ABSTRACT
PURPOSE: To compare the 12-month efficacy of intravitreous aflibercept (IVA) injection between eyes with pachychoroid neovasculopathy and neovascular age-related macular degeneration (AMD). METHODS: Retrospective, comparative case series analysis. Twenty-seven eyes with pachychoroid neovasculopathy and sixty-three eyes with neovascular AMD. All patients received three initial monthly, followed by bimonthly, IVA injections. RESULTS: Twelve months after initial treatment, the mean best-corrected visual acuity (BCVA) had improved both in pachychoroid neovasculopathy (from 0.28 to 0.14 logMAR; P = 0.001) and neovascular AMD (from 0.40 to 0.29 logMAR; P < 0.001). Twelve months after initial treatment, eyes with pachychoroid neovasculopathy exhibited decreased mean central retinal thickness (CRT) and subfoveal choroidal thickness (both, P < 0.001) and presence of polyps (P = 0.039) and improved integrity of external limiting membrane (ELM) (P = 0.008) and ellipsoid zone band (P = 0.001). At the 12-month follow-up, 77% and 68% of eyes with pachychoroid neovasculopathy and neovascular AMD, respectively, exhibited dry macula (P = 0.30). Baseline CRT was correlated with 12-month BCVA in eyes with pachychoroid neovasculopathy (P = 0.02). In eyes with neovascular AMD, CRT (P = 0.005) and presence of intact ELM (P = 0.007) were significant predictors of 12-month BCVA. CONCLUSION: Periodic IVA injection leads to anatomical and functional improvement in eyes with pachychoroid neovasculopathy and in eyes with neovascular AMD.
ABSTRACT
OBJECTIVES: To compare the effects of intensive and standard statin therapy on severity of diabetic retinopathy (DR) complicated by hypercholesterolaemia in a prespecified substudy of the standard vs. intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study. METHODS: Among 5144 patients in the multicentre, prospective, randomized EMPATHY study, this substudy considered 157 patients with seven-field fundus photographs of sufficient quality taken during study enrolment and at the 3-year visit. Eighty-five and seventy-two patients received intensive and standard statin treatments, respectively, in a treat-to-target manner. The primary endpoint was a two-step change in the Early Treatment Diabetic Retinopathy Study (ETDRS) DR severity scale at 36 months. Surrogate markers included changes in hard exudates, changes in visual acuity, and additional ocular treatments during study follow-up. RESULTS: Intensive and standard treatment groups did not differ significantly in terms of changing two or more steps on the DR severity scale (P = 0.4380). In patients with severe DR, defined as ≥47 on the severity scale, exploratory analysis showed more frequent improvement of DR, by at least one step, with intensive vs. standard treatment (83.3% vs. 40.0%; P = 0.0346). The intensive and standard groups did not differ in changes on the hard exudates severity scale (P = 0.3460), logarithm of minimum angle of resolution visual acuity (P = 0.5500), or additional ocular treatment during follow-up. CONCLUSIONS: Intensive and standard statin treatment may have similar effects on DR in the population of all patients with DR and hypercholesterolaemia, but intensive therapy may be more beneficial in patients with severe DR.
