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The microstructures of brazing porous Nickel (Ni) to copper and stainless steel (Cu/Porous Ni/SS304) was investigated. A porous Ni with pore densities of 15 PPI (pores per inch) and filler with compositions of 72Ag-28Cu and 77.4Cu-9.3Sn-7P-6.3Ni (Ag: Silver; Cu: Copper; Sn: Tin; P: Phosphorus; Ni: Nickel) were employed. The brazing process was conducted at different brazing temperatures: 830˚C, 870˚C and 910˚C for 15 minutes brazing time with heating and cooling rate of 10˚C/min, respectively. The aim of this research is to analyse and compare the microstructure of using different types of filler metal in order for joint porous Ni to copper and stainless steel. According to the initial observations from an optical microscope (OM) after cross-section, the used of filler metal BAg-8 and VZ2250 acquired a bonding joining than the used of filler metal BAg-8 solely. Thus, Field Emission Scanning Electron Microscope (FESEM) equipped with Energy Dispersive X-Ray Spectroscopy (EDS) was used to characterise the bonding of microstructure of filler metal BAg-8 and VZ2250. Besides, the joint strength of Cu/Porous Ni/SS304 with filler metal BAg-8 and VZ2250 was evaluated with shear strength at different brazing parameters. Consequently, it can be concluded that used of filler metal BAg-8 and VZ2250 performed a better joint microstructure as compared to the used solely of filler metal BAg-8.

In this study, the synergetic effect of multi-walled carbon nanotubes (MWCNTs) and porous Cu interlayer (PCI) on the intermetallic compound (IMC) formation and shear strength of Sn–3.0Ag–0.5Cu (SAC 305) solder system was investigated. The solder joints were prepared by subjecting two different series of MWCNTs-reinforced SAC 305 solder systems (i.e., SAC–0.01CNT and SAC–0.04CNT) sandwiched with porous Cu interlayer having pores per inch (PPI) of 15, 25 and 50 to reflow soldering on Cu substrate. Electron microscopy and spectroscopy techniques were used to view and detect the intermetallic compound phases, respectively. The scallop-shaped Cu6Sn5 IMC phase was observed at the solder/PCI interface, while on the other hand, an additional layer-type Cu3Sn IMC phase formed alongside the Cu6Sn5 IMC at the solder/Cu interface. Given the promising properties of PCI material, empirical findings showed that the presence of PCI in the solder joint inhibited the formation of interfacial IMC layer at the solder/Cu substrate with the SAC–0.01CNT–25PCI exhibiting the least IMC thickness. More so, the PCI material effectively enhanced the shear strength of the MWCNTs-reinforced composite solder joints. Generally, the strengthening capacity of the PCI material was greatly underscored in the SAC–0.01CNT–xPCI series with the sample prepared with PCI of 15 PPI demonstrating the superior shear strength of 21.1 MPa.

Although acute poststreptococcal glomerulonephritis (APSGN) and acute rheumatic fever (ARF) are well-known complications of group A streptococcus infection, concomitant occurrence of both diseases is rare. We report an 11-year-old Japanese girl with primary Sjögren's syndrome complicated by acute renal failure about 2 weeks after the onset of pharyngitis. Although histopathological findings of the kidney were not confirmative, APSGN was suggested by the spontaneous recovery of her renal function, typical latent period with high levels of antistreptolysin O and low serum levels of C3 but not of C4. In addition, cardiac hypomotility and regurgitation of the 4 valves progressed in the convalescent phase of APSGN, which was accompanied by elevation of serum C-reactive protein and plasma brain natriuretic peptide (BNP) levels. Myocarditis was suggested by delayed gadolinium-enhancement of cardiac walls on cardiac magnetic resonance imaging. She was diagnosed with APSGN and ARF and was treated with a combination of short course prednisolone and prophylactic penicillin G. There is no relapse of renal or cardiac symptoms during 6 years follow-up. Unexpected elevation of plasma BNP in a convalescent stage of APSGN suggests the development of ARF. Underlying Sjögren's syndrome (SS) may modify the histopathological findings and make it difficult to differentiate APSGN from CTD-associated nephritis such as lupus nephritis (LN) even by renal biopsy.

