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Purpose: Patients with inborn errors of immunity (IEI) manifest various initial symptoms; however, those that are critical for the early diagnosis of IEI have not been identified. Also, the significance of the ten warning signs of primary immunodeficiency (PID) among infants has not been established. This study aimed to conduct a nationwide survey of IEI in Japan and investigated the initial manifestations based on onset age. Methods: Among 1,298 patients, data regarding the initial manifestation were available from 505 patients. Patients with autoinflammatory diseases, complement deficiency, and phenocopies of IEI were excluded. Results: The ten warning signs were positive in 67.3 % of the cases. The positivity rate was low (20.5 %) in patients with immune dysregulation. Although the positivity rate was low (36.6 %) in patients aged less than 3 months, they were highly positive for family history of IEI (26.8 %). Infectious symptoms were the most commonly observed in all age groups and in all disease categories. Symptoms of “immune dysregulation” were present in approximately 15 % of the patients. Regarding the anatomical category, almost all initial symptoms were “systemic” infections in patients with X-linked severe combined immunodeficiency. Moreover, “respiratory” symptoms were the most common in patients with IEI aged ≥ 1 year and accounted for more than 50 % in all age groups in patients with common variable immunodeficiency. Conclusion: These results highlight the significance of the 10 warning signs and may serve as clinical indicators for early diagnosis, considering the initial presentation of IEI.

CTR9 is one of five genes that form the PAF1 complex, which binds to RNA polymerase II and plays critical roles in transcriptional elongation and transcription-coupled histone modifications including histones H3K4me3 and H3K36me3. In this study, de novo CTR9 non-synonymous variants (p.(Glu15Asp) and p.(Pro25Arg)) were detected in two unrelated patients with macrocephaly, motor delay, and intellectual disability. A pull-down assay showed that the mutant CTR9 proteins had stronger affinities to the PAF1 protein than the wild-type protein. Functional analyses using zebrafish showed that the knockout of the ctr9 gene caused motor defects and enlargement of the telencephalon, which is homologous to the mammalian cerebrum. The rescue experiment, in which the human CTR9 mutants were introduced into ctr9-knockout zebrafish, failed to maintain the swimming posture of the ctr9-knockout fish, suggesting that the human CTR9 mutant proteins do not function normally in vivo. In addition, the overexpression of human CTR9 mutant mRNA caused telencephalon enlargement in zebrafish larvae, suggesting that the human CTR9 mutant proteins interfered with normal endogenous CTR9 function. We concluded that the two missense variants in CTR9 (p.(Glu15Asp) and p.(Pro25Arg)) cause a new syndrome involving macrocephaly, motor delay and intellectual disability through the loss of the normal function of CTR9 and the inhibition of the normal intrinsic CTR9 function of the contralateral allele.

Background Kawasaki disease (KD), which was first described by Tomisaku Kawasaki in 1967, is a syndrome that results in acute systemic vasculitis, affecting mainly infants and children, and is a major cause of acquired heart disease in developed countries. KD is diagnosed based on certain characteristic symptoms and echocardiogram results. It has been reported that neck and abdominal ultrasound is also reliable diagnostic method. Nevertheless, abdominal ultrasound is not a routine procedure in KD. Moreover, dilatation of the common bile duct (CBD) has been rarely reported in previous cases. Case presentation: A 4-year-old boy presented with fever and markedly high transaminase level (AST, 5,323 U/L, ALT, 1,554 U/L). The patient was diagnosed as having KD based on characteristic symptoms and echocardiogram findings. Neck and abdominal ultrasound revealed dilatation of the CBD as well as cervical lymphadenopathy resembling a cluster of grapes, thickening of the gallbladder wall, and increased periportal echogenicity throughout the liver parenchyma. The patient received initial treatment with intravenous immunoglobulin (IVIG) at day 4 of fever, following which, transaminase level decreased. The patient received second-line treatment with IVIG and prednisolone because of recurrent fever on day 6. Dilatation of the CBD was improved from 6.6 mm on day 4 to 3.1 mm on day 8. Although re-dilatation was observed, it gradually diminished and normalized (4.3 mm on day 28, 4.0 mm on day 63, 3.3 mm on day 105, and 2.8 mm on day 182). Conclusion This case highlights the usefulness of abdominal ultrasound and the importance of considering dilatation of the CBD as one of the complications of KD. Because abdominal ultrasound is not a routine procedure in KD, it is possible that dilatation of the CBD in KD is quite latent if not investigated thoroughly. Further prospective studies to support these findings are warranted.

