Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To evaluate 10-year outcome of infliximab (IFX) treatment for uveitis in Behçet disease (BD) patients using a standardized follow-up protocol. DESIGN: Retrospective longitudinal cohort study. PARTICIPANTS: 140 BD uveitis patients treated with IFX enrolled in our previous study. METHODS: Medical records were reviewed for demographic information, duration of IFX treatment, number of ocular attacks before IFX initiation, best corrected visual acuity (VA) at baseline and 1, 2, 3, 4, 5, and 10 years after IFX initiation, uveitis recurrence after IFX initiation and main anatomical site, concomitant therapies, and adverse events (AEs). MAIN OUTCOME MEASURES: 10-year IFX continuation rate and change in LogMAR VA. RESULTS: Of 140 BD patients, 106 (75.7%) continued IFX treatment for 10 years. LogMAR VA improved gradually after initiation of IFX, and the improvement reached statistical significance from 2 years of treatment. Thereafter, significant improvement compared with baseline was maintained until 10 years, despite a slight deterioration of logMAR VA from 5 years. However, eyes with worse baseline decimal VA < 0.1 showed no significant improvement from baseline to 10 years. Uveitis recurred after IFX initiation in 50 patients (recurrence group) and did not recur in 56 (non-recurrence group). Ocular attacks/year before IFX initiation was significantly higher in the recurrence group (2.82 ± 3.81) than in the non-recurrence group (1.84 ± 1.78). In the recurrence group, uveitis recurred within 1 year in 58% and within 2 years in 74%. Seventeen patients (34%) had recurrent anterior uveitis, 17 (34%) had posterior uveitis, and 16 (32%) had panuveitis, with no significant difference in VA outcome. In addition, logMAR VA at 10 years did not differ between the recurrence and non-recurrence groups. AEs occurred among 43 patients (30.7%), and 24 (17.1%) resulted in IFX discontinuation before 10 years. CONCLUSIONS: Among BD patients with uveitis who initiated IFX, approximately 75% continued treatment for 10 years, and their VA improved significantly and was maintained for 10 years. Uveitis recurred in one-half of the patients, but visual acuity did not differ significantly from the patients without recurrence.

DOI： 10.3389/fmed.2023.1095423

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To reveal optimal antibiotic prophylactic regimen for postoperative endophthalmitis (POE), we conducted systematic review and network meta-analysis. A total of 51 eligible original articles, including two randomized controlled trials, were identified. In total, 4502 POE cases occurred in 6,809,732 eyes (0.066%). Intracameral injection of vancomycin had the best preventive effect (odds ratio [OR] 0.03, 99.6% confidence interval [CI] 0.00-0.53, corrected P-value = 0.006, P-score = 0.945) followed by intracameral injection of cefazoline (OR 0.09, 99.6% CI 0.02-0.42, corrected P-value < 0.001, P-score = 0.821), cefuroxime (OR 0.18, 99.6% CI 0.09-0.35, corrected P-value < 0.001, P-score = 0.660), and moxifloxacin (OR 0.36, 99.6% CI 0.16-0.79, corrected P-value = 0.003, P-score = 0.455). While one randomized controlled trial supported each of intracameral cefuroxime and moxifloxacin, no randomized controlled trial evaluated vancomycin and cefazoline. Sensitivity analysis focusing on the administration route revealed that only intracameral injection (OR 0.19, 99.4% CI 0.12-0.30, corrected P-value < 0.001, P-score = 0.726) significantly decreased the risk of postoperative endophthalmitis. In conclusion, intracameral injection of either vancomycin, cefazoline, cefuroxime, or moxifloxacin prevented POE.

DOI： 10.1038/s41598-022-21423-w

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PURPOSE: To clarify the proportion of ocular sarcoidosis with severe, refractory, and prolonged inflammation and their association with ocular complications and visual prognosis. STUDY DESIGN: Multicenter, retrospective, longitudinal cohort study. METHODS: Three hundred and twenty-three eyes of 164 patients (45 men; 119 women) with ocular sarcoidosis who visited Hokkaido University Hospital and Yokohama City University Hospital from 2010 to 2015. We newly defined severe, refractory, and prolonged inflammation in ocular sarcoidosis, and investigated their proportions, ocular complications and final visual acuity from medical records of our sarcoidosis patients. RESULTS: The eyes with severe inflammation numbered 72/323 (22.3%), with refractory inflammation, 80/323 (24.8%), and with prolonged inflammation, 91/323 (28.2%). The number of eyes having neither severe, refractory, nor prolonged inflammation (defined as none) was 114/323 (35.3%). The numbers of eyes that reached irreversible visual dysfunction were 6/72 (8.3%) of those with severe inflammation, 10/80 (12.5%) with refractory inflammation, 12/91 (13.2%) with prolonged inflammation, and 4/114 (6.2%) with none. As complications, cataract (62.2%), glaucoma (28.5%), epiretinal membrane (24.1%), cystoid macular edema (22.6%), vitreous hemorrhage (2.8%), choroidal atrophy (2.5%), macular degeneration (1.2%), macular hole (0.9%) and retinal detachment (0.3%) were identified. Among them, secondary glaucoma (16 eyes) and macular degeneration (4 eyes) were major complications related to irreversible visual dysfunction. CONCLUSIONS: Although most of the patients with ocular sarcoidosis had a relatively good visual prognosis, some developed severe, refractory, and/or prolonged inflammation related to the development of ocular complications, that resulted in poor visual prognosis.

DOI： 10.1007/s10384-022-00927-y

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The induction of T cell-mediated immunity is crucial in vaccine development. The most effective vaccine is likely to employ both cellular and humoral immune responses. The efficacy of a vaccine depends on T cells activated by antigen-presenting cells. T cells also play a critical role in the duration and cross-reactivity of vaccines. Moreover, pre-existing T-cell immunity is associated with a decreased severity of infectious diseases. Many technical and delivery platforms have been designed to induce T cell-mediated vaccine immunity. The immunogenicity of vaccines is enhanced by controlling the kinetics and targeted delivery. Viral vectors are attractive tools that enable the intracellular expression of foreign antigens and induce robust immunity. However, it is necessary to select an appropriate viral vector considering the existing anti-vector immunity that impairs vaccine efficacy. mRNA vaccines have the advantage of rapid and low-cost manufacturing and have been approved for clinical use as COVID-19 vaccines for the first time. mRNA modification and nanomaterial encapsulation can help address mRNA instability and translation efficacy. This review summarizes the T cell responses of vaccines against various infectious diseases based on vaccine technologies and delivery platforms and discusses the future directions of these cutting-edge platforms.

DOI： 10.3390/vaccines10081367

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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PURPOSE: We investigated efficacy and safety of adalimumab (ADA) treatment for exacerbation or recurrence of Vogt-Koyanagi-Harada (VKH) patients. METHODS: Medical records of 70 VKH patients who received ADA treatment for more than 6 months were retrospectively investigated. RESULTS: The mean age of VKH patients was 54.8 ± 15.1 years, and male/female ratio was 34/36, and sunset glow fundus was observed in 71.4%. Subfoveal choroidal thickness, indocyanine green angiography scores, and corticosteroid and cyclosporine doses were significantly reduced by ADA treatment for 6 months compared to baseline, while LogMAR and flare counts were also improved without being statistically significant. Adverse events were observed in 17.1%, in which tuberculosis was at 7.14% and psoriasis was at 2.86%; however, ADA treatment was continued in 91.4%. CONCLUSIONS: ADA was shown to be effective to achieve remission of VKH disease refractory to conventional treatments and was generally well tolerated with few serious adverse events.

DOI： 10.1080/09273948.2022.2092007

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Language：Japanese   Publisher：(株)医学書院  

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Language：Japanese   Publisher：(株)医学書院  

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Language：Japanese   Publisher：(公社)日本皮膚科学会  

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Language：Japanese   Publisher：(株)メディカル葵出版  

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Language：Japanese   Publisher：(株)医学書院  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J01537&link_issn=&doc_id=20220405150022&doc_link_id=10.11477%2Fmf.1410214358&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1410214358&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：Japanese   Publisher：(公財)日本眼科学会  

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PURPOSE: To compare the efficacy and safety of a combination therapy of prednisolone and cyclosporine and corticosteroid pulse therapy in Vogt-Koyanagi-Harada (VKH) disease. STUDY DESIGN: A prospective, multicenter, randomized, non-inferiority trial. METHODS: Patients of new-onset acute VKH disease at 11 centers in Japan between 2014 and 2018 were randomized to a combination (oral prednisolone 60 mg daily with gradual taper-off to 35 mg/day and cyclosporine 3 mg/kg/day) and corticosteroid (methylprednisolone 1000 mg for 3 days followed by oral prednisolone) groups, and were followed for 1 year. RESULTS: Thirty-four were assigned to the combination and thirty-six patients to the corticosteroid group. Recurrence/worsening risk was 0.15 (95% confidence-interval [CI] 0.03-0.27) in the combination group and 0.25 (95% CI 0.11-0.39) in the corticosteroid group, with a risk difference of - 0.10 (90% CI - 0.27 to 0.06), demonstrating non-inferiority of the combination group with a non-inferiority margin of 0.20 (P = 0.0013). Serious adverse events occurred in three patients (two with hyponatremia and one with severe headaches) in the combination group and none in the corticosteroid group. Sunset glow fundus grades and cataract rates at 1 year were 0.57 (95% CI 0.42-71) and 4.3% in the combination group and 0.91 (95% CI 0.78-1.04) and 34.0% in the corticosteroid group, respectively. CONCLUSIONS: Combination therapy was noninferior to corticosteroid therapy with respect to recurrence/worsening risk. Notably, the recurrence/worsening risk, sunset glow fundus grade, and cataract rate were lower in the combination group than in the corticosteroid group.

DOI： 10.1007/s10384-021-00878-w

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Language：Japanese   Publisher：(公財)日本眼科学会  

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Language：Japanese   Publisher：(公財)日本眼科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Refractive changes are reportedly affected by age, sex, and current refractive error. To clarify the pattern of refractive changes in a Japanese population, we conducted a 5-year follow-up longitudinal analysis of spherical equivalent (SE) refractive changes with stratification by sex, age, and SE in 593,273 eyes from Japanese individuals ages 3-91 years. The 5-year SE change with myopic shift dramatically increased over time after age 4 years, and the largest change was observed in both males and females who were age 8 years at baseline [males: - 2.654 ± 0.048 diopters (D); females: - 3.110 ± 0.038 D]. During school age, the 5-year myopic change was greater in females than in males, and emmetropic and low-to-moderate myopic eyes underwent larger myopic changes than hyperopic and high-to-severe myopic eyes. After the peak at age 8 years, the 5-year myopic change gradually declined with age and fell below - 0.25 D at age 27 in males and age 26 years in females. The 5-year SE changes transitioned from a myopic to a hyperopic shift at age 51 in both sexes, and hyperopization advanced more quickly in hyperopic eyes. Our findings highlight the importance of myopia prevention in school-aged children.

DOI： 10.1038/s41598-022-06898-x

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Language：English   Publishing type：Research paper (scientific journal)  

AIM: To investigate the causes of low prevalence of Fuchs' uveitis syndrome (FUS) in Japan. METHODS: Medical records of 160 patients diagnosed with FUS at 14 uveitis specialty facilities in Japan were reviewed retrospectively. RESULTS: In 160 FUS patients, mean follow-up period before referral to our uveitis facilities was 31.6 ± 50.9 months. The most common reason for referral was idiopathic uveitis (61.9%), followed by cataract (25.0%), high intraocular pressure (IOP) including glaucoma (16.3%), and FUS (14.4%). Unilateral involvement was 96.9%. The most frequent ocular finding of FUS was anterior inflammation (91.9%), followed by stellate-shaped keratic precipitates (88.1%), cataract/pseudophakia (88.1%), diffuse iris atrophy (84.4%), vitreous opacity (62.5%), heterochromia (53.1%) and high IOP including glaucoma (36.3%). As treatments of these ocular findings, cataract surgery was performed in 52.5%, glaucoma surgery in 10.6%, and vitrectomy in 13.8%. Mean logMAR VA was 0.28 ± 0.59 at the initial visit, and decreased significantly to 0.04 ± 0.32 at the last visit. Proportions of FUS patients with BCVA <0.1 and 0.1 to <0.5 decreased, while that of ≥0.5 increased at the last visit compared with the initial visit. CONCLUSIONS: Ocular findings of FUS in Japanese FUS patients were consistent with the characteristic features. The low prevalence of FUS in Japan may be a result of being overlooked and misdiagnosed as mild idiopathic uveitis, cataract, and/or glaucoma.

DOI： 10.3389/fmed.2022.999804

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: We investigated the efficacy and safety of adalimumab (ADA) treatment for chronic recurrent Vogt-Koyanagi-Harada (VKH) patients with sunset glow fundus (SGF). METHODS: Medical records of 50 chronic recurrent VKH patients with SGF who received ADA treatment for more than 6 months were retrospectively reviewed. RESULTS: The mean age of chronic recurrent VKH patients with SGF was 55.9 ± 14.4 years, and the male/female ratio was 26/24. Before ADA treatment, the mean daily dose of systemic corticosteroids was 16.5 ± 12.7 mg, and 22 patients (44%) were under immunosuppressors. LogMAR visual acuity (VA), flare counts, subfoveal choroidal thickness (SFCT), indocyanine green angiography scores, and corticosteroid and cyclosporine doses were significantly reduced by ADA treatment at 6 months compared to baseline. Among all parameters, flare count was significantly related to LogMAR VA. LogMAR VA was significantly related to flare counts but not to SFCT nor to ICGA scores. ADA treatment was continued in 94%. CONCLUSION: ADA was shown to be effective in achieving remission of chronic recurrent VKH disease with SGF refractory to conventional treatments, and was generally well tolerated with few serious adverse events.

DOI： 10.4103/sjopt.sjopt_204_22

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Language：English   Publishing type：Research paper (scientific journal)  

Immune tolerance is established in the eye to prevent permanent blindness associated with destructive damage to the cornea and retina caused by immune cell infiltration; hence, the immune responses and subsequent inflammations are strongly suppressed. While non-infectious uveitis develops from a disruption of immune tolerance in the eye, its onset is a result of accumulating etiologic factors, including genetic predisposition, environmental factors, and aging. Many non-infectious uveitis cases are genetically predisposed to human leukocyte antigen (HLA) as the most substantial disease susceptibility region. HLA class I molecules are critical for natural killer (NK) cells to distinguish between self and non-self. The killer cell Ig-like receptor (KIR) family is one of the essential components of these receptors. Evidence has accumulated that NK cells are involved in innate and acquired immunity by interacting with other immunocompetent cells to develop several autoimmune diseases. This review summarizes the possible role of KIR in the development of non-infectious uveitis.

DOI： 10.2174/1566524021666211027092124

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Adis  

DOI： 10.1007/s40123-021-00390-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Adis  

DOI： 10.1007/s40123-021-00368-9

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title><sec>
<title>Background</title>
We hypothesized that Behçet’s disease (BD) consists of several clinical subtypes with different severity, resulting in heterogeneity of the disease. Here, we conducted a study to identify clinical clusters of BD.


</sec><sec>
<title>Methods</title>
A total of 657 patients registered in the Yokohama City University (YCU) regional BD registry between 1990 and 2018, as well as 6754 patients who were initially registered in the Japanese Ministry of Health, Labour and Welfare (MHLW) database between 2003 and 2014, were investigated. The YCU registry data regarding the clinical manifestations of BD, human leukocyte antigen (HLA) status, treatments, and hospitalizations were analyzed first, followed by similar analyses of the MHLW for validation. A hierarchical cluster analysis was independently performed in both patient groups.


</sec><sec>
<title>Results</title>
A hierarchical cluster analysis determined five independent clinical clusters in the YCU cohort. Individual counterparts of the YCU clusters were confirmed in the MHLW registry. Recent phenotypical evolutions of BD in Japan, such as increased gastrointestinal (GI) involvement, reduced complete type according to the Japan Criteria, and reduced HLA-B51 positivity were associated with chronologically changing proportions of the clinical clusters.


</sec><sec>
<title>Conclusions</title>
In this study, we identified independent clinical clusters among BD patients in Japan and found that the proportion of each cluster varied over time. We propose five independent clusters namely “mucocutaneous”, “mucocutaneous with arthritis”, “neuro”, “GI”, and “eye.”


</sec>

DOI： 10.1186/s13075-020-02406-6

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Other Link： http://link.springer.com/article/10.1186/s13075-020-02406-6/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: This study aimed to determine the clinical efficacy of apremilast for oral ulcers, extra-oral manifestations, and overall disease activity in patients with Behçet's disease (BD). METHODS: A systematic literature search was performed in PubMed, EMBASE, Cochrane Library, and Web of Science Core Collection. Studies assessing the treatment effects of apremilast in BD were included. The odds ratios (ORs) of being symptom free for individual manifestations and mean difference (MD) of Behçet's Disease Current Activity Form (BDCAF) scores were calculated with 95% confidence intervals (CIs) at 12 and 24 weeks using a random-model meta-analysis. RESULTS: Of 259 screened articles, eight were included. After 12 weeks of apremilast treatment the OR of symptom-free was as followings: oral ulcers, 45.76 (95% CI, 13.23-158.31); genital ulcers, 4.56 (95% CI, 2.47-8.44); erythema nodosum, 3.59 (95% CI, 1.11-11.61); pseudofolliculitis, 2.81 (95% CI, 1.29-6.15); and arthritis, 3.55 (95% CI, 1.71-7.40). Furthermore, BDCAF scores at 12 weeks were significantly reduced (MD=-1.38; -1.78 to -0.99). However, the proportion of oral-ulcer free patients increased at 24 weeks (OR=14.88; 4.81 to 46.07). CONCLUSION: The currently accumulated data indicates an improvement in mucocutaneous and articular symptoms by short-term apremilast treatment in patients with BD.

DOI： 10.1093/mr/roab098

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Churchill Livingstone  

DOI： 10.1016/j.bjps.2021.03.086

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Although infliximab (IFX) decreases the risk of blindness due to refractory uveitis in patients with Behçet's disease (BD), there are no standard criteria for IFX switching or withdrawal. To evaluate the effect of IFX switching in patients with BD in long-term remission, a prospective, single-arm intervention trial was conducted, switching from IFX to cyclosporine A (CYA). STUDY DESIGN: A prospective open-label study. METHODS: Eligible patients met the following criteria: administration of IFX without concomitant immunosuppressants for more than 5 years with no episodes of ocular attacks, no retinal vasculitis on fluorescein fundus angiography, negative C-reactive protein in serum, and no extraocular lesions at the time of IFX withdrawal. CYA 5 mg/kg/day was administered from 6 weeks after IFX withdrawal. The primary outcome was the rate of readministration of tumor necrosis factor inhibitors at 1 year after IFX withdrawal. RESULTS: Three of 45 BD patients treated with IFX for refractory uveitis were included in the study. At 1 year after withdrawal of IFX, no patient had experienced any ocular attacks or needed readministation of IFX. However, extraocular lesions, such as recurrent oral ulcers, folliculitis, and recurrent fevers, occurred in all patients. Liver or renal dysfunction, which may have been caused by CYA, was also observed in all patients. CONCLUSIONS: Although no ocular attacks were observed for at least 1 year after IFX withdrawal, this prospective study indicates that IFX withdrawal should be considered carefully, even for patients in long term remission of ocular and extraocular lesions.

DOI： 10.1007/s10384-021-00872-2

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Language：Japanese   Publisher：(公社)日本眼科手術学会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(公社)神奈川県医師会  

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Language：Japanese   Publisher：(株)日本医事新報社  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01024&link_issn=&doc_id=20210701010007&doc_link_id=%2Faf9mdcla%2F2021%2F005071%2F009%2F0028b0032%26dl%3D3&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faf9mdcla%2F2021%2F005071%2F009%2F0028b0032%26dl%3D3&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_4.gif

Language：Japanese   Publisher：(公社)神奈川県医師会  

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Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

<title>Abstract</title>
<sec>
<title>Objectives</title>
No large-scale registration study has comprehensively evaluated the activities of daily living (ADL) in patients with Behçet's disease (BD).


</sec>
<sec>
<title>Methods</title>
The Japanese government provided us with a dataset of confirmed or suspected BD cases derived from ongoing national registration. ADL were categorized and analyzed into four categories in patients who satisfied the international criteria for BD.


</sec>
<sec>
<title>Results</title>
Data from 2960 patients (men, 38.9%; women, 61.1%; median age 39 years) were assessed. While 1767 patients (59.7%) had normal ADL, the others had impaired ADL comprising: limited but not assisted, 1058 (35.7%); partially assisted, 116 (3.9%); and fully assisted, 19 (0.6%). Logistic regression analysis showed that chronic ocular lesions (odds ratio (OR) 1.85, 95% confidence interval (CI) 1.46–2.35, p&amp;lt; 0.001), paralysis (OR 2.51, 95% CI 1.58–3.97, p&amp;lt; 0.001), psychosis (OR 3.16, 95% CI 2.02–4.95, p&amp;lt; 0.001), and arthritis (OR 1.69, 95% CI 1.44–1.99, p&amp;lt; 0.001) led to the risk of impaired ADL (not normal ADL). Chronic ocular lesions (OR 3.61, 95% CI 2.27–5.72, p&amp;lt; 0.001), paralysis (OR 3.43, 95% CI 1.87–6.30, p&amp;lt; 0.001), and psychosis (OR 3.60, 95% CI 2.00–6.50, p&amp;lt; 0.001) were related to the requirement of physical assistance (partially or fully assisted), although arthritis (OR 1.39, 95% CI 0.93–2.06, p= 0.108) was not a significant factor in this model.


</sec>
<sec>
<title>Conclusion</title>
Ocular lesion, neurological manifestations, and arthritis affected ADL. Patients with ocular lesion or neurological manifestations more frequently required physical assistance.


</sec>

DOI： 10.1093/rheumatology/keab499

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Language：English   Publishing type：Research paper (scientific journal)  

Adenovirus infections are a major cause of epidemic keratoconjunctivitis (EKC), which can lead to corneal subepithelial infiltrates and multifocal corneal opacity. In the current study, we investigated the use of an E1/E3-deleted adenovirus serotype 5 (Ad5) vector as a vaccine administered intramuscularly (IM) or intranasally (IN) against subsequent challenges with a luciferase-expressing Ad5 (Ad5-Luci) vector via eyedrop. We evaluated the adaptive immune response to Ad5 vector vaccination and confirmed a robust polyfunctional CD8 T cell response in splenic cells. Neutralizing Ad5 antibodies were also measured in the sera of vaccinated mice as well as Ad5 antibody in the eye wash solutions. Upon challenge with Ad5-Luci vector 8 weeks post the primary immunization, transduction was significantly reduced by > 70% in the vaccinated mice, which was slightly better in IM- vs. that in IN-vaccinated animals. Resistance to subsequent challenge was observed 10 months post primary IM vaccination, with sustained reduction up to 60% in the Ad5-Luci vector transduction. Passive immunization of naive mice with antisera from IM to vaccinated mice subsequently challenged with the Ad5-Luci vector resulted in approximately 40% loss in transduction efficiency. Furthermore, the mice that received IM immunization with or without CD8 T cell depletion showed > 40% and 70% reductions, respectively, in Ad8 genomic copies after Ad8 topical challenge. We conclude that Ad-vector vaccination successfully induced an adaptive immune response that prevented subsequent Ad transduction in the cornea and conjunctiva-associated tissues in a mouse model of adenovirus keratoconjunctivitis, and that both cellular and humoral immunity play an important role in preventing Ad transduction.

DOI： 10.1016/j.vaccine.2021.05.010

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Language：Japanese   Publisher：(株)日本臨床社  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01205&link_issn=&doc_id=20210603150002&doc_link_id=%2Fag6niria%2F2021%2F007906%2F002%2F0800-0804%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag6niria%2F2021%2F007906%2F002%2F0800-0804%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(株)日本臨床社  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01205&link_issn=&doc_id=20210603150022&doc_link_id=%2Fag6niria%2F2021%2F007906%2F022%2F0925b0930%26dl%3D3&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fag6niria%2F2021%2F007906%2F022%2F0925b0930%26dl%3D3&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_4.gif

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Pseudomonas aeruginosa (P. aeruginosa) infection is one of the major causes of keratitis. However, effective prophylactic and therapeutic vaccines against P. aeruginosa keratitis have yet to be developed. In this study, we explored the use of P. aeruginosa membrane vesicles (MVs) as a prophylactic vaccine as well as the use of immune sera derived from P. aeruginosa MV-immunized animals as a treatment for P. aeruginosa corneal infections in C57BL/6 mice. METHODS: C57BL/6 mice were intramuscularly immunized with P. aeruginosa MVs; the mouse corneas were then scarified and topically infected with several P. aeruginosa strains, followed by determination of corneal clinical score and corneal bacterial load. Next, immune sera derived from P. aeruginosa MV-immunized ICR mice were administered intraperitoneally to naïve C57BL/6 mice, followed by topical P. aeruginosa challenge. Finally, the immune sera were also used as a topical treatment in the mice with established P. aeruginosa corneal infections. RESULTS: P. aeruginosa-specific IgG and IgA antibodies induced by intramuscular immunization were detected not only in the sera but also in the eye-wash solution. Both active and passive immunization significantly inhibited P. aeruginosa corneal infection. Finally, topical treatment with immune sera in the mice with established P. aeruginosa corneal infections notably decreased the corneal clinical score and corneal bacterial load. CONCLUSIONS: P. aeruginosa keratitis can be attenuated by vaccination of P. aeruginosa MVs and topical application of P. aeruginosa MV-specific immune sera.

DOI： 10.1016/j.vaccine.2021.04.035

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Guidelines and systematic reviews frequently warn of inhaled corticosteroid (ICS)-induced glaucoma. However, most of the published studies deny it. METHODS: We performed a systematic review of randomized, cohort, nested-case control, cross-sectional studies by using Meta-analyses of Observational Studies in Epidemiology statement. Four major databases, PubMed, EMBASE, Cochrane Search Manager, and the Web of Science Core Collection as well as meta-analysis were used. Studies comparing incidence, prevalence and intraocular pressure (IOP) between patients who were treated with and without ICSs were included. A random-model meta-analysis was performed using the inverse variance method. RESULTS: Out of 623 studies screened, 18 with 31,665 subjects were finally included. No significant difference between the 2 groups was observed for crude glaucoma incidence (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.86-1.04; P = 0.26; I² = 0%; P for heterogeneity = 0.57) as a primary endpoint, adjusted glaucoma incidence (OR, 0.90; 95% CI, 0.65-1.24; P = 0.64), crude prevalence (OR, 1.82; 95% CI, 0.23-14.19; P = 0.57), adjusted prevalence (OR, 1.22; 95% CI, 0.50-2.96; P = 0.66), IOP change during ICS treatment (mean difference [MD] +0.01 mmHg; 95% CI, -0.19-0.20; P = 0.95), and single measurement IOP (MD +0.37 mmHg; 95% CI, -0.24-0.97; P = 0.23). Time-to-event analysis for glaucoma development as one of the secondary endpoints (adjusted hazard ratio, 0.52; 95% CI, 0.28-0.96) suggested a reverse association between ICS and glaucoma. CONCLUSIONS: The ophthalmological side effects of ICSs, such as glaucoma and intraocular hypertension, should not be exaggerated. TRIAL REGISTRATION: University Hospital Medical Information Network Center Clinical Trial Registry Identifier: UMIN000040351.

DOI： 10.4168/aair.2021.13.3.435

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Language：Japanese   Publisher：(公財)日本眼科学会  

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Language：Japanese   Publisher：(公財)日本眼科学会  

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Language：Japanese   Publisher：(公財)日本眼科学会  

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Language：Japanese   Publisher：(公財)日本眼科学会  

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Language：Japanese   Publisher：(公財)日本眼科学会  

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Language：English   Publishing type：Research paper (scientific journal)  

The threat of the current coronavirus disease pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is accelerating the development of potential vaccines. Candidate vaccines have been generated using existing technologies that have been applied for developing vaccines against other infectious diseases. Two new types of platforms, mRNA- and viral vector-based vaccines, have been gaining attention owing to the rapid advancement in their methodologies. In clinical trials, setting appropriate immunological endpoints plays a key role in evaluating the efficacy and safety of candidate vaccines. Updated information about immunological features from individuals who have or have not been exposed to SARS-CoV-2 continues to guide effective vaccine development strategies. This review highlights key strategies for generating candidate SARS-CoV-2 vaccines and considerations for vaccine development and clinical trials.

