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Purpose: Inflammation is involved in the pathogenesis of diabetes, however the impact of diabetes on organ-specific autoimmune diseases remains unexplored. Experimental autoimmune uveoretinitis (EAU) is a widely accepted animal model of human endogenous uveitis. In this study, we investigated the effects of diabetic conditions on the development of EAU using a mouse diabetes model., Methods: EAU was induced in wild-type C57BL/6 (WT) mice and Ins2 Akita (Akita) mice with spontaneous diabetes by immunization with IRBP peptide. Clinical and histopathological examinations, and analysis of T cell activation state were conducted. In addition, alternations in the composition of immune cell types and gene expression profiles of relevant immune functions were identified using single-cell RNA sequencing., Results: The development of EAU was significantly attenuated in immunized Akita (Akita-EAU) mice compared with immunized WT (WT-EAU) mice, although T cells were fully activated in Akita-EAU mice, and the differentiation into Th17 cells and regulatory T (Treg) cells was promoted. However, Th1 cell differentiation was inhibited in Akita-EAU mice, and single-cell analysis indicated that gene expression associated AP-1 signaling pathway (JUN, FOS, and FOSB) was downregulated not only in Th1 cells but also in Th17, and Treg cells in Akita-EAU mice at the onset of EAU., Conclusions: In diabetic mice, EAU was significantly attenuated. This was related to selective inhibition of Th1 cell differentiation and downregulated AP-1 signaling pathway in both Th1 and Th17 cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Takeuchi, Nishio, Someya, Sato, Yoshimura, Ito and Harimoto.)

Purpose: The purpose of this study is to investigate outcomes of visual acuity (VA) and intraocular pressure (IOP) in proliferative diabetic retinopathy (PDR)-associated neovascular glaucoma (NVG) in Japanese patients treated with surgical therapies without the use of glaucoma drainage devices. Methods: A retrospective analysis of medical records was conducted for 31 consecutive PDR-associated NVG patients who underwent surgical treatments in our institution between 2013 and 2022. Patient demographics, clinical characteristics, VA, and IOP were recorded at the first and last visits, and surgical procedures, including pars plana vitrectomy with extensive panretinal and ciliary photocoagulation (PPV-PRCP), diode laser trans-scleral cyclophotocoagulation (DCPC), and trabeculectomy with mitomycin C (TLE-MMC), with or without a prior intravitreal bevacizumab (IVB) injection, were reviewed. Results: Of the thirty-one PDR patients with NVG, two patients received PPV-PRCP or DCPC alone (6.5%), respectively, three patients received TLE-MMC alone (9.7%), two patients received TLE-MMC after IVB (6.5%), six patients received PPV-PRCP and TLE-MMC (19.4%), seven patients received PPV-PRCP and TLE-MMC after IVB (22.6%), five patients received PPV-PRCP and DCPC and TLE-MMC (16.1%), and four patients received PPV-PRCP and DCPC and TLE-MMC after IVB (12.9%). The VA of two patients (6.5%) deteriorated to no light perception. In all patients, the mean logMAR VA was 1.28 ± 1.05 at the first visit and remained at 1.26 ± 1.08 at the last visit, with no significant change; the mean IOP was 33.0 ± 15.2 mmHg at the initial visit and decreased significantly to 14.0 ± 7.4 mmHg at the last visit. The number of eyes with IOP ≥ 21 decreased from twenty-eight (90.3%) to three (9.7%). Although IOP in patients with IOP > 30 mmHg at the initial visit reduced to a level comparable to that of patients with IOP ≤ 30 mmHg, the IOP > 30 mmHg group received IVB more frequently and had significantly higher logMAR VA at the last visit compared to the IOP ≤ 30 mmHg group. Hypotony (<6 mmHg) was observed in four eyes (12.9%). Conclusions: In PDR patients with NVG, various combinations of PPV-PRCP, DCPC, and TLE-MMC after adjunctive IVB without the use of glaucoma drainage devices lowered IOP sufficiently; for these patients, neovascular regression was observed, with no further deterioration of VA. However, surgical procedures should be performed for PDR patients with NVG before visual impairment occurs. On the other hand, approximately less than 15% of patients developed blindness or low IOP.

Background:  The response of jugular venous pressure (JVP) to increased preload with inspiration has been recognized as a method of stratifying risk in the management of heart failure (HF). Whether the JVP response to inspiration may be more effective than other simple approaches in this setting remains unclear., Methods:  This study enrolled 79 patients with stable HF. JVP was assessed from the right internal jugular vein in the sitting position and was considered high if visible above the right clavicle at rest. JVP responses to inspiration, the five-repetition sit-to-stand test (5-STS), and squatting were also evaluated. The primary outcome was a composite of all-cause death and hospitalization for worsening HF., Results:  JVP assessment after 5-STS and during squatting was not conducted in two and 14 HF patients, respectively, due to physical limitations. During a mean follow-up of 837 days, the primary outcome was associated with a high JVP at rest (hazard ratio, 2.47; 95% confidence interval [CI], 1.09 to 5.60; P <0.05), with inspiration (hazard ratio, 2.53; 95% CI, 1.17 to 5.46; P <0.05), after 5-STS (hazard ratio, 2.61; 95% CI, 1.23 to 5.97; P <0.05), and during squatting (hazard ratio, 2.40; 95% CI, 1.03 to 6.06; P <0.05). Among patients without a high JVP at rest, the specificity of the primary outcome at one year was greater for the JVP response to inspiration (89%) and squatting (92%) than for the response to 5-STS (80%)., Conclusions:  JVP response to increased preload with inspiration may be a simple and practical method for risk assessment in patients with stable HF., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Noguchi et al.)