Thin, metallic wires can easily penetrate the gastrointestinal system if ingested and cause serious cardiac issues in children. We report a pediatric case of such an object that caused cardiac tamponade after lodging in the left ventricle. The wire was extracted without cardiopulmonary bypass and a full recovery was made. Cardiac issues after ingestion of foreign objects are rare but immediate surgery is required for resolution.

We note the risk of paradoxical embolism in patients with congenital heart defects with a right‐to‐left shunt. These patients should be managed to ensure that abdominal aortic thrombi are not overlooked when their clinical conditions change.

Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A) gene mutation. Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with severe motor dysfunction. Here, we report an 8-year-old boy with CDCBM3 showing a typical, but relatively mild, clinical presentation of CDCBM3 features. Whole-exome sequencing identified a heterozygous mutation of NM_001098511.2:c.1298C>A [p.(Ser433Tyr)]. To our knowledge, the mutation has never been reported previously. The variant was located distal to the nucleotide binding domain (NBD), in which previously-reported variants in CDCBM3 patients have been located. The computational structural analysis showed the p.433 forms the pocket with NBD. Variants in KIF2A have been reported in the NBD for CDCBM3, in the kinesin motor 3 domain, but not in the NBD in epilepsy, and outside of the kinesin motor domain in autism spectrum syndrome, respectively. Our patient has a variant, that is not in the NBD but at the pocket with the NBD, resulting in a clinical features of CDCBM3 with mild symptoms. The clinical findings of patients with KIF2A variants appear restricted to the central nervous system and facial anomalies. We can call this spectrum "KIF2A syndrome" with variable severity.

Juvenile polyposis syndrome (JPS) is one of the hereditary polyposis syndromes caused by abnormal regulation of transforming growth factor β signaling because of mutations in BMPR1A and SMAD4. Juvenile polyposis syndrome patients with SMAD4 mutations develop cardiovascular events, whereas those with BMPR1A usually do not. Analysis of genetic mutations in JPS patients can be helpful in devising suitable strategies for medical management. In this study, we demonstrate the pathogenicity of a novel intronic mutation in BMPR1A using mRNA extracted from colonic mucosa of a boy with JPS.Genomic DNA extracted from peripheral blood and total RNA isolated from the colonic mucosa were used for DNA sequencing and reverse transcription polymerase chain reaction (RT-PCR) analyses, respectively.A 13-year-old boy, with no previous medical history, presented to the hospital complaining of bloody stools. Colonoscopy revealed multiple polyps in the colon, and the resected polyps were compatible with juvenile polyps. Sequencing analysis revealed a novel intronic mutation (c.778+5GC) in BMPR1A. Reverse transcription polymerase chain reaction analysis of RNA extracted from the colonic mucosa showed an aberrant splicing form of BMPR1A. Trio analysis showed that his mother also had the same BMPR1A mutation. She was diagnosed with cancer of the cecum and polyposis of the colon at the age of 41.We demonstrate the presence of a novel BMPR1A intronic mutation that exhibits splicing abnormality in a family with JPS. Further research and development will help elucidate the genotype-phenotype relationship in JPS.

The etiology of multiple inflammatory syndrome in children (MIS-C) remains poorly understood. As clues to elucidate the pathogenic condition, several characteristic peripheral immunophenotypes have been reported in MIS-C. However, no report has demonstrated the time course of the peripheral immunophenotype along with the clinical course in the same patient. Herein, we clarified the immunological characteristics of a Japanese patient with MIS-C. There was an initial cytokine storm followed by T-cell activation, especially of CD8