DOI： 10.1016/j.vaccine.2020.11.054

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Language：Japanese   Publisher：(株)医学書院  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J01537&link_issn=&doc_id=20210108070008&doc_link_id=10.11477%2Fmf.1410213875&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1410213875&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Dove Medical Press Ltd  

DOI： 10.2147/OPTH.S327660

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Uveitis is a generic term for inflammation of the uvea, which includes the iris, ciliary body, and choroid. Prevalence of underlying non-infectious uveitis varies by race and region and is a major cause of legal blindness in developed countries. Although the etiology remains unclear, the involvement of both genetic and environmental factors is considered important for the onset of many forms of non-infectious uveitis. Major histocompatibility complex (MHC) genes, which play a major role in human immune response, have been reported to be strongly associated as genetic risk factors in several forms of non-infectious uveitis. Behçet's disease, acute anterior uveitis (AAU), and chorioretinopathy are strongly correlated with MHC class I-specific alleles. Moreover, sarcoidosis and Vogt-Koyanagi-Harada (VKH) disease are associated with MHC class II-specific alleles. These correlations can help immunogenetically classify the immune pathway involved in each form of non-infectious uveitis. Genetic studies, including recent genome-wide association studies, have identified several susceptibility genes apart from those in the MHC region. These genetic findings help define the common or specific pathogenesis of ocular inflammatory diseases by comparing the susceptibility genes of each form of non-infectious uveitis. Interestingly, genome-wide association of the interleukin (IL)23R region has been identified in many of the major forms of non-infectious uveitis, such as Behçet's disease, ocular sarcoidosis, VKH disease, and AAU. The interleukin-23 (IL-23) receptor, encoded by IL23R, is expressed on the cell surface of Th17 cells. IL-23 is involved in the homeostasis of Th17 cells and the production of IL-17, which is an inflammatory cytokine, indicating that a Th17 immune response is a common key in the pathogenesis of non-infectious uveitis. Based on the findings from the immunogenetics of non-infectious uveitis, a personalized treatment approach based on the patient's genetic make-up is expected.

DOI： 10.3389/fimmu.2021.640473

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Research  

DOI： 10.1038/s42003-020-0802-y

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Language：Japanese   Publisher：(株)医学書院  

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Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/14397595.2020.1830504

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Purpose: To identify the clinical characteristics of acute retinal necrosis (ARN) and clarify factors associated with poor visual prognosis. Methods: a nationwide multi-center retrospective chart review study was performed in Japan using data from the medical records of 149 consecutive ARN patients. Demographics, ocular signs, virologic testing of intraocular fluids, and treatment were examined. Factors associated with poor visual prognosis were investigated by regression analysis. Results: At initial presentation, anterior chamber cells or mutton-fat keratic precipitates (97%), unilaterality (93%), and yellow-white retinal lesions (86%) were recognized. In the clinical course, rapid circumferential expansion of retinal lesions (39%), development of retinal break or retinal detachment (55%), and optic atrophy (43%) were recorded. Four variables were identified as associated with poor visual prognosis. Conclusions: The present study identified clinical characteristics and factors associated with poor visual prognosis of ARN.

DOI： 10.1080/09273948.2020.1789179

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Lippincott Williams and Wilkins  

DOI： 10.1097/APO.0000000000000310

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Language：Japanese   Publisher：(株)医学書院  

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Oncoprotein E6 of high-risk human papillomavirus (HPV) plays a critical role in inducing cell immortalization and malignancy. E6 downregulates caspase-dependent pathway through the degradation of p53. However, the effect of HPV E6 on other pathways is still under investigation. In the present study, we found that HPV E6 directly binds to all three forms (precursor, mature, and apoptotic) of apoptosis-inducing factor (AIF) and co-localizes with apoptotic AIF. This binding induced MG132-sensitive reduction of AIF expression in the presence of E6 derived from HPV16 (16E6), a cancer-causing type of HPV. Conversely, E6 derived from a non-cancer-causing type of HPV, HPV6 (6E6), did not reduce the levels of AIF despite its interaction with AIF. Flow cytometric analysis revealed that 16E6, but not 6E6, suppressed apoptotic AIF-induced chromatin degradation (an indicator of caspase-independent apoptosis) and staurosporine (STS, a protein kinase inhibitor)-induced apoptosis. AIF knockdown reduced STS-induced apoptosis in both of 16E6-expressing and 6E6-expressing cells; however, the reduction in 16E6-expressing cells was lower than that in 6E6-expressing cells. These findings indicate that 16E6, but not 6E6, blocks AIF-mediated apoptosis, and that AIF may represent a novel therapeutic target for HPV-induced cervical cancer.

DOI： 10.1038/s41598-020-71134-3

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Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10-8) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.

DOI： 10.1038/s42003-020-01185-9

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Language：English   Publishing type：Research paper (scientific journal)  

Keratoconus is a common ocular disorder that causes progressive corneal thinning and is the leading indication for corneal transplantation. Central corneal thickness (CCT) is a highly heritable characteristic that is associated with keratoconus. In this two-stage genome-wide association study (GWAS) of CCT, we identified a locus for CCT, namely STON2 rs2371597 (P = 2.32 × 10-13), and confirmed a significant association between STON2 rs2371597 and keratoconus development (P = 0.041). Additionally, strong STON2 expression was observed in mouse corneal epithelial basal cells. We also identified SMAD3 rs12913547 as a susceptibility locus for keratoconus development using predictive analysis with IBM's Watson question answering computer system (P = 0.001). Further GWAS analyses combined with Watson could effectively reveal detailed pathways underlying keratoconus development.

DOI： 10.1038/s42003-020-01137-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BioMed Central  

DOI： 10.1186/s12886-020-01571-1

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Behçet's disease (BD) is an intractable systemic inflammatory disease characterized by four main symptoms: oral and genital ulcers and ocular and cutaneous involvement. The Japanese diagnostic criteria of BD classify intestinal BD as a specific disease type. Volcano-shaped ulcers in the ileocecum are a typical finding of intestinal BD, and punched-out ulcers can be observed in the intestine or esophagus. Tumor necrosis factor inhibitors were first approved for the treatment of intestinal BD in Japan and have been used as standard therapy. In 2007 and 2014, the Japan consensus statement for the diagnosis and management of intestinal BD was established. Recently, evidence-based JSBD (Japanese Society for BD) Clinical Practice Guidelines for BD (Japanese edition) were published, and the section on intestinal BD was planned to be published in English. Twenty-eight important clinical questions (CQs) for diagnosis (CQs 1-6), prognosis (CQ 7), monitoring and treatment goals (CQs 8-11), medical management and general statement (CQs 12-13), medical treatment (CQs 14-22), and surgical treatment (CQs 23-25) of BD and some specific situations (CQs 26-28) were selected as unified consensus by the members of committee. The statements and comments were made following a search of published scientific evidence. Subsequently, the levels of recommendation were evaluated based on clinical practice guidelines in the Medical Information Network Distribution Service. The degree of agreement was calculated using anonymous voting. We also determined algorithms for diagnostic and therapeutic approaches for intestinal BD. The present guidelines will facilitate decision making in clinical practice.

DOI： 10.1007/s00535-020-01690-y

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Language：Japanese   Publisher：(株)医学書院  

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Language：Japanese   Publisher：金原出版(株)  

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To identify novel susceptibility loci for high myopia. DESIGN: Genome-wide association study (GWAS) followed by replication and meta-analysis. PARTICIPANTS: A total of 14 096 samples from East and Southeast Asian populations (2549 patients with high myopia and 11 547 healthy controls). METHODS: We performed a GWAS in 3269 Japanese individuals (1668 with high myopia and 1601 control participants), followed by replication analysis in a total of 10 827 additional samples (881 with high myopia and 9946 control participants) from Japan, Singapore, and Taiwan. To confirm the biological role of the identified loci in the pathogenesis of high myopia, we performed functional annotation and Gene Ontology (GO) analyses. MAIN OUTCOME MEASURES: We evaluated the association of single nucleotide polymorphisms with high myopia and GO terms enriched among genes identified in the current study. RESULTS: We identified 9 loci with genome-wide significance (P < 5.0 × 10-8). Three loci were previously reported myopia-related loci (ZC3H11B on 1q41, GJD2 on 15q14, and RASGRF1 on 15q25.1), and the other 6 were novel (HIVEP3 on 1p34.2, NFASC/CNTN2 on 1q32.1, CNTN4/CNTN6 on 3p26.3, FRMD4B on 3p14.1, LINC02418 on 12q24.33, and AKAP13 on 15q25.3). The GO analysis revealed a significant role of the nervous system related to synaptic signaling, neuronal development, and Ras/Rho signaling in the pathogenesis of high myopia. CONCLUSIONS: The current study identified 6 novel loci associated with high myopia and demonstrated an important role of the nervous system in the disease pathogenesis. Our findings give new insight into the genetic factors underlying myopia, including high myopia, by connecting previous findings and allowing for a clarified interpretation of the cause and pathophysiologic features of myopia at the molecular level.

DOI： 10.1016/j.ophtha.2020.05.014

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Language：Japanese   Publisher：(株)メディカルレビュー社  

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To evaluate the efficacy of a mydriatic agent for posterior synechiae after phacoemulsification and intraocular lens (IOL) implantation followed by Descemet membrane endothelial keratoplasty (staged DMEK). METHODS: In this prospective study, the outcomes of DMEK with or without mydriasis (0.5% tropicamide and 0.5% phenylephrine hydrochloride [Mydrin-P; Santen, Osaka, Japan]) after the DMEK procedure were analyzed. Patients underwent IOL implantation approximately 4 weeks before DMEK. Six months after DMEK, the iris posterior synechiae severity score was evaluated based on the extent of posterior synechiae affecting the eight areas (45° each) of the pupillary rim (posterior synechiae score; grades 0-8). Best spectacle-corrected visual acuity, central corneal thickness, endothelial cell density, axial length, and the amount of air at the end of the surgery were also evaluated. RESULTS: Fifteen eyes of 15 patients (mydriatic: n=8, control: n=7) were eligible for inclusion. Iris posterior synechiae were detected in all seven eyes (100.0%) in the control group, whereas they were noted in two eyes in the mydriatic group (25%). The mean iris posterior synechiae score was 0.69±1.20 in the mydriatic group and was significantly lower than that in the control group (4.57±0.90; P<0.001). There was no significant difference in other clinical factors. Although the incidence and scores of posterior synechiae in the control group were higher, the incidence was significantly reduced with the use of a mydriatic agent (in the mydriatic group). CONCLUSIONS: Use of a mydriatic agent is an effective measure to prevent postoperative synechiae after DMEK.

DOI： 10.1097/ICL.0000000000000616

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Language：Japanese   Publisher：(公財)日本眼科学会  

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In the current study, we present guidelines for the diagnosis and treatment of the mucocutaneous lesions of Behçet's disease, which is a chronic inflammatory disease characterized by the involvement of various organs, including mucocutaneous, ocular, vascular, intestinal and central nervous system lesions. It is often identified in the Middle East Mediterranean to East Asia region. Skin manifestations include erythema nodosum, papulopustular lesions and thrombophlebitis, and mucosal manifestations include oral and genital ulcers. These mucocutaneous lesions are characteristically the first signs of Behçet's disease and are important to be recognized for the early diagnosis of the disease. Moreover, these manifestations also recur and persist over the long-term course of the disease. The management of mucocutaneous lesions is important to prevent recurrence. We developed consensus guidelines that provide recommendations for general practitioners and dermatologists and physicians on the management of the mucocutaneous lesions of Behçet's disease.

DOI： 10.1111/1346-8138.15207

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Background: How HLA-A26 modulates Behçet's disease (BD) ocular lesions such as iridocyclitis and retinochorioiditis has not been scrutinized.Methods: Ministry of Health, Labour and Welfare of Japan provided us a database of BD patients who were registered from 2003 to 2014. We selected patients who satisfied International Criteria for BD and whose data for HLA-A26 was available.Results: Eligible 557 patients consisting of 238 men (42.7%) and 319 women (57.3%), whose median age was 38 years old (interquartile range 29-47) were analyzed. Prevalence of general ocular lesions, iridocyclitis, retinochorioiditis, and chronic lesions were 43.1%, 30.7%, 34.1%, and 17.4%, respectively. The prevalence of ocular lesions was higher among HLA-A26 carriers compared to that among HLA-A26 non-carriers with odds ratio (OR) of 2.5 (95% confidence interval (95% CI) 1.8-3.5, p < .001) for general ocular lesions, OR of 2.5 (95% CI 1.7-3.6, p < .001) for iridocyclitis, OR of 2.8 (95% CI 1.9-4.0, p < .001) for retinochorioiditis, and OR of 2.7 (95% CI 1.7-4.3, p < .001) for 'chronic ocular lesion following iridocyclitis or retinochorioiditis'. The HLA-A26 had a similar impact on ocular lesions between HLA-B51 positive and negative cases (Breslow-Day test, p > .05). However, the HLA-A26 had a larger impact on iridocyclitis for men compared to women (Breslow-Day test, p = .040). The male HLA-A26 carriers had higher risk of iridocyclitis with OR of 3.4 (95% CI 2.0-5.9, p < .001), while the OR for women was 1.5 (95% CI 0.9-2.6, p = .146).Conclusion: HLA-A26 carriers had higher risk for iridocyclitis and retinochorioiditis. However, the impact was more prominent for men.

DOI： 10.1080/14397595.2019.1705538

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Optic perineuritis (OPN), which is an inflammatory disorder affecting the optic nerve sheath, is one of the rare complications in granulomatosis with polyangiitis (GPA). Although several groups have reported that immunosuppressive therapies are generally effective against GPA-associated OPN, so far, there is little information as to other options for refractory cases. Here we demonstrate a case of GPA-associated OPN, which is refractory to potent immunosuppressive therapy including high-dose glucocorticoid, intravenous cyclophosphamide and rituximab therapy, and effective application of therapeutic plasma exchange. We also report here that CSF IL-6 levels may serve as a new biomarker for GPA-associated OPN.

DOI： 10.1080/24725625.2019.1649857

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

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BACKGROUND: Behçet's disease (BD) is a chronic multi-systemic vasculitis with a considerable prevalence in Asian countries. There are many genes associated with a higher risk of developing BD, one of which is endoplasmic reticulum aminopeptidase-1 (ERAP1). In this study, we aimed to investigate the interactions of ERAP1 single nucleotide polymorphisms (SNPs) using a novel data mining method called Model-based multifactor dimensionality reduction (MB-MDR). METHODS: We have included 748 BD patients and 776 healthy controls. A peripheral blood sample was collected, and eleven SNPs were assessed. Furthermore, we have applied the MB-MDR method to evaluate the interactions of ERAP1 gene polymorphisms. RESULTS: The TT genotype of rs1065407 had a synergistic effect on BD susceptibility, considering the significant main effect. In the second order of interactions, CC genotype of rs2287987 and GG genotype of rs1065407 had the most prominent synergistic effect (β = 12.74). The mentioned genotypes also had significant interactions with CC genotype of rs26653 and TT genotype of rs30187 in the third-order (β = 12.74 and β = 12.73, respectively). CONCLUSION: To the best of our knowledge, this is the first study investigating the interaction of a particular gene's SNPs in BD patients by applying a novel data mining method. However, future studies investigating the interactions of various genes could clarify this issue.

DOI： 10.1371/journal.pone.0227997

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Vogt-Koyanagi-Harada (VKH) disease is a systemic inflammatory disorder that affects pigment cell-containing organs such as the eye (e.g., chronic and/or recurrent granulomatous panuveitis). While the exact etiology and pathogenic mechanism of VKH disease are unclear, HLA-DR4 alleles have been documented to be strongly associated with VKH disease in various ethnic groups. Recently, a genome-wide association study (GWAS) found two new genetic risk factors (IL23R-C1orf141 and ADO-ZNF365-EGR2) in a non-HLA region from a Han Chinese population. In this study, we replicated these GWAS findings in a Japanese population. A total of 1,643 Japanese samples (380 cases with VKH disease and 1,263 healthy controls) were recruited. We assessed four single nucleotide polymorphisms (SNPs) shown in previous GWAS: rs78377598 and rs117633859 in IL23R-C1orf141, and rs442309 and rs224058 in ADO-ZNF365-EGR2. A significant allelic association with VKH disease was observed for all of the four SNPs (rs78377598: pc = 0.0057; rs117633859: pc = 0.0017; rs442309: pc = 0.021; rs224058: pc = 0.035). In genotypic association analysis, the minor alleles of IL23R-C1orf141 rs78377598 and rs117633859 had the strongest association with disease susceptibility under the additive model (pc = 0.0075 and pc = 0.0026, respectively). The minor alleles of ADO-ZNF365-EGR2 rs442309 and rs224058 were most strongly associated with disease susceptibility under the dominant model (pc = 0.00099 and pc = 0.0023, respectively). The meta-analysis of the current and previous studies found that all of the four SNPs exhibited a significantly strong association with VKH disease (meta-p < 0.00001: rs78377598, meta-odds ratio (OR) = 1.69; rs1176338, meta-OR = 1.82; rs442309, meta-OR = 1.34; rs224058, meta-OR = 1.33). In summary, our study replicated significant associations with VKH disease susceptibility reported in a previous GWAS. Thus, the IL23R-C1orf141 and ADO-ZNF365-EGR2 loci may play important roles in the development of VKH disease through genetic polymorphisms.

DOI： 10.1371/journal.pone.0233464

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PURPOSE: Angiotensin-converting enzyme (ACE) is conventionally used as a biomarker in the diagnosis of uveitis associated with sarcoidosis, but its sensitivity is relatively low. In this study, we investigated whether serum soluble interleukin-2 receptor (sIL-2R) is also useful as a diagnostic marker, in addition to ACE, in the detection of uveitis associated with sarcoidosis. PATIENTS AND METHODS: Data were analyzed from 126 patients with uveitis (52 sarcoidosis and 74 non-sarcoid uveitis) and 12 with primary intraocular lymphoma (PIOL) who had their serum sIL-2R and ACE levels measured. RESULTS: Serum sIL-2R level was elevated in 69.2% of patients with sarcoid uveitis, 5.4% of those with non-sarcoid uveitis, and 16.7% of those with PIOL. The sensitivity and specificity of an elevated sIL-2R level for the detection of sarcoidosis were 69.2% and 93.0%, respectively. In contrast, serum ACE levels were elevated only in patients with sarcoid uveitis, with a sensitivity of 44.2% and specificity of 100%. Furthermore, serum sIL-2R and/or ACE level was elevated in 75.0% of patients with sarcoid uveitis, which is higher than those who had elevated serum ACE level only (44.2%, P = 0.0025). The sensitivity and specificity of elevated sIL-2R and/or ACE in detecting sarcoid uveitis were 75.0% and 93.0%, respectively. The PPV was 0.87, and the NPV was 0.86. CONCLUSION: Compared with the sensitivity of serum ACE levels alone, combined measurement of both serum sIL-2R and ACE levels improves sensitivity in the detection of uveitis associated with sarcoidosis. Nevertheless, serum ACE alone remains useful thanks to its high specificity in the differentiation of uveitis patients, with sarcoidosis from those without sarcoidosis.

DOI： 10.2147/OPTH.S264595

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Dove Medical Press Ltd  

DOI： 10.2147/IMCRJ.S271669

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DOI： 10.2147/IMCRJ.S280403

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Objectives: To scrutinize the influence of HLA-B51 to each clinical manifestation of patients with Behçet's disease (BD) using a database of the Ministry of Health, Labour and Welfare of Japan. Methods: The database of newly registered patients with BD was obtained from the Japanese Ministry of Health, Labour and Welfare. Patients who met International Criteria for Behçet's Disease (ICBD) and had data for HLA-B51 were selected and analyzed. Results: Among the 3044 analyzable cases, 1334 (43.8%) were men and 1710 (56.2%) were women; the median age was 38 years (IQR 29-48). HLA-B51 was positive for 1334 (44.5%). Prevalence of selected manifestations was 98.5% for oral ulceration, 85.5% for skin lesion, 42.1% for ocular lesion, 69.1% for genital ulceration, and 29.0% for gastrointestinal symptom. HLA-B51-positive patients had higher risk for ocular lesion (OR 1.59, 95%CI: 1.37-1.84; p < .001) and lower risk for genital ulceration (OR 0.72, 95%CI: 0.62-0.84; p < .001) and gastrointestinal symptom (OR 0.65, 95%CI: 0.55-0.77; p < .001). No significant difference was observed for other organ involvement; oral ulceration, skin lesion, positive pathergy test, arthritis, epididymitis, vascular lesion, or neurological manifestation. Subgroup analyses revealed that HLA-B51 was not related to genital ulceration in the cases with an ICBD score of 6 or higher and that HLA-B51 tended to more largely affect the risk of three manifestations for men compared to that for women. Conclusion: HLA-B51 positive is a risk factor for ocular lesion and vice versa for genital ulceration and gastrointestinal symptoms in patients with Japanese BD.

DOI： 10.1080/14397595.2019.1649103

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Background: Clinical data of patients with entro-, vasculo-, and neuro-variant possible Behçet's disease (BD) based on Japanese criteria has not yet comprehensively reported. Methods: This ongoing nation-wide registration has been carried out by the Japanese Ministry of Health, Labour and Welfare. The Ministry asked physicians who diagnosed a patient with confirmed or possible BD to register the patient data by filling out a registration form. The Ministry provided us with the dataset after unlinkable anonymization. We analyzed 2003-2014 database generated from the early stage new cases. Results: Among the 7950 analyzable cases, 694 (8.7%) had variant-type possible BD without satisfying complete/incomplete criteria. Of the 694 patients, 479, 46, and 169 had entero-, vasculo-, and neuro-variant possible BD, respectively. Out of these 694 patients, 35 (5.0%) and 154 (22.2%) satisfied the International Study Group criteria and the International Criteria of BD, respectively. Entero-variant possible patients rarely (1.8%) had ocular lesions. Patients with vasculo-variant possible BD were featured by low genital ulceration risk (6.8%) and frequent positive HLA-B51 (60.0%). Neuro-variant possible BD was featured by high median age at registration (48 year). Vasculo- (69.6%) and neuro-variant (68.6%) BD patients showed clear male dominance. Epididymitis was very rare among variant-type possible BD men. Conclusion: We analyzed 694 early-stage variant-type possible BD cases. We believe the data from our study will contribute to further international discussion regarding BD diagnostic criteria and clarification of the clinical presentations of the Japanese variant-type possible BD patients.

DOI： 10.1080/14397595.2018.1494501

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BACKGROUND: To evaluate the clinical outcomes and features of Descemet's membrane endothelial keratoplasty (DMEK) for eyes with pseudoexfoliation syndrome (PEX). METHODS: In this retrospective study, 37 DMEK cases were reviewed from available medical records. Patients who exhibited endothelial dysfunction derived from PEX or Fuchs endothelial corneal dystrophy (FECD) and successfully underwent cataract surgery about four weeks before DMEK were enrolled. The best spectacle-corrected visual acuity (BSCVA), central corneal thickness (CCT), endothelial cell density (ECD), and incidence of intra-operative/post-operative complications of DMEK were analyzed. RESULTS: This study included 14 eyes of 14 patients (PEX: n = 6, FECD: n = 8). There was no primary graft failure. In the PEX group, BSCVA improved from 0.67 ± 0.28 at the preoperative point to 0.43 ± 0.14 at 1 month, 0.27 ± 0.10 at 3 months, and 0.19 ± 0.08 at 6 months after DMEK. The donor corneal ECD was 2704 ± 225 cells/mm2 at the preoperative point and decreased to 1691 ± 498 cells/mm2 at 1 month, 1425 ± 366 cells/mm2 at 3 months, and 1281 ± 340 cells/mm2 (52.7 ± 11.7% less than ECD of the donor graft) at 6 months after DMEK. None of the patients required rebubbling. When compared with the FECD group, no statistical difference was observed in CCT (p = 0.821); BSCVA (p = 0.001) and the reduction rate of ECD (p = 0.010) were relatively worse. CONCLUSIONS: DMEK is effective for the treatment of endothelial dysfunction due to PEX.

DOI： 10.1186/s12886-019-1130-1

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The strongest genetic risk factor of Behçet's disease (BD) is HLA-B*51. Our group previously reported that HLA-A*26 is independently associated with the risk of the onset of BD apart from HLA-B*51. Here, we re-evaluated the association between HLA-A*26 and BD in the Japanese population. We also performed a comprehensive literature search and meta-analyzed the extracted published data concerning the relationship between HLA-A*26 and BD to estimate the odds ratio (OR) of HLA-A*26 to BD. In this study, we genotyped 611 Japanese BD patients and 2,955 unrelated ethnically matched healthy controls. Genotyping results showed that the phenotype frequency of HLA-A*26 was higher in BD patients than in controls (OR = 2.12, 95% CI: 1.75-2.56). Furthermore, within the HLA-B*51-negative populations, the phenotype frequency of HLA-A*26 was significantly higher in BD patients than in controls (OR = 3.10, 95% CI: 2.43-3.95). Results obtained from meta-analysis combined with our data showed that the modified OR of HLA-A*26 became 1.80 (95% CI:1.58-2.06), whereas within the HLA-B*51-negative population, the modified OR became 4.02 (95% CI: 2.29-7.05). A subgroup analysis arranged by the geographical regions showed HLA-A*26 is in fact associated with the onset of BD in Northeast Asia (OR = 2.11, 95% CI: 1.75-2.56), but not in the Middle East or in Europe.

DOI： 10.1038/s41598-019-40824-y

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OBJECTIVES: This study aimed to identify patients with high-probability of ocular involvement of Behçet's disease (BD). METHODS: The Japanese Ministry of Health, Labour and Welfare provided dataset of ongoing nationwide BD registration project. A patient who had confirmed BD and who was suspected to have BD was registered. We mainly analyzed newly registered patients who had the data for all demographic and diagnostic parameters regardless of fulfilment of any diagnostic criteria. RESULTS: Among 3213 patients with confirmed or possible BD, 1382 (43.0%) were men and 1831 (57.0%) were women with a median age of 38 years (interquartile range (IQR) 30-49 years). The median duration between onset and registration was 0 year (IQR 0-3). A binomial multivariable logistic regression analysis revealed that being female (odds ratio (OR) 0.63, 95% confidence interval (CI) 0.53-0.75, p < .001), duration since onset (OR 1.33 per 10 years, 95% CI 1.18-1.51, p < .001), genital ulceration (OR 0.28, 95% CI 0.23-0.34, p < .001), and gastrointestinal symptoms (OR 0.36, 95% CI 0.30-0.44, p < .001) were related to the ocular lesion. Analyses based on data of 2800 patients who satisfied International criteria of BD, age-, sex-, duration-based subgroup analyses, analyses targeting iridocyclitis and retino-uveitis, and analysis including patients with missing data confirmed that the four factors were associated with the probability of eye involvement. CONCLUSION: The ocular involvement did not accompany with genital ulcer or gastrointestinal symptoms at the early stage of BD.

DOI： 10.1080/14397595.2018.1457424

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Noninfectious uveitis (NIU), which pathogenesis is often autoimmune nature, occurs as a symptom of systemic syndromes or only in the eye. The standard treatment of NIU is local, topical, and oral administration of corticosteroids (CS) in combination with immunomodulatory therapy (IMT). However, additional therapeutic strategies involving topical and systemic administration of CS or others to treat relapse or exacerbation of ocular inflammation in NIU which present as various ocular manifestations have not been established. The aim of this study was to investigate therapeutic strategies used for various ocular inflammations in relapse or exacerbation of NIU and to evaluate factors associated with the treatment pattern in Japan. The subjects were 198 eyes of 156 NIU patients with relapse or exacerbation of ocular inflammation at 6 university hospitals in Japan. The most frequent disease was sarcoidosis in 23.7% of the cases, followed by Behçet disease (BD) in 21.2%, Vogt-Koyanagi-Harada (VKH) disease in 13.6%, acute anterior uveitis (AAU) in 5.6%, tubulointerstitial nephritis and uveitis syndrome (TINU) in 4.0%, and juvenile idiopathic arthritis (JIA)-associated uveitis in 3.0%. Common ocular findings were worsened anterior inflammation (AI) in 67.2% of the cases, vitreous opacity (VO) in 46.5%, macular edema (ME) in 26.8%, retinal vasculitis (RV) in 23.7%, serous retinal detachment (SRD) in 9.1%, and optic perineuritis (OPN) in 4.0%. Reinforcement of betamethasone eye drop (ED) monotherapy for only AI in both unilateral and bilateral AI, sub-tenon injection of triamcinolone acetonide (STTA) for unilateral posterior inflammation including VO and ME, and systemic therapy using CS and/or IMT for bilateral anterior and posterior inflammation were significantly more frequent. Frequencies of exacerbated individual ocular findings in sarcoidosis and BD were similar, and severe ocular inflammation associated with panuveitis required both topical and systemic therapies. These results demonstrate that reinforcement of betamethasone EDs, topical administration of triamcinolone acetonide, and long-term administration of systemic corticosteroids are the major therapeutic strategies, and reinforcement of betamethasone EDs was used for exacerbated AI independently from its use for posterior inflammation. In addition, STTA was preferentially used for VO and ME associated with posterior inflammation.

