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Issues related to transitioning from paediatric to adult healthcare are currently receiving international attention. In Japan, 1000 patients with childhood-onset chronic rheumatological diseases reach adulthood every year and require transition from care by paediatric to care by adult rheumatologists. Here, we propose a guide for the latter, wherein the adult caregiver poses the clinical questions about transitional support that they need to have answered, and the paediatric caregiver mainly compiles the plans for the transition. To formulate the guide, we sought comments from both the Japan College of Rheumatology and the Pediatric Rheumatology Association of Japan and obtained their approval. Here, we present the outcome of this consultation in the form of a Guide for Supporting Transitional Care, aiming to provide essential knowledge to physicians in the fields of adult internal medicine and orthopaedics who may be involved in treating patients with rheumatic disease during the transition from paediatric to adult care. The features of transitional support that are common for patients with various different rheumatic diseases are presented in this guide, with the aim of informing policy and strategies to deliver optimal outcomes in transitional care by non-paediatric rheumatologists.

Background Although Lowe syndrome and Dent disease-2 are caused by Oculocerebrorenal syndrome of Lowe (OCRL) mutations, their clinical severities differ substantially and their molecular mechanisms remain unclear. Truncating mutations in OCRL exons 1–7 lead to Dent disease-2, whereas those in exons 8–24 lead to Lowe syndrome. Herein we identified the mechanism underlying the action of novel OCRL protein isoforms. Methods Messenger RNA samples extracted from cultured urine-derived cells from a healthy control and a Dent disease-2 patient were examined to detect the 5′ end of the OCRL isoform. For protein expression and functional analysis, vectors containing the full-length OCRL transcripts, the isoform transcripts and transcripts with truncating mutations detected in Lowe syndrome and Dent disease-2 patients were transfected into HeLa cells. Results We successfully cloned the novel isoform transcripts from OCRL exons 6–24, including the translation-initiation codons present in exon 8. In vitro protein-expression analysis detected proteins of two different sizes (105 and 80 kDa) translated from full-length OCRL, whereas only one protein (80 kDa) was found from the isoform and Dent disease-2 variants. No protein expression was observed for the Lowe syndrome variants. The isoform enzyme activity was equivalent to that of full-length OCRL; the Dent disease-2 variants retained >50% enzyme activity, whereas the Lowe syndrome variants retained Conclusions We elucidated the molecular mechanism underlying the two different phenotypes in OCRL-related diseases; the functional OCRL isoform translated starting at exon 8 was associated with this mechanism.

Thin basement membrane nephropathy (TBMN) is diagnosed by diffuse thinning of the glomerular basement membrane (GBM) without any clinical and pathologic findings of Alport syndrome and the other renal diseases. TBMN is characterized clinically by benign familial hematuria but rarely develops into end-stage renal disease. In 27 cases of biopsy-proven TBMN, we evaluated the pathologic characteristics of TBMN, and examined the correlation between these pathologic characterizations and renal dysfunction. All patients had hematuria, and 21 patients (77.8%) had proteinuria. In six patients (28.6%) who were more than 50 years of age, the estimated glomerular filtration rate (eGFR) decreased from G3a to G4 in the chronic kidney disease stage. Pathologically, an irregular decrease in intensity of type IV collagen α5(IV) chain was seen in GBM, and irregular thinning with diffuse rough etched images was observed on the GBM surface with several sizes of holes by low-vacuum scanning electron microscopy. The glomerular morphology of TBMN was characterized by an increased number of small glomerular capillaries with an increased extracellular matrix (ECM). These characteristic morphologic alterations were evident from a young age in patients with TBMN, but were not correlated directly with the decrease of eGFR, the degree of hematuria, and proteinuria. The decrease of eGFR in patients with TBMN who were more than 50 years of age might be primarily mediated by arteriolosclerosis-associated glomerulosclerosis and interstitial fibrosis. Characteristic pathological glomerular findings and GBM alterations occurred from a young age but were not associated directly with renal impairment in biopsy-proven TBMN.

Background Brain-derived neurotrophic factor (BDNF) may be involved in the pathogenesis of glaucoma. BDNF concentrations reported in previous studies have varied widely, and the concentration of BDNF in aqueous humor is unknown. In this study, BDNF concentrations in the aqueous humor of glaucoma patients and control patients were measured with ELISA kits. Methods This prospective, observational study examined BDNF levels in aqueous humor in 62 eyes of 43 patients who underwent cataract surgery or trabeculectomy (11 glaucoma patients and 32 non-glaucoma cataract patients as controls). BDNF concentrations were examined by 4 different enzyme-linked immunosorbent assay (ELISA) techniques. Results The mean ± SD patient age was 72.0 ± 10.1 (range 35 to 87) years. Two of the techniques detected no BDNF in aqueous humor in any samples (n=3 and n=9, respectively); the average value was less than zero. An ultrasensitive ELISA kit did not yield reliable measurements. Finally, in an even more sensitive ELISA (Simoa-HD1), performed by an outside contractor, 25 (54.3%) eyes were below the detection limit, including 20 (55.6%) control and 5 (50%) glaucoma cases. For eyes with detectable BDNF, the overall BDNF concentration was 0.158 pg/mL (n=21): 0.196 pg/mL (n=16) in controls and 0.034 pg/mL (n=5) in glaucoma cases. Conclusions BDNF level in aqueous humor varies widely.