Subject(s)
Diabetes Mellitus , Diabetic Retinopathy , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypercholesterolemia , Hyperlipidemias , Diabetic Retinopathy/drug therapy , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/complications , Hypercholesterolemia/drug therapy , Prospective StudiesABSTRACT
Recently, several research groups have reported a newly recognized clinical entity of choroidal neovascularization, termed pachychoroid neovasculopathy. However, its characteristics have yet to be well described. The purpose of this study was to investigate the clinical and genetic characteristics of pachychoroid neovasculopathy regardless of treatment modality. This study included 99 eyes of 99 patients with treatment-naïve pachychoroid neovasculopathy. Mean initial best-corrected visual acuity (BCVA) was 0.20 ± 0.32 logMAR, and did not change (P = 0.725) during follow-up period (mean ± SD, 37.0 ± 17.6 months). Subretinal hemorrhage (SRH) (≥ 4 disc areas in size) occurred in 20 eyes (20.2%) during follow-up. Age, initial BCVA, central retinal thickness, SRH (≥ 4 disc areas in size) and treatment (aflibercept monotherapy) were significantly associated with the final BCVA (P = 0.024, < 0.001, 0.031, < 0.001, and 0.029, respectively). Multiple regression analysis showed initial BCVA and presence of SRH to be significant predictors of final BCVA (both P < 0.001). Polypoidal lesions were more common in the SRH group than in the non-SRH group (85.0% vs 48.1%, P = 0.004). There was no significant difference in the frequency of the risk allele in ARMS2 A69S, CFH I62V, CFH Y402H between these groups (P = 0.42, 0.77, and 0.85, respectively). SRH (29.1% vs 9.1%, P = 0.014) and choroidal vascular hyperpermiability (65.5% vs 43.2%, P = 0.027) were seen more frequently in the polypoidal lesion (+) group than in the polypoidal lesion (-) group. There was considerable variation in lesion size and visual function in patients with pachychoroid neovasculopathy, and initial BCVA and presence of SRH at the initial visit or during the follow-up period were significant predictors of final BCVA.
Subject(s)
Choroidal Neovascularization/pathology , Adult , Age Factors , Aged , Aged, 80 and over , Choroidal Neovascularization/diagnosis , Choroidal Neovascularization/diagnostic imaging , Choroidal Neovascularization/genetics , Female , Fundus Oculi , Humans , Male , Middle Aged , Retina/diagnostic imaging , Retina/pathology , Retinal Diseases/diagnosis , Retinal Diseases/pathology , Retinal Hemorrhage/etiology , Retinal Hemorrhage/pathology , Tomography, Optical Coherence , Visual AcuityABSTRACT
Kyoto University Substance (KUS) 121, an ATPase inhibitor of valosin-containing protein, is a novel neuroprotectant. We tested the safety and effectiveness of KUS121 in patients with acute central retinal artery occlusion (CRAO). We conducted an investigator-initiated, first-in-humans, phase 1/2 clinical trial. Nine patients with non-arteritic CRAO symptoms lasting for 4-48 h were enrolled. These patients received daily intravitreal injections of KUS121 for 3 days: 25 µg (low-dose) in the first three patients and 50 µg (high-dose) in the next six patients. The primary endpoint was the safety of the drug. As a secondary endpoint, pharmacokinetics was evaluated. Other key secondary endpoints were changes in best-corrected visual acuity (BCVA), measured using the Early Treatment Diabetic Retinopathy Study chart, visual field scores, and retinal sensitivities between baseline and week 12; and decimal BCVA at week 12. Administration of KUS121 did not result in serious adverse events. All nine patients (100%) showed significant improvement of BCVA. Average readable letter counts, visual field scores, and retinal sensitivities also improved. Decimal BCVA at week 12 was better than 0.1 in four patients (44%) and equal to or better than 0.05 in seven patients (78%). This first-in-humans clinical trial provides support for the safety and efficacy of intravitreal KUS121 injection. To substantiate the safety and effectiveness for patients with acute CRAO, further larger scale clinical studies will be needed.
