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A continuous, simple, and versatile pH monitoring method based on digital-movie-based colorimetry is proposed. A constructed flow system was of a two-channel configuration mainly composed of two peristaltic pumps, a digital microscope-based detector, a pH meter with a flow-through combination pH-reference electrode, and a laptop computer. While the total flow rate (FT) was held constant, the flow rate (FB) of a base solution for Britton-Robinson buffer containing a universal indicator (Yamada's indicator or Van Urik's indicator) was changed in proportion to the control signal (Vc) from the computer. An acid solution for the buffer containing the indicator was aspirated to the confluence point at the flow rate of FT – FB and mixed with the base solution. Thus, buffer solutions with arbitrary pH could be easily prepared. The image of the mixed solution was captured with the microscope downstream; the pH of the solution was measured with the pH meter at the most downstream. An in-house program written in Visual Basic .NET was developed to control the system, acquire and analyze the signals (image data and pH), and display the results automatically; the color of the image was expressed as tristimulus values (i.e., R, G, B), hue, and luminance. The relationships between these color-specific values and pH were analyzed after optimizing the Vc scan rate. Van Uik's indicator was superior to Yamada's regarding the applicable pH range (ca. 2.5 – 10). A sigmoid-like calibration curve was established between hue and pH, which was used to determine sample pH. The proposed method was validated by measuring the pH of different drugs and vinegar samples.

Abstract Introduction Dry eye can compromise corneal astigmatism measurement repeatability during preoperative cataract surgery examination. No previous studies have analyzed the effectiveness of long-acting 3% diquafosol sodium (LA-DQS) on astigmatism measurement repeatability. This research assessed the effect of LA-DQS on astigmatism measurement repeatability in preoperative patients with cataract and short tear break-up time (TBUT) type dry eyes in both eyes of the same patient. Correlations between repeatability and TBUT, corneal high-order aberrations (HOAs), and corneal astigmatism magnitude were also analyzed. Methods In total, 122 eyes (61 patients) with short TBUT-type dry eye were enrolled. Preoperatively, only one eye of all patients was treated with LA-DQS for 4 weeks. TBUT and corneal HOAs were checked using CASIA 2 before and 4 weeks post-treatment. The cylindrical power and meridian of astigmatism were measured at 3- and 4-week post-treatment using IOLMaster 700. Power vectors J0 and J45 were used for astigmatism calculations. Repeatability of astigmatism measurements was assessed as the within-subject standard deviation (Sw). The relative effects of TBUT and HOAs on J0 Sw and J45 Sw were also analyzed. Comparative changes in these variables were evaluated between treated and non-treated eyes, with additional analysis of their correlations. Results Treated eyes exhibited significant improvements in TBUT, HOAs, and post-treatment measurements of J0 Sw and J45 Sw at 3 and 4 weeks. In non-treated eyes, J0 Sw and J45 Sw showed significant correlation with TBUT and corneal HOAs. HOAs showed stronger relative associations with J0 Sw and J45 Sw than TBUT. In non-treated eyes, no significant correlation was found between cylindrical power and astigmatism measurement repeatability. Conclusions In short TBUT-type dry eye, preoperative treatment with LA-DQS significantly improved astigmatism measurement repeatability. This may improve the precision of intraocular lens (IOL) power calculations regardless of the magnitude of corneal astigmatism, especially when toric IOLs are used.

Abstract Several studies have evaluated immune checkpoint inhibitors (ICIs) for metastatic uveal melanoma; however, the efficacy of ICIs in the previous studies varied greatly. In this systematic review, we searched for prospective or retrospective studies on single or dual-ICIs for metastatic uveal melanoma treatment. A random-effect model meta-analysis with generic inverse-variance was conducted, and 36 articles representing 41 cohorts of 1414 patients with metastatic uveal melanoma were included. The pooled outcomes were as follows: objective response rate (ORR) was 5.6% (95% confidence interval [95%CI] 3.7–7.5%; I2, 36%), disease control rate (DCR) was 32.5% (95% CI 27.2–37.7%; I2, 73%), median progression-free survival was 2.8 months (95% CI 2.7–2.9 months; I2, 26%), and median overall survival (OS) was 11.2 months (95% CI 9.6–13.2 months; I2, 74%). Compared to single-agent ICI, dual ICI led to better ORR (single-agent: 3.4% [95% CI 1.8–5.1]; dual-agent: 12.4% [95% CI 8.0–16.9]; P