DOI： 10.1097/MD.0000000000014668

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PURPOSE: Report global adalimumab safety and efficacy outcomes in patients with non-infectious uveitis. METHODS: Adults with non-infectious intermediate, posterior, or panuveitis were randomized 1:1 to receive placebo or adalimumab in the VISUAL I (active uveitis) or VISUAL II (inactive uveitis) trials. Integrated global and Japan substudy results are reported. The primary endpoint was time to treatment failure (TF). RESULTS: In the integrated studies, TF risk was significantly reduced (hazard ratio [95% CI]) with adalimumab versus placebo (VISUAL I: HR = 0.56 [0.40-0.76], p < 0.001; VISUAL II: HR = 0.52 [0.37-0.74], p < 0.001). In Japan substudies, no consistent trends were observed between groups (VISUAL I: HR = 1.20 [0.41-3.54]; VISUAL II: HR = 0.45 [0.20-1.03]). Adverse event rates were similar between treatment groups in both studies (854 to 1063 events/100 participant-years). CONCLUSIONS: Adalimumab lowered time to TF versus placebo in the integrated population; no consistent trends were observed in Japan substudies. Safety results were consistent between studies.

DOI： 10.1080/09273948.2018.1491605

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Purpose: Lattice degeneration of the retina is a vitreoretinal disorder characterized by a visible fundus lesion that predisposes the patient to retinal detachment. It has been suggested that collagen type II alpha 1 (COL2A1) gene variants may contribute to the development of disorders associated with retinal detachment. Here we investigated whether COL2A1 gene variants were associated with the risk of lattice degeneration of the retina. Methods: We recruited 634 Japanese patients with lattice degeneration of the retina and 1694 Japanese healthy controls. We genotyped 13 tagging single-nucleotide polymorphisms (SNPs) in COL2A1. We also performed imputation analysis to evaluate the potential association of un-genotyped COL2A1 SNPs, involving the imputation of 65 SNPs. Results: Two intronic SNPs-rs1793954 and rs1635533-were significantly associated with lattice degeneration of the retina. The SNP rs1793954 showed the strongest association, with its C allele carrying an increased disease risk (p = 0.0016, corrected p = 0.021, OR = 1.25). The rs1793954 and rs1635533 SNPs were in strong linkage disequilibrium with each other (r2 = 0.99), and conditional analysis revealed that rs1793954 could account for the association between rs1635533 and the disease. Conclusions: Our results suggested that COL2A1 gene variants may contribute to the development of lattice degeneration of the retina. Further genetic and functional analyses of COL2A1 variants are needed to clarify the present findings.

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The recently emerged pachychoroid concept has changed the understanding of age-related macular degeneration (AMD), which is a major cause of blindness; recent studies attributed AMD in part to pachychoroid disease central serous chorioretinopathy (CSC), suggesting the importance of elucidating the CSC pathogenesis. Our large genome-wide association study followed by validation studies in three independent Japanese and European cohorts, consisting of 1546 CSC samples and 13,029 controls, identified two novel CSC susceptibility loci: TNFRSF10A-LOC389641 and near GATA5 (rs13278062, odds ratio = 1.35, P = 1.26 × 10-13; rs6061548, odds ratio = 1.63, P = 5.36 × 10-15). A T allele at TNFRSF10A-LOC389641 rs13278062, a risk allele for CSC, is known to be a risk allele for AMD. This study not only identified new susceptibility genes for CSC, but also improves the understanding of the pathogenesis of AMD.

DOI： 10.1038/s42003-019-0712-z

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Zonulopathy is a major concern if found during cataract surgery as it can cause further complications. Such complications may occur during continuous curvilinear capsulorhexis (CCC), lens fragmentation and intraocular lens (IOL) implantation. Femtosecond laser-assisted cataract surgery (FLACS) devices, such as the LenSX (Alcon Laboratories) are advantageous because they can detect the area and largest point of zonulopathy via anterior segment optical coherent tomography (AS-OCT) before the manual part of the procedure. CCC and lens fragmentation can also minimize further zonular stress. A symmetrical CCC is ideal for IOL implantation in the sulcus with optic capture. In the present study, we did not detect significant zonular dehiscence preoperatively in either of the eyes of our 68-year-old patient when using AS-OCT (CASIA2 Tomey). However, LenSx AS-OCT revealed zonular dehiscence in both eyes, perioperatively. We created CCC and lens fragmentation without causing stress to the zonules. In the subsequent manual part of procedure, we found zonular dehiscence in the same area as indicated by LenSx AS-OCT, which extended to approximately 200° in the right eye and 180° in the left. After lens fragmentation by LenSx, we successfully removed the lens without further zonular dialysis. However, zonular dialysis (>180°) in the right eye was too large to insert an IOL, either in the capsule or the sulcus. Therefore, we performed scleral IOL implantation. In the left eye, we avoided using capsular tension ring (CTR) for IOL placement to avoid further iatrogenic damage to the zonule. Instead, an IOL was inserted into the sulcus with optic capture to reduce the possibility of further stress to the zonula and phimosis. Post-surgically, the patient regained good eyesight in both eyes. This case illustrates the advantages of FLACS in addressing zonulopathy. The consistent creation of CCC and lens fragmentation by FLACS may increase success rates, even in unexpectedly challenging cases.

DOI： 10.2147/IMCRJ.S189367

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Purpose: To investigate whether variants in the ARMC9 gene encoding KU-MEL-1 are associated with Vogt-Koyanagi-Harada (VKH) disease in a Japanese population. Methods: We recruited 380 Japanese patients with VKH disease and 744 Japanese healthy controls to genotype seven single-nucleotide polymorphisms (SNPs) in ARMC9. We also performed imputation analysis of the ARMC9 region and 195 imputed SNPs were included in the statistical analysis. Results: We observed an increased frequency of the A allele of rs28690417 in patients compared with controls (P = 0.0097, odds ratio (OR) = 1.46). The A allele had a dominant effect on VKH disease risk (P = 0.011, OR = 1.51). However, these significant differences disappeared after Bonferroni correction (corrected P > 0.05). The remaining 201 SNPs did not show any significant association with disease risk. Conclusions: Our study suggests that ARMC9 variants do not play a critical role in the development of VKH disease.

DOI： 10.1080/09273948.2018.1523438

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Takayasu arteritis (TAK) is a systemic vasculitis with severe complications that affects the aorta and its large branches. HLA-B*52 is an established susceptibility locus to TAK. To date, there are still only a limited number of reports concerning non-HLA susceptibility loci to TAK. We conducted a genome-wide association study (GWAS) and a follow-up study in a total of 633 TAK cases and 5,928 controls. A total of 510,879 SNPs were genotyped, and 5,875,450 SNPs were imputed together with HLA-B*52. Functional annotation of significant loci, enhancer enrichment, and pathway analyses were conducted. We identified four unreported significant loci, namely rs2322599, rs103294, rs17133698, and rs1713450, in PTK2B, LILRA3/LILRB2, DUSP22, and KLHL33, respectively. Two additional significant loci unreported in non-European GWAS were identified, namely HSPA6/FCGR3A and chr21q.22. We found that a single variant associated with the expression of MICB, a ligand for natural killer (NK) cell receptor, could explain the entire association with the HLA-B region. Rs2322599 is strongly associated with the expression of PTK2B Rs103294 risk allele in LILRA3/LILRB2 is known to be a tagging SNP for the deletion of LILRA3, a soluble receptor of HLA class I molecules. We found a significant epistasis effect between HLA-B*52 and rs103294 (P = 1.2 × 10-3). Enhancer enrichment analysis and pathway analysis suggested the involvement of NK cells (P = 8.8 × 10-5, enhancer enrichment). In conclusion, four unreported TAK susceptibility loci and an epistasis effect between LILRA3 and HLA-B*52 were identified. HLA and non-HLA regions suggested a critical role for NK cells in TAK.

DOI： 10.1073/pnas.1808850115

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Behçet's Disease (BD) pathogenesis remains unclear, but some genetic loci and environmental factors are proposed to play a role. Here, we investigate the association of the endoplasmic reticulum aminopeptidase-1 (ERAP1) gene variants and HLA-B*51 with BD susceptibility and clinical manifestations in Iranian patients. In the study, 748 BD patients and 776 healthy individuals were included. The MGB-TaqMan Allelic Discrimination method was used to genotype 10 common missense single nucleotide polymorphisms (SNPs) and one intronic SNP in the ERAP1 gene region. We found no significant association between the 11 SNPs and BD in allelic and genotypic association tests. However, rs30187 showed the strongest association with BD in the recessive genotype model of the risk T allele in HLA-B*51 carriers. Although this became insignificant after correcting for multiple comparisons, the homozygous rs30187 risk allele genotype (TT) increased disease susceptibility in HLA-B*51 carriers in epistasis analysis, and the rs30187 TT recessive genotype showed a significant association with risk of cardiac involvement in the all patients and articular involvements in HLA-B*51 positive patients. Our findings suggest that gene-gene interactions between HLA-B*51 and ERAP1 variants is important for BD development, however, ERAP1 variants which interact with HLA-B*51 may differ among disease phenotypes or populations.

DOI： 10.1038/s41598-018-35700-0

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PURPOSE: Sarcoidosis is a major cause of granulomatous uveitis but rarely manifests as multiple choroidal granulomas. This report describes the use of enhanced depth imaging optical coherence tomography (EDI-OCT) to visualize changes occurring in multiple choroidal granulomas during treatment. METHODS: The patient was a 36-year-old Japanese man with histopathologically confirmed sarcoidosis, who was examined using EDI-OCT and showed multiple yellowish-white subretinal lesions in the peripapillary region and the arcade of the right eye. RESULTS: EDI-OCT revealed homogeneous hyporeflective choroidal lesions with choriocapillaris thinning, consistent with a diagnosis of choroidal granulomas. Subretinal fluid adjacent to one of the peripapillary choroidal lesions was also apparent. EDI-OCT during oral prednisolone administration revealed a decrease in lesion size at as early as 3 weeks and complete resolution of the lesions after 6 months of treatment. However, 2 months after prednisolone discontinuation, EDI-OCT revealed recurrence of choroidal granulomas in the peripapillary region and the arcade of the right eye. After injection of triamcinolone acetonide into the posterior sub-Tenon's capsule (sub-Tenon's injection), EDI-OCT demonstrated a reduction in granuloma lesion size within 3 months of the injection. CONCLUSION: EDI-OCT allowed detailed morphologic visualization of the choroidal granulomas caused by sarcoidosis. This imaging technique was useful for monitoring changes in granuloma size in response to steroid administration and for early detection of recurrence. Injection of triamcinolone acetonide into the posterior sub-Tenon's capsule was as effective as oral prednisolone for the treatment of choroidal granulomas.

DOI： 10.1007/s10792-017-0720-2

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PURPOSE: To evaluate the frequency and severity of iris posterior synechiae after Descemet membrane endothelial keratoplasty (DMEK) and to investigate possible causes of iris posterior synechiae. METHODS: Twenty-three eyes were investigated in 20 Asian patients who underwent DMEK 1 month after phacoemulsification and intraocular lens implantation surgery. A preexisting iris damage score was defined by iris damage and classified into 5 grades. Six months after DMEK, the iris posterior synechiae severity score was evaluated based on the extent of posterior synechiae, according to every 45 degrees of the pupillary rim (posterior synechiae score, 0-8). Correlations were analyzed between the posterior synechiae score and preexisting factors (preexisting iris damage score, axial length [AXL], anterior chamber depth, and anterior chamber volume, both before and after cataract surgery). RESULTS: Iris posterior synechiae appeared in 20 of 23 eyes (87.0%). Best spectacle-corrected visual acuity significantly improved at 6 months after DMEK (P < 0.001). Endothelial cell density was 1596 ± 530 cells/mm (P < 0.001); loss of cell density was 37.8 ± 19.9% at 6 months. Single regression analysis showed that the onset of iris posterior synechiae was correlated with the preexisting iris damage score (P = 0.006, r = 0.55), AXL (P < 0.001, r = -0.71), anterior chamber depth (P < 0.001, r = -0.70), and anterior chamber volume before cataract surgery (P < 0.001, r = -0.79). CONCLUSIONS: Iris posterior synechiae after DMEK frequently appeared in Asian eyes with shorter AXLs or a damaged iris.

DOI： 10.1097/ICO.0000000000001698

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BACKGROUND: Neurosarcoidosis is a rare complication, and cranial neuropathy is the most frequent manifestation of this disease. However, few cohesive reports have discussed multiple cranial neuropathies in Japanese patients with sarcoidosis. The present report discusses the case of a patient with sarcoid uveitis and multiple neurological findings. We further review relevant literature regarding Japanese patients with multiple cranial nerve palsies published within the past 34 years (from January 1982 to December 2016). CASE PRESENTATION: We report findings associated with the case of a 56-year-old Japanese woman with granulomatous pan-uveitis who was later diagnosed as having sarcoidosis by skin and transbronchial lung biopsies. She presented right-sided Bell's palsy and was treated with orally administered prednisolone. However, while prednisolone was tapered, she developed facial (VII) and vagus (X) nerve palsies, followed by brain parenchyma lesions, which were not associated with any additional neurological symptoms. Furthermore, she exhibited increased intraocular pressure in her right eye, and she underwent trabeculectomy. Our review of the literature revealed that 64 Japanese patients with sarcoidosis experienced multiple cranial nerve palsies between 1982 and 2016. The most commonly affected cranial nerves were the facial (VII) (73.4%) and glossopharyngeal/vagus (IX/X) nerves (48.4%). Palsies of two distinct cranial nerves were found in 40.6% of the patients, followed by palsies of three (23.4%) and four (18.8%) nerves. Almost all patients (98.3%) received systemic steroid therapy, and total or partial remission was achieved in almost all patients (96.5%). CONCLUSIONS: According to the literature, patients with multiple cranial nerve palsies associated with sarcoidosis respond well to orally administered steroid therapy. However, our findings suggest that careful follow-up is necessary for patients with neurosarcoidosis due to potential aggravation of neuropathy.

DOI： 10.1186/s13256-018-1842-5

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

DOI： 10.1038/s41588-018-0127-7

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Graft insertion into the anterior chamber is one of the most important procedures for successful Descemet membrane endothelial keratoplasty (DMEK). Especially in eyes with fragile zonular fibers and a shallow anterior chamber, smooth graft insertion tends to become more difficult. Ophthalmic viscoelastic devices (OVDs) can usually help to retain the space in the anterior chamber and to improve the safety of manipulations during various ophthalmic surgeries. Therefore, we postulated that graft insertion into the anterior chamber could be improved by their use. The purpose of this study is to investigate the availability and efficacy of OVDs during graft insertion in DMEK surgery.A total of 11 eyes of 9 patients with bullous keratopathy who underwent DMEK were retrospectively analyzed. The cause of bullous keratopathy was corneal endothelial decompensation following laser iridotomy in all eyes. We used low viscous dispersive OVD (Opegan) to maintain the anterior chamber depth during graft insertion in all of the eyes.The graft insertion was uneventful in all of the eyes. The inserted graft was attached to the back surface of the cornea. However, 2 eyes needed rebubbling, and after rebubbling, all of the 2 grafts completely attached to the back surface of the cornea. The best spectacle-corrected visual acuity significantly improved 6 months after surgery (P < .001) and the central corneal thickness significantly decreased (P < .001).The use of OVD facilitates safer graft insertion during DMEK, and subsequently prevents endothelial cell loss, which leads to a successful procedure.

DOI： 10.1097/MD.0000000000011245

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At present, only one design is available for trifocal intraocular lens (IOL); unfortunately, this particular design is not suitable for implantation in the sulcus with optic capture when posterior capsule rupture (PCR) occurs. Although three-piece bifocal IOLs can be implanted in the sulcus, this form of IOL can be vulnerable to tilt and decentration, thus causing aberration and photopic phenomena, such as halos and glares. However, visual axis centered optic capture using femtosecond laser-assisted cataract surgery (FLACS) is able to manage such complex operations. In the present study, we implanted a three-piece +4.0 D bifocal IOL into the sulcus of a patient who experienced PCR using optic capture and FLACS following the straightforward implantation of a one-piece trifocal IOL in the other eye. Defocus curves showed that the weakness of the trifocal IOL (nearest distances) was compensated for by the strength of the +4.0 D bifocal IOL, whereas the weakness of the +4.0 D bifocal IOL (middle distance) was compensated for by the strength of the trifocal IOL. Therefore, this combination provided the patient with a wider range of depth of focus. The contrast sensitivity in both eyes was within the normal range. Photopic phenomena were comparable with the bilateral implantation of the trifocal IOL. Anterior segment optical coherence tomography showed that tilt and decentration in the trifocal IOL implanted in the bag was significantly higher than the +4.0 D bifocal IOL implanted in the visual axis centered optic capture. This case showed that the intraindividual implantation of a single-piece trifocal IOL in the bag and a three-piece +4.0 D bifocal IOL in the sulcus, using a combination of optic capture and FLACS, is promising particularly in cases of PCR and can provide a wider range of vision without losing visual quality.

DOI： 10.2147/IMCRJ.S176095

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Purpose: To evaluate the influence of pupil dilation on predicted postoperative refraction (PPR) and recommended intraocular lens (IOL) power to obtain target postoperative refraction calculated by using the third- and fourth-generation IOL power calculation formulas with a new optical biometer. Methods: This retrospective study included 162 eyes with cataract that underwent uneventful phacoemulsification with IOL implantation. PPR, recommended IOL power, anterior chamber depth (ACD), and lens thickness (LT) were measured pre- and post-pupil dilation. The change in PPR detected by using third-generation (Hoffer Q and SRK/T) and fourth-generation formulas (Haigis and Holladay 2) and the changes in ACD and LT were evaluated pre- and postdilation. The influence of dilation on the recommended IOL power calculated by each formula was analyzed. Result: ACD and LT significantly changed from pre- to postdilation. The mean absolute change in PPR between pre- and postdilation was significantly higher for fourth-generation formulas compared with third-generation formulas. The change in PPR between pre- and postdilation showed a significantly positive correlation with change in ACD and a significantly negative correlation with change in LT with fourth-generation formulas, but not with third-generation formulas. The discrepancy rate of recommended IOL power between pre- and postdilation calculated by fourth-generation formulas was significantly higher than that calculated by third-generation formulas. Conclusion: ACD and LT significantly changed by dilation. PPR and recommended IOL power significantly changed more by dilation when using fourth-generation formulas compared with third-generation formulas. Given the significant correlations of the change in PPR (between the pre- and postdilation) in the fourth-generation formulas and the changes in ACD and LT, the latter changes may be key in influencing dilation in the fourth-generation power calculation. Knowledge of the influence of dilation on fourth-generation formulas could help improve IOL calculation.

DOI： 10.2147/OPTH.S172846

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Objective: This report aimed to scrutinize the prevalence of Behçet's disease (BD)-related clinical manifestations based on age- and sex-specific subgroups using a Japanese nationwide registration database. Methods: The database of newly registered BD was obtained from the Japanese Ministry of Health, Labour and Welfare. Patients who met the International Criteria for Behçet's Disease were selected and analysed. Results: Among 6627 International Criteria for Behçet's Disease cases, 2651 (40.0%) were men and 3976 (60.0%) were women with a median age of 39 years (interquartile range: 31-50 years). Ocular lesion was more common in male [odds ratio (male: female) 2.64 (95% CI: 2.35, 2.95, P < 0.001)] and genital ulceration was more common in female (odds ratio = 0.29, 95% CI: 0.25, 0.32, P < 0.001). Ocular lesion (P < 0.001), arthritis (P < 0.001) and vascular lesions (P < 0.001) were more frequently observed in elderly registered patients. Contrarily, genital ulceration (P < 0.001), epididymitis of males (P = 0.023) and oral ulceration (P = 0.003) were more common in younger patients. Simultaneous assessment of sex and age revealed that male predominance of ocular involvement was found in the young adult generation, but not in patients over 70 year of age. A female predominance of genital ulcer was prominently observed in patients 20-59 year of age; however, the sex difference was not found in patients over 60 years of age. Sensitivity analysis using International Study Group criteria replicated the results. Conclusion: We showed that clinical phenotype in early phase of BD was different depending on onset age and sex.

DOI： 10.1093/rheumatology/kex285

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PURPOSE: To describe a simple technique that uses posterior chandelier illumination during Descemet membrane endothelial keratoplasty in cases of severe bullous keratopathy (BK). METHODS: Five eyes of 4 patients with advanced BK undergoing Descemet membrane endothelial keratoplasty were retrospectively analyzed. The pupil of the host eye was not treated with mydriatic or miotic agents. The chandelier illuminator was inserted transconjunctivally into the vitreous cavity from the pars plana. RESULTS: In all eyes, BK was secondary to laser iridotomy, which was performed for prevention or treatment of angle closure glaucoma. The implanted graft was clearly confirmed in the anterior chamber using activated chandelier illumination. The graft was immediately attached to the host cornea, with eventual healing of BK in all eyes. No complication involving insertion or removal of the 25-gauge trocar and the chandelier illuminator was observed. No vision-threatening complication was observed in any of the 5 eyes. CONCLUSIONS: The chandelier illuminator provided good visibility of the anterior chamber and enhanced the safety of surgery by preventing formation of an inverted graft.

DOI： 10.1097/ICO.0000000000001254

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Neuro-Behçet's disease (NBD) is subcategorized into parenchymal-NBD (P-NBD) and non-parenchymal-NBD types. Recently, P-NBD has been further subdivided into acute P-NBD (A-P-NBD) and chronic progressive P-NBD (CP-P-NBD). Although an increasing number of studies have reported the various clinical features of A-P-NBD and CP-P-NBD over the last two decades, there was a considerable inconsistency. Two investigators systematically searched four electrical databases to detect studies that provided sufficient data to assess the specific characteristics of A-P-NBD and CP-P-NBD. All meta-analysis was carried out by employing the random-model generic inverse variance method. We included 11 reports consisted of 184 A-P-NBD patients and 114 CP-P-NBD patients. While fever (42% for A-P-NBD, 5% for CP-P-NBD, p < 0.001, I2 = 93%) was more frequently observed in A-P-NBD cases; sphincter disturbances (9%, 34%, P = 0.005, I2 = 87%), ataxia (16%, 57%, P < 0.001, I2 = 92%), dementia (7%, 61%, P < 0.001, I2 = 97%), confusion (5%, 18%, P = 0.04, I2 = 76%), brain stem atrophy on MRI (4%, 75%, P < 0.001, I2 = 98%), and abnormal MRI findings in cerebellum (7%, 54%, P = 0.02, I2 = 81%) were more common in CP-P-NBD. Cerebrospinal fluid cell count (94/mm3, 11/mm3, P = 0.009, I2 = 85%) was higher in A-P-NBD cases. We demonstrated that A-P-NBD and CP-P-NBD had clearly different clinical features and believe that these data will help future studies investigating P-NBD.

DOI： 10.1038/s41598-017-09938-z

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We here describe three different clinical manifestations of tubulointerstitial nephritis and uveitis (TINU) syndrome. We examined and diagnosed the following 3 patients: a 15-year-old boy with bilateral anterior uveitis (Case 1), a 14-year-old girl with bilateral papilledema (Case 2), and a 49-year-old woman with panuveitis (Case 3). The findings are presented herein. Case 1: The patient had bilateral anterior uveitis. Urinalysis revealed markedly increased β2-microglobulin and N-acetyl-β-D-glucosaminidase levels. As the patient was pathologically diagnosed with tubulointerstitial nephritis (TIN), we diagnosed TINU based on the presence of both uveitis and TIN. He was treated with oral corticosteroids. Case 2: This patient showed anterior uveitis and papilledema in both eyes. On initial examination, the urine test results did not show any abnormality. Three months later, high β2-microglobulin and N-acetyl-β-D-glucosaminidase levels were detected. As the patient was clinically diagnosed with TIN, we subsequently diagnosed TINU. Both the ocular and renal findings improved without treatment. Case 3: The patient developed bilateral panuveitis, retinal vasculitis, and macular edema, which were initially suspected to be sarcoidosis. However, she was pathologically diagnosed with TIN 12 months before the onset of uveitis; therefore, she was finally diagnosed with TINU. She recovered with local corticosteroid administration only. TINU may present with fundal features in addition to anterior uveitis. Detailed history taking and urinalysis are important to determine the presence of tubular disorders in similar patients.

DOI： 10.1007/s10792-016-0321-5

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Behçet's disease (BD) is reportedly associated with polymorphisms of the ubiquitin-associated domain containing 2 (UBAC2) gene in Turkish, Italian, and Chinese populations. Here we investigated whether UBAC2 polymorphisms were associated with BD in a Japanese population. Using data from 611 Japanese BD patients and 737 Japanese controls who participated in our previous genome-wide association study, we analyzed the 58 genotyped single-nucleotide polymorphisms (SNPs) in the region 100 kb upstream and downstream of UBAC2. We also performed imputation analysis in the region, with 562 imputed SNPs included in the statistical analyses. Association testing revealed that the T allele of rs9517723 in the lncRNA LOC107984558 was significantly associated with ocular and central nervous system (CNS) lesions and showed the strongest association under the recessive model (TT vs. CT+CC: ocular lesion, Pc = 0.0099, OR = 1.56; CNS lesion, Pc = 0.0052, OR = 3.42). Expression analysis revealed that rs9517723 TT homozygotes showed significantly increased UBAC2 expression (P < 0.05). Our findings suggest that enhanced UBAC2 expression associated with the homozygous risk allele (TT) of rs9517723 could induce overactivation of ubiquitination-related pathway, resulting in the development of ocular and CNS lesions in BD.

DOI： 10.1038/s41598-017-00877-3

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DOI： 10.3109/13816810.2016.1145698

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We analyzed 1,900 Turkish Behçet's disease cases and 1,779 controls genotyped with the Immunochip. The most significantly associated SNP was rs1050502, a tag SNP for HLA-B*51. In the Turkish discovery set, we identified three new risk loci, IL1A-IL1B, IRF8, and CEBPB-PTPN1, with genome-wide significance (P < 5 × 10-8) by direct genotyping and ADO-EGR2 by imputation. We replicated the ADO-EGR2, IRF8, and CEBPB-PTPN1 loci by genotyping 969 Iranian cases and 826 controls. Imputed data in 608 Japanese cases and 737 controls further replicated ADO-EGR2 and IRF8, and meta-analysis additionally identified RIPK2 and LACC1. The disease-associated allele of rs4402765, the lead marker at IL1A-IL1B, was associated with both decreased IL-1α and increased IL-1β production. ABO non-secretor genotypes for two ancestry-specific FUT2 SNPs showed strong disease association (P = 5.89 × 10-15). Our findings extend the list of susceptibility genes shared with Crohn's disease and leprosy and implicate mucosal factors and the innate immune response to microbial exposure in Behçet's disease susceptibility.

DOI： 10.1038/ng.3786

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PURPOSE: Behçet disease (BD) is predominantly found between East Asia and the Mediterranean basin along the historic Silk Road. HLA-B51 is known to be strongly associated with BD. We investigated the association between HLA-B51 and the ocular manifestations of BD among various ethnic groups. METHODS: A literature survey was conducted, and 18 articles written in English were reviewed. RESULTS: A strong correlation was found between HLA-B51 and ocular lesions in the entire cohort discussed in the reviewed articles (OR = 1.76, p = 0.000057). HLA-B51 was shown to have a strong association with ocular manifestations of BD patients in East-Eurasian (OR = 2.40, p = 0.0030) and Middle-Eurasian (OR = 1.87, p = 0.0045), but not in West-Eurasian (OR = 1.28, p = 0.35) areas. This correlation seemed to become stronger towards the east. CONCLUSIONS: A meta-analysis showed that the correlation became stronger towards the east along the Silk Road. The study results may facilitate understanding of the etiology and characteristics of BD.

DOI： 10.3109/09273948.2015.1136422

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Purpose: The crystallin beta A4 (CRYBA4) gene variant, rs2009066, was previously reported to be associated with high myopia in a southern Chinese population. In the present study, we investigated whether CRYBA4 variants were associated with high myopia in a Japanese population. Methods: We recruited 1,063 Japanese patients with high myopia (spherical equivalent [SE] ≤-9.00 D in both eyes) and 1,009 healthy Japanese subjects (SE >-1.00 D). We genotyped rs2009066 and three tagging single-nucleotide polymorphisms (SNPs), rs16982456, rs2071861, and rs4276, in the CRYBA4 region. Results: We did not find any significant association between these four SNPs and high myopia in an allele analysis. However, rs2009066 and rs2071861, which were in strong linkage disequilibrium (LD; r2=0.86), showed a marginal association with high myopia in the recessive genotype model of risk alleles (rs2009066 G allele: P=0.032, odds ratio [OR] =1.31; rs2071861 A allele: P=0.037, OR =1.31). Nevertheless, this association became insignificant after correcting for multiple testing (Pc >0.05). Conclusion: This study showed no significant association between CRYBA4 variants and high myopia in a Japanese population. Our findings did not correspond with a previous study. Further genetic studies with other populations are needed to elucidate a potential contribution of the CRYBA4 region in the development of high myopia.