Subject(s)
Neuroprotective Agents/therapeutic use , Retinal Artery Occlusion/drug therapy , Adult , Aged , Aged, 80 and over , Female , Humans , Macular Edema/drug therapy , Male , Middle Aged , Retina/drug effects , Retinal Vein Occlusion/drug therapy , Visual Acuity/drug effectsABSTRACT
Purpose: To elucidate the variant spectrum of the EYS gene in a large cohort of Japanese patients with autosomal recessive and simplex retinitis pigmentosa (arRP and sRP). Methods: We performed a direct sequencing analysis of 44 exons of the EYS gene in 469 patients with RP (including 144 arRP, 288 sRP, and 17 autosomal dominant RP (adRP) cases) in eastern and western regions of Japan and a multiplex ligation-dependent probe amplification (MLPA) of patients who had a single heterozygous pathogenic variant. Results: We identified six pathogenic and 16 likely pathogenic variants from a total of 186 nucleotide sequence variants, of which five variants, c.2528G>A (p.(Gly843Glu)), c.4957dupA (p.(Ser1653Lysfs*2)), c.6557G>A (p.(Gly2186Glu)), c.6563T>C (p.(Ile2188Thr)), and c.8868C>A (p.(Tyr2956*)), were prevalent in patients with arRP and sRP. The homozygous and heterozygous combinations of these five variants accounted for 32.4% (140/432) of Japanese patients with arRP and sRP. Five patients with adRP also had these variants. These five variants segregated with the phenotype in 15 families with RP. MLPA revealed seven copy number variations (CNVs) of the EYS exon(s). Conclusions: This study showed that five major sequence variants and CNVs in the EYS gene account for one-third of Japanese patients with arRP and sRP, and these variants are also responsible for RP showing an autosomal dominant inheritance pattern. This is the first report showing the pathogenicity of three missense variants (p.(Gly843Glu), p.(Gly2186Glu), and p.(Ile2188Thr)) and the presence of CNVs in the EYS gene of Japanese patients with arRP and sRP.
Subject(s)
Asian People/genetics , DNA Copy Number Variations/genetics , Eye Proteins/genetics , Genes, Recessive , Genetic Predisposition to Disease , Mutation/genetics , Retinitis Pigmentosa/genetics , Chromosome Segregation/genetics , Female , Heterozygote , Humans , Japan , Male , PedigreeABSTRACT
PURPOSE: To investigate whether the decorrelation stretching method can be used to reveal hidden information in color fundus photographs. METHODS: Five healthy subjects and 16 patients diagnosed with various eye diseases (five eyes with an epiretinal membrane, five eyes with geographic atrophy, five eyes with glaucoma, and one eye with pit-macular syndrome). Fundus photographs, obtained using a TRC-NW8F Plus Mydriatic/Non-Mydriatic Retinal Camera, were used for analyses, and the corresponding lesions were confirmed by other imaging modalities. Decorrelation stretching was performed using ImageJ. RESULTS: The decorrelation stretching method successfully enhanced color fundus photographs. In eyes with epiretinal membrane, retinal folds, and the irregular reflex of the macula were markedly enhanced. In eyes with geographic atrophy, the area of the retinal pigment epithelium atrophy was clearly delineated after decorrelation stretching. Images of a laminar defect and nerve fiber layer defect were emphasized in glaucoma. In pit-macular syndrome, the pit was enhanced as minor color changes in the disk rim. CONCLUSION: The decorrelation stretching method has the potential to reveal hidden information in a color fundus photograph. Decorrelation stretching can be a powerful tool in a clinical setting in which only color fundus photography is available.
Subject(s)
Diagnostic Techniques, Ophthalmological , Fundus Oculi , Glaucoma/diagnostic imaging , Image Processing, Computer-Assisted/methods , Photography/methods , Retinal Diseases/diagnostic imaging , Humans , Retrospective StudiesABSTRACT
PURPOSE: To assess changes in the posterior vitreous caused directly by phacoemulsification with implantation of an intraocular lens, using the enhanced vitreous swept-source optical coherence tomography system (Topcon, Tokyo, Japan). METHODS: Consecutive patients with cataract without posterior vitreous detachment were enrolled. Swept-source optical coherence tomography examinations were performed 1 day before and several days after surgery, using enhanced vitreous visualization. We compared preoperative and postoperative posterior vitreous status and measured the distance between the internal limiting membrane and the posterior vitreous membrane at 26 locations at the posterior pole. RESULTS: Images of 33 eyes (21 patients) could be analyzed. The perifoveal posterior vitreous detachment was not extended in any eyes, and the internal limiting membrane to posterior vitreous membrane distance before and after surgery did not differ at any location measured (P = 0.071-1.000). The posterior precortical vitreous pocket was dilated in three eyes. Age, gender, axial length, preoperative visual activity, nuclear sclerosis, duration of surgery, and duration between surgery and swept-source optical coherence tomography did not differ between the dilated vitreous pocket group (n = 3) and the unchanged group (n = 30). CONCLUSION: The height of the posterior vitreous membrane remained unchanged after surgery, although the posterior precortical vitreous pocket was dilated in three patients. Cataract surgery procedures seem to have little influence on the posterior vitreous membrane.
