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Glucocorticoids (GCs) are highly effective yet problematic agents against bronchopulmonary dysplasia (BPD). The dimeric trans-activation of GCs induces unfavorable effects, while monomeric trans-repression suppresses inflammation-related genes. Recently, non-steroidal-selective glucocorticoid-receptor agonists and modulators (SEGRAMs) with only the trans-repressive action have been designed.Using a bleomycin (Bleo)-induced alveolar simplification newborn rat model (recapitulating arrested alveolarization during BPD), we evaluated the therapeutic effects of compound-A (CpdA), a SEGRAM. Sprague-Dawley rats were administered Bleo from postnatal day (PD) 0 to 10 and treated with dexamethasone (Dex) or CpdA from PD 0 to 13. The morphological changes and mRNA expression of inflammatory mediators, including interleukin (IL)-1β, C-X-C motif chemokine ligand 1 (CXCL1), and C-C motif chemokine 2 (CCL2) were investigated.Similar to the effects of Dex, CpdA exerted protective effects on morphological derangements and inhibited macrophage infiltration and production of pro-inflammatory mediators in Bleo-treated animals. The effects of CpdA were probably mediated by GC receptor (GR)-dependent trans-repression, because unlike the Dex-treated group, anti-inflammatory genes specifically induced by GR-dependent trans-activation (such as "glucocorticoid-induced leucine zipper, GILZ") were not upregulated.CpdA improved lung inflammation, inhibited the arrest of alveolar maturation, and restored histological and biochemical changes in a Bleo-induced alveolar simplification model.SEGRAMs have attracted widespread attention because they are expected to not exhibit unfavorable effects of GCs. Compound A, one of the SEGRAMs, improved lung morphometric changes and decreased lung inflammation in a bleomycin-induced arrested alveolarization, a newborn rat model representing one of the main features of BPD pathology. Compound A did not elicit bleomycin-induced poor weight gain, in contrast to dexamethasone treatment. SEGRAMs, including compound A, may be promising candidates for the therapy of BPD with less adverse effects compared with GCs.

Neofusicoccum parvum is a polyxenous phytopathogenic fungus that infects important fruits, such as grapes and mangoes. Here, we report the genome sequences of N. parvum strains that were isolated from mango in Okinawa, Japan (strain PPO83), and an invasive weed (rice-paper plant [ Tetrapanax papyrifer ]) in Nagoya, Japan (strain NSSI1).

Background Postural tachycardia syndrome (POTS), a subset of orthostatic dysregulation, has been reported to be associated with anxiety. POTS can be classified into two forms based on the degree of tachycardia during orthostasis. Reportedly, POTS with decreased orthostatic heart rate increase is associated with suppressed cardiac parasympathetic activity and increased sympathetic activity in the supine position. In this study, the relationship between the two types of POTS and anxiety was evaluated in terms of autonomic function. Methods Fifty-two patients (23 males, aged 10–15 years) who were diagnosed with POTS at the Department of Pediatrics, Osaka Medical and Pharmaceutical University from 2019 to 2021, provided completed the State-Trait Anxiety Scale for Children (STAIC) questionnaire. They then completed a standing test and were accordingly classified into the two groups of POTS, the Su group, with tachycardia from the supine position and a low heart rate increase on standing, and the SI group, with a high heart rate increase during standing. Autonomic function was assessed by frequency analysis (MemCalc method) based on heart rate, blood pressure changes, heart rate, and blood pressure variability during the orthostatic test. Results Patients in the Su group had higher characteristic anxiety, lower cardiac parasympathetic activity (RR-HF) in the supine position, and greater variability in cardiac parasympathetic activity during orthostasis than those of patients in the SI group. The Su group had a greater decrease in cardiac index on standing than that of the SI group. Conclusions The Su group results may be partly attributed to chronically low venous return. We also found that patients in the Su group had low parasympathetic activity in the supine position, which may interact with the anxiety-prone characteristics of these patients. Therefore, it seems necessary to consider both physical and psychosomatic treatment approaches for patients with POTS. Trial registration The clinical trial registry of Osaka Medical and Pharmaceutical University, Clinical Trial Registration No. 2662-2. Registered 5 March 2019. https://ompu.bvits.com/rinri/Common/print_approve.aspx?ID=3479

Atherosclerosis can develop in adult patients with congenital heart disease (CHD) and should be given attention. Endothelial function is well known as a predictor of the development of atherosclerosis but has not been well investigated in patients with repaired CHD. This study aimed to clarify the endothelial function and its relationship with clinical backgrounds and parameters in adolescents with various types of repaired CHD. Endothelial function was evaluated using peripheral arterial tonometry (PAT). The reactive hyperemia index (RHI) was evaluated and compared between adolescents with repaired CHD and those in the control group. The relationship between the clinical background and parameters was also investigated in patients with repaired CHD. Forty-eight patients with repaired CHD (age 14.0 ± 3.3 years) and 114 healthy volunteers were included in this study. The patients with repaired CHD comprised 16 with repaired non-cyanotic CHD, 14 with repaired tetralogy of Fallot, and 18 who underwent Fontan procedure. RHI in the repaired CHD group was significantly lower than in the control group. There was no significant correlation between the RHI and biochemical blood markers, such as uric acid, creatine, and brain natriuretic peptide levels. The RHI was significantly higher in patients taking angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) than in those who did not. Endothelial function was impaired in adolescents with repaired CHD compared to that in the control group. Microvascular endothelial dysfunction developed even in adolescents with simple non-cyanotic CHD.

