Microglia, as phagocytes and antigen-presenting cells in the central nervous system, are activated in such disease processes as stroke and multiple sclerosis. Because peripheral macrophages are capable of producing endocannabinoids, we have examined endocannabinoid production in a macrophage-colony stimulating factor (M-CSF)-dependent rat microglial cell line (RTMGL1) using reversed phase high-pressure liquid chromatography and liquid chromatography-mass spectroscopy. We determined that cultured microglial cells produce the endocannabinoid 2-arachidonylglycerol (2-AG) as well as anandamide in smaller quantities. When 2-AG, but not anandamide, is added exogenously, RT-MGL1 microglia increase their proliferation. This increased proliferation is blocked by an antagonist of the CB 2 receptor N-[(1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) and mimicked by the CB 2 receptor-specific agonist 1,1-dimethylbutyl-1-deoxy-⌬ 9 -tetrahydrocannabinol (JWH133). Accompanying the increase in proliferation seen with 2-AG is an increase in active ERK1 that is also blocked with SR144528. The RTMGL1 microglial cells, which exist in a primed state, express the CB 1 and CB 2 receptors as demonstrated by reverse transcription-polymerase chain reaction and immunostaining. The CB 2 receptor in untreated cells is expressed both at the cell surface and internally, and exposure of the cells to 2-AG significantly increases receptor internalization. These data suggest that 2-AG activation of CB 2 receptors may contribute to the proliferative response of microglial cells, as occurs in neurodegenerative disorders.

Objective To evaluate the association of subretinal hyper-reflective material (SHRM) with visual acuity (VA), geographic atrophy (GA) and scar in the Comparison of Age related Macular Degeneration Treatments Trials (CATT) Design Prospective cohort study within a randomized clinical trial. Participants The 1185 participants in CATT. Methods Participants were randomly assigned to ranibizumab or bevacizumab treatment monthly or as-needed. Masked readers graded scar and GA on fundus photography and fluorescein angiography images, SHRM on time domain (TD) and spectral domain (SD) optical coherence tomography (OCT) throughout 104 weeks. Measurements of SHRM height and width in the fovea, within the center 1mm2, or outside the center 1mm2 were obtained on SD-OCT images at 56 (n=76) and 104 (n=66) weeks. VA was measured by certified examiners. Main Outcome Measures SHRM presence, location and size, and associations with VA, scar, and GA. Results Among all CATT participants, the percentage with SHRM at enrollment was 77%, decreasing to 68% at 4 weeks after treatment and 54% at 104 weeks. At 104 weeks, scar was present more often in eyes with persistent SHRM than eyes with SHRM that resolved (64% vs. 31%; p<0.0001). Among eyes with detailed evaluation of SHRM at weeks 56 (n=76) and 104 (n=66), mean [SE] VA letter score was 73.5 [2.8], 73.1 [3.4], 65.3 [3.5], and 63.9 [3.7] when SHRM was absent, present outside the central 1mm2, present within the central 1mm2 but not the foveal center, or present at the foveal center (p=0.02). SHRM was present at the foveal center in 43 (30%), within the central 1mm2 in 21 (15%) and outside the central 1mm2 in 19 (13%). When SHRM was present, the median maximum height in microns under the fovea, within the central 1 mm2 including the fovea and anywhere within the scan was 86; 120; and 122, respectively. VA was decreased with greater SHRM height and width (p<0.05). Conclusions SHRM is common in eyes with NVAMD and often persists after anti-VEGF treatment. At 2 years, eyes with scar were more likely to have SHRM than other eyes. Greater SHRM height and width were associated with worse VA. SHRM is an important morphological biomarker in eyes with NVAMD.