Background The antibody response after pneumococcal vaccines and their effectiveness against invasive pneumococcal disease (IPD) in patients with interleukin-1 receptor-associated kinase 4 (IRAK4) deficiency have not been fully evaluated. Here, we evaluated pneumococcal serotype-specific opsonophagocytic activity (OPA) in IRAK4-deficient patients along with their clinical course. Methods We investigated 6 IRAK4-deficient patients in Japan, whose attending physicians could be contacted. We performed OPA measurements using stored and more recent serum samples obtained from these patients. Results All patients had received pneumococcal vaccination. Among the 3 patients who had IPD, 2 had an episode of pneumococcal meningitis and the other developed pneumococcal bacteremia 3 years after the occurrence of pneumococcal meningitis. Only one episode of invasive bacterial infection was caused by a Streptococcus pneumoniae vaccine-type strain. An increased opsonization index was found in the sera after vaccination for all IRAK-deficient patients, including when the 23-valent pneumococcal polysaccharide vaccine was used. Conclusions A significant increase in levels of OPA against most of the pneumococcal vaccine antigens was observed for all IRAK4-deficient patients. However, IPD could not be prevented by pneumococcal vaccination alone. Therefore, adequate prophylaxis should be provided with antibiotics at least until 8 years of age, along with regular immunoglobulin therapy, particularly during the infantile period.

Recent studies have reported that pediatric acute liver failure of unknown origin is immune-mediated, with CD8

We conducted a nationwide survey of inborn errors of immunity (IEI) in Japan for the second time in 10 years, focusing on protective measures for IEI patients against infectious diseases. Questionnaires were sent to various medical departments nationwide, and a total of 1307 patients were reported. The prevalence of IEI was 2.2 patients per 100,000 population, which was comparable with the previous nationwide study. The most common disease category was autoinflammatory disorders (25%), followed by antibody deficiencies (24%) and congenital defects of phagocyte number or function (16%). We found that a significant number of patients received contraindicated vaccines, principally because the patients were not diagnosed with IEI by the time of the vaccination. Regarding diseases for which BCG vaccination is contraindicated, 43% of patients had actually received BCG, of which 14% developed BCG-related infections. BCG-related infections were mainly observed among patients with CGD and MSMD. In order to prevent IEI patients from receiving inadequate vaccines, continuous education to parents and physicians is needed, along with the expansion of newborn screening, but efforts to screen IEI at the site of vaccination also remain important.

We report a patient with autism and cleft lip and palate carrying a de novo heterozygous AUTS2 mutation, c.1464_1467del ACTC (p.Tyr488*). Although the causal relationship between cleft lip and palate and this mutation is unclear, this case report may expand the clinical phenotype of AUTS2 syndrome.

To delineate the diagnostic efficacy of medical exome, whole exome, and whole genome sequencing according to primary symptoms, the contribution of small copy number variations, and the impact of molecular diagnosis on clinical management.This was a prospective study of 17 tertiary care centers in Japan, conducted between April 2019 and March 2021. Critically ill neonates and infants less than 6 months of age were recruited in neonatal intensive care units and in outpatient clinics. The patients underwent medical exome, whole exome, or whole genome sequencing as the first tier of testing. Patients with negative results after medical exome or whole exome sequencing subsequently underwent whole genome sequencing. The impact of molecular diagnosis on clinical management was evaluated through contacting primary care physicians.Of the 85 patients, 41 (48%) had positive results. Based on the primary symptoms, patients with metabolic phenotypes had the highest diagnostic yield (67%, 4/6 patients), followed by renal (60%, 3/5 patients), and neurologic phenotypes (58%, 14/24 patients). Among them, 4 patients had pathogenic small copy number variations identified using whole genome sequencing. In the 41 patients with a molecular diagnosis, 20 (49%) had changes in clinical management.Genome analysis for critically ill neonates and infants had a high diagnostic yield for metabolic, renal, and neurologic phenotypes. Small copy number variations detected using whole genome sequencing contributed to the overall molecular diagnosis in 5% of all the patients. The resulting molecular diagnoses had a significant impact on clinical management.

Gastrointestinal endoscopy is fundamental to diagnostic and therapeutic procedures in pediatric gastroenterology. In the decades since endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) for hepatobiliary and pancreatic disease were introduced into clinical practice, there has been increasing interest in these procedures, and practice guidelines and position papers that clearly define the role of ERCP and EUS in children have been published. Based on the distinction of endoscopy between children and adults, this review focuses on the current state of ERCP and EUS procedures in children, including the types of endoscopes used in children, general anesthesia and radiation exposure, biliary and pancreatic indications, considerations of education and training for ERCP and EUS procedures in children, and expectations for development of endoscopes for children.