IgA vasculitis (IgAV) is the most frequent form of vasculitis in childhood which classically presents with purpura of the lower extremities, joint pain or swelling and abdominal pain. Though it is a self-limiting disease, and its prognosis is generally good, glomerulonephritis is one of the most important complications. IgAV is classified as a small vessel vasculitis, and though glomerulonephritis develops in IgAV, necrotizing arteritis is rarely seen. Here, we present a case of a 13-year-old girl with IgAV, glomerulonephritis, and necrotizing arteritis in the small renal arteries. There have been only a few reports of adult cases of IgAV with necrotizing arteritis in the kidneys, but there have been no pediatric cases. Some previous reports showed a high mortality rate and implied the possibility of overlap with other vasculitides. In the current report, a rare case of IgAV is described which exhibited necrotizing arteritis rather than overlap with another vasculitis, with a relatively typical clinical course for IgAV and laboratory tests.

Background Regular assessment of bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA) is essential for detecting glucocorticoid-induced osteoporosis in juvenile-onset autoimmune diseases. Z-score is used in children for standardization of osteoporosis assessment. Z-score in children can be evaluated with only one of the three models in Japan. The purpose of this study was to investigate how many domestic medical facilities for pediatric rheumatic diseases could not evaluate osteoporosis using Z-score exist. Methods Electronic questionnaires were distributed between 2017 and 2019 to hospitals belonging to the Pediatric Rheumatology Association of Japan and to university hospitals and public children' s hospitals that provide medical care for pediatric rheumatic diseases. The questionnaire included the location of DXA measurement, manufacturer (Hologic, GE healthcare, Hitachi), and measurement site, and the answers were collected using Google Forms. Statcel 4 was used for analysis. Results Overall,120 facilities responded to the survey, of which 117 had DXA. In the remaining three facilities, DXA was not installed in two and was out of order in one. Bone loss in childhood was evaluated using a Z-score calculated from age-based reference values. It was revealed that 30% of hospitals without HOLOGIC DXA could not evaluate osteoporosis by Z-score in Japanese childhood. The characteristics of the hospitals enrolled in this study did not bias the selection of Hologic DXA. Conclusions Neighboring institutions should consider sharing access to Hologic DXA equipment to ensure the use of uniform reference values. GE BMD reference values for Japanese children should be established.

In preparation for the 2021 Tokyo Olympic/Paralympic Games, the Japanese government assessed the risks of infectious disease outbreaks and identified necessary preparations. This present study reviewed efforts made during a previous measles epidemic and describes the roles of hospitals.This descriptive study investigated the records of 198 children with measles. All children were treated at a general hospital during the period from January 1997 through February 1998. We also examined the actions of pediatricians during and after a measles outbreak in the community.Of the 198 children, 145 (73%) were hospitalized. The measles vaccination rate in the previous year was approximately 75%. Of the patients examined, 53% were younger than 2 years of age; mean age was 2.75 years. Pneumonia and gastroenteritis accounted for 46% and 30% of the complications, respectively. Issues requiring attention included the number of hospital beds located in a negative pressure room or private room with a window, the need for gamma globulin preparations with high measles antibody titers, the necessity of increasing vaccination opportunities, and extension of physician working hours.Visitors from other countries could cause measles outbreaks in Japan. Measures that might mitigate an outbreak were maintenance of high vaccination rates, ready availability of information on the location of negative pressure hospital rooms, knowledge of the status of the measle outbreak, and flexible medical staffing. There is a risk of measles outbreaks among infants and among those who do not have a measles antibody titer.

This study was conducted to assess the real-world safety and effectiveness of adalimumab in patients with juvenile idiopathic arthritis (JIA). In this all-case, postmarketing surveillance study (NCT01412021) conducted in Japan, patients receiving adalimumab for JIA affecting multiple joints were observed for 24 weeks. The safety (adverse drug reactions [ADRs]/serious ADRs) and effectiveness (4-variable Disease Activity Score in 28 joints using erythrocyte sedimentation rate [DAS28-4/ESR] remission rate) were assessed. In the safety population (n = 356), 90.3% (65/72; weight, ≥15–p = .0072), those with comorbidities vs. without (38.3% vs. 25.7%, p = .0155), and those receiving dose p = .0418). DAS28-4/ESR remission rate improved from 21.7% (36/166) at baseline to 74.7% (112/150) at week 24. Adalimumab was well tolerated and had acceptable safety and effectiveness in patients with JIA in the real-world setting.