Subject(s)
Lens Implantation, Intraocular/adverse effects , Phacoemulsification/adverse effects , Tomography, Optical Coherence/methods , Vitreous Body/pathology , Vitreous Detachment/etiology , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Visual Acuity , Vitreous Body/diagnostic imagingABSTRACT
PURPOSE: To report cases that showed partition-like, dark areas in the cone mosaic on adaptive optics scanning laser ophthalmoscopy (AO-SLO) images in eyes with inner nuclear layer (INL) microcystic changes. METHODS: Eyes with INL microcystic changes were imaged by prototype AO-SLO. RESULTS: An eye with Leber hereditary optic neuropathy, an eye with traumatic optic neuropathy, and an eye with retinitis pigmentosa that showed microcystic lesions in the INL were imaged by AO-SLO. The images revealed characteristic, dark, partition-like lesions in the cone mosaic of all the eyes in areas where microcystic changes in the INL were shown by spectral domain optical coherence tomography. The AO-SLO findings in eyes with optic neuropathy were quite similar in shape and size to those seen in eyes with retinitis pigmentosa. CONCLUSION: We report cases that manifest dark, partition-like areas in the cone mosaic on AO-SLO images. Microcystic lesions in the INL may affect the images of the cone mosaic.
Subject(s)
Ophthalmoscopy/methods , Optic Atrophy/pathology , Retinitis Pigmentosa/pathology , Adult , Humans , Male , Middle Aged , Optic Atrophy, Hereditary, Leber/pathology , Young AdultABSTRACT
AIMS/HYPOTHESIS: In diabetic macular oedema (DMO), blood components passing through the disrupted blood-retinal barrier cause neuroinflammation, but the mechanism by which autoantibodies induce neuroglial dysfunction is unknown. The aim of this study was to identify a novel autoantibody and to evaluate its pathological effects on clinically relevant photoreceptor injuries. METHODS: Biochemical purification and subsequent peptide fingerprinting were applied to identify autoantigens. The titres of autoantibodies in DMO sera were quantified and their associations with clinical variables were evaluated. Two animal models (i.e. passive transfer of autoantibodies and active immunisation) were characterised with respect to autoimmune mechanisms underlying photoreceptor injuries. RESULTS: After screening serum IgG from individuals with DMO, fumarase, a Krebs cycle enzyme expressed in inner segments, was identified as an autoantigen. Serum levels of anti-fumarase IgG in participants with DMO were higher than those in diabetic participants without DMO (p < 0.001) and were related to photoreceptor damage and visual dysfunction. Passively transferred fumarase IgG from DMO sera in concert with complement impaired the function and structure of rodent photoreceptors. This was consistent with complement activation in the damaged photoreceptors of mice immunised with fumarase. Fumarase was recruited to the cell surface by complement and reacted to this autoantibody. Subsequently, combined administration of anti-fumarase antibody and complement elicited mitochondrial disruption and caspase-3 activation. CONCLUSIONS/INTERPRETATION: This study has identified anti-fumarase antibody as a serum biomarker and demonstrates that the generation of this autoantibody might be a pathological mechanism of autoimmune photoreceptor injuries in DMO.
Subject(s)
Autoantibodies/immunology , Diabetic Retinopathy/pathology , Fumarate Hydratase/immunology , Immunoglobulin G , Macular Edema/pathology , Photoreceptor Cells, Vertebrate/pathology , Diabetic Retinopathy/immunology , Female , Humans , Macular Edema/immunology , MaleABSTRACT
PURPOSE: To assess the efficacy and safety of sub-Tenon injection of triamcinolone acetonide (WP-0508ST) for the patients with diabetic macular edema (DME). METHODS: This multicenter, randomized, double-masked, comparative, controlled study was performed in 95 patients with DME. The patients were randomly divided into 20 mg WP-0508ST, 40 mg WP-0508ST, and control groups. RESULTS: A significant improvement in central macular thickness (CMT) was observed (p < 0.001) at 12 weeks after a single sub-Tenon injection of 20 mg WP-0508ST. The 40 mg group also demonstrated improvement in CMT, but the difference was not significant. In addition, the best-corrected visual acuity was improved in both the 20 mg and 40 mg groups at 12 weeks. The major side effects were increased intraocular pressure (9.4% in the 20 mg group and 13.3% in the 40 mg group) and lenticular opacity (6.3% in the 20 mg group and 10.0% in the 40 mg group). However, none of the patients with increased intraocular pressure required surgery. CONCLUSION: The efficacy and tolerability of WP-0508ST in the treatment of DME were confirmed, and 20 mg was determined to be the optimal dose.