Background Patients with refractory nephrotic syndrome (NS) are at high risk of medication-induced glucose metabolism disorders, because of their long-term use of diabetogenic medications, particularly glucocorticoids and calcineurin inhibitors (CNIs). However, there have been no comprehensive evaluations of glucose metabolism disorders in pediatric patients with refractory NS. Moreover, glucocorticoids and CNIs could not be discontinued in these patients until the effectiveness of rituximab on refractory NS was shown, and therefore, there has been limited opportunity to evaluate glucose metabolism disorders after discontinuation of these medications. Methods Consecutive pediatric patients who started rituximab treatment for refractory NS were enrolled. Their glucose metabolism conditions were evaluated using the oral glucose tolerance tests (OGTT) and HbA1c levels at the initiation of rituximab treatment. Patients with glucose metabolism disorders at the first evaluation were reevaluated after approximately 2 years. Results Overall, 57% (20/35) of study patients had glucose metabolism disorders, and 40% (8/20) of these patients were detected only by their 2-h OGTT blood glucose levels and not by their fasting blood glucose or HbA1c levels. Non-obese/non-overweight patients had significantly more glucose metabolism disorders than obese/overweight patients (p = 0.019). In addition, glucose metabolism disorders in 71% (10/14) of patients persisted after the discontinuation of glucocorticoids and CNIs. Conclusions Whether the patient is obese/overweight or not, patients with refractory NS are at high risk of developing glucose metabolism disorders, even in childhood. Non-obese/non-overweight patients who are at high risk of diabetes need extra vigilance.

A copper (Cu) foam was brazed with Cu-4.0Sn-9.9Ni-7.8P filler foil for joint strength and interface analysis. Brazed 50 pores per inch (PPI) Cu foam yielded a maximum compressive strength of 14.4 M...

Background: Recently, comprehensive genetic approaches for steroid-resistant nephrotic syndrome (SRNS) using next-generation sequencing (NGS) have been established, but causative gene mutations could not be detected in almost 70% of SRNS patients. Main reason for the low variant detection rate is that most of them are SRNS caused not by genetic but by immunological factors. But some of them are probably because of the difficulty of detecting copy number variations (CNVs) in causative genes by NGS. Methods: In this study, we performed two analytical methods of NGS data-dependent pair analysis and custom array comparative genomic hybridization (aCGH) in addition to NGS analysis in an infantile nephrotic syndrome case. Results: We detected only one known pathogenic heterozygous missense mutation in exon 7 of COQ6 c.782C > T, p.(Pro261Leu) by NGS. With pair analysis, heterozygous exon 1–2 deletion was suspected and was confirmed by custom aCGH. As a result, a small CNV was successfully detected in the COQ6 gene. Because we could detect variants in COQ6 and could start treatment by coenzyme Q10 (CoQ10) in his very early stage of SRNS, the patient achieved complete remission. Conclusions: These relatively novel methods should be adopted in cases with negative results in gene tests by NGS analysis. Especially, in cases with CoQ10 deficiency, it is possible to delay initiating dialysis by starting treatment at their early stages.

X-linked inhibitor of apoptosis protein (XIAP) deficiency is one of inborn errors of immunity characterized by recurrent hemophagocytic lymphohistiocytosis and refractory inflammatory bowel disease (IBD), mimicking Crohn's disease. The aim of this study is to make an accurate diagnosis of XIAP deficiency based on genetic and XIAP expression studies and to investigate endoscopic findings shared by patients with this disease.Four male patients with recurrent hemophagocytic lymphohistiocytosis and long-term refractory IBD were studied for the diagnosis of XIAP deficiency. Endoscopic findings of the four patients were also studied in parallel.These four patients were diagnosed with XIAP deficiency based on the absent XIAP expression in cultured T-cell blasts. Sequence analysis of the responsible gene, XIAP, demonstrated two novel nonsense mutations of p.Gln114X and p.Glu25X, and a previously reported nonsense mutation of p.Arg381X. Although no mutations in the coding region were detected in the fourth patient, further studies demonstrated a novel 2,199 bp deletion encompassing non-coding exon 1, presumably affecting transcription and stability of XIAP mRNA. All of the patients eventually underwent hematopoietic stem cell transplantation, leading to a complete or partial remission of IBD. These four patients shared an endoscopic finding of multiple wide and longitudinal ulcers with straight and non-raised edge in the colon.X-linked inhibitor of apoptosis protein expression in T-cell blasts could facilitate the diagnosis of this disease, especially with causal mutations in non-coding regions.

