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Purpose: To assess the impact of genetic risk estimation for primary open-angle glaucoma (POAG) in Japanese individuals., Design: Cross-sectional analysis., Participants: Genetic risk scores (GRSs) were constructed based on a genome-wide association study (GWAS) of POAG in Japanese people. A total of 3625 Japanese individuals, including 1191 patients and 2434 controls (Japanese Tohoku), were used for the model selection. We also evaluated the discriminative accuracy of constructed GRSs in a dataset comprising 1034 patients and 1147 controls (the Japan Glaucoma Society Omics Group [JGS-OG] and the Genomic Research Committee of the Japanese Ophthalmological Society [GRC-JOS]) and 1900 participants from a population-based study (Hisayama Study)., Methods: We evaluated 2 types of GRSs: polygenic risk scores using the pruning and thresholding procedure and a GRS using variants associated with POAG in the GWAS of the International Glaucoma Genetics Consortium (IGGC). We selected the model with the highest areas under the receiver operating characteristic curve (AUC). In the population-based study, we evaluated the correlations between GRS and ocular measurements., Main Outcome Measure: Proportion of patients with POAG after stratification according to the GRS., Results: We found that a GRS using 98 variants, which showed genome-wide significance in the IGGC, showed the best discriminative accuracy (AUC, 0.65). In the Japanese Tohoku, the proportion of patients with POAG in the top 10% individuals was significantly higher than that in the lowest 10% (odds ratio [OR], 6.15; 95% confidence interval [CI], 4.35-8.71). In the JGS-OG and GRC-JOS, we confirmed similar impact of POAG GRS (AUC, 0.64; OR [top vs. bottom decile], 5.81; 95% CI, 3.79-9.01). In the population-based study, POAG prevalence was significantly higher in the top 20% individuals of the GRS compared with the bottom 20% (9.2% vs. 5.0%). However, the discriminative accuracy was low (AUC, 0.56). The POAG GRS was correlated positively with intraocular pressure (r = 0.08: P = 4.0 × 10 -4 ) and vertical cup-to-disc ratio (r = 0.11; P = 4.0 × 10 -6 )., Conclusions: The GRS showed moderate discriminative accuracy for POAG in the Japanese population. However, risk stratification in the general population showed relatively weak discriminative performance., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Central neuropathic pain after foramen magnum decompression (FMD) for Chiari malformation type 1 (CM-1) with syringomyelia can be residual and refractory. Here we present a case of refractory central neuropathic pain after FMD in a CM-1 patient with syringomyelia who achieved improvements in pain following spinal cord stimulation (SCS) using fast-acting sub-perception therapy (FAST™)., Case Presentation: A 76-year-old woman presented with a history of several years of bilateral upper extremity and chest-back pain. CM-1 and syringomyelia were diagnosed. The pain proved drug resistant, so FMD was performed for pain relief. After FMD, magnetic resonance imaging showed shrinkage of the syrinx. Pain was relieved, but bilateral finger, upper arm and thoracic back pain flared-up 10 months later. Due to pharmacotherapy resistance, SCS was planned for the purpose of improving pain. A percutaneous trial of SCS showed no improvement of pain with conventional SCS alone or in combination with Contour™, but the combination of FAST™ and Contour™ did improve pain. Three years after FMD, percutaneous leads and an implantable pulse generator were implanted. The program was set to FAST™ and Contour™. After implantation, pain as assessed using the McGill Pain Questionnaire and visual analog scale was relieved even after reducing dosages of analgesic. No adverse events were encountered., Conclusion: Percutaneously implanted SCS using FAST™ may be effective for refractory pain after FMD for CM-1 with syringomyelia., (© 2024. The Author(s).)

