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Hip fractures are fragility fractures frequently seen in persons over 80-years-old. Although various factors, including decreased bone mineral density and a history of falls, are reported as hip fracture risks, few large-scale studies have confirmed their relevance to individuals older than 80, and tools to assess contributions of various risks to fracture development and the degree of risk are lacking. We recruited 1395 fresh hip fracture patients and 1075 controls without hip fractures and comprehensively evaluated various reported risk factors and their association with hip fracture development. We initially constructed a predictive model using Extreme Gradient Boosting (XGBoost), a machine learning algorithm, incorporating all 40 variables and evaluated the model's performance using the area under the receiver operating characteristic curve (AUC), yielding a value of 0.87. We also employed SHapley Additive exPlanation (SHAP) values to evaluate each feature importance and ranked the top 20. We then used a stepwise selection method to determine key factors sequentially until the AUC reached a plateau nearly equal to that of all variables and identified the top 10 sufficient to evaluate hip fracture risk. For each, we determined the cutoff value for hip fracture occurrence and calculated scores of each variable based on the respective feature importance. Individual scores were: serum 25(OH)D levels (<10 ng/ml, score 7), femoral neck T-score (<-3, score 5), Barthel index score (<100, score 3), maximal handgrip strength (<18 kg, score 3), GLFS-25 score (≥24, score 2), number of falls in previous 12 months (≥3, score 2), serum IGF-1 levels (<50 ng/ml, score 2), cups of tea/day (≥5, score -2), use of anti-osteoporosis drugs (yes, score -2), and BMI (<18.5 kg/m 2 , score 1). Using these scores, we performed receiver operating characteristic (ROC) analysis and the resultant optimal cutoff value was 7, with a specificity of 0.78, sensitivity of 0.75, and AUC of 0.85. These ten factors and the scoring system may represent tools useful to predict hip fracture., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: Oxidative stress is considered one of the etiologic factors involved in ulcerative colitis (UC), yet there is limited epidemiologic information regarding the relationship between antioxidant intake and the risk of UC. The aim of the present case-control study in Japan was to examine the association between intake of green and yellow vegetables, other vegetables, fruit, vitamin C, vitamin E, retinol, alpha-carotene, beta-carotene, and cryptoxanthin and UC risk., Methods: A total of 384 cases within 4 y of diagnosis with UC and 665 controls were included in the study. Data on dietary intake and confounders were obtained using a self-reported questionnaire. Information on dietary factors was collected using a 169-item semiquantitative food-frequency questionnaire. Adjustment was made for sex, age, pack-y of smoking, alcohol consumption, history of appendicitis, family history of UC, education level, and body mass index., Results: Higher intake levels of other vegetables, vitamin C, and retinol were independently associated with a reduced risk of UC. The adjusted odds ratio between extreme quartiles was 0.51 (95% confidence interval [CI], 0.34-0.76; P for trend ≤ 0.001) for other vegetables, 0.45 (95% CI, 0.30-0.69, P for trend ≤ 0.001) for vitamin C, and 0.64 (95% CI, 0.43-0.95, P for trend = 0.04) for retinol. There were no associations between intake of green and yellow vegetables, fruit, vitamin E, alpha-carotene, beta-carotene, or cryptoxanthin and UC risk (P for trend = 0.29, 0.56, 0.89, 0.20, 0.69, and 0.22, respectively)., Conclusions: Intake of other vegetables, vitamin C, and retinol was inversely associated with UC risk., Competing Interests: Declaration of Competing Interest All authors have no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the corticospinal tract and leading to motor neuron death. According to a recent study, magnetic resonance imaging-visible changes suggestive of neurodegeneration seem absent in the motor cortex of G93A-SOD1 ALS mice. However, it has not yet been ascertained whether the cortical neural activity is intact, or alterations are present, perhaps even from an early stage. Here, cortical neurons from this model were isolated at post-natal day 1 and cultured on multielectrode arrays. Their activity was studied with a comprehensive pool of neurophysiological analyses probing excitability, criticality and network architecture, alongside immunocytochemistry and molecular investigations. Significant hyperexcitability was visible through increased network firing rate and bursting, whereas topological changes in the synchronization patterns were apparently absent. The number of dendritic spines was increased, accompanied by elevated transcriptional levels of the DLG4 gene, NMDA receptor 1 and the early pro-apoptotic APAF1 gene. The extracellular Na + , Ca 2+ , K + and Cl - concentrations were elevated, pointing to perturbations in the culture micro-environment. Our findings highlight remarkable early changes in ALS cortical neuron activity and physiology. These changes suggest that the causative factors of hyperexcitability and associated toxicity could become established much earlier than the appearance of disease symptoms, with implications for the discovery of new hypothetical therapeutic targets., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

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 (IFNβ). Anionic and cationic gelatin microspheres were prepared and immersed in bFGF and IFNβ 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 IFNβ-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 8 weeks by ophthalmoscopy, fundus photography, and fluorescein angiography. The eyes also were evaluated histologically. In the group with both bFGF and IFNβ, 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 IFNβ-impregnated gelatin microspheres induced reproducible PVR in rabbit eyes. This study guaranteed delivery of bioactive proteins with gelatin microspheres., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Functional and morphological changes in C-fiber bladder afferent pathways are reportedly involved in neurogenic detrusor overactivity (NDO) after spinal cord injury (SCI). This study examined the morphological changes in different populations of bladder afferent neurons after SCI using replication-defective herpes simplex virus (HSV) vectors encoding the mCherry reporter driven by neuronal cell-type-specific promoters. Spinal intact (SI) and SCI mice were injected into the bladder wall with HSV mCherry vectors driven by the cytomegalovirus (CMV) promoter, CGRP promoter, TRPV1 promoter or neurofilament 200 (NF200) promoter. Two weeks after vector inoculation into the bladder wall, L1 and L6 dorsal root ganglia (DRG) were removed bilaterally for immunofluorescent staining using anti-mCherry antibody. The number of CMV promoter vector-labeled neurons was not altered after SCI. The number of CGRP and TRPV1 promoter vector-labeled neurons was significantly increased whereas the number of NF200 vector-labeled neurons was decreased in L6 DRG after SCI. The median size of CGRP promoter-labeled C-fiber neurons was increased from 247.0 in SI mice to 271.3μm 2 in SCI mice whereas the median cell size of TRPV1 promoter vector-labeled neurons was decreased from 245.2 in SI mice to 216.5μm 2 in SCI mice. CGRP and TRPV1 mRNA levels of laser-captured bladder afferent neurons labeled with Fast Blue were significantly increased in SCI mice compared to SI mice. Thus, using a novel HSV vector-mediated neuronal labeling technique, we found that SCI induces expansion of the CGRP- and TRPV1-expressing C-fiber cell population, which could contribute to C-fiber afferent hyperexcitability and NDO after SCI., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)

Purpose: To investigate photoreceptor changes in eyes with glaucoma., Design: Cross-sectional study., Methods: The study included 35 eyes of 35 patients with primary open-angle glaucoma who had suffered parafoveal visual field loss at least 3 years previously, as well as 21 eyes of 21 normal subjects. Eyes with an axial length ≥26.0 mm were excluded. All subjects underwent a full ophthalmologic examination, including spectral-domain optical coherence tomography (SDOCT) and prototype adaptive-optics scanning laser ophthalmoscopy (AO-SLO) imaging., Results: As determined using AO-SLO, eyes with glaucoma did not differ significantly from normal eyes in terms of either cone density (26 468 ± 3392 cones/m 2 vs 26 147 ± 2700 cones/m 2 , respectively; P = .77; measured 0.5 mm from the foveal center) or cone spatial organization (ratio of hexagonal Voronoi domain: 43.7% ± 4.4% vs 44.3% ± 4.9%; P = .76; measured 0.5 mm from the foveal center). Furthermore, SDOCT showed that the 2 groups did not differ significantly in terms of the photoreceptor-related layer thickness, and that the photoreceptor ellipsoid zone band was continuous in all normal and glaucoma eyes. In glaucoma eyes with vertically asymmetric severity, the more affected side did not significantly differ from the less affected side in terms of cone density, cone spatial organization, or photoreceptor-related layer thickness. In 8 eyes (22.9%) with glaucoma, dark, partition-like areas surrounded the cones on the AO-SLO., Conclusions: Both AO-SLO and SDOCT showed cone integrity in eyes with glaucoma, even in areas with visual field and nerve fiber loss. In AO-SLO, microcystic lesions in the inner nuclear layer may influence images of the cone mosaic., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To