BackgroundLittle is known about the relationship between the disease activity of Behçet disease (BD) and the incidence of inflammatory major organ events.ObjectivesIn this prospective registry study, we investigated the association between the Behçet Disease Current Activity Form (BDCAF) and incidence of inflammatory major organ events, defined as the inflammation of the ocular, central nervous, intestinal, and vascular systems in BD.MethodsWe enrolled participants from Japanese multicenter prospective cohorts. The BDCAF was evaluated annually. BD-related symptoms, including inflammatory major organ events, were monitored. The association between BDCAF and inflammatory major organ events was analyzed by time-to-event analysis. An unsupervised clustering of the participants’ BDCAF, therapeutic agents, and multiple serum cytokines was also performed to examine their association with inflammatory major organ events.ResultsA total of 260 patients were included. The patients had a median BDCAF score of 2 [Interquartile range, 1-3] at the enrolment and remained disease active at 1- and 2-year follow-ups, indicating residual disease activity in BD. Patients with a BDCAF score of 0 had a longer inflammatory major organ event-free survival at 52 weeks than those with a score of 1 or higher (p=2.2 x 10-4). Clustering analysis revealed that patients who did not achieve remission despite treatment with tumor necrosis factor inhibitors had high serum inflammatory cytokine levels and incidences of inflammatory major organ events. Among the elevated cytokines, IL-6 was associated with inflammatory major organ events.ConclusionThis study suggests that treatment strategies targeting overall disease activity and monitoring residual serum IL-6 may help prevent inflammatory major organ events in BD.

Abstract Corneal astigmatism is reportedly associated with polymorphisms of the platelet-derived growth factor receptor alpha (PDGFRA) gene region in Asian populations of Chinese, Malay, and Indian ancestry and populations of European ancestry. In this study, we investigated whether these PDGFRA polymorphisms are associated with corneal astigmatism in a Japanese population. We recruited 1,535 cases with corneal astigmatism (mean corneal cylinder power across both eyes: ≤ − 0.75 diopters [D]) and 842 controls (> − 0.75 D) to genotype 13 single-nucleotide polymorphisms (SNPs) in the PDGFRA gene region. We also performed imputation analysis in the region, with 179 imputed SNPs included in the statistical analyses. The PDGFRA SNPs were not significantly associated with the cases with corneal astigmatism ≤ − 0.75 D. However, the odds ratios (ORs) of the minor alleles of SNPs in the upstream region of PDGFRA, including rs7673984, rs4864857, and rs11133315, tended to increase according to the degree of corneal astigmatism, and these SNPs were significantly associated with the cases with corneal astigmatism ≤ − 1.25 D or ≤ − 1.50 D (Pc

Abstract Immune checkpoint inhibitors (ICIs) activate anti-tumor activity by inhibiting immune checkpoint molecules that suppress inflammatory T-cell activity. However, ICIs can initiate excessive immune responses, thereby causing immune-related adverse events (irAEs). ICI-associated uveitis (ICIU) is an irAE that affects the eyes. Although Vogt–Koyanagi–Harada disease (VKH)-like uveitis is a common form of ICIU, it is unclear which factors determine the ICIU form. We retrospectively reviewed the medical records of nine ICIU cases treated with ICIs for malignancies. We also performed HLA typing in seven cases to investigate the association between HLA and disease type. Fisher's exact test was used for the statistical analysis. Five of the ICIU cases were VKH-like ICIUs, and four were non-VKH-like ICIUs. No association was found between mean age, sex, primary disease, ICI, time to onset, and disease type. Four patients with VKH-like uveitis underwent HLA genotyping and were all positive for HLA-DRB1*04:05. All 3 patients with non-VKH-like uveitis were negative for HLA-DRB1*04:05. Statistical analysis showed that HLA-DRB1*04:05 was significantly associated with developing VKH-like ICIU (P = 0.029). In ICIU, HLA-DRB1*04:05 was associated with the pathogenesis of VKH-like uveitis, suggesting that ICI-associated VKH-like uveitis has a similar pathogenesis to VKH.