We report a Japanese boy with Graves’ disease (GD) which developed during drug-free remission of juvenile dermatomyositis (JDM). He had been diagnosed with JDM at the age of 6 years by typical skin rashes, muscle weakness, elevated serum transaminase levels, and typical findings of both magnetic resonance imaging and muscle biopsy. Although anti-melanoma differentiation antigen 5 autoantibody was positive, there was no complication of interstitial lung disease. He showed good response to methylprednisolone pulse therapy followed by oral prednisolone in combination with weekly methotrexate (MTX) and achieved drug-free remission after 3.5 years of treatment. Nevertheless, serum levels of soluble interleukin-2 receptor (sIL-2R) gradually elevated to 3185 U/ml despite no signs of relapse or malignancy. Hyperactivity and attention deficit was also noted. One year and 3 months after the cessation of MTX, he presented with abdominal pain, tachycardia, and apparent goitre. Laboratory tests showed elevated free triiodothyronine, undetectable thyroid stimulating hormone (TSH), and positive anti-TSH receptor antibodies. 99mTc scintigraphy showed high levels of thyroid uptake. He was diagnosed with GD and treated with 15 mg/day of thiamazole. Although transient drug eruption was observed, his thyroid functions are currently well-controlled on 5 mg/day of thiamazole. In conclusion, to our knowledge, this is the first report in English literature describing complication of GD with JDM. Unexpected elevation of sIL-2R could be a clue to the diagnosis of GD during the follow-up of JDM.

BACKGROUND Rituximab (RTX) is an effective treatment for maintaining remission in patients with nephrotic syndrome (NS), but there are few reports on the effect of RTX treatment on quality of life (QOL). The purpose of this study was to examine the effect of periodically repeated RTX treatment from the perspective of QOL. METHODS We systematically assessed the QOL of pediatric patients with refractory NS and parents' perceptions of their children's QOL through a 2 year RTX treatment protocol. Pediatric patients from Hokkaido University Hospital with refractory NS who met our specific criteria were enrolled between January 2015 and December 2015. The RTX infusion was performed 4 times at 6-month intervals, followed by mizoribine administration with early discontinuation of calcineurin inhibitors. Quality of life scores were measured by the Pediatric Quality of Life Inventory version 4.0 (PedsQL) at each RTX administration and evaluated 2 years later. RESULTS Twenty-two patients were analyzed. The patients' QOL and their parents' perceptions of their QOL improved over our 2 year treatment protocol. Nevertheless, the parents' scores were lower than the patients' scores on all scales, with slower improvement. CONCLUSIONS Our treatment protocol showed a significant improvement of QOL in patients with refractory NS. Although the risk of the RTX treatment should be considered, the treatment is useful for patients with refractory NS.

