Does GDNF exert its neuroprotective effects on photoreceptors in the rd1 retina through the glial glutamate transporter GLAST?

PURPOSE: We previously demonstrated that exogenous glial cell line-derived neurotrophic factor (GDNF) induces histological and functional protection of photoreceptors in the retinal degeneration (rd1) mouse model. The mechanisms underlying such neuroprotection remain elusive. In parallel to this work, we provided evidence for the occurrence of glutamate-mediated excitotoxic phenomena contributing to rod photoreceptor death in the rd1 retina in the companion paper. In the present study, we investigated whether, as demonstrated in other models, GDNF could exert its neuroprotective effect on photoreceptors through Muller glial cells (MGC) by promoting the expression of the glial L-glutamate/L-aspartate transporter (GLAST), an endogenous neuroprotective mechanism against glutamate-mediated excitotoxicity. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to compare the mRNA expression levels of GDNF receptors between rd1 and wild-type mouse retinas as well as between MGC and mixed retinal cell cultures. Recombinant GDNF was applied to pure MGC cultures, to rd1 retinal organ cultures and injected subretinally into rd1 mouse eyes. GLAST expression following GDNF treatment was measured by RT-PCR, immunoblotting and immunohistochemistry. Free glutamate and glutamine levels were quantified in rd1 retinas after GDNF or control treatment using an amino acid analyzer. RESULTS: mRNA expression studies of GDNF receptors, GFRalpha-1 and Ret, demonstrated that GDNF receptors were not exclusively expressed by the degenerating photoreceptor cells but mainly by MGC. Exogenous GDNF application to MGC cultures, rd1 mouse retinal explants and in vivo rd1 mouse retinas increased the expression of GLAST by 48% in retinal explants (p<0.005) and by 25% in vivo (p<0.0005). GLAST protein expression in MGC was particularly increased around degenerative photoreceptors. Free glutamate and glutamine levels in the rd1 retina were not significantly modified by exogenous GDNF. CONCLUSIONS: Our data suggest that, in the rd1 mouse retina, GDNF neuroprotective effect on photoreceptors can be mediated indirectly through the activation of MGC. We demonstrate that injection of recombinant GDNF enhances the expression of GLAST and more particularly around the degenerating photoreceptors. Since we failed to demonstrate that GDNF decreases free glutamate levels, we could not ascertain whether GDNF promoted photoreceptor-survival via an increase of glutamate uptake and, therefore, a change in glutamate distributio

Evidence for glutamate-mediated excitotoxic mechanisms during photoreceptor degeneration in the rd1 mouse retina

PURPOSE: Kinetic studies of photoreceptor cell death in the retinal degeneration (rd1) mouse model suggest that photoreceptor degeneration could result from cumulative damage. Since alterations in glutamate metabolism have been described in different models of retinitis pigmentosa, we investigated in the present work whether changes in glutamate turnover occur in the degenerating rd1 retina and whether glutamate-mediated excitotoxic mechanisms may contribute to rod photoreceptor death in this model. METHODS: Free amino acid levels were quantified in rd1 and wild-type retinas using an amino acid analyzer selecting times corresponding to early, intermediate, and terminal phases of rod photoreceptor degeneration. Reverse transcription-polymerase chain reaction (RT-PCR) was used to compare the mRNA expression levels of the glial L-glutamate/L-aspartate transporter GLAST, glutamine synthetase (GS), and vimentin, a marker for retinal glia, between rd1 and wild-type mouse retinas. 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist of both AMPA and kainate subtypes of ionotropic glutamate receptors, was then daily administered from postnatal day 3 (PN3) to PN21 to rd1 mice while control rd1 mice received only physiological saline solution (7 per treatment). At PN22, the respective numbers of surviving rods i

Foreword

In his recent anthology, Gérard-Georges Lemaire observes that gold is omnipresent in the history of art from the early Bronze Age. Among contemporary artists too, the art critic notes the renewed fascination for gold in works by Yves Klein, Anish Kapoor, James Lee Byars, Jean-Pierre Raynaud, or Orlan (Lemaire 2). This is further evidenced in several recent art exhibitions, such as “Gold” (Belvedere, Vienna, 2012), “Going for Gold” (Seattle Art Museum, 2013), “Beyond El Dorado: power and gold ..