Background Eculizumab was approved for atypical haemolytic uraemic syndrome (aHUS) in Japan in 2013. Post-marketing surveillance (PMS) was mandated by regulatory authorities to assess the safety and effectiveness of eculizumab in patients with aHUS in a real-world setting. Methods Paediatric patients in the PMS cohort who were Results A total of 40 paediatric patients (median age 5 years) were included. The median eculizumab treatment duration was 66 weeks. PLT count, LDH and eGFR significantly improved at 10 days post-treatment. Complete TMA response, haematologic normalization, sCr decrease, eGFR improvement and TMA event-free status were achieved by 73.3%, 73.3%, 70.0%, 78.3% and 77.5% of patients, respectively. Discontinuation criteria were met by 18 patients: 13 patients maintained treatment discontinuation at the end of observation and 5 patients, including 1 patient with aHUS relapse, continued the treatment but extended the treatment interval. During eculizumab treatment, 59 SAEs (0.66/person-year) were reported. Although four deaths were reported, none of them were related to eculizumab. Conclusion Eculizumab was well tolerated and effective for paediatric patients with aHUS in the real-world setting in Japan.

Botrytis cinerea, a generalist fungal pathogen of economically important crop species, has been shown to exhibit reduced sensitivity to fungicides and plant toxins. Specifically, previous reports indicateB. cinerea’s efficacy in tolerating a wide array of phytoalexins, toxic plant metabolites that play key role in plant immune defense strategies. Previously, we have shown that a distinct set of genes was induced inB. cinereawhen treated with phytoalexins derived from different plant species such as rishitin (tomato and potato), capsidiol (tobacco and bell pepper) or resveratrol (grape and blueberry). In this study, we focused on the functional analyses ofB. cinereagenes induced by rishitin treatment.B. cinereacan metabolize rishitin to at least 4 oxidized forms. Heterologous expression of rishitin-inducedB. cinereagenes in the plant symbiotic fungus,Epichloë festucae, revealed that oxidoreductase (Bcin08g04910) and cytochrome P450 (Bcin16g01490) genes are involved in the oxidation of rishitin. BcatrB is an exporter of structurally unrelated anti-microbial compounds such as resveratrol, camalexin and fungicide fenpicionil. Expression ofBcatrBis upregulated by rishitin, but not by structurally resembling capsidiol.BcatrBknock out transformants (ΔbcatrB) showed enhanced sensitivity to rishitin, but not to capsidiol. Likewise,ΔbcatrBshowed reduced virulence on tomato fruits (which produce rishitin), but showed full virulence onNicotiana benthamiana(which mainly produces capsidiol), suggesting thatB. cinereadistinguishes phytoalexins and activates expression of appropriate transporter genes during the infection. Activation ofBcatrBpromoter was detected using P_BcatrB:GFPtransformant during theB. cinereainfection in plant tissues. Surveying of 26 plant species across 13 families revealed that theBcatrBpromoter is mainly activated during the infection of plants belonging to the Solanaceae, Fabaceae and Brassicaceae families. TheBcatrBpromoter is activated by the treatment with Fabaceae phytoalexins medicarpin and glyceollin, andΔbcatrBshowed reduced virulence on red clover, which produces medicarpin. These results suggest thatBcatrBplays a critical role in the strategy employed byB. cinereato bypass the plant innate immune responses in a wide variety of important crops belonging to the Solanaceae, Brassicaceae and Fabaceae families.

The gray mold pathogen Botrytis cinerea has a broad host range, causing disease in >400 plant species, but it is not known how this pathogen evolved this polyxenous nature. Botrytis cinerea can metabolize a wide range of phytoalexins, including the stilbenoid resveratrol in grape, and the sesquiterpenoids capsidiol in tobacco and rishitin in potato and tomato. In this study, we analyzed the metabolism of sesquiterpenoid phytoalexins by B. cinerea. Capsidiol was dehydrogenated to capsenone, which was then further oxidized, while rishitin was directly oxidized to epoxy- or hydroxyrishitins, indicating that B. cinerea has separate mechanisms to detoxify structurally similar sesquiterpenoid phytoalexins. RNA-seq analysis revealed that a distinct set of genes were induced in B. cinerea when treated with capsidiol or rishitin, suggesting that B. cinerea can distinguish structurally similar phytoalexins to activate appropriate detoxification mechanisms. The gene most highly upregulated by capsidiol treatment encoded a dehydrogenase, designated Bccpdh. Heterologous expression of Bccpdh in a capsidiol-sensitive plant symbiotic fungus, Epichloë festucae, resulted in an acquired tolerance of capsidiol and the ability to metabolize capsidiol to capsenone, while B. cinerea Δbccpdh mutants became relatively sensitive to capsidiol. The Δbccpdh mutant showed reduced virulence on the capsidiol producing Nicotiana and Capsicum species but remained fully pathogenic on potato and tomato. Homologs of Bccpdh are found in taxonomically distant Ascomycota fungi but not in related Leotiomycetes species, suggesting that B. cinerea acquired the ancestral Bccpdh by horizontal gene transfer, thereby extending the pathogenic host range of this polyxenous pathogen to capsidiol-producing plant species.