Background/Aims: Calcineurin inhibitors (CNIs) such as cyclosporine A (CsA) and tacrolimus are immunosuppressants that are frequently used as “key drugs” in the fields of transplantation, steroid resistance, refractory nephrotic syndrome, and autoimmune disease. However, long-term CNI use causes nephrotoxicity, the features of which are arteriolar hyalinosis, tubular atrophy, striped interstitial fibrosis, and focal segmental glomerulosclerosis (FSGS). We investigated whether FSGS in CNI-induced nephrotoxicity is associated with CD44-positive glomerular parietal epithelial cells (PECs), which play a significant role in experimental and human FSGS pathogenesis. Methods: We utilized the mouse model of CsA-induced nephrotoxicity, as well as controls. Histopathological and functional data were sequentially collected from 1 to 25 weeks after CsA injection. Glomerular expression of CD44 was immunohistochemically evaluated, as were markers for glomerular podocytes and PECs. Results: Glomerular CD44 expression occurred from 2 weeks after CsA injection and gradually increased in the CsA group. CD44-positive glomerular cells showed coexpression of claudin-1 (PEC marker) but not of synaptopodin (podocyte marker). From 20 weeks after CsA injection, the cells formed a bridge between Bowman’s capsule and the capillary tuft. These features are compatible with those of activated PECs, in which increased foot process effacement leads to bridge formation, and subsequently to an increase in glomerulosclerosis and a decrease in the expression of podocyte markers from 20 weeks. Conclusion: CD44-positive (activated) PECs reflect extremely early podocyte injury in the progression of FSGS formation and may be a good marker for early detection of CNI-induced nephrotoxicity.

Porous Copper (Cu) was brazed to Cu plates using Cu-9.7Sn-5.7Ni-7P amorphous filler metal. The effects of brazing parameters on the porous Cu and brazed joints were investigated. The furnace brazing temperatures employed were 660 &deg, C and 680 &deg, C, and the holding times were 10 and 15 min. After brazing, the microstructure was analyzed using Scanning Electron Microscope (SEM) equipped with Electron Dispersive X-ray Spectroscope (EDS). SEM results showed that the thickness of the brazed seam at the base joint decreased with increasing temperature and time. At low brazing temperature, microvoids and cracks were observed at the joint interface. The microvoids and cracks disappeared in the sample brazed at 680 &deg, C for 15 min, and higher diffusion of the filler was noted in the overall bonded region. The formation of Cu-P, Cu-Ni, and Ni-Sn phases at the joint interface was validated using X-ray diffraction. The phases formed increased the hardness of the brazed joints and porous Copper. It was observed that the rigidity of porous Copper tends to increase due to surface hardening effects. The rigidity of porous Cu after brazing is important in ensuring minimal deformation during cooling device servicing, which is an integral feature of prospect product development.

Approximately 80% of patients with Alport syndrome have X-linked Alport syndrome (XLAS), which is caused by mutations in the type IV collagen alpha 5 gene (COL4A5). In patients with XLAS, approximately 10-15% of COL4A5 mutations occur as spontaneous events. Here, we describe maternal germline mosaicism in a family of XLAS patients. Since our patient's parents showed normal urinary findings without COL4A5 mutation using genomic DNA isolated from peripheral leukocytes, the patient was initially diagnosed with "sporadic" XLAS. However, genetic analysis of the patient's sister with microscopic hematuria identified the same COL4A5 heterozygous mutation. Therefore, we concluded that our patient and the sister had XLAS caused by maternal germline mosaicism, not "sporadic" XLAS. Our case suggests that "sporadic" XLAS may in some patients be caused by the transmission of an abnormal allele from either parent with germline mosaicism in COL4A5. Germline mosaicism is thought to be rare, but we should consider that even asymptomatic parents of "sporadic" XLAS patients could carry a somatic and/or germline mosaicism. More cautious genetic counseling is advisable for all "sporadic" XLAS patients. Furthermore, urinalysis screening of "sporadic" XLAS patients' siblings is also important to enable an earlier detection of parental germline mosaicism.

The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014-2015 to 2016-2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients (p < 0.001). The number of biphasic fever episodes in influenza A-or B-infected patients aged 0-4 years was 2.89-times greater than that in patients aged 10-18 years (p = 0.010), and the number of episodes in influenza A-or B-infected patients aged 5-9 years was 2.13times greater than that in patients aged 10-18 years (p = 0.012).