DOI： 10.2147/OPTH.S146038

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Introduction: Maintaining the correct orientation of the donor graft is important during Descemet's membrane endothelial keratoplasty (DMEK). We describe a new method of marking the donor graft prior to DMEK. Methods: Twelve eyes of 10 patients with bullous keratopathy who underwent DMEK were retrospectively analysed. Donor discs were created by stripping the endothelium-Descemet's membrane layer from corneoscleral buttons. Four semicircular marks, two 1.0 mm and two 1.5 mm in diameter, were created at the edge of the donor disc. The small and large marks were paired. Each donor graft was inserted into the anterior chamber, unfolded and attached to the posterior corneal stroma with an air bubble. Results: The inserted grafts were all appropriately orientated when attached to the back surfaces of the corneas. The two pairs of asymmetric marks afforded valuable guidance. Even when the graft was partially folded or decentred, and one pair of marks was obscured, the other pair was always visible to indicate graft orientation. Best spectacle-corrected visual acuity improved significantly in all patients (p<0.001). Compared with the preoperative endothelial cell density of the donor graft, that of the corneal endothelium had decreased 44.0%±10.0% by 6 months after surgery. Conclusions: Two pairs of asymmetrical semicircular marks placed on the edge of the donor graft allowed appropriate graft orientation during DMEK.

DOI： 10.1136/bmjophth-2017-000080

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BACKGROUND: It has been hypothesized that dysfunction of the solute carrier family 1, member1 gene (SLC1A1), which encodes the glutamate aspartate transporter, may play a role in normal tension glaucoma. In this study we investigate whether SLC1A1 is associated with normal tension glaucoma in Japanese patients. METHODS: A total of 292 Japanese patients with normal tension glaucoma and 500 healthy control subjects were recruited. We genotyped 12 single-nucleotide polymorphisms in SLC1A1. We also performed an imputation analysis to evaluate the potential association of un-genotyped SLC1A1 single-nucleotide polymorphisms, and 165 single-nucleotide polymorphisms were imputed. RESULTS: We observed an increased frequency of the G allele of rs10739062 in patients compared to controls (p = 0.043, OR = 1.25). The rs10739062 polymorphism exhibited a dominant effect: individuals with genotype GG and GC showed a 1.91-fold increase in risk compared to genotype CC (p = 0.0082). However, the statistical significance disappeared after Bonferroni correction for multiple testing (pc > 0.05). We did not find any significant association between any of the remaining 176 single-nucleotide polymorphisms and disease risk. CONCLUSIONS: Our study showed a lack of association between SLC1A1 variants and normal tension glaucoma in Japanese patients, suggesting that the SLC1A1 gene does not play a critical role in the development of the disorder in this patient population. However, further genetic studies with larger sample sizes are needed to clarify whether SLC1A1 may make some contribution that affects the risk of developing normal tension glaucoma.

DOI： 10.3109/13816810.2015.1028649

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DOI： 10.1111/1346-8138.13251

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

DOI： 10.1038/srep25853

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PURPOSE: Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder that generally affects the optic nerve and spinal cord. The etiology of this disease is still uncertain, but autoantibodies to aquaporin-4 (AQP4) are specific and pathogenic for NMO. Recent studies show that AQP4 gene variants are associated with NMO. In this study, we assessed the contribution of AQP4 genetic variants to susceptibility to anti-AQP4 antibody (AQP4-Ab)-positive NMO in a Japanese population. METHODS: The subjects were 16 patients with AQP4-Ab-positive NMO (13 sporadic cases, and 3 familial cases from 2 families) and 255 healthy controls. All coding exons of AQP4 were sequenced and five tag single-nucleotide polymorphisms (SNPs) in AQP4 were genotyped. We also performed an imputation analysis to evaluate the potential association of un-genotyped SNPs in AQP4. RESULTS: Known or novel mutations were not detected in any coding exon regions. The T allele frequency of polymorphism (-810 bp (C/T): rs2075575) of the promoter region in patients with AQP4-Ab-positive NMO was significantly higher than that in controls (50.0 vs 25.7 %, P = 0.0036, Pc = 0.018 odds ratio = 2.89). No other tag or imputed SNPs were significant. CONCLUSIONS: These findings suggest that the T allele of rs2075575 is a risk for AQP4-Ab-positive NMO. However, the results are the opposite of a previous study in the southern Han Chinese population, and therefore further genetic studies are needed to determine the possible contribution of the AQP4 region to development of NMO.

DOI： 10.1007/s10384-016-0441-5

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Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.

DOI： 10.1038/ncomms11008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：DOVE MEDICAL PRESS LTD  

Components of fish roe possess antioxidant and antiaging activities, making them potentially very beneficial natural resources. Here, we investigated chum salmon eggs (CSEs) as a source of active ingredients, including vitamins, unsaturated fatty acids, and proteins. We incubated human dermal fibroblast cultures for 48 hours with high and low concentrations of CSE extracts and analyzed changes in gene expression. Cells treated with CSE extract showed concentration-dependent upregulation of collagen type I genes and of multiple antioxidative genes, including OXR1, TXNRD1, and PRDX family genes. We further conducted in silico phylogenetic footprinting analysis of promoter regions. These results suggested that transcription factors such as acute myeloid leukemia-1a and cyclic adenosine monophosphate response element-binding protein may be involved in the observed upregulation of antioxidative genes. Our results support the idea that CSEs are strong candidate sources of antioxidant materials and cosmeceutically effective ingredients.

DOI： 10.2147/CIA.S102092

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PURPOSE: Many studies have investigated the relationship of the lumican gene (LUM) rs3759223 variant with the risk of high myopia, but the results have been inconsistent and inconclusive. In this study, we investigated whether LUM rs3759223 is associated with high myopia in a Japanese population. METHODS: We recruited 1,585 Japanese patients with high myopia (spherical equivalent [SE] <-9.00 diopters [D]) and 1,011 Japanese healthy controls (SE ≥-1.00 D). The rs3759223 variant was genotyped using the TaqMan assay, and the allelic and genotypic diversity among cases and controls was analyzed according to the SE level. RESULTS: In the allelic tests, the odds ratio (OR) for the T allele of rs3759223 tended to increase with the progression of SE, and the highest OR (1.56) was found in patients with SE <-15 D in both eyes. The OR of the T allele tended to increase with the progression of SE in the additive, dominant, and recessive inheritance models. However, we found no significant associations for any of the alleles or genotype models. CONCLUSION: These data support the possibility that the LUM rs3759223 T allele accelerates the progression of SE in the Japanese population, although no significant associations were observed in this study. Additional genetic studies with larger samples that take into account the degree of SE are needed to clarify the contribution of rs3759223 to the risk of high myopia.

DOI： 10.2147/OPTH.S104761

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical and Experimental Rheumatology S.A.S.  

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Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are killer lymphocytes that provide defense against viral infections and tumor transformation. Analogous to that of CTL, interactions of killer-cell immunoglobulin-like receptors (KIR) with specific human leukocyte antigen (HLA) class I ligands calibrate NK cell education and response. Gene families encoding KIRs and HLA ligands are located on different chromosomes, and feature variation in the number and type of genes. The independent segregation of KIR and HLA genes results in variable KIR-HLA interactions in individuals, which may impact disease susceptibility. We tested whether KIR-HLA combinations are associated with Vogt-Koyanagi-Harada (VKH) disease, a bilateral granulomatous panuveitis that has strong association with HLA-DR4. We present a case control study of 196 VKH patients and 209 controls from a highly homogeneous native population of Japan. KIR and HLA class I genes were typed using oligonucleotide hybridization method and analyzed using two-tailed Fisher's exact probabilities. The incidence of Bx-KIR genotypes was decreased in VKH patients (odds ratio [OR] 0.58, P = 0.007), due primarily to a decrease in centromeric B-KIR motif and its associated KIRs 2DS2, 2DL2, 2DS3, and 2DL5B. HLA-B22, implicated in poor immune response, was increased in VKH (OR = 4.25, P = 0.0001). HLA-Bw4, the ligand for KIR3DL1, was decreased in VKH (OR = 0.59, P = 0.01). The KIR-HLA combinations 2DL2+C1/C2 and 3DL1+Bw4, which function in NK education, were also decreased in VKH (OR = 0.49, P = 0.012; OR = 0.59, P = 0.013). Genotypes missing these two inhibitory KIR-HLA combinations in addition to missing activating KIRs 2DS2 and 2DS3 were more common in VKH (OR = 1.90, P = 0.002). These results suggest that synergistic hyporesponsiveness of NK cells (due to poor NK education along with missing of activating KIRs) and CTL (due to HLA-B22 restriction) fail to mount an effective immune response against viral-infection that may trigger VKH pathogenesis in genetically susceptible individuals, such as HLA-DR4 carriers.

DOI： 10.1371/journal.pone.0160392

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Components of fish roe possess antioxidant and antiaging activities, making them potentially very beneficial natural resources. Here, we investigated chum salmon eggs (CSEs) as a source of active ingredients, including vitamins, unsaturated fatty acids, and proteins. We incubated human dermal fibroblast cultures for 48 hours with high and low concentrations of CSE extracts and analyzed changes in gene expression. Cells treated with CSE extract showed concentration-dependent upregulation of collagen type I genes and of multiple antioxidative genes, including OXR1, TXNRD1, and PRDX family genes. We further conducted in silico phylogenetic footprinting analysis of promoter regions. These results suggested that transcription factors such as acute myeloid leukemia-1a and cyclic adenosine monophosphate response element-binding protein may be involved in the observed upregulation of antioxidative genes. Our results support the idea that CSEs are strong candidate sources of antioxidant materials and cosmeceutically effective ingredients.

DOI： 10.2147/CIA.S102092

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Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P=1.6×10(-5), odds ratio [OR]=1.86). This rs3181077 association was replicated with the independent sample set (P=0.032, OR=1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function.

DOI： 10.1016/j.bbi.2015.05.003

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DOI： 10.1038/ejhg.2014.288

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Language：Japanese   Publishing type：Research paper (international conference proceedings)   Publisher：Igaku-Shoin Ltd  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

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Behçet's disease (BD) is a multi-system inflammatory disorder of unknown etiology. Two recent genome-wide association studies (GWASs) of BD confirmed a strong association with the MHC class I region and identified two non-HLA common genetic variations. In complex diseases, multiple factors may target different sets of genes in the same pathway and thus may cause the same disease phenotype. We therefore hypothesized that identification of disease-associated pathways is critical to elucidate mechanisms underlying BD, and those pathways may be conserved within and across populations. To identify the disease-associated pathways, we developed a novel methodology that combines nominally significant evidence of genetic association with current knowledge of biochemical pathways, protein-protein interaction networks, and functional information of selected SNPs. Using this methodology, we searched for the disease-related pathways in two BD GWASs in Turkish and Japanese case-control groups. We found that 6 of the top 10 identified pathways in both populations were overlapping, even though there were few significantly conserved SNPs/genes within and between populations. The probability of random occurrence of such an event was 2.24E-39. These shared pathways were focal adhesion, MAPK signaling, TGF-β signaling, ECM-receptor interaction, complement and coagulation cascades, and proteasome pathways. Even though each individual has a unique combination of factors involved in their disease development, the targeted pathways are expected to be mostly the same. Hence, the identification of shared pathways between the Turkish and the Japanese patients using GWAS data may help further elucidate the inflammatory mechanisms in BD pathogenesis.

DOI： 10.1038/ejhg.2014.158

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Myopia can cause severe visual impairment. Here, we report a two-stage genome-wide association study for three myopia-related traits in 9,804 Japanese individuals, which was extended with trans-ethnic replication in 2,674 Chinese and 2,690 Caucasian individuals. We identify WNT7B as a novel susceptibility gene for axial length (rs10453441, Pmeta=3.9 × 10(-13)) and corneal curvature (Pmeta=2.9 × 10(-40)) and confirm the previously reported association between GJD2 and myopia. WNT7B significantly associates with extreme myopia in a case-control study with 1,478 Asian patients and 4,689 controls (odds ratio (OR)meta=1.13, Pmeta=0.011). We also find in a mouse model of myopia downregulation of WNT7B expression in the cornea and upregulation in the retina, suggesting its possible role in the development of myopia.

DOI： 10.1038/ncomms7689

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For the purpose of investigating Behcet&#039;s disease (BD) in Russia, 250 consecutive patients (177 men and 73 women) diagnosed with BD between 1990 and 2010 at the Research Institute of Rheumatology, Russian Academy of Medical Sciences in Moscow were enrolled in this study. The ethnic backgrounds of the patients were reported as follows: 23.2% (58 cases) from Russia, 12.8% (32 cases) from Azerbaijan, 14.4% (36 cases) from Armenia, 8.8% (22 cases) from Chechnya, and 21.6% (55 cases) from Dagestan. The remaining 19.2% (48 cases) were from other regions or of unknown origin. More than half (57.6%) of the Behcet&#039;s disease patients originated from Central Asia, specifically Azerbaijan, Armenia, Chechnya, and Dagestan. The mean age at disease onset was 31.5 ± 9.38 (13-60) years old, and the most typical initial manifestations were oral aphthous ulcers. Patients aged 20-39 years old were more commonly affected and displayed a wide clinical spectrum of the disease, with varieties of severe internal organ involvement. The manifestations observed throughout the course of the disease included oral aphthous ulcers (100%), various cutaneous lesions (88.8%), genital ulcers (81.2%), and ocula

DOI： 10.1007/s10067-013-2442-9

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For the purpose of investigating Behcet's disease (BD) in Russia, 250 consecutive patients (177 men and 73 women) diagnosed with BD between 1990 and 2010 at the Research Institute of Rheumatology, Russian Academy of Medical Sciences in Moscow were enrolled in this study. The ethnic backgrounds of the patients were reported as follows: 23.2% (58 cases) from Russia, 12.8% (32 cases) from Azerbaijan, 14.4% (36 cases) from Armenia, 8.8% (22 cases) from Chechnya, and 21.6% (55 cases) from Dagestan. The remaining 19.2% (48 cases) were from other regions or of unknown origin. More than half (57.6%) of the Behcet's disease patients originated from Central Asia, specifically Azerbaijan, Armenia, Chechnya, and Dagestan. The mean age at disease onset was 31.5 ± 9.38 (13-60) years old, and the most typical initial manifestations were oral aphthous ulcers. Patients aged 20-39 years old were more commonly affected and displayed a wide clinical spectrum of the disease, with varieties of severe internal organ involvement. The manifestations observed throughout the course of the disease included oral aphthous ulcers (100%), various cutaneous lesions (88.8%), genital ulcers (81.2%), and ocular lesions (54.0%). Besides these, many organs/systems were implicated in patient cases, namely joint (53.2%), vascular (25.2%), neurological (8.0%), gastrointestinal (25.2%), and cardiac (5.6%) systems. Involvements of ocular (p < 0.01) and skin (p < 0.01) lesions were more frequent in men than in women. HLA-B51 and HLA-A26 typing was performed in 127 patients and 508 healthy controls. HLA-B51 was found in 63.0% of BD patients compared to 20.7% of the healthy control subjects (p < 0.001), and HLA-A26 was present in 11.3% of BD patients and 18.9% of the control group. This study shows the presence of BD in Russia, and it is suggested that its prevalence in Central Asian people is much higher than that in White Russian.

DOI： 10.1007/s10067-013-2442-9

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DOI： 10.1007/978-4-431-54487-6_3

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PURPOSE: The purposes of this study are to develop and validate new diagnostic criteria for acute retinal necrosis (ARN) based on the ocular findings, clinical course, and virologic testing of intraocular fluids. SUBJECTS AND METHODS: The Japanese ARN Study Group, comprising 8 uveitis specialists and 1 statistician, was formed to develop new diagnostic criteria for ARN. The criteria used a combination of clinical features consistent with ARN including 6 early-stage ocular findings ([1a] anterior chamber cells or mutton-fat keratic precipitates; [1b] yellow-white lesion(s) in the peripheral retina [granular or patchy in the early stage, then gradually merging]; [1c] retinal arteritis; [1d] hyperemia of the optic disc; [1e] inflammatory vitreous opacities; and [1f] elevated intraocular pressure), 5 clinical courses ([2a] rapid expansion of the retinal lesion(s) circumferentially, [2b] development of retinal breaks or retinal detachment, [2c] retinal vascular occlusion, [2d] optic atrophy, and [2e] response to antiviral agents), and the results of virologic testing of intraocular fluids by means of either polymerase chain reaction or the Goldmann-Witmer coefficient for herpes simplex virus or varicella zoster virus. Various combinations of findings were analyzed to maximize the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The criteria were then used to retrospectively analyze patients who had been diagnosed as having ARN or control uveitis. Patients were followed at 1 of 7 tertiary uveitis clinics between 2009 and 2011. RESULTS: Analysis of the data allowed delineation of 2 levels of diagnosis: "virus-confirmed ARN" (defined as the presence of both early-stage ocular findings 1a and 1b, the presence of any 1 of the 5 clinical courses, and a positive virologic test result) and "virus-unconfirmed ARN" (defined as the presence of 4 of 6 early-stage ocular findings including 1a and 1b, presence of any 2 of the 5 clinical courses, and a negative virologic test result, or when virologic testing had not been performed). The new diagnostic criteria were applied to 45 patients with ARN and 409 patients with control uveitis, resulting in a sensitivity of 0.89, a specificity of 1.00, a PPV of 1.00, and an NPV of 0.99. CONCLUSIONS: New diagnostic criteria for ARN were developed and found to achieve high statistical values.

DOI： 10.1007/s10384-014-0362-0

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AIM: To assess the efficacy of topical Semaphorin-3A (SEMA3A) in the treatment of allergic conjunctivitis. METHODS: Experimental allergic conjunctivitis (EAC) mice model induced by short ragweed pollen (SRW) in 4-week-old of BALB/c mice, mice were evaluated using haematoxylin and eosin (H&E) staining, immunofluorescence and light microscope photographs. Early phase took the samples in 24h after instillation and late phase took the samples between 4 to 14d after the start of treatment. The study use of topical SEMA3A (10 U, 100 U, 1000 U) eye drops and subconjunctival injection of SEMA3A with same concentration. For comparison, five types of allergy eyedrops were quantified using clinical characteristics. RESULTS: Clinical score of composite ocular symptoms of the mice treated with SEMA3A were significantly decreased both in the immediate phase and the late phase compared to those treated with commercial ophthalmic formulations and non-treatment mice. SEMA3A treatment attenuates infiltration of eosinophils entering into conjunctiva in EAC mice. The score of eosinophil infiltration in the conjunctiva of SEMA3A 1000 U-treated group were significantly lower than low-concentration of SEMA3A treated groups and non-treated group. SEMA3A treatment also suppressed T-cell proliferation in vitro and decreased serum total IgE levels in EAC mice. Moreover, Treatment of SEMA3A suppressed Th2-related cytokines (IL-5, IL-13 and IL-4) and pro-inflammatory cytokines (IFN-γ, IL-17 and TNF-α) release, but increased regulatory cytokine IL-10 concentration in the conjunctiva of EAC mice. CONCLUSIONS: SEMA3A as a biological agent, showed the beneficial activity in ocular allergic processes with the less damage to the intraocular tissue. It is expected that SEMA3A may be contributed in patients with a more severe spectrum of refractory ocular allergic diseases including allergic conjunctivitis in the near future.

DOI： 10.3980/j.issn.2222-3959.2015.01.01

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Language：Japanese   Publisher：日本サルコイドーシス/肉芽腫性疾患学会  

【目的】今回、サルコイドーシス(サ症)診断基準の全身検査項 目に、血清可溶性 IL-2 受容体(s IL-2R)が加わった。血清 s IL-2R はサ症の他、悪性リンパ腫や膠原病、結核などでも上昇すること が知られている。我々は、ぶどう膜炎患者における血清 s IL-2R 測定が、サ症鑑別・診断に有用か否かを検討した。 【対象・方法】2014 年 8 月から 2015 年 5 月までに当院眼科外来 を受診し、確定診断がついたサ症 43 例、眼内悪性リンパ腫 10 例、 サ症以外の原因の明らかなぶどう膜炎 48 例について、ERISA 法 にて血清 s IL-2R を測定した。 【結果】血清 s IL-2R (Cut-Off 値:534U/ml)はサ症では 31 例 (72.1%、平均値:913.7 U/ml)、眼内悪性リンパ腫では 2 例(20%、 平均値:521 U/ml)、サ症以外のぶどう膜炎では 3 例(6.3%)に上 昇が見られた。サ症における血清 s IL-2R の感度は 72.1%、特異 度は 91.4%であった。 【結論】眼内悪性リンパ腫との鑑別を考慮に入れる必要はあるが、 血清 s IL-2R 測定は、サ症に伴うぶどう膜炎を鑑別・診断するた めに有用であると考えられた。

DOI： 10.7878/jjsogd.35.Suppl1_50-2

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Diagnosis and treatment of Behçet's disease (BD) have continued to undergo new changes in recent years. We organized a Compilation Committee for Guidelines on Diagnosis and Treatment of Ocular Behçet's Disease with five ophthalmology research facilities in Japan (Hokkaido University, Health Sciences University of Hokkaido, University of Tokyo, Tokyo Medical University, and Yokohama City University), and accomplished the Major review of Current aspects of Ocular Behçet's Disease in Japan. The review consist of four chapters: introduction, ocular lesions, diagnosis, and treatment. We are very pleased if the guidelines are found to be effective and useful in improving the quality of life (QOL) and quality of vision (QOV) of BD patients in the world.

DOI： 10.3109/09273948.2014.981547

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PURPOSE: Many studies have investigated the relationship of paired box 6 (PAX6) gene polymorphisms with the risk of high myopia, but the results across studies remain inconsistent and ambiguous. In the present work, we investigated whether PAX6 polymorphisms are associated with high myopia in a Japanese population. METHODS: A total of 1,585 Japanese patients with high myopia (spherical equivalent [SE] <-9.00 diopters [D]) and 1,011 Japanese healthy controls (SE≥-1.00 D) were recruited. To compare genotype frequencies between cases and controls, we genotyped five single nucleotide polymorphisms in the PAX6 gene that are reportedly associated with high/extreme myopia: rs662702, rs3026393, rs644242, rs3026390, and rs667773. RESULTS: For rs662702, rs644242, and rs667773, odds ratios (ORs) for their risk alleles tended to increase with the progression of SE and axial length in the additive and recessive models. Of these, rs644242 had the highest OR (2.56) in patients with SE<-15 D in both eyes in the recessive model. On the other hand, for rs3026393 and rs3026390, the ORs for their risk alleles tended to increase according to the progression of SE and axial length in the dominant model. Of the two, rs3026393 had the highest OR (2.32) in patients with SE<-15 D in both eyes in the dominant model. However, no significant associations were identified in this study. CONCLUSION: We found that these PAX6 single nucleotide polymorphisms were associated with an increased risk of extreme myopia. Although the results, which are in agreement with some previous studies, did not reach statistical significance, PAX6 single nucleotide polymorphisms may be important risk factors for the development of extreme myopia. Further genetic studies with larger sample sizes and taking into account the degree of myopia are needed to clarify the contribution of PAX6 variants in myopia development.

DOI： 10.2147/OPTH.S95167

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PURPOSE: To evaluate the long-term efficacy and safety of infliximab for the treatment of uveitis in Behçet's disease (BD). DESIGN: Retrospective multicenter study using a questionnaire. PARTICIPANTS: A total of 164 consecutive patients with BD treated with infliximab for more than 1 year were studied. The mean age at initiation of infliximab treatment was 42.6±11.7 years, and the mean treatment duration was 32.9±14.4 months. METHODS: Data before and at the last visit during infliximab treatment were analyzed in 4 groups divided by duration of treatment: group A (n = 43, 12-<24 months), group B (n = 62, 24-<36 months), group C (n = 42, 36-<48 months), and group D (n = 17, ≥48 months). MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), relapse of ocular inflammation, numbers of ocular inflammatory attacks per year, and adverse effects of infliximab therapy. RESULTS: The frequency of ocular attacks decreased in all groups (from 5.3±3.0 to 1.0±0.3 in group A, 4.8±4.6 to 1.4±0.3 in group B, 4.1±2.9 to 0.9±0.3 in group C, and 9.5±5.8 to 1.6±0.5 in group D; all P < 0.05). The BCVA was improved in approximately 55% of the eyes after treatment. Mean BCVA converted to logarithm of the minimum angle of resolution was improved after treatment with infliximab in groups A to C (from 0.79±1.04 to 0.59±0.94 in group A, 0.59±1.07 to 0.41±1.04 in group B, and 1.15±1.77 to 0.92±1.73 in group C; all P < 0.05) but not in group D. Uveitis relapsed in 59.1% of all patients after infliximab treatment, and no difference in duration until relapse was observed between individual groups. Approximately 80% of relapses occurred within 1 year after the initiation of infliximab treatment in all groups, 90% of which were controlled by increasing doses of topical corticosteroids and shortening the interval of infliximab infusion. Adverse effects were observed in 65 cases or 35% of all subjects. Infliximab treatment was continued in 85% of the patients, but 15% of the patients discontinued infliximab treatment because of adverse effects or insufficient efficacy. CONCLUSIONS: Infliximab reduced the frequency of ocular attacks and improved visual acuity in patients with BD-related uveitis and was generally well tolerated with few serious adverse events.

DOI： 10.1016/j.ophtha.2014.04.042

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To investigate differences between preoperative target refraction and postoperative spherical equivalent refraction in eyes with the first attack of acute angle closure glaucoma before and after surgery. We retrospectively examined eyes of 36 patients who suffered the first attack of acute primary angle closure after undergoing cataract extraction and intraocular lens implant. We measured keratometric values (K1, K2) due to medical therapy for high ocular tension and the mean time interval until surgery. We compared the axial length, expected diopter, logMAR visual acuity, K1, K2, refractive spherical equivalent, and intraocular pressure (IOP) before and 6 months after surgery. The average preoperative IOP was 51.3 ± 9.0 mmHg, but it decreased to 14.8 ± 3.6 mmHg after surgery. No corneal edema was observed after surgery. The average axial length was 22.12 ± 1.03 mm and there was no significant change in keratometric values, which were 7.72 ± 0.33 mm (K1) and 7.51 ± 0.31 mm (K2) before surgery and 7.67 ± 0.33 mm (K1) and 7.49 ± 0.29 mm (K2) after surgery. Similarly, no significant difference was observed in average preoperative target refractive error (-0.57 ± 0.53 D) and average postoperative refractive spherical equivalent (-0.67 ± 0.97 D). The inability to accurately determine preoperative refractive error due to corneal edema or other complications is a concern during the first attack of acute angle closure glaucoma. However, our results indicate that no differences should be expected between preoperative refractive error and postoperative refractive spherical equivalent.

DOI： 10.1007/s10792-013-9878-4

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DOI： 10.1111/aos.12349

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PURPOSE: To describe a new technique to perform trabeculotomy ab interno on eyes with open-angle glaucoma (OAG). METHODS: This was a retrospective study. We inserted a 25-gauge forceps that is usually used for internal limiting membrane peeling into the anterior chamber, and grasped and pulled the inner wall of Schlemm's canal away from the canal. The inner wall of Schlemm's canal was stripped for about 100° to 120° in 26 eyes of 23 patients. The intraocular pressure (IOP) and number of glaucoma medications were recorded before, and 1 day, 1 week, 2 weeks, and 1, 3, 6, 10, 12, 15, 17, 19, 24, 27, 30, and 33 months after the surgery. The intra- and postoperative complications were recorded. RESULTS: The mean ± standard deviation of the preoperative IOP was 20.0 ± 6.8 mmHg with a range from 10 to 38 mmHg (n = 26). The IOP was significantly reduced (P < 0.05; paired t-tests) at 1 week, 2 weeks, and 1, 3, 6, 10, 12, 15, 17, 24, 19, 27, 30, and 33 months after the surgery. The mean preoperative number of glaucoma medications was significantly reduced (P < 0.001; paired t-tests) at 1 week, 2 weeks, and 1, 3, 6, 10, 12, 15, 17, 19, 24, 27, 30, and 33 months after the surgery. No vision-threatening complications were found in any of the cases, but there were blood clots in the anterior chamber postoperatively in 92.3 % of the cases. CONCLUSIONS: Trabeculotomy ab interno for OAG is effective but with some minor complications. A larger number of patients with longer follow-up periods are needed to determine the long-term effectiveness of this procedure.