Purpose: The purpose of the study was to investigate clinical relevance of fibrin membranous structure (FMS) in the photoreceptor outer segments on spectral-domain optical coherence tomography (SD-OCT) in untreated initial-onset acute Vogt-Koyanagi-Harada (VKH) disease., Methods: Clinical charts of 39 patients (78 eyes) diagnosed with initial-onset VKH disease were retrospectively reviewed. Age, gender, period from the onset of symptoms to first visit, visual acuity (VA), intraocular pressure (IOP), anterior chamber cells, serous retinal detachment (SRD), SD-OCT findings, as well as fluorescein (FA), and indocyanine green angiography (ICGA) were collected., Results: FMS was observed in 24 out of 39 VKH patients in either eye (61.5%). VKH patients with FMS (FMS group) were significantly younger and had the shorter period from the onset of symptoms to the first visit compared with those without FMS (non-FMS group). Mean logMAR VA and proportion of pooling of dye, mean central retinal thickness (CRT) were significantly higher in FMS group than in non-FMS group. In contrast, hyperfluorescence of the optic disc on FA was more in non-FMS group than in FMS group. Significant positive correlations between CRT and logMAR VA or IOP were only observed in the FMS group. Total amount of corticosteroids was significantly greater in FMS group than in non-FMS group. However, there were no significant differences in LogMAR VA and IOP between two groups at 6 months after treatment initiation., Conclusion: FMS on SD-OCT is a critical feature observed in the early stage of initial-onset acute VKH disease, which is more common in younger patients and is related to the disease activity., (© 2022 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Purpose: To elucidate detailed epidemiological profile of common types of anterior uveitis (AU) in real-world clinical setting of a tertiary facility in Japan, and to evaluate the characteristic clinical findings at initial presentation., Study Design: Retrospective cohort study., Methods: Clinical charts of 275 patients (335 eyes) aged 52.5 ± 19.1 years were reviewed retrospectively. Herpetic AU was diagnosed by multiplex polymerase chain reaction tests using aqueous humor. Time of uveitis onset, gender, laterality, disease course since the initial onset of AU, visual acuity (VA) and intraocular pressure (IOP) at first visit, and definitive diagnosis were collected from clinical charts., Results: Acute AU (AAU) was the most common (21.8%) form of AU; followed by herpetic AU (20.7%) comprising Herpes Simplex Virus (HSV) (8.0%), Varicella Zoster Virus (VZV) (9.1%) and cytomegalo virus (CMV) (3.6%); scleritis (13.5%); diabetic iritis (7.6%), and Posner-Schlossman syndrome (5.5%). Unilateral AU constituted 78.2%, and VA less than 20/30 accounted for 31.2%. Of all the eyes, 16.1% had an IOP higher than 20 mmHg, out of which 37.0% had herpetic AU, followed by scleritis in 25.9%, and Posner-Schlossman syndrome (PSS) in 11.1%. AU patients over 60 years of age were 40.4%, in which 34.2% had herpetic AU, followed by scleritis in 14.4% and AAU in 13.5%. Herpetic AU patients were significantly older and had higher IOP compared with AAU patients., Conclusion: The most frequent AU was AAU, followed by herpetic AU. Herpetic AU patients were older and had higher intraocular pressure than AAU patients, although VA was equally impaired in both groups., (© 2022. Japanese Ophthalmological Society.)

Purpose: To report a case of cytomegalovirus retinitis (CMVR) with hypopyon and intense ocular inflammation., Case Report: An 81-year-old female was referred to our hospital with a suspicion of postoperative endophthalmitis in the left eye. She had been treated with etoposide and prednisolone for non-Hodgkin's lymphoma. Examination revealed mutton-fat keratic precipitates and numerous infiltrating cells in the anterior chamber with hypopyon. The fundus was invisible due to intense vitreous opacity. Systemic and topical administration of antibiotics was started, and vitrectomy was performed. However, the ocular symptoms did not respond to treatment. Vitrectomy was repeated twice, but severe endophthalmitis findings recurred soon after surgery. Finally, a comprehensive viral PCR test using the intraocular fluid detected CMV with 3.34 × 10 9 copies/ml, leading to a diagnosis of CMV retinitis., Conclusions: If the causative agent is not identified in endophthalmitis that develops in immunosuppressive patients, CMV may also be considered as the possible cause.

Conventional phonocardiography is useful for objective assessment of cardiac auscultation, but its availability is limited. More recently, an ankle-brachial index (ABI) measurement system equipped with simple phonocardiography has become widely used for diagnosing peripheral artery disease, however, whether this simple phonocardiography can be an alternative to conventional phonocardiography remains unclear.This retrospective study consisted of 48 patients with hypertrophic cardiomyopathy (HCM) and 107 controls. The presence of the fourth sound (S4) was assessed by conventional phonocardiography, in addition to apexcardiography and auscultation, in all patients with HCM. S4 was also estimated by the ABI measurement system with the phonocardiographic microphone on the sternum (the standard method) or at the apex (the apex method) in HCM patients and controls.S4 on conventional phonocardiography was detected in 42 of 48 patients (88%) with HCM. Auscultation for the detection of S4 had a sensitivity of 0.78, specificity of 0.57, and accuracy of 0.75. These diagnostic values were generally superior to those of the standard method using the ABI measurement system, whereas the apex method using the ABI measurement system had better diagnostic values, with an excellent specificity of 1.0, sensitivity of 0.77, and accuracy of 0.80. No significant differences were observed in low ABI defined as < 0.9.Simple phonocardiography equipped with the ABI measurement system may be an alternative to conventional phonocardiography for the detection of S4 in patients with HCM when the phonocardiographic microphone is moved from the sternum to the apex.