Atypical hemolytic uremic syndrome (aHUS) is an ultra-rare and life-threatening disease. For decades, plasma therapy was used to manage patients with aHUS. Since eculizumab, a recombinant humanized anti-C5 monoclonal antibody, was approved for treatment of aHUS, it has been used to treat patients with aHUS. Here, we examined the effectiveness of eculizumab and plasma therapy, respectively in the treatment of pediatric patients with aHUS.Data were collected from questionnaires sent to 75 institutions known to be treating thrombotic microangiopathy (TMA).A total of 24 patients were evaluable, in which no recurrence of TMA was reported at last observation. There were four therapy groups: two patients receiving supportive therapy, one receiving plasma therapy alone, 17 switching from plasma therapy to eculizumab (therapy switched), and four receiving eculizumab alone. Among 17 patients of therapy-switched group, only one patient achieved complete remission at the end of plasma therapy, 15 patients achieved complete remission after eculizumab initiation, and two patients reached end-stage renal disease. Adverse events were reported in nine cases; among these, meningococcal infection, anaphylaxis, and eculizumab-related infusion reaction were reported among those treated with eculizumab.This study provided substantial evidence from a Japanese population that the conversion from plasma therapy to eculizumab therapy should be considered in patients with aHUS who show an incomplete response to plasma therapy. In addition, although no new safety events were detected, careful attention should be paid to meningococcal infection, eculizumab-related infusion reactions and allergic reactions with administration of eculizumab.

Dyskeratosis congenita (DKC) is a rare, multisystem, bone marrow failure disease characterized by abnormalities such as in the skin, mucosa, nervous system, and lungs. Here we report a rare case of presumed DKC causing total retinal detachment in the right eye and severe peripheral retinal vascular occlusion in the left eye. A 3-year-old boy was presented with vitreous hemorrhage and total retinal detachment in the right eye and was scheduled to undergo vitreous surgery in the right eye and detailed ophthalmologic examination of the left eye under general anesthesia. Since a systemic examination revealed anemia and marked thrombocytopenia, he underwent a detailed pediatric examination. Although genetic testing revealed no significant pathologic mutations, the presence of shortened telomere length and other clinical findings suggested the possibility of DKC. His right eye had severe proliferative vitreoretinopathy, and retinal reattachment was not achieved with vitreous surgery, thus resulting in phthisis bulbi. The left eye showed a wide retinal avascular area in the temporal retina, retinal neovascularization, and hard exudates on fluorescein fundus angiography and was treated with laser photocoagulation using a binocular indirect ophthalmoscopic photocoagulator. Following laser surgery, the new blood vessels regressed, and the visual acuity was maintained at 1.0. The findings in this rare case indicate that DKC can cause severe retinal vascular occlusion, thus leading to vitreous hemorrhage and retinal detachment. Therefore, early detection with fundus examination and early treatment with photocoagulation are important.

Background Rapid-onset dystonia–parkinsonism (RDP) is a disease characterized by an abrupt onset of dystonia accompanied by signs of parkinsonism and prominent bulbar symptoms. Case report We describe a case of a female patient, born after normal delivery, but diagnosed with mild intellectual disability at age 7. She presented with an abrupt onset of upper limb dystonia and bradykinesia without tremor in parkinsonism, as well as dysarthria and dysphagia caused by prominent bulbar symptoms, at age 9. She had normal findings on brain magnetic resonance imaging, electroencephalography, and blood examination but was diagnosed with a psychogenic disorder. At age 10, she developed left lower limb paroxysmal stiffness with pain, and at 14, she was hospitalized due to lasting paroxysmal symptoms. Whole-exome sequencing was performed for this index case and her parents, and a de novo missense variant c.829G > A, p.Glu277Lys in ATP1A3 was identified. Discussion This RDP case highlights a rare clinical feature of paroxysmal dystonia that affects the lower left limb and develops after the abrupt onset of permanent dystonia. Currently, there are only three reported RDP cases associated with the same missense mutation, and we summarized the clinical features of all cases including ours, such as onset of age, time for stable, RDP score, relapse and exacerbation. Various symptoms owing to ATP1A3 mutation could develop as ATP1A3-related neurological disorders beyond classical phenotypes such as alternating hemiplegia of childhood (AHC) or RDP. Although RDP is extremely rare during childhood, it is important to understand its clinical characteristics in children.

We aimed to compare the profile of the Wechsler Intelligence Scale for Children Fourth Edition (WISC-IV) between Japanese schoolchildren born very preterm (VP) and with very low birthweight (VLBW) and those with attention deficit hyperactivity disorder (ADHD), and to identify the specific neurocognitive characteristics of VLBW/VP children.The VLBW/VP group in the present study included 50 (19 male, 31 female) first- to third-grade elementary school children born between January 2008 and February 2013 at Osaka Medical and Pharmaceutical University Hospital and Saiseikai Suita Hospital with birthweights1,500 g and32 gestational weeks. The ADHD group included 18 (13 male, 5 female) first- to third-grade elementary school children who visited Osaka Medical and Pharmaceutical University Hospital between January 2019 and October 2021. Full-scale intelligence quotient scores, four indices, and 12 subtests of the WISC-IV were calculated for all participants and compared between the VLBW/VP and ADHD groups. We assessed whether the patients' clinical history was associated with a low score on the cancellation task in the VLBW/VP group.The WISC-IV profiles showed similar between-group patterns, and the VLBW/VP group had lower cancellation task scores than the ADHD group.This is the first study to compare WISC-IV profiles between VLBW/VP children and those with ADHD. Further investigation is needed on the association between academic performance and the score of the cancellation task, and the neural mechanism of low performance for cancellation tasks in VLBW/VP children.