DOI： 10.1007/s00417-014-2616-4

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DOI： 10.1007/s00417-014-2597-3

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PURPOSE: We developed a novel scoring system for uveitis due to Behçet's disease (BD), termed Behçet's disease ocular attack score 24 (BOS24), and examined its validity and usefulness by estimating changes in ocular disease activities both before and after initiation of infliximab therapy. METHODS: BOS24 consists of a total 24 points divided into 6 parameters of ocular inflammatory symptoms. To examine the validity of our scoring system, 5 uveitis specialists examined the severity of 50 ocular attacks in clinical charts using both our system and a physician's impression score (grade 1-10). In addition, ocular disease activities both before and after initiation of infliximab were retrospectively examined in 150 cases of ocular BD using BOS24. RESULTS: The average BOS24 for the 5 doctors was highly correlated with the average physician's impression score (p < 0.0001), whereas the coefficient of variance for BOS24 among doctors was much lower than that for the physician's impression score (p < 0.0001). Summation of BOS24 over a 6-month period (BOS24-6M) was significantly reduced after starting infliximab therapy (p < 0.0001). The average BOS24 for individual ocular attacks was also significantly decreased after starting infliximab, with scores for the posterior pole and fovea notably improved. CONCLUSIONS: BOS24 was highly related to severity noted by the physician's impression and had a low level of variability among the examined doctors. Using our novel scoring system, infliximab therapy was shown to reduce not only the frequency of ocular attacks, but also the severity of each attack. BOS24 is a promising tool for evaluating ocular BD activities.

DOI： 10.1007/s10384-013-0294-0

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

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Language：English   Publishing type：Part of collection (book)   Publisher：Springer Nature  

DOI： 10.1007/978-88-470-5477-6_4

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Igaku-Shoin Ltd  

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BACKGROUND: It is not common to quantify visual acuity worse than 2.0 logarithm of the minimal angle resolution (logMAR) (commensurate with decimal visual acuity 0.01) at ophthalmology clinics. Recently, the Berkeley rudimentary vision test (BRVT) was developed as a simple measurement tool of logMAR with angular vision for quantifying poor levels of visual acuity. We compared the difference between BRVT and conventional Landolt ring logMAR chart with angular vision measured by the logMAR one target Landolt ring eye chart (LogMAR LEC). METHODS: We reviewed 110 patients with best-corrected visual acuity (BCVA) in the better eye from light perception (LP) to 0.8 logMAR measured by LogMAR LEC. The reproducibility of the log MAR LEC and BRVT was evaluated on 39 eyes from 20 patients, and 33 eyes from 20 patients respectively. The comparison of logMAR between BRVT and logMAR LEC was evaluated by surveying 61 eyes from 70 patients. In addition, regardless of their BCVA, the eyes from patients with worse than 2.0 logMAR by LogMAR LEC were re-evaluated by BRVT. RESULTS: The logMAR of patients examined by BRVT or logMAR LEC did not show any significant difference between the first and second examinations, and there was a strong correlation between the examinations in both eye charts. The BRVT significantly produced better logMAR compared with logMAR LEC, and the strong correlation was shown between both eye charts. Although 35 eyes from 28 patients among 110 patients could not be quantified by logMAR LEC, 18 eyes of 35 eyes could be quantified logMAR by BRVT. CONCLUSIONS: The BRVT and logMAR LEC are reliable visual acuity measurement tools. Moreover, the BRVT is potentially effective in quantifying visual acuity of the more severe visually impaired patients.

DOI： 10.1007/s00417-013-2469-2

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BACKGROUND: To evaluate changes in retinal and choroidal thickness changes after three intravitreal ranibizumab (IVR) injections for polypoidal choroidal vasculopathy (PCV) using enhanced depth-imaging-optical coherence tomography (EDI-OCT). METHODS: In this retrospective, observational case series, EDI-OCT was used to measure changes in choroidal thickness at nine points in a lattice shape in the macula before and after introductory-stage IVR. RESULTS: Choroidal thickness was decreased at all nine points in the lattice shape, but was significantly decreased only at the fovea. CONCLUSION: The subfoveal choroidal thickness may be reduced by introductory-stage IVR in patients with PCV. In particular, choroidal thickness at the fovea was reduced during the early stage of treatment.

DOI： 10.1007/s00417-013-2419-z

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OBJECTIVES: To identify non-major histocompatibility complex susceptible genes that might contribute to Behçet's disease (BD). METHODS: We performed a genome-wide association study using DNA samples from a Korean population consisting of 379 BD patients and 800 controls. A replication study was performed in a Japanese population (363 BD patients and 272 controls). To evaluate the functional implication of the target single nucleotide polymorphisms (SNP), gene expression levels in peripheral T cells, allele-specific modulation of promoter activity and biological effect of mRNA knockdown were investigated. RESULTS: We found a novel association of BD to the GIMAP locus, mapped to chromosome 7q36.1 (rs1608157, p=6.01×10(-8) in a minor allele dominant model; rs11769828, allele based p=1.60×10(-6)). A fine mapping study identified an association with four additional SNP: rs1522596 (OR=1.45, p=7.70×10(-6)) in GIMAP4; rs10266069 (OR=1.32, p=2.67×10(-4)) and rs10256482 (OR=1.27, p=5.27×10(-4)) in GIMAP2; and rs2286900 (OR=1.61, p=3.53×10(-5)) in GIMAP1 areas. Replication study using DNA samples from the Japanese population validated the significant association between BD and the GIMAP locus. The GIMAP4 promoter construct plasmid with the minor allele of rs1608157 displayed significantly lower activity than one with the major allele. Moreover, CD4 T cells from BD patients showed a lower level of GIMAP4 mRNA, and GIMAP4 knockdown was protective against Fas-mediated apoptosis. CONCLUSIONS: These results suggest that a GIMAP cluster is a novel susceptibility locus for BD, which is involved in T-cell survival, and T-cell aberration can contribute to the development of BD.

DOI： 10.1136/annrheumdis-2011-200288

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DOI： 10.1007/s00417-012-2232-0

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DOI： 10.5301/ejo.5000252

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Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways.

DOI： 10.1016/j.ajhg.2013.06.016

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AIMS: To evaluate the intraoperative applicability and safety of a mixture of brilliant blue G and sodium hyaluronate (visco-BBG) for staining the inner limiting membrane (ILM). METHODS: A retrospective consecutive case series. Seventy-four eyes that had undergone ILM peeling were studied. During vitrectomy, ILM peeling with visco-BBG (visco-BBG group) was performed on 40 eyes; 12 with a macular hole (MH), 26 with an epimacular membrane (ERM) and 2 with a retinal detachment due to a MH (MHRD). ILM peeling with BBG dissolved in balanced salt solution (BSS-BBG group) was performed on 34 eyes; 9 with a MH, 23 with an ERM and 2 with a MHRD. The main outcome measures were the distribution of the dye within the vitreous cavity and the retinal sensitivity in the MH patients of the two groups by microperimetry. RESULTS: The visco-BBG was injected over the retina where the ILM was intended to be peeled, and it stained the ILM in all cases. It did not disperse throughout the vitreous cavity or into the subretinal space. The BSS-BBG dispersed throughout the vitreous cavity, and its distribution was difficult to control. The two solutions did not stain the epiretinal membranes or any residual posterior hyaloid membrane. The difference in the retinal sensitivity between the two patients with MH of two groups was not significant. No complications were found in the visco-BBG group, although an accidental retinal perforation was found in one eye of the BSS-BBG group. Transmission electron microscopy confirmed that the membrane peeled was the ILM. CONCLUSIONS: Visco-BBG can be a useful method to assist macular surgery and can overcome some of the disadvantages of conventional BBG solutions dissolved in BSS.

DOI： 10.1136/bjophthalmol-2012-302289

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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DOI： 10.3109/09273948.2012.756114

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Genome-wide association studies (GWAS) are a powerful means of identifying genes with disease-associated common variants, but they are not well-suited to detecting genes with disease-associated rare and low-frequency variants. In the current study of Behçet disease (BD), nonsynonymous variants (NSVs) identified by deep exonic resequencing of 10 genes found by GWAS (IL10, IL23R, CCR1, STAT4, KLRK1, KLRC1, KLRC2, KLRC3, KLRC4, and ERAP1) and 11 genes selected for their role in innate immunity (IL1B, IL1R1, IL1RN, NLRP3, MEFV, TNFRSF1A, PSTPIP1, CASP1, PYCARD, NOD2, and TLR4) were evaluated for BD association. A differential distribution of the rare and low-frequency NSVs of a gene in 2,461 BD cases compared with 2,458 controls indicated their collective association with disease. By stringent criteria requiring at least a single burden test with study-wide significance and a corroborating test with at least nominal significance, rare and low-frequency NSVs in one GWAS-identified gene, IL23R (P = 6.9 × 10(-5)), and one gene involved in innate immunity, TLR4 (P = 8.0 × 10(-4)), were associated with BD. In addition, damaging or rare damaging NOD2 variants were nominally significant across all three burden tests applied (P = 0.0063-0.045). Furthermore, carriage of the familial Mediterranean fever gene (MEFV) mutation Met694Val, which is known to cause recessively inherited familial Mediterranean fever, conferred BD risk in the Turkish population (OR, 2.65; P = 1.8 × 10(-12)). The disease-associated NSVs in MEFV and TLR4 implicate innate immune and bacterial sensing mechanisms in BD pathogenesis.

DOI： 10.1073/pnas.1306352110

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PURPOSE: To report a case of corneal endotheliitis following the mumps parotitis. METHODS: A 46-year-old man noticed ciliary infection and visual loss in the right eye after mumps parotitis. To determine the cause of the disease, reverse transcription-polymerase chain reaction (RT-PCR) was used to amplify mumps virus RNA in samples from the aqueous humor. RESULTS: RT-PCR revealed mumps virus RNA in an aqueous humor sample. Although full recovery of vision was achieved within 1 month of the onset, corneal endothelial cells were severely damaged. CONCLUSIONS: The authors have detected mumps virus in the aqueous humor by RT-PCR for the first time.

DOI： 10.3109/09273948.2012.747619

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DOI： 10.1136/bjophthalmol-2012-302704

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Individuals with Behçet's disease suffer from episodic inflammation often affecting the orogenital mucosa, skin and eyes. To discover new susceptibility loci for Behçet's disease, we performed a genome-wide association study (GWAS) of 779,465 SNPs with imputed genotypes in 1,209 Turkish individuals with Behçet's disease and 1,278 controls. We identified new associations at CCR1, STAT4 and KLRC4. Additionally, two SNPs in ERAP1, encoding ERAP1 p.Asp575Asn and p.Arg725Gln alterations, recessively conferred disease risk. These findings were replicated in 1,468 independent Turkish and/or 1,352 Japanese samples (combined meta-analysis P < 2 × 10(-9)). We also found evidence for interaction between HLA-B*51 and ERAP1 (P = 9 × 10(-4)). The CCR1 and STAT4 variants were associated with gene expression differences. Three risk loci shared with ankylosing spondylitis and psoriasis (the MHC class I region, ERAP1 and IL23R and the MHC class I-ERAP1 interaction), as well as two loci shared with inflammatory bowel disease (IL23R and IL10) implicate shared pathogenic pathways in the spondyloarthritides and Behçet's disease.

DOI： 10.1038/ng.2520

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PURPOSE: To examine the factors associated with anatomic and visual outcomes in Japanese patients with acute retinal necrosis (ARN). METHODS: One hundred four patients with ARN who were followed for more than 1 year at nine referral centers were reviewed. Retinal involvement at initial presentation was classified into four groups: zone 1 (posterior pole, n = 22), zone 2 (midperiphery, n = 54), zone 3 (periphery, n = 25), and unknown (n = 3). Forty-eight eyes underwent prophylactic vitrectomy before development of retinal detachment (vitrectomy group); 56 eyes were treated conventionally without prophylactic vitrectomy (observation group). RESULTS: The retina was attached in 28 of 48 eyes (58.3 %) in the vitrectomy group and 42 of 56 eyes (75.0 %) in the observation group at the final visit (P = 0.071). At 1 year, 56 eyes (53.8 %) had a best-corrected visual acuity (BCVA) of 20/200 or worse. Multivariate logistic regression analyses identified zone 1 disease (odds ratio = 4.983) and optic nerve involvement (odds ratio = 5.084) as significantly associated with BCVA of 20/200 or worse. Among the zone 3 eyes, significantly (P = 0.012) more eyes in the observation group than in the vitrectomy group had an attached retina. CONCLUSIONS: Prophylactic vitrectomy did not improve the final BCVA in any eyes. Zone 3 eyes had better outcomes without prophylactic vitrectomy.

DOI： 10.1007/s10384-012-0211-y

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Glaucoma is a degenerative optic neuropathy that is associated with elevated intraocular pressure. Primary open angle glaucoma is the most common type of glaucoma in canines, and its highest incidence among dog breeds has been reported in Shiba-Inus, followed by Shih-Tzus. These breeds are known to have an abnormal iridocorneal angle and dysplastic prectinate ligament. However, the hereditary and genetic backgrounds of these dogs have not yet been clarified. In this study, we investigated the association between polymorphisms of the glaucoma candidate genes, SRBD1, ELOVL5, and ADAMTS10, and glaucoma in Shiba-Inus and Shih-Tzus. We analyzed 11 polymorphisms in these three genes using direct DNA sequencing. Three SRBD1 SNPs, rs8655283, rs22018514 and rs22018513 were significantly associated with glaucoma in Shiba-Inus, while rs22018513, a synonymous SNP in exon 4, showed the strongest association (P = 0.00039, OR = 3.03). Conditional analysis revealed that rs22018513 could account for most of the association of these SNPs with glaucoma in Shiba-Inus. In Shih-Tzus, only rs9172407 in the SRBD1 intron 1 was significantly associated with glaucoma (P = 0.0014, OR = 5.25). There were no significant associations between the ELOVL5 or ADAMTS10 polymorphisms and glaucoma in Shiba-Inus and Shih-Tzus. The results showed that SRBD1 polymorphisms play an important role in glaucoma pathology in both Shiba-Inus and Shih-Tzus. SRBD1 polymorphisms have also been associated with normal- and high-tension glaucomas in humans. Therefore, SRBD1 may be a common susceptibility gene for glaucoma in humans and dogs. We anticipate that the nucleotide sequencing data from this study can be used in genetic testing to determine for the first time, the genetic status and susceptibility of glaucoma in dogs, with high precision. Moreover, canine glaucoma resulting from SRBD1 polymorphisms could be a useful animal model to study human glaucoma.

DOI： 10.1371/journal.pone.0074372

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Language：Japanese   Publishing type：Research paper (international conference proceedings)  

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Language：Japanese   Publishing type：Research paper (international conference proceedings)  

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Language：Japanese   Publishing type：Research paper (international conference proceedings)  

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Language：Japanese   Publishing type：Research paper (international conference proceedings)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

DOI： 10.1038/eye.2013.123

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PURPOSE: Polymorphisms in the interleukin 1 alpha (IL1A) and IL1B gene regions were previously associated with keratoconus in a Korean population. In the present study, we investigated whether the IL1A and IL1B polymorphisms are associated with keratoconus in a Japanese population. METHODS: A total of 169 Japanese patients with keratoconus and 390 Japanese healthy controls were recruited. We genotyped one IL1A single nucleotide polymorphism (SNP; rs2071376) and two IL1B SNPs (rs1143627 and rs16944) to compare the frequencies of alleles, genotypes, and haplotypes between cases and controls. RESULTS: Statistically significant association was observed for rs1143627 (-31 T>C) in the IL1B promoter region; the T allele of rs1143627 was associated with an increased risk of keratoconus (p=0.014, corrected p value [pc]=0.043, odds ratio=1.38). The C allele of rs16944 (-511 C>T) in the IL1B promoter region had a 1.33-fold increased risk of keratoconus, although this increase did not reach statistical significance (p=0.033, pc=0.098). The TT genotype of rs1143627 was weakly associated with an increased risk of keratoconus (p=0.033, pc=0.099, odds ratio=1.52). However, no significant differences were found in the allele and genotype frequencies between the cases and controls for rs2071376 in IL1A. Regarding haplotypic diversity, the haplotype created by the T allele of rs1143627 and C allele of rs16944 was associated with a 1.72-fold increased risk of keratoconus (p=4.0×10(-5), pc=1.6×10(-4)). CONCLUSIONS: Our results replicate associations reported recently in a Korean population. Thus, IL1B may play an important role in the development of keratoconus through genetic polymorphisms.

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PURPOSE: The fibroblast growth factor 10 (FGF10) gene polymorphism rs339501 was previously reported to be associated with high myopia in a Chinese population. In the present study, we investigated whether FGF10 polymorphisms are associated with extreme myopia in a Japanese population as well. METHODS: A total of 433 Japanese patients with extreme myopia (≤ -10.00 diopters) and 542 Japanese healthy controls (+1.50 to -1.50 diopters) were recruited. We genotyped seven tagging single-nucleotide polymorphisms (SNPs), including rs339501, in FGF10. We also performed an imputation analysis to evaluate the potential association of ungenotyped FGF10 SNPs, and 34 SNPs were imputed. RESULTS: It was found that rs339501 and rs12517396 exhibited the strongest association with extreme myopia (p=3.9 × 10⁻⁴, corrected p [Pc]=0.0030). A significant association was also observed for rs10462070 (p=6.5 × 10⁻⁴, Pc=0.0059). These three SNPs were in strong linkage disequilibrium (D' ≥0.99, r² ≥0.96). However, the frequency of the A allele of rs339501 was increased in cases compared to controls, which differs from the increased frequency of the G allele in cases in the previous Chinese population. CONCLUSIONS: Three FGF10 SNPs in complete linkage disequilibrium--rs339501, rs12517396, and rs10462070--were associated with extreme myopia in the Japanese population, and the risk allele of rs339501 differed from the previous Chinese population. Therefore, these three SNPs may not be an important risk factor for susceptibility to extreme myopia. Further studies are needed to elucidate the possible contribution of the FGF10 region in the development of extreme myopia.

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PURPOSE: Polymorphisms in the insulin-like growth factor 1 (IGF1) gene were previously associated with high or extreme myopia in Caucasian and Chinese populations. In the present study, we investigated whether IGF1 polymorphisms are associated with high myopia in a Japanese population. METHODS: A total of 446 Japanese patients with high myopia (≤-9.00 diopters) and 481 Japanese healthy controls (+1.50 diopters to -1.50 diopters) were recruited. We genotyped seven tagging single-nucleotide polymorphisms (SNPs) in IGF1 and assessed allelic and haplotypic diversity in cases and controls. RESULTS: There were no statistically significant differences in the allele frequencies of IGF1 SNPs and genotypes between cases and controls (P>0.05). However, the A allele of rs5742629 and the G allele of rs12423791 were associated with a moderately increased risk of high myopia (odds ratio [OR] =1.20 and OR =1.21, respectively) with borderline statistical significance (P=0.0502, corrected P (Pc) =0.21 and P=0.064, Pc=0.29, respectively). The haplotype consisting of the A allele of rs5742629 and the G allele of rs12423791 was marginally associated with the risk of high myopia (P=0.041; OR =1.21); this association was not significant after correction (Pc=0.19). CONCLUSION: We found that the IGF1 SNPs are not significantly associated with high myopia in our Japanese population. Our results are in contrast to a previous study in which extreme myopia cases had significantly higher frequencies of the G allele of rs5742629 and the C allele of rs12423791 than controls. Therefore, the IGF1 SNPs may not be important factors for susceptibility to high myopia in all populations. Further genetic studies are needed to elucidate the possible contributions of the IGF1 region to the development of high myopia.

DOI： 10.2147/OPTH.S52726

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BACKGROUND: Cases of cataract surgery without penetrating keratoplasty in patients with Peters' anomaly are very rare. We report a case of Peters' anomaly type 2 with tilted lens due to synechia between the lens and iris that was treated with cataract surgery without penetrating keratoplasty. CASE PRESENTATION: A 16-year-old girl had Peters' anomaly in both eyes. Corneal opacity was severe in the left eye due to high-grade dysgenesis of the anterior segment. In the right eye, corneal opacity had spread from the center of the cornea to the inferotemporal side, and there was synechia between the iris and corneal endothelium from the inferonasal side to the inferotemporal side. Opacity was observed in the anterior pole of the lens, and there was synechia between the anterior iris and the lens. Ultrasound biomicroscopy (UBM) revealed that the lens was tilted because of synechia. The tilted lens induced astigmatism, which reduced visual acuity to 20/250, in conjunction with a cataract. Cataract surgery was performed; the synechia between the lens capsule and the iris was severed, an intraocular lens was inserted, and the tilt was repaired. UBM was used postoperatively to confirm that the lens capsule synechia had been corrected and that the intraocular lens was not tilted. As a result, visual acuity improved to 20/100; glaucoma and expansion of corneal opacity were not observed. CONCLUSIONS: Severing of the synechia between the cataract and iris, during cataract surgery, in a patient with Peters' anomaly type 2 resulted in favorable postoperative visual acuity.

DOI： 10.1159/000354611

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PURPOSE: To describe a technique for treating pterygium by combining a subpterygial injection of bevacizumab followed by pterygial ligation. METHODS: Bevacizumab (1.25 mg/0.05 mL) was injected into the base of pterygia in 4 patients, and the pterygial necks were ligated. RESULTS: The heads of the pterygia regressed and disappeared within 7 days after treatment. The bodies also partially regressed and well-defined vessels were not seen on the bodies; however, the concentration of microvessels was higher on the pterygial bodies than in the normal conjunctiva after 1 month. A recurrence was defined as fibrovascular growth of conjunctival tissue that extended beyond the limbus. No complications or recurrences were noted during the follow-up period. CONCLUSIONS: Although only 4 cases were studied, the uniform finding demonstrated that combined subpterygial bevacizumab injection and pterygial ligation is a potential effective procedure for removing pterygium.

DOI： 10.1097/ICO.0b013e3182408bc7

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PURPOSE: Sarcoidosis is a heterogeneous and multisystem granulomatous disorder. The etiology still is uncertain, but the disease currently is thought to be triggered by various genetic as well as environmental factors. Recently, an association between sarcoidosis and the butyrophilin-like 2 (BTNL2) gene located in close proximity to the HLA-DRB1 gene was reported. The purpose of our study was to verify the relationship between BTNL2 and HLA risk alleles for the susceptibility to sarcoidosis, and to assess whether the BTNL2 association is independent of the HLA risk alleles. METHODS: In our study, 11 single nucleotide polymorphisms (rs28362677, rs2076533, rs2076530, rs2076529, rs2294881, rs3763304, rs2076523, rs28362682, rs3806156, rs9268499, rs3763317), including the functional rs2076530 (G > A) of the BTNL2 gene, and HLA-DRB1 and -DQB1 alleles, were genotyped in 237 Japanese patients diagnosed with sarcoidosis and 287 healthy Japanese control subjects. RESULTS: In the patient group, the HLA-DRB1*08:03 (P = 6.15 × 10(-5), odds ratio [OR] = 2.43) and BTNL2 rs2076530_A (P = 6.90 × 10(-6), OR = 1.84) were associated with disease susceptibility. Upon stratification analysis in search for a synergistic effect given the extensive linkage disequilibrium between BTNL2 rs2076530_A and HLA-DRB1*08:03, our results suggested that the risk-bearing allele of these two loci interact negatively. No significant differences were observed in allele frequencies for alleles in patients with ocular and other systemic sarcoidosis. CONCLUSIONS: Our studies implicated that the HLA-DRB1 allele is a major contributing genetic factor in the development of sarcoidosis in Japan. However, further studies are needed to verify how HLA or BTNL2 alleles confer the disease phenotype, severity of sarcoidosis.

DOI： 10.1167/iovs.12-10491

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We investigated the neurophysiological correlates of stereoscopic 3-dimensional (3-D) depth perception by studying human visual evoked potentials (VEPs) with an integral imaging method characterized by horizontal but not vertical disparity. The VEPs were recorded in 10 healthy men under 4 conditions. In condition I, stimuli A (flat, 2-dimensional [2-D] image) and B (concave 3-D image) were presented at random. In condition II, stimuli A and C (convex 3-D image) were presented at random. In condition III, stimuli B and C were presented at random. In condition IV, stimuli A, B, and C were presented at random. The data for flat VEPs to stimulus A were combined in conditions I and II. The data for concave VEPs to stimulus B were combined in conditions I and III. The data for convex VEPs to stimulus C were combined in conditions II and III. When 2-way analysis of variance (ANOVA) for 2 factors, stimulus conditions (flat VEPs, concave VEPs, and convex VEPs) and electrode positions, was applied for VEP data, the N1 and N2 peak amplitudes differed significantly among the 3 stimulus conditions. In condition IV, the N1 peak amplitudes differed significantly among the 3 stimuli. Multiple comparisons followed by Bonferroni adjustment did not detect differences in the N1 peak amplitude between stimuli A and B, between stimuli A and C, or between stimuli B and C. We concluded that VEPs to concave or convex 3-D stimuli were significantly different from VEPs to flat 2-D stimuli. This is the first report showing modulation of human VEPs in 3-D perception with an integral imaging method.

DOI： 10.1177/1550059412445608

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AIM: To describe a new method of removing dislocated nuclear fragments smaller than one-fourth the size of the lens nucleus through the sclerocorneal incision made for cataract surgery. METHODS: Dislocated lens nuclear fragments on the surface of the retina were removed from six eyes of six consecutive patients. An anterior vitreous cutter with a 27-gauge chandelier endoilluminator (Twinlight illumination) tied to its sleeve was inserted into the eye through the incision made for cataract surgery and used for core vitrectomy. A fragmatome with another 27-gauge chandelier endoilluminator (Twinlight illumination) fibre was used to grasp and move the larger dislocated nuclear fragments into the anterior chamber where they were divided and removed. RESULTS: All dislocated nuclear fragments were removed through the incision for cataract surgery, and a posterior chamber lens was implanted in each patient without major complications. CONCLUSIONS: The procedure can be used to remove dislocated lens nuclear fragments from the surface of the retina through the incision for cataract surgery. Neither a second surgery, which would require three ports, nor the body of instruments for vitreal surgery are needed with this procedure.

DOI： 10.1136/bjophthalmol-2011-300864

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DOI： 10.1007/s10384-012-0150-7

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PURPOSE: To determine the factors significantly associated with an enlargement of the area of a chorioretinal atrophy (ChRA) after intravitreal bevacizumab (IVB) to treat myopic choroidal neovascularization (mCNV). METHODS: The medical charts of 27 eyes with a mCNV that had received IVB were reviewed. The ophthalmic examinations included measurements of the best-corrected visual acuity, visual fields with the Humphrey 10-2 Field Analyzer, fluorescein angiography, and indocyanine green angiography. The area of the mCNV and the chorioretinal atrophy (ChRA) were measured on the FA images. RESULTS: Eyes with an enlargement of the ChRA had significantly larger mCNVs at the baseline, a greater reduction in the size of the mCNV, a higher incidence of subretinal hemorrhage, longer duration of follow-up, received more injections of IVB, and had a greater decrease of retinal sensitivity (P ≤ 0.041). Multiple regression analyses showed that the factors most significantly associated with an enlargement of the ChRA were the CNV size at baseline, the number of IVB injections, and the duration of the follow-up period (P < 0.0001). CONCLUSIONS: Our findings showed that eyes with a larger CNV at the baseline and longer follow-up period had a greater risk of developing a ChRA like non-treatment, even if IVB treatment was performed for mCNV.

DOI： 10.1007/s00417-011-1921-4

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DOI： 10.1038/hr.2012.41

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Language：Japanese  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, beta = -0.16 mm per minor allele, P-meta = 2.69x10(-10)). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) = 0.75, 95% CI: 0.68-0.84, P-meta = 4.38x10(-7)) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

DOI： 10.1371/journal.pgen.1002753

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PURPOSE: To compare infliximab monotherapy with infliximab and colchicine combination therapy in Behçet's disease. METHODS: Clinical records of 14 Behçet's disease patients who were administered infliximab with or without colchicine were retrospectively reviewed. Patients who were given other immunosuppresants after initiation of infliximab therapy were excluded. The frequency of ocular attacks and best-corrected visual acuity were investigated. RESULTS: Seven patients received monotherapy and 7 received combination therapy. The mean frequency of ocular attacks significantly decreased from 2.14 to 0.22 per 6 months in monotherapy group and from 2.57 to 0.18 per 6 months in combination therapy group. No significant difference was observed between both groups in the frequency of ocular attacks and in changes in best-corrected visual acuity during 0 to 24 months. CONCLUSIONS: Infliximab is as efficacious as infliximab and colchicines together in Behçet's disease treatment. This study suggests that colchicine administration is not necessary in Behçet's disease patients receiving infliximab.

DOI： 10.3109/09273948.2012.665124

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OBJECTIVE: Behçet's disease is one of the major aetiologies of uveitis causing blindness in Asian countries. A genome-wide association study identified six microsatellite markers as disease susceptibility loci for Japanese patients with Behçet's disease. To confirm our recent results, these microsatellite markers were examined in a Korean population as a replication study. METHODS: Study participants included 119 Behçet's disease patients and 141 controls. All were enrolled in Korea. Association between the six reported microsatellite markers (D3S0186i, D6S0014i, D6S0032i, 536G12A, D12S0645i and D22S0104i) and Behçet's disease was analysed. HLA-B was genotyped by sequence-based typing methods. RESULTS: A microsatellite marker located near the HLA-B region demonstrated significant association with Behçet's disease (P = 0.028). The genotype and phenotype frequencies of the HLA-B*51 gene were significantly increased in patients (23.1 and 39.5%, respectively) compared with healthy controls (11.2 and 20.1%, respectively; P < 0.001). CONCLUSION: Microsatellite analysis revealed that the HLA-B*51 gene was strongly associated with Behçet's disease in a Korean population.