Cortical dysplasia, complex, with other brain malformations 3 (CDCBM3) is a rare autosomal dominant syndrome caused by Kinesin family Member 2A (KIF2A) gene mutation. Patients with CDCBM3 exhibit posterior dominant agyria/pachygyria with severe motor dysfunction. Here, we report an 8-year-old boy with CDCBM3 showing a typical, but relatively mild, clinical presentation of CDCBM3 features. Whole-exome sequencing identified a heterozygous mutation of NM_001098511.2:c.1298CA [p.(Ser433Tyr)]. To our knowledge, the mutation has never been reported previously. The variant was located distal to the nucleotide binding domain (NBD), in which previously-reported variants in CDCBM3 patients have been located. The computational structural analysis showed the p.433 forms the pocket with NBD. Variants in KIF2A have been reported in the NBD for CDCBM3, in the kinesin motor 3 domain, but not in the NBD in epilepsy, and outside of the kinesin motor domain in autism spectrum syndrome, respectively. Our patient has a variant, that is not in the NBD but at the pocket with the NBD, resulting in a clinical features of CDCBM3 with mild symptoms. The clinical findings of patients with KIF2A variants appear restricted to the central nervous system and facial anomalies. We can call this spectrum "KIF2A syndrome" with variable severity.

Alagille syndrome is an inherited multisystemic disorder. We herein report an atypical case of a Japanese adult patient with Alagille syndrome. He had been diagnosed with Alagille syndrome as an infant based on a liver biopsy. At 27 years of age, he needed to start hemodialysis therapy, but an arteriovenous fistula was not created because his peripheral blood vessels were too narrow. He also had a recurrent brain infarction due to cerebral vascular stenosis. Alagille syndrome is generally recognized as a pediatric hepatic disease, but general physicians should be aware of its potential existence with renal involvement and vascular abnormalities.

The function of hepatocytes largely depends on their position in the liver lobule. Although the method of differentiating hepatocytes from human pluripotent stem cells has been largely improved over the past decade, there remains no technique for generating hepatocyte-like cells (HLCs) with zone-specific hepatic properties. In this study, we searched for the factors that promote acquisition of zone-specific properties of HLCs. Here, we identified that WNT7B and WNT8B secreted from hepatocytes and cholangiocytes play important roles in achieving perivenous zone-specific characteristics, such as the enhancement of glutamine secretion, citric acid cycle, cytochrome P450 (CYP) 1A2 metabolism, and CYP1A2 induction capacities. We also found that WNT inhibitory factor (WIF-1) secreted from cholangiocytes was necessary for achieving periportal zone-specific characteristics, such as the enhancement of urea secretion and gluconeogenesis capacities. Therefore, WNT signal modulators secreted from hepatocytes or cholangiocytes conferred zone-specific hepatic properties onto HLCs.

Aim Bile salt export pump (BSEP) deficiency manifests a form of progressive intrahepatic cholestasis. This study aimed to establish a scoring system of liver histology for the uncommon genetic condition. Methods After a roundtable discussion and histology review, a scoring system for BSEP deficiency was established. Eleven tissue samples were independently evaluated by three pathologists based on the proposed standard for an interobserver agreement analysis. In four cases with serial tissue samples available, correlation between changes in histology scores and clinical outcome was examined. Results Of 14 initially listed histopathological findings, 12 were selected for scoring and grouped into the following four categories: cholestasis, parenchymal changes, portal tract changes and fibrosis. Each category consisted of two to four microscopic findings that were further divided into three to six scores; therefore, each category had a maximum score of 8-11. Interobserver agreement was highest for pericellular fibrosis (κ = 0.849) and lowest for hepatocellular cholestasis (κ = 0.241) with the mean and median κ values of the 12 parameters being 0.561 and 0.602, respectively. For two patients whose clinical features worsened, score changes between two time points were interpreted as deteriorated. In two patients, who showed a good clinical response to preprandial treatment with sodium 4-phenylbutyrate, histological changes were evaluated as improved or unchanged. Conclusions The proposed histology-based scoring system for BSEP deficiency with moderate interobserver agreement may be useful not only for monitoring microscopic changes in clinical practice but also for a surrogate endpoint in clinical trials.

