Summary Retinal ganglion cells (RGCs) serve as the connection between the eye and the brain, with this connection disrupted in glaucoma. Numerous cellular mechanisms have been associated with glaucomatous neurodegeneration, and useful cellular models of glaucoma allow for the precise analysis of degenerative phenotypes. Human pluripotent stem cells (hPSCs) serve as powerful tools for studying human disease, particularly cellular mechanisms underlying neurodegeneration. Thus, efforts focused upon hPSCs with an E50K mutation in the Optineurin (OPTN) gene, a leading cause of inherited forms of glaucoma. CRISPR/Cas9 gene editing introduced the OPTN(E50K) mutation into existing lines of hPSCs, as well as generating isogenic controls from patient-derived lines. RGCs differentiated from OPTN(E50K) hPSCs exhibited numerous neurodegenerative deficits, including neurite retraction, autophagy dysfunction, apoptosis, and increased excitability. These results demonstrate the utility of OPTN(E50K) RGCs as an in vitro model of neurodegeneration, with the opportunity to develop novel therapeutic approaches for glaucoma.

Multiple growth factors (e.g., BMP2, TGF-β1, FGF2) and isolated genes have been shown to improve osteoblastic proliferation and mineralization, advancing bone tissue engineering. Among these factors, both polydopamine (PDA) and dopamine (DA) monomer have recently been reported to increase osteoblast proliferation and mineralization in vitro. Although a well-characterized neurotransmitter, DA’s role in the bone is unknown. We hypothesize that DA can directly act on osteoblasts, and examined whether osteoblasts express DA receptors that respond to exogenous DA. mRNAs and protein cell lysates were obtained from MC3T3-E1 cells during osteogenic differentiation phase. Reverse transcription polymerase chain reaction and western blot analysis were used to examine the expression of DA receptors, D1–D5. Dose-response effect and time course of DA treatment on cell proliferation, mineralization, and osteogenic differentiation were investigated at pre-determined days. Real-time PCR was performed to investigate whether DA affects osteogenic gene expression (ALP, BSP, OC, OSX, RUNX2, and Collagen1a2) with or without receptor antagonists (SCH233390 and GR103691). Two-way ANOVA was used for statistical analysis. All five DA receptors (D1, D2, D3, D4, and D5) mRNAs and proteins were expressed in MC3T3-E1 cells. DA treatment increased cell proliferation for up to 7 days (P < 0.05). Osteogenic mineralization was significantly greater in the DA-treated group than control group (P < 0.05). Finally, expression of all the osteogenic genes was inhibited by DA receptor antagonists for D1, D3, and D5. Our findings suggest that MC3T3-E1 osteoblasts express functional DA receptors that enhance proliferation and mineralization. PDA is not biologically inert and has important implications in orthopedic applications. Furthermore, osteoblast differentiation might be regulated by the nervous system, presumably during bone development, remodeling, or repair.

ObjectivesThe purpose of this study was to identify risk factors for exposure of glaucoma drainage devices (GDD).SettingThis retrospective, observational study was conducted in the eye clinic of an academic medical centre.ParticipantsParticipants included 1073 consecutive adults who underwent GDD surgery between 1 January 2005 and 1 January 2011. Participants were included if chart review indicated GDD surgery during the study period and excluded if at least 12 months of clinical follow-up was not available in the medical record.Primary outcome measureThe primary outcome measure was exposure of the GDD occurring at least 1 month after implant surgery. The characteristics of participants who experienced exposure of the implant were compared to the characteristics of participants who did not experience exposure.ResultsOf the 1073 participants having undergone GDD surgery, 67 experienced exposure of the device. Neither the type of GDD, type of patch graft (eye bank sclera, Tutoplast sclera and Tutoplast pericardium), surgeon, location of GDD, number of GDD previously implanted into the eye, nor history of diabetes or uveitis were associated with likelihood of exposure. Women were more likely than men to experience exposure of the GDD (OR 2.004 (95% CI1.170 to 3.431)) in both univariable (p=0.011) and multivariable (p=0.013) analyses. In survival analysis, exposure of the GDD occurred earlier for women than for men (58 vs 61 months; p=0.024).White race (vs black) was also associated with increased risk of GDD exposure (OR 1.693 (95% CI 1.011 to 2.833)) in univariable (p=0.044) and multivariable (p=0.046) analyses.ConclusionsWomen are two times more likely to experience GDD exposure than men, independent of age. White race is also a risk factor for exposure.

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