investigate the choroidal vascular structural changes in eyes with central serous chorioretinopathy (CSC) by using swept-source optical coherence tomography (SS-OCT)., Design: Prospective cross-sectional study., Methods: We prospectively examined 40 eyes of 34 consecutive patients with CSC. Three-dimensional choroidal images of the macular area, covering 3 × 3 mm and 6 × 6 mm, were obtained with SS-OCT. En face images of the microvasculature of the inner choroid and large choroidal vessel layers were converted to binary images. Choroidal vascular areas were analyzed quantitatively using the binary images., Results: The choroidal vascular area was larger in eyes with CSC (the microvasculature of the inner choroid: 53.4% ± 2.4%, P = .028; 3 × 3-mm large choroidal vessels: 66.9% ± 7.1%, P < .001; and 6 × 6-mm large choroidal vessels: 64.8% ± 7.3%, P < .001) than in age-matched normal eyes (52.2% ± 1.8%, 54.9% ± 4.4%, and 53.8% ± 4.3%, respectively). The choroidal vascular area at the microvasculature of the inner choroid level was larger in multifocal posterior pigment epitheliopathy (55.8% ± 2.2%) than in classic CSC (53.1% ± 2.1%, P = .038) and in diffuse retinal pigment epitheliopathy (52.9% ± 2.6%, P = .042). The subfoveal choroidal thickness was significantly associated with the choroidal vascular area at the level of large choroidal vessels (P < .001)., Conclusions: Increased choroidal vascular area was observed in the whole macula area in eyes with CSC. This finding suggests that CSC may originate from a choroidal circulatory disturbance., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To define a minimum set of outcome measures for tracking, comparing, and improving macular degeneration care., Design: Recommendations from a working group of international experts in macular degeneration outcomes registry development and patient advocates, facilitated by the International Consortium for Health Outcomes Measurement (ICHOM)., Methods: Modified Delphi technique, supported by structured teleconferences, followed by online surveys to drive consensus decisions. Potential outcomes were identified through literature review of outcomes collected in existing registries and reported in major clinical trials. Outcomes were refined by the working group and selected based on impact on patients, relationship to good clinical care, and feasibility of measurement in routine clinical practice., Results: Standardized measurement of the following outcomes is recommended: visual functioning and quality of life (distance visual acuity, mobility and independence, emotional well-being, reading and accessing information); number of treatments; complications of treatment; and disease control. Proposed data collection sources include administrative data, clinical data during routine clinical visits, and patient-reported sources annually. Recording the following clinical characteristics is recommended to enable risk adjustment: age; sex; ethnicity; smoking status; baseline visual acuity in both eyes; type of macular degeneration; presence of geographic atrophy, subretinal fibrosis, or pigment epithelial detachment; previous macular degeneration treatment; ocular comorbidities., Conclusions: The recommended minimum outcomes and pragmatic reporting standards should enable standardized, meaningful assessments and comparisons of macular degeneration treatment outcomes. Adoption could accelerate global improvements in standardized data gathering and reporting of patient-centered outcomes. This can facilitate informed decisions by patients and health care providers, plus allow long-term monitoring of aggregate data, ultimately improving understanding of disease progression and treatment responses., (Published by Elsevier Inc.)

Purpose: To investigate microcirculation of peripapillary retina and optic disc in eyes with primary open-angle glaucoma (POAG) and hemifield visual field (VF) defects., Design: Prospective observational case series with normal comparison group., Methods: Sixty eyes with POAG (41 with superior and 19 with inferior hemifield VF defects) and 21 normal eyes were included in this study. Optical coherence tomography (OCT) angiography was used to acquire 3 × 3-mm optic disc cubes, and circumpapillary retinal nerve fiber layer thickness was also measured using OCT. Vessel densities in the peripapillary superficial retina and whole-signal-mode optic disc were individually analyzed based on the sectorial division., Results: The peripapillary vessel densities were significantly reduced at the corresponding location of the VF defects in both non-highly myopic (P < .001, P = .006) and highly myopic glaucomatous eyes (P < .001, P = .005) compared with the normal eyes. Vessel densities of the optic discs were significantly reduced at locations corresponding to the VF defects in eyes without high myopia but with inferior hemifield VF defects (P = .006), but not in the other eyes. The vessel densities in the peripapillary retina were significantly associated with visual field total deviation values at their corresponding sides. The choroidal microvascular reduction in the peripapillary area extended to the α-peripapillary atrophy (PPA) as well as β-PPA zones., Conclusions: Microvascular reduction was associated with VF defects in a region-specific manner: significantly and partially in the peripapillary retina and optic disc, respectively., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To quantify the area of photoreceptor damage surrounding geographic atrophy (GA) and evaluate the relationship between structural abnormalities and retinal function in eyes with GA., Design: Prospective cross-sectional study., Methods: Twenty-five eyes of 25 patients with GA associated with age-related macular degeneration underwent a full ophthalmologic examination, including spectral-domain optical coherence tomography (SDOCT), fundus autofluorescence (FAF), and microperimetry. ImageJ software was used to quantify the disruption of the ellipsoid zone on SDOCT images. Hypofluorescent areas of the FAF images indicated areas of retinal pigment epithelium (RPE) loss. Areas of interest graded by SDOCT (photoreceptor damage) and FAF (RPE loss) were registered with microperimetry within a 6-mm circle centered on the fovea., Results: The mean area of photoreceptor damage was 7.69 ± 5.36 mm(2), which was significantly greater than the mean area of RPE loss (4.57 ± 4.07 mm(2), P < .001). The average retinal sensitivity of the area with photoreceptor damage outside the area of RPE loss was lower than that of the area without photoreceptor damage (6.57 ± 4.13 dB vs 11.27 ± 3.78 dB, P < .001). The area of photoreceptor damage surrounding the area of RPE loss was larger in eyes with pseudodrusen than in eyes without pseudodrusen (4.96 mm(2) vs 1.91 mm(2), P = .008). The only significant predictor of decreased retinal sensitivity was the area of the photoreceptor damage (P < .001)., Conclusions: Widespread photoreceptor damage surrounding sites of RPE loss occurred in eyes with GA, and it correlated with visual function. Evaluation of photoreceptor damage surrounding sites of RPE loss using OCT is important in patients with GA associated with AMD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To report novel vitreous body microarchitecture findings using high-resolution spectral-domain optical coherence tomography (HR-SD-OCT)., Design: Prospective, cross-sectional study., Methods: Horizontal and vertical retinal cross-sectional images that were 10 mm long were acquired from 17 eyes of 17 young healthy volunteers using HR-SD-OCT with enhanced vitreous imaging (EVI). Images were acquired through the fovea, upper vessel arcade, and lower vessel arcade., Results: Three new findings on vitreous body microarchitecture were found. First, material located between the retina and posterior vitreous cortex was easily detected in 90% of upper and lower vessel arcade scans. Most scans contained hyperreflective dots and multilayered hyperreflective lines around the detached vitreous cortex. Second, a lamellar structure was observed in the vitreous body in 70%-80% of all scans, excluding vertical scans of the upper arcade vessel area. Third, tubular zones of hypodensity were detected in >80% of scans, excluding horizontal scans of the macula. Interestingly, the location of tubular zones of hypodensity seemed to correspond with the location of retinal vessels. Subject age, refractive error, and axial length were not significantly different in scans with and without material between the retina and vitreous, lamellar structures, and tubular zones of hypodensity., Conclusions: The microarchitecture of the vitreous body can be visualized using HR-SD-OCT and EVI., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To assess whether optical coherence tomography angiography (OCTA) can be used as an alternative to conventional fundus fluorescein angiography (FFA) for the detection of myopic choroidal neovascularization (CNV)., Design: Validity and reliability analysis., Methods: Twenty-eight eyes of 26 consecutive Japanese patients with exudative lesions associated with pathologic myopia were included in this institutional study. Myopic CNV was detected in 23 eyes of 22 patients; 5 eyes exhibited simple hemorrhage. The main outcome measure was CNV detection by OCTA and FFA. The CNV area was individually measured by FFA and OCTA. Intraclass correlation coefficients (ICCs) for the CNV area, independently measured by 2 investigators using OCTA and FFA, were determined., Results: OCTA images with sufficient quality for CNV assessment were obtained for 17 eyes with CNV and 4 without. FFA alone detected CNV in all 17 eyes, while OCTA alone detected CNV in 16 (94.1%). The 1 eye for which CNV was not detected by OCTA exhibited a 0.01 mm(2) area on FFA. Both FFA and OCTA did not detect CNV in eyes with simple hemorrhage. The mean CNV areas on FFA and OCTA were 0.59 ± 0.56 mm(2) and 0.51 ± 0.55 mm(2), respectively; the 2 values were significantly correlated (P < .001, r = .86). The ICC (2, 1) values for FFA and OCTA were 0.944 and 0.997, respectively., Conclusions: Our results indicate that OCTA can detect most myopic CNVs if high-quality images are acquired and can preclude the requirement for FFA in these settings., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To investigate the time-dependent changes in expression of cytokines that characterizes the spontaneous recovery of reflex voiding after spinal cord injury (SCI). SCI is known to reorganize the neural circuitry of micturition reflex after injury., Methods: Under isoflurane anesthesia, spinal cord of 18 adult female Sprague-Dawley rats was completely transected at the Th9-10 level. Awake cystometry was performed at each time point on controls and 6 SCI animals, and bladder was then harvested for analysis of 29 proteins Millipore kit or enzyme-linked immunosorbent assay. Prophylactic dose of ampicillin 100 mg/kg was administered periodically to all SCI animals., Results: Spontaneous recovery of voiding after SCI at 12 weeks was evident from increased intercontractile interval and voiding efficiency during cystometry. Expression of proinflammatory interleukins ([IL] IL-1α and IL-1β, IL-2, IL-5, IL-6, IL-18, tumor necrosis factor alpha [TNF-α]) and CXC chemokines (CXCL1, CXCL2, CXCL10), CX3CL1, and CCL2 showed significant elevation at 4 and at 8 weeks with slight decrease at 12 weeks. In contrast, expression of anti-inflammatory IL-10 and neuroprotective factors, CXCL-5, and leptin, was elevated at 8 and at 12 weeks (P < .05). In contrast, expression of CCL3, CCL5, and growth factors (vascular endothelial growth factor, nerve growth factor, epidermal growth factor, granulocyte colony-stimulating factor, and granulocyte macrophage colony-stimulating factor) did not show any significant temporal change after SCI., Conclusion: Spontaneous recovery of reflex voiding at 12 weeks was marked by increased endogenous expression of anti-inflammatory cytokine IL-10 and neuroprotective factors, CXCL-5, and leptin, which suggests that pharmacological suppression of inflammation, can hasten the emergence of reflex voiding after SCI., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To investigate the risk factors for development and progression of retinal pigment epithelial (RPE) atrophy during ranibizumab treatment for neovascular age-related macular degeneration (AMD) in Japanese patients., Design: Retrospective interventional case series., Methods: This study included 195 eyes with treatment-naïve subfoveal neovascular AMD. All patients were treated with an as-needed regimen after 3 monthly ranibizumab treatments. Color fundus photography, spectral-domain optical coherence tomography, and fundus autofluorescence were evaluated for RPE atrophy diagnosis. Baseline characteristics and ARMS2 A69S and CFH I62V polymorphisms were analyzed for their association with development and progression of RPE atrophy., Results: Ten of 195 eyes (5.1%) had RPE atrophy at baseline; 3 had typical AMD and 7 had polypoidal choroidal vasculopathy (PCV). Among 185 eyes without preexisting RPE atrophy at baseline, 7 (3.8%) developed RPE atrophy at 12 months and 10 (5.4%) during the mean follow-up of 26.7 months. The incidence of newly developed RPE atrophy was lower in PCV than in typical AMD (P = .036), while the progression of the RPE atrophy area was faster in typical AMD than in PCV (0.57 ± 0.35 and 0.31 ± 0.13 mm/year, respectively; P = .018). The ARMS2 A69S and CFH I62V polymorphisms were significantly associated with the baseline RPE atrophy (P = .014 and P = .009, respectively)., Conclusions: The RPE atrophy developed in 5.4% of eyes with neovascular AMD during the 26.7 months of ranibizumab treatment. When compared with white individuals, RPE atrophy developed less frequently in Japanese patients, but the progression rate was similar. The subtype of AMD thus affects the development of RPE atrophy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To evaluate photoreceptors in Bietti crystalline dystrophy patients with CYP4V2 mutations using high-resolution images of the macula obtained with adaptive optics scanning laser ophthalmoscopy (AO-SLO)., Design: Prospective observational case series with comparison to healthy controls., Methods: Seven eyes of 7 Bietti crystalline dystrophy patients with CYP4V2 mutations and 12 normal eyes of 12 age- and axial length-matched healthy volunteers were studied. All participants underwent ophthalmologic examinations and AO-SLO assessments. All patients underwent spectral-domain optical coherence tomography, fundus autofluorescence, Humphrey field analysis, and electroretinography. AO-SLO images were analyzed 0.5 mm and 1.0 mm from the center of the fovea in the superior, inferior, nasal, and temporal quadrants., Results: Mean ± standard deviation cone density (cells/mm(2)) 0.5 mm from the center of the fovea was 17,209 ± 2276 in patients and 20 493 ± 2758 in controls, which was statistically different (P = .001); however, mean cone density 1.0 mm from the center of the fovea was 15 685 ± 2302 in patients and 15 705 ± 1848 in controls, which was not statistically different (P = .20). There was no correlation between cone density and mean deviation measured using a Humphrey field analysis or visual acuity in patients., Conclusions: In Bietti crystalline dystrophy patients with CYP4V2 mutations, cone density remained for visual dysfunction by evaluation using high-resolution AO-SLO. These findings support the theory that disorder of the retinal pigment epithelium and the photoreceptors in the patients are the primary and secondary pathologic changes, respectively. This is consistent with results from previous basic studies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To investigate whether the photoreceptor layer status of the detached retina, which has the potential to plug the macular hole (MH), can predict postoperative visual acuity (VA)., Design: Retrospective, consecutive, observational case series., Methods: A consecutive series of 48 eyes in 48 patients with surgically closed MHs were recruited into the study. Spectral-domain optical coherence tomography (SD OCT) images were obtained preoperatively and postoperatively. Length gaps between photoreceptor layers and the preoperative diameter of the basal MH in the detached part of the retina was calculated for the photoreceptor outer segment (OS) and the external limiting membrane (ELM). The postoperative photoreceptor layer status at the fovea, including continuity of the ELM line, inner segment ellipsoid line (ISe), and cone outer segment tip (COST) line, was categorized by graders., Results: The preoperative OS gap length and ELM gap length correlated significantly with postoperative VA. A larger OS or ELM gap length was associated with a more severe postoperative photoreceptor layer status. Eyes with a moderately reflective lesion had a significantly longer OS gap length and ELM gap length, significantly worse postoperative VA, and more severe photoreceptor layer status than did eyes without such a moderately reflective lesion. Eyes with a better postoperative COST status had significantly better postoperative VA (P = .0465)., Conclusions: OS and ELM gap length, which represent the degree of insufficiency of MH plugging, was strongly correlated with postoperative VA; moreover, these preoperative parameters were associated with the postoperative photoreceptor layer status, including glial cell proliferation., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Vascular endothelial cells can absorb higher radiation doses than any other tissue in the body, and post-radiation impaired endothelial nitric oxide synthase (eNOS) function may be developed as a potential contributor to the pathogenesis of vascular injury. In this study, we investigated early alterations of eNOS signaling in human umbilical venous endothelial cells (HUVECs) exposed to X-ray radiation. We found that ionizing radiation increased eNOS phosphorylation at Ser-1177 and dephosphorylation at Thr-495 in HUVECs in a dose-dependent (≤ 20 Gy) and time-dependent (6-72 h) manner. The total expression levels of eNOS were unchanged by radiation. Although a transient but significant increase in extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation and a biphasic decline in Akt phosphorylation were observed after irradiation, these inhibitors were without effect on the radiation-induced changes in eNOS phosphorylation. There was an increase in protein kinase C-βII (PKC-βII) expression and the ablation of PKC-βII by small interfering RNA (siRNA) negated the radiation effect on the two eNOS phosphorylation events. Furthermore, when the radiation-induced increase in reactive oxygen species (ROS) generation was prevented by the anti-oxidant N-acetyl-L-cysteine, eNOS Ser-1177 phosphorylation and Thr-495 dephosphorylation in irradiated HUVECs were significantly reduced. However, transfection of PKC-β siRNA did not alter ROS production after irradiation, and NAC failed to block the radiation-induced increase in PKC-βII expression. Taken together, our results suggest that ionizing radiation-induced eNOS activation in human vascular endothelial cells is attributed to both the up-regulation of PKC-βII and the increase in ROS generation which were independent of each other., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To investigate the voiding function in a