Visible/invisible/visuel : spectralité et hantologie dans The Gateless Barrier de Lucas Malet

The Gateless Barrier (1900) est un roman qui accorde une place centrale au visuel tel que l’entend Georges Didi-Huberman, c’est-à-dire à l’insondable, l’impalpable, l’inexplicable de l’image. En choisissant pour héroïne une jeune morte-vivante, la charmante Agnes Rivers, Malet déroge aux lois du roman réaliste comme à celles du roman esthétique décadent pour mieux semer le désordre dans le récit, le politiser autour de la question du genre, et même jeter le trouble dans l’historiographie littéraire, en ramenant au centre de ses préoccupations les questions de hantise, de survivance, d’héritage, de tradition, de responsabilité, de dette et de justice. Comme la fable d’Oscar Wilde « The Fisherman and His Soul » et The Picture of Dorian Gray, ce roman de « Lucas Malet » (Mary St Leger Kingsley Harrison, 1852-1931) mêle la fascination fin-de-siècle pour les rites catholiques, l’occulte, le surnaturel, les portraits vivants, l’ésotérique et le spiritisme avec les ingrédients classiques du roman gothique, qui repose sur la dialectique de l’impalpable rendu visible.The Gateless Barrier (1900) is a novel concerned with the visual as defined by Georges Didi-Huberman, that is, with the inexplicable but compelling, spectral power of images. Focusing on the fate of the charming Agnes Rivers, whose ghost haunts the Rivers’ ancestral house, The Gateless Barrier breaks with the realist tradition as well as with the aesthetic novel, in order to challenge contemporary gender politics and ultimately revise literary historiography. Part New Woman novel, part Gothic romance, the novel explores matters of haunting and the spectral and addresses issues of memory, responsibility, justice and debt. Not unlike Oscar Wilde’s tale « The Fisherman and His Soul » or The Picture of Dorian Gray, this novel by « Lucas Malet » (Mary St Leger Kingsley Harrison, 1852-1931) combines a fin-de-siècle fascination for Catholic rituals, the occult, the supernatural, living portraits, esoterism, and spiritism with the classic ingredients of the Gothic novel, in order to examine the dialectics of the visible and the invisible

Associations of biomechanical properties of the cornea with environmental and metabolic factors in an elderly population : the ALIENOR study

PURPOSE: The purpose of this study was to assess the associations of biomechanical properties of the cornea with metabolic and environmental factors in an elderly population. METHODS: The ALIENOR (Antioxydants, Lipides Essentiels, Nutrition, and Maladies OculaiRes) study is a population-based study. In 2009-2010, 624 subjects, aged 74 years or more, underwent an eye examination, including intraocular pressure (IOP), central corneal thickness (CCT), and biomechanical properties of the cornea measurements using the Ocular Response Analyzer. Socio-demographic, lifestyle, and medical history data were collected using standardized questionnaires. Mean lifetime ambient ultraviolet (UV) exposure was estimated using residential history and statistics of UV radiation at each location using the Eurosun UV database. RESULTS: Mean age was 82.2 ± 4.3 years. Mean corneal hysteresis (CH), corneal resistance factor (CRF), and CCT were 9.4 ± 1.9, 9.8 ± 1.9 mm Hg, and 551.6 ± 36.8 μm, respectively. In the multivariate analysis, CH and CRF values were significantly lower in subjects older than 80 years (-0.56; 95% confidence interval [CI]: -0.89;-0.24); P < 0.001 and -0.48; 95% CI: -0.75;-0.20; P < 0.001, respectively), in subjects having higher ambient UV exposure (-0.50; 95% CI: -0.88;-0.12; P < 0.01; and -0.46; 95% CI: -0.78;-0.13); P < 0.05, respectively), and in subjects with high plasma LDL cholesterol (CH: -0.46; 95% CI: -0.86;-0.03; P < 0.05; and CRF: -0.37; 95% CI: -0.72;-0.008; P < 0.05). Central corneal thickness was significantly higher in former smokers than in never smokers (+11.01; 95% CI: 0.48;21.55; P < 0.05) and was not significantly associated with age, ambient UV exposure, diabetes, or LDL cholesterol. CONCLUSIONS: Biomechanical properties of the cornea are modified by metabolic and lifetime environmental factors, especially UV exposure. The manner these factors may influence onset and progression of ocular diseases or IOP measurements need further investigation