Bosutinib is a second-generation tyrosine kinase inhibitor indicated for treatment of chronic myeloid leukemia (CML) in adult patients. The safety and efficacy of bosutinib in patients younger than 18 years of age have not been established. We here report the case of a 4-year-old male with CML who was treated with bosutinib during coordination of human leukocyte antigen–matched unrelated bone-marrow transplantation because of insufficient responses to imatinib and dasatinib. The patient achieved a complete cytogenetic response immediately after starting bosutinib at 180 mg/day (290 mg/m2/day). Because toxicity was tolerable, the dose was increased to 200 mg/day (330 mg/m2/day). A complete cytogenetic response was maintained, but a major molecular response was not achieved 6 months after initiation of treatment with bosutinib. At steady state, maximum plasma concentration, minimum plasma concentration, and area under the plasma concentration-time curve were 89.2 ng/mL, 16.7 ng/mL, and 1017.4 ng·hr/mL, respectively, at 290 mg/m2/day; and 141.1 ng/mL, 18.9 ng/mL, and 1278.5 ng·hr/mL, respectively, at 330 mg/m2/day. To the best of our knowledge, this is the first case report to show the pharmacokinetics of bosutinib with efficacy and safety in a pediatric patient with CML. This rare case in a very young child with CML can also be valuable reference for clinical practice.

Background Senior–Løken syndrome (SLS) and Bardet–Biedl syndrome (BBS) are ciliopathies. SLS is characterized by retinitis pigmentosa (RP) and familial nephronophthisis, leading to end-stage kidney disease, while BBS is characterized by six major symptoms: RP, polydactyly, obesity, genital abnormalities, learning difficulties, and renal defects. Ciliopathies have been diagnosed on a phenotypic basis, but diagnosis can now be established by genetic testing, using techniques such as next-generation sequencing. Here, we report a patient clinically diagnosed with SLS but diagnosed with BBS 13 years later using next-generation sequencing. Case presentation The patient was diagnosed with RP at the age of 6 years. She had some difficulty in social interactions and pre-obesity, but no polydactyly. At the age of 8 years, she was diagnosed with chronic kidney disease, anemia, and liver dysfunction. Kidney and liver biopsy revealed renal tubule cysts, tubule membrane disruption, and liver fibrosis. Therefore, SLS was diagnosed but no NPHP1 mutations were detected. Peritoneal dialysis was started at the age of 9 years, and she underwent kidney transplantation with a graft from her father at the age of 13 years. At the age of 21 years, she again underwent genetic testing for most of the mutations associated with ciliopathy. This revealed a homozygous frameshift mutation in intron 11 of SDCCAG8. Conclusions Mutations in SDCCAG8 are known to be causative of SLS and BBS without polydactyly. The fact that the patient had RP, some difficulty in social interactions, pre-obesity, juvenile nephronophthisis, liver fibrosis, bronchial asthma, and otitis media suggested BBS. However, some of these are not specific symptoms for BBS and she had few typical symptoms of BBS. Therefore, a definitive diagnosis of BBS was difficult without genetic analysis. Because many more patients with SDCCAG8 mutations have extrarenal manifestations like the current patient than standard nephronophthisis patients, careful monitoring of extrarenal manifestations is needed to improve patient management.

Objective Febrile seizures (FSs) typically occur in infants and children between 6 and 60 months of age. Rarely, FS can occur in late childhood (late FS [LFS]; >5 years of age); however, the clinical features of LFS remain unclear. We aimed to clarify the clinical features of LFS. Methods We retrospectively analyzed data from patients with LFS who visited Hirakata City Hospital between January 2004 and December 2014. We defined LFS as a seizure accompanied by fever (temperature ≥38 °C) occurring after 5 years of age, without a central nervous system infection. Results A total of 505 patients (349 boys, 156 girls: 5–14 years old) were included. A history of FS before 60 months of age was observed in 319 of 460 patients (69.3%) with sufficient information about previous FS history among the 505 patients enrolled. LFS was more likely to occur in males (69.1%). Seizure duration was ≤15 min in 87.4% of cases. A family history of FS in first-degree relatives was observed in 103/327 cases (31.5%). Among LFS cases, 45% occurred at 5 years of age, and 92.1% experienced only one seizure after 5 years of age. The number of seizure episodes gradually lessened with age, decreasing drastically to 5.6% of cases older than 9 years. Conclusions Our findings suggest that sex differences, seizure duration, and family history were similar for LFS and FS. Over 90% patients with LFS experienced no recurrence after 5 years of age. Further study is needed to verify the recurrence rate of LFS.