DOI： 10.1093/rheumatology/ker444

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DOI： 10.5301/ejo.5000032

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PURPOSE: To describe a thermocautery technique to treat symptomatic inferior conjunctivochalasis. METHODS: Thirty-nine eyes of 23 patients with symptomatic inferior conjunctivochalasis were treated with thermocautery. The mean age of the patients was 78.6 ± 5.4 years (±SD) with a range of 69-89 years. Patients with symptomatic inferior conjunctivochalasis were initially treated with topical medication, and the eyes that were unresponsive underwent a ligation test. We treated those eyes in which symptoms improved or disappeared during the ligation test. The redundant bulbar conjunctival tissue was grasped with smooth forceps and cauterized with the OPTEMP variable low temperature cauterizer until the redundant conjunctival tissue was gone. The mean follow-up period was 469.5 ± 234.6 days (range, 101-823 days). RESULTS: After the thermocautery, the symptoms disappeared in 36 of 39 eyes (92.3%) and improved in the remaining 3 eyes (7.7%). The conjunctival laxity disappeared in 36 of 39 eyes (92.3%) and improved in 3 eyes (7.7%). There were no recurrences of the conjunctival laxity during the follow-up period. CONCLUSIONS: Thermocautery is a simple and effective treatment for symptomatic inferior conjunctivochalasis.

DOI： 10.1097/ICO.0b013e3181dc81d2

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DOI： 10.1016/j.exer.2011.12.021

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DOI： 10.1016/j.exer.2011.12.021

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DOI： 10.1007/s00417-011-1800-z

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Myelin-derived axon growth inhibitors, such as Nogo, bind to Nogo receptor-1 (NgR1) and thereby limit the action of axonal regeneration after injury in the adult central nervous system. Recently, we have found that cartilage acidic protein-1B (Crtac1B)/lateral olfactory tract usher substance (LOTUS) binds to NgR1 and functions as an endogenous NgR1 antagonist. To examine the functional domain of LOTUS in the antagonism to NgR1, analysis using the deletion mutants of LOTUS was performed and revealed that the carboxyl-terminal region (UA/EC domain) of LOTUS bound to NgR1. The UA/EC fragment of LOTUS overexpressed together with NgR1 in COS7 cells abolished the binding of Nogo66 to NgR1. Overexpression of the UA/EC fragment in cultured chick dorsal root ganglion neurons suppressed Nogo66-induced growth cone collapse. These findings suggest that the UA/EC region is a functional domain of LOTUS serving for an antagonistic action to NgR1.

DOI： 10.1016/j.bbrc.2012.01.033

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PURPOSE: To investigate whether interleukin 10 (IL10) gene polymorphisms are associated with the development of sarcoidosis in Japanese patients. METHODS: Two hundred and eighty-eight Japanese sarcoidosis patients and 310 Japanese healthy controls were recruited. We genotyped 9 single-nucleotide polymorphisms in IL10 and assessed the allelic diversity between cases and controls. RESULTS: No significant differences in the frequency of IL10 alleles, genotypes, and haplotypes in the sarcoidosis cases compared to the controls were detected. CONCLUSIONS: Our results suggest that IL10 polymorphisms are not significantly related to the pathogenesis of sarcoidosis in the Japanese population.

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As one of the leading causes of visual impairment and blindness, myopia poses a significant public health burden in Asia. The primary determinant of myopia is an elongated ocular axial length (AL). Here we report a meta-analysis of three genome-wide association studies on AL conducted in 1,860 Chinese adults, 929 Chinese children, and 2,155 Malay adults. We identified a genetic locus on chromosome 1q41 harboring the zinc-finger 11B pseudogene ZC3H11B showing genome-wide significant association with AL variation (rs4373767, β = -0.16 mm per minor allele, P(meta) =2.69 × 10(-10)). The minor C allele of rs4373767 was also observed to significantly associate with decreased susceptibility to high myopia (per-allele odds ratio (OR) =0.75, 95% CI: 0.68-0.84, P(meta) =4.38 × 10(-7)) in 1,118 highly myopic cases and 5,433 controls. ZC3H11B and two neighboring genes SLC30A10 and LYPLAL1 were expressed in the human neural retina, retinal pigment epithelium, and sclera. In an experimental myopia mouse model, we observed significant alterations to gene and protein expression in the retina and sclera of the unilateral induced myopic eyes for the murine genes ZC3H11A, SLC30A10, and LYPLAL1. This supports the likely role of genetic variants at chromosome 1q41 in influencing AL variation and high myopia.

DOI： 10.1371/journal.pgen.1002753

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Lattice degeneration of the retina is a vitreoretinal disorder characterized by a visible fundus lesion predisposing the patient to retinal tears and detachment. The etiology of this degeneration is still uncertain, but it is likely that both genetic and environmental factors play important roles in its development. To identify genetic susceptibility regions for lattice degeneration of the retina, we performed a genome-wide association study (GWAS) using a dense panel of 23,465 microsatellite markers covering the entire human genome. This GWAS in a Japanese cohort (294 patients with lattice degeneration and 294 controls) led to the identification of one microsatellite locus, D2S0276i, in the collagen type IV alpha 4 (COL4A4) gene on chromosome 2q36.3. To validate the significance of this observation, we evaluated the D2S0276i region in the GWAS cohort and in an independent Japanese cohort (280 patients and 314 controls) using D2S0276i and 47 single nucleotide polymorphisms covering the region. The strong associations were observed in D2S0276i and rs7558081 in the COL4A4 gene (Pc = 5.8 × 10(-6), OR = 0.63 and Pc = 1.0 × 10(-5), OR = 0.69 in a total of 574 patients and 608 controls, respectively). Our findings suggest that variants in the COL4A4 gene may contribute to the development of lattice degeneration of the retina.

DOI： 10.1371/journal.pone.0039300

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PURPOSE OF REVIEW: Sarcoidosis is a multisystem disorder that can include ocular lesions. Although the precise etiology of the disease is as yet not well known, it is gradually becoming clearer as a result of much intensive research. The scope of this review is to evaluate the current understanding of sarcoidosis, specifically the pathogenesis of the disease and the therapeutic possibilities. RECENT FINDINGS: Inherited factors for this disease are gradually being identified by many large-scale genetic studies. As for treatment, biological drugs against inflammatory cytokines, such as tumor necrosis factor-α, are beginning to be used in sarcoidosis patients. SUMMARY: The exact etiology of sarcoidosis is still unknown. Further genetic studies in various ethnic populations are required to gain a better understanding of the pathogenesis of sarcoidosis. The data of clinical trials of biological drugs are accumulating, and it is necessary to produce a guideline for the use of these drugs on the basis of the benefits and risks to the patient.

DOI： 10.1097/ICU.0b013e32834bbd7e

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PURPOSE: Vogt-Koyanagi-Harada (VKH) disease is an autoimmune disorder affecting melanocytes in the skin, eyes, inner ear, and meninges. The Epstein-Barr virus and cytomegalovirus (CMV) antigen have been hypothesized as possible triggering factors for the disease. Toll-like receptors (TLRs) play an important role in the induction of defense mechanisms of the innate and adaptive immune responses to microbial pathogens. Among TLRs, TLR9 recognizes unmethylated 2'-deoxyribo (cytidine-phosphate guanosine)(CpG) DNA motifs that are frequently present in viruses and plays a central role in the host defense against viral infection. The aim of this study was to investigate whether TLR9 polymorphisms were associated with VKH in a Japanese population. METHODS: Ninety-four Japanese patients diagnosed with VKH and 125 healthy control subjects were recruited. Five single-nucleotide polymorphisms (SNPs: rs187084, rs5743836, rs352139, rs352140, rs5743845) in the TLR9 gene were genotyped, and allelic and phenotypic diversity was assessed between cases and control subjects. RESULTS: Strong linkage disequilibrium was observed among three SNPs (D' > 0.99), which were located in one haplotype block. Two SNPs (rs5743836 and rs5743845) were monopolymorphic in both cases and controls. No statistically significant association was observed for any of the SNPs between cases and controls. CONCLUSION: Three SNPs in the TLR9 gene were not significantly associated with susceptibility to VKH.

DOI： 10.3109/09273948.2011.553981

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PURPOSE: Patients with Behçet's disease often need intraocular surgeries for the treatment of secondary cataract or glaucoma. This study aims to report the clinical course before and after the intraocular surgeries of 5 patients who were systematically treated with infliximab. METHODS: Retrospective case series. RESULTS: Seven eyes of 5 male patients with Behçet's disease, who underwent intraocular surgery while under systemic infliximab therapy at Yokohama City University Hospital from 2007 to 2009, were included in the study. The mean age at surgery was 44.2 years. Phacoemulsification was performed on 4 eyes, and trabeculectomy was done on the remaining 3 eyes. The mean duration since the onset of the ocular symptoms was 107 months. Control of the ocular attacks with the use of other systemic medications was difficult for all patients; however, the use of infliximab enabled adequate control of the attacks. The visual acuity status during the preoperative stage did not worsen during the postoperative period. No infectious complication was observed in all cases. CONCLUSIONS: Our results suggest that infliximab treatment does not complicate any subsequent intraocular surgery. Patients with Behçet's disease in need of intraocular surgery can benefit from control of attacks with infliximab treatment.

DOI： 10.1159/000329190

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PURPOSE: To investigate whether the solute carrier family 1, member 3 (SLC1A3) gene, which encodes the glutamate aspartate transporter, is associated with normal tension glaucoma (NTG) in Japanese patients. METHODS: Two hundred and ninety-five Japanese patients with NTG and 518 Japanese healthy controls were recruited. Patients exhibiting comparatively early NTG onset were selected because early onset suggests that genetic factors may show stronger involvement. We genotyped 5 single-nucleotide polymorphisms (SNPs) in SLC1A3 and assessed the allelic and genotypic diversity among cases and controls. RESULTS: There were no statistically significant differences in the frequency of SLC1A3 alleles and genotypes between cases and controls. CONCLUSIONS: Our study showed no association between SLC1A3 and NTG, suggesting that the SLC1A3 gene may not be an associated factor in NTG pathogenesis.

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PURPOSE: Sarcoidosis is a systemic inflammatory disease characterized by the formation of non-caseating granulomas, with varied clinical manifestations. The common etiology of sarcoidosis is uncertain, but it is thought to be triggered by an exogenous antigenic stimulus, such as some bacterial proteins. Toll-like receptors (TLRs) recognize microbial components and elicit innate as well as adaptive immune responses. It has been reported that polymorphisms in TLR2 might be important in a small group of Caucasian sarcoidosis patients. The present study aimed to establish whether these findings are relevant to the Japanese population. METHODS: We genotyped 5 single-nucleotide polymorphisms (SNPs) in TLR2 and assessed the allelic diversity between 257 Japanese sarcoidosis patients and 193 Japanese healthy controls. RESULTS: No significant differences in the frequency of TLR2 alleles and haplotypes in the sarcoidosis cases were found in comparison with the controls. However, marginal associations were observed for TLR2 at rs3804099 and rs3804100 in sarcoidosis patients with cutaneous manifestations. CONCLUSIONS: Our results suggest that TLR2 polymorphisms are not significantly related to the pathogenesis of sarcoidosis in the Japanese population.

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Juvenile idiopathic arthritis (JIA) is one of the most common forms of pediatric chronic arthritis. JIA is a clinically heterogeneous disease. Therefore, the genetic background of JIA may also be heterogeneous. The aim of this study was to investigate associations between human leukocyte antigen (HLA) and susceptibility to JIA and/or uveitis, which is one of the most devastating complications of JIA. A total of 106 Japanese articular JIA patients (67 with polyarthritis and 39 with oligoarthritis) and 678 healthy controls were genotyped for HLA-A, -B and -DRB1 by PCR-sequence-specific oligonucleotide probe methodology. HLA-A(*)02:06 was the risk factor for JIA accompanied by uveitis after adjustment for clinical factors (corrected P-value < 0.001, odds ratio (OR) 11.7, 95% confidence interval (CI) 3.2-43.0). On the other hand, HLA-DRB1(*)04:05 was associated with polyarticular JIA (corrected P-value < 0.001, OR 2.9, 95% CI 1.7-4.8). We found an association of HLA-A(*)02:06 with susceptibility to JIA accompanied by uveitis, which might be considered a separate clinical JIA entity. We also found an association between HLA-DRB1(*)04:05 and polyarticular JIA. Thus, clinical subtypes of JIA can be classified by the presence of the specific HLA alleles, HLA-A(*)02:06 and DRB1(*)04:05.

DOI： 10.1038/jhg.2010.159

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Juvenile idiopathic arthritis (JIA) is one of the most common forms of pediatric chronic arthritis. JIA is a clinically heterogeneous disease. Therefore, the genetic background of JIA may also be heterogeneous. The aim of this study was to investigate associations between human leukocyte antigen (HLA) and susceptibility to JIA and/or uveitis, which is one of the most devastating complications of JIA. A total of 106 Japanese articular JIA patients (67 with polyarthritis and 39 with oligoarthritis) and 678 healthy controls were genotyped for HLA-A, -B and -DRB1 by PCR-sequence-specific oligonucleotide probe methodology. HLA-A(*)02:06 was the risk factor for JIA accompanied by uveitis after adjustment for clinical factors (corrected P-value &lt; 0.001, odds ratio (OR) 11.7, 95% confidence interval (CI) 3.2-43.0). On the other hand, HLA-DRB1(*)04:05 was associated with polyarticular JIA (corrected P-value &lt; 0.001, OR 2.9, 95% CI 1.7-4.8). We found an association of HLA-A(*)02:06 with susceptibility to JIA accompanied by uveitis, which might be considered a separate clinical JIA entity. We also found an association between HLA-DRB1(*)04:05 and polyarticular JIA. Thus, clinical subtypes of

DOI： 10.1038/jhg.2010.159

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Action of Toll-like receptors (TLRs) is deeply associated with defense mechanisms of the innate and adaptive immune responses to microbial pathogens. There have been reports of genetic polymorphisms within the TLR7 gene being closely related to a variety of inflammatory and infectious diseases. Behçet's disease (BD) is an autoinflammatory disease, and the pathogenesis has yet to be fully discovered. We investigated whether polymorphisms of Toll-like receptor 7 (TLR7) are associated with BD by analyzing the frequency of eight single nucleotide polymorphisms (SNPs) within 200 Japanese BD patients and 102 randomized controls. We genotyped nine SNPs in the TLR7 gene and assessed the allele/genotype diversity between cases and controls for all SNPs. In all eight SNPs, statistically significant differences were not observed between cases and controls.

DOI： 10.1016/j.humimm.2010.12.007

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Behcet's disease (BD) is a chronic inflammatory autoimmune disease and strongly associated with human leukocyte antigen (HLA)-B∗51 and -A∗26. We examined whether other genetic factors may exist in HLA region by 135 single nucleotide polymorphisms (SNPs) in 384 pairs of Japanese BD patients and controls. Multiple logistic regression analysis identified two novel susceptibility SNPs: rs9261365 near a ring finger protein (RNF) 39 and rs2074474 on exon 9 of tripartite motif-containing (TRIM) 39 independently of HLA-B∗51 and -A∗26 alleles. Our findings suggest that RNF39 and TRIM39 are involved in the etiology of BD.

DOI： 10.1016/j.bbrc.2010.09.088

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PURPOSE: Normal tension glaucoma (NTG) is a subtype of glaucoma in which intraocular pressure is within the statistically normal range. NTG may be associated with an immune disorder. The aim of this study was to determine whether specific alleles in the human leukocyte antigen (HLA)-DRB1 and HLA-DQB1 genes correlated with NTG in Japanese patients. METHODS: We genotyped the HLA-DRB1 and HLA-DQB1 alleles in 113 Japanese patients with NTG and in 184 healthy Japanese control subjects using the polymerase chain reaction-sequence-specific oligonucleotide probes (PCR-SSOP) Luminex method. We assessed the allelic diversity in patients and controls. RESULTS: There were no statistically significant differences in the allele frequency of HLADRB1 and HLA-DQB1 between NTG patients and control subjects, and no HLA-DRB1-HLA-DQB1 haplotypes demonstrated any significant association with NTG. CONCLUSIONS: Our findings suggest that HLA-DRB1 and HLA-DQB1 polymorphisms have no significant effect on the development of NTG in Japanese patients.

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Behçet&#039;s disease is a chronic systemic inflammatory disorder characterized by four major manifestations: recurrent ocular symptoms, oral and genital ulcers and skin lesions. We conducted a genome-wide association study in a Japanese cohort including 612 individuals with Behçet&#039;s disease and 740 unaffected individuals (controls). We identified two suggestive associations on chromosomes 1p31.3 (IL23R-IL12RB2, rs12119179, P = 2.7 x 10(-8)) and 1q32.1 (IL10, rs1554286, P = 8.0 x 10(-8)). A meta-analysis of these two loci with results from additional Turkish and Korean cohorts showed genome-wide significant associations (rs1495965 in IL23R-IL12RB2, P = 1.9 x 10(-11), odds ratio = 1.35; rs1800871 in IL10, P = 1.0 x 10(-14), odds ratio = 1.45).

DOI： 10.1038/ng.624

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Behçet's disease is a chronic systemic inflammatory disorder characterized by four major manifestations: recurrent ocular symptoms, oral and genital ulcers and skin lesions. We conducted a genome-wide association study in a Japanese cohort including 612 individuals with Behçet's disease and 740 unaffected individuals (controls). We identified two suggestive associations on chromosomes 1p31.3 (IL23R-IL12RB2, rs12119179, P = 2.7 x 10(-8)) and 1q32.1 (IL10, rs1554286, P = 8.0 x 10(-8)). A meta-analysis of these two loci with results from additional Turkish and Korean cohorts showed genome-wide significant associations (rs1495965 in IL23R-IL12RB2, P = 1.9 x 10(-11), odds ratio = 1.35; rs1800871 in IL10, P = 1.0 x 10(-14), odds ratio = 1.45).

DOI： 10.1038/ng.624

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PURPOSE: To investigate the effect of eicosapentaenoic acid (EPA) on acute ocular inflammation in an animal model of endotoxin-induced uveitis (EIU). METHODS: C57Bl/6 mice (6-week-old males) were orally treated with EPA at a dose of 50 mg/kg/day for 5 days. EIU was then induced in the animals by intraperitoneal injection of 160 microg lipopolysaccharide (LPS). Twenty-four hours after LPS injection, leukocyte adhesion to the retinal vasculature was evaluated by the concanavalin A lectin perfusion-labeling technique, and leukocyte infiltration into the vitreous cavity was quantified. Furthermore, the protein levels of monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, intercellular adhesion molecule-1 and phospholyrated nuclear factor (NF)-kappaB p65 in the retina and retinal pigment epithelium (RPE)-choroid complex were examined by enzyme-linked immunosorbent assay (ELISA). RESULTS: At 24 h after LPS injection, the EIU animals treated with oral EPA administration showed a significant decrease in leukocyte adhesion to the retinal vessels by 43.4% (p<0.01) and leukocyte infiltration into the vitreous cavity by 49.2% (p<0.05). In addition, EPA significantly reduced the protein levels of MCP-1 and IL-6 in the retina and the RPE-choroid complex. Furthermore, phosphorylation of NF-kappaB was suppressed by EPA treatment. CONCLUSIONS: Our data suggest that EPA inhibits multiple inflammatory molecules in vivo. EPA may become a novel strategy in the prevention and/or treatment of ocular inflammatory diseases.

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PURPOSE: Factors contributing to the development of normal tension glaucoma (NTG), degenerative optic neuropathy characterized by the progressive loss of retinal ganglion cells, optic nerve axons, and visual fields, have not been determined. To identify genetic risk factors for NTG, we performed a genome-wide association study of NTG. DESIGN: Case-control study. PARTICIPANTS: The study cohort consisted of 305 Japanese patients with NTG and 355 controls. METHODS: We genotyped 500,568 single-nucleotide polymorphisms (SNPs) and assessed the allelic diversity among cases and controls. MAIN OUTCOME MEASURES: Genotypes of 500,568 SNPs. RESULTS: The 2 most strongly NTG-associated SNPs, rs3213787 and rs735860, are located in an intron of SRBD1 and the 3'-untranslated region of ELOVL5 (P = 2.5 x 10(-9), odds ratio = 2.80 and P = 4.1 x 10(-6), odds ratio = 1.69), respectively. Real-time quantitative reverse transcription-polymerase chain reaction assays showed significantly increased expression of each gene in the white blood cells of subjects harboring the risk allele of these SNPs. CONCLUSIONS: Our genome-wide association study identified SRBD1 and ELOVL5 as new susceptibility genes for NTG. Because SRBD1 and ELOVL5 are reportedly involved in the induction of cell growth inhibition or apoptosis, the regulation of SRBD1 and ELOVL5 cascades may play an important physiologic role in the risk of NTG development. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

DOI： 10.1016/j.ophtha.2009.12.001

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BACKGROUND: Behçet disease (BD) is a rare, chronic, systemic, inflammatory disorder characterised by recurrent ocular, genital and skin lesions. Although its aetiology is still uncertain, an intricate interplay between the environment (eg, viruses) and the host seems to initiate and/or perpetuate the disease, although the mechanism remains speculative. Since the identification of HLA-B*5101 (and more recently of MICA) as a susceptibility locus for BD, the identification of additional genetic locus/loci, whether inside, or perhaps more importantly outside the MHC has clearly stalled. OBJECTIVE: To carry out a genome-wide association study (GWAS) of BD. METHODS: 300 Japanese patients with BD and an equal number of controls were recruited. The samples were screened using a dense panel of 23 465 microsatellites (MS) covering the entire genome. RESULTS: The six best (of a total of 147) positively associated MS with BD were identified. Of these six, two were located within the human leucocyte antigen (HLA) class I region itself. Although one of these was clearly reminiscent of the association with HLA-B, the second, not in linkage disequilibrium with the former, was in the telomeric side of the class I region and remained to be formally identified. HLA genotyping and haplotype analysis conclusively led to the deciphering of a dual, independent, contribution of two HLA alleles to the pathogenesis of BD: HLA-B*5101 and HLA-A*26. CONCLUSIONS: This GWAS highlights the premier genetic susceptibility locus for BD as the major histocompatibility complex itself, wherein reside two independent loci: HLA-B and HLA-A.

DOI： 10.1136/ard.2009.108571

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PURPOSE: To investigate whether the GLC1F locus is associated with normal tension glaucoma (NTG) in Japanese patients. METHODS: We recruited 242 unrelated Japanese subjects, including, 141 NTG patients and 101 healthy controls. The patients exhibiting a comparatively early onset were selected as they suggest that genetic factors may show stronger involvement. Genotyping and assessment of allelic diversity was performed on 11 highly polymorphic microsatellite markers in and around the GLC1F locus. RESULTS: Individuals carrying the 163 allele of D7S1277i had a statistically significant increased risk of NTG (p=0.0013, pc=0.016, OR=2.47, 95%CI=1.42-4.30). None of the other markers identified significant loci (pc>0.05) after Bonferroni's correction. CONCLUSIONS: These findings suggested that the genes in the GLC1F locus may be associated with the pathogenesis of NTG.

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OBJECTIVE: To determine the cerebral activity correlated with depth perception of 3-dimensional (3D) images, by recording of human visual evoked potentials (VEPs). METHODS: Two figures consisting of smaller and larger squares were presented alternately. VEPs were recorded in two conditions. In condition I, we used two figures which yielded flat 2-dimensional images. In condition II, we used two figures which yielded 3D images, which were concave and convex, respectively. RESULTS: P1, P2, and N1/P2 amplitude were significantly greater in condition II than in condition I. The P1/N1 amplitude tended to be greater in condition II than in condition I. P1 and N1 were predominantly distributed over the right temporo-parieto-occipital regions. P2 and N2 were distributed over bilateral parieto-occipital regions. CONCLUSIONS: The difference in P1 amplitude between two conditions can be explained by the difference between conditions, one of which yielded depth perception while the other did not, since previous studies showed that P1 and N1 are modulated by perception of images in depth. The role of P2 and the mechanism responsible for the increase in P2 amplitude during condition II remain unknown. SIGNIFICANCE: We recorded VEPs and identified electrophysiological correlates of depth perception with 3D images produced by concave/convex figures.

DOI： 10.1016/j.clinph.2009.12.005

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DOI： 10.1038/gt.2009.122

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INTRODUCTION: Behçet's disease (BD) is a multisystem inflammatory disorder, in which a T-helper 1 (Th1)-polarized immune response plays a major role in the pathogenic process. We evaluated the regulatory role of natural killer (NK) cells in Th1-biased immune responses in patients with BD. METHODS: We studied 47 patients with BD, including 10 with active disease (aBD) and 37 with inactive disease (iBD), and 29 healthy controls. The activation status and cytotoxic activity of NK cells were examined by flow cytometry. The levels of mRNAs for immune modulatory and cytotoxic molecules in NK cells were determined by quantitative PCR. The IL-12 signal strength in NK cells was determined by assessing the phosphorylation state of its downstream component, signal transducer and activator of transduction 4, by immunoblotting. Finally, NK cells' ability to modulate the Th1 response was evaluated by co-culturing NK cells and T cells without cell contact. RESULTS: CD69+-activated NK cells were significantly increased in aBD compared with iBD or control samples, although their cytotoxic activities were similar. The iBD NK cells showed downregulated IL-12 receptor beta2 mRNA levels compared with aBD or control NK cells. The increased IL-13 expression was detected in a subset of BD patients: most of them had iBD. The IL-13 expression level in iBD patients was significantly higher than the level in controls, but was not statistically different compared with the level in aBD patients. The gene expression profile in iBD patients was consistent with the NK type 2 phenotype, and the shift to NK type 2 was associated with disease remission. NK cells from iBD patients showed impaired IL-12-induced signal transducer and activator of transduction 4 phosphorylation. Finally, iBD, but not control, NK cells suppressed IFNgamma expression by aBD-derived CD4+ T cells in vitro. CONCLUSIONS: NK cells may control disease flare/remission in BD patients via NK type 2-mediated modulation of the Th1 response.

DOI： 10.1186/ar3005

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PURPOSE: Toll-like receptor 2 (TLR2) is a transmembrane receptor that mediates immune responses to exogenous and endogenous ligands, and interacts with heat-shock proteins, which are reportedly involved in normal tension glaucoma (NTG). We investigated whether TLR2 polymorphisms are associated with NTG. METHODS: 200 Japanese patients with NTG and 128 healthy Japanese controls were recruited. We genotyped five single-nucleotide polymorphisms (SNPs) in the TLR2 gene and assessed the allele and haplotype diversities between cases and controls for all SNPs. RESULTS: No significant differences in the frequency of TLR2 alleles and haplotypes in the NTG cases were detected, compared with the controls. CONCLUSIONS: Our study showed no evidence for an association between TLR2 polymorphisms and NTG. TLR2 polymorphisms may not play an important role in NTG pathogenesis in the Japanese population.

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PURPOSE: Toll-like receptors (TLRs) are pattern-recognition receptors that play an important role in innate and adaptive immune responses to microbial pathogens. Among TLRs, TLR4 recognizes lipopolysaccharides of Gram-negative bacteria. Genetic polymorphisms within the TLR4 gene have been reported to be associated with various inflammatory diseases; therefore, TLR4 appears to be a susceptibility gene for sarcoidosis. Although sarcoidosis has various clinical manifestations, its association with uveitis is more common in Japan than in other countries. The aim of this study was to investigate whether TLR4 polymorphisms were associated with sarcoidosis-related uveitis in a Japanese population. METHODS: Two hundred twenty-three patients with sarcoidosis and 206 healthy control subjects were recruited at seven sites in Japan. Eight single-nucleotide polymorphisms (SNPs) in TLR4 were genotyped with a TaqMan assay, and allelic and phenotypic diversity were assessed in affected and control subjects. RESULTS: We found no association with susceptibility to sarcoid-related uveitis for any of the SNPs analyzed. Strong linkage disequilibrium was observed among all the SNPs analyzed (D'>/=0.78), which were located in one haplotype block. CONCLUSION: TLR4 polymorphisms do not play an important role in the development of uveitis in Japanese patients with sarcoidosis.