rat model of lumbar canal stenosis (LCS) using pharmacologic and molecular approaches., Methods: Sixty-one female Sprague-Dawley rats were broadly split into a sham and an LCS group. A hole was surgically drilled in the L5-L6 epidural space and filled with a rectangular piece of silicone rubber. Metabolic cage study at week 2 and continuous cystometry (CMG) under urethane anesthesia at weeks 2 and 4 were performed. During CMG, prostaglandin E2 or sulprostone, an prostaglandin E receptor 1 and prostaglandin E receptor 3 agonist was administered locally and intravenously, respectively, and the bladder was then harvested for histology and Western blot., Results: Compared with sham, the LCS group showed dribbling urination and progressive increase in bladder size. CMG under urethane anesthesia in the LCS group was marked by overflow incontinence and acontractile bladder. Administration of intravesical prostaglandin E2 (200 μM) or intravenous sulprostone (0.1 mg/kg) in the sham group induced bladder overactivity, but decreased the compliance and failed to restore the bladder emptying function in the LCS group. The LCS group showed edematous changes and muscle thinning at week 2, which were partially restored by week 4. Histologic changes were accompanied by downregulation of agrin protein (64.0%) at week 2 and upregulation of M2 receptor (65.4%) at week 4. Expression of M3, protein gene product 9.5, and nerve growth factor did not differ between groups., Conclusion: LCS-induced underactive bladder is associated with altered expression of agrin and M2 receptor. The underactive bladder model is clinically relevant, and the findings indicate potential molecular targets for new therapies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To investigate the efficacy of periodic injection of aflibercept in each subtype of age-related macular degeneration (AMD) and to explore the predictive factors for visual outcome in clinical settings., Design: Prospective nonrandomized interventional case series., Methods: Patients with AMD were recruited and were administered aflibercept injections once a month for 3 months followed by once every 2 months for 8 months. The logarithm of the minimal angle of resolution (logMAR) at 12 months and improvement of vision from baseline were compared among polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and typical AMD. Regression rate of polypoidal lesions was assessed. We also performed regression analysis with logMAR at 12 months as the dependent variable., Results: The study sample consisted of 98 patients: 46 had typical AMD, 42 had PCV, and 10 had RAP. Mean logMAR improved from 0.36 to 0.21 in 12 months. While there was no difference in visual improvement between typical AMD and PCV, final logMAR was better in PCV (0.32 ± 0.09 vs 0.08 ± 0.04, P = .016). Thirty-nine PCV patients underwent follow-up angiography, and regression of polyps was observed in 27 cases (69.2%). Multiple regression analysis showed that the presence of external limiting membrane (ELM), smaller greatest linear dimension, and the presence of polypoidal lesion were associated with better visual outcome (R(2) = 0.53, P = 2.73 × 10(-14))., Conclusions: Periodic injection of aflibercept is effective for PCV as well as for typical AMD. The statuses of ELM, greatest linear dimension, and polypoidal lesion are predictive for visual outcome., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Neural cross-sensitization has been postulated as a mechanism underlying overlaps of chronic pelvic pain disorders such as bladder pain syndrome/interstitial cystitis (BPS/IC) and irritable bowel syndrome (IBS). Animals with experimental colitis have been used to study the underlying mechanisms for overlapped pelvic pain symptoms, and shown to exhibit bladder overactivity evidenced by frequent voiding; however, it has not directly been evaluated whether pain sensation derived from the lower urinary tract is enhanced in colitis models. Also, the cross-sensitization between the colon and urethra has not been studied previously. In the present study, we therefore investigated pain behaviors induced by nociceptive stimuli in the lower urinary tract and the involvement of C-fiber afferent pathways using rats with colitis induced by intracolonic application of 2,4,6-trinitrobenzenesulfonic acid (TNBS). In TNBS-induced colitis rats at 10 days, intravesical application of resiniferatoxin (RTx) induced a significantly greater number of episodes of both licking and freezing behaviors, which were reduced by capsaicin-sensitive C-fiber afferent desensitization. Histochemical studies using fluorescent dye tracers injected into the colon, bladder or urethra showed that dichotomized afferent neurons comprised 6.9-14.5% of L1, L6 and S1 dorsal root ganglion (DRG) neurons innervating the colon or the lower urinary tract. Transient receptor potential vanilloid 1 (TRPV1) mRNA expression was significantly increased in, the bladder, urethra and S1 DRG in colitis rats. An increase in myeloperoxidase (MPO) activity was found in the colon, but not in the bladder or urethra after intracolonic TNBS treatment. These results indicate that TNBS-induced colitis increased pain sensitivity in the bladder and urethra via activation of C-fiber afferent pathways due to colon-to-bladder and colon-to-urethral cross-sensitization, suggesting the contribution of pelvic organ cross-sensitization mechanisms to overlapped pain symptoms in BPS/IC and IBS., (Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.)

Purpose: To determine if asymmetry in thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer, ganglion cell complex, and total retina between upper and lower macula halves can predict glaucoma., Design: Retrospective case-control series., Methods: One hundred twenty-two eyes of 122 patients (30 normal eyes and 30 preperimetric, 31 early, and 31 advanced glaucoma eyes) were studied. The RNFL, ganglion cell layer, ganglion cell complex, and total retina were segmented and measured on 10 vertical B-scans over a 30 × 15 degree macular area. The equation asymmetry index =|log10 (lower hemiretinal thickness/upper hemiretinal thickness)| was used to calculate asymmetry indices for 8 pairs of upper and lower 0.5-mm segments equidistant from the fovea on each scan. Areas under the receiver operating characteristic curve (AROCs) for mean thickness and mean asymmetry index of 10 B-scans were compared., Results: The overlap in values for normal and glaucomatous eyes was minimal for the ganglion cell layer asymmetry index. Thickness parameters decreased with the severity of glaucoma, whereas asymmetry indices did not. AROCs for thickness measurements tended to increase with increasing glaucoma severity (preperimetric, 0.746-0.808; early, 0.842-0.940; advanced, 0.943-0.995), whereas AROCs for asymmetry indices did not have distinct ranges according to glaucoma severity (advanced, 0.819-0.996; early, 0.861-0.998; preperimetric, 0.773-0.994). The AROC for the ganglion cell layer asymmetry index remained almost perfect regardless of glaucoma severity (0.994-0.998)., Conclusions: Macular retinal layer thickness asymmetry indices, particularly for the ganglion cell layer, show promise as early indicators of glaucomatous retinal damage., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To study longitudinal changes in the posterior pole in eyes with dome-shaped macular configuration within the staphyloma., Design: Prospective, longitudinal study., Methods: We prospectively examined the macular area in 35 eyes (26 patients) with dome-shaped macular configuration and high myopia (mean spherical equivalent, -14.83 ± 4.50 diopters) using swept-source optical coherence tomography. Scleral and choroidal thicknesses were measured at the fovea and at 4 parafoveal locations 2000 μm from the foveal center. Height of the macular bulge was measured as well., Results: During the mean follow-up of 24.8 ± 2.5 months, the scleral thickness significantly decreased at the fovea from 496.1 ± 95.7 μm to 484.7 ± 96.2 μm (P < .001) and at all 4 parafoveal locations (P < .001, respectively). The scleral thinning was asymmetric, with an estimated decrease per year of 5.6 μm at the foveal center, 11.1 μm superiorly, 12.1 μm inferiorly, 10.4 μm temporally, and 5.8 μm nasally. The ocular concavities deepened over time, and mean macular bulge height increased from 136.5 ± 60.9 μm to 157.6 ± 67.0 μm (P < .001). The choroid within the staphyloma showed generalized thinning during follow-up. Mean choroidal thickness decreased significantly at the fovea from 28.3 ± 17.2 μm at baseline to 22.9 ± 17.2 μm (P < .001)., Conclusions: Progressive asymmetric scleral thinning occurred in the macular region of eyes with dome-shaped macular configuration. The scleral thinning was more pronounced in the parafoveal area than at the foveal center, resulting in an increase of the macular bulge height., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To compare and analyze differences and similarities between Japanese and French patients in subtype diagnosis of exudative age-related macular degeneration (AMD) as determined by fundus photography (FP) and fluorescein angiography (FA), and a multimodal imaging involving FP, FA, indocyanine green angiography (ICGA), and optical coherence tomography (OCT)., Design: Retrospective chart review., Methods: We determined the subtype diagnosis for 99 consecutive Japanese eyes and 94 consecutive French eyes with exudative AMD. The first-step diagnosis was made using FP and FA, while the second-step diagnosis was made using FP, FA/ICGA, and OCT. The diagnoses made by Japanese and French physicians were compared, and when the diagnoses differed, a third institute was