Presumed Necrotizing Viral Retinitis after Intravitreal Triamcinolone Injection: Case Report

A 56-year-old man presented with anterior chamber inflammation, increased intraocular pressure, peripheral retinal infiltration, and generalized retinal arterial obstruction suggesting acute retinal necrosis five months after intravitreal triamcinolone acetonide injection (IVTA). He was treated with intravenous antiviral agents and aspirin. Shortly after treatment, retinal infiltrations were resolved, and partial recanalization of the obstructed vessel was observed. Viral retinitis may occur as an opportunistic infection following IVTA due to the local immune modulatory effect of the steroid; hence, close observation following IVTA is necessary

Ophthalmol Ther

There is little understanding of long-term treatment persistence in patients receiving anti-vascular endothelial growth factor (anti-VEGF) injections for diabetic macular edema (DME), particularly relating to treatment intervals. The aim of this study was to investigate the association between treatment interval and discontinuation rate after 24 months of unilateral anti-VEGF treatment in patients with DME under routine clinical care in the USA. This was a non-interventional, retrospective cohort study to review the health insurance claims of adults with DME linked with the IBM MarketScan Commercial and Medicare Supplemental databases, who were continuously enrolled in a health plan for at least 6 months prior to their first anti-VEGF treatment and for a duration of at least 24 months between July 2011 and June 2017. Patients were grouped on the basis of the injection interval they achieved at 24 months of treatment. Discontinuation rate beyond 24 months and its association with treatment intervals at 24 months was estimated using the Kaplan-Meier method and Cox proportional hazards models. The overall discontinuation rate among the 1702 eligible patients from 24 to 60 months after treatment initiation was 30%. At 60 months, patients were more likely to remain on treatment in shorter (75.3% [4-week interval group]) versus longer treatment interval groups (62.1% [> 12-week interval group], difference = 13.2%, [95% confidence interval (CI) 1.06, 2.06], p = 0.01). Patients on a > 12-week interval were twice as likely to discontinue treatment compared with those on an 8-week interval (hazard ratio = 2.01 [95% CI 1.43, 2.82], p < 0.001). Patients with DME on longer anti-VEGF treatment intervals at 24 months consistently had higher discontinuation rates in the following years than those on shorter treatment intervals

Lifetime exposure to ambient ultraviolet radiation and the risk for cataract extraction and age-related macular degeneration : the Alienor Study