Phosphatase and tensin homolog (PTEN) plays an important role in tumor suppression. A germline mutation in the PTEN gene induces not only PTEN hamartoma tumor syndrome, including Cowden syndrome, but also macrocephaly/autism syndrome. Here, we describe a boy with macrocephaly/autism syndrome harboring a novel missense heterozygous PTEN mutation, c.959T>C (p.Leu320Ser). Interestingly, a previously reported nonsense mutation resulting in p.Leu320X was found in Cowden syndrome patients. Our case may be suggestive of a genotype-phenotype correlation.

Phosphatase and tensin homolog (PTEN) plays an important role in tumor suppression. A germline mutation in the PTEN gene induces not only PTEN hamartoma tumor syndrome, including Cowden syndrome, but also macrocephaly/autism syndrome. Here, we describe a boy with macrocephaly/autism syndrome harboring a novel missense heterozygous PTEN mutation, c.959T>C (p.Leu320Ser). Interestingly, a previously reported nonsense mutation resulting in p.Leu320X was found in Cowden syndrome patients. Our case may be suggestive of a genotype-phenotype correlation.

The pharmacokinetics among children has been altered dynamically. The difference between children and adults is caused by immaturity in things such as metabolic enzymes and transport proteins. The periods when these alterations happen vary from a few days to some years after birth. We hypothesized that the effect of gene polymorphisms associated with the dose of medicine could be influenced by age. In this study, we analyzed 51 patients with childhood acute lymphoblastic leukemia (ALL) retrospectively. We examined the associations between the polymorphism in NUDT15 and clinical data, especially the dose of 6-mercaptopurine (6-MP). Ten of the patients were heterozygous for the variant allele in NUDT15. In patients under 7 years old with NUDT15 variant allele, the average administered dose of 6-MP was lower than that for the patients homozygous for the wild-type allele (P=0.04). Genotyping of NUDT15 could be a beneficial to estimate the tolerated dose of 6-MP for patients with childhood ALL, especially at a preschool age in Japan. Furthermore, the analysis with stratification by age might be useful in pharmacogenomics among children.

Schuurs-Hoeijmakers syndrome is a rare disease characterized by intellectual disability and dysmorphic facial features among various physical abnormalities due to PACS1 mutation. To date, 28 patients with a recurrent de novo PACS1 mutation (c.607C > T) have been reported, primarily in Western populations. Here, we describe two Japanese patients with Schuurs-Hoeijmakers syndrome with a recurrent PACS1 mutation. In addition to the typical clinical symptoms, each patient presented novel clinical phenotypes. One patient presented with involuntary movements and was treated with trihexyphenidyl hydrochloride. We hypothesized that the PACS1 mutation leads to an inherent dopaminergic insufficiency that underlies the developing symptoms along with the neurodevelopmental processes. The second patient was diagnosed with lipomyelomeningocele during an examination for severe constipation at the age of 2 years and 8 months. The diagnosis of lipomyelomeningocele in this patient was delayed due to the lack of cutaneous lesions. As the majority of patients with PACS1 mutation present constipation, underdiagnosis of lipomyelomeningocele is a possibility. As the phenotypic expansion of the patients with Schuurs-Hoeijmakers syndrome was not fully recognized, additional studies are needed to clarify the clinical spectrum.

Aim To assess the feasibility of transferring to the University of Tsukuba Hospital for proton beam therapy (PBT) during intensive chemotherapy in children with Ewing sarcoma family of tumors (ESFT) who had been diagnosed and started their first-line treatment at prefectural or regional centers for pediatric oncology. Background The treatment of ESFT relies on a multidisciplinary approach using intensive neoadjuvant and adjuvant chemotherapies with surgery and radiotherapy. Multi-agent chemotherapy comprising vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide (VDC-IE) is widely used for ESFT, and the interval between each course is very important for maintaining the intensity and effect of chemotherapy. Materials and methods Clinical information of patients who received PBT and VDC-IE between April 2009 and May 2016 was collected retrospectively. The intervals between each course of VDC-IE and adverse events were assessed. Results Fifteen patients were evaluated. No delays in the intervals of chemotherapy due to transfer were observed. There were no adverse events caused during/just after transfer and no increases in adverse events. The estimated 4-year overall and event-free survival rates were 94.6% and 84.8%, respectively. Discussion Although the results of efficacy are preliminary, survival rates were comparable with past studies. More experience and follow-up are required to further assess the efficacy of PBT for patients with ESFT. Conclusion Multidisciplinary therapy for children with ESFT involving transfer to our hospital for PBT during VDC-IE was feasible without treatment delay or an increase in adverse events.

