Validating Variational Bayes Linear Regression Method With Multi-Central Datasets.

PurposeTo validate the prediction accuracy of variational Bayes linear regression (VBLR) with two datasets external to the training dataset.MethodThe training dataset consisted of 7268 eyes of 4278 subjects from the University of Tokyo Hospital. The Japanese Archive of Multicentral Databases in Glaucoma (JAMDIG) dataset consisted of 271 eyes of 177 patients, and the Diagnostic Innovations in Glaucoma Study (DIGS) dataset includes 248 eyes of 173 patients, which were used for validation. Prediction accuracy was compared between the VBLR and ordinary least squared linear regression (OLSLR). First, OLSLR and VBLR were carried out using total deviation (TD) values at each of the 52 test points from the second to fourth visual fields (VFs) (VF2-4) to 2nd to 10th VF (VF2-10) of each patient in JAMDIG and DIGS datasets, and the TD values of the 11th VF test were predicted every time. The predictive accuracy of each method was compared through the root mean squared error (RMSE) statistic.ResultsOLSLR RMSEs with the JAMDIG and DIGS datasets were between 31 and 4.3 dB, and between 19.5 and 3.9 dB. On the other hand, VBLR RMSEs with JAMDIG and DIGS datasets were between 5.0 and 3.7, and between 4.6 and 3.6 dB. There was statistically significant difference between VBLR and OLSLR for both datasets at every series (VF2-4 to VF2-10) (P < 0.01 for all tests). However, there was no statistically significant difference in VBLR RMSEs between JAMDIG and DIGS datasets at any series of VFs (VF2-2 to VF2-10) (P > 0.05).ConclusionsVBLR outperformed OLSLR to predict future VF progression, and the VBLR has a potential to be a helpful tool at clinical settings

Orally Active Multi-Functional Antioxidants Are Neuroprotective in a Rat Model of Light-Induced Retinal Damage

Progression of age-related macular degeneration has been linked to iron dysregulation and oxidative stress that induce apoptosis of neural retinal cells. Since both antioxidants and chelating agents have been reported to reduce the progression of retinal lesions associated with AMD in experimental animals, the present study evaluates the ability of multi-functional antioxidants containing functional groups that can independently chelate redox metals and quench free radicals to protect the retina against light-induced retinal degeneration, a rat model of dry atrophic AMD.Proof of concept studies were conducted to evaluate the ability of 4-(5-hydroxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 4) and 4-(5-hydroxy-4,6-dimethoxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 8) to reduce retinal damage in 2-week dark adapted Wistar rats exposed to 1000 lx of light for 3 hours. Assessment of the oxidative stress markers 4- hydroxynonenal and nitrotyrosine modified proteins and Thioredoxin by ELISA and Western blots indicated that these compounds reduced the oxidative insult caused by light exposure. The beneficial antioxidant effects of these compounds in providing significant functional and structural protection were confirmed by electroretinography and quantitative histology of the retina.The present study suggests that multi-functional compounds may be effective candidates for preventive therapy of AMD

Visible Blood Flow in a Case of Rubeosis Iridis

A 72-year-old Japanese woman presented to our hospital with decreased vision. At the initial visit, her best-corrected visual acuity (BCVA) and intraocular pressure (IOP) in her right eye (OD) were 0.02 and 36 mm Hg, respectively. By slit lamp examination, rubeosis iridis was observed on the iris surface. With higher magnification observation, movement of clustered RBCs were clearly observed; the blood drained into episcleral vessels that were connected with the main trunk of rubeosis iridis. She was diagnosed with the neovascular glaucoma secondary to central retinal vein occlusion OD. She underwent panretinal photocoagulation, intravitreal injection of aflibercept, and Ahmed Glaucoma Valve implantation. At 2 weeks postoperatively, the BCVA and IOP OD were 0.2 and 7 mm Hg, respectively; rubeosis iridis was partially regressed and movement of RBCs was not observed. Acquisition of directional flow by the connection of the main trunk of neovessels with the episcleral vessels and reduction of flow speed by the high IOP could explain the reason for visible blood flow in our case

Phacoemulsification Alone versus Phacoemulsification Combined with Trabeculectomy for Primary Angle-Closure Glaucoma

Surgical outcomes of phacoemulsification only and phacoemulsification combined with trabeculectomy were compared in patients with primary angle-closure glaucoma (PACG). Clinical records of 41 consecutive patients were retrospectively reviewed, and there was no difference in best-corrected visual acuity and intraocular pressure preoperatively and at the final follow-up in both study groups. Regarding the number of anti-glaucoma medications, it was higher in the phacoemulsification combined with trabeculectomy group preoperatively than the phacoemulsification only group (p = 0.045), but both groups were taking similar quantities of medication at the final follow-up (p = 0.6). In addition, postoperative hypotony (two cases) occurred only after phacoemulsification combined with trabeculectomy, but not after phacoemulsification only. In one case after phacoemulsification only, a second operation was needed. There were no additional postoperative complications. In conclusion, both phacoemulsification only and phacoemulsification combined with trabeculectomy showed good surgical outcomes in PACG patients. Both procedures might be equally effective in treating patients with PACG