Purpose The aim of this study was to measure the serum levels of brain-derived neurotrophic factor (BDNF) in primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) patients in Japan. Methods This was a prospective, observational study that examined serum BDNF levels in 78 patients who underwent cataract surgery or trabeculectomy (27 glaucoma patients and 51 non-glaucoma cataract patients as controls). The patients' age was 68.8 ± 11.1 years (mean ± standard deviation; range 35-86 years). The number of patients with POAG and NTG was 16 and 11, respectively. The diagnosis of POAG was done by intraocular pressure measurement, gonioscopy, optic nerve head change, and the presence of a visual field defect. Results The serum BDNF concentration was significantly lower in the glaucoma group, including both POAG and NTG, than in the control group (7.2 ± 3.6 ng/mL vs. 12.2 ± 9.3 ng/mL, p=0.004). The serum BDNF concentration was lower in the early phase than in the moderate phases of glaucoma. There was no correlation between the serum BDNF concentration and age. When the NTG and POAG patient groups were compared, the serum BDNF concentration was lower in NTG patients than in POAG patients. No significant correlations were found between glaucoma parameters, including optical coherence tomography and visual field defects, and the serum BDNF concentration. Conclusion This is the first study to have investigated serum BDNF concentrations in glaucoma patients in Japan. Further investigations are needed to evaluate the role of BDNF as a potential biomarker of glaucoma.

Childhood-onset systemic lupus erythematosus (cSLE) has been recognised as a more acute and severe autoimmune disease than adult-onset SLE. With the development of medications for the disease and supportive therapy, the mortality rate associated with cSLE has drastically improved; the 10-year survival rate among patients with cSLE between 1995 and 2006 in Japan was 98.3%. However, the 10-year survival rate without any permanent functional impairment remained low at 66.1%. Therefore, the current treatment goal for cSLE is to ensure that they can perform normal daily activities throughout their lives by preventing the occurrence and/or progression of organ damage. For this purpose, appropriate treatments and evaluations are required according to the severity and risk of organ damage; however, there are no established guidelines for cSLE. Therefore, the Pediatric Rheumatology Association of Japan and the Pediatric Rheumatology Subcommittee in the Japan College of Rheumatology developed a comprehensive guidance for clinical practice based on cSLE-related data collected from Japanese national surveys and relevant articles from both domestic and international sources. However, due to the lack of indications for defined and objective evidence quality levels, this guidance should be used on the basis of the judgement of the attending physicians for individual patients.

Background In preparation for the 2020 Tokyo Olympic/Paralympic Games, the Japanese government assessed the risks of infectious disease outbreaks and determined necessary preparations. This present study reviews efforts made during a previous measles epidemic and describes the roles of hospitals. Methods This descriptive study investigated the records of 198 children with measles. Each child was treated at a general hospital January 1997 and February 1998. The study also examined the actions of pediatricians during and after the measles outbreak in the community. Results Of the 198 children, 145 (73%) were hospitalized. The measles vaccination rate in the previous year was approximately 75%. Of the patients examined, 53% were below two years of age. The mean age was two years and nine months. Pneumonia and gastroenteritis accounted for 46% and 30% of the complications, respectively. Issues requiring attention included the number of hospital beds located in a negative pressure room or a private room with a window, obtaining gamma globulin preparation with a high measles antibody titer, increased vaccination opportunities, and extended working hours for doctors. Conclusions Measles outbreaks are possible in Japan as a result of visitors from abroad. Items to mitigate an outbreak were identified as maintenance of high vaccination rates, readily available information regarding the location of negative pressure hospital rooms, the status of measles development, and finally medical staffing issues. There is a continued risk of measles outbreaks occurring in infants and individuals who do not have a measles antibody titer.

This study finds a necessary and sufficient condition for mutual fund separation, in which investors have the same portfolio of risky assets regardless of their utility functions. Unlike previous studies, the market condition is obtained in analytic form, using the Clark–Ocone formula of Ocone and Karatzas (Stoch Stoch Rep 34(3–4):187–220, 1991). We also find that the condition for separation among arbitrary utility functions is equivalent to the condition for separation among utility functions with constant relative risk aversion (CRRA utility functions). The condition is that a conditional expectation of an infinitesimal change in the uncertainty of an instantaneous Sharpe ratio maximizing portfolio can be hedged by the Sharpe ratio maximizer itself. In a Markovian market, such an infinitesimal change is characterized as an infinitesimal change in state variables. A closer look at the Clark–Ocone formula offers an intuition of the condition: an investor invests in (1) the Sharpe ratio maximizer; and (2) another portfolio in such a way as to reduce the uncertainty produced by an infinitesimal change in the Sharpe ratio maximizer, depending on four components: the investor’s wealth level, marginal utility and risk tolerance, at the time of consumption, and the shadow price. This decomposition is also valid in non-Markovian markets.