We investigated the relationship between subjective symptoms and objective findings in patients with allergic conjunctival diseases (ACD) and test results for tear total IgE (t-tIgE), conjunctival eosinophils (c-Eo), serum total IgE (s-tIgE), serum-antigen specific IgE (s-sIgE), and serum eosinophils (s-Eo). Subjective symptoms and objective findings of patients with ACD were evaluated using Japanese Allergic Conjunctival Disease Quality of Life Questionnaire (JACQLQ), which described disability score and emotional score written by patient and clinical findings score written by ophthalmologist. We investigated the relationship between questionnaire scores and laboratory data for t-tIgE, c-Eo, s-tIgE, s-sIgE, and s-Eo. Scores of impediments to life and of moods were highest in vernal keratoconjunctivitis among ACD. Cases with positive pollen-sIgE showed significantly more nasal symptom score than those with negative pollen-sIgE (P < 0.05). Cases with positive t-tIgE or c-Eo showed significantly more objective symptoms' JACQLQ score than those with negative t-tIgE or c-Eo (P < 0.05), respectively. Cases positive for house dust/mite-sIgE, showed significantly more objective symptoms' JACQLQ score than those without for house dust/mite-sIgE (P < 0.05). These results indicate that ACD could be analyzed more accurately by the combination of JACQLQ and laboratory data., (© 2024. The Author(s).)

Mucosal-associated invariant T (MAIT) cells are a unique subset of T cells that recognizes metabolites derived from the vitamin B2 biosynthetic pathway. Since the identification of cognate antigens for MAIT cells, knowledge of the functions of MAIT cells in cancer, autoimmunity, and infectious diseases has been rapidly expanding. Recently, MAIT cells have been found to contribute to visual protection against autoimmunity in the eye. The protective functions of MAIT cells are induced by T-cell receptor (TCR)-mediated activation. However, the underlying mechanisms remain unclear. Thus, this mini-review aims to discuss our findings and the complexity of MAIT cell-mediated immune regulation in the eye., 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 © 2024 Fukui, Yamana, Xue, Shirane, Tsutsui, Asahara, Yoshitomi, Ito, Lestari, Hasegawa, Yawata, Takeda, Sonoda and Shibata.)

Purpose: This study aimed to assess the clinical features of pediatric uveitis at a tertiary referral center in Western Japan., Methods: One hundred forty eyes of 80 patients aged <20 years at the time of uveitis onset, who visited Kyushu University Hospital between January 2010 and December 2019 were included in this study. Clinical records were retrospectively reviewed. Demographics, clinical findings, treatments, and visual prognoses were compared between the disease groups., Results: Of 80 patients, 32 were males and 48 were females. The average age of onset was 12.5 ± 4.8 (0-19) years. Tubulointerstitial nephritis and uveitis (TINU) and juvenile idiopathic arthritis (JIA) were the most frequent causes, accounting for 11.3% and 10% of cases, respectively, followed by sarcoidosis (5%), Behçet's disease, acute anterior uveitis, Vogt-Koyanagi-Harada disease, and juvenile chronic iridocyclitis (3.8% each). Infectious uveitis accounted for 7.6% of the cases: cytomegalovirus was the most frequent agent. Of these cases, 43.8% were unclassified. Systemic therapies were administered to 87.5% of the patients with JIA, 33.3% of those with TINU, and 28.6% of the other diagnostic groups. In the unclassified group, 80% of the patients were followed up with only topical corticosteroids. LogMAR visual acuity of 0 or less accounted for more than 80% in the final examination., Conclusion: TINU and JIA were the most common causes of pediatric uveitis. Although each required systemic therapy, most unclassified cases of pediatric uveitis were managed by topical corticosteroids alone with good visual prognosis. Accurate diagnosis is important for pediatric uveitis management.