Abstract Introduction Although uncommon, incomplete capsulotomy, anterior capsule tags and anterior capsule tears are still encountered during femtosecond laser-assisted cataract surgery (FLACS), resulting in surgical complications. This highlights the need to improve femtosecond laser-assisted capsulotomy technique to reduce capsulotomy-related complications. Therefore, the purpose of this study was to investigate the efficacy of a newly developed, modified technique of setting capsulotomy irradiation thickness in lowering the incidence of capsulotomy-related complications in FLACS. Methods This open-label prospective, comparative cohort study included 440 eyes (220 patients) treated with FLACS using the LenSx laser system (Alcon Laboratories, Inc. Fort Worth, TX, USA). Varying capsulotomy irradiation thicknesses were applied in each eye of the same patient. In Group 1, capsulotomy irradiation thickness was set between the upper edge of the highest point of the anterior capsule and the lower edge of the lowest point of the anterior capsule (modified technique). In Group 2, this was set between the center of the highest point of the anterior capsule and the center of the lowest part of the anterior capsule (conventional technique). Incidence rates of incomplete capsulotomy, anterior capsule tags and tears, and posterior capsule tears were compared. Results Preoperative baseline characteristics showed no significant differences. Mean total of the irradiation thicknesses was 877.1 ± 81.9 µm in Group 1 and 808.9 ± 80.0 in Group 2, with a statistically significant difference (P

Abstract A multicenter randomized controlled trial was conducted to compare the effectiveness of incisional and nonincisional surgical techniques for treating lower lid epiblepharon in children. The study included 89 eyes from 50 children aged 3–15 years (mean, 7.5 ± 2.4 years) with moderate lower lid epiblepharon. Patients were randomly assigned to either incisional (modified Hotz procedure with lid margin splitting; 45 eyes of 25 patients) or nonincisional (44 eyes of 25 patients) surgery groups. Treatment outcomes and changes in astigmatism were evaluated 6 months after surgery. Incisional surgery provided a significantly higher percentage (77.8%) of well-corrected treatment results (P = 0.026; odds ratio, 2.88; 95% confidence interval, 1.07–8.22) than nonincisional surgery (55.4%). The mean change in astigmatism 6 months after surgery was − 0.24 ± 0.42 and − 0.01 ± 0.47 D in the incisional and nonincisional surgery groups, respectively. The improvement in astigmatism was significantly higher in the incisional surgery group than in the nonincisional surgery group (P = 0.008). The incisional surgical treatment for moderate epiblepharon in children resulted in a higher number of well-corrected patients, indicating an absence of both ciliary touch and superficial keratitis as well as statistically significant improvements in astigmatism correction.

Abstract 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

Mountain observatories at high altitudes, far from local anthropogenic emission sources, are considered ideal for monitoring temporal variations of tropospheric air pollutants. During August 17–21 in 2013, we measured sulfur dioxide and nitric acid concentrations in the free troposphere at the top (3776 m a.s.l.) of Mt. Fuji, Japan. A parallel plate wet denuder-ion chromatographic system was used for the online measurement with 15 min temporal resolution. The continuous observations were successfully achieved without any problems. Of the samples collected, 97.8% of sulfur dioxide and 75.7% of nitric acid were above the limits of quantification. The average gas concentrations ± standard deviation (n = 408) were 0.106 ± 0.377 ppbv for sulfur dioxide and 0.015 ± 0.014 ppbv for nitric acid, respectively. Episodic elevations of sulfur dioxide concentration were recorded from August 20 to 21. Backward trajectory analyses indicated that the high-temporal resolution monitor detected the volcanic sulfur dioxide from Mt. Sakurajima, located 857 km from the sampling point. High-time-resolved observations in the free troposphere proved useful for source identification of air pollutants.

Abstract 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.

PurposeTo evaluate 10-year outcome of infliximab (IFX) treatment for uveitis in Behçet disease (BD) patients using a standardized follow-up protocol.DesignRetrospective longitudinal cohort study.Participants140 BD uveitis patients treated with IFX enrolled in our previous study.MethodsMedical 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 measures10-year IFX continuation rate and change in LogMAR VA.ResultsOf 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.ConclusionsAmong 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.

