in the central nervous system. Adult mice deficient in ephrin-A2 and -A3 (A2(-/-)A3(-/-)) displayed active ongoing neurogenesis throughout the brain, and mice deficient in ephrin-A3 alone showed increased proliferation of ciliary epithelium derived retinal stem cells. This study aimed to detect that the increase in proliferation and neurogenic potential of Müller cells is influenced by the absence of ephrin-A2 and -A3. METHODS: We assessed the retinal and Müller cell expression of ephrin-As and their receptor and neural progenitor cell markers by immunostaining and real-time PCR. We cultured purified primary Müller cells derived from wild-type and A2(-/-)A3(-/-) mice in a defined culture medium that enables trans-differentiation of Müller cells into retinal neurons. To evaluate proliferating Müller cells in vivo, we injected 5'-ethylnyl-2'-deoxiuridine (EdU) intraperitoneally to adult mice. RESULTS: Expression of ephrin-A2/A3 and their receptor EphA4 were detected in the retinas of adult mice, with EphA4 expression particularly enriched in Müller cells. Müller cells of A2(-/-)A3(-/-) mice exhibited significantly elevated expression of retinal progenitor cell markers, Pax6 and Chx10, when compared with those from wild-type mice. Moreover, a higher percentage of Müller cells of A2(-/-)A3(-/-) mice trans-differentiated and became recoverin+ and β-III-tublin+ in the culture than those from wild type mice. Strikingly, an increased number of EdU+ retinal cells was detected in the retinas of adult A2(-/-)A3(-/-) mice as compared with wild-type mice. CONCLUSIONS: Ephrin-A2 and -A3 are negative regulators of the proliferative and neurogenic potentials of Müller cells. Manipulating ephrin-A signaling may thus represent a novel strategy for stimulating neuroregeneration from endogenous progenitors to participate in retinal repair in case of disease or damage.
Hysi P, Cheng CY, Springelkamp H, Macgregor S, Bailey JC, Wojciechowski R, Vitart V, Nag A, Hewitt A, Höhn R, Venturini C, Mirshahi A, Ramdas W, Thorleifsson G, Vithana E, Khor CC, Stefansson A, Liao J, Haines J, Amin N, Wang YX, Wild P, Ozel A, Li J, Fleck B, Zeller T, Staffieri S, Teo YY, Cuellar-Partida G, Luo X, Allingham R, Richards J, Senft A, Karssen L, Zheng Y, Bellenguez C, Xu L, Iglesias A, Wilson J, Kang J, Leeuwen E, Jonsson V, Thorsteinsdottir U, Despriet D, Ennis S, Moroi S, Martin N, Jansonius N, Yazar S, Tai ES, Amouyel P, Kirwan J, Koolwijk L, Hauser M, Jonasson F, Leo P, Loomis S, Fogarty R, Rivadeneira F, Kearns L, Lackner K, Jong P, Simpson C, Pennell C, Oostra B, Uitterlinden A, Saw SM, Lotery A, Bailey-Wilson J, Hofman A, Vingerling J, Maubaret C, Pfeiffer N, Wolfs R, Lemij H, Young T, Pasquale L, Delcourt C, Spector T, Klaver C, Small K, Burdon K, Stefansson K, Wong TY, BMES GWAS Group, NEIGHBORHOOD Consortium, Wellcome Trust Case Control Consortium 2, Viswanathan A, Mackey D, Craig J, Wiggs J, Duijn C, Hammond C, Aung T. Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma.. Nat Genet. 2014;46(10):1126–30.

Elevated intraocular pressure (IOP) is an important risk factor in developing glaucoma, and variability in IOP might herald glaucomatous development or progression. We report the results of a genome-wide association study meta-analysis of 18 population cohorts from the International Glaucoma Genetics Consortium (IGGC), comprising 35,296 multi-ancestry participants for IOP. We confirm genetic association of known loci for IOP and primary open-angle glaucoma (POAG) and identify four new IOP-associated loci located on chromosome 3q25.31 within the FNDC3B gene (P = 4.19 × 10(-8) for rs6445055), two on chromosome 9 (P = 2.80 × 10(-11) for rs2472493 near ABCA1 and P = 6.39 × 10(-11) for rs8176693 within ABO) and one on chromosome 11p11.2 (best P = 1.04 × 10(-11) for rs747782). Separate meta-analyses of 4 independent POAG cohorts, totaling 4,284 cases and 95,560 controls, showed that 3 of these loci for IOP were also associated with POAG.

Gharahkhani P, Burdon K, Fogarty R, Sharma S, Hewitt A, Martin S, Law M, Cremin K, Bailey JC, Loomis S, Pasquale L, Haines J, Hauser M, Viswanathan A, McGuffin P, Topouzis F, Foster P, Graham S, Casson R, Chehade M, White A, Zhou T, Souzeau E, Landers J, Fitzgerald J, Klebe S, Ruddle J, Goldberg I, Healey P, Wellcome Trust Case Control Consortium 2, NEIGHBORHOOD Consortium, Mills R, Wang JJ, Montgomery G, Martin N, Radford-Smith G, Whiteman D, Brown M, Wiggs J, Mackey D, Mitchell P, Macgregor S, Craig J. Common variants near ABCA1, AFAP1 and GMDS confer risk of primary open-angle glaucoma.. Nat Genet. 2014;46(10):1120–5.

Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide. We performed a genome-wide association study in an Australian discovery cohort comprising 1,155 cases with advanced POAG and 1,992 controls. We investigated the association of the top SNPs from the discovery stage in two Australian replication cohorts (932 cases and 6,862 controls total) and two US replication cohorts (2,616 cases and 2,634 controls total). Meta-analysis of all cohorts identified three loci newly associated with development of POAG. These loci are located upstream of ABCA1 (rs2472493[G], odds ratio (OR) = 1.31, P = 2.1 × 10(-19)), within AFAP1 (rs4619890[G], OR = 1.20, P = 7.0 × 10(-10)) and within GMDS (rs11969985[G], OR = 1.31, P = 7.7 × 10(-10)). Using RT-PCR and immunolabeling, we show that these genes are expressed within human retina, optic nerve and trabecular meshwork and that ABCA1 and AFAP1 are also expressed in retinal ganglion cells.

Sanderson J, Dartt DA, Trinkaus-Randall V, Pintor J, Civan M, Delamere N, Fletcher E, Salt T, Grosche A, Mitchell C. Purines in the eye: recent evidence for the physiological and pathological role of purines in the RPE, retinal neurons, astrocytes, Müller cells, lens, trabecular meshwork, cornea and lacrimal gland. Exp Eye Res. 2014;127:270–9.
This review highlights recent findings that describ how purines modulate the physiological and pathophysiological responses of ocular tissues. For example, in lacrimal glands the cross-talk between P2X7 receptors and both M3 muscarinic receptors and α1D-adrenergic receptors can influence tear secretion. In the cornea, purines lead to post-translational modification of EGFR and structural proteins that participate in wound repair in the epithelium and influence the expression of matrix proteins in the stroma. Purines act at receptors on both the trabecular meshwork and ciliary epithelium to modulate intraocular pressure (IOP); ATP-release pathways of inflow and outflow cells differ, possibly permitting differential modulation of adenosine delivery. Modulators of trabecular meshwork cell ATP release include cell volume, stretch, extracellular Ca(2+) concentration, oxidation state, actin remodeling and possibly endogenous cardiotonic steroids. In the lens, osmotic stress leads to ATP release following TRPV4 activation upstream of hemichannel opening. In the anterior eye, diadenosine polyphosphates such as Ap4A act at P2 receptors to modulate the rate and composition of tear secretion, impact corneal wound healing and lower IOP. The Gq11-coupled P2Y1-receptor contributes to volume control in Müller cells and thus the retina. P2X receptors are expressed in neurons in the inner and outer retina and contribute to visual processing as well as the demise of retinal ganglion cells. In RPE cells, the balance between extracellular ATP and adenosine may modulate lysosomal pH and the rate of lipofuscin formation. In optic nerve head astrocytes, mechanosensitive ATP release via pannexin hemichannels, coupled with stretch-dependent upregulation of pannexins, provides a mechanism for ATP signaling in chronic glaucoma. With so many receptors linked to divergent functions throughout the eye, ensuring the transmitters remain local and stimulation is restricted to the intended target may be a key issue in understanding how physiological signaling becomes pathological in ocular disease.
Zinn E, Vandenberghe L. Adeno-associated virus: fit to serve.. Curr Opin Virol. 2014;8C:90–97.

Adeno-associated virus (AAV) is a helper-dependent parvovirus which has not been linked with human disease. This aspect, in combination with its broad cell and tissue tropism, and limited viral host response has made it an attractive vector system for gene therapy. The viral protein capsid, the primary interface with the host, is the main determinant for these phenotypes, is highly variable, and is most subject to pressures during replication. Here, we explore the evolutionary path of AAV and other parvoviruses in respect to these phenotypes, as well as directed evolution and engineering strategies that have exploited the lessons learned from natural selection in order to address remaining limitations of AAV as a therapeutic gene transfer platform.

Kazlauskas A. Plakophilin-2 promotes activation of epidermal growth factor receptor.. Mol Cell Biol. 2014;34(20):3778–9.

While growth factor-driven dimerization of receptor tyrosine kinases (RTKs) is a simple and intuitive mechanism of activating RTKs, K.-I. Arimoto et al. (Mol. Cell. Biol. 34:3843-3854, 2014, doi:10.1128/MCB.00758-14) describe a novel means of promoting the activity of RTKs. Namely, plakophilin-2 (PKP2) associates with the epidermal growth factor receptor (EGFR) and enhances its ligand-dependent and ligand-independent activity. This discovery suggests that antagonizing PKP2 may be a new therapeutic opportunity to combat tumors in which activation of EGFR contributes to pathogenesis.