Background and Purpose: Contrast-induced encephalopathy can result from neurotoxicity of contrast medium in the affected area. The development of intermediate catheters has allowed guidance of catheters to more distal arteries. This study focused on the association between contrast-induced encephalopathy and contrast injection from an intermediate catheter guided into a distal intradural artery during neurointervention for cerebral aneurysms., Materials and Methods: We retrospectively reviewed 420 consecutive aneurysms in 396 patients who underwent neurointervention for extracranial aneurysms and unruptured intracranial aneurysms at our institution from February 2012 to January 2023. Patients were divided into a group with contrast-induced encephalopathy and a group without. To identify risk factors for contrast-induced encephalopathy, we compared clinical, anatomic, and procedural factors between groups by multivariate logistic regression analysis and stepwise selection., Results: Among the 396 patients who underwent neurointervention for cerebral aneurysms, 14 (3.5%) developed contrast-induced encephalopathy. Compared with the group without contrast-induced encephalopathy, the group with contrast-induced encephalopathy showed significantly higher rates of patients on hemodialysis, previously treated aneurysms, intradural placement of a catheter for angiography, nonionic contrast medium, and flow-diversion procedures in univariate analyses. Stepwise multivariate logistic regression analysis revealed intradural placement of a catheter for angiography (OR = 40.4; 95% CI, 8.63-189) and previously treated aneurysms (OR = 8.20; 95% CI, 2.26-29.6) as independent predictors of contrast-induced encephalopathy., Conclusions: Contrast injection from an intradural artery and retreatment of recurrent aneurysms were major risk factors for contrast-induced encephalopathy. Attention should be paid to the location of the intermediate catheter for angiography to avoid developing contrast-induced encephalopathy., (© 2023 by American Journal of Neuroradiology.)

Objectives: To evaluate long-term outcomes of infliximab (IFX) treatment in patients with Behçet's disease (BD)-associated uveitis., Patients and Methods: We retrospectively analyzed the cases of patients with BD-associated uveitis treated with IFX for > 5 years. We compared the numbers of ocular inflammatory attacks, ocular disease activities, and visual acuity before and after the initiation of IFX treatment., Results: The 24 patients were 20 men and 4 women. Their mean age at the initiation of IFX treatment was 37.3 ± 9.2 years. The mean term from the initiation of IFX treatment was 10.3 ± 2.4 years. The average number of ocular inflammatory attacks was 5.4 ± 2.1 per 12 months before the IFX treatment and significantly lower at 0.83 ± 0.96 per 12 months after the initiation of IFX treatment (p < 0.05). We used a scoring system for BD-associated uveitis named the Behçet's disease ocular attack score 24 (BOS24) to estimate the changes in ocular disease activities between before and after initiation of IFX treatment. The average score decreased significantly from 7.58 ± 2.77 to 2.55 ± 2.74 after the initiation of IFX treatment (p < 0.05). Even after > 5 years of the treatment, both the number of ocular attacks and the BOS24 score kept decreasing. The visual acuity in 42 of 48 eyes (24 patients) was improved or maintained., Conclusions: IFX was effective for controlling ocular inflammatory attacks and diminishing ocular disease activities in patients with BD-associated uveitis, and it maintained the patients' visual acuity., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Human cytomegalovirus (HCMV) infections develop into CMV diseases that result in various forms of manifestations in local organs. CMV-retinitis is a form of CMV disease that develops in immunocompromised hosts with CMV-viremia after viruses in the peripheral circulation have entered the eye. In the HCMV genome, extensive diversification of the UL40 gene has produced peptide sequences that modulate NK cell effector functions when loaded onto HLA-E and are subsequently recognized by the NKG2A and NKG2C receptors. Notably, some HCMV strains carry UL40 genes that encode peptide sequences identical to the signal peptide sequences of specific HLA-A and HLA-C allotypes, which enables these CMV strains to escape HLA-E-restricted CD8 + T cell responses. Variations in UL40 sequences have been studied mainly in the peripheral blood of CMV-viremia cases. In this study, we sought to investigate how ocular CMV disease develops from CMV infections. CMV gene sequences were compared between the intraocular fluids and peripheral blood of 77 clinical cases. UL40 signal peptide sequences were more diverse, and multiple sequences were typically present in CMV-viremia blood compared to intraocular fluid. Significantly stronger NK cell suppression was induced by UL40-derived peptides from intraocular HCMV compared to those identified only in peripheral blood. HCMV present in intraocular fluids were limited to those carrying a UL40 peptide sequence corresponding to the leader peptide sequence of the host's HLA class I, while UL40-derived peptides from HCMV found only in the peripheral blood were disparate from any HLA class I allotype. Overall, our analyses of CMV-retinitis inferred that specific HCMV strains with UL40 signal sequences matching the host's HLA signal peptide sequences were those that crossed the blood-ocular barrier to enter the intraocular space. UL40 peptide repertoires were the same in the intraocular fluids of all ocular CMV diseases, regardless of host immune status, implying that virus type is likely to be a common determinant in ocular CMV disease development. We thus propose a mechanism for ocular CMV disease development, in which particular HCMV types in the blood exploit peripheral and central HLA-E-mediated tolerance mechanisms and, thus, escape the antivirus responses of both innate and adaptive immunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflict of interest., (Copyright © 2022 Shirane, Yawata, Motooka, Shibata, Khor, Omae, Kaburaki, Yanai, Mashimo, Yamana, Ito, Hayashida, Mori, Numata, Murakami, Fujiwara, Ohguro, Hosogai, Akiyama, Hasegawa, Paley, Takeda, Maenaka, Akashi, Yokoyama, Tokunaga, Yawata and Sonoda.)