Subject(s)
Diabetic Retinopathy/drug therapy , Fluorescein Angiography/methods , Macular Edema/drug therapy , Tomography, Optical Coherence/methods , Triamcinolone Acetonide/administration & dosage , Visual Acuity , Adult , Aged , Diabetic Retinopathy/complications , Diabetic Retinopathy/diagnosis , Dose-Response Relationship, Drug , Double-Blind Method , Female , Follow-Up Studies , Fundus Oculi , Glucocorticoids/administration & dosage , Humans , Injections, Intraocular , Macular Edema/diagnosis , Macular Edema/etiology , Male , Middle Aged , Tenon Capsule , Time Factors , Treatment OutcomeABSTRACT
AIMS: To assess the benefits of intensive statin therapy on reducing cardiovascular (CV) events in patients with type 2 diabetes complicated with hyperlipidaemia and retinopathy in a primary prevention setting in Japan. In the intension-to-treat population, intensive therapy [targeting LDL cholesterol <1.81 mmol/L (<70 mg/dL)] was no more effective than standard therapy [LDL cholesterol ≥2.59 to <3.10 mmol/L (≥100 to <120 mg/dL)]; however, after 3 years, the intergroup difference in LDL cholesterol was only 0.72 mmol/L (27.7 mg/dL), and targeted levels were achieved in <50% of patients. We hypothesized that the intergroup difference in CV events would have been statistically significant if more patients had been successfully treated to target. MATERIALS AND METHODS: This exploratory post hoc analysis focused on intergroup data from patients who achieved their target LDL cholesterol levels. The primary endpoint was the composite incidence of CV events. A Cox proportional hazards model was used to estimate hazard ratios (HRs) for incidence of the primary endpoint in patients who achieved target LDL cholesterol levels in each group. RESULTS: Data were analysed from 1909 patients (intensive: 703; standard: 1206) who achieved target LDL cholesterol levels. LDL cholesterol at 36 months was 1.54 ± 0.30 mmol/L (59.7 ± 11.6 mg/dL) in the intensive group and 2.77 ± 0.46 mmol/L (107.1 ± 17.8 mg/dL) in the standard group (P < 0.05). After adjusting for baseline prognostic factors, the composite incidence of CV events or deaths associated with CV events was significantly lower in the intensive than the standard group (HR 0.48; 95% confidence interval 0.28-0.82; P = 0.007). CONCLUSIONS: This post hoc analysis suggests that achieving LDL cholesterol target levels <1.81 mmol/L may more effectively reduce CV events than achieving target levels ≥2.59 to <3.10 mmol/L in patients with hypercholesterolaemia and diabetic retinopathy.