consulted to arrive at a final consensus and diagnosis., Results: The first-step diagnosis showed 20%-30% disagreement against the final diagnosis, but the second-step diagnosis showed only 10% disagreement. Polypoidal choroidal vasculopathy (PCV) was observed more in Japanese patients (48%) than in French (9%), and the rate of PCV with type 1 or 2 choroidal neovascularization (CNV) was extremely low: 3% in Japanese and 0% in French. Type 1 CNV was found significantly more in French cases (53.3% vs 35.1%, P=.018), while the rate of eyes with type 2 CNV only or chorioretinal anastomosis was similar between populations., Conclusions: Multimodality imaging significantly improved the sub-classification of AMD. There were significant differences between the 2 series in the proportions of type 1 CNV and PCV, while the proportions of type 2 CNV only and chorioretinal anastomosis were similar between groups., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To assess macular photoreceptor abnormalities in eyes with resolved branch retinal vein occlusion (BRVO) using adaptive optics scanning laser ophthalmoscopy (AO-SLO)., Design: Prospective observational cross-sectional case series., Methods: After complete resolution of macular edema and retinal hemorrhage, 21 eyes (21 patients) with BRVO underwent full ophthalmologic examination and imaging with optical coherence tomography (OCT) and a prototype AO-SLO system. Cone density and spatial mosaic organization were assessed using AO-SLO images., Results: Regular parafoveal cone mosaic patterns were clearly visualized with the prototype AO-SLO imaging system in the BRVO-unaffected side. However, in the side of the retina previously affected by the BRVO, cone mosaic patterns were disorganized and dark regions missing wave-guiding cones were apparent. Additionally, retinal capillaries were dilated, no longer had a uniform caliber, and had less direct paths through the retina. In the affected side, parafoveal cone density was significantly decreased, compared with the corresponding retinal area on the unaffected side (P < .001). Furthermore, the hexagonal Voronoi domain ratio and the nearest-neighbor distances were significantly lower than in the unaffected side (P < .05). These parameters were also correlated with photoreceptor layer integrity in the parafovea., Conclusions: After BRVO-associated retinal hemorrhage and macular edema resolved, affected parafoveal cone density decreases and the cone mosaic spatial arrangement is disrupted, becoming more irregular. These cone microstructural abnormalities may extend to parafovea in the BRVO-unaffected side., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To investigate the correlation between choroidal and retinal lesions in eyes with acute Vogt-Koyanagi-Harada disease (VKH) using optical coherence tomography (OCT) by using a new parameter, retinal pigment epithelium (RPE) undulation index, which quantitatively describes choroidal deformations., Design: Retrospective, observational, cross-sectional study., Methods: Spectral-domain OCT (SD OCT) and swept-source OCT images from a consecutive series of 42 eyes in 22 patients with acute VKH who underwent steroid therapy and 20 healthy eyes in 20 volunteers were analyzed retrospectively. Correlations between best-corrected visual acuity (BCVA), axial length change, and OCT parameters were examined. The RPE undulation index was defined as RPE line length to the total scan length ratio on a foveal-centered scan in the SD OCT image., Results: Eyes with acute VKH showed increased RPE undulation index, choroidal thickness, and retinal thickness compared to normal subjects, which were reduced following steroidal treatment (P < .0001, P = .0003, and P < .0001, respectively). RPE undulation index was related to choroidal thickness (r = 0.624, P = .0043), retinal thickness (r = 0.483, P = .0028), and BCVA (r = 0.588, P = .0002). Meanwhile, no statistically significant relationship was observed between choroidal thickness and retinal thickness. Axial length changes were significantly correlated with both choroidal thickness (r = 0.842, P < .0001) and RPE undulation index (r = 0.600, P = .0139)., Conclusions: This study demonstrated that the choroid was diffusely undulated and bulged inward in eyes with acute VKH. Correlations between RPE undulation index and choroid morphology, retinal thickness, and poor BCVA suggest that choroidal folding, quantified by RPE undulation index, is useful in assessing VKH disease severity., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To investigate the choroidal thickness/volume of eyes with reticular pseudodrusen using high-penetration swept-source optical coherence tomography (SS-OCT) and to evaluate the choroidal vasculature changes using en face images., Design: Prospective cross-sectional study., Methods: Thirty-eight eyes with reticular pseudodrusen and 14 normal eyes were studied with prototype SS-OCT. Eyes with reticular pseudodrusen were classified into 3 subgroups: eyes without late age-related macular degeneration (AMD) (Group1), eyes with neovascular AMD (Group2), and eyes with geographic atrophy (Group3). Mean regional choroidal thickness/volume measurements were obtained by 3-dimensional (3D) raster scanning. The choroidal vascular area was measured using en face images reconstructed from a 3D SS-OCT data set., Results: Mean age and axial length did not differ between eyes with reticular pseudodrusen and normal eyes. The mean choroidal thickness and volume of each sector was significantly reduced in eyes with reticular pseudodrusen compared with normal eyes (P < .020 for all). Mean choroidal thickness and volume of each area showed no significant difference between the 3 groups; however, most of them showed decreased thickness compared with normal eyes. En face images through the choroid revealed narrow and sparse choroidal vessels in eyes with reticular pseudodrusen. The area of choroidal vasculature was significantly reduced in eyes with reticular pseudodrusen compared with normal eyes (P = .037)., Conclusions: In eyes with reticular pseudodrusen, macular choroidal thickness/volume was reduced regardless of choroidal neovascularization/geographic atrophy. Thinned vessels in the choroid suggest choroidal involvement in the pathogenesis of reticular pseudodrusen., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To assess macular photoreceptor abnormalities in eyes with fundus albipunctatus with RDH5 mutation by using adaptive optics scanning laser ophthalmoscopy (AO-SLO)., Design: Prospective cross-sectional study., Methods: Ten eyes with fundus albipunctatus and 11 normal eyes underwent a full ophthalmologic examination, microperimetry, spectral-domain optical coherence tomography (SD OCT), and imaging with a prototype AO-SLO system. Cone density and spatial organization of the cone mosaic were assessed using AO-SLO images. Statistical analysis was done using data from right eyes of all patients., Results: Four patients had the same mutation in RDH5 (c.928delC/insGAAG), and 1 patient had a novel mutation in RDH5 (c.718delG). AO-SLO revealed the presence of small patchy dark areas representing cone loss in the macula of all eyes with fundus albipunctatus, including eyes for which fundus photographs showed no macular abnormalities and SD OCT did not reveal any visible defects in the photoreceptor layer. Compared to normal eyes, eyes with fundus albipunctatus demonstrated significantly lower cone density in areas at 0.5 mm from the center of the fovea (P = .020). At 0.5 mm and 1.0 mm from the center of the fovea, eyes with fundus albipunctatus showed fewer cones with 6 neighbors (P = .041 and P = .006). AO-SLO revealed hyperreflective mosaics surrounded by hyporeflective rings in areas corresponding to the retinal flecks., Conclusions: Macular cone density is lower and the regularity of the macular cone mosaic spatial arrangement is disrupted in eyes with fundus albipunctatus. AO-SLO imaging is a sensitive quantitative tool for detecting photoreceptor abnormalities in eyes with fundus albipunctatus., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To propose a new parameter, "Parallelism," to evaluate retinal layer integrity on spectral-domain optical coherence tomography (SDOCT), and to investigate the association between parallelism and visual function in eyes with idiopathic epiretinal membrane (ERM)., Design: Retrospective, observational evaluation of a diagnostic test., Methods: We evaluated a consecutive series of 57 eyes of 57 patients with ERM and 30 healthy eyes of 30 volunteers for whom M-CHARTS testing and SDOCT were performed on the same day. OCT images were skeletonized, and the orientation of segmented lines in the image was termed "Parallelism" and was expressed as a value ranging from 0-1 and increasing as the retinal layers ran more parallel with each other. The relationships between parallelism and visual acuity and between parallelism and metamorphopsia score were evaluated., Results: In normal eyes, parallelism was nearly homogeneous and varied slightly with the location. Parallelism in eyes with ERM was significantly lower than that in normal eyes. In the horizontal and vertical scans, parallelism was significantly correlated with visual acuity, horizontal metamorphopsia score, and vertical metamorphopsia score. Parallelism of the center (1 mm) in the horizontal scan was strongly correlated with horizontal metamorphopsia score (R = -0.632; P < .0001). Significant negative correlation was found between parallelism and retinal thickness both in horizontal and vertical scans., Conclusions: Parallelism was significantly lower in eyes with ERM than in normal eyes, and correlated strongly with