Background In 2015, infliximab was approved for the treatment of patients with intravenous immunoglobulin-refractory Kawasaki disease (KD) in Japan. However, limited real-world data exist on the usefulness of infliximab for acute KD patients. We conducted a postmarketing surveillance study in patients with acute KD refractory to conventional therapies to evaluate the safety (including any live vaccine-related infections) and the effectiveness of infliximab. Methods This was a multicenter, prospective, open-label, single-cohort, observational study in patients with acute KD refractory to conventional therapy who were prescribed a single 5 mg/kg dose of infliximab. Safety and effectiveness of infliximab were evaluated at 1 month, and live vaccine-related infections were further observed until 6 months from KD onset. Effectiveness assessments included fever resolution rate, the incidence of coronary artery lesions and change in coronary diameter Z scores. Results A total of 291 patients were enrolled, and all patients completed the study. Adverse drug reactions and serious adverse drug reactions were reported in 12.4% and 3.1% of patients, respectively. Live vaccine-related infections were not observed. In the 208 patients with effectiveness assessments, the fever resolution rate within 48 hours after infliximab infusion was 77.4% (95% confidence interval: 71.1-82.9). Median time until fever resolution was 16.6 hours. After infliximab administration, the incidence (at baseline: 10.9%; at the final observation point: 12.0%; maximum value: 14.6%) and severity of coronary artery lesions did not change notably. Conclusions In this study, Infliximab for patients with acute KD refractory to conventional therapies was well tolerated and effective.

Branchio-oto-renal (BOR) syndrome is a rare autosomal dominant disorder characterized by branchiogenic anomalies, hearing loss, and renal anomalies. The aim of this study was to reveal the clinical phenotypes and their causative genes in Japanese BOR patients. Patients clinically diagnosed with BOR syndrome were analyzed by direct sequencing, multiplex ligation-dependent probe amplification (MLPA), array-based comparative genomic hybridization (aCGH), and next-generation sequencing (NGS). We identified the causative genes in 38/51 patients from 26/36 families; EYA1 aberrations were identified in 22 families, SALL1 mutations were identified in two families, and SIX1 mutations and a 22q partial tetrasomy were identified in one family each. All patients identified with causative genes suffered from hearing loss. Second branchial arch anomalies, including a cervical fistula or cyst, preauricular pits, and renal anomalies, were frequently identified (>60%) in patients with EYA1 aberrations. Renal hypodysplasia or unknown-cause renal insufficiency was identified in more than half of patients with EYA1 aberrations. Even within the same family, renal phenotypes often varied substantially. In addition to direct sequencing, MLPA and NGS were useful for the genetic analysis of BOR patients.

Background The transition from pediatric to adult healthcare systems has recently received worldwide attention, and it is “the purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions from child-centered to adult-oriented healthcare systems.” In Japan, 1,000 patients with childhood-onset chronic disease reach adulthood every year, and many of them survive without serious sequelae or disabilities. The Japan Pediatric Society convened a committee of healthcare transition, summarized their statements, and the working group launched its activities in 2013. Objectives A clinical practice guidance for the transitional care of young people with childhood-onset rheumatic disorders has been established in Japan. Methods The guidance was designed to support pediatric and non-pediatric rheumatologic health care professionals make decisions about appropriate transitional health care for childhood-onset rheumatic disorders. It offered statements and recommendations addressing key clinical questions regarding transitional care proposed by leading pediatric and non-pediatric rheumatology medical experts and consisted of general core and disease-specific guidance. Results Category of clinical questions in the general core guidance involved the following: (1) initial statement of transitional care in rheumatology; (2) management of social life environment and public funded health care; (3) issues specific to adolescence; (4) risk management in childhood-onset rheumatic disorders; and (5) decision-making, privacy and consent, access to information, adherence to care, and preferred methods of communication, including attending to health literacy needs. In the disease-specific guidance, issues focused on each rheumatic disorder such as juvenile idiopathic arthritis, childhood-onset systemic lupus erythematosus, juvenile dermatomyositis, and Sjogren’s syndrome were brought up. Conclusion The guidance informs policy and strategies to reach optimal outcomes in transitional care for both pediatric and non-pediatric rheumatologists based on available evidence and expert opinion. References [1] Miyamae T, et al. Survey of attitudes of non-pediatric rheumatologists among councilors of the Japan College of Rheumatology regarding transitional care. Mod Rheumatol. 2017;27(6):1047-1050. [2] Matsui T, et al. Survey of the awareness of adult rheumatologists regarding transitional care for patients with juvenile idiopathic arthritis in Japan. Mod Rheumatol. 2018;28(6):981-985. Disclosure of Interests Takako Miyamae Speakers bureau: AbbVie, Eisai, Bristol-Meyers, Novartis, Ayumi, Taisyo-Toyama, Chugai, Shinji Akioka Grant/research support from: Eli Lily, Speakers bureau: Pfizer, Maruho, CSL Behring, Astellas, Chugai, Toru Igarashi: None declared, Yuzaburo Inoue Grant/research support from: MSD, Speakers bureau: Novartis, CSL Behring, MSD, Taishotoyama, Ono, Motomu Hashimoto Grant/research support from: Astellas, Brystol-Meyers, Eisai, Employee of: M. H. is affiliated with the department (Department of Advanced Medicine for Rheumatic Diseases, Kyoto University), which is financially supported by four pharmaceutical companies (Tanabe-Mitsubishi, Chugai, Ayumi, UCB Japan), Speakers bureau: Tanabe Mitsubishi, Brystol-Meyers, Toshihiro Matsui Speakers bureau: Takeda, Chugai, Eisai, Pfizer, Astellas, Eli Lilly, Ono, AbbVie, Mitsubishi Tanabe, AsahiKASEI, UCB, Teijin, Susumu Nishiyama Paid instructor for: Kissei Pharmaceutical Co., Ltd, Takeda Pharmaceutical Company, Mitsubishi Tanabe Pharma, Astellas Pharma, Eisai Pharmaceutical company, AbbVie Inc., TEIJIN Pharma, Asahi Kasei Corporation, Bristol- Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Santen Pharmaceutical Co., Ltd., AYUMI Pharmaceutical Corporation, Speakers bureau: Kissei Pharmaceutical Co., Ltd, DAIICHI SANKYO COMPANY, LIMITED, Shiro Ohshima Grant/research support from: AbbVie, Eisai, Asahikasei, Speakers bureau: AbbVie, Eisai, Bristol-Meyers, Novartis, Astellas, Nippon-Kayaku, Pfizer, UCB, Ayumi, Daiichi-Sankyo, Takeda, Tanabe-Matsubishi, Chugai, Hiroaki Umebayashi Speakers bureau: AbbVie, Eisai, Novartis, Ono, Chugai, Takahiro Yasumi Shareholder of: Takeda, Speakers bureau: AbbVie, Novartis, CSL Behring, Masaaki Mori Grant/research support from: Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Towa Pharmaceutical Co., Ltd., UCB Japan Co. Ltd.