Diabetic retinopathy is a major cause of blindness in developed countries, and is characterized by deterioration of barrier function causing vascular hyperpermeability and retinal edema. Vascular endothelial growth factor (VEGF) is a major mediator of diabetic macular edema. Although anti-VEGF drugs are the first-line treatment for diabetic macular edema, some cases are refractory to anti-VEGF therapy. Osteopontin (OPN) is a phosphoglycoprotein with diverse functions and expressed in various cells and tissues. Elevated OPN level has been implicated in diabetic retinopathy, but whether OPN is involved in hyperpermeability remains unclear. Using streptozotocin-induced diabetic mice (STZ mice) and human retinal endothelial cells (HRECs), we tested the hypothesis that up-regulated OPN causes tight junction disruption, leading to vascular hyperpermeability. The serum and retinal OPN concentrations were elevated in STZ mice compared to controls. Intravitreal injection of anti-OPN neutralizing antibody (anti-OPN Ab) suppressed vascular hyperpermeability and prevented decreases in claudin-5 and ZO-1 gene expression levels in the retina of STZ mice. Immunohistochemical staining of retinal vessels in STZ mice revealed claudin-5 immunoreactivity with punctate distribution and attenuated ZO-1 immunoreactivity, and these changes were prevented by anti-OPN Ab. Intravitreal injection of anti-OPN Ab did not change VEGF gene expression or protein concentration in retina of STZ mice. In an in vitro study, HRECs were exposed to normal glucose or high glucose with or without OPN for 48 h, and barrier function was evaluated by transendothelial electrical resistance and Evans blue permeation. Barrier function deteriorated under high glucose condition, and was further exacerbated by the addition of OPN. Immunofluorescence localization of claudin-5 and ZO-1 demonstrated punctate appearance with discontinuous junction in HRECs exposed to high glucose and OPN. There were no changes in VEGF and VEGF receptor-2 expression levels in HRECs by exposure to OPN. Our results suggest that OPN induces tight junction disruption and vascular hyperpermeability under diabetic conditions. Targeting OPN may be an effective approach to manage diabetic retinopathy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Simplifying jugular venous pressure (JVP), visibility of the right internal jugular vein above the right clavicle in the sitting position, has been proposed in the management of heart failure (HF) because of its convenience. However, this method may be undervalued for the detection of mildly to moderately increased JVP. Increased JVP on inspiration, known as Kussmaul sign, may be a useful physical finding in this condition. This study consisted of 138 patients who were admitted for the management of HF. Using this simple method, JVP was assessed at rest in the sitting position before discharge; its response to inspiration was also examined if no high JVP was noted at rest. The primary outcome was a composite of cardiac death and hospitalization for worsening HF. Among all the patients, 16 patients (12%) had high JVP at rest and another 16 patients (12%) had high JVP not at rest but on inspiration. During a follow-up period of 249 ± 182 days, a primary outcome event occurred in 63 patients (46%). The incidence of adverse cardiac events was higher in patients with a high JVP at rest (69%; hazard ratio 3.31, 95% confidence interval 1.64 to 6.67, p = 0.0009) and in patients with a high JVP on inspiration (56%; hazard ratio 2.18, 95% confidence interval 1.02 to 4.63, p = 0.043) than in patients without a high JVP in both conditions (41%). In conclusion, a high JVP not only at rest but also on inspiration was associated with a poor prognosis. The response of JVP to inspiration using this simple technique of physical examination may be a new approach in the management of HF., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Patients with hypertrophic cardiomyopathy (HCM) in sinus rhythm commonly show the fourth heart sound (S4). The lack of S4 may be a marker of impaired atrial function in HCM patients with sinus rhythm., Methods and Results: This retrospective study consisted of 47 patients with HCM who had undergone phonocardiography and a cardiopulmonary exercise test. The primary outcome was a composite of cardiac death, stroke, hospitalization for worsening heart failure, and newly developed atrial fibrillation (AF). S4 was detected in 38 of 43 patients with sinus rhythm (88%). Peak oxygen consumption was the highest in 38 sinus rhythm patients with S4 (23.6 ± 5.6 mL/kg/min), middle in five sinus rhythm patients without S4 (19.3 ± 6.7 mL/kg/min), and lowest in four patients with AF (15.7 ± 3.3 mL/kg/min, p = 0.01). After a median of 40.5 months, the incidence of the primary outcome was higher in patients without S4 than in those with S4 (33% vs. 8%; hazard ratio, 6.17; 95% confidence interval, 1.02 - 37.4; p = .04) and higher in sinus rhythm patients without S4 than in those with S4 (60% vs. 8%; hazard ratio, 12.05; 95% confidence interval, 2.31 - 71.41; p = .007)., Conclusions: The absence of S4 on phonocardiography was associated with impaired exercise tolerance and adverse cardiac events in HCM patients with sinus rhythm., (© 2022 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)

