Reliability and validity of the Japanese version of the Ocular Surface Disease Index for dry eye disease.

OBJECTIVES: The Ocular Surface Disease Index (OSDI) questionnaire is widely used to evaluate subjective symptoms of dry eye disease (DED) as a primary diagnostic criterion. This study aimed to develop a Japanese version of the OSDI (J-OSDI) and assess its reliability and validity. DESIGN AND SETTING: Hospital-based cross-sectional observational study. PARTICIPANTS: A total of 209 patients recruited from the Department of Ophthalmology at Juntendo University Hospital. METHODS: We translated and culturally adapted the OSDI into Japanese. The J-OSDI was then assessed for internal consistency, reliability and validity. We also evaluated the optimal cut-off value to suspect DED using an area under the receiver operating characteristic curve (AUC) analysis. PRIMARY OUTCOME MEASURES: Internal consistency, test-retest reliability and discriminant validity of the J-OSDI as well as the optimal cut-off value to suspect DED. RESULTS: Of the participants, 152 had DED and 57 did not. The J-OSDI total score showed good internal consistency (Cronbach's alpha=0.884), test-retest reliability (interclass correlation coefficient=0.910) and discriminant validity by known-group comparisons (non-DED, 19.4±16.0; DED, 37.7±22.2; p<0.001). Factor validity was used to confirm three subscales within the J-OSDI according to the original version of the questionnaire. Concurrent validity was assessed by Pearson correlation analysis, and the J-OSDI total score showed a strong positive correlation with the Dry Eye-Related Quality-of-Life Score (γ=0.829). The optimal cut-off value of the J-OSDI total score was 36.3 (AUC=0.744). CONCLUSIONS: The J-OSDI was developed and validated in terms of reliability and validity as an effective tool for DED assessment and monitoring in the Japanese population.

An independent construct for conditional expression of atonal homolog-1.

The mammalian homolog of the basic helix-loop-helix transcription factor atonal-1 (Atoh1 or Math1) is required for development of cochlear hair cells that function as the mechanosensory cells required for audition. Forced expression of Atoh1 in cochlear-supporting cells may provide a way to regenerate hair cells and provide for a therapy for hearing loss. Additionally, Atoh1 is an inhibitor of proliferation and has further clinical applications in anticancer therapies. The goal of these experiments was to improve the method for Atoh1 expression by engineering a genetic construct that may be used in future translational applications. To address the poor control of Atoh1 expression in standard gene expression systems where Atoh1 is expressed constitutively at abnormally elevated levels, our aim was to engineer an inducible system whereby Atoh1 was upregulated by an inducer and downregulated once the inducer was removed. A further aim was to engineer a single genetic construct that allowed for conditional expression of Atoh1 independent of secondary regulatory elements. Here we describe a stand-alone genetic construct that utilizes the tamoxifen sensitivity of a mutated estrogen receptor (ER) ligand-binding domain for the conditional expression of Atoh1. The Atoh1-ER-DsRed construct is translated into an ATOH1-ER-DSRED fusion protein that remains sequestered in the cytoplasm and therefore rendered inactive because it cannot enter the nucleus to activate Atoh1 signaling pathways. However, application of 4-hydroxytamoxifen results in translocation of the fusion protein to the nucleus, where it binds to the Atoh1 enhancer, upregulates transcription and translation of endogenous ATOH1 and activates downstream Atoh1 signaling such as upregulation of the hair cell protein MYOSIN 7A. Removal of tamoxifen reverses the upregulation of endogenous Atoh1 signaling. This construct serves as an independent genetic construct that allows for the conditional upregulation and downregulation of Atoh1, and may prove useful for manipulating Atoh1 expression in vivo.

Ephrin-A3 suppresses Wnt signaling to control retinal stem cell potency.

The ciliary epithelium (CE) of adult mammals has been reported to provide a source of retinal stem cells (RSCs) that can give rise to all retinal cell types in vitro. A recent study, however, suggests that CE-derived cells possess properties of pigmented ciliary epithelial cells and display little neurogenic potential. Here we show that the neurogenic potential of CE-derived cells is negatively regulated by ephrin-A3, which is upregulated in the CE of postnatal mice and presents a strong prohibitory niche for adult RSCs. Addition of ephrin-A3 inhibits proliferation of CE-derived RSCs and increases pigment 349 cell 359. In contrast, absence of ephrin-A3 promotes proliferation and increases expression of neural progenitor cell markers and photoreceptor progeny. The negative effects of ephrin-A3 on CE-derived RSCs are mediated through activation of an EphA4 receptor and suppression of Wnt3a/ß-catenin signaling. Together, our data suggest that CE-derived RSCs contain the intrinsic machinery to generate photoreceptors and other retinal neurons, while the CE of adult mice expresses negative regulators that prohibit the proliferation and neural differentiation of RSCs. Manipulating ephrin and Wnt/ß-catenin signaling may, thus, represent a viable approach in activating the endogenous neurogenic potential of CE-derived RSCs for treating photoreceptor damage and retinal degenerative disorders.