This study investigated the impact of coronavirus disease 2019 pandemic school closures on the mental health of school students with chronic diseases.Questionnaires were distributed to students from 4th-9th grade diagnosed with chronic diseases at Osaka Medical College Hospital and their parents or caregivers. Questionnaires from 286 families were returned by mail after the schools reopened. The students were divided into the "psychosomatic disorder" group (group P, n = 42), the "developmental disorder" group (group D, n = 89), and the "other disease" group (group O, n = 155). Using students' self-reports on the Questionnaire for Triage and Assessment with 30 items, we assessed the proportion of students with a high risk of psychosomatic disorder in three groups. We investigated how the students requiring the support of somatic symptom (SS) felt about school during school closure. Further, using parents' and caregivers' answers, SS scores were calculated before and during school closure and after school reopening.The proportion of students with a high risk of developing psychosomatic disorder increased in all groups. For the students in Group P, the response "I did not want to think about school" indicated an increase in SS scores, and for the students in Group O, "I wanted to get back to school soon" indicated a decrease. Furthermore, especially in Group P students, SS scores decreased transiently during school closure and increased after school reopening.The impact of school closure on mental health differed depending on students' diagnoses and feelings about school during school closures.

Small bowel capsule endoscopy (SBCE) for Crohn's disease is useful; however, its use has some limitations, such as invasiveness when endoscopic assistance is required in patients who cannot swallow the capsule, and the burden of interpretation on a physician. In contrast, intestinal ultrasonography (IUS) is a non-invasive modality for children. The purpose of this study is to evaluate the accuracy of IUS for pediatric patients with established Crohn's disease.Small bowel capsule endoscopy and IUS findings from the same period in pediatric patients with established Crohn's disease were analyzed retrospectively. First, we compared the Lewis score (LS), small bowel endoscopic activity, and IUS findings by small bowel wall thickness (SBWT) and mesenteric lymph node size (MLNS). Second, we compared the performance of IUS findings with those of some biomarkers.In 22 procedures, SBWT and MLNS were correlated with LS (r = 0.52, P0.05, and r = 0.45, P0.05, respectively). Small bowel wall thickness, erythrocyte sedimentation rate, and fecal calprotectin levels had the highest accuracy (81.8%, 81.8%, and 81.8%, respectively). The combination of SBWT and MLNS had the highest positive predictive value and negative predictive value (100% and 83.3%, respectively).Intestinal ultrasonography findings, including SBWT and MLNS, are useful for monitoring small bowel lesions in pediatric patients with established Crohn's disease. We suggest first evaluating small bowel inflammation by IUS in pediatric patients with Crohn's disease before SBCE because IUS is less invasive than SBCE.

BACKGROUND Several studies have demonstrated that non-osmotic antidiuretic hormone activity contributes to the development of hyponatremia in children with common febrile diseases. However the relationship between hyponatremia and body temperature has remained unclear. Therefore, we examined this relationship in children with common diseases. METHODS In this retrospective case study based on chart review, 1,973 children presenting with acute illnesses at Hirakata City Hospital between November 2008 and October 2009, and for whom blood test data were available, were enrolled. The median age of this cohort was 2.7 years and the mean serum sodium concentration was 136.4 mEq/L; 454 patients showed hyponatremia (

Most of the diseases for which apheresis therapy is indicated are intractable and rare, and each patient has a different background and treatment course prior to apheresis therapy initiation. Therefore, it is difficult to conduct large-scale randomized controlled trials to secure high-quality evidence. Under such circumstances, the American Society for Apheresis (ASFA) issued its guidelines in 2007, which were repeatedly revised until the latest edition in 2019. The ASFA guidelines are comprehensive. However, in the United States, a centrifugal separation method is mainly used for apheresis, whereas the mainstream procedure in Japan is the membrane separation method. The target diseases and their backgrounds are different from those in Japan. Due to these differences, the direct adoption of the ASFA guidelines in Japanese practice creates various problems. One of the features of apheresis in Japan is the development of treatment methods using hollow-fiber devices such as double filtration plasmapheresis (DFPP) and selective plasma exchange and adsorption-type devices such as polymyxin B-immobilized endotoxin adsorption columns. Specialists in emergency medicine, hematology, collagen diseases/rheumatology, respiratory medicine, cardiovascular medicine, gastroenterology, neurology, nephrology, and dermatology who are familiar with apheresis therapy gathered for this guideline, which covers 86 diseases. In addition, since apheresis therapy involves not only physicians but also clinical engineers, nurses, dieticians, and many other medical professionals, this guideline was prepared in the form of a worksheet so that it can be easily understood at the bedside. Moreover, to the clinical purposes, this guideline is designed to summarize apheresis therapy in Japan and to disseminate and further develop Japanese apheresis technology to the world. As diagnostic and therapeutic techniques are constantly advancing, the guidelines need to be revised every few years. In order to ensure the high quality of apheresis therapy in Japan, both the Japanese Society for Apheresis Registry and the guidelines will be inseparable.