Introduction: Apical dissection and control of the dorsal vascular complex (DVC) affects blood loss, positive surgical margins, and urinary control during robot-assisted laparoscopic radical prostatectomy. Soft coagulation is widely used for hemostasis. However, using soft coagulation to the DVC may affect the continence outcomes. In this study, we described technique and outcomes for division of the DVC after soft coagulation (DVC-SC) compared with delayed ligation of the DVC (D-DVC)., Material and Methods: Medical records of 170 patients who underwent robot-assisted laparoscopic radical prostatectomy from June 2016 to March 2020 were retrospectively reviewed. To reduce the selection bias, the two groups were matched in a 1:1 ratio on the basis of propensity scores. Perioperative data and results were compared in both groups., Results: Patients undergoing DVC-SC experienced less estimated blood loss compared to patients undergoing D-DVC (median: 105.5 vs 225 ml, p = 0.017). Postoperative continence rates at 1 week, 1, 3, 6 months in DVC-SC group and D-DVC group were 32.5% versus 15%, 62.5% versus 32.5%, 85% versus 67.5%, 95% versus 90%, respectively. Continence was significantly better at 1 month with DVC-SC versus D-DVC (p = 0.013)., Conclusions: Division of the DVC after soft coagulation technique did not affect continence after robot-assisted laparoscopic radical prostatectomy despite the thermal division and gave the surgeon good hemostasis with simple procedure., Competing Interests: The authors declare no conflicts of interest., (Copyright by Polish Urological Association.)

Background: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness in older people. Low-grade inflammation is well-known as one of the pathogenic mechanisms in nAMD. Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for nAMD, although macula atrophy (MA) developed under anti-VEGF therapy causes irreversible visual function impairment and is recognized as a serious disorder. Here, we show specific expression patterns of aqueous humor (AH) cytokines in nAMD eyes developing MA under intravitreal injection of aflibercept (IVA) as an anti-VEGF antibody and present predictive cytokines as biomarkers for the incidence of MA in nAMD eyes under IVA treatment., Methods: Twenty-eight nAMD patients received three consecutive monthly IVA, followed by a pro re nata regimen for 2 years. AH specimens were collected before first IVA (pre-IVA) and before third IVA (post-IVA). AH cytokine levels, visual acuity (VA), and central retinal thickness (CRT) were measured., Results: Two-year incidence of MA was 21.4%. In nAMD eyes developing MA [MA (+) group], pre-IVA levels of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1β, VEGF and post-IVA level of MCP-1 were higher than those in nAMD eyes without MA [MA (-) group]. In hierarchical cluster analysis, pre-IVA MCP-1 and VEGF were grouped into the same subcluster, as were post-IVA MCP-1 and CRT. In principal component analysis, principal component loading (PCL) of pre-IVA interferon-γ-inducible protein 10 (IP-10) was 0.61, but PCL of post-IVA IP-10 decreased to -0.09. In receiver operating characteristic analysis and Kaplan-Meier curves, pre-IVA MCP-1, MIP-1β, and VEGF and post-IVA interleukin-6, MCP-1, and MIP-1β were detected as predictive factors for MA incidence. In 2-year clinical course, changes of VA in groups with high levels of pre-IVA MIP-1β (over 39.9 pg/ml) and VEGF (over 150.4 pg/ml) were comparable to those in MA (+) group., Conclusion: Substantial loss of IP-10 effects and persistent inflammation contribute to incidence of MA, and screening of AH cytokine levels could be a useful method to predict MA incidence in nAMD eyes under anti-VEGF therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sato, Enoki, Karasawa, Someya, Taguchi, Harimoto, Takayama, Kanda, Ito and Takeuchi.)