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy reduced the development and progression of retinopathy in type 1 diabetes (T1D) compared with conventional therapy. The Epidemiology of Diabetes Interventions and Complications (EDIC) study observational follow-up showed persistent benefits. In addition to glycemia, we now examine other potential retinopathy risk factors (modifiable and nonmodifiable) over more than 30 years of follow-up in DCCT/EDIC. RESEARCH DESIGN AND METHODS The retinopathy outcomes were proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), and ocular surgery. The survival (event-free) probability was estimated using the Kaplan-Meier method. Cox proportional hazards models assessed the association between risk factors and subsequent risk of retinopathy. Both forward-and backward-selection approaches determined the multivariable models. RESULTS Rate of ocular events per 1,000 person-years was 12 for PDR, 14.5 for CSME, and 7.6 for ocular surgeries. Approximately 65%, 60%, and 70% of participants remained free of PDR, CSME, and ocular surgery, respectively. The greatest risk factors for PDR in descending order were higher mean HbA 1c , longer duration of T1D, elevated albumin excretion rate (AER), and higher mean diastolic blood pressure (DBP). For CSME, risk factors, in descending order, were higher mean HbA 1c , longer duration of T1D, and greater age and DBP and, for ocular surgeries, were higher mean HbA 1c , older age, and longer duration of T1D. CONCLUSIONS Mean HbA 1c was the strongest risk factor for the progression of retinopathy. Although glycemic control is important, elevated AER and DBP were other modifiable risk factors associated with the progression of retinopathy. Retinopathy is a major complication of type 1 diabetes. The Diabetes Control and Complications Trial (DCCT) demonstrated that a mean of 6.5 years of intensive diabetes therapy with a mean HbA 1c of ;7% substantially reduced microvascular complications, including retinopathy, compared with conventional therapy with a mean HbA 1c of ;9% (1). Thereafter, observational follow-up of DCCT participants continued in the Epidemiology of Diabetes Interventions and Complications (EDIC) study (1994 to present) (2). Over the first 4 years of EDIC, the former DCCT intensive

Intravitreal injections of anti-VEGF medications increased annually from 2006 to 2015. Bevacizumab was the most common medication used, despite its lacking U.S. Food and Drug Administration approval to treat ophthalmic disease, and AMD was the most common condition treated. Ranibizumab use declined after 2014 while both the absolute and relative use of bevacizumab and aflibercept increased.

Background: Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath's four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results: Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18-20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions: Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

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Objective To examine whether oral fluoroquinolone antibiotics are associated with an increase in subsequent rhegmatogenous retinal detachment and symptomatic retinal breaks in a large, population-based cohort. Design Population-based cohort study Participants and Controls Adult residents of Olmsted County, Minnesota who were prescribed oral fluoroquinolone medications from 1/01/03 – 6/30/11. Comparison cohorts consisted of patients prescribed oral macrolide and β-lactam antibiotics during the study period. Methods Procedure codes were used to identify retinal detachment repair and prophylaxis procedures occurring within 1 year of prescription dates. Travel clinic, pro re nata, and self-treatment prescriptions were excluded. Patients with tractional retinal detachment, previous retinal detachment repair, endophthalmitis, and necrotizing retinitis were excluded, as were those with intraocular surgery or severe head/eye trauma ≤ 90 days prior to the procedure. Main Outcome Measures Rates of retinal detachment repair and prophylaxis procedures within 7, 30, 90, and 365 days of the first prescription were calculated and compared between antibiotic prescription cohorts using Chi-square tests. Retinal detachment repair rates were also compared to the expected Olmsted County, Minnesota rates using the one-sample log rank test. Results Oral fluoroquinolones were prescribed for 38,046 patients (macrolide n=48,074, β-lactam n=69,079) during the study period. Retinal detachment repair procedures were performed within 365 days of the first prescription in 0.03% (95% confidence interval [CI] 0.01–0.06%) of the fluoroquinolone, 0.02% (95% CI 0.01–0.03%) of the macrolide, and 0.03% (95% CI 0.02–0.05%) of the β-lactam cohorts (p>0.05). Retinal detachment prophylaxis procedures for symptomatic retinal breaks were performed within 365 days of the first prescription in 0.01% (95% CI 0.00–0.03%) of the fluoroquinolone, 0.02% (95% CI 0.01–0.04%) of the macrolide, and 0.02% (95% CI 0.01–0.04%) of the β-lactam cohorts (p>0.05). Similar comparisons of treatment rates within 7, 30, and 90 days of the first prescription were all non-significant between cohorts. Post-fluoroquinolone retinal detachment repair rates were similar to expected rates (36.8 per 100,000/year vs 28.8 per 100,000/year for age- and sex-matched historical rates, p = 0.35). Conclusions Oral fluoroquinolone use was not associated with an increased risk of rhegmatogenous retinal detachment or symptomatic retinal breaks in this population-based study.

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