Plants recognize molecular patterns unique to a certain group of microbes to induce effective resistance mechanisms. Elicitins are secretory proteins produced by plant pathogenic oomycete genera including Phytophthora and Pythium. Treatment of INF1 (an elicitin produced by P. infestans) induces a series of defense responses in Nicotiana species, including reactive oxygen species (ROS) production, transient induction of ethylene production, hypersensitive cell death and accumulation of the sesquiterpenoid phytoalexin capsidiol. In this study, we analyzed the expression profiles of N. benthamiana genes after INF1 treatment by RNAseq analysis. Based on their expression patterns, N. benthamiana genes were categorized into 20 clusters and 4,761 (8.3%) out of 57,140 genes were assigned to the clusters for INF1-induced genes. All genes encoding enzymes dedicated to capsidiol production, 5-epi-aristolochene (EA) synthase (NbEAS, 10 copies) and EA dehydrogenase (NbEAH, 6 copies), and some genes for ethylene production, such as 1-aminocyclopropane 1-carboxylate (ACC) synthase (NbACS) and ACC oxidase (NbACO), were significantly upregulated by INF1 treatment. Analysis of NbEAS1 and NbEAS4 promoters revealed that AGACGCC (GCC box-like motif) is the essential cis-element required for INF1-induced expression of NbEAS genes. Given that the GCC box is known to be targeted by ERF (ethylene-responsive factor) transcription factors, we created a complete list of N. benthamiana genes encoding AP2/ERF family transcription factors, and identified 45 out of 337 AP2/ERF genes in the clusters for INF1-induced genes. Among INF1-induced NbERF genes, silencing of NbERF-IX-33 compromised resistance against P. infestans and INF1-induced production of capsidiol. Recombinant NbERF-IX-33 protein can bind to the promoter sequence of NbEAS4, suggesting that NbERF-IX-33 is a transcription factor directly regulating the expression of genes for phytoalexin production.

Plants recognize molecular patterns unique to a certain group of microbes to induce effective resistance mechanisms. Elicitins are secretory proteins produced by plant pathogenic oomycete genera including

Limited data are available on the survival and causes of death in pediatric patients with chronic kidney disease (CKD) stage 5 receiving kidney replacement therapy (KRT) in Asia.Data were obtained from the Japanese nationwide cross-sectional CKD stage 5 survey on pediatric patients (20 years of age) who started KRT from 2006 to 2013. The cohort was divided into three groups according to age at the start of KRT:1, 1-5, and 6-19 years.Among the 701 children who were included, 59.3% were boys. Peritoneal dialysis was the most common initial modality of KRT (60.3%). Median age at KRT initiation was 10.2 years. Infants (1 year old) accounted for 16.0% of the total cohort. Overall survival at 1 and 5 years was 97.2% and 92.5%, respectively. Infants had significantly lower survival rates than the other groups (hazard ratio, 5.35; 95% CI, 2.60-11.03; P0.001). In contrast, after the age of 1 year, the survival rate improved and did not differ from that of other age groups. The most common causes of death were infection (35.9%) and sudden death (15.4%).The overall survival rate of pediatric patients with CKD stage 5 in Japan is like that in other high-income countries. Age at initiation of KRT is an important factor affecting survival since the poorest survival rate was observed in infants. Further improvement in infant dialysis therapy is still needed to improve survival of the youngest children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Down syndrome (DS) is caused by the trisomy of chromosome 21. Among the many disabilities found in individuals with DS is an increased risk of early-onset Alzheimer's disease (AD). Although higher oxidative stress and an upregulation of amyloid β (Aβ) peptides from an extra copy of the APP gene are attributed to the AD susceptibility, the relationship between the two factors is unclear. To address this issue, we established an in vitro cellular model using neurons differentiated from DS patient-derived induced pluripotent stem cells (iPSCs) and isogenic euploid iPSCs. Neurons differentiated from DS patient-derived iPSCs secreted more Aβ compared to those differentiated from the euploid iPSCs. Treatment of the neurons with an antioxidant, N-acetylcysteine, significantly suppressed the Aβ secretion. These findings suggest that oxidative stress has an important role in controlling the Aβ level in neurons differentiated from DS patient-derived iPSCs and that N-acetylcysteine can be a potential therapeutic option to ameliorate the Aβ secretion., ダウン症患者さん由来の神経細胞からのアミロイドβ分泌は抗酸化剤で抑止される. 京都大学プレスリリース. 2021-08-31., Stopping dementia in Down syndrome patients. 京都大学プレスリリース. 2021-08-31.

Background The prevalence of overweight and obesity has increased not just in adults, but also in children. In Japan, percentage of overweight (POW) is widely used for the estimation and assessment of percent body fat (PBF) for children. We examine whether or not there is a difference between normal height and short stature children in terms of the relationship between POW and PBF. Methods A total of 321 children of normal height (163 boys, 158 girls) and 106 children with short stature (78 boys, 28 girls) were assessed according to sex. POW was used to represent the degree of obesity. PBF of the total body was examined by dual energy X-ray absorptiometry (DXA). Results According to their PBF examined by DXA, normal height subjects of both sexes were classified as obese if they had a POW of more than 20%, as per the definition. However, short stature subjects of both sexes were not classified as obese until the boys had a POW of 40%, and girls had a POW of 35%, respectively. Thus, overweight or obesity is overestimated in short stature children in both males and females with the rule "POW above 20% is recognized as obesity". Conclusion POW is commonly considered as a good surrogate measure to determine overweight and obesity in children of both sexes. However, this study has clarified that body fat accumulation is overestimated in children with short stature when using the POW measurement.