Background: The Bezold-Jarisch reflex is a depressor reflex of the heart due to the preferential distribution of vagal nerves in the inferior wall of the left ventricle. We report a case of Stanford type A acute aortic dissection, in which coronary spastic angina caused the Bezold-Jarisch reflex in the acute phase., Case Report: A 53-year-old man presented with left chest pain and cold sweating. An electrocardiogram was normal and the high-sensitivity cardiac troponin T level was negative. A diagnosis of Stanford type A acute aortic dissection was made based on computed tomography (CT); there was no evidence of ischemic heart disease on coronary CT angiogram obtained simultaneously. While waiting for emergency surgical repair, chest pain worsened, followed by bradycardia and hypotension, along with ST-segment elevations in the inferior leads, all of which were resolved by conservative treatment. During surgery, no evidence to suggest an extension of the dissection to the ostium of the right coronary artery was observed. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The present case highlights the importance of recognizing the Bezold-Jarisch reflex because this depressor reflex may require different management than other conditions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Elevated level of interleukin (IL)-17, predominantly produced by T helper (Th) 17 cells, has been implicated in diabetic retinopathy (DR), but it remains unclear whether IL-17 is involved in the pathogenesis of DR. Ins2 Akita (Akita) mice spontaneously develop diabetes, and show early pathophysiological changes in diabetic complications. On the other hand, interferon-γ knock out (GKO) mice exhibit high differentiation and activation of Th2 and Th17 cells as a result of Th1 cell inhibition. In this study, Ins2 Akita IFN-γ-deficient (Akita-GKO) mice were established by crossbreeding Akita mice with GKO mice, and Th17-mediated immune responses on DR were investigated. Blood glucose levels (BGL) of Akita mice and Akita-GKO mice were significantly higher than those of age-matched wild type (WT) or GKO mice, and there was no significant difference in BGL between Akita and Akita-GKO mice. Relative mRNA expression of ROR-γt that is a transcriptional factor of Th17 cells but not GATA-3 that is for Th2 cells was significantly upregulated only in Akita-GKO mice compared with WT mice, and the proportions of IL-17 and IL-22-producing splenic CD4 + cells were significantly higher in Akita-GKO mice than in wild type (WT), Akita, or GKO mice. In the retina, mRNA expression of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule-1 (ICAM-1) were increased in Akita-GKO mice more than in Akita or GKO mice, and statistically significant differences were observed between Akita-GKO mice and WT mice. Leukostasis in retinal vessels and ocular level of VEGF protein increased significantly in Akita-GKO mice compared with the other groups. Edematous change in the retinal surface layer, retinal exudative lesions depicted as areas of hyperfluorescence in fluorescein angiography (FA), and vascular basement membrane thickening in all layers of the retina were also observed in Akita-GKO mice at 9-week-old but not in age-matched Akita or GKO mice. These results suggested that Th17 cell-mediated immune responses might be involved in promotion of functional and morphological changes in the retina of mice spontaneously developing diabetes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Before the androgen target therapy era, flutamide was widely used for castration-resistant prostate cancer in Japan. Enzalutamide is currently the recommended treatment; however, the efficacy and safety of enzalutamide and flutamide after combined androgen blockade therapy with bicalutamide, has not been compared., Methods: Patients with castration-resistant prostate cancer who received combined androgen blockade therapy with bicalutamide were randomly assigned to receive either enzalutamide or flutamide. The primary endpoint for efficacy was the 3-month prostate-specific antigen response rate. This trial is registered with ClinicalTrials.gov (NCT02346578) and the University hospital Medical Information Network (UMIN000016301)., Results: Overall, 103 patients were enrolled. The 3- (80.8% vs. 35.3%; p < 0.001) and 6-month (73.1% vs. 31.4%; p < 0.001) prostate-specific antigen response rates were higher in the enzalutamide than in the flutamide group. The 3-month disease progression rates (radiographic or prostate-specific antigen progression) were 6.4% and 38.8% in the enzalutamide and flutamide groups, respectively [hazard ratio (HR): 0.16; 95% confidence interval (CI): 0.05-0.47; p < 0.001]; the 6-month rates were 11.4% and 51.1%, respectively (HR 0.22; 95% CI 0.09-0.50; p < 0.001). Enzalutamide provided superior prostate-specific antigen progression-free survival compared with flutamide (HR 0.29; 95% CI 0.15-0.54; p < 0.001). Median time to prostate-specific antigen progression-free survival was not reached and was 6.6 months in the enzalutamide and flutamide groups, respectively., Conclusions: As an alternative anti-androgen therapy in patients with castration-resistant prostate cancer who fail bicalutamide-combined androgen blockade therapy, enzalutamide provides superior clinical outcomes compared with flutamide. Enzalutamide should be preferred over flutamide in these patients.

Purpose: To investigate the clinical characteristics and visual outcomes of patients with work-related open globe injuries (OGIs) and compare them with patients with non-work-related OGIs., Design: Retrospective, observational, multicentre, case-control study., Methods: A total of 374 patients with work-related OGIs and 170 patients with non-work-related OGIs who presented to hospitals that belong to the Japan-Clinical Research of Study group from 2005 to 2015 were included in this study. Clinical data including age, sex, initial and final visual acuity, type of open globe injury, lens status, zone of injury, wound length, and presence of proliferative vitreoretinopathy, retinal detachment, expulsive haemorrhage, and endophthalmitis were recorded., Main Outcome Measures: Visual acuity. Results Work-related OGIs were associated with younger age, male sex, better initial and final visual acuity, more laceration, smaller wounds, presence of retinal detachment, and expulsive haemorrhage, compared with non-work-related OGIs. Multiple regression analysis revealed that final visual acuity is significantly associated with initial visual acuity, wound length, and the presence of proliferative vitreoretinopathy in work-related OGIs., Conclusions: Work-related OGIs showed better visual outcomes than other OGIs. Initial visual acuity, wound length, and the presence of proliferative vitreoretinopathy are predictors of visual outcomes in patients with work-related OGIs.

Aims: Ventricular late potentials (VLPs) represent delayed conduction due in part to myocardial fibrosis. We sought to examine the relationship of signal-averaged electrocardiography findings with myocardial fibrosis as assessed by cardiac magnetic resonance (CMR) in patients with hypertrophic cardiomyopathy (HCM)., Methods: This study consisted of 41 HCM patients with sinus rhythm who had undergone risk assessment including CMR and signal-averaged electrocardiography such as VLPs, filtered QRS duration, low amplitude signal duration of the terminal filtered QRS below 40 μV (LAS), and root mean square voltage of the late 40 ms of the filtered QRS (RMS). The concordance rate between VLPs and myocardial fibrosis as assessed by CMR was examined., Results: Late gadolinium enhancement (LGE) on CMR was detected in 13 patients, and VLPs were detected in 14. Filtered QRS duration, LAS, RMS, and VLPs were not associated with LGE. The results of LGE and VLPs were concordant in 26 patients, whereas 15 exhibited discordance. Patients with discordance had a higher maximum wall thickness (24.1 ± 4.0 mm versus 21.0 ± 5.9 mm, p < 0.05), higher LGE volume (2.3 ± 1.2 g/cm versus 0.0 ± 0.8 g/cm, p < 0.01), lower LGE volume/the total number of sites with LGE (1.5 ± 0.7 versus 3.1 ± 2.8, p < 0.01), and predominant LGE location of the interventricular septum and anterior wall (60% versus 8%, p < 0.01) than patients with concordance., Conclusion: VLPs were not a reliable marker for the detection of myocardial fibrosis as assessed by LGE on CMR in our cohort of patients with HCM., Condensed Abstract: Ventricular late potentials on signal-averaged electrocardiography represent delayed conduction due in part to myocardial fibrosis but were not an alternative to cardiac magnetic resonance for detecting myocardial fibrosis in patients with hypertrophic cardiomyopathy., Competing Interests: Declaration of competing interest None declared., (Copyright © 2018. Published by Elsevier Inc.)