The purpose of this study is to evaluate systemic disease activity of pediatric Sjögren's syndrome (SS) using European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI).We retrospectively reviewed medical records of patients with SS who have been diagnosed according to 1999 Japanese diagnostic criteria for SS before 16 years old at KKR Sapporo Medical Center, Hokkaido University Hospital, and affiliated hospitals. We analyzed clinical and laboratory data and calculated ESSDAI at both diagnosis and peak activity.Twenty-five patients (2 boys and 23 girls) were enrolled. Only 4 patients had sicca symptoms at diagnosis. Mean ESSDAI scores at diagnosis and peak activity were 12.68 (2-31) and 15.08 (2-38), respectively. Only 3 patients were inactive (ESSDAI score 5) at diagnosis. Frequently involved domains at diagnosis were the biological (96%) followed by the constitutional (68%), glandular (44%), articular (44%), cutaneous domains (28%), renal (16%), and central nervous system (12%). At peak activity, biological domain (96%) was followed by the constitutional (72%), glandular (60%), articular (44%), cutaneous (28%), central nervous system (20%), and renal domains (16%).Pediatric SS is suspected from active systemic manifestations. The items of ESSDAI are useful clues to the diagnosis of pediatric SS.

Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of a surfactant-like substance in alveolar spaces and hypoxemic respiratory failure. Genetic PAP (GPAP) is caused by mutations in genes encoding surfactant proteins or genes encoding a surfactant phospholipid transporter in alveolar type II epithelial cells. GPAP is also caused by mutations in genes whose products are implicated in surfactant catabolism in alveolar macrophages (AMs). We performed whole-exome sequence analysis in a family affected by infantile-onset PAP with hypogammaglobulinemia without causative mutations in genes associated with PAP: SFTPB , SFTPC , ABCA3 , CSF2RA , CSF2RB , and GATA2 . We identified a heterozygous missense variation in OAS1 , encoding 2,′5′-oligoadenylate synthetase 1 (OAS1) in three affected siblings, but not in unaffected family members. Deep sequence analysis with next-generation sequencing indicated 3.81% mosaicism of this variant in DNA from their mother's peripheral blood leukocytes, suggesting that PAP observed in this family could be inherited as an autosomal-dominant trait from the mother. We identified two additional de novo heterozygous missense variations of OAS1 in two unrelated simplex individuals also manifesting infantile-onset PAP with hypogammaglobulinemia. PAP in the two simplex individuals resolved after hematopoietic stem cell transplantation, indicating that OAS1 dysfunction is associated with impaired surfactant catabolism due to the defects in AMs.

In this study, austenitic stainless steel 316L and titanium alloy (ASTM grade 5) were welded together by micro-resistance spot welding at different combinations of welding parameters and by using specifically designed electrode geometry. The welded joints were subjected to tensile shear strength test in order to determine the strength of the welded zones. In addition, micro-hardness and microstructural examinations of the fracture mode (failure analysis) were carried out in order to examine the influence of welding parameters on the welded joints. The results showed that using a combination of 2.0 kN welding current, 100 ms welding time, and 241 N welding force yield the highest load value, 378.25 N by using full factorial design of experiment (DOE). Welding current is the most significant parameter which is obtained through analysis of variance (ANOVA). However, the increase in welding current should be controlled to avoid weld metal expulsion. The microstructure of these resistance-welded metals are detailed and investigated by using SEM and EDS mapping analysis. Based on the SEM observations, columnar dendritic structures can be seen at the fusion zone (FZ) of the welded nugget.

Double-sided laser beam welding of skin-stringer joints is a proven method for many industrial applications such as in aircraft assemblies where riveted differential joints are being replaced with welded integral structures. In the present study, dissimilar aluminum alloys of AA2024-0 and AA7075-T6 were laser welded on both sides in a T-joint configuration using a low-power Yb-fiber laser with the addition of a BA4047 filler wire. The optimized parameters were determined by developing a Mamdani fuzzy smart model. The influence of BA4047 filler wires on weld morphology was investigated using optical microscopy (OM) and scanning electron microscope (SEM). The cross-section of the joints revealed that the fusion zone (FZ) and heat affected zones (HAZ) are wider when filler wire was added as compared to those without it. This result shows that the low-power fiber laser has sufficient energy to melt the tip of the filler wire and subsequently the base materials, forming a liquid bridge to facilitate the smooth flow of molten metal between the stringer and the skin. No obvious voids were observed in the cross-sections of the joint interface. The strengths of joints were evaluated using a pull test, and hardness values were measured at the base metal (BM), FZ, and HAZ using the Vickers hardness test. At lower welding speeds with constant low-laser power, it was shown that the addition of the aluminum-silicon base alloy has increased the overall hardness and welding strengths of the samples.