Aim School urine screening has been established in several countries of Asia, including Japan, Korea and Taiwan. In Osaka prefectural schools, the urine screening system had some problematic issues including an unclear referral procedure for students with abnormal urinary findings. Therefore, the school urine screening system was reviewed and restructured in 2004. The aim of this study was to assess the improvement in school urine screening through evaluation of the restructured Osaka prefectural school urinary screening system. Methods The Osaka prefectural school urinary screening system was reviewed, mainly considering two points. One was the incorporation of standard urinary protein/creatinine ratio measurement instead of the traditional urine dipstick and urine sediment tests; the second point was that all students requiring further examination were referred to regional nephrologists. Results After restructuring, the number of students who were referred to a medical institute for detailed examinations decreased to 10%, although the number of students newly diagnosed with kidney disease and the types of diagnosis did not change. The positive predictive value of screening increased to about 8 times the value before the system restructuring. The reductions enabled students who required further examination to be referred to regional nephrologists and has contributed to a decreased cost for these examinations. Conclusion Incorporating urinary protein/creatinine ratio measurement into the school urinary screening system, and updating the guiding principles, including referral to nephrology specialists, has enabled the school urinary screening system in Osaka Prefecture to become more efficient and have better cost performance.

Background:Cardiac dysfunction, arrhythmia, and hepatic fibrosis are well-known complications after right heart bypass surgery in patients with single-ventricle physiology. However, little is known about coronary arterial fistulae, and only a few reports have been published. This study aimed to elucidate the clinical characteristics of these rare coronary arterial fistulae that developed as complications in cases of single-ventricle physiology after right heart bypass surgery.Methods:We retrospectively investigated the clinical features and courses of patients who developed acquired and progressive coronary arterial fistulae after right heart bypass surgery in our hospital.Results:We identified three cases of coronary arterial fistulae out of 21 patients who underwent right heart bypass surgery. All three cases underwent cardiac catheterisation for post-operative evaluation and were administered pulmonary vasodilators of phosphodiesterase type V inhibitors, antiplatelet, anticoagulation, and diuretics. Moreover, they had common clinical features such as right-dominant single ventricle and long-term exposure to chronic hypoxia. Serial angiograms revealed acquired and progressive coronary arterial fistulae. In addition, coronary arterial fistulae contributed to their symptoms of heart failure.Conclusion:Patients with chronic hypoxia and dominant right ventricle, who are treated with phosphodiesterase type V inhibitors, should be followed up after right heart bypass surgery to monitor the possible development of coronary arterial fistulae. Moreover, the indication for pulmonary vasodilators in single-ventricle physiology after right heart bypass surgery should be optimised to avoid adverse effects.

The safety and efficacy of landiolol have not been fully elucidated in pediatric patients. This study aimed to clarify the safety and efficacy of landiolol in a pediatric cohort. We retrospectively assessed the clinical features of 21 pediatric patients who were administered landiolol at our hospital. We also investigated the rates of sinus rhythm conversion and heart rate response. The median patient age was 7 months (interquartile range 1–13 months). The etiology of tachyarrhythmia was junctional ectopic tachycardia in 10 patients (47.6%), atrial tachycardia in 10 patients (47.6%), and ventricular tachycardia in 1 patient (4.8%). Of the 21 children, 18 (85.7%) had congenital heart defects, including 14 (77.8%) in whom a landiolol infusion was performed perioperatively. The landiolol infusion was effective in 18 pediatric patients (85.7%), as measured by the conversion to sinus rhythm or a reduced heart rate. Atrial tachycardia in the perioperative period was terminated in all patients. Of 7 patients with tachyarrhythmias unrelated to the perioperative period, landiolol was effective in 5. No adverse effects were reported in any patient. Landiolol infusion is effective and safe in pediatric patients with tachyarrhythmia of various etiologies, especially those with atrial tachyarrhythmia during the perioperative period.

BACKGROUND The aim of this study was to assess the treatment response to conventional antiepileptic drugs and low-dose adrenocorticotropic hormone therapy for infantile spasms in children with Down syndrome. METHODS We retrospectively investigated the response and relapse rates, electroencephalography findings, patient characteristics during drug withdrawal, and developmental outcome in 10 children with Down syndrome treated for infantile spasms in our hospital. RESULTS All patients showed cessation of infantile spasms and achieved electroencephalographic normalization. Spasm relapse occurred in one of 10 patients (10%). Antiepileptic drugs have been withdrawn for seven of 10 patients (70%), none of whom have experienced seizure relapse since drug withdrawal. The median developmental quotient (n = 8) was 20.5, which shows that the developmental outcome was unfavorable. Low-dose adrenocorticotropic hormone therapy achieved a low seizure remission rate of 28.6%. CONCLUSIONS Elucidation of the optimal treatment for infantile spasms in children with Down syndrome is needed to reduce the duration of infantile spasms and improve the developmental outcome.