metamorphopsia and visual acuity in eyes with ERM., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the effect of macular reticular pseudodrusen on retinal function using multiple imaging methods., Design: Prospective cross-sectional study., Methods: Thirteen eyes with reticular pseudodrusen, but without any other macular abnormality or glaucoma, and 20 normal eyes were evaluated. All subjects underwent color fundus photography, infrared reflectance (IR), fundus autofluorescence (FAF), and microperimetry., Results: The similarity in the number of reticular pseudodrusen was evaluated through inter-observer intraclass correlation coefficients, which ranged from 0.852-0.944. IR could detect reticular pseudodrusen within the center circle area in 12 eyes, whereas blue-channel fundus photography and FAF could only detect these lesions in 1 and 3 eyes, respectively. The number of reticular pseudodrusen correlated among the different imaging modalities (P < .001 for all) for all areas of the macula, except the center. The mean retinal sensitivity in eyes with reticular pseudodrusen was lower in all areas of the macula, compared with normal eyes (P < .001 for all). The number of reticular pseudodrusen correlated with retinal sensitivity in all areas by IR imaging (P = .003, P < .001, P = .003 for center, inner ring, outer ring, respectively), in the inner and outer rings by blue-channel fundus photography (P < .001 for both), and in the inner and outer rings by FAF (P < .001 and P = .001, respectively)., Conclusions: Although multiple imaging modalities are capable of quantifying reticular pseudodrusen, IR appears to have the best ability to do so as compared to blue-channel photography and FAF. The distribution and number of reticular pseudodrusen lesions are closely associated with retinal sensitivity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To estimate the age- and sex-specific prevalence of early age-related macular degeneration (AMD; drusen and retinal pigment abnormalities) and late AMD (exudative AMD and geographic atrophy) in the Japanese population., Design: Community-based, cross-sectional study., Methods: The study was held in Nagahama, Japan, and included 6065 Japanese individuals (aged ≥50 years) recruited in 2008-2010. We graded fundus photographs of both eyes for the AMD phenotype based on drusen size, the presence of retinal pigment abnormalities, and late AMD. The associations between smoking and AMD phenotypes were also evaluated., Results: We assessed 5595 subjects (women, 65%) with a gradable macular condition. Early and late AMD prevalence increased from 16.1% and 0.27% at 50-59 years to 31.2% and 0.98%, respectively, at 70-74 years and was predominant in male subjects in each age group. Smoking was associated with both early and late AMD stages and retinal pigment abnormalities (P < .0001), but not with drusen (P = .305). The prevalence of retinal pigment abnormalities was significantly higher in men (P < .0001), which was associated with high rates of cigarette smoking. We found no sex difference for the prevalence of large drusen (P = .264)., Conclusions: The prevalence of early AMD among adult Japanese persons was similar to the rates in white populations. The prevalence of late AMD in Japanese people aged <70 years was similar to that observed in white populations, whereas that in Japanese people aged ≥70 years was relatively lower., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the predictive ability of macular parameters defined in the significance map created using spectral-domain optical coherence tomography (SD-OCT) for paracentral visual field defects in early glaucoma., Design: Prospective comparative study., Methods: We studied 78 early-glaucomatous eyes of 78 patients, who underwent SD-OCT and standard automated perimetry 10-2. Macular layer parameters included the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL) + inner plexiform layer (IPL), and RNFL + GCL + IPL. The minimal distance between the area with abnormal (P < 1%) thickness and foveal center was defined as the shortest distance. A wider area of an abnormally thinned (<1%) region, within either an inferior or a superior hemicircle with a diameter of 6 mm centered at the fovea, was defined as the macular abnormal area. A circumpapillary RNFL parameter was defined in its 36 sectors. Areas under the receiver operating characteristic curves (ROCs) were calculated to discriminate between eyes with (n = 39) and without (n = 39) paracentral visual field defects in the central 5 degrees., Results: Measurement reproducibility was almost perfect in the macular parameters at P < 1% (intraclass correlation, 0.907-0.942). Areas under the ROC were significantly higher (P ≤ 0.01) in the macular parameters (0.870-0.930), including the shortest distance of GCL + IPL/RNFL + GCL + IPL, and the macular abnormal area of RNFL/GCL + IPL/RNFL + GCL + IPL than in the circumpapillary RNFL parameter (0.676). When specificity was fixed at ≥90%, the shortest distance of GCL + IPL (area under the ROC = 0.874) and the macular abnormal area of RNFL (area under the ROC = 0.894) showed sensitivities greater than 50%., Conclusions: Macular structural parameters defined on an SD-OCT significance map may be potentially useful predictors of the presence of paracentral scotoma., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To investigate the effect of intrathecal galanin on the micturition reflex in rats., Methods: Continuous cystometrograms (0.04 mL/min infusion rate) were performed in female Sprague-Dawley rats (225-248 g) under urethane anesthesia. After stable micturition cycles were established, galanin was administered intrathecally to evaluate changes in bladder activity. Then, to examine the involvement of opioid systems in the galanin effects, galanin was administered intrathecally when the first bladder contraction was observed after intrathecal administration of naloxone, an opioid receptor antagonist., Results: Intrathecal administration of galanin (1-10 μg) increased intercontraction intervals in a dose-dependent fashion. Intrathecal administration of galanin (1-10 μg) also increased pressure threshold in a dose-dependent fashion. These inhibitory effects of galanin (10 μg) were partially antagonized by intrathecal administration of naloxone (10 μg)., Conclusion: These results indicate that in urethane-anesthetized rats, galanin delays the onset of micturition through activation of the opioid mechanism, suggesting the inhibitory role of galanin system in the control of the micturition reflex., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To study the prevalence and 3-dimensional (3-D) tomographic features of focal choroidal excavations in eyes with central serous chorioretinopathy (CSC) using swept-source optical coherence tomography (OCT)., Design: Prospective, cross-sectional study., Methods: We examined 116 consecutive eyes with CSC with a prototype 3-D swept-source OCT. 3-D images of the shape of the macular area, covering 6 × 6 mm(2), were reconstructed by segmentation of the outer surface of the retinal pigment epithelium (RPE)., Results: The 3-D swept-source OCT detected focal choroidal excavations in 9 eyes (7.8%). The 3-D scanning protocol, coupled with en face scans, allowed for clear visualization of the excavation morphology. In 5 eyes with focal excavations, unusual choroidal tissue was found beneath the excavation, bridging the bottom of the excavation and the outer choroidal boundary. Additionally, 3 of those 5 eyes showed a suprachoroidal space below the excavation, as if the outer choroidal boundary is pulled inward by this bridging tissue. The focal choroidal excavations were located within fluorescein leakage points and areas of choroidal hyperpermeability. Eyes with focal choroidal excavations were more myopic (-4.42 ± 2.92 diopters) than eyes without excavations (-0.27 ± 1.80 diopters, P = .001). Subfoveal choroidal thickness was significantly thinner (301.3 ± 60.1 μm) in eyes with focal excavations than in eyes without the excavations (376.6 ± 104.8 μm, P = .036)., Conclusions: Focal choroidal excavations were present in 7.8% of eyes with CSC. In these eyes, focal choroidal excavations may have formed from RPE retraction caused by focal scarring of choroidal connective tissue., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To validate and evaluate the reliability of retinal vessel diameter measurements by optical coherence tomography (OCT). The effects of age and hypertension on vessel diameter were also examined., Design: Prospective, cross-sectional study., Methods: Two hundred thirty-eight eyes (238 subjects) with no ocular disease were included. Hypertension was present in 106 subjects and absent in 132 subjects. Spectralis HRA+OCT was used to scan a circular region around the optic disc. Outer and inner diameters of the 4 largest retinal arteries and veins were measured using OCT vascular wall reflections, and vessel wall thickness was calculated., Results: Intervisit, interexaminer, and interevaluator intraclass correlation coefficients of randomly selected vessel measurements were all greater than 0.90. Mean inner arterial and venous diameters were 87.8 ± 9.4 μm and 113.7 ± 12.5 μm, respectively. The OCT-measured mean inner arterial and venous diameters were significantly correlated to fundus photography caliber measurements (P = .005 and P = .001, respectively). Arterial and venous wall thicknesses were 17.4 ± 2.4 μm and 13.7 ± 2.1 μm, respectively, both of which were highly correlated with subject age (arterial: r = 0.612, P < .001, venous: r = 0.455, P < .001). Additionally, both mean arterial and venous wall thicknesses were significantly greater in subjects with