Purpose Hydrogen (H2) has been reported to scavenge free radicals, particularly the hydroxyl radical (·OH). Ultrasound oscillation in an aqueous solution produces ·OH. Our recent study demonstrated that H2 dissolved in an irrigation solution prevented corneal endothelial damage during phacoemulsification in an animal model. We examined the effects of H2 during clinical phacoemulsification. Design A single-center, prospective, randomized, double-masked clinical trial. Methods Thirty-two patients who had cataracts of similar nucleus hardness in both eyes (age: 75.4±7.68 years; 17 males, 15 females) were recruited. Phacoemulsification was performed using a solution of dissolved H2 in one eye, and a conventional solution in the contralateral eye. Endothelial cell density (ECD) at the center of the cornea was measured using noncontact specular microscopy preoperatively and at 1 day, 1 week, and 3 weeks postoperatively. Results Reduction rates of ECD (mean ± standard deviation) were 16.0%±15.7% at 1 day, 15.4%±16.1% at 1 week, and 18.4%±14.9% at 3 weeks in the control group, compared to 6.5%±8.7% at 1 day (P = .003), 9.3%±11.0% at 1 week (P = .039), and 8.5%±10.5% at 3 weeks (P = .004) in the H2 groups. These rates were significantly smaller in the H2 group at all time points. Conclusions H2 dissolved in irrigation solution reduced corneal endothelial damage during phacoemulsification. This suggests that a considerable part of the corneal endothelial damage during phacoemulsification is caused by oxidative stress, and that H2 is useful in clinical phacoemulsification.

We tested the hypothesis that deep anesthesia with sevoflurane, known as a potent immunomodulator, for 4 h would worsen the 24-h outcomes of rats through modulation of the inflammatory responses. Forty-nine male Wistar rats, administered low dose of lipopolysaccharide (0.5 mg/kg) intravenously to elicit moderate inflammatory responses mimicked mild surgical stress, underwent one minimum alveolar concentration (MAC) or 2 MAC sevoflurane anesthesia for 4 h. The 24-h survival rate, arterial blood gases, plasma interleukin (IL)-6 and tumor necrosis factor (TNF)-α concentrations, and rate of T lymphocyte apoptosis in spleen were evaluated. We further examined the effects of hypotension and TNF-α discharge on the survival rate. The survival rate in 2 MAC group was significantly lower accompanied with decreased base excess and increased level of cytokines (IL-6, TNF-α) compared to 1 MAC group. The apoptosis rate did not differ between the two groups. Neither norepinephrine infusion to restore hypotension nor administration of anti-TNF-α antibody improved the outcome in the 2 MAC group. Deep anesthesia with sevoflurane even for a short-term period augments the release of inflammatory cytokines evoked by inflammatory insults like surgical stress, impairs the acid–base balance, and subsequently deteriorates the outcomes.