Introduction: Free flap lower extremity repair is associated with a high complication rate (>31%); higher rates are observed in more severe patients. In cases requiring prior systemic/local stabilization, delayed repair increases complication rate (+10% at 7 days): Negative-pressure Wound Therapy (NPWT) decreases complications but only when applied for less than 7 days. Recent limited evidence suggests that augmentation of NPWT with instillation for wound irrigation (NPWTi) might safely extend such window. This study hypothesizes that, through the combined cleansing effect of NPWT and instillation, NPWTi allows safe (low complication rate) delayed free flap repair in severe patients with Gustilo IIIb injuries (GIIIb). Methods: A prospective case series was designed (inclusion criteria: GIIIb requiring microsurgical repair, severe patient/injury condition preventing immediate/early repair; exclusion criteria: allergy to NPWTi dressing). Patients received NPWTi (suction: 125 mmHg continuous; irrigation: NaCl 0.9%) until considered clinically ready for repair. Preoperative/postoperative complications (dehiscence, wound infection, bone non-union, osteomyelitis, flap failure) were monitored with clinical signs, imaging, and serum markers (CRP, WBC). Results: Four patients (male: N = 4, female N = 1; Age: 59 [44–75] years-old) were treated. NPWTi was applied for 15.2 [9–28] days. No complication (0%) was observed preoperatively or postoperatively. Delayed repair occurred by latissimus dorsi musculocutaneous flap (N = 3), and anterolateral thigh flap (N = 2). All patients walked weight-bearing 12 [6–20] weeks after injury. Conclusions: NPWTi seems to allow safe delayed free flap repair in patients with severe lower extremity injuries unable to undergo immediate/early repair.

AimTo investigate the causes of low prevalence of Fuchs' uveitis syndrome (FUS) in Japan.MethodsMedical records of 160 patients diagnosed with FUS at 14 uveitis specialty facilities in Japan were reviewed retrospectively.ResultsIn 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

Gaseous ammonia (NH3) is a primary basic substance in the atmosphere, and its global emission has been increasing in recent decades. It is vital to continuously monitor the atmospheric NH3 to clarify the impact of NH3 on sensitive ecosystems. This paper proposes a simple gaseous NH3 monitor utilizing a parallel plate wet denuder (PPWD) and a conductometric flow injection analysis (FIA) with an ammonia transfer device (ATD). In the present study, water-soluble basic gases, NH3, are selectively detected by the conductivity detector (CD). The ATD-CD ammonium detector requires no coloring reagents commonly used in FIA. Five-day field measurement of ambient NH3 was successfully performed with 30 min time resolution. All the air samples over the observation period (n = 186) contained NH3 above the limit of quantification (11.4 nmol m−3). The NH3 data showed excellent agreement with the values using ion chromatography in the field measurements.

Iron is an essential plant nutrient that is poorly bioavailable in alkaline soils, resulting in reduced agricultural productivity. Here, the authors report the synthesis of stable and cheap iron-chelator, proline-2’-deoxymugineic acid (PDMA), and demonstrate its utility as potential fertilizer.

Abstract Background 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. Methods 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. Results 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. Conclusions 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.”

Introduction: This study examined the usefulness of basic fibroblast growth factor impregnated collagen-gelatin sponge (bFGF-CGS) in reconstructive surgery for various acute skin defects including deep dermal burns, facial full-thickness skin defects, and finger amputations as the first clinical application. Methods: Reconstructive surgery was performed in two stages with bFGF-CGS in 8 male subjects, ranging in age from 6 to 84 years, with acute full-thickness skin defects. Following the adequate debridement of the defect, surgeons prepared a bFGF-CGS with bFGF solution at a dose of 7–14 mg/cm2 approximately 10 min just before application and then secured the bFGF-CGS in place with non-absorbable sutures. Second-stage wound closure was performed with autologous skin grafting following adequate dermis-like tissue regeneration at the site postoperatively. Follow-up was continued for 6 months. Results: Of the 8 subjects, the mean duration from the adequate vascularization of the dermis-like tissue until the second-stage autologous skin graft was 22 ± 4 days. Wound closure was achieved in all cases; the mean duration until wound closure was 32 ± 8 days. During the 6-month follow-up period, no wound infection, recurrent skin ulceration, and no exposure of tendon, bone, and cartilage were observed, and there were no cases of indirectly restricted range of motion from postoperative scar contracture and none with disfiguring scars. Conclusion: The authors achieved favorable outcomes following reconstructive surgery with a hybrid artificial dermis impregnated with bFGF for treating acute full-thickness skin defects. bFGF-CGS serves as a convenient regenerative device requiring no specialized medical facilities. Keywords: Drug delivery system, Basic fibroblast growth factor, Artificial dermis