Subject(s)
Cardiovascular Diseases/prevention & control , Cholesterol, LDL/metabolism , Diabetes Mellitus, Type 2/metabolism , Diabetic Retinopathy/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hyperlipidemias/drug therapy , Aged , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/mortality , Diabetes Mellitus, Type 2/complications , Diabetic Retinopathy/etiology , Female , Glycated Hemoglobin/metabolism , Humans , Hyperlipidemias/complications , Hyperlipidemias/metabolism , Intention to Treat Analysis , Japan , Male , Middle Aged , Patient Care Planning , Primary Prevention , Proportional Hazards ModelsABSTRACT
Polypoidal choroidal vasculopathy (PCV) is a degenerative macular disease. The study determined the topographical concordance in the areal extent of PCV, defined by indocyanine green angiography (ICGA), and the corresponding outcomes from spectral-domain optical coherence tomography (SD-OCT) and microperimetry, in 25 individuals (25 eyes) who had undergone 3 months of anti-vascular endothelial growth factor treatment. The differential light sensitivity within 10° eccentricity was evaluated by Pattern Deviation probability analysis. The concordances and proportional areal extents of the abnormality for ICGA, SD-OCT and microperimetry were compared. The concordance in the areal extent between all three modalities was 59%. The median concordance between ICGA and microperimetry was 60%; between ICGA and SD-OCT, 70%; and between SD-OCT and microperimetry, 72%. SD-OCT and microperimetry each identified a greater areal extent (>20%) compared to ICGA in 13 and 19 eyes, respectively. A greater areal extent (>20%) was present in 9 eyes for microperimetry compared to SD-OCT and in 5 eyes for SD-OCT compared to microperimetry. SD-OCT and microperimetry each identified a greater area of abnormality than ICGA which supports the clinical utility of SD-OCT. Strong concordance was present between SD-OCT and microperimetry; however, microperimetry identified additional areas of functional abnormality.
Subject(s)
Choroidal Neovascularization/diagnostic imaging , Multimodal Imaging , Visual Field Tests , Aged , Aged, 80 and over , Female , Fluorescein Angiography , Humans , Indocyanine Green/metabolism , Male , Tomography, Optical CoherenceABSTRACT
[This corrects the article DOI: 10.1016/j.heliyon.2018.e00544.].
ABSTRACT
Lacrimal canaliculus (LC) has a key role in tear drainage, but it is difficult to evaluate the LC in detail, using the existing examinations. In this study, our novel LC imaging technique provided the high-resolution images of LC in a non-invasive manner. Three-dimensional images of LC were acquired via the palpebral conjunctiva from 20 healthy volunteers (20 eyes) and 10 patients with various lacrimal disorders (10 eyes), using optical coherence tomography (OCT) dacryography (OCTD). The LC images showed morphological differences between the vertical and horizontal segments. The function of LC could be evaluated by measuring the intralumen signal intensity over time after instillation of a contrast agent (2% rebamipide ophthalmic suspension). OCTD clearly visualised the blind extremity of the LC in four patients with punctal obstruction, which was useful for deciding the punctal incision location. In one patient with canalicular obstruction, contrast agent successfully highlighted the LC that had become narrow toward the site of obstruction. Significant differences were not found in the function and morphology of LC between the patients with NLDO and the healthy subjects. OCTD may be a useful tool for LC imaging, because it facilitates quantitative and simultaneous evaluation of LC morphology and function.
Subject(s)
Imaging, Three-Dimensional , Lacrimal Apparatus/diagnostic imaging , Tomography, Optical Coherence , Adult , Aged , Aged, 80 and over , Female , Healthy Volunteers , Humans , Lacrimal Apparatus/pathology , Lacrimal Apparatus/physiopathology , Lacrimal Duct Obstruction/diagnostic imaging , Lacrimal Duct Obstruction/pathology , Lacrimal Duct Obstruction/physiopathology , Male , Middle AgedABSTRACT
Age-related macular degeneration (AMD) is a leading cause of blindness among elderly people. The appearance of drusen is a clinical manifestation and a harbinger of both exudative and atrophic AMD. Recently, antibody-based medicines have been used to treat the exudative type. However, they do not restore good vision in patients. Moreover, no effective treatment is available for atrophic AMD. We have created small chemicals (Kyoto University Substances; KUSs) that act as ATP regulators inside cells. In the present study, we examined the in vivo efficacy of KUS121 in C-C chemokine receptor type 2-deficient mice, a mouse model of AMD. Systemic administration of KUS121 prevented or reduced drusen-like lesions and endoplasmic reticulum stress, and then substantially mitigated chorioretinal pathologies with significant preservation of visual function. Additionally, we confirmed that long-term oral administration of KUS121 caused no systemic complications in drusen-affected monkeys. ATP regulation by KUSs may represent a novel strategy in the treatment of drusen and prevention of disease progression in AMD.