Background and Aim: Because neutrophil gelatinase-associated lipocalin (NGAL) is known to provide significant bacteriostatic effects during infectious conditions, we tested the hypothesis that this protein is up-regulated and secreted into the intraluminal cavity of the gut under critically ill conditions and is thus responsible for the regulation of bacterial overgrowth. Methods: With our institutional approval, male C57BL/6J mouse (6–7 weeks) were enrolled and applied for lipopolysaccharide or peritonitis model compared with naive control. We assessed NGAL protein concentrations in intestinal lumen and up-regulation of NGAL expression in intestinal tissues in in vivo as well as ex vivo settings. Simultaneously, we examined the effects of NGAL protein administration on the growth of Escherichia coli (E. coli) in in vivo and in vitro experimental settings. The localization of NGAL in intestinal tissues and lumen was also assessed by immunohistological approach using NGAL antibody. Results: Both lipopolysaccharide and peritonitis insults evoked the marked up-regulation of NGAL mRNA and protein levels in gut tissues such as crypt cells. In addition, the administration of NGAL protein significantly inhibited the outgrowth of enteric E. coli under both in vitro and in vivo conditions, accompanied by histological evidence. Conclusion: Neutrophil gelatinase-associated lipocalin protein accompanied by apparent bacteriostatic action accumulated in the intestinal wall and streamed into the mucosal layer during critically ill state, thereby possibly shaping microbiota homeostasis in the gut.

Background X-linked Alport syndrome (XLAS) is a progressive hereditary nephropathy caused by mutations in the COL4A5 gene. Genotype-phenotype correlation in male XLAS is relatively well established; relative to truncating mutations, nontruncating mutations exhibit milder phenotypes. However, transcript comparison between XLAS cases with splicing abnormalities that result in a premature stop codon and those with nontruncating splicing abnormalities has not been reported, mainly because transcript analysis is not routinely conducted in patients with XLAS. Methods We examined transcript expression for all patients with suspected splicing abnormalities who were treated at one hospital between January of 2006 and July of 2017. Additionally, we recruited 46 males from 29 families with splicing abnormalities to examine genotype-phenotype correlation in patients with truncating ( n =21, from 14 families) and nontruncating ( n =25, from 15 families) mutations at the transcript level. Results We detected 41 XLAS families with abnormal splicing patterns and described novel XLAS atypical splicing patterns ( n =14) other than exon skipping caused by point mutations in the splice consensus sequence. The median age for developing ESRD was 20 years (95% confidence interval, 14 to 23 years) among patients with truncating mutations and 29 years (95% confidence interval, 25 to 40 years) among patients with nontruncating mutations ( P =0.001). Conclusions We report unpredictable atypical splicing in the COL4A5 gene in male patients with XLAS and reveal that renal prognosis differs significantly for patients with truncating versus nontruncating splicing abnormalities. Our results suggest that splicing modulation should be explored as a therapy for XLAS with truncating mutations.

BACKGROUND: Neutrophil-derived lipocalin-2 exerts bacteriostatic effects through retardation of iron uptake by the Gram-negative organisms like Escherichia coli. We tested the hypothesis that the expression of lipocalin-2, a bacteriostatic protein, was upregulated by induction of surgical site infection (SSI) with E coli in healthy and diseased rats and that epidural anesthesia modulated its expression. METHODS: Male Wistar rats were randomized into a healthy or disease group, the latter of which was administered lipopolysaccharide. Both groups were further divided into 3 subgroups, the control, saline, and lidocaine groups: group healthy control (n = 10), healthy saline (n = 10), and healthy lidocaine (n = 10) versus group disease control (n = 15), disease saline (n = 18), and disease lidocaine (n = 19), respectively. While saline was epidurally administered to the control and saline groups, lidocaine was administered to the lidocaine groups. Except for the control groups, E coli was injected to the pseudosurgical site to mimic SSI after abdominal surgery. Plasma concentrations of inflammatory cytokine and lipocalin-2 were measured. At 72 hours, the surgical site tissues were obtained to evaluate mRNA expression of lipocalin-2 and E coli DNA expression. RESULTS: All disease subgroups showed markedly increased plasma inflammatory cytokines versus the healthy subgroups. Among the disease subgroups, plasma concentrations of lipocalin-2 and tissue mRNA expression of lipocalin-2 were significantly increased in group disease lidocaine versus the others. Concurrently, E coli DNA expression in the tissue specimens was also significantly lower in group disease lidocaine as compared with group disease saline. CONCLUSIONS: Epidural anesthesia was associated with an increase in the expression lipocalin-2 and a decrease in the expression of E coli DNA at pseudosurgical sites in sick but not healthy rats. These observations suggest a potential mechanism by which epidural anesthesia could reduce the risk of SSI.

Cytokines are immunomodulatory proteins important in cell signaling. Complex interactions of innate and adaptive immune cells, as well as structural cells and their cytokines, play crucial roles in regulating allergic airway inflammation. Here, we summarize current knowledge about the potential roles of known and newly identified helper T cells and epithelial cell-derived cytokines [interleukin (IL)-9, IL-17, IL-22, IL-25, and IL-33] in allergic rhinitis and asthma.Although T-helper (Th)2 cells were considered to be the main orchestrators of allergic airway inflammation, recent studies have revealed the potential interaction of other helper T cells and their cytokines in this process. Th17 cells may have a role in allergic rhinitis and asthma, and chronic rhinosinusitis with nasal polyps. An IL-9-producing subset called Th9 cells, Th22 cells which primarily secrete IL-22, IL-13, tumor necrosis factor-α, Th25 cells via producing IL-25 and epithelial cell-derived thymic stromal lymphopoietin, IL-33, IL-31, and IL-25 are believed to be important for the initiation of allergic reactions and inducing airway inflammation.A new paradigm of an interplay of cytokines is important in allergic rhinitis and asthma in orchestrating the allergic inflammatory response. Potential therapeutic applications emerging from the roles of these cytokines are promising, but need further research.

