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October 2014

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Yamaguchi T, Calvacanti BM, Cruzat A, Qazi Y, Ishikawa S, Osuka A, Lederer JA, Hamrah P. Correlation between Human Tear Cytokine Levels and Cellular Corneal Changes in Patients with Bacterial Keratitis by In Vivo Confocal Microscopy. Invest Ophthalmol Vis Sci 2014;Abstract

Purpose: To investigate bilateral tear cytokine levels in patients with unilateral bacterial keratitis (BK) as associated with in vivo confocal microscopic (IVCM) alterations in corneal nerves and dendritiform immune cells (DCs). Methods: Fifty-four (13 BK, 13 contralateral, 28 healthy controls) tear samples were collected prospectively and analyzed by multiplex microbeads assay. IVCM of the central cornea was performed on the same day and assessed for corneal nerve and DC alterations Results: Interleukin (IL)-1β, IL-6, and IL-8 were significantly elevated only in affected eyes (66.6±26.8 ρg/ml, 7,174±2,430, 810±315, P=0.04, P<0.001 and P<0.001), compared to healthy controls (13.0±4.0 ρg/ml, 171.8±32.1, 56.5±33.8). CCL-2, IL-10 and IL-17a were elevated only in contralateral eyes (813±478 ρg/ml, 86.7±38.3, 3,350±881, P=0.02, P=0.01, P=0.04), compared to controls (73.7±25.3 ρg/ml, 17.5 ±4.9, 1,350±337). Triggering receptor expressed on myeloid cells (TREM)-1 was significantly elevated in both affected (551±231 ρg/ml, P=0.02) and contralateral unaffected eyes (545±298 ρg/ml, P=0.03), compared to controls (31.3±12.4 ρg/ml). The density of DCs was significantly increased in both affected (226.9±37.3 cells/mm2, P<0.001) and unaffected eyes (122.3±23.7 cells/mm2, P<0.001) compared to controls (22.7±5.9 cells/mm2). Subbasal nerve density significantly decreased in affected eyes (3,337±1,615 μm/mm2, P<0.001) and contralateral eyes (13,230±1,635 μm/mm2, P<0.001) compared to controls (21,200±545 μm/mm2). IL-1β, IL-6 and IL-8 were significantly correlated with DC density (R=0.40, R=0.55 and R=0.31, all P<0.02) and nerve density (R=-0.30, R=-0.53 and R=-0.39, all P<0.01). Conclusions: Pro-inflammatory tear cytokines are elevated bilaterally in patients with unilateral BK, and are correlated strongly with alterations in DCs and nerve density as detected by IVCM.

Yonekawa Y, Kim IK. Clinical Characteristics and Current Treatment of Age-Related Macular Degeneration. Cold Spring Harb Perspect Med 2014;Abstract

Age-related macular degeneration (AMD) is a multifactorial degeneration of photoreceptors and retinal pigment epithelium. The societal impact is significant, with more than 2 million individuals in the United States alone affected by advanced stages of AMD. Recent progress in our understanding of this complex disease and parallel developments in therapeutics and imaging have translated into new management paradigms in recent years. However, there are many unanswered questions, and diagnostic and prognostic precision and treatment outcomes can still be improved. In this article, we discuss the clinical features of AMD, provide correlations with modern imaging and histopathology, and present an overview of treatment strategies.

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Zhu R, Cho K-S, 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.Abstract
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.
Zinn E, Vandenberghe LH. Adeno-associated virus: fit to serve. Curr Opin Virol 2014;8C:90-97.Abstract

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.

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