hypertension than in age-matched subjects without hypertension (P = .020 and P = .015, respectively)., Conclusions: Retinal vessel diameter measurements obtained with OCT were highly reproducible and vessel wall thicknesses, calculated using outer and inner diameter measurements, were significantly thickened by both aging and systemic hypertension., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To determine how evaluations of macular structures on spectral-domain optical coherence tomography compare with those of the optic disc and circumpapillary retinal nerve fiber layer (RNFL) in discriminating between highly myopic eyes with and without glaucoma., Design: Retrospective, comparative study., Methods: The appearances of ganglion cell layer and RNFL on Spectralis macular scans (Heidelberg Engineering) and optic disc on photographs were evaluated by 2 observers. The receiver operating characteristic regression was conducted for macular ganglion cell complex and circumpapillary RNFL measurements on RTVue-100 (Optovue)., Results: Ninety highly myopic eyes (-6.0 to -15.0 diopters; mean deviation [MD], -5.6 ± 5.1 dB) and 91 non-highly myopic eyes (1.0 to -5.5 diopters; MD, -4.9 ± 5.7 dB) were enrolled. In highly myopic eyes (<-6 diopters), the Cohen κ for qualitative decisions by observers was 0.363 for photographs and 0.946 for Spectralis macular scans, and observers' evaluations of Spectralis macular scans were more accurate (94.5% and 94.5%, respectively; P < .0001) than their evaluations of photographs (71.4% and 80.2%, respectively). In the receiver operating characteristic regression analyses assessing the influences of age, sex, MD, and axial length, the better MD (P = .002 to .016) and longer axial length (P = .031 to .041) were associated significantly with diagnostic performances for all or some spectral-domain optical coherence tomography parameters. The receiver operating characteristic curves of average macular ganglion cell complex and circumpapillary RNFL thicknesses were comparable at low MD., Conclusions: In high myopes, observers' assessments of the spectral-domain optical coherence tomography macular scans may agree better and be more accurate than observers' optic disc assessments. Glaucoma diagnostic performance of the macular ganglion cell complex may be less affected by axial length compared with that of circumpapillary RNFL., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To compare pathologic changes in the photoreceptors of eyes with idiopathic macular telangiectasia types 1 and 2 using adaptive optics scanning laser ophthalmoscopy (AO-SLO)., Design: Prospective cross-sectional study., Methods: Eleven eyes with idiopathic macular telangiectasia type 1, 14 eyes with type 2, and 10 normal eyes underwent a full ophthalmologic examination, spectral-domain optical coherence tomography (SD-OCT), and imaging with an original prototype AO-SLO system. All eyes with idiopathic macular telangiectasia were examined with fluorescein angiography (FA), confocal blue reflectance, and microperimetry., Results: Compared with normal eyes (29 017 ± 5507 cones/mm(2)), those with idiopathic macular telangiectasia type 1 had significantly lower cone density on the temporal side (18 427 ± 4908 cones/mm(2), P = .010). The FA leakage area (5.90 ± 3.23 mm(2)) was larger than the dark regions (2.45 ± 2.40 mm(2)) on AO-SLO (P = .003)-which were observed only in the FA leakage area. Compared with normal eyes, those with idiopathic macular telangiectasia type 2 had significantly lower cone density in all areas (P < .05 for all). Patchy dark regions were also seen in areas without FA abnormalities in 12 eyes. Higher mean retinal sensitivity correlated with greater mean cone density 0.5 mm from the center of the fovea (type 1: P = .010; type 2: P < .001)., Conclusions: Idiopathic macular telangiectasia type-specific differences in the distribution of photoreceptor abnormalities were shown in the AO-SLO images. For both idiopathic macular telangiectasia types 1 and 2, visual impairment was associated with cone damage., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To study peripapillary morphologic changes in highly myopic eyes using swept-source optical coherence tomography at a longer wavelength., Design: Prospective cross-sectional study., Methods: Peripapillary regions of 196 eyes of 107 patients with high myopia (refractive error, <-8.0 diopters or axial length, >26.0 mm) were analyzed quantitatively and qualitatively with an swept-source optical coherence tomography prototype system that uses a tunable laser light source operated at a 100,000-Hz A-scan repetition rate in the 1-μm wavelength region. The visual field was evaluated by standard automated perimetry. Area of peripapillary atrophy β and presence of scleral protrusion temporal to the optic disc were assessed., Results: Peripapillary atrophy β area, but not disc area, was significantly larger in eyes with visual field defect (3.16 ± 2.70 mm(2); range, 0.00 to 12.85 mm(2)) than those without visual field defect (2.31 ± 2.83 mm(2); range, 0.00 to 17.70 mm(2)). Temporal scleral protrusion was detected by color stereo disc photography in 22 (19.5%) of 113 eyes with visual field defect and in 4 (4.8%) of 83 eyes without visual field defect. Scleral bending demonstrated a wide range of angles (mean, 31.0 ± 21.1 degrees; range, 2 to 80 degrees). The angle of scleral bending, but not the distances from scleral bend to disc margin or foveal center, correlated significantly with retinal nerve fiber layer thickness above the bend (r = -0.557, P = .007) and visual field defect severity (r = -0.445, P = .038)., Conclusions: Swept-source optical coherence tomography visualizes peripapillary deep structures in high myopia. Some cases of high myopia may be affected by direct scleral compression or stretching at the peripapillary region., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To detect pathologic changes in retinal nerve fiber bundles in glaucomatous eyes seen on images obtained by adaptive optics (AO) scanning laser ophthalmoscopy (AO SLO)., Design: Prospective cross-sectional study., Methods: Twenty-eight eyes of 28 patients with open-angle glaucoma and 21 normal eyes of 21 volunteer subjects underwent a full ophthalmologic examination, visual field testing using a Humphrey Field Analyzer, fundus photography, red-free SLO imaging, spectral-domain optical coherence tomography, and imaging with an original prototype AO SLO system., Results: The AO SLO images showed many hyperreflective bundles suggesting nerve fiber bundles. In glaucomatous eyes, the nerve fiber bundles were narrower than in normal eyes, and the nerve fiber layer thickness was correlated with the nerve fiber bundle widths on AO SLO (P < .001). In the nerve fiber layer defect area on fundus photography, the nerve fiber bundles on AO SLO were narrower compared with those in normal eyes (P < .001). At 60 degrees on the inferior temporal side of the optic disc, the nerve fiber bundle width was significantly lower, even in areas without nerve fiber layer defect, in eyes with glaucomatous eyes compared with normal eyes (P = .026). The mean deviations of each cluster in visual field testing were correlated with the corresponding nerve fiber bundle widths (P = .017)., Conclusions: AO SLO images showed reduced nerve fiber bundle widths both in clinically normal and abnormal areas of glaucomatous eyes, and these abnormalities were associated with visual field defects, suggesting that AO SLO may be useful for detecting early nerve fiber bundle abnormalities associated with loss of visual function., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To study the tomographic and pathomorphologic features of dome-shaped maculas with swept-source optical coherence tomography (OCT)., Design: Prospective, cross-sectional study., Methods: The macular area of 51 highly myopic eyes (35 patients) with dome-shaped maculas was studied with swept-source OCT at 1050 nm. Three-dimensional (3-D) data sets were obtained with raster scanning covering a 12 × 8-mm(2) area; 3-D images of the posterior pole were constructed by autosegmentation of the retinal pigment epithelium (RPE)., Results: In all reconstructed 3-D images of the RPE, 2 outward concavities were seen within the posterior staphyloma and a horizontal ridge was formed between these 2 concavities. In 42 of these eyes, this horizontal ridge was band shaped. The vertical OCT section through the fovea showed a convex configuration of RPE, but the horizontal section showed an almost flat RPE line. In 9 eyes, 3-D images showed a typical dome-shaped convexity within the staphyloma. OCT scans showed no outward protrusions in the external scleral surface, but marked scleral thinning was seen consistent with the 2 outward concavities of the RPE. The sclera of the fovea (518.6 ± 97.6 μm) was significantly thicker than that in all 4 quadrants of the parafoveal area (range, 277.2 to 360.3 μm; P < .001)., Conclusions: In highly myopic eyes with a dome-shaped macula, a horizontal ridge is formed within the posterior staphyloma by uneven thinning of the sclera., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: To survey the prevalence of reticular pseudodrusen in late age-related macular degeneration (AMD) using multiple imaging methods, and to investigate the association between reticular pseudodrusen and polymorphisms in complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes., Design: Retrospective case series., Methods: This study included 216 consecutive patients with late AMD (typical AMD, polypoidal choroidal vasculopathy [PCV], retinal angiomatous proliferation [RAP], or geographic atrophy). Eyes were assessed for reticular