A 6Gb/s 9.8pJ/b rotatable non-contact connector applicable to robot arms is developed. The proposed rotatable transmission line coupler (RTLC) has a wide bandwidth at all rotation angles. An interface bridge IC is also developed to transfer a wide range of interface signals from slow legacy ones to high-speed ones. The proposed system improves power efficiency by a factor of 3.7, space efficiency by a factor of 1.8, and satisfies EMC regulations.

Background: Intravenous cyclophosphamide (IVCY pulse therapy has been used for lupus nephritis since the latter half of the 1980s; it has been shown to be effective for lupus nephritis and vasculitis and has become a standard therapy for the diffuse proliferative type of lupus nephritis in adults. IVCY therapy has also come to be used in children. This paper reports the long‑term outcomes of IVCY therapy in children. Methods: Six female patients (age range 13 to 18 years with systemic lupus erythematosus (SLE were enrolled in this retrospective study. Three patients had lupus nephritis (World Health Organization class IIb IVa IVc 2 had central nervous system (CNS lupus and 1 had neither lupus nephritis nor CNS lupus. The mean pretreatment SLE disease activity index (SLEDAI score was 18.8 � 4.6. Cyclophosphamide (initial dose 500 mg m 2 was administered intravenously each month for 6 months and then given every 3 months for maintenance. Prednisolone was given in dosages ranging from 5 to 60 mg day adjusted according to laboratory data and clinical symptoms. Levels of C3 C4 CH50 and creatinine; the SLEDAI score; and the SLE responder index were monitored and evaluated. Th eS LE responder index was considered to have improved if the SLEDAI score had decreased by 4 points or more after 52 weeks. Results: Prednisolone doses were reduced in all patients. Because methylprednisolone pulse therapy was administered before IVCY therapy some patients had low titers of immunoglobin G antibodies against double‑stranded DNA at the start of IVCY therapy. All patients had low serum creatinine levels. Proteinuria resolved in 1 of the 3 patients with lupus nephritis. The SLEDAI scores improved after 52 weeks in 5 of 6 patients (mean 5.2 � 2.6. No patients had severe bone marrow suppression or hemorrhagic cystitis during IVCY pulse therapy. Conclusions: IVCY pulse therapy for SLE in children achieved good long‑term outcomes with no serious adverse effects such as digestive symptoms bone marrow suppression infection and hemorrhagic cystitis. IVCY pulse therapy for children with SLE has recently been approved by the Ministry of Health Labour and Welfare. Accordingly this paper might become a guideline for this treatment. (J Nippon Med Sch 2013; 80: 396―400

Membranous nephropathy (MN is caused by subepithelial deposition of immune complexes in the glomerular basement membrane with secondary MN arising in association with infection. In secondary MN caused by hepatitis B virus (HBV seroconversion has been known to occur after the onset of MN particularly in children. In patients with high serum concentrations of HBV DNA treatment with interferon‑α2b or a nucleoside analog has been reported to induce seroconversion and suppress HBV‑DNA levels. We treated a 7‑year‑old boy who presented with proteinuria and liver dysfunction. He had a history of HBV infection since shortly after birth as his mother was HBV‑positive and he was neither vaccinated nor treated with immunoglobulin at birth. Chronic hepatitis related to HBV was diagnosed following percutaneous needle biopsy of the liver. Percutaneous renal biopsy revealed HBV‑related glomerulonephritis with diffuse global subepithelial and focal segmental mesangial and subendothelial deposits. Therefore HBV‑associated MN was diagnosed. Treatment with the nucleoside analog lamivudine was started to reduce serum HBV‑DNA levels but lamivudine was discontinued and treatment with entecavir was started at a dosage of 0. 5m g day after 6 weeks because of possible adverse effects. Tests for HB envelope antibody were positive in week 16 of treatment and proteinuria had resolved by week 22. Elevated levels of aspartate aminotransferase and alanine aminotransferase were seen with both treatments but were probably attributable to the developing immune response to HBV. In the present case HBV levels needed to be reduced to: 1 lower elevated serum HBV‑DNA titers which put the patient at high risk of hepatocellular carcinoma; and 2 remove the immune complexes causing MN. Use of nucleoside analogs to suppress the HBV load may facilitate early remission of MN and entecavir therapy did not cause any serious adverse reactions in this case. Given the advent of lamivudine‑resistant HBV entecavir appears promising for patients with elevated serum levels of HBV DNA. (J Nippon Med Sch 2013; 80: 387―395