ABSTRACT
Proliferative vitreoretinopathy (PVR) is a challenging pathological condition, often causing failure of retinal detachment surgery. The purpose of this study was to evaluate the feasibility of a delivery system of bioactive proteins using anionic and cationic gelatin microspheres and to establish a new PVR model in rabbits by intraocular sustained delivery of basic fibroblast growth factor (bFGF) and interferon-beta (IFNß). Anionic and cationic gelatin microspheres were prepared and immersed in bFGF and IFNß solution, respectively, to yield a polyion complex between gelatin matrix and a bioactive protein. The bFGF-impregnated microspheres were injected into the subretinal space in rabbit eyes. At week 2, the IFNß-impregnated microspheres also were injected into the same space. Control eyes received gelatin microspheres without bFGF or IFNß, or both. The eyes then were observed for 8â¯weeks by ophthalmoscopy, fundus photography, and fluorescein angiography. The eyes also were evaluated histologically. In the group with both bFGF and IFNß, the number of eyes with more severe PVR increased over time. Histologic examination showed retinal folds. In contrast, no proliferative changes were seen in any control groups. Subretinal implantation of bFGF and IFNß-impregnated gelatin microspheres induced reproducible PVR in rabbit eyes. This study guaranteed delivery of bioactive proteins with gelatin microspheres.
Subject(s)
Disease Models, Animal , Drug Delivery Systems/methods , Rabbits , Retina/drug effects , Vitreoretinopathy, Proliferative/chemically induced , Animals , Feasibility Studies , Fibroblast Growth Factor 2/administration & dosage , Fibroblast Growth Factor 2/toxicity , Gelatin/chemistry , Humans , Injections, Intraocular , Interferon-beta/administration & dosage , Interferon-beta/toxicity , Microspheres , Ophthalmoscopy , Recombinant Proteins/administration & dosage , Recombinant Proteins/toxicity , Reproducibility of Results , Retina/diagnostic imaging , Retina/pathology , Vitreoretinopathy, Proliferative/diagnostic imaging , Vitreoretinopathy, Proliferative/pathologyABSTRACT
OBJECTIVE: Diabetes is associated with high risk of cardiovascular (CV) events, particularly in patients with dyslipidemia and diabetic complications. We investigated the incidence of CV events with intensive or standard lipid-lowering therapy in patients with hypercholesterolemia, diabetic retinopathy, and no history of coronary artery disease (treat-to-target approach). RESEARCH DESIGN AND METHODS: In this multicenter, prospective, randomized, open-label, blinded end point study, eligible patients were randomly assigned (1:1) to intensive statin therapy targeting LDL cholesterol (LDL-C) <70 mg/dL (n = 2,518) or standard statin therapy targeting LDL-C 100-120 mg/dL (n = 2,524). RESULTS: Mean follow-up was 37 ± 13 months. LDL-C at 36 months was 76.5 ± 21.6 mg/dL in the intensive group and 104.1 ± 22.1 mg/dL in the standard group (P < 0.001). The primary end point events occurred in 129 intensive group patients and 153 standard group patients (hazard ratio [HR] 0.84 [95% CI 0.67-1.07]; P = 0.15). The relationship between the LDL-C difference in the two groups and the event reduction rate was consistent with primary prevention studies in patients with diabetes. Exploratory findings showed significantly fewer cerebral events in the intensive group (HR 0.52 [95% CI 0.31-0.88]; P = 0.01). Safety did not differ significantly between the two groups. CONCLUSIONS: We found no significant decrease in CV events or CV-associated deaths with intensive therapy, possibly because our between-group difference of LDL-C was lower than expected (27.7 mg/dL at 36 months of treatment). The potential benefit of achieving LDL-C <70 mg/dL in a treat-to-target strategy in high-risk patients deserves further investigation.