pseudodrusen using the blue channel of color fundus photography, infrared reflectance, fundus autofluorescence, and spectral-domain optical coherence tomography. The major AMD-associated single nucleotide polymorphisms (CFH Y402 rs1061170, CFH I62V rs800292, and ARMS2 A69S rs10490924) were genotyped., Results: Forty-nine eyes of 30 patients had a reticular pattern in ≥2 imaging modalities and were diagnosed with reticular pseudodrusen. Of these, 16 had bilateral late AMD, whereas 32 of 186 patients without reticular pseudodrusen had bilateral late AMD (P < .001). The prevalence of reticular pseudodrusen was 83% in RAP, 50% in geographic atrophy, 9% in typical AMD, and 2% in PCV. The frequency of the T allele in ARMS2 A69S in patients with and without reticular pseudodrusen was 78.6% and 59.9%, respectively (P=.007)., Conclusions: The prevalence of reticular pseudodrusen was low in PCV cases. About 50% of patients with reticular pseudodrusen had bilateral late AMD. The connection of ARMS2 risk allele and reticular pseudodrusen was confirmed in a Japanese population., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The objective of this study was to clarify the associations of physical performance and bone and joint diseases with single and multiple falls in Japanese men and women using a population-based longitudinal cohort study known as Research on Osteoarthritis/osteoporosis Against Disability (ROAD). A total of 452 men and 896 women were analyzed in the present study (mean age, 63.9 years). A questionnaire was used to assess the number of falls during the 3-year follow-up. Grip strength, 6-m walking time, and chair stand time were measured at baseline. Knee osteoarthritis (OA) and lumbar spondylosis were defined as Kellgren Lawrence=2, 3 or 4. Vertebral fracture (VFx) was assessed with the Japanese Society of Bone and Mineral Research criteria. Osteoporosis was defined by bone mineral density using dual energy X-ray absorptiometry based on World Health Organization criteria. Knee and lower back pain were estimated by an interview. During a 3-year follow-up, 79 (17.4%) men and 216 (24.1%) women reported at least one fall, and 54 (11.9%) men and 111 (12.4%) women reported multiple falls. Knee pain was a risk factor for multiple falls in women, but not in men. VFx tended to be associated with multiple falls in women, but not in men. A longer 6-m walking time was a risk factor for multiple falls in women, whereas a longer chair stand time was a risk factor for multiple falls in men. We found gender differences in risk factors for falls., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objective: To investigate the effects of activation of somatostatin subtype 4 (SST4) on the micturition reflex in rats., Methods: Continuous cystometrograms (0.04 mL/min infusion rate) were performed in female Sprague-Dawley rats (242-265 g) under urethane anesthesia. After stable micturition cycles were established, a selective SST4 receptor agonist, NNC 26-9100, was administered intravenously in normal rats or rats pretreated with capsaicin 4 days before the experiments. The micturition parameters were recorded and compared before and after drug administration., Results: Intravenous administration of NNC 26-9100 (10-300 μg/kg) significantly increased the intercontraction interval in a dose-dependent fashion. Intravenous administration of NNC 26-9100 (10-300 μg/kg) also significantly increased the pressure threshold in a dose-dependent fashion. No significant changes were seen in the baseline pressure, maximum voiding pressure, or postvoid residual urine volume. However, NNC 26-9100-induced increases in the intercontraction intervals and pressure threshold were not seen in rats with C-fiber desensitization induced by capsaicin pretreatment., Conclusion: These results indicate that in urethane-anesthetized rats, activation of the SST4 receptor can inhibit the micturition reflex by suppression of capsaicin-sensitive C-fiber afferent pathways. Thus, the SST4 receptor could be a potential target for the treatment of C-fiber afferent-mediated bladder dysfunction., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Glycine is a major inhibitory neurotransmitter in the spinal cord, the concentration of which is regulated by two types of glycine transporters (GlyTs): GlyT1 and GlyT2. We hypothesized that the inhibition of GlyTs could ameliorate bladder overactivity and/or pain sensation in the lower urinary tract., Objective: Investigate the effects of GlyT inhibitors on bladder overactivity and pain behavior in rats., Design, Setting, and Participants: Cystometry was performed under urethane anesthesia in cyclophosphamide (CYP)-treated rats. In behavioral studies using conscious rats, nociceptive responses were induced by intravesical administration of resiniferatoxin (3μM). Selective GlyT1 or GlyT2 inhibitors were administered intrathecally to evaluate their effects., Measurements: Cystometric parameters, nociceptive behaviors (licking and freezing), and messenger RNA (mRNA) levels of GlyTs and glycine receptor (GlyR) subunits in the dorsal spinal cord (L6-S1) were measured., Results and Limitations: During cystometry in CYP-treated rats, significant increases in intercontraction interval and micturition pressure threshold were elicited by ALX-1393, a selective GlyT2 inhibitor, but not by sarcosine, a GlyT1 inhibitor. These effects were completely reversed by strychnine, a GlyR antagonist. ALX-1393 also significantly suppressed nociceptive behaviors in a dose-dependent manner. In sham rats, GlyT2 mRNA was expressed at a much higher level (23-fold) in the dorsal spinal cord than GlyT1 mRNA. In CYP-treated rats, mRNA levels of GlyT2 and the GlyR α1 and β subunits were significantly reduced., Conclusions: These results indicate that GlyT2 plays a major role in the clearance of extracellular glycine in the spinal cord and that GlyT2 inhibition leads to amelioration of CYP-induced bladder overactivity and pain behavior. GlyT2 may be a novel therapeutic target for the treatment of overactive bladder and/or bladder hypersensitive disorders such as bladder pain syndrome/interstitial cystitis., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To study the association of ARMS2 A69S genotype with the development of exudative age-related macular degeneration (AMD) in the unaffected fellow eye and to estimate the duration until the development of AMD in the second eye., Design: Retrospective cohort study., Methods: We retrospectively reviewed 326 patients who had exudative AMD in at least 1 eye, genotyping of ARMS2 A69S, and a minimum follow-up of 2 years. Survival analysis and Cox proportional hazard regression analysis were used to examine the association between candidate factors and the duration until the development of AMD in the second eye., Results: One hundred nineteen patients (36.5%) had bilateral exudative AMD at the initial visit. A risk allele of ARMS2 A69S was more frequently seen in patients with bilateral AMD (P = .0270) than in those with unilateral AMD. Of the 207 unilateral AMD patients, 23 (11.1%) had AMD in the fellow eye after a mean duration of 56.3 ± 40.4 months. Fellow-eye involvement was associated with ARMS2 A69S genotype (hazard ratio [HR], 2.673; P = .0013), age (HR, 1.102; P = .0005), and smoking history (HR, 0.680; P = .3663). As HRs indicate, correlation of genotype (2.673) was as high as that of 10-year aging (1.102(10) = 2.641). Survival analysis revealed that patients with risk homozygous (TT) genotype had second-eye involvement significantly earlier than those with other genotypes (P = .0028). When the observation duration reached 120 months, second-eye involvement had developed in 50%, 6.6%, and 11.2% of the TT, GT, and GG cohorts, respectively., Conclusion: ARMS2 A69S genotype is associated with second-eye involvement of exudative AMD and with the period between first- and second-eye involvements., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To investigate factors affecting patient response to intravitreal ranibizumab treatment for age-related macular degeneration (AMD)., Design: Retrospective chart review., Methods: We reviewed medical records of 105 consecutive eyes with AMD treated with intravitreal ranibizumab injections and followed for more than 1 year after treatment. Response to ranibizumab treatment was compared between typical neovascular AMD and polypoidal choroidal vasculopathy (PCV). Furthermore, we investigated associations of age, lesion size, and single nucleotide polymorphisms (SNPs) in CFH and ARMS2 genes with treatment response., Results: Forty-nine eyes were diagnosed with typical neovascular AMD and 56 eyes with PCV. Serous retinal detachment and retinal edema resolved similarly in both typical neovascular AMD and PCV after treatment. However, visual acuity (VA) significantly improved in eyes with PCV, whereas VA was maintained in typical neovascular AMD. At the third and twelfth months after injection, VA was better in PCV than in typical neovascular AMD (P = .027 and P = .044, respectively), although there were no differences in baseline VA between the 2 groups. Age and size of greatest linear dimension were significantly associated with visual prognosis in typical neovascular AMD but not in PCV. There was no clear association between 3 SNPs and responsiveness to ranibizumab treatment., Conclusions: Although exudative changes were equivalent following ranibizumab treatment in both typical neovascular AMD and PCV, there was a significant increase in VA in PCV compared to typical neovascular AMD. Age and greatest linear dimension correlated with visual prognosis only in typical neovascular AMD and not in PCV., (Copyright © 2012 Elsevier Inc. All rights reserved.)