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Disruption of the precise balance of positive and negative molecular regulators of blood and lymphatic vessel growth can lead to myriad diseases. Although dozens of natural inhibitors of hemangiogenesis have been identified, an endogenous selective inhibitor of lymphatic vessel growth has not to our knowledge been previously described. We report the existence of a splice variant of the gene encoding vascular endothelial growth factor receptor-2 (Vegfr-2) that encodes a secreted form of the protein, designated soluble Vegfr-2 (sVegfr-2), that inhibits developmental and reparative lymphangiogenesis by blocking Vegf-c function. Tissue-specific loss of sVegfr-2 in mice induced, at birth, spontaneous lymphatic invasion of the normally alymphatic cornea and hyperplasia of skin lymphatics without affecting blood vasculature. Administration of sVegfr-2 inhibited lymphangiogenesis but not hemangiogenesis induced by corneal suture injury or transplantation, enhanced corneal allograft survival and suppressed lymphangioma cellular proliferation. Naturally occurring sVegfr-2 thus acts as a molecular uncoupler of blood and lymphatic vessels; modulation of sVegfr-2 might have therapeutic effects in treating lymphatic vascular malformations, transplantation rejection and, potentially, tumor lymphangiogenesis and lymphedema (pages 993-994).

DOI： 10.1038/nm.2018

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PURPOSE: To analyze outcomes and immunologic features after cultured corneal endothelial cell (CEC) transplantation in a murine model. METHODS: CEC-deprived BALB/c corneas were reconstituted in vitro with an immortalized C3H-CEC cell line and then transplanted orthotopically into recipient BALB/c mice with experimental bullous keratopathy. Graft survival rates, donor-specific delayed hypersensitivity (DTH), and mixed lymphocyte reactions were evaluated in recipient mice after grafting. Fates of CEC transplantation were assessed after adoptive transfer, regrafting, and immunization with C3H splenocytes. RESULTS: Chimeric CEC allografts composed of cultured allogeneic CECs did not provoke rejection reaction, DTH, or mixed-lymphocyte reactions, unlike the high rejection rate that occurred in full-thickness corneal allografts. Adoptive transfer of splenocytes from mice that had accepted chimeric CEC allografts did not increase the graft survival rate after full-thickness corneal transplantation, and the rejection rate of a second full-thickness graft was not improved in these mice, suggestive of no active immunosuppression. Pre-sensitization by subcutaneous injection of splenocytes with the same haplotype as cultured CECs induced systemic DTH to the same allogeneic antigens but did not promote the rejection of chimeric CEC allografts, suggesting that chimeric CEC allografts are ignored by the host immune system. CONCLUSIONS: These findings indicate that immunologic ignorance rather than active immunosuppression is important for the rejection-free acceptance of chimeric CEC allografts. Transplantation of corneal grafts formed with allogeneic CECs could be an ideal treatment strategy to overcome postoperative rejection.

DOI： 10.1167/iovs.08-2530

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DOI： 10.1097/IAE.0b013e3181a3b946

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PURPOSE: Vogt-Koyanagi-Harada (VKH) disease is an autoimmune disorder against melanocytes. Polymorphisms of the protein tyrosine phosphatase non-receptor 22 gene (PTPN22) have recently been reported to be associated with susceptibility to several autoimmune diseases. In this study, genetic susceptibility to VKH disease was investigated by screening for single nucleotide polymorphisms (SNPs) of PTPN22. METHODS: A total of 167 Japanese patients with VKH disease and 188 healthy Japanese controls were genotyped by direct sequencing methods for six SNPs (rs3811021, rs1217413, rs1237682, rs3761935, rs3789608, and rs2243471) of PTPN22 including the uncoding exons. RESULTS: The six SNPs in PTPN22 showed no significant association with susceptibility to VKH disease or its ocular, neurologic, or dermatological manifestation. CONCLUSIONS: Further studies are needed to clarify the genetic mechanisms underlying VKH disease.

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OBJECTIVES: HLA-B51 is strongly associated with Behçet's disease (BD) in any ethnic background. We recently reported that another gene, Toll-like receptor-4 (TLR4) is also implicated in BD in a Japanese population. To confirm these results, we investigated polymorphisms in the TLR4 gene in Korean patients with BD. METHODS: In this study, 119 patients with BD and 141 healthy controls were enrolled; every participant was a Korean. Nine single nucleotide polymorphisms previously detected in TLR4 by direct sequencing were analysed for an association with BD. RESULTS: The most frequent haplotype, TAGCGGTAA, was significantly increased in HLA-B*51-positive BD patients (49.5%), compared with healthy control participants [32.3%; P = 0.029; odds ratio (OR) = 2.01; 95% CI 1.25-3.23]. This haplotype was also significantly increased in BD patients with arthritis (48.2%; P = 0.003; OR = 1.96; 95% CI 1.26-3.26). There were no significant differences in the allele and genotype frequencies of patients and controls for each single nucleotide polymorphism. CONCLUSIONS: The haplotype of TLR4 may increase the risk for developing BD and the complication of arthritis in the Korean population.

DOI： 10.1093/rheumatology/kep077

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Beta-tricalcium phosphate (beta-TCP) was grafted into rat mandibular bone defects to assess its potential as a scaffold material for bone regeneration. For this purpose, beta-TCP (TCP), allogenic bone (Allograft), and allogenic bone combined with beta-TCP (Combined) were employed as graft materials. To the left side of the graft materials in the bone defects, platelet-rich plasma (PRP) was added. The rats were sacrificed at one, three, and five weeks. Bone formation rate (BFR), remaining beta-TCP rate (RTR), beta-TCP absorption rate (TAR), whole amount of beta-TCP (WTCP), and total rate of BFR and RTR (TBR) were measured. Combined showed equivalent BFR to Allograft at five weeks, and showed higher RTR at one week and higher BFR at five weeks than TCP. Combined with PRP showed higher TAR than that without PRP at three weeks. Therefore, combination with allogenic bone showed reduced beta-TCP absorption, hence enhancing the role of beta-TCP in bone regeneration. These findings suggested that beta-TCP is a better scaffold for bone regeneration if its early absorption is reduced when used in combination with an osteogenic material.

DOI： 10.4012/dmj.28.153

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DOI： 10.1038/eye.2008.152

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Behçet's disease (BD) is a chronic systemic inflammatory disorder characterized by recurrent ocular symptoms, oral and genital ulcers, and skin lesions. The etiology of BD is still uncertain, but genetic and environmental factors likely both play an important role in BD development. In the present study, we investigated whether polymorphisms of Toll-like receptor 2 (TLR2), previously reported to recognize BD candidate antigens, are associated with BD. Two hundred Japanese patients with BD and 128 Japanese healthy controls were recruited. We genotyped five single-nucleotide polymorphisms (SNPs) in the TLR2 gene and assessed the allele/genotype diversity between cases and controls for all SNPs. No significant differences in the frequency of TLR2 alleles, genotypes, and haplotypes in the BD cases were detected compared with the controls. These data indicate that TLR2 polymorphisms do not play an important role in the development of BD.

DOI： 10.1016/j.humimm.2008.10.014

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BACKGROUND: To investigate whether the GPDS1 locus, a potential causative locus of pigment-dispersion syndrome, is associated with normal-tension glaucoma (NTG) in Japanese patients. MATERIALS AND METHODS: We used polymerase chain reaction amplification with sequence-specific primers to analyze 20 polymorphic microsatellite markers in and around the GPDS1 locus with an automated DNA analyzer and automated fragment detection by fluorescent-based technology. The DNA samples used for these analyses were obtained from ethnicity- and gender-matched patients, including 141 Japanese patients with NTG and 101 healthy controls. Patients exhibiting a comparatively early onset were selected as this suggests that genetic factors may show stronger involvement. RESULTS: One allele of D7S2462 exhibited a frequency that was significantly decreased in NTG cases compared to controls (P = 0.0013, Pc = 0.019, OR = 0.48, 95% CI = 0.30-0.75). Alleles at another six microsatellite loci were positively or negatively associated with NTG, but these associations did not retain statistical significance after Bonferroni correction (P < 0.05, Pc > 0.05). CONCLUSION: Our study showed a significant association between the GPDS1 locus and NTG, suggesting that there may be some genetic risk factor(s) in the development of NTG.

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PURPOSE: To investigate whether the GLC3A locus harboring the CYP1B1 gene is associated with normal tension glaucoma (NTG) in Japanese patients. MATERIALS AND METHODS: One hundred forty-two Japanese patients with NTG and 101 Japanese healthy controls were recruited. Patients exhibiting a comparatively early onset were selected as this suggests that genetic factors may show stronger involvement. Genotyping and assessment of allelic diversity was performed on 13 highly polymorphic microsatellite markers in and around the GLC3A locus. RESULTS: There were decreased frequencies of the 444 allele of D2S0416i and the 258 allele of D2S0425i in cases compared to controls (P = 0.022 and P = 0.034, respectively). However, this statistical significance disappeared when corrected (Pc > 0.05). We did not find any significant association between the remaining 11 microsatellite markers, including D2S177, which may be associated with CYP1B1, and NTG (P > 0.05). CONCLUSIONS: Our study showed no association between the GLCA3 locus and NTG, suggesting that the CYP1B1 gene, which is reportedly involved in a range of glaucoma phenotypes, may not be an associated factor in the pathogenesis of NTG.

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PURPOSE: To report on the toxicity of bupivacaine that was accidentally injected into the eye. METHODS: Observational case report. Clinical and electroretinographic examinations of a 78-year-old woman who had an ocular rupture after an accidental intraocular injection of 0.25% bupivacaine. RESULTS: The a- and b-waves of the electroretinographics were normal after the repair of the eye by vitrectomy. The corneal opacification and edema present after the rupture did not recover. CONCLUSION: The exposure of the retina to 0.25% bupivacaine may not alter the function of the human retina.

DOI： 10.1097/ICB.0b013e31817f2e2e

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OBJECTIVE: To describe vertical distraction osteogenesis of a scapular flap and removable lip support for oral rehabilitation after surgical creation of an ablative defect of the mandible. CASE REPORT: A 70-year-old man who was diagnosed with squamous cell carcinoma of the left lower gingiva underwent segmental mandibulectomy for tumor ablation and reconstruction with a scapular bone flap. To augment bone height of this flap, vertical distraction osteogenesis was performed. After denture fabrication, a removable lip support was placed between the implant-supported denture and the lower lip. RESULTS: The bone height of the scapular bone flap increased by 9 mm. Implants with adequate length could be placed in the distracted bone. The lip support was effective. Two years after masticatory loading, the implants remained stable. CONCLUSION: Vertical distraction osteogenesis of the scapular bone flap was suitable to facilitate postoperative functional and esthetic restoration after tumor resection. A removable lip support was also useful as a supplementary tool for oral rehabilitation.

DOI： 10.1016/j.tripleo.2008.05.048

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DOI： 10.1111/j.1399-0039.2008.01111.x

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Previously, we reported that phorbol 12-myristate 13-acetate (PMA)-activated protein kinase C (PKC) induced Rac1 activation in A172 glioblastoma cells. In this study, we investigated the mechanism of PMA-activated PKC-induced migration of glioblastoma cells by focusing on Rac1. PMA-induced formation of lamellipodia and focal complexes following migration were blocked by inhibiting Rac1 with small interfering RNA (siRNA), implicating Rac1 in PMA-induced glioblastoma cell migration. PMA-activated PKC induced phosphorylation of c-jun N-terminal kinase (JNK), one of the downstream effectors of Rac1. Immunohistochemical analysis showed that phosphorylated JNK was translocated to paxillin-containing focal complexes upon PMA stimulation and that Rac1 siRNA blocked these phenomena. These results suggest that phosphorylated JNK functions in cell migration and that JNK phosphorylation and translocation are mediated by Rac1. Furthermore, inhibition of Rac1 reduced phosphorylation of paxillin, a focal adhesion component and a downstream effector of JNK, at serine 178 (Ser178). Paxillin phosphorylation at this site has been shown to be involved in cell migration. Immunohistochemical analysis detected phosphorylation of paxillin (Ser178) in focal complexes upon PMA stimulation that was blocked by Rac1 siRNA. SP600125, a JNK inhibitor, also blocked PMA-induced phosphorylation of paxillin and aggregation of phosphorylated paxillin (Ser178) in focal complexes. In conclusion, paxillin is a critical downstream effector of Rac1 that may be involved in PMA-stimulated migration presumably by modulating the integrity of focal complex formation.

DOI： 10.3892/or_00000063

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PURPOSE: Toll-like receptor 4 (TLR4) is a transmembrane receptor that mediates immune responses to exogenous and endogenous ligands and interacts with heat shock proteins, which are reportedly involved in normal tension glaucoma (NTG). This study was undertaken to investigate whether TLR4 polymorphisms are associated with NTG. METHODS: Two hundred fifty Japanese patients with NTG and 318 Japanese healthy control subjects were recruited. Eight single-nucleotide polymorphisms (SNPs) in the TLR4 gene were genotyped, and allelic and phenotypic diversity was assessed between cases and control subjects. RESULTS: Strong linkage disequilibrium was observed among all SNPs (D' >or= 0.85), which were located in one haplotype block. With respect to allelic diversity, the minor allele of three SNPs (rs10759930, rs1927914, and rs7037117) carried a significantly increased risk of NTG. With regard to genotypic diversity, individuals with the minor allele of six SNPs (rs10759930, rs1927914, rs1927911, rs12377632, rs2149356, and rs7037117) had a 1.47- to 1.65-fold increased risk of NTG. rs7037117, located in the 3'-untranslated region of TLR4, was most strongly associated with NTG, and when incorporated into a haplotype with rs10759930, the strongest association was detected (P = 0.0038, P(c) = 0.0095). CONCLUSIONS: Multiple SNPs in the TLR4 gene are associated with the risk of NTG. This finding suggests that the ligands and/or cytokines involved in the TLR4 signaling network may be risk factors for the development of NTG.

DOI： 10.1167/iovs.07-1575

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DOI： 10.1136/bjo.2008.139980

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PURPOSE: Corneal endothelial cell (CEC) transplantation should become clinically applicable in the near future. However, the immunologic changes after allo-CEC transplantation are poorly understood at present. We tried to establish a mouse model of allogeneic CEC transplantation for immunologic studies. METHODS: Benzalkonium chloride was injected into the anterior chamber of the eyes of recipient BALB/c mice to create bullous keratopathy. Full-thickness corneal transplantation was performed by using 4 types of corneas: BALB/c corneas (isograft group), BALB/c corneas denuded of CEC (no endothelium group), C3H/He mouse corneas (allograft group), and corneas reconstituted by seeding immortalized C3H/He mouse CECs onto BALB/c corneas denuded of endothelium (CEC allograft group). Eyes were observed with an operating microscope for 4 weeks after transplantation and were subjected to histologic examination and fluorescein microscopy. RESULTS: All corneal grafts were transparent in the isograft group (n = 12), whereas none of the grafts were clear by 4 weeks after transplantation in the no endothelium group (n = 13). Corneal grafts were transparent at 4 weeks in 75% of the CEC allograft group (n = 12). The histologic rejection rate was 0% in the CEC allograft group, which was significantly lower than in the allograft group (67%; n = 18; P < 0.01). CONCLUSIONS: We established a mouse allo-CEC transplantation model by using cultured cells. This model should be useful for studying the immunologic processes after CEC transplantation.

DOI： 10.1097/QAI.0b013e31815e722b

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DOI： 10.1111/j.1399-0039.2008.01043.x

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PURPOSE: To describe a case of bilateral herpes simplex keratitis accompanying chronic graft-versus-host disease (GVHD). DESIGN: Observational case report. CASE REPORT: An 11-year-old boy with myelocytic leukemia underwent allogeneic bone marrow transplantation. He developed symptoms of the skin, eyes, and mouth, and lip biopsy indicated chronic GVHD. Persistent keratitis with corneal filaments and neovascularization was noted in both eyes. Sodium hyaluronate, autoserum, and 0.1% fluorometholone eyedrops were instilled for approximately 2 years to treat this keratitis, and there were no other ocular changes. Bilateral herpes simplex keratitis developed with geographic ulcers after topical betamethasone therapy, but responded to acyclovir ointment. CONCLUSIONS: Herpes keratitis should be considered in the differential diagnosis of bilateral keratitis in patients with reduced immunocompetence. During the course of chronic GVHD, corneal herpes may occur, so ocular treatment with topical corticosteroids should be managed by an ophthalmologist to monitor sight-threatening conditions such as corneal herpes.

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DOI： 10.1016/j.ijom.2008.01.002

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DOI： 10.1136/ard.2007.079871

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DOI： 10.1080/09273940802051100

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PURPOSE: High resolution (four-digit) allele genotyping was used to determine the association of the HLA-A and -B alleles with Behçet's disease (BD) in Japanese patients. We also analyzed our results for the association of these alleles with the individual clinical features of BD. SUBJECTS AND METHODS: We enrolled 389 Japanese BD patients and 254 healthy controls in this study. Genotyping of the HLA-A, -B alleles was performed by the PCR-SSOP-Luminex method and the phenotype frequencies of the HLA-A, and -B alleles were estimated. RESULTS: Some HLA-A and -B alleles were significantly associated with BD. When we recalculated the phenotype frequencies for the HLA-B*51-negative subjects to exclude the effects of the linkage disequilibrium with the HLA-B*51 allele, HLA-A*2601 was most strongly associated with BD. In addition, we observed a significant association between several clinical features and some alleles, including HLA-A*2602. CONCLUSION: The significant increase of HLA-A* 26 in the BD patients without HLA-B*51 suggests that this allele itself might be one of the primary susceptibility genes involved in the development of BD independently of HLA-B*51.

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INTRODUCTION: Toll-like receptors (TLRs) mediate signaling that triggers activation of the innate immune system, whereas heme oxygenase (HO)-1 (an inducible heme-degrading enzyme that is induced by various stresses) suppresses inflammatory responses. We investigated the interaction between TLR and HO-1 in an inflammatory disorder, namely Behçet's disease. METHODS: Thirty-three patients with Behçet's disease and 30 healthy control individuals were included in the study. Expression levels of HO-1, TLR2 and TLR4 mRNA were semiquantitatively analyzed using a real-time PCR technique, and HO-1 protein level was determined by immunoblotting in peripheral blood mononuclear cells (PBMCs) and polymorphonuclear leukocytes. In some experiments, cells were stimulated with lipopolysaccharide or heat shock protein-60; these proteins are known to be ligands for TLR2 and 4. RESULTS: Levels of expression of HO-1 mRNA were significantly reduced in PBMCs from patients with active Behçet's disease, whereas those of TLR4, but not TLR2, were increased in PBMCs, regardless of disease activity. Moreover, HO-1 expression in PBMCs from patients with Behçet's disease was repressed in the presence of either lipopolysaccharide or heat shock protein-60. CONCLUSION: The results suggest that upregulated TLR4 is associated with HO-1 reduction in PBMCs from patients with Behçet's disease, leading to augmented inflammatory responses.

DOI： 10.1186/ar2367

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Toll-like receptors (TLRs) mediate signaling that triggers activation of the innate immune system, whereas heme oxygenase (HO)-1 (an inducible heme-degrading enzyme that is induced by various stresses) suppresses inflammatory responses. We investigated the interaction between TLR and HO-1 in an inflammatory disorder, namely Behçet&#039;s disease.Thirty-three patients with Behçet&#039;s disease and 30 healthy control individuals were included in the study. Expression levels of HO-1, TLR2 and TLR4 mRNA were semiquantitatively analyzed using a real-time PCR technique, and HO-1 protein level was determined by immunoblotting in peripheral blood mononuclear cells (PBMCs) and polymorphonuclear leukocytes. In some experiments, cells were stimulated with lipopolysaccharide or heat shock protein-60; these proteins are known to be ligands for TLR2 and 4.Levels of expression of HO-1 mRNA were significantly reduced in PBMCs from patients with active Behçet&#039;s disease, whereas those of TLR4, but not TLR2, were increased in PBMCs, regardless of disease activity. Moreover, HO-1 expression in PBMCs from patients with Behçet&#039;s disease was repressed in the presence of either lipopolysaccharide or heat shock

DOI： 10.1186/ar2367

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PURPOSE: Interferon-gamma (IFN-gamma) is a key cytokine in inflammatory disorders. Elevated aqueous and serum levels of IFN-gamma levels have been reported to be elevated in patients with Vogt-Koyanagi-Harada (VKH) disease. The aim of this study was to determine the IFN-gamma gene polymorphisms in VKH disease. METHODS: The study involved 136 VKH patients and 176 healthy controls, who were genotyped for functional single nucleotide polymorphism (SNP; rs2430561; A/T) and functional microsatellite (CA) repeats (rs3138557) in the first intron of the IFN-gamma gene. Moreover, clinical manifestations of the patients were also analyzed. RESULTS: Diffuse choroiditis/staining of fluorescein angiography was seen in all VKH patients in this study. Sunset glow fundus and nummular chorioretinal depigmented scars were observed in 83.9%, and 36.1% of the patients, respectively. Neurological and auditory disorders were observed in 90.1% of the patients: meningismus (79.8%), tinnitus (53.0%), and cerebrospinal fluid pleocytosis (70.0%). Dermatologic manifestations were observed in 22.9% of the patients, manifesting as alopecia (6.9%), poliosis (17.6%), and vitiligo (13.0%). In addition, 22.1% of the patients were classified as having complete VKH disease, while 65.4% as having incomplete VKH disease, and 12.5% as having probable VKH disease. There were no significant differences in the allele and genotype frequencies between VKH patients and healthy controls. In addition, we found no association between each clinical manifestation and SNP (re2430561) in the healthy control subject. A strong linkage disequilibrium (LD) was found in the functional SNP T allele and functional microsatellite 12 (CA) repeats (D'=0.96-0.99). CONCLUSIONS: The functional SNP T allele and microsatellite 12 (CA) repeats were found to have a strong LD, although a genetic susceptibility for the IFN-gamma gene could not be demonstrated among the Japanese VKH patients.

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Ten subjects were asked to pay attention to green or to red, when each visual stimulus was presented as two small squares, one green and the other red. They were instructed to push a button with the right hand, when the attended color was on the right side, and to push a button with the left hand, when the attended color was on the left side. The P1/N1 peak-to-peak amplitudes of visual event-related potentials were significantly higher when subjects focused attention on green rather than on red. We assume that the attended color had the effect of modulating the P1/N1 components.

DOI： 10.1016/j.neulet.2007.09.075

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Purpose: Behcet&apos;s disease (BD) is known to be associated with HLA-B*51 in many different ethnic groups. Recently, the major histocompatibility complex class I chain-related gene A (MICA), located near the HLA-B gene, has been proposed as a candidate gene for BD susceptibility in several ethnic groups. To compare the relative contribution of MICA polymorphisms and HLA-B*51 to BD in different ethnic groups, we studied MICA polymorphisms in Turkish BD patients.
Methods: Thirty-three Turkish BD patients and 65 healthy controls were enrolled for analysis of polymorphisms in the extracellular domains of MICA.
Results: The phenotype frequencies of MICA*009 were significantly higher in BD patients (75.8%) than in controls (29.2%) (P = 0.000015). HLA-B*51 was also significantly more frequent in BD patients (81.8%) than in controls (29.2%) (P = 0.0000007). A strong association existed between MICA*009 and HLA-B*51. To assess the confounding effect of MICA*009 on HLA-B*51, we performed a stratification analysis that showed that BD was distinctly associated only with HLA-B*51.
Conclusion: Our results indicate that the major susceptibility gene for BD is HLA-B*51 and that the association between MICA*009 and BD arises from a strong linkage disequilibrium with HLA-B*51. However, we suggest that MICA*009 likely elicits an immune effect secondary to BD. Jpn J Ophthalmol 2007;51: 431-436 (c) Japanese Ophthalmological Society 2007.

DOI： 10.1007/s10384-007-0473-y

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BACKGROUND: Thyroid hormone increases oxygen consumption and regulates mitochondrial biogenesis. On the other hand, in Leber's hereditary optic neuropathy(LHON), retinal ganglion cells are exposed to the oxidative stress generated during the process of adenosine 5'-triphosphate (ATP) synthesis, eventually leading to a loss of vision. Although there is a possibility that the thyroid hormone may have a role in the development or the course of LHON, no case has been reported indicating a relation between them. We report a female case with LHON who also presented exacerbation of hyperthyroidism during the course of the disease. CASE: The patient was a thirty-nine-year-old woman who complained of bilateral loss of vision. Her corrected visual acuity was 0.2 in the right eye, and 0.1 in the left. Fundus examination showed characteristic findings of LHON in both eyes. The blood free thyroxin(FT4) level at that time was abnormally high. The diagnosis of LHON was confirmed by the presence of mitochondrial DNA mutation at the nucleotide position 11778. Her visual acuity improved after one month of FT4 normalization. A year later, her corrected visual acuity recovered to 0.9 in the right eye and 1.0 in the left. CONCLUSION: Hyperthyroidism may be a trigger in the development of LHON.

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DOI： 10.1111/j.1399-0039.2007.00924.x

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Cyclosporine (CYA) is used to preventing ocular attacks in Behçet's disease patients. Yet there are inter-individual variations in efficacy. In order to analyze the relationship between CYA fluctuation with treatment effectiveness and genetic factors, an association of area under the plasma concentration time at 0-4 hours (AUC0-4) values and polymorphism for multidrug resistance 1 (MDR1) and cytochrome3A5 (CYP3A5) genes was investigated. Genomic DNA was collected from 17 Japanese patients with Behçet's disease. MDR1 polymorphisms were determined by direct sequencing from amplified products for promoter and two exons regions and CYP3A5 polymorphisms were analyzed using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. AUC0-4 value was determined by the trapezoidal rule from the data of 5 times blood sampling at 0-4 hours. The haplotype 2 in the promoter region of MDR1 influenced significantly lower AUC0-4 values, implying absorption decline of CYA. The CYP3A5 polymorphisms had no direct influence on the effectiveness for CYA treatment. In the relation of CYA and AUC0-4 in the patients, 7 cases were grouped effective and 4 ineffective. Though there was no difference in dosage, the trough values for AUC0-4 were higher in the effective group compared to the ineffective group.

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Although a myopia susceptibility gene has not yet been elucidated, ten candidate regions (MYP1-MYP10) have been associated with myopia by linkage analysis employing large pedigrees. We report herein on the results of our analysis pertaining to polymorphisms of LAMA1 (alpha subunit of laminin), a promising candidate gene for high myopia present in the MYP2 region of Japanese subjects with high myopia. Three hundred and thirty Japanese subjects with high myopia at a level of greater than -9.25 D and ethnically and sex matched 330 normal controls without high myopia was enrolled in this study. The thirteen SNPs located on the LAMA1 gene were analyzed using PCR and SNP-specific fluorogenic probes. Two of the SNPs were monomorphic and none of the 11 SNPs showed statistically significant association with high myopia in the Japanese population. There is no convincing evidence to prove a connection between nucleotide sequence variations in LAMA1 and high myopia. The pairwise linkage disequilibrium (LD) mapping disclosed a strong value (D' > 0.8) and narrow ranged block within these SNPs.

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The collagen type Iota alpha Iota (COL1A1) gene encodes the extracellular matrix component, collagen, and resides in candidate MYP5 for high myopia on the chromosome 17q22-q23.3. This locus has recently been implicated in playing an important role in the pathogenesis of experimental myopia. We investigated the association of disruptions of COL1A1 gene with high myopia by analyzing the frequency of ten SNPs in a Japanese population of 330 subjects with high myopia of -9.25 D or less and 330 randomized controls without high myopia. Two SNPs (rs2075555 and rs2269336) were significantly associated with high myopia (P < 0.05, Pc < 0.1). Two different haplotype blocks in COL1A1 were observed by the pair-wise linkage disequilibrium between the SNPs. The frequency of GGC/GGC diplotype constructed by the three SNPs (rs2075555, rs2269336, rs1107946) was significantly high (OR = 1.6) and associated with high myopia (P = 0.028, Pc< 0.084). Together our results provide the first evidence for COL1A1 as a gene associated with high myopia.

DOI： 10.1007/s00439-007-0388-1

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OBJECTIVE: To report a case of neurosarcoidosis with rapid progression of visual field defects. CASE: A 28-year-old woman presented with bilateral uveitis and was diagnosed as having sarcoidosis after skin and cervical lymph node biopsy. Since bilateral excavations of the optic nerve head and visual field defects were observed, endocranial lesion was suspected. However, a computed tomography (CT) scan of the head detected nothing abnormal. It was regarded as a case of sarcoidosisaccompanied by normal-tension glaucoma and treatment was initiated with latanoprost. Four months later, the patient's visual field deteriorated rapidly. A CT scan showed a pituitary mass. Neurologicalfindings and hypopituitarism were found which improved with systemic prednisolone therapy. Diabetes insipidus developed after the start of treatment, and was treated with intranasal desmopressin therapy. After 6 weeks, head magnetic resonance imaging (MRI) showed a remarkable reduction of the enhanced regions. CONCLUSIONS: Although ocular sarcoidosis is often accompanied by secondary glaucoma or optic nerve atrophy, the progression of neurosarcoidosis can lead to visual field defects. Central nervous system (CNS) sarcoidosis is rare, but a precise examination with enhanced MRI should be considered when the visual field defect progresses rapidly.