Subject(s)
Cardiovascular Diseases/epidemiology , Diabetic Retinopathy/epidemiology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hypercholesterolemia/drug therapy , Aged , Cardiovascular Diseases/blood , Cholesterol, LDL/blood , Comorbidity , Diabetic Retinopathy/blood , Diabetic Retinopathy/complications , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/blood , Hypercholesterolemia/blood , Hypercholesterolemia/epidemiology , Incidence , Japan/epidemiology , Male , Middle Aged , Prospective StudiesABSTRACT
Retinal neuronal cell death underlies many incurable eye diseases such as retinitis pigmentosa (RP) and glaucoma, and causes adult blindness. We have shown that maintenance of ATP levels via inhibiting ATP consumption is a promising strategy for preventing neuronal cell death. Here, we show that branched chain amino acids (BCAAs) are able to increase ATP production by enhancing glycolysis. In cell culture, supplementation of the culture media with BCAAs, but not glucose alone, enhanced cellular ATP levels, which was canceled by a glycolysis inhibitor. Administration of BCAAs to RP mouse models, rd10 and rd12, significantly attenuated photoreceptor cell death morphologically and functionally, even when administration was started at later stages. Administration of BCAAs in a glaucoma mouse model also showed significant attenuation of retinal ganglion cell death. These results suggest that administration of BCAAs could contribute to a comprehensive therapeutic strategy for retinal neurodegenerative diseases such as RP and glaucoma.
ABSTRACT
Myopia is increasing rapidly worldwide. We performed a cross-sectional study to investigate the prevalence of posterior staphyloma, a complication of myopia, and its shape characteristics in relation to age, sex, and axial length (AL) in a Japanese community-based cohort. The right eyes of 3748 participants who underwent fundus photography and optical coherence tomography (OCT) examination were evaluated. Posterior staphyloma prevalence was evaluated using fundus photographs and OCT images. Furthermore, fundus shapes were analyzed by measuring local fundus curvatures on 6 mm cross-line OCT images at intervals of 1 µm. The mean and variance of the curvatures were calculated to represent the fundus shape of each eye for investigation of the relationship between fundus curvature and age, sex, and AL. Seventy-seven eyes (2.05%) had posterior staphyloma. The mean and variance of the fundus curvatures were significantly greater in women than in men and became greater with age, suggesting that the shape of the staphyloma was steeper and less smooth in women and elderly subjects. AL and mean curvature showed a significant correlation (P = 2 × 10-16, R = 0.480), which was significantly affected by age (P < 2 × 10-16). Quantitative analysis of fundus shapes was useful for statistical analysis of posterior staphyloma in relation to age, sex, and AL.
Subject(s)
Myopia, Degenerative/epidemiology , Adult , Aged , Area Under Curve , Axial Length, Eye/diagnostic imaging , Axial Length, Eye/physiology , Cross-Sectional Studies , Female , Humans , Japan/epidemiology , Male , Middle Aged , Myopia, Degenerative/pathology , Photography , Prevalence , ROC Curve , Tomography, Optical CoherenceABSTRACT
Bietti's crystalline dystrophy (BCD) is an intractable and progressive chorioretinal degenerative disease caused by mutations in the CYP4V2 gene, resulting in blindness in most patients. Although we and others have shown that retinal pigment epithelium (RPE) cells are primarily impaired in patients with BCD, the underlying mechanisms of RPE cell damage are still unclear because we lack access to appropriate disease models and to lesion-affected cells from patients with BCD. Here, we generated human RPE cells from induced pluripotent stem cells (iPSCs) derived from patients with BCD carrying a CYP4V2 mutation and successfully established an in vitro model of BCD, i.e., BCD patient-specific iPSC-RPE cells. In this model, RPE cells showed degenerative changes of vacuolated cytoplasm similar to those in postmortem specimens from patients with BCD. BCD iPSC-RPE cells exhibited lysosomal dysfunction and impairment of autophagy flux, followed by cell death. Lipidomic analyses revealed the accumulation of glucosylceramide and free cholesterol in BCD-affected cells. Notably, we found that reducing free cholesterol by cyclodextrins or δ-tocopherol in RPE cells rescued BCD phenotypes, whereas glucosylceramide reduction did not affect the BCD phenotype. Our data provide evidence that reducing intracellular free cholesterol may have therapeutic efficacy in patients with BCD.