Acute leukemia often causes osteoarthralgia. The aim of this study is characterization of leukemia-associated osteoarthralgia in comparison with juvenile idiopathic arthritis (JIA).We retrospectively reviewed clinical records of 31 patients with acute leukemia and 13 patients with articular JIA diagnosed between January 2008 and March 2013. Clinical and laboratory findings at the initial examination were compared among the three groups; 10 leukemia with and 21 leukemia without osteoarthralgia and 13 JIA groups.Eleven of the 31 leukemic patients (35%) had osteoarthralgia before the diagnosis of leukemia. Peripheral leukemic cells were initially absent in 10 of the 31 leukemia patients including three with osteoarthralgia. Platelet counts over 300 × 10Leukemia-associated osteoarthralgia is often indistinguishable from rheumatic diseases by imaging and laboratory findings and should be confirmed by bone marrow examination.

Bulk copper and Cu-7.0Ni-9.3Sn-6.3P (in wt %) filler alloys were brazed by microwave hybrid heating (MHH) and the results were compared with brazing using conventional furnace heating. Characterizations of the brazed joint were investigated through field emission scanning electron microscope, X-ray diffraction, shear strength test and Vicker's microhardness test. It was observed that microwave heating decreased to 94 % of total processing time compared to conventional heating. Metallurgical study showed the formation of the alpha-copper, copper phosphide and nickel phosphide intermetallics at the joint interface for both heating methods. The reaction layer thickness of microwave brazed joint was three times thinner compared to the conventionally brazed joint. The optimum shear strength of the microwave brazed joints was found to be 108.8 MPa while it was 16 % higher for the samples brazed using the conventional method. The failures of the microwave brazed joints showed a brittle cleavage structure while a mixed cleavage structure with tearing regions was observed for the conventionally brazed joints.

Background Wolfram syndrome (WS) is a disorder characterized by the association of insulin-dependent diabetes mellitus (DM), diabetes insipidus, deafness, and optic nerve atrophy. WS is caused by WFS1 mutations encoding WFS1 protein expressed in endoplasmic reticulum (ER). During ER protein synthesis, misfolded and unfolded proteins accumulate, known as “ER stress”. This is attenuated by the unfolded protein response (UPR), which recovers and maintains ER functions. Because WFS1 is a UPR component, mutant WFS1 might cause unresolvable ER stress conditions and cell apoptosis, the major causes underlying WS symptoms. We encountered an 11-month-old Japanese female WS patient with insulin-dependent DM, congenital cataract and severe bilateral hearing loss. Objective Analyze the WFS1 and functional consequence of the patient WFS1 in vitro. Results The patient WFS1 contained a heterozygous 4 amino acid in-frame deletion (p.N325_I328del). Her mutant WFS1 increased GRP78 and ATF6α promoter activities in the absence of thapsigargin, indicating constitutive ER stress and nuclear factor of activated T-cell reporter activity, reflecting elevated cytosolic Ca2+ signals. Mutant transfection into cells reduced mRNA expression levels of sarcoplasmic/endoplasmic reticulum Ca2+ transport ATPase 2b (SERCA2b) compared with wild type. Because SERCA2b is required for ER and cytoplasmic Ca2+ homeostasis, decreased SERCA2b expression might affect ER Ca2+ efflux, causing cell apoptosis. Conclusion A novel heterozygous mutation of WFS1 induced constitutive ER stress through ATF6α activation and ER Ca2+ efflux, resulting in cell apoptosis. These results provide new insights into the roles of WFS1 in UPR and mechanism of monogenic DM.

