NODULAR EPIRETINAL MÜLLER CELL GLIOSIS IN THE FOVEA.

PURPOSE: The purpose of this study was to report the findings of a hyperreflective nodular epiretinal gliosis observed with optical coherence tomography presumed to be due to subclinical hyaloidal traction causing Mϋller cell cone gliosis. METHODS: Retrospective, observational case series. RESULTS: Six eyes of six patients (mean age: 57 years, range 35-81 years) presented with a nodular epiretinal gliosis and had an average follow-up interval of 26 months (range 1-82 months). The mean baseline best-corrected visual acuity was 0.25 ± 0.17 (Snellen equivalent 20/38.3 ± 16.9). Fundus photography demonstrated a yellowish lesion overlying the fovea. Optical coherence tomography imaging revealed a hyperreflective preretinal lesion with a mean vertical length of 267 µ m (range 185-497) and a mean greatest linear diameter of 312 µ m (range 124-640). There was no vitreoretinal abnormality including vitreomacular traction or epiretinal membrane noted in any eye, and two of six eyes displayed a definitive posterior vitreous detachment. These nodules may have occurred before and persisted even after a posterior vitreous detachment or may have been acquired after the posterior vitreous detachment. The nodules typically remained stable with minimal change although in one eye, a posterior vitreous detachment occurred 6 months after initial presentation and lifted the gliosis off of the retinal surface where it remained attached to the posterior hyaloid. CONCLUSION: Foveal nodular epiretinal gliosis may occur due to subclinical hyaloidal traction on the Müller cell cone even without obvious vitreoretinal interface abnormality on optical coherence tomography.

Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies.

Longitudinal preclinical and clinical studies suggest that Aß drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling networks regulated by the p75 neurotrophin receptor (p75NTR) substantially overlap with those linked to Aß and to tau. Here we examine the hypothesis that modulation of p75NTR will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect dendritic spines and processes from Aß-induced injury. In neurons exposed to oligomeric Aß in vitro and APP mutant mouse models, modulation of p75NTR signaling using the small-molecule LM11A-31 was found to inhibit Aß-associated degeneration of neurites and spines; and tau phosphorylation, cleavage, oligomerization and missorting. In line with these effects on tau, LM11A-31 inhibited excess activation of Fyn kinase and its targets, tau and NMDA-NR2B, and decreased Rho kinase signaling changes and downstream aberrant cofilin phosphorylation. In vitro studies with pseudohyperphosphorylated tau and constitutively active RhoA revealed that LM11A-31 likely acts principally upstream of tau phosphorylation, and has effects preventing spine loss both up and downstream of RhoA activation. These findings support the hypothesis that modulation of p75NTR signaling inhibits a broad spectrum of Aß-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.

Correlation of Quantitative Measurements with Diabetic Disease Severity Using Multiple En Face OCT Angiography Image Averaging.