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MYP2 was reported for a candidate locus associated with high grade myopia by linkage analysis, but no candidate gene has been detected. We report an association study in the Japanese population using 750 microsatellite markers on chromosome 18 that include MYP2 locus. 450 Japanese subjects with high myopia whose refractive error was greater than or equal to -9.25D in at least one eye and equal number of normal control subjects were recruited in this study. Three steps screening on the pooled DNA of patients and the pooled DNA of controls were performed in this study. A total of 722 microsatellite markers could be analyzed, and we obtained 4 positive markers. Then to avoid experimental errors and artifacts, we confirmed true allele frequency by individual genotyping using initial set of 450 patients and controls. Only marker D18S0301i showed statistically significance, and no marker showed statistically significance on the MYP2 locus. Near the marker D18S0301i, GALNT1 gene was located, but its relation to high myopia has remained to be identified.

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DOI： 10.1080/09273940701346338

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PURPOSE: We intravenously administered flomoxef sodium (FMOX) 0.5-3.5 hours before cataract surgery and measured the concentration of the agent in the aqueous humor to investigate its penetration into the aqueous humor and its efficacy in the prevention of postoperative endophthalmitis. METHODS: 56 patients who underwent cataract surgery were enrolled in this study. They received 1 g FMOX via a 20-minute intravenous drip beginning 0.5-3.5 hours before the operation. Aqueous humor was aspirated from the anterior chamber and assayed for FMOX concentration using high-performance liquid chromatography. RESULTS: The mean intraoperative FMOX concentrations in the patients' aqueous humor were 0.79 +/- 0.24 microg/ml (administered 3.5 hours before surgery)--1.47 0.79 microg/ml (administered 1.5 hours before surgery). These concentrations administered 0.5-3.0 hours before surgery sufficiently exceeded the minimum inhibitory concentration (MIC) 90 values against Staphylococcus epidermidis, Staphylococcus aureus and Propionibacterium acnes, but did not achieve the MIC90 values against Enterococcus faecalis and Pseudomonas aeruginosa. CONCLUSIONS: The FMOX concentrations in the aqueous humor sampling were adequate to kill bacteria in vitro. This drug may be efficacious in the prevention of postoperative endophthalmitis in patients undergoing cataract surgery.

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DOI： 10.1007/s10384-006-0417-y

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During the past decade, considerable efforts and resources have been devoted to elucidating the multiple genetic and environmental determinants responsible for hypertension and its associated cardiovascular diseases. The success of positional cloning, fine mapping, and linkage analysis based on whole-genome screening, however, has been limited in identifying multiple genetic determinants affecting diseases, suggesting that new research strategies for genome-wide typing may be helpful. Disease association (case-control) studies using microsatellite markers, distributed every 150 kb across the human genome, may have some advantages over linkage, candidate, and single nucleotide polymorphism typing methods in terms of statistical power and linkage disequilibrium for finding genomic regions harboring candidate disease genes, although it is not proven. We have carried out genome-wide mapping using 18,977 microsatellite markers in a Japanese population composed of 385 hypertensive patients and 385 normotensive control subjects. Pooled sample analysis was conducted in a 3-stage genomic screen of 3 independent case-control populations, and 54 markers were extracted from the original 18,977 microsatellite markers. As a final step, each single positive marker was confirmed by individual typing, and only 19 markers passed this test. We identified 19 allelic loci that were significantly different between the cases of essential hypertension and the controls.

DOI： 10.1161/01.HYP.0000257256.77680.02

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Over a 2-year period between 2001 and 2003, a total of 115 conjunctival scrapings were collected from patients with keratoconjuctivitis from several hospitals in Yokohama, Japan. Out of 115, 94 (82.4%) cases of adenoviruses were detected by polymerase chain reaction (PCR); 60 (52.1%) by cell culture isolation; and 16 (14.0%) by enzyme-linked immunosorbent assay (ELISA). The serotypes were determined by PCR- restriction fragment length polymorphism analysis (PCR-RFLP) and by the neutralization test (NT). PCR-RFLP was performed using a combination of endonucleases such as HhaI, AluI, and HaeIII. Of the 94 PCR-positive samples, the serotypes of 91 (96.8%) were identified by PCR-RFLP analysis (adenovirus 3: 50%, 4: 11%, and 8: 32%). Out of the 115 samples, 60 samples were identified by the neutralization (adenovirus 3, 4, 7, and 8). When both PCR-RFLP and the neutralization techniques were used, 53.2%, 11.7%, 1.1%, and 34% of the samples were identified as adenovirus 3, 4, 7, and 8, respectively. In contrast to the results of a nationwide surveillance report, adenovirus 3 was found as a major cause of keratoconjunctivitis in the Yokohama area. The nationwide surveillance report did not reflect accurately the epidemiological situation in the local area. In order to obtain surveillance data that would be useful for the prevention of an adenovirus conjunctivitis epidemic, it seems that local epidemiology is more important than that nationwide surveillance.

DOI： 10.1002/jmv.20779

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DOI： 10.1167/iovs.06-0991

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PURPOSE: The aim of the present study was to examine the genetic background of Vogt-Koyanagi-Harada (VKH) disease in a Japanese population by analyzing the tyrosinase gene family (TYR, TYRP1, and dopachrome tautomerase (DCT)). METHODS: 87 VKH patients and 122 healthy controls were genotyped using seven microsatellite markers on the candidate loci. We analyzed microsatellite (MS) polymorphisms at regions within tyrosinase gene family loci. In addition, the haplotype frequencies were also estimated and statistical analysis was performed. HLA-DRB1 genotyping was performed by the PCR-restriction fragment length polymorphism (RFLP) method. RESULTS: No significant evidence for an association was found. HLA-DRB1*0405 showed a highly significant association with VKH disease compared with the healthy controls (Pc=0.000000079), as expected. CONCLUSIONS: We concluded that there is no genetic susceptibility or increased risk attributed to the tyrosinase gene family. Our results suggest the need for further genetic study and encourage a search for novel genetic loci and predisposing genes in order to elucidate the genetic mechanisms underlying VKH disease.

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A previous study in China first indicated that the transforming growth factor-induced factor (TGIF) is a probable candidate gene for high myopia. The purpose of our study was to investigate whether there are significant associations between high myopia and single nucleotide polymorphism (SNP) variants in the TGIF gene of Japanese subjects. Genomic DNA was collected from 330 Japanese subjects with high myopia and at a level refractive error was less than -9.25 Dsph and 330 randomized controls without high myopia. Thirteen SNPs were detected by polymerase chain reaction (PCR) and primer extension or by PCR and SNP-specific fluorogenic probes in all of the cases and controls. Thirteen SNPs were found within the TGIF genes of the cases and controls. Two of the SNPs were monomorphic and none of the 13 SNPs showed a significant result. The pairwise linkage disequilibrium (LD) mapping confirmed that these alleles have a comparatively strong LD index of >0.8 for D' and >0.4 for r(2). We found no statistical association between any of the 13 SNPs located on the TGIF gene and high myopia in Japanese subjects. Based on our study using Japanese subjects and the previous studies of TGIF gene polymorphism in Chinese and northern European subjects with myopia, there is no convincing evidence to prove a connection between nucleotide sequence variations in TGIF and high myopia.

DOI： 10.1007/s00251-006-0155-9

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BACKGROUND: Genetic susceptibility to Behçet's disease (BD) is well documented for HLA-B51 positivity. However, BD is not a simple hereditary disease and it is exaggerated by exogenous stimuli such as microorganisms' infections. Ficolin 2 is a lectin that binds to the surface of microbial cells and kills microbial cells through the activation of complement system. Novel single nucleotide polymorphisms (SNPs) of human Ficolin 2 gene (FCN2 gene) have been recently identified in Caucasian people. OBJECTIVE: The aim of the study was to elucidate the contribution of FCN2 gene in the pathogenesis of BD. METHODS: The frequencies of genotypes and alleles of FCN2 gene SNPs in the promoter regions (-987, -602, -557, -64, -4) and exon 8 (+6359, +6424) were examined in 83 patients with BD and 64 healthy controls by genotyping with a DNA sequencing method. RESULTS: There were no significant differences in genotype and allele frequencies of FCN2 gene SNPs between BD patients and healthy controls. No significant differences in genotype and allele frequencies of FCN2 gene SNPs were detected among different clinical subgroups in BD patients. Significant differences in allele frequencies of FCN gene SNPs at both -557 and -64 sites in the promoter regions were found between HLA-B51 positive groups and HLA-B51 negative groups of BD patients. CONCLUSION: The significant differences in allele frequencies of FCN2 gene SNPs in the promoter lesions (-557 and -64 sites) among HLA-B51 positive BD patients may reveal the possibility that ficolin may contribute to the innate immunity of BD among HLA-B51 haplotypes in BD patients.

DOI： 10.1016/j.jdermsci.2006.05.010

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Adamantiades-Behcet's disease (ABD) is a chronic inflammatory multisystem disorder. Although the precise etiology is unclear, high prevalence of human leukocyte antigen (HLA)-B51 predisposition and predominantly involved T-helper type 1 cells (Th1)-type proinflammatory cytokines and extrinsic Streptococcal infection suggest a substantial association with an immunogenetic basis and strengthens the hypothesis that IL-12, a potent inducer of Th-1 immune reaction, is a putative candidate in its pathogenesis. These clinicopathological findings led us to examine interleukin 12 p40 (IL-12B) promoter polymorphism, for which the 4-base pair (bp) heterozygous insertion has been shown to affect the gene transcription and subsequent protein production. We analyzed IL-12B promoter genotypes in 194 Japanese subjects (92 with ABD and 102 normal controls) by PCR-based restriction enzyme digestion. The frequency of the insertion heterozygosity was significantly higher in patients than in controls (49/92, 53.3% vs 39/102, 38.2%, respectively). Comparing these with HLA haplotype data, this trend was more significant in HLA-B51-negative patients (29/42, 69.0% vs 20/50, 40.0%; P = 0.005). As assessed by semiquantitative reverse transcription-PCR and ELISA, stimulation with Streptococcal antigens specifically increased expression of IL-12 p40 mRNA and protein, in conjunction with IL-12 p70 induction, in peripheral blood mononuclear cells from heterozygous patients. Our results provide evidence for anti-bacterial host response toward Th1-immunity mediated by IL-12 in patients with ABD, and the possible insight into the genetic susceptibility that is independent of HLA background.

DOI： 10.1038/sj.jid.5700203

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DOI： 10.1111/j.1399-0039.2006.00586.x

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PURPOSE: To increase the degree of specificity for nomenclature in the current "Guidelines for Diagnosis of Ocular Sarcoidosis" published in 1990 by the Diffuse Pulmonary Disease Research Committee of Japan. SUBJECTS AND METHODS: We reviewed the records of patients with uveitis from the Uveitis Clinic in the Department of Ophthalmology at Yokohama City University. Subjects were selected from the records of uveitis patients with histologically proven sarcoidosis (78), and others with non-sarcoidosis uveitis (81). We examined the sensitivity and specificity of suspected characteristics of ocular sarcoidosis in the current "Guidelines for Diagnosis of Ocular Sarcoidosis". RESULTS: The definition specificity was improved by changing anterior uveitis to granulomatous anterior uveitis, and by simplifying to cloudy mass (snowball, string of pearls) from the previous diffused/cloudy mass vitreous opacity (snowball, string of pearls), and also by changing from retinal peripheral vasculitis (in many cases retinal periphlebitis, also at times retinal peripheral arteritis) to retinal periphlebitis. CONCLUSION: This newly proposed "Guidelines for Diagnosis of Ocular Sarcoidosis" gives a much clearer definition of sarcoidosis, as well as improved nomenclature for specific categories of ocular symptoms.

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We have developed a new high-throughput, high-resolution genotyping method for the detection of alleles at the human leukocyte antigen (HLA)-A, -B, -C, and -DRB1 loci by combining polymerase chain reaction (PCR) and sequence-specific oligonucleotide probes (SSOPs) protocols with the Luminex 100 xMAP flow cytometry dual-laser system to quantitate fluorescently labeled oligonucleotides attached to color-coded microbeads. In order to detect the HLA alleles with a frequency of more than 0.1% in the Japanese population, we created 48 oligonucleotide probes for the HLA-A locus, 61 for HLA-B, 34 for HLA-C, and 51 for HLA-DRB1. The accuracy of the PCR-SSOP-Luminex method was determined by comparing it to the nucleotide sequencing method after subcloning into the plasmid vector using 150 multinational control samples obtained from the International HLA DNA Exchange University of California Los Angeles. In addition, we performed the PCR-SSOP-Luminex method for HLA allele typing on DNA samples collected from 1,018 Japanese volunteers. Overall, the genotyping method exhibited an accuracy of 85.91% for HLA-A, 85.03% for HLA-B, 97.32% for HLA-C, and 90.67% for HLA-DRB1 using 150 control samples, and 100% for HLA-A and -C, 99.90% for HLA-B, and 99.95% for HLA-DRB1 in 1,018 Japanese samples. The PCR-SSOP-Luminex method provides a simple, accurate, and rapid approach toward multiplex genotyping of HLA alleles to the four-digit or higher level of resolution in the Japanese population. It takes only approximately 5 h from DNA extraction to the definition of HLA four-digit alleles at the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci for 96 samples when handled by a single typist.

DOI： 10.1007/s00251-005-0048-3

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Language：Japanese   Publishing type：Research paper (international conference proceedings)  

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PURPOSE: To investigate the relationships between contact lens wearers, their lens wear, and treatment to provide correct instructions for use. METHOD: A total of 55,056 consumers, who purchased contact lenses in the two institutions of Okada Eye Clinic in the 1-year period from April 1, 2002 to March 31, 2003, were analyzed with regard to age, sex, contact lens brands, treatments and lens-solution combinations purchased, and patterns of wear. RESULTS: The 2-week frequent-replacement soft contact lenses were the most popular type of contact lens, and most wearers of these lenses were those in their 20s. Saline solution was the treatment purchased most often with conventional soft contact lenses. Hard contact lens wearers tended to buy treatments of the same brand as their hard contact lenses. Hydrogen peroxide was the most purchased product with the 2-week frequent-replacement soft contact lenses and multipurpose treatment the next, especially with consumers in their 20s. There were no significant sex gaps. CONCLUSIONS: The survey was conducted on a wide age range of more than 50,000 people and can be assumed to accurately reflect the tendencies of contact lens wearers in Japan. The results clearly show the actual use of contact lenses and treatments of each age group and will be useful in instructing wearers to the correct use of their treatments.

DOI： 10.1097/01.ICL.0000152490.39831.4D

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PURPOSE: To investigate whether daily-disposable and 2-week disposable soft contact lenses are being used correctly. METHODS: The number of purchases made and brands selected by the 44,566 consumers who purchased daily-disposable and 2-week disposable soft contact lenses in Okada Eye Clinic institutions between April 1, 2002 and November 1, 2002 were monitored. From the 7,759 respondents to a survey conducted in the clinic between November 1, 2002 and March 31, 2003, the number of purchases made and brands selected by the 1,584 respondents, whose sales records could be traced, were analyzed in further detail. RESULTS: The total number of consumers purchasing daily-disposable soft contact lenses was 14,909, and their annual average purchase was 10.56 boxes. Most purchases were of two boxes followed by purchases of four and then six. Only 6.4% of consumers purchased 24 boxes at a time. Consumers purchasing four or fewer boxes at a time accounted for 37.8%. A total of 25,705 consumers purchased 2-week disposable soft contact lenses, with an annual average purchase of 6.37 boxes per consumer. Nineteen percent of the consumers purchased eight boxes of 2-week disposable soft contact lenses per year. Most consumers tended to purchase their contact lenses in even numbers for daily-disposable and 2-week disposable soft contact lenses. Johnson & Johnson Vision Care (Jacksonville, FL) was the most popular manufacturer. According to the survey, 86.6% of the 2-week disposable soft contact lens wearers followed instructions correctly, whereas 13.4% did not. That is, they exceeded the instructed 14 days of wear. CONCLUSIONS: Annual average purchases of daily-disposable and 2-week disposable soft contact lenses tended to be in even numbers and showed differences in their sales depending on contact lens brands. The results obtained from the survey and the actual sales records correlated.

DOI： 10.1097/01.ICL.0000152491.96155.B4

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The aim of this study was to assess the tolerability and efficacy of N-chlorotaurine (NCT), an endogenous antimicrobial agent, in epidemic keratoconjunctivitis. In a prospective double-blind, randomized phase 2b study, the infected eyes were treated for 7 days with eye drops containing 1% aqueous solution of N-chlorotaurine (33 subjects) or gentamicin (27 subjects, control group). Adenovirus types 3, 4, 8, 19, and 37 were detected in 39 subjects (65%), enteroviruses in 8 (13.3%), and staphylococci in 5 (8.3%). Subjective and objective symptoms were scaled and added to a subjective and objective score, respectively, on day 1 (baseline), day 4, and day 8. Analyzing the whole study population, the subjective score on day 8 was lower in the NCT group (P = 0.016), whereas there were no differences in the objective score. However, in severe infections caused by adenovirus type 8 (n = 20) both the subjective and objective score were lower in the NCT group on day 4 (P = 0.003 and 0.015, respectively), which was also true for the subjective score on day 8 (P = 0.004) in this subgroup. The frequency of subepithelial infiltrates was similar in both groups. N-chlorotaurine was well-tolerated, shortened the duration of illness, and seems to be a useful causative therapeutic approach in severe epidemic keratoconjunctivitis.

DOI： 10.1089/jop.2005.21.157

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Although Behçet's disease (BD) is a multisystem disorder of unknown causes, both genetic and environmental factors have been suggested. This is the second reported case of monozygotic twins concordant for Behçet's disease and the first such report of intestinal Behçet's disease. Patient 1 was a 17-year-old man with fever, recurrent oral aphthae, and skin eruptions. He developed hematochezia and was given corticosteroid empirically. One month after he was discharged, he again developed oral ulcerations, fever, and hematochezia. Colonoscopy was performed again, showing aphthous ulcerations in the entire colon, and deep oval ulcers with marginal elevation around the ileocecal valve, which are characteristics of intestinal Behçet's disease. He was treated with colchicine and azathioprine in combination with salazosulfapyridine (SASP) and prednisolone (PSL) and achieved remission. Patient 2 was the twin brother of patient 1. He was admitted because of oral aphthous ulcerations, fever, pustules on his face and body, and genital ulcers. Two weeks later he developed hematochezia. Colonoscopic and barium enema findings were similar to those of his brother. SASP, PSL, colchicines, and azathioprine were also required to achieve remission. Both of the patients were diagnosed with intestinal Behçet's disease. Their monozygosity was confirmed by detailed genetic typing, and HLA-B51 was negative.

DOI： 10.1007/s00535-004-1560-1

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DOI： 10.1080/09273940590928607

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Drug-induced hypersensitivity syndrome (DIHS), characterized by serious adverse systemic reactions in addition to skin rash, has unknown pathogenesis. Its association with human herpesvirus (HHV), mainly HHV-6, has been reported recently. A 46-year-old Japanese man is described in whom a generalized eruption developed about 1 month after taking cyanamide, a drug for alcoholism. This was associated with the following manifestations: high fever, lymphadenopathy, facial edema, marked leukocytosis with eosinophilia and atypical lymphocytes, lymphocytopenia, liver and renal dysfunction, and low IgG level. He was treated with 8 mg betamethasone daily and his condition improved, but he needed low-dose corticosteroid for almost 1 year because of several episodes of recurrence. HHV-6, HHV-7, herpes simplex virus (HSV), and cytomegalovirus (CMV) specific IgG titers showed more than a four-fold rise sequentially. Significant numbers of copies of HHV-6 and HHV-7 DNA were detected in the peripheral white blood cells by real-time polymerase chain reaction (PCR). HHV-6 and CMV DNA were detected in the serum by nested PCR. A patch test for cyanamide was positive. The diagnosis of DIHS due to cyanamide, which has never been reported as a causal drug of DIHS, accompanied by reactivation of not only HHV-6, but also HHV-7, CMV, and HSV, was made. Disturbance of the immune system was suggested by the persistent low level of IgG, and consecutive viral reactivation may have participated in the prolonged course in this case.

DOI： 10.1002/jmv.20295

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We have investigated whether a Vogt-Koyanagi-Harada (VKH)-like disease can be induced in Akita dogs by immunizing them with tyrosinase related protein 1 (TRP1), and compared the alterations induced to those of Akita dogs with a spontaneously occurring disease that resembles human VKH disease. Two Akita dogs were immunized with a peptide mixture of human TRP1. The changes in the eyes were followed by slit-lamp biomicroscopy, ophthalmoscopy, and fluorescein angiography (FA). The eyes, skin, and brains were studied by standard histological methods at about 20 months after the first immunization in one dog (dog 1), and at 3 weeks after the second immunization in the second dog (dog 2). Both dogs developed chorioretinal disease 3-4 weeks after the first immunization. Many inflammatory cells infiltrated into the anterior chamber and anterior vitreous. The fundus showed geographic, multifocal exudative retinal detachments. Multifocal leakages of fluorescein were detected from the choroid. Histologically, exudative retinal detachment was present, and inflammatory cells were seen in the subretinal space in the eyes of dog 2 taken three weeks after the second immunization. The choroid was thickened by the infiltration of inflammatory cells in some lesions. Dalen-Fuchs nodules were seen in the eye of dog 2. Depigmentation, pigment dispersion, and infiltration of many inflammatory cells around hair follicles and vessels were seen in the skin taken three weeks post-immunization. The clinical course and changes in the eyes and skin were very similar to those seen in the Akita dogs with spontaneously occurring VKH disease. We concluded that a VKH-like disease had been induced in these dogs, and this supports the tentative conclusion that the spontaneously occurring chorioretinal disease in Akita dogs is VKH disease.

DOI： 10.1016/j.exer.2004.09.010

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DOI： 10.1016/j.jdermsci.2004.07.011

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PURPOSE: We examined the effects of the immunosuppressive neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) on rat endotoxin-induced uveitis, and to measure the expression of inflammatory cytokines and chemokines with and without the alpha-MSH treatment over the course of the disease. METHODS: We injected Lewis rats once with Salmonella typhimurium lipopolysaccharide (LPS) to induce uveitis. The rats were given intravenous injections of 250, 500 or 1000 microg of alpha-MSH. The eyes were examined over the next 24 h for inflammation. Aqueous humor was collected 6, 12 and 24 h after endotoxin injections and the number of infiltrating cells were counted in anterior chamber. In addition, we assayed the concentration of protein, nitric oxide, TNF-alpha, IL-6, MCP-1 and MIP-2. RESULTS: Rats injected with alpha-MSH showed a significant decrease in the number of infiltrating cells in anterior chamber. Moreover, alpha-MSH-treated rats with endotoxin-induced uveitis (EIU) showed significantly lower concentrations of protein, nitric oxide, proinflammatory cytokines and chemokines in their aqueous humor. Even the early stages of EIU were suppressed by the injection of alpha-MSH. CONCLUSIONS: Our results demonstrate that the immunosuppressive neuropeptide alpha-MSH inhibits the early induction events of endotoxin-induced inflammation in the eye; therefore, suppresses the subsequent infiltration of cells and intraocular production of inflammatory cytokines and chemokines in eyes. alpha-MSH has a possibility of being a therapeutic strategy for anterior uveitis.

DOI： 10.1016/j.intimp.2004.04.011

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DOI： 10.1016/j.jdermsci.2003.12.004

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Ephrin-As are repulsive axonal guidance cues that regulate retinotectal projection. EphA tyrosine kinases, which are the receptors of ephrin-As, activate signaling cascades leading to cytosckeleton reorganization. Here, we address the role of cyclin-dependent kinase (Cdk) 5 in Eph receptor signaling induced by ephrin-A5. Ephrin-A5 induced a cell morphological response in PC-3M cells that endogenously express Cdk5 and EphA2, a receptor for ephrin-A5. This response was augmented by the transfection of p35, which is a neuronal regulator of Cdk5. While the morphological response of native PC-3M cells was not affected by olomoucine, an inhibitor of Cdk, the response was inhibited in the p35-transfected cells. In retinal ganglion cells, either olomoucine at 20 microM or Y-27632 at 10 microM, an inhibitor of Rho-kinase/ROKalpha/ROCKII, showed maximum inhibitory effect against ephrin-A5 (10 microg/ml)-induced growth cone collapse. Combined application of olomoucine and Y-27632 further suppressed the ephrin-A5-induced response. Ephrin-A5 evoked phosphorylation of Cdk5 at Tyr15 and tau, a substrate of Cdk5 in retinal growth cones. Recombinant herpes simplex virus expressing Cdk5 mutant (kinase-negative or Tyr15 to Ala) showed a dominant-negative effect on the ephrin-A5-induced growth cone collapse. These findings demonstrate that both Cdk5 and the Rho kinase pathway independently contribute to the downstream of ephrin-A-induced signaling in retinal ganglion cells.

DOI： 10.1016/S1044-7431(03)00220-3

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PURPOSE: Human cationic antimicrobial protein 18 (hCAP18, 18 kDa) was originally identified in leukocytes on the basis of its antimicrobial activity. The peptide composed of the 27 C-terminal amino acids of hCAP18 (hCAP18(109-135)) binds lipopolysaccharide (LPS). The purpose of the present study was to investigate the effects of hCAP18 peptide on endotoxin-induced uveitis (EIU) in rats. METHODS: EIU was induced by footpad injection of LPS. Each rat was injected intravenously with 1, 10, or 100 micro g hCAP18 peptide in 0.1 mL of PBS immediately after LPS injection in male Lewis rats. At 24 hours after LPS injection, enzyme-linked immunosorbent assay was performed to evaluate concentrations of protein, nitric oxide (NO), tumor necrosis factor (TNF)-alpha, prostaglandin (PG)-E2, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-2 in aqueous humor. Also, EIU was evaluated by counting inflammatory cells in aqueous humor. RESULTS: hCAP18 peptide at 10 and 100 micro g significantly suppressed an LPS-induced increase in the number of inflammatory cells and the levels of protein, NO, TNF-alpha, PGE2, MCP-1, and MIP-2. The anti-inflammatory effect of 10 micro g hCAP18 peptide was as strong as that of 100 micro g hCAP18 peptide. Treatment with 1 micro g hCAP18 peptide did not suppress EIU, compared with the LPS group. CONCLUSIONS: The present results indicate that hCAP18 peptide suppresses development of EIU. A possible mechanism for the ocular anti-inflammatory effect of hCAP18 peptide is that it suppresses onset of LPS-triggered inflammatory reactions by binding directly to LPS.

DOI： 10.1167/iovs.03-0246

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DOI： 10.1007/s00018-003-2333-3

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PURPOSE: Astaxanthin (AST) is a carotenoid that is found in marine animals and vegetables. Several previous studies have demonstrated that AST exhibits a wide variety of biological activities including antioxidant, antitumor, and anti-Helicobacter pylori effects. In this study, attention was focused on the antioxidant effect of AST. The object of the present study was to investigate the efficacy of AST in endotoxin-induced uveitis (EIU) in rats. In addition, the effect of AST on endotoxin-induced nitric oxide (NO), prostaglandin E2 (PGE2), and tumor necrosis factor (TNF)-alpha production in a mouse macrophage cell line (RAW 264.7) was studied in vitro. METHODS: EIU was induced in male Lewis rats by a footpad injection of lipopolysaccharide (LPS). AST or prednisolone was administered intravenously at 30 minutes before, at the same time as, or at 30 minutes after LPS treatment. The number of infiltrating cells and protein concentration in the aqueous humor collected at 24 hours after LPS treatment was determined. RAW 264.7 cells were pretreated with various concentrations of AST for 24 hours and subsequently stimulated with 10 microg/mL of LPS for 24 hours. The levels of PGE2, TNF-alpha, and NO production were determined in vivo and in vitro. RESULTS: AST suppressed the development of EIU in a dose-dependent fashion. The anti-inflammatory effect of 100 mg/kg AST was as strong as that of 10 mg/kg prednisolone. AST also decreased production of NO, activity of inducible nitric oxide synthase (NOS), and production of PGE2 and TNF-alpha in RAW264.7 cells in vitro in a dose-dependent manner. CONCLUSIONS: This study suggests that AST has a dose-dependent ocular anti-inflammatory effect, by the suppression of NO, PGE2, and TNF-alpha production, through directly blocking NOS enzyme activity.

DOI： 10.1167/iovs.02-0822

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DOI： 10.1034/j.1399-0039.2003.00014.x

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DOI： 10.1034/j.1399-0039.2002.600506.x

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DOI： 10.1034/j.1399-0039.2002.590207.x

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DOI： 10.1016/S0895-4356(01)00388-2

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DOI： 10.1034/j.1399-0039.2001.580306.x

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DOI： 10.1034/j.1399-0039.2001.580201.x

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DOI： 10.1034/j.1399-0039.2001.580202.x

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DOI： 10.1101/gr.175801

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DOI： 10.1034/j.1399-0039.2001.057005457.x

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DOI： 10.1006/geno.2000.6371

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