We propose a novel concept of flow-based analysis for spectrophotometric speciation based on flow rate modulation and fast Fourier transform (FFT). A redox reagent solution's and a sample solution's flow rates are varied by sinusoidal control signals with periods of T and 0.5T, respectively. Both solutions are merged with a color reagent, while the total flow rate is held constant. Downstream, the absorbance of the mixed solution is measured and acquired as the detector output voltage (Vd). The Vd is analyzed by FFT with the window's time length of T. One species that directly reacts with the color reagent contributes only to the amplitude (A2) of the second harmonic wave component in Vd. The other species that needs the redox conversion before the coloration contributes to the amplitude (A1) of the fundamental wave component, in addition to A2. The former species+' concentration can be estimated from A2 by taking the latter's contribution to A2 into account. The latter species’ concentration can be determined only from A1. The proposed concept was demonstrated by applying it to the speciation of Fe2+ and Fe3+ by an o-phenanthroline spectrophotometry, where Fe3+ was reduced to Fe2+ by L-ascorbic acid before the coloration.

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.

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.

Summary:. The authors describe a surgical treatment that optimally combined the use of the hydrosurgical system and a free multiperforator anterolateral thigh flap to prevent lower limb amputation in a severe case of necrotizing fasciitis. A 43-year-old woman was diagnosed with necrotizing fasciitis, and amputation was performed at the level of the metatarsal shafts with an emergency debridement using the hydrosurgical system. In the second reconstructive surgery, a free anterolateral thigh flap measuring 28 × 8 cm2 was harvested using the left thigh as the donor site and the vascular pedicle was made up of a total of 3 vessels, 2 perforating arteries from the descending branch of the lateral circumflex femoral artery, and 1 oblique branch from the lateral circumflex femoral artery. To thin the flap, we first resected as much subcutaneous fat as possible in the distal part of the flap (which would eventually cover the ankle joint) and ensured adequate residual volume of the proximal part of the flap (which would cover the metatarsal stumps). We then sutured the flap to the tissue defect on the left foot and then end-to-side anastomosing the lateral femoral circumflex artery and posterior tibial artery while the 2 veins were anastomosed to the posterior tibial veins under a microscope. Six months after the surgery, adequate flap volume was maintained over the metatarsal stumps with no postoperative complications such as infection or ulcer formation, and there were no other complications such as motor dysfunction at the donor site on the left thigh.

Summary:. Despite medical advances, the mortality rate associated with Fournier gangrene has remained largely unchanged and extremely high. In addition, conventional surgical treatment of Fournier gangrene of the scrotum requires excision of the testicles in some cases, which can result in loss of fertility. We report herein the favorable results of reconstruction of the scrotum following Fournier gangrene, using the hydrosurgery system and pedicled deep inferior epigastric perforator flap. A 60-year-old male patient was urgently transported to our hospital for fever, lower abdominal pain, and scrotal pain for several days. He was diagnosed with Fournier gangrene and underwent an emergency debridement procedure on the same day. Later, we performed a 2-phase reconstruction with a hydrosurgery system and pedicled deep inferior epigastric perforator flap under general anesthesia for the postoperative tissue defect. At 6 months postoperatively, there was no ulceration or scar contracture, and the results were aesthetically pleasing. There are no reported cases of reconstruction of the scrotum following Fournier gangrene using this procedure, and it might be an effective treatment option.