Autoimmune uveitis is a sight-threatening disease induced by pathogenic T cells that recognize retinal antigens; it is observed in disorders including Vogt-Koyanagi-Harada disease (VKH). The roles of specific T cell subsets and their therapeutic potential against autoimmune uveitis are not fully understood. Here we conducted multi-parametric single-cell protein quantification which shows that the frequency of CD161 high TRAV1-2 + mucosal-associated invariant T (MAIT) cells that recognize vitamin B2 metabolite-based antigens is decreased in relapsing VKH patients compared to individuals without active ocular inflammation. An experimental autoimmune uveitis (EAU) mouse model revealed that genetic depletion of MAIT cells reduced the expression of interleukin (Il) 22 and exacerbated retinal pathology. Reduced IL-22 levels were commonly observed in patients with relapsing VKH compared to individuals without active ocular inflammation. Both mouse and human MAIT cells produced IL-22 upon stimulation with their antigenic metabolite in vitro. An intravitreal administration of the antigenic metabolite into EAU mice induced retinal MAIT cell expansion and enhanced the expressions of Il22, as well as its downstream genes related to anti-inflammatory and neuroprotective effects, leading to an improvement in both retinal pathology and visual function. Taken together, we demonstrate that a metabolite-driven approach targeting MAIT cells has therapeutic potential against autoimmune uveitis., (© 2021. The Author(s), under exclusive licence to Society for Mucosal Immunology.)

Background: Recently, the number of patients with pollinosis, particularly Japanese cedar pollinosis, has markedly increased. We previously reported about local allergic conjunctivitis, which is a phenotype of allergic conjunctivitis (AC). AC cases are often sensitized by various antigens. This study aimed to investigate the relationship among total tear IgE (t-tIgE), specific serum IgE (s-sIgE), and total serum IgE (t-sIgE) levels in patients with pollen-induced AC., Methods: In 2019, 1372 patients were clinically diagnosed with AC at the Yamana Eye Clinic using t-tIgE, t-sIgE, and s-sIgE tests against 39 allergens. Among the pollen-induced AC patients who underwent allergen testing, 99 tested positives for s-sIgE against pollen. The subjects comprised 33 (33.3%) male and 66 (66.7%) female individuals aged 9-86 years., Results: The t-tIgE test was positive in 68 (68.7%) patients and negative in 31 (31.3%) patients. In the t-sIgE test, 45 (45.5%) patients had t-sIgE levels above the reference value of 170 IU/mL. The higher the total score of the positive class value of each pollen-specific IgE (pollen-sIgE) antibody, the higher the positive rate of t-tIgE (p < 0.001). Of 32 patients in whom food-specific IgE (food-sIgE) was detected, 81.3% of the pollen-sIgE-positive and food-sIgE-positive cases were also positive for t-sIgE and t-tIgE. However, significant difference was not found between the total score of food-sIgE of the t-tIgE positive group and negative group., Conclusions: Pollen-induced AC is caused by pollen sensitization of the conjunctiva. Food-induced AC might be induced by the different pathological mechanism involved in pollen-induced AC., (© 2021. The Author(s).)