PURPOSE: To evaluate the effect of averaging en face OCT angiography (OCTA) images on quantitative measurements of the retinal microvasculature and their correlation to diabetic retinopathy (DR) disease severity. DESIGN: Cross-sectional cohort study. PARTICIPANTS: One hundred five eyes (65 patients) comprising 28 eyes from 19 healthy, aged-matched control participants, 14 eyes from 9 diabetics without DR, and 63 eyes from 37 diabetics with varying levels of DR. METHODS: Spectral-domain CIRRUS 5000 (Carl Zeiss Meditec, Dublin, CA) OCTA images with no macular edema or significant motion artifact were acquired 5 times with the 3 × 3-mm scan pattern. En face images of the superficial retinal layer (SRL) and deep retinal layer were registered and averaged. Vessel length density (VLD), perfusion density (PD), and foveal avascular zone (FAZ) parameters were measured on averaged versus single OCTA images. MAIN OUTCOME MEASURES: Univariate and multivariate linear regression correlated quantitative metrics to DR severity and best-corrected visual acuity (BCVA). RESULTS: Eighty-four eyes (55 patients) met the inclusion criteria. Almost uniformly, lower VLD and PD parameters were associated significantly with worse DR severity and BCVA. Multivariate linear regression for DR severity resulted in an R2 value of 0.82 and 0.77 for single and averaged groups, respectively. No variables remained associated significantly with DR severity in multivariate analysis with single images, but in averaged images, increased superior SRL PD significantly predicted worse DR severity (coefficient, 52.7; P = 0.026). Multivariate linear regression for BCVA had an R2 value of 0.42 and 0.47 for single and averaged groups, respectively. Foveal avascular zone size was not associated with DR severity when single OCTA images (P = 0.98) were considered, but was highly associated when using averaged images (coefficient, 6.18; P < 0.001). Foveal avascular zone size was predictive for logarithm of the minimum angle of resolution BCVA with averaged images (0.21; P = 0.004), but not with single images (P = 0.31). CONCLUSIONS: Averaging of en face OCTA images improves the visualization of capillaries, particularly increasing the clarity of the FAZ borders, and therefore improves the correlation of vessel density and FAZ-specific parameters to DR severity and BCVA.

Cytomegalovirus Retinal Necrosis With Occlusive Vasculopathy Secondary to Steroid Immunosuppression for Giant Cell Arteritis.

Purpose: This case report discusses an atypical case of cytomegalovirus (CMV) retinal necrosis with panretinal occlusive vasculopathy in a 77-year-old man who was immunosuppressed following treatment for giant cell arteritis (GCA). Methods: A case report is presented. Results: Clinical examination demonstrated a central retinal artery occlusion and pale disc suspicious for arteritic ischemic optic neuropathy in the right eye. Biopsy-proven GCA prompted treatment with oral prednisone. While on glucocorticoid immunosuppression, the patient suffered vision loss in the left eye from CMV-necrotizing retinitis with occlusive vasculopathy. Treatment controlled the CMV infection but tapering of his steroids resulted in worsening GCA, requiring a steroid-sparing treatment, tocilizumab. Conclusions: Corticosteroid immunosuppression for GCA may lead to immune dysfunction allowing for an atypical occlusive vasculitis with retinal necrosis from CMV. Early identification and treatment are essential to adjust the level of immunosuppression and consider alternate therapies to control the GCA and prevent worsening of this opportunistic infection.

A modular approach to creating large engineered cartilage surfaces.

Native articular cartilage has limited capacity to repair itself from focal defects or osteoarthritis. Tissue engineering has provided a promising biological treatment strategy that is currently being evaluated in clinical trials. However, current approaches in translating these techniques to developing large engineered tissues remains a significant challenge. In this study, we present a method for developing large-scale engineered cartilage surfaces through modular fabrication. Modular Engineered Tissue Surfaces (METS) uses the well-known, but largely under-utilized self-adhesion properties of de novo tissue to create large scaffolds with nutrient channels. Compressive mechanical properties were evaluated throughout METS specimens, and the tensile mechanical strength of the bonds between attached constructs was evaluated over time. Raman spectroscopy, biochemical assays, and histology were performed to investigate matrix distribution. Results showed that by Day 14, stable connections had formed between the constructs in the METS samples. By Day 21, bonds were robust enough to form a rigid sheet and continued to increase in size and strength over time. Compressive mechanical properties and glycosaminoglycan (GAG) content of METS and individual constructs increased significantly over time. The METS technique builds on established tissue engineering accomplishments of developing constructs with GAG composition and compressive properties approaching native cartilage. This study demonstrated that modular fabrication is a viable technique for creating large-scale engineered cartilage, which can be broadly applied to many tissue engineering applications and construct geometries.

Agarose-Based Hydrogels as Suitable Bioprinting Materials for Tissue Engineering.