Purpose: To evaluate underlying subclinical ocular inflammation in Vogt-Koyanagi-Harada (VKH) disease with sunset glow fundus (SGF) by multiple analyses., Study Design: Retrospective observational study., Methods: Clinical records of 34 eyes of 17 VKH patients with SGF in whom laser flare photometry (LFP), enhanced depth imaging optical coherence tomography (EDI-OCT), and indocyanine green angiography (ICGA) were performed on the same day were reviewed. The mean age was 57.3 ± 16.3 years, and the mean duration from the initial onset of uveitis was 47.1 ± 22.1 months. Flare counts, ICGA scores, and subfoveal choroidal thickness (SFCT) were compared between eyes., Results: Although clinical ocular inflammation was observed only in 4 eyes (11.8%), inflammatory signs were observed in 23 out of 34 eyes by LFP (67.6%), in 27 eyes by ICGA (79.4%), and in 10 eyes by SFCT (29.4%). Active inflammatory signs detected by ICGA were observed in 77.8% by LFP and in 25.9% by SFCT. The strength of agreement (Cohen's kappa coefficient) between positive ICGA score and positive flare score was 0.406 (95% CI: 0.076-0.7359, P < 0.01), but there was no association between positive ICGA score and increased SFCT. In addition, positive flare count was the significant prognostic factor of positive ICGA score with odds ratio 11.7., Conclusions: Subclinical ocular inflammation signs were detected in most VKH patients with SGF by ICGA and a substantial proportion of which were also detected by LFP, whereas SFCT was less sensitive to detect subclinical inflammation., Competing Interests: There are no conflicts of interest to declare., (Copyright © 2019 Toshihiko Murata et al.)

Aims/introduction: To determine the current clinical preferences of anti-vascular endothelial growth factor (VEGF) treatment protocols for diabetic macular edema (DME) in Japan., Materials and Methods: This was a descriptive cross-sectional study. Answers to a questionnaire consisting of 16 questions were obtained from 176 of 278 (63.3%) surveyed ophthalmologists., Results: The results showed that 81.2% preferred intravitreal injections of anti-VEGF antibodies as the first-line therapy. The most important indicators for beginning anti-VEGF therapy were: the best-corrected visual acuity in 44.3% and the retinal thickness in 30.7%. In the loading phase, 53.4% preferred a single injection, and in the maintenance phase, 75.0% preferred the pro re nata regimen. Financial limitation (85.8%) was reported as the most important difficulty in the treatment. For combination therapy with anti-VEGF treatment, panretinal photocoagulation, focal photocoagulations and a sub-Tenon steroid injection were preferred. The contraindications for anti-VEGF therapy were: prior cerebral infarction (72.7%). Regarding the use of both approved anti-VEGF agents in Japan, ranibizumab and aflibercept, 39.8% doctors used them appropriately., Conclusions: Our results present the current clinical preferences of anti-VEGF treatment for DME in Japan. The best-corrected visual acuity and the retinal thickness are important indicators to institute this therapy. The majority of the ophthalmologists use anti-VEGF treatment as first-line therapy and prefer the 1 + pro re nata regimen., (© 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Hypoxia-induced retinal edema primarily induced by vascular lesion is seen in various conditions such as diabetic retinopathy (DR) and retinal vein occlusion (RVO). The edematous changes in these conditions occur mainly in intermediate and deep layers of retina as a result of disruption of the inner blood-retinal barrier (iBRB). However, the effect of direct and acute hypoxia on iBRB remains to be elucidated. To investigate direct and acute hypoxia-induced changes in retina, especially in astrocytes/Müller cells that are involved in the maintenance of retinal structure and function, we developed an adult mouse model of hypoxia-induced retinal edema by 24-h exposure in a 6% oxygen environment. Immunohistochemical staining of glial fibrillary acidic protein (GFAP) was enhanced mainly in the superficial layer of the hypoxic retina, corresponding to edematous change. Electron microscopic observation of the hypoxic retina showed vacuole formation in astrocyte/Müller cell foot processes around capillaries in the superficial layer, while no abnormal findings in the perivascular areas were found in intermediate and deep layers. Increase in vascular leakage quantified by Evans blue dye and tight junction breakdown detected by electron-dense tracer were observed in the hypoxia group. In the hypoxic retina, microglia was activated and relative gene expressions of pro-inflammatory cytokines were significantly upregulated. Dexamethasone suppressed these hypoxia-induced pathological reactions. Thus, unlike DR and RVO that induce iBRB breakdown in deeper retinal layers, atmospheric hypoxia induced iBRB disruption with subsequent edematous change mainly in the superficial layer of the retina, and that dexamethasone prevented these pathological changes. In this mouse model, direct and acute hypoxia induces retinal edema in the superficial layer of the retina with morphological changes of astrocytes/Müller cells, and is potentially useful for ophthalmic research in the field related to retinal hypoxia and its treatment., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The distribution of age at diagnosis in ocular sarcoidosis has shifted towards the older age groups in developed countries. In systemic sarcoidosis, age-related differences in the clinical presentation, which reflect the therapeutic strategies, was reported. We retrospectively compared 100 consecutive patients from April 2010 to March 2016 who were initially diagnosed with ocular sarcoidosis by International Workshop on Ocular Sarcoidosis criteria. They were classified into elder (>65 years: 50 patients) and younger (≤65 years: 50 patients) groups by the age at diagnosis of uveitis associated with sarcoidosis. All patients received ophthalmic examination to assess the presence of seven intraocular signs and 4 laboratory parameters. Significantly fewer ocular signs (2.8 ± 1.5 and 3.6 ± 1.5; P = 0.0034) and abnormal laboratory results (1.5 ± 1.2 and 2.0 ± 1.2; P = 0.023) were detected in the elder group than in the younger group; statistical differences were found between the groups regarding the frequencies of mutton-fat keratic precipitates (40% and 64%; P = 0.012), vitreous opacities (60% and 78%; P = 0.0059), bilateral inflammation (64% and 80%; P = 0.012), and bilateral hilar lymphadenopathy between the groups (52% and 78%; P < 0.001). Multiple linear regression analysis showed negative correlations between age and number of detected ocular signs (r = -0.36, P < 0.001) and laboratory results (r = -0.20, P = 0.023). The characteristic ocular signs and abnormal laboratory results had a lower frequency in the elder patients compared with the younger patients. Probable or possible ocular sarcoidosis by the international criteria should increase with increased life expectancy in developed countries., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To investigate the clinical characteristics and visual outcomes in patients with fall-related open globe injuries and to evaluate differences between fall-related and non-fall-related open globe injuries in Japan., Methods: A retrospective review of patients with open globe injury who presented to Japan-Clinical Research of Study (J-CREST) hospitals between 2005 and 2015 was enrolled. Clinical information including age, sex, initial visual acuity, final visual acuity, type of injury, status of the crystalline lens, zone of injury, wound length, presence of retinal detachment, proliferative vitreoretinopathy, expulsive hemorrhage, and endophthalmitis was recorded., Results: A total of 374 eyes were enrolled, of which 120 (32.1%) suffered from fall-related injury with average age of 73.7 ± 15.9 years (range, 11-101 years). A majority of patients were female (55.8%). Of 120 patients with fall-related injury, 109 (90.8%) presented with rupture and 11 (9.2%) with laceration. A multiple regression analysis revealed that final visual acuity was significantly associated with initial visual acuity (r = 0.99, P < 0.001). Compared to non-fall-related open globe injuries, fall-related open globe injuries were associated with elderly age, female sex, poorer initial and final visual acuity, rupture, absence of the lens, larger wound size, retinal detachment, expulsive hemorrhage, and absence of endophthalmitis (P < 0.01)., Conclusions: Fall-related open globe injuries were more frequent in elderly female and accompanied by larger wound lengths and severer ocular complications. Visual outcomes in patients with fall-related open globe injuries were related to initial visual acuity.

