Identification of a novel neurotrophic factor from primary retinal Müller cells using stable isotope labeling by amino acids in cell culture (SILAC).

Retinal Müller glial cells (RMGs) have a primary role in maintaining the homeostasis of the retina. In pathological situations, RMGs execute protective and regenerative effects, but they can also contribute to neurodegeneration. It has recently been recognized that cultured primary RMGs secrete pro-survival factors for retinal neurons for up to 2 weeks in culture, but this ability is lost when RMGs are cultivated for longer durations. In our study, we investigated RMG supernatants for novel neuroprotective factors using a quantitative proteomic approach. Stable isotope labeling by amino acids in cell culture (SILAC) was used on primary porcine RMGs. Supernatants of RMGs cultivated for 2 weeks were compared with supernatants from cells that had already lost their protective capacity. Using this approach, we detected established neurotrophic factors such as transferrin, osteopontin, and leukemia inhibitory factor and identified C-X-C motif chemokine 10 (CXCL10) as a novel candidate neuroprotective factor. All factors prolonged photoreceptor survival in vitro. Ex vivo treatment of retinal explants with leukemia inhibitory factor or CXCL10 demonstrated a neuroprotective effect on photoreceptors. Western blots on CXCL10- and leukemia inhibitory factor-stimulated explanted retina and photoreceptor lysates indicated activation of pro-survival signal transducer and activator of transcription signaling and B-cell lymphoma pathways. These findings suggest that CXCL10 contributes to the supportive potential of RMGs toward retinal neurons.

Network oscillations in rod-degenerated mouse retinas.

In the mammalian retina, excitatory and inhibitory circuitries enable retinal ganglion cells (RGCs) to signal the occurrence of visual features to higher brain areas. This functionality disappears in certain diseases of retinal degeneration because of the progressive loss of photoreceptors. Recent work in a mouse model of retinal degeneration (rd1) found that, although some intraretinal circuitry is preserved and RGCs maintain characteristic physiological properties, they exhibit increased and aberrant rhythmic activity. Here, extracellular recordings were made to assess the degree of aberrant activity in adult rd1 retinas and to investigate the mechanism underlying such behavior. A multi-transistor array with thousands of densely packed sensors allowed for simultaneous recordings of spiking activity in populations of RGCs and of local field potentials (LFPs). The majority of identified RGCs displayed rhythmic (7-10 Hz) but asynchronous activity. The spiking activity correlated with the LFPs, which reflect an average synchronized excitatory input to the RGCs. LFPs initiated from random positions and propagated across the retina. They disappeared when ionotrophic glutamate receptors or electrical synapses were blocked. They persisted in the presence of other pharmacological blockers, including TTX and inhibitory receptor antagonists. Our results suggest that excitation-transmitted laterally through a network of electrically coupled interneurons-leads to large-scale retinal network oscillations, reflected in the rhythmic spiking of most rd1 RGCs. This result may explain forms of photopsias reported by blind patients, while the mechanism involved should be considered in future treatment strategies targeting the disease of retinitis pigmentosa.

Navigated laser in diabetic macular edema: the impact of reduced injection burden on patients and physicians-who wins and who loses?

We inquired the impact of reduced therapy discontinuation in diabetic macular edema (DME) on physician's revenue considering anti-vascular endothelial growth factor (VEGF) monotherapy and its combination with Navilas treatment. Data were collected on injection frequency, treatment discontinuation and reimbursement fees for DME treatment with anti-VEGF compared to anti-VEGF in combination with navigated laser. Based on these data an economic model was built to compare physicians revenue over a 5y period using either therapy for 4 European countries and the USA. Due to patients' higher therapy adherence, physicians using navigated laser therapy with anti-VEGF generate similar or higher revenues compared to VEGF monotherapy in all analyzed countries. The use of Navilas decreases the patient's injection burden at the same clinical outcome, while the physician's revenue remained stable or increased. Therewith, therapy discontinuation in DME can be reduced using the combination therapy with Navilas.

Incidence and prevalence of vitreomacular traction with and without macular hole in Germany.

PURPOSE: Symptomatic vitreomacular adhesion (sVMA) comprises vitreomacular traction (VMT) and stage 1 and 2 full-thickness macular holes (MHs) associated with vitreomacular adhesion (VMA). We aimed to estimate the incidence and prevalence of sVMA in Germany. MATERIALS AND METHODS: A systematic literature review was conducted to identify the incidence and prevalence of sVMA based on international epidemiologic studies, weighted for study size and then averaged across eligible studies. A second systematic review aimed to estimate the proportion of vitrectomy undertaken for sVMA in Germany. This was combined with the reported number of vitrectomies in Germany in 2016 to estimate the number of patients undergoing vitrectomy for sVMA. RESULTS: The prevalence of sVMA is 1,365 per 100,000 population, with an incidence of 6.96 per 100,000 per year. For Germany, this translates to 1,119,300 cases, with 5,700 new cases reported annually. Analyzing the national hospital statistics, ~2,300 patients undergo vitrectomy due to sVMA in Germany each year, of which about 1,700 patients have VMT. CONCLUSION: Incidence figures, driven by patients presenting to clinic, are much lower than expected based on population-based studies, suggesting that many patients with sVMA exist outside of the clinic system.

Rhythmic ganglion cell activity in bleached and blind adult mouse retinas.

In retinitis pigmentosa--a degenerative disease which often leads to incurable blindness--the loss of photoreceptors deprives the retina from a continuous excitatory input, the so-called dark current. In rodent models of this disease this deprivation leads to oscillatory electrical activity in the remaining circuitry, which is reflected in the rhythmic spiking of retinal ganglion cells (RGCs). It remained unclear, however, if the rhythmic RGC activity is attributed to circuit alterations occurring during photoreceptor degeneration or if rhythmic activity is an intrinsic property of healthy retinal circuitry which is masked by the photoreceptor's dark current. Here we tested these hypotheses by inducing and analysing oscillatory activity in adult healthy (C57/Bl6) and blind mouse retinas (rd10 and rd1). Rhythmic RGC activity in healthy retinas was detected upon partial photoreceptor bleaching using an extracellular high-density multi-transistor-array. The mean fundamental spiking frequency in bleached retinas was 4.3 Hz; close to the RGC rhythm detected in blind rd10 mouse retinas (6.5 Hz). Crosscorrelation analysis of neighbouring wild-type and rd10 RGCs (separation distance <200 µm) reveals synchrony among homologous RGC types and a constant phase shift (∼70 msec) among heterologous cell types (ON versus OFF). The rhythmic RGC spiking in these retinas is driven by a network of presynaptic neurons. The inhibition of glutamatergic ganglion cell input or the inhibition of gap junctional coupling abolished the rhythmic pattern. In rd10 and rd1 retinas the presynaptic network leads to local field potentials, whereas in bleached retinas additional pharmacological disinhibition is required to achieve detectable field potentials. Our results demonstrate that photoreceptor bleaching unmasks oscillatory activity in healthy retinas which shares many features with the functional phenotype detected in rd10 retinas. The quantitative physiological differences advance the understanding of the degeneration process and may guide future rescue strategies.