Hydrogels are useful materials as scaffolds for tissue engineering applications. Using hydrogels with additive manufacturing techniques has typically required the addition of techniques such as cross-linking or printing in sacrificial materials that negatively impact tissue growth to remedy inconsistencies in print fidelity. Thus, there is a need for bioinks that can directly print cell-laden constructs. In this study, agarose-based hydrogels commonly used for cartilage tissue engineering were compared to Pluronic, a hydrogel with established printing capabilities. Moreover, new material mixtures were developed for bioprinting by combining alginate and agarose. We compared mechanical and rheological properties, including yield stress, storage modulus, and shear thinning, as well as construct shape fidelity to assess their potential as a bioink for cell-based tissue engineering. The rheological properties and printability of agarose-alginate gels were statistically similar to those of Pluronic for all tests (p > 0.05). Alginate-agarose composites prepared with 5% w/v (3:2 agarose to alginate ratio) demonstrated excellent cell viability over a 28-day culture period (>∼70% cell survival at day 28) as well matrix production over the same period. Therefore, agarose-alginate mixtures showed the greatest potential as an effective bioink for additive manufacturing of biological materials for cartilage tissue engineering.

A small molecule TrkB/TrkC neurotrophin receptor co-activator with distinctive effects on neuronal survival and process outgrowth.

Neurotrophin (NT) receptors are coupled to numerous signaling networks that play critical roles in neuronal survival and plasticity. Several non-peptide small molecule ligands have recently been reported that bind to and activate specific tropomyosin-receptor kinase (Trk) NT receptors, stimulate their downstream signaling, and cause biologic effects similar to, though not completely overlapping, those of the native NT ligands. Here, in silico screening, coupled with low-throughput neuronal survival screening, identified a compound, LM22B-10, that, unlike prior small molecule Trk ligands, binds to and activates TrkB as well as TrkC. LM22B-10 increased cell survival and strongly accelerated neurite outgrowth, superseding the effects of brain-derived neurotrophic factor (BDNF), NT-3 or the two combined. Additionally, unlike the NTs, LM22B-10 supported substantial early neurite outgrowth in the presence of inhibiting glycoproteins. Examination of the mechanisms of these actions suggested contributions of the activation of both Trks and differential interactions with p75(NTR), as well as a requirement for involvement of the Trk extracellular domain. In aged mice, LM22B-10 activated hippocampal and striatal TrkB and TrkC, and their downstream signaling, and increased hippocampal dendritic spine density. Thus, LM22B-10 may constitute a new tool for the study of TrkB and TrkC signaling and their interactions with p75(NTR), and provides groundwork for the development of ligands that stimulate unique combinations of Trk receptors and activity patterns for application to selected neuronal populations and deficits present in various disease states.

Nemitin, a novel Map8/Map1s interacting protein with Wd40 repeats.

In neurons, a highly regulated microtubule cytoskeleton is essential for many cellular functions. These include axonal transport, regional specialization and synaptic function. Given the critical roles of microtubule-associated proteins (MAPs) in maintaining and regulating microtubule stability and dynamics, we sought to understand how this regulation is achieved. Here, we identify a novel LisH/WD40 repeat protein, tentatively named nemitin (neuronal enriched MAP interacting protein), as a potential regulator of MAP8-associated microtubule function. Based on expression at both the mRNA and protein levels, nemitin is enriched in the nervous system. Its protein expression is detected as early as embryonic day 11 and continues through adulthood. Interestingly, when expressed in non-neuronal cells, nemitin displays a diffuse pattern with puncta, although at the ultrastructural level it localizes along the microtubule network in vivo in sciatic nerves. These results suggest that the association of nemitin to microtubules may require an intermediary protein. Indeed, co-expression of nemitin with microtubule-associated protein 8 (MAP8) results in nemitin losing its diffuse pattern, instead decorating microtubules uniformly along with MAP8. Together, these results imply that nemitin may play an important role in regulating the neuronal cytoskeleton through an interaction with MAP8.