Background: The 4th heart sound (S4) is commonly heard in patients with hypertrophic cardiomyopathy (HCM). The 3rd heart sound (S3) is also audible in HCM patients regardless of the presence or absence of heart failure. These extra heart sounds may be associated with myocardial fibrosis because myocardial fibrosis has been suggested to affect left ventricular compliance.Methods and Results:The present retrospective study evaluated 53 consecutive HCM patients with sinus rhythm who had no symptoms of heart failure and underwent an initial assessment including phonocardiography, echocardiography, and late gadolinium enhancement (LGE) magnetic resonance imaging (MRI). S3 was detected on phonocardiography in 13% of all patients, and S4 was recorded in 75% of patients. Patients with S3 had a higher incidence of LGE and larger LGE volumes (86% and 11.5±2.4 g/cm, respectively) than patients without S3 (33% and 2.5±0.8 g/cm, respectively; P=0.02 and P=0.002). The presence of S4 was not associated with MRI findings, including the incidence of LGE and LGE volume. The diagnostic value of S3 for the detection of LGE was highly specific (97%), with a low sensitivity (29%)., Conclusions: Myocardial fibrosis, as assessed by LGE, was associated with S3 but not with S4 in patients with HCM. These results may contribute to the risk stratification of patients with HCM.

Inflammation is known to be involved in the progression of diabetic retinopathy. We have recently reported that vitreous levels of IL-4, IL-17A, IL-22, IL-31, and TNFα are higher than the respective serum levels in proliferative diabetic retinopathy (PDR) patients, and that vitreous levels of these cytokines are higher in PDR than in other non-inflammatory vitreoretinal diseases or uveitis associated with sarcoidosis. In the present study, we investigated inflammatory cytokines including Th17 cell-related cytokines in aqueous humor samples obtained from eyes with PDR, and analyzed the association between the aqueous humor and vitreous fluid levels of individual cytokines. The study group consisted of 31 consecutive type 2 diabetic patients with PDR who underwent cataract surgery and vitrectomy for vitreous hemorrhage and/or tractional retinal detachment. Undiluted aqueous humor was collected during cataract surgery, and then vitreous fluid was obtained using a 25G vitreous cutter inserted into the mid-vitreous cavity at the beginning of vitrectomy. IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble CD40 ligand (sCD40L), and TNFα levels in the aqueous humor and vitreous fluid were measured using a beads-array system. Although IL-17A was detected in the aqueous humor of eyes with PDR and the level correlated with IL-17A level in the vitreous fluid, both percent detectable and level of IL-17A in the aqueous humor were significantly lower than those in the vitreous fluid. Vitreous IL-17A level was related significantly to IL-10, IL-22, and TNFα levels in aqueous humor as well as in vitreous fluid, On the other hand, aqueous IL-17A level was not related significantly to aqueous or vitreous levels of IL-10, IL-22 or TNFα level. The present study demonstrated that IL-17A level and detectable rate in the aqueous humor of patients with PDR are markedly lower than those in the vitreous fluid and aqueous IL-17A does not correlate with vitreous levels of other cytokines, and hence should not be used as a surrogate for IL-17A in the vitreous fluid.