The emerging role of Nrf2 in mitochondrial function

The transcription factor NF-E2 p45-related factor 2 (Nrf2; gene name NFE2L2) allows adaptation and survival under conditions of stress by regulating the gene expression of diverse networks of cytoprotective proteins, including antioxidant, anti-inflammatory, and detoxification enzymes as well as proteins that assist in the repair or removal of damaged macromolecules. Nrf2 has a crucial role in the maintenance of cellular redox homeostasis by regulating the biosynthesis, utilization, and regeneration of glutathione, thioredoxin, and NADPH and by controlling the production of reactive oxygen species by mitochondria and NADPH oxidase. Under homeostatic conditions, Nrf2 affects the mitochondrial membrane potential, fatty acid oxidation, availability of substrates (NADH and FADH2/succinate) for respiration, and ATP synthesis. Under conditions of stress or growth factor stimulation, activation of Nrf2 counteracts the increased reactive oxygen species production in mitochondria via transcriptional upregulation of uncoupling protein 3 and influences mitochondrial biogenesis by maintaining the levels of nuclear respiratory factor 1 and peroxisome proliferator-activated receptor γ coactivator 1α, as well as by promoting purine nucleotide biosynthesis. Pharmacological Nrf2 activators, such as the naturally occurring isothiocyanate sulforaphane, inhibit oxidant-mediated opening of the mitochondrial permeability transition pore and mitochondrial swelling. Curiously, a synthetic 1,4-diphenyl-1,2,3-triazole compound, originally designed as an Nrf2 activator, was found to promote mitophagy, thereby contributing to the overall mitochondrial homeostasis. Thus, Nrf2 is a prominent player in supporting the structural and functional integrity of the mitochondria, and this role is particularly crucial under conditions of stress

Acceleration of Age-Related Changes in the Retina in ␣-Tocopherol Transfer Protein Null Mice Fed a Vitamin E-Deficient Diet

PURPOSE. To assess the role of vitamin E (VE) in age-related changes in the retinal tissues by using a mouse model of severe VE deficiency. METHODS. Pups of ␣-tocopherol transfer protein null (a-TTP Ϫ/Ϫ ) mice were fed a VE-deficient diet for 4 or 18 months (VE (Ϫ) group). Wild-type C57BL/6 mice were fed a 0.002% ␣-tocopherol-supplemented diet (VE (ϩ) group). In various ocular tissues, the VE levels were measured by high-performance liquid chromatography; the fatty acid composition by gas chromatography (GC); and the hydroxyoctadecadienoic acid and 8-iso-prostaglandin F 2␣ levels, which are biomarkers for lipid peroxidation, by GC-mass spectrometry. The retinal structure was assessed by light, electron, and fluorescence microscopy. RESULTS. The ␣-tocopherol level in the retinas obtained from 4-month-old VE (Ϫ) animals was 71-fold lower than that in the retinas obtained from the VE (ϩ) group. In addition, ␥-tocopherol was not detected; thus, the VE (Ϫ) group demonstrated a more severe VE deficiency than ever reported. In this group, the concentration of n-3 polyunsaturated fatty acids decreased (0.3-to 0.9-fold), whereas that of other classes of fatty acids was unchanged or increased. At 18 months of age, the number of the outer nuclear layer (ONL) nuclei was observed to be 17% lower in the VE (Ϫ) than in the VE (ϩ) group (P Ͻ 0.05). Electron microscopy revealed larger amounts of matrix between the ONL nuclei indicating the Müller cell hypertrophy, greatly expanded rod outer segment discs, and a larger number of inclusion bodies in the retinal pigment epithelium (RPE; P Ͻ 0.05) in the VE (Ϫ) group. Fluorescence microscopy revealed that the autofluorescence signal was increased in the RPE layer in this group. When the observations of the 18-month-old animals were compared to those of the 4-month-old animals, the hydroxyoctadecadienoic acid and 8-iso-prostaglandin F 2␣ levels were found to be increased in the retina and RPE obtained from both the VE (Ϫ) and VE (ϩ) groups; however, the age-related increases were more remarkable in the VE (Ϫ) group (2.6-to 43.5-fold) than in the VE (ϩ) group (0.8-to 8.7-fold). CONCLUSIONS. The combined use of a-TTP Ϫ/Ϫ mice and a VEdeficient diet leads to a severe deficiency of VE, enhances lipid peroxidation in the retina, and accelerates degenerative damage of the retina with age. (Invest Ophthalmol Vis Sci. 2007; 48:396 -404

Acute Hypoglycemia Induces Retinal Cell Death in Mouse

BACKGROUND: Glucose is the most important metabolic substrate of the retina and maintenance of normoglycemia is an essential challenge for diabetic patients. Glycemic excursions could lead to cardiovascular disease, nephropathy, neuropathy and retinopathy. A vast body of literature exists on hyperglycemia namely in the field of diabetic retinopathy, but very little is known about the deleterious effect of hypoglycemia. Therefore, we decided to study the role of acute hypoglycemia in mouse retina. METHODOLOGY/PRINCIPAL FINDINGS: To test effects of hypoglycemia, we performed a 5-hour hyperinsulinemic/hypoglycemic clamp; to exclude an effect of insulin, we made a hyperinsulinemic/euglycemic clamp as control. We then isolated retinas from each group at different time-points after the clamp to analyze cells apoptosis and genes regulation. In parallel, we used 661W photoreceptor cells to confirm in vivo results. We showed herein that hypoglycemia induced retinal cell death in mouse via caspase 3 activation. We then tested the mRNA expression of glutathione transferase omega 1 (Gsto1) and glutathione peroxidase 3 (Gpx3), two genes involved in glutathione (GSH) homeostasis. The expression of both genes was up-regulated by low glucose, leading to a decrease of reduced glutathione (GSH). In vitro experiments confirmed the low-glucose induction of 661W cell death via superoxide production and activation of caspase 3, which was concomitant with a decrease of GSH content. Moreover, decrease of GSH content by inhibition with buthionine sulphoximine (BSO) at high glucose induced apoptosis, while complementation with extracellular glutathione ethyl ester (GSHee) at low glucose restored GSH level and reduced apoptosis. CONCLUSIONS/SIGNIFICANCE: We showed, for the first time, that acute insulin-induced hypoglycemia leads to caspase 3-dependant retinal cell death with a predominant role of GSH content