Background:. Pressure injuries (PIs) are common in hospitalized patients, with incidence exceeding 50% in high-risk patients. Immobilization causes a prolonged compression of vascular networks in tissues overlying bony prominences, leading to ischemia and ulceration. Traditionally, PIs are treated with a combination of surgical debridement and reconstruction. This approach can be invasive for debilitated patients who cannot tolerate prolonged surgeries and extensive tissue resection. Hydrosurgery uses high-pressure irrigation to low-invasively debride and cleanse wounds; its use has shown positive outcomes in burn and chronic wounds care. Here, we hypothesize that hydrosurgery allows low-invasive yet effective wound bed preparation in truncal PIs. Methods:. We conducted a single-center, prospective, uncontrolled case series. Inclusion criteria for this study were presence of a truncal PI (stage III or IV) and an American Society of Anesthesiologists physical status of ≥2 (no exclusion criteria). Measured outcomes included duration of hydrosurgery, postsurgical local (dehiscence, infection, seroma) or systemic complications in the first 30 days, and PI recurrence rate (6-month follow-up). Results:. Seven patients (3 sacral, 2 greater trochanteric, and 2 ischial tuberosity PIs) were enrolled for this study. Average duration of hydrosurgery was 12 minutes (±3.1). No local or systemic complications were observed at a 30-day follow-up (0/7, 0%). All flaps (6/7, 86%) and graft (1/7, 14%) reconstructions successfully survived, and no PI recurrence was reported within a 6-month follow-up (0/7, 0%). Conclusions:. Hydrosurgery seems to allow safe, low-invasive, and effective wound bed preparation in truncal PIs. Larger controlled trials are needed to confirm this preliminary evidence, to guide its broader adoption for improved care of high-risk patients with PIs.

Summary: Incisional hernia often complicates kidney transplant. However, there are few reports showing pitfalls after the repair of incisional hernia following living-donor kidney transplant. A 55-year-old man underwent living-donor kidney transplant from his wife at the Department of Urology at the authors’ hospital. He noticed abdominal distension 6 months postoperatively and was diagnosed with incisional hernia by computed tomography (CT) imaging. Clinical examination revealed the extensive distension of the right abdomen; noncontrast abdominal CT showed transverse colon, descending colon, and mesenteric prolapse through a hernial orifice measuring 11 × 14 cm, located slightly cranial to the anterior superior iliac spine. Repair was performed under general anesthesia the following day; the right thigh was the donor site. A pedicled anterolateral thigh flap from the donor site was used for abdominal wall reconstruction. He developed fever, and pain and swelling were noted in the right leg on postoperative day 14. Contrast-enhanced thoracic CT confirmed a diagnosis of pulmonary embolism (PE) and deep vein thrombosis. He was quickly started on an oral factor Xa inhibitor (edoxaban) and continuous intravenous heparin; contrast-enhanced thoracic CT on postoperative day 23 showed that PE had disappeared. At 6 months postoperatively, there was no recurrence of the venous thromboembolism or incisional hernia. The authors reported a case of incisional hernia repair after living-donor kidney transplant with a pedicled anterolateral thigh flap, complicated by deep vein thrombosis and PE. Adequate preoperative evaluation was required to determine optimal surgical techniques and preventive measures in cases with myriad thrombogenic risk factors.

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.

Abstract 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

Summary:. In the field of plastic surgery, subcutaneous masses in the buttocks are frequently observed. However, squamous cell carcinoma (SCC) after epidermoid cyst, which appears in the presacral space, is extremely rare. This report described a case of a 71-year-old woman, who previously received a skin incision by a doctor for treating a cystic lesion in the buttock; she was diagnosed with SCC by preoperative biopsy at the authors’ department. In addition, computed tomography suspected that the tumor originated in the presacral space. Under general anesthesia, an extended resection of the malignant tumor with gastrointestinal surgery was performed. After resection, the defect of buttocks region was reconstructed with a V-Y advancement gluteus maximus myocutaneous flap. After pathological examination the tumor was diagnosed as SCC after epidermoid cyst; peplomycin sulfate at 50 mg/d was administered intramuscularly for 2 weeks as chemotherapy. No wound complications were observed after surgery, and no recurrence was noted for 5 years. For managing tumor in the gluteal region, a possibility of malignancy must be considered, and thorough radiographic studies must be pursued before surgery.

Negative pressure wound therapy (NPWT) is a method for treating wound. However, there are no case reports using NPWT for treating congestion after arterialized venous flap. Therefore, this study reported favorable outcomes after using a single-use NPWT system for managing congestion. A 39-year-old man had his index finger caught by a press machine. The finger had a soft tissue defect at the ventral part. An arterialized venous flap taken from the right forearm was transplanted. Perfusion of the flap was favorable, but on postoperative day 5, congestion and the edema of the flap were found. Then, NPWT was initiated. The congestion and edema in the flap were improved without complications such as flap necrosis and wound infection. At 4 months postoperatively, the morphology of the finger was favorable. In this study, NPWT was speculated to force the deeper blood vessels within the flap to dilate with inducing drainage and the simultaneous reduction in excess blood flow to the cortical layer, resulting in the improvement of congestion. Negative pressure wound therapy was used for treating congestion after the transplantation of arterialized venous flap, and the wound was favorably managed.