Purpose: To examine antigen-stimulated cytokine production by Behçet disease patients (BD) before and after infliximab infusion., Methods: PBMCs were obtained before and after infliximab infusion in BD patients with or without recurrent uveitis during at least 1 year of infliximab therapy, and from healthy subjects. PBMCs were cultured with IRBP, and Th-related cytokines in cultures were measured., Results: Levels of IL-4, IL-6, IL-10 IL-17A, IL-17F, IL-31, IFN-γ, and TNFα were higher in BD before infliximab infusion than in healthy subjects, and these levels were the highest in BD with recurrent uveitis. After infliximab infusion, these cytokine levels were reduced to a greater extent in BD without recurrent uveitis than in BD with recurrence., Conclusions: Th-related cytokines produced by IRBP-stimulated PBMCs were elevated in BD, and infliximab infusion suppressed these cytokines to a greater extent in BD without recurrent uveitis than in those with recurrence.

Purpose: High-mobility group box-1 (HMGB1) is a nonhistone DNA-binding nuclear protein released from necrotic cells, which is also secreted by activated leukocytes and acts as a primary proinflammatory cytokine. In this study, we compared vitreous HMGB1 levels in ocular sarcoidosis with those in noninflammatory vitreoretinal diseases and evaluated its association with Th cell-related and proinflammatory cytokines., Methods: The study group consisted of 24 patients with ocular sarcoidosis. The control group consisted of 27 patients with proliferative diabetic retinopathy (PDR) and 24 with idiopathic epiretinal membrane (ERM). Vitreous fluid samples were obtained at the beginning of vitrectomy. Vitreous levels of HMGB1 and IL-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL-33, IFN-γ, soluble CD40 ligand (sCD40L), and TNFα were measured., Results: High-mobility group box-1 was detected in the vitreous of 23 of 24 patients (95.8%) with ocular sarcoidosis. Mean vitreous level of HMGB1 was the highest in the sarcoidosis group, followed by the PDR and ERM groups, with significant differences between the three groups. In the sarcoidosis group, vitreous levels of IL-6, IL-10, IL-31, IFN-γ, sCD40L, and TNFα were significantly higher than those in the idiopathic ERM group, and IFN-γ and sCD40L were significantly higher than those in the PDR group. Vitreous HMGB-1 level correlated significantly with IL-10, IFN-γ, and sCD40L levels but not with IL-6, IL-17, IL-31, or TNFα levels., Conclusions: The vitreous level of HMGB1 is elevated in ocular sarcoidosis and is associated with vitreous levels of Th1- and regulatory T-related cytokines, but not with proinflammatory or Th17-related cytokines.

Aneurysms of the sinus of Valsalva are characterized by dilatation of at least one of the three aortic sinuses. We experienced a case with unruptured aneurysm of the right sinus of Valsalva, in which serial imaging studies were useful in assessing a rare complication after surgical repair. An asymptomatic 75-year-old man underwent patch closure of the aneurysm orifice because of progressive enlargement of the aneurysm. The postoperative course was uneventful, and computed tomography (CT), performed a week after the patch repair, showed no leakage of contrast medium into the isolated aneurysm. Three months later, echocardiography showed decreased size of the aneurysm with heterogeneous echogenicity and possible blood flow in the aneurysm, findings suggestive of thrombus formation and a recurrent fistula. CT with contrast medium showed partial recanalization between the patched aneurysm and the right sinus of Valsalva. Follow-up echocardiography, performed 1 year after surgery, revealed neither definite aneurysm nor shunt flow of Valsalva. The present case highlights that non-invasive follow-up can be an alternative option when carried out with caution in selected patients with incomplete closure of Valsalva aneurysm.

Background: Behçet's disease (BD)-associated uveitis causes retinal damage leading to severe visual disturbance. The early morphological changes in the retina are revealed by disappearance or disruption of the external limiting membrane (ELM), inner segment ellipsoid zone (EZ) and cone interdigitation zone (CIZ) in the outer retina shown on spectral domain-optical coherence tomography (SD-OCT). However, it is unknown whether these changes in the retina are reversible in BD-associated uveitis., Case Presentation: A 38-year-old man was referred to our hospital with 5 years history of panuveitis in both eyes. Recurrent oral ulcer, folliculitis, and genital ulcer were noted as systemic complications. Moderate cell infiltration into the anterior chamber, and diffuse vitritis were observed in both eyes, and best corrective visual acuity (BCVA) was 20/60 in the right and 20/200 in the left eye. Fluorescein angiography (FA) showed severe dye leakage from extensive retinal vessels in both eyes. Spectral domain-optical coherence tomography (SD-OCT) revealed retinal cysts and disruption of the external limiting membrane (ELM), inner segment ellipsoid zone (EZ) and cone interdigitation zone (CIZ) in the macular region of both eyes. BD was diagnosed based on the ocular features and systemic lesions, and infliximab therapy was initiated for the severe visual disturbance. After treatment with infliximab, foveal excavation was first recovered with disappearance of retinal cysts, and then ELM and EZ were gradually reconstituted on SD-OCT. Finally, CIZ became distinguishable after 24 months of infliximab therapy. BCVA was recovered to 20/25 in both eyes, and ocular inflammatory attack did not recur after the initiation of infliximab therapy., Conclusion: Disruption of ELM, EZ, and CIZ shown on SD-OCT in BD-associated uveitis could be reconstituted by continuous infliximab treatment, which leaded to the improvement of visual acuity.