Background Disease‐causing mutations that activate transposon‐derived exons without creating a new splice‐site consensus have been reported rarely, but they provided unique insights into our understanding of structural motifs required for inclusion of intronic sequences in mature transcripts. Methods We employ a combination of experimental and computational techniques to characterize the first de novo bipartite exon activation in genetic disease. Results The exon originated from two separate introns as a result of an in‐frame COL4A5 deletion associated with a typical Alport syndrome. The deletion encompassed exons 38 through 41 and activated a cryptic 3′ and 5′ splice site that were derived from intron 37 and intron 41, respectively. The deletion breakpoint was in the middle of the new exon, with considerable complementarity between the two exonic parts, potentially bringing the cryptic 3′ and 5′ splice site into proximity. The 3′ splice site, polypyrimidine tract and the branch site of the new exon were derived from an inactive, 5′ truncated LINE‐1 retrotransposon. This ancient LINE‐1 copy sustained a series of mutations that created the highly conserved AG dinucleotide at the 3′ splice site early in primate development. The exon was fully included in mature transcripts and introduced a stop codon in the shortened COL4A5 mRNA, illustrating pitfalls of inferring disease severity from DNA mutation alone. Conclusion These results expand the repertoire of mutational mechanisms that alter RNA processing in genetic disease and illustrate the extraordinary versatility of transposed elements in shaping the new exon‐intron structure and the phenotypic variability.

OBJECTIVES The objectives of the present study were (i) to identify a novel tumor suppressor gene whose expression level was regulated by transforming growth factor (TGF-β) and (ii) to evaluate the effect of Ras/MEK/ERK signaling on TGF-β-dependent Lefty up-regulation. METHODS Human pancreatic cancer cell lines were used. The effect of Ras/MEK/ERK pathway on TGF-β-mediated Lefty up-regulation was tested by adding K-ras small interfering RNA, MEK inhibitor U0126, or extracellular signal-regulated kinase (ERK) inhibitor LY294002. RESULTS Transforming growth factor β upregulated Lefty messenger RNA levels within 6 of the 7 cell lines. Lefty exerts an antagonistic effect against the tumor-promoting molecule, Nodal, as recombinant Lefty suppressed Nodal-mediated proliferation. Interestingly, inhibition of the Ras/MEK/ERK pathway dramatically enhanced TGF-mediated Lefty up-regulation, suggesting that Ras/MEK/ERK signaling suppresses TGF-β-Lefty pathway. CONCLUSIONS Our data suggest that Lefty is a novel TGF-β target molecule that mediates growth inhibition of pancreatic cancer cells. In addition, activation of the Ras/MEK/ERK pathway serves as a mechanism by which pancreatic cancer escapes from growth inhibition by the TGF-β-Lefty axis. The results imply a novel therapeutic strategy for pancreatic cancer, that is, combination treatment with Ras/MEK/ERK inhibitors and TGF-β.

The hollow inner spaces of single-wall carbon nanotubes (SWCNTs) can confine various types of molecules. Many remarkable phenomena have been observed inside SWCNTs while encapsulating organic molecules (peapods). However, a mixed electronic structure state of the surrounding SWCNTs has impeded a detailed understanding of the physical/chemical properties of peapods and their device applications. We present a single-chirality purification method for SWCNTs that can encapsulate organic molecules. A single-chiral state of (11,10) SWCNTs with a diameter of 1.44 nm, which is large enough for molecular encapsulation, was obtained after a two-step purification method: metal-semiconductor sorting and cesium-chloride sorting. The encapsulation of C(60) to the (11,10) SWCNTs was also succeeded, promising a route toward single-chirality peapod devices.

Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that regulates apoptosis sensitivity in a variety of cell types. Here we evaluate the roles of Mcl-1 in chemotherapy-associated apoptosis in gastric cancer cells. In addition, our study examined whether Mcl-1 contributed to apoptosis resistance in so-called cancer stem cell (CSC)-like populations in gastric cancer.Seven gastric cancer cell lines were used. The expression of Mcl-1 was assessed by either real-time polymerase chain reaction or Western blot analysis. Apoptosis was quantitated by morphological observation and caspase activity measurement. Adenovirus-mediated RNA interference (RNAi) technology was used to knockdown the expression of Mcl-1. The release of cytochrome c was evaluated by subcellular fractionation and immunoblot analysis. To identify and isolate the CSC-like populations, we used the CSC-associated cell surface marker CD44 and flow cytometry.Six out of the 7 gastric cancer cell lines overexpressed Mcl-1 protein. These Mcl-1-expressing cell lines were relatively resistant to chemotherapeutic agents such as 5-fluorouracil (5-FU) and cisplatin (CDDP). Depletion of Mcl-1 protein by RNAi technology effectively sensitized the cells to anticancer drug-induced mitochondrial cytochrome c release, caspase activation, and apoptosis. In addition, vast amounts of Mcl-1 mRNA were expressed in CD44-positive CSC-like cells. Mcl-1 suppression enhanced the apoptosis in CD44-positive cells to a level equivalent to that in CD44-negative cells, suggesting that Mcl-1 mediates chemotherapy resistance in CSC-like populations.These results suggest that Mcl-1 mediates the resistance to apoptosis in gastric cancer cells by blocking the mitochondrial pathway of cell death. Mcl-1 depletion appears to be an attractive strategy to overcome chemotherapy resistance in gastric cancer cells.