Objectives: This study aimed to identify therapeutic predictors of abatacept (ABT) treatment in rheumatoid arthritis (RA) in vitro and in patients., Methods: T cell cytokine, monokine, and chemokine levels in culture supernatants or serum were determined using flow cytometry bead-based immunoassays. CXCL10 mRNA and protein expressions were also assessed using qPCR and ELISA analyses, respectively. In the patient study, 25 ABT-treated patients were analysed retrospectively. The patients were divided into low disease activity (LDA) or non-low disease activity (non-LDA) groups at 24 weeks of ABT treatment. Seven T cell cytokines and CXCL10 levels were compared in these two groups., Results: Peripheral blood mononuclear cells (PBMC) from healthy donors were stimulated by immobilised anti-CD3 with or without ABT for three days, and the levels of 13 T cell cytokines in culture supernatants were determined. ABT significantly inhibited anti-CD3-induced production of IFN-γ. To examine the effect of these T cell cytokines in rheumatoid synovial cells (RSC), RSCs were stimulated with 10% of culture supernatants from anti-CD3-stimulated PBMCs with or without ABT, and the levels of 23 cytokines were determined. Only CXCL10 was significantly reduced by ABT-treated supernatants. In the patient study, CXCL10 levels at baseline were not different between the LDA and non-LDA groups, whereas CXCL10 levels at 24 weeks were significantly decreased in the LDA group only., Conclusions: ABT treatment significantly affected IFN-γ and CXCL10 cytokine levels in vitro. In addition, serum CXCL10 levels were associated with better responses in ABT treatment.

Background/objectives: Immunosuppressant medications (ISPs) increase the occurrence of Pneumocystis jirovecii pneumonia (PCP) in rheumatoid arthritis (RA) patients. The prophylactic administration of trimethoprim/sulfamethoxazole (TMP/SMX) for PCP is effective but has serious adverse effects and so should be selectively used for patients at high risk. The aims of this study were to clarify the risk factors for PCP in RA patients and to establish the indications for administering TMP/SMX., Methods: This retrospective cohort study analyzed data from 2640 patients (2010-2014) diagnosed as having RA who had not received a prophylactic administration of TMP/SMX. The risk factors for PCP were evaluated by comparing the clinical parameters between patients with PCP (PCP group, n = 19) and those without (non-PCP group, n = 2621)., Results: The PCP group was older (70 vs. 64 years), received higher doses of prednisolone (6.2 vs. 2.4 mg/d) and methotrexate (7.7 vs. 5.2 mg/wk), and had a greater number of ISPs (1.3 vs. 0.8) (p < 0.05). We stratified the PCP risk using a scoring system based on odds ratios (ORs) calculated for these parameters (methotrexate ≥6 mg/wk OR = 4.5, 1 point; age ≥65 years, OR = 3.7, 1 point; ≥2 ISPs, OR = 3.7, 1 point; prednisolone ≥5 mg/d, OR = 12.4, 3 points). The incidence of PCP among patients scoring 0 to 2 points was 0.04%; 3 to 4 points, 2.3%; and 5 points or more, 5.8%., Conclusions: The prophylactic administration of TMP/SMX for PCP is recommended for RA patients who score at least 5 points with our system.

We have reported that knockdown of Necl-4 decreases vascular endothelial growth factor (VEGF)-induced phosphorylation of extracellular signal-regulated kinase (ERK) without affecting phosphorylation of VEGF receptor 2 (VEGFR2) in sparsely cultured human umbilical vein endothelial cells (HUVECs). However, the underlying molecular mechanism is unknown. Compared with control HUVECs, VEGF-induced phosphorylation of phospholipase Cγ (PLCγ), c-Raf, mitogen-activated protein kinase/ERK kinase (MEK) and ERK were all inhibited in Necl-4-knockdown HUVECs. However, VEGF-induced internalization of VEGFR2 was not different between control and Necl-4-knockdown HUVECs. We have reported that protein-tyrosine phosphatase, non-receptor type 13 (PTPN13) and Rho-associated kinase (ROCK) are involved in the Necl-4-knockdown-induced inhibition of the VEGF-induced activation of Rac1. However, the effects of Necl-4-knockdown on VEGF-induced phosphorylation of VEGFR2 and ERK were not affected either by knockdown of PTPN13 or by ROCK inhibitors. These results suggest that Necl-4 enhances VEGF-induced activation of PLCγ-c-Raf-MEK-ERK pathway without affecting the phosphorylation and internalization of VEGFR2., (Copyright © 2017 Elsevier Inc. All rights reserved.)