Summary: A 21-year-old woman had become aware of a mass on the palmar aspect of the distal phalanx of her left thumb 11 years earlier. Her medical history was unremarkable, with no traumatic injury of the left thumb. Initial examination revealed a hard but elastic, immovable tumor of 30 × 25 mm on the palmar aspect of the distal phalanx of the left thumb, with an ulcer formed at the center. No pain, sensory disturbance, or motor dysfunction was noted. The patient underwent punch biopsy at the outpatient clinic, and the tumor was histopathologically diagnosed as benign schwannoma. Total excision of the tumor was performed with digital nerve block under surgical microscope. Histopathological findings revealed a fibrous capsule covering the tumor, directional growth of tightly organized spindle-shaped cells, and mixed Antoni A and B patterns. The tumor also contained many various sized cysts and showed histological degenerative changes not observed in ordinary schwannoma, such as hemorrhage and prominent blood vessels with hyalinized walls. The S-100 stain was positive. Based on these findings, the patient was diagnosed as having ancient schwannoma. There was no evidence of infection, pain, complications such as ulcer formation, or recurrent tumor at 6 months postoperative.

Background: This study describes the use of a bioabsorbable suture for skin suturing during surgery for lateral ray polydactyly followed by favorable postoperative outcome without the need for postoperative suture removal. Methods: A 5-0 Vicryl Rapide suture was used for skin suturing during surgery for lateral ray polydactyly in 9 children (mean age, 12.4 mo). Children were allowed to walk and bathe 2 weeks after surgery when over-the-suture taping therapy was started. Results: In all cases, the Vicryl Rapide suture disappeared completely within 3 weeks of surgery, and no removal of residual suture was required. No postoperative complications, such as suture abscess, wound dehiscence, or ulcer, were observed. During a mean 24-month postoperative follow-up, no elevation of the interdigital space due to hypertrophic scarring or scar contracture was observed, and no revision surgery was required. Conclusions: Although the breaking strength of Vicryl Rapide declines within the first 10 days after surgery, this property will unlikely lead to postoperative wound dehiscence due to a relatively light load being applied to the lateral toes. The use of a bioabsorbable suture for skin suturing during surgery for lateral lay polydactyly is highly beneficial as it eliminates pain caused by suture removal and the risk of tissue damage while reducing the burden on medical staff.

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.

Islets of Langerhans are a pancreatic endocrine compartment consisting of insulin-producing β cells together with several other hormone-producing cells. While some insulin-producing cells or immature pancreatic cells have been generated in vitro from ES and iPS cells, islets with proper functions and a three-dimensional (3D) structure have never been successfully produced. To test whether islets can be formed in vitro, we first examined the potential of mouse fetal pancreatic cells. We found that E16.5 pancreatic cells, just before forming islets, were able to develop cell aggregates consisting of β cells surrounded by glucagon-producing α cells, a structure similar to murine adult islets. Moreover, the transplantation of these cells improved blood glucose levels in hyperglycemic mice. These results indicate that functional islets are formed in vitro from fetal pancreatic cells at a specific developmental stage. By adopting these culture conditions to the differentiation of mouse iPS cells, we developed a two-step system to generate islets, i.e. immature pancreatic cells were first produced from iPS cells, and then transferred to culture conditions that allowed the formation of islets from fetal pancreatic cells. The islets exhibited distinct 3D structural features similar to adult pancreatic islets and secreted insulin in response to glucose concentrations. Transplantation of the islets improved blood glucose levels in hyperglycemic mice. In conclusion, the two-step culture system allows the generation of functional islets with a 3D structure from iPS cells.