We report a 10-year-old girl with Bardet–Biedl syndrome caused by a novel mutation in the Bardet–Biedl syndrome 10 (BBS10) gene. She had multiple malformations, including a dysmorphic face, postaxial polydactyly, polycystic kidney and amblyopia. She presented with typical BBS features, including intellectual disability with emotional outbursts and mild obesity. Whole-exome sequencing identified compound heterozygous mutations with NM_024685.3:c.1677C>A [p.(Tyr559*)] and c.1974T>G [p.(Tyr658*)]. To our knowledge, the latter mutation has never been reported previously.

The bile salt export pump (BSEP) plays an important role in biliary secretion. Mutations in ABCB11, the gene encoding BSEP, induce progressive familial intrahepatic cholestasis type 2 (PFIC2), which presents with severe jaundice and liver dysfunction. A less severe phenotype, called benign recurrent intrahepatic cholestasis type 2, is also known. About 200 missense mutations in ABCB11 have been reported. However, the phenotype-genotype correlation has not been clarified. Furthermore, the frequencies of ABCB11 mutations differ between Asian and European populations. We report a patient with PFIC2 carrying a homozygous ABCB11 mutation c.386G>A (p.C129Y) that is most frequently reported in Japan. The pathogenicity of BSEPC129Y has not been investigated. In this study, we performed the molecular analysis of this ABCB11 mutation using cells expressing BSEPC129Y. We found that trafficking of BSEPC129Y to the plasma membrane was impaired and that the expression of BSEPC129Y on the cell surface was significantly lower than that in the control. The amount of bile acids transported via BSEPC129Y was also significantly lower than that via BSEPWT. The transport activity of BSEPC129Y may be conserved because the amount of membrane BSEPC129Y corresponded to the uptake of taurocholate into membrane vesicles. In conclusion, we demonstrated that c.386G>A (p.C129Y) in ABCB11 was a causative mutation correlating with the phenotype of patients with PFIC2, impairment of biliary excretion from hepatocytes, and the absence of canalicular BSEP expression in liver histological assessments. Mutational analysis in ABCB11 could facilitate the elucidation of the molecular mechanisms underlying the development of intrahepatic cholestasis.

Wiedemann-Steiner syndrome (WDSTS) is an autosomal dominant disorder characterized by hypertrichosis, intellectual disability, and dysmorphic facial appearances (down-slanted vertically narrow palpebral fissures, wide nasal bridge, broad nasal tip, and thick eyebrows). In 2012, Jones and co-workers identified heterozygous mutations in KMT2A (lysine methyltransferase 2A) as the molecular cause of WDSTS. Although the phenotype of this syndrome continues to expand, the associated features are not fully understood. Here, we report WDSTS in a 12-year-old Japanese boy with a novel nonsense mutation in KMT2A. He had right preaxial polydactyly, which has not been previously reported in WDSTS. We could not identify a causal relationship between the KMT2A mutation and preaxial polydactyly, and cannot exclude the preaxial polydactyly is a simple coincidence. We summarized the clinical features of WDSTS associated with KMT2A mutation and discussed the cardinal symptoms in detail.

We report a 10-year-old girl with Bardet–Biedl syndrome caused by a novel mutation in the Bardet–Biedl syndrome 10 (BBS10) gene. She had multiple malformations, including a dysmorphic face, postaxial polydactyly, polycystic kidney and amblyopia. She presented with typical BBS features, including intellectual disability with emotional outbursts and mild obesity. Whole-exome sequencing identified compound heterozygous mutations with NM_024685.3:c.1677C>A [p.(Tyr559*)] and c.1974T>G [p.(Tyr658*)]. To our knowledge, the latter mutation has never been reported previously.