While exposure to ultraviolet radiation (UVR) is a recognized risk factor for cataract, its association is more controversial with age-related macular degeneration (AMD). We report the associations of lifetime exposure to ambient UVR with cataract extraction and AMD. The Alienor Study is a population-based study of 963 residents of Bordeaux (France), aged 73 years or more. Lifetime exposure to ambient UVR was estimated from residential history and Eurosun satellite-based estimations of ground UVR. It was divided in three groups (lower quartile, intermediate quartiles, upper quartile), using the intermediate quartiles as the reference. Early and late AMD was classified from retinal color photographs. Cataract extraction was defined as absence of the natural lens at slit-lamp. After multivariate adjustment, subjects in the upper quartile of lifetime ambient UVR exposure were at increased risk for cataract extraction (odds ratio [OR] = 1.53; 95% confidence interval [CI], 1.04-2.26; P = 0.03) and for early AMD (OR = 1.59; 95% CI, 1.04-2.44; P = 0.03), by comparison with subjects in the intermediate quartiles. Subjects in the lower quartile of UVR exposure also were at increased risk for early AMD (OR = 1.69; 95% CI, 1.06-2.69; P = 0.03), by comparison with those with medium exposure. Associations of late AMD with UVR exposure was not statistically significant. This study further confirms the increased risk for cataract extraction in subjects exposed to high ambient UVR. Moreover, it suggests that risk for early AMD is increased in subjects exposed to high UVR, but also to low UVR, by comparison with medium exposures

Pharmaceutics

To assess real-world outcomes of fluocinolone acetonide (FAc) implant in treating diabetic macular edema (DME), a systematic literature review was conducted on PubMed in order to identify publications assessing the efficacy and safety of the FAc implant in DME in daily practice. Case reports and randomized controlled trials were excluded. Twenty-two observational real-world studies analyzing a total of 1880 eyes were included. Mean peak visual gain was +8.7 letters (11.3 months post-FAc injection) and was greater for lower baseline best corrected visual acuity (BCVA) and for more recent DME. Mean central retinal thickness (CRT) decreased 34.3% from baseline. 77.0% of the analyzed studies reported both BCVA improvement of at least five letters and a CRT decrease by 20% or more. Rescue therapy was needed more frequently when FAc was administered for chronic DME. FAc-induced ocular hypertension was reported in 20.1% of patients but only 0.6% needed surgery. Cataract extraction was performed in 43.2% of phakic patients. Adequate patient selection is essential for optimal FAc response and better safety profile. Currently positioned as second- or third-line treatment in the management algorithm, FAc implant decreases treatment burden and provides better letter gain when administered for more recent DME

Clinical and Epidemiologic Research Vitreomacular Adhesion and Its Association With Age- Related Macular Degeneration in a Population-Based Setting: The Alienor Study

PURPOSE. The purpose of this study was to describe vitreomacular adhesion (VMA), diagnosed with spectral-domain optical coherence tomography (SD-OCT), its risk factors, and its association with AMD in a population-based study of French elderly subjects. METHODS. Six hundred twenty-two of 624 (99.7%) participants of the Alienor study (Bordeaux, France), ‡75 years of age, had gradable SD-OCT scans of the macula in at least one eye. VMA was defined as visible perifoveal vitreous separation with remaining vitreomacular attachment and unperturbed foveal morphologic features. Late AMD was classified from retinal color photographs, SD-OCT, and ophthalmologic history. Early AMD was classified from retinal photographs and defined by the presence of large drusen and/or reticular drusen and/or pigmentary abnormalities. RESULTS. The prevalence of VMA was 15.8%, decreased with age (18.1% in subjects 75 to 84 years of age versus 8.9% after 85 years of age), and was higher in men than women (20.6% vs. 12.8%). VMA also tended to be less frequent in eyes with a history of cataract surgery (odds ratio [OR] ¼ 0.66, P ¼ 0.05), after adjustment for age and sex. No associations of VMA with other risk factors (cardiovascular risk factors, dietary intake of omega-3 fatty acids, lifetime ultraviolet radiation exposure, major AMD genetic polymorphisms) were found. After multivariate adjustment, VMA was not significantly associated with early or late AMD (OR ¼ 1.14, P ¼ 0.70 and OR ¼ 0.78, P ¼ 0.51 for early and late AMD, respectively). CONCLUSIONS. VMA was visible on SD-OCT in 16% in this sample of elderly French subjects but was not associated with AMD. Prospective studies of the associations of VMA with AMD are needed