Networks of protein-protein interactions play key roles in numerous important biological processes in living subjects. An effective methodology to assess protein-protein interactions in living cells of interest is protein-fragment complement assay (PCA). Particularly the assays using fluorescent proteins are powerful techniques, but they do not directly track interactions because of its irreversibility or the time for chromophore formation. By contrast, PCAs using bioluminescent proteins can overcome these drawbacks. We herein describe an imaging method for real-time analysis of protein-protein interactions using multicolor luciferases with different spectral characteristics. The sensitivity and signal-to-background ratio were improved considerably by developing a carboxy-terminal fragment engineered from a click beetle luciferase. We demonstrate its utility in spatiotemporal characterization of Smad1-Smad4 and Smad2-Smad4 interactions in early developing stages of a single living Xenopus laevis embryo. We also describe the value of this method by application of specific protein-protein interactions in cell cultures and living mice. This technique supports quantitative analyses and imaging of versatile protein-protein interactions with a selective luminescence wavelength in opaque or strongly auto-fluorescent living subjects.

Aim Congenital nasolacrimal duct obstruction (CNLDO) is the most common cause of epiphora and mucous discharge in the newborn. We conducted a multicentre randomised controlled trial to determine whether Crigler massage promotes the resolution of CNLDO in infants under 1 year of age. Methods A total of 102 infants aged 3-11 months with unilateral CNLDO were enrolled in the study. Patients were randomly assigned to the massage and non-massage groups (n=51/group). As an allocation adjustment factor, the patients were divided into age groups of 3-5, 6-8 and 9-11 months. In the massage group, the guardian performed 10 strokes two times per day for each day until resolution or 1 month. The primary endpoint was a comparison of the 1-month resolution rate in the massage and non-massage groups. Results This study included 49 male and 53 female patients with a mean age of 6.4±2.4 months. Overall, in this study, the resolution rate was not significantly different between the massage and non-massage groups (31.4% and 33.3%, respectively). However, the resolution rate was higher in the massage group in the 3-5 months age group among the protocol-compliant patients after excluding those with insufficient massage frequency (the massage group, 68.8% and the non-massage group, 28.6%, p=0.022). Conclusions There was no increase in the resolution rate after 1 month of lacrimal sac massage in patients 3-11 months old with unilateral CNLDO. However, in protocol-compliant younger age groups, Crigler massage may be effective. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether polymorphisms of GAS6 and PROS1, which each encode protein ligands for a family of tyrosine kinase receptors, are associated with Behçet's disease (BD) in a Japanese population. Methods: We recruited 734 Japanese patients with BD and 1789 Japanese healthy controls. In all participants, we genotyped two single-nucleotide polymorphisms (SNPs) reportedly associated with BD: rs9577873 in GAS6 and rs4857037 in PROS1. Results: We found that GAS6 rs9577873 was not significantly associated with BD. In contrast, PROS1 rs4857037, specifically the A allele, was associated with increased risk for BD. The A allele was also significantly associated with BD under additive and recessive genetic models. Expression analysis revealed that this allele was significantly associated with increased PROS1 expression. Conclusions: Our findings suggest that increased PROS1 expression related to the A risk allele of rs4857037 affects tyrosine kinase receptor signaling, contributing to the development of BD. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Little is known about the relationship between the disease activity of Behçet disease (BD) and the incidence of inflammatory major organ events. Objectives: In this prospective registry study, we investigated the association between the Behçet Disease Current Activity Form (BDCAF) and incidence of inflammatory major organ events, defined as the inflammation of the ocular, central nervous, intestinal, and vascular systems in BD. Methods: We enrolled participants from Japanese multicenter prospective cohorts. The BDCAF was evaluated annually. BD-related symptoms, including inflammatory major organ events, were monitored. The association between BDCAF and inflammatory major organ events was analyzed by time-to-event analysis. An unsupervised clustering of the participants' BDCAF, therapeutic agents, and multiple serum cytokines was also performed to examine their association with inflammatory major organ events. Results: A total of 260 patients were included. The patients had a median BDCAF score of 2 [Interquartile range, 1-3] at the enrolment and remained disease active at 1- and 2-year follow-ups, indicating residual disease activity in BD. Patients with a BDCAF score of 0 had a longer inflammatory major organ event-free survival at 52 weeks than those with a score of 1 or higher (p=2.2 x 10-4). Clustering analysis revealed that patients who did not achieve remission despite treatment with tumor necrosis factor inhibitors had high serum inflammatory cytokine levels and incidences of inflammatory major organ events. Among the elevated cytokines, IL-6 was associated with inflammatory major organ events. Conclusion: This study suggests that treatment strategies targeting overall disease activity and monitoring residual serum IL-6 may help prevent inflammatory major organ events in BD. [ABSTRACT FROM AUTHOR]