To assess the safety and efficacy of infliximab (IFX) for the treatment of patients with Kawasaki disease (KD).This was a nationwide survey of 274 Japanese institutions exploring how IFX was used to treat patients with KD. The patients' sex, age, treatment course, pre- and post-IFX therapy blood test results, coronary artery lesions (CALs), and adverse events (AEs) were evaluated.We analyzed 434 patients with KD who received IFX between March 2005 and November 2014. The median age at onset was 33 months (range 1-138), and 66 patients (15.2%) were under 1 year old. In all cases, IFX was administered as additional treatment. The median days of illness at the initiation of IFX was 9 days. In 275 patients (63.4%), IFX was administered as third-line treatment, and in 106 patients (24.4%), IFX was administered as fourth-line treatment. Single dose IFX 5 mg/kg was administered to 412 patients (94.9%). After IFX, 363 patients (83.6%) became afebrile within 2 days, and the white blood cell count, percentage of neutrophils, and serum C-reactive protein levels significantly decreased (P .001), although 119 patients (27.4%) received additional treatment. Before IFX, 132 patients (30.4%) had already developed CALs. In patients without CALs before IFX, 31 patients (10.3%) newly developed CAL after IFX, whereas 32 patients (24.2%) with CAL before IFX showed increased CAL severity. Eighty AEs were observed in 69 patients (15.9%); however, serious AEs were few and reversible.IFX might be an effective and tolerable treatment for refractory KD.

A thermal spraying process contains various individual and fundamental processes. Among them, the flattening process is important and governs the quality of sprayed coatings. Therefore the flattening behaviors of spraying particles must be clearly understood. Ceramic and metal particles are generally sprayed onto the roughened substrates to enhance the adhesion strength of the coatings in plasma spraying technique. This report describes the flattening profile of the metal droplets impinging on the roughened substrates. Introducing the unevenness ratio, the droplet profile is evaluated with respect to surface roughness of the substrate surfaces, R e and W e numbers. The experimental results show that the unevenness ratio increases with surface roughness of the substrates. Under the droplets of almost the same size the unevenness ratio has a bilinear relationship with the impinging velocity, R e and W e numbers. Defining this corner point by a critical value of the droplets, the splat behaves the splash-like shape above the critical point. It was concluded that the critical value is influenced not only by the flattening parameters, but also by the surface roughness of the substrates.

Interindividual differences in hepatic metabolism, which are mainly due to genetic polymorphism in its gene, have a large influence on individual drug efficacy and adverse reaction. Hepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem (iPS) cells have the potential to predict interindividual differences in drug metabolism capacity and drug response. However, it remains uncertain whether human iPSC-derived HLCs can reproduce the interindividual difference in hepatic metabolism and drug response. We found that cytochrome P450 (CYP) metabolism capacity and drug responsiveness of the primary human hepatocytes (PHH)-iPS-HLCs were highly correlated with those of PHHs, suggesting that the PHH-iPS-HLCs retained donor-specific CYP metabolism capacity and drug responsiveness. We also demonstrated that the interindividual differences, which are due to the diversity of individual SNPs in the CYP gene, could also be reproduced in PHH-iPS-HLCs. We succeeded in establishing, to our knowledge, the first PHH-iPS-HLC panel that reflects the interindividual differences of hepatic drug-metabolizing capacity and drug responsiveness.

Proportional-Integral-Derivative (PID) control has been most commonly used to operate mechanical systems. In PID control, however, there are limits to the accuracy of the resulting movement because of the influence of gravity, friction, and interaction of joints. We have proposed a digital acceleration control (DAC) that is robust over these modeling errors. One of the most practicable advantages of DAC is robustness against modeling errors. However, it does not always work effectively. If there are modeling errors in the inertia term of the model, the DAC controller cannot control a mechanical system properly. Generally an inertia term is easily modeled in advance, but it has a possibility to change. Therefore, we propose an online estimation method of an inertia term by using a system identification method. By using the proposed method, the robustness of DAC is considerably improved. This paper shows the simulation results of the proposed method using 2-link manipulator.Copyright © 2010 by ASME