Objective Reversible splenium lesions during febrile illness (RESLEF) are found in a spectrum. There are two types of corpus callosum (CC) lesions: CC-only type, with limited lesions and the CC (+) type, with extensive white-matter lesions. This retrospective study aimed to describe the differences in clinical findings between CC-only and CC (+) lesions and the association between onset age and clinico-radiological features in RESLEF. Methods Fifty-two episodes of CC-only or CC (+) lesions accompanied by neurological symptoms, e.g., seizures, delirious behavior (DB), and disturbance of consciousness (DC), from January 2008 to October 2019 were included. We analyzed the etiology (pathogen), clinical course, laboratory data, magnetic resonance imaging and electroencephalography findings, therapy, and prognosis. Results The rate of DC in the CC (+) was significantly higher than that in the CC-only group (5/6 [83%] vs 7/46 [15%]; p = 0.0016). The median number of seizures in the CC (+) was also significantly higher than that in the CC-only group (4 [0–7] vs 0 [0–7]; p = 0.034). Further, in RESLEF, the median onset age (months) in the seizure was significantly lower than that in the no-seizure group (39 [12–74] vs 83 [28–174]; p = 0.0007). The median onset age (months) in the DB was significantly higher than that in the no-DB group (74.5 [26–174] vs 28 [12–139]; p = 0.003). Conclusions In RESLEF, CC (+) is a more severe neurological symptom than CC-only. Furthermore, the onset age is related to the type of neurological symptoms that appear.

Background Brain abscesses are relatively rare, but they are a potentially life-threatening condition. Predictive factors for poor outcome are a young age and the presence of multiple abscesses. We report a case of a 15-month-old girl with cyanotic congenital heart disease who developed multiple brain abscesses caused by Streptococcus intermedius. The patient was treated with a combination of surgical aspiration and antimicrobial therapy without apparent neurological sequelae. To the best of our knowledge, this is the youngest such patient to have been reported in the literature. We explore the possible causes of her good outcome. Case presentation At the age of 15 months, the Japanese patient initially was presented to our hospital with transient eye deviation to the left and vomiting. In a blood examination, her white blood cell count (12,720 per mm3 with a left shift) and C-reactive protein level (1.23 mg/ml) were slightly elevated. Magnetic resonance imaging of the brain showed three mass lesions. These were 1.5-cm, 1.9-cm, and 1.2-cm rim-enhancing lesions with extensive surrounding edema. Brain abscesses were diagnosed, and vancomycin (50 mg every 12 hours) and meropenem (40 mg every 8 hours) were started empirically. However, because each brain abscess was enlarged at 8 days after admission, surgical aspiration was performed at 10 days after admission, and cultures of the aspirated pus grew S. intermedius. Penicillin G (0.7 million units every 4 hours) and ceftriaxone (280 mg every 12 hours), to which this isolate is susceptible, were then administered, and the brain abscesses reduced in size. After 1 month of ceftriaxone and 3 months of penicillin G treatment, all of the brain abscesses disappeared. Apparent neurological sequelae were not observed at 6 months after onset. Conclusions A good outcome can be obtained if multiple brain abscesses develop in infancy or early childhood in cases without unconsciousness at admission, meningitis, or sepsis. Appropriate antimicrobial therapy should be started immediately after diagnosis, with surgical aspiration performed to identify the causative pathogen and avoid intraventricular rupture of the brain abscesses.

To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P=4.94E-20, odds ratio (OR) =1.90) and TNFSF15 (rs6478109, P=2.54E-8, OR=0.72) regions achieved genome-wide significance and were replicated in Korean, South Asian and African populations. Trans-ethnic meta-analyses including Japanese, Korean, South Asian, African, European, Hispanic and Maghrebian populations confirmed the significant associations of variants in NPHS1-KIRREL2 (P(meta)=6.71E-28, OR=1.88) and TNFSF15 (P(meta)=5.40E-11, OR=1.33) loci. Analysis of the NPHS1 risk alleles with glomerular NPHS1 mRNA expression from the same person revealed allele specific expression with significantly lower expression of the transcript derived from the risk haplotype (Wilcox test p=9.3E-4). Because rare pathogenic variants in NPHS1 cause congenital nephrotic syndrome of the Finnish type (CNSF), the present study provides further evidence that variation along the allele frequency spectrum in the same gene can cause or contribute to both a rare monogenic disease (CNSF) and a more complex, polygenic disease (SSNS).

SIGNIFICANCE Our study revealed that the validity of a new Japanese visual-perceptual test was acceptable. Visual-perceptual abilities are important to activities of daily living; thus, accurate assessment of visual perception is especially important for children with neurodevelopmental disorders and particularly so for those with learning problems. PURPOSE Visual perception refers to the process by which one receives visual information through sensory impulses and then translates those impulses into meaning based on a previously developed view of the environment. A problem in Japan is the paucity of visual perception tests that use normative data from children who are native Japanese. The Wide-range Assessment of Vision-related Essential Skills (WAVES), which measures visual perception and eye-hand coordination skills and is based on Japanese normative data, was recently published in Japan. The validity of this test has not been comprehensively established. METHODS To investigate the validity of the WAVES, we used the Pearson correlation coefficient to calculate the degrees of association among WAVES scaled and index scores compared with Developmental Test of Visual Perception, Third Edition, scores from 108 elementary school children with symptoms of learning problems. Participants were recruited at Osaka Medical College Learning Disability Center and Sakai Seikeikai Learning Disability Center. RESULTS The concurrent validity of the WAVES was supported by moderate correlation (r = 0.67, P < .01) between the total scores for visual perception and eye-hand coordination index from the WAVES and general visual perception index from the Developmental Test of Visual Perception, Third Edition, even though a correlation analysis of subtests found differences between the two tests. CONCLUSIONS Our results showed that the indices from the two tests measured nearly the same underlying visual-perceptual constructs and indicated that the WAVES had acceptable levels of concurrent validity.