INTRODUCTION AND OBJECTIVES:Fully understanding and defining how the normal brain responds to bladder filling in healthy adults is essential for identifying central abnormalities in patients with b...

Generalised oedema, or anasarca, is a rare complication of systemic lupus erythematosus (SLE) and Sjogren’s syndrome (SS) and usually results from nephrotic syndrome or protein-losing enteropathy. We report a 14-year-old girl presented with anasarca and persistent fever. Despite hypoalbuminemia, no or little protein loss was observed in her urine or stool. She was diagnosed as having SS by positive anti-SSA antibodies and ductal dilation and glandular destruction of her parotid gland on magnetic resonance sialography. Elevated levels of serum C-reactive protein, ferritin and plasma D-dimer suggested that systemic inflammation caused anasarca by both decreased production of albumin and hyperpermeability associated with vascular endothelial damage similar to systemic capillary leak syndrome. Methylprednisolone pulse therapy and low-dose intravenous cyclophosphamide therapy followed by oral prednisolone and azathioprine were effective.

Aim This retrospective study was performed to determine the frequency of malformed infants born at a tertiary center in Hokkaido, Japan. The accuracy of prenatal diagnosis rates was also investigated. Methods An observational study was performed using data of 1509 and 1743 newborn infants at a single center during two study periods, 2005–2009 (first) and 2010–2014 (second), respectively. Cases including minor anomalies (accessory auricle, nevus and fistula auris congenita) were not included. Results In total, 274 and 569 malformations were identified in 191 and 337 newborn infants in the first and second study periods, respectively. The number of malformed infants increased significantly over time (13% [191/1509] vs 19% [337/1743], respectively; P < 0.001), mainly as a result of an increase in cases of congenital heart disease (CHD), from 59 to 141 (31% [59/191] vs 42% [141/337] of all malformed infants in the first and second periods, respectively). The overall accurate prenatal diagnosis rate improved over time from 47% (128/274) to 58% (329/569) because of significant improvements in accurate prenatal diagnosis of CHD subtypes (23% [16/70] vs 65% [151/232] in the first and second periods, respectively, P < 0.0001). Conclusions The frequency of malformed newborns was higher in the tertiary center than in the general population. The increased number of cases with prenatal suspicion and diagnosis of CHD contributed to the increased frequency of malformed infants during the study period.

Microwave hybrid heating (MHH) technique was used to investigate the formation of intermetallic compound layer at Cu-7.0Ni-9.3Sn-6.3P/Cu interface. Two different susceptor materials; graphite and silicon carbide were used to provide initial heating of the filler alloy before it starts couple with the microwaves and melted on the Cu surface. The interface of IMC layer was characterized using Scanning Electron Microscope (SEM), energy dispersive X-ray spectrometry (EDS) and microhardness. Metallurgical study showed the formation of the IMC layer with multiphase at the joint interface for microwave heating of both susceptor materials. The thickness of IMC layer heating in silicon carbide susceptor was three times thinner than heating in graphite susceptor; 16.5 μm and 50.5 μm, respectively. The findings showed that microwave hybrid heating can be used to join Cu-7.0Ni-9.3Sn-6.3P/Cu and controlled the thickness of IMC layer.

Background The aim of this study was to determine the sensitivity and specificity of a novel immunochromatographic assay (ICA) kit, ALSONIC® Adeno (Alfresa Pharma Co., Osaka, Japan), for the detection of human adenovirus (HAdV) from throat swab samples based on the results of real-time PCR. The incubation time required for the novel assay kit (5 minutes) is shorter than that required for other ICA kits that are available in Japan. Methods Throat swab samples were taken from 151 patients aged 6 months to 15 years who were suspected of having respiratory tract infections caused by HAdV. Results The sensitivity and specificity of the ICA for detection of HAdV were 92.2% (83/90) and 95.1% (58/61), respectively, and the assay showed positive and negative predictive values of 96.5% (83/86) and 89.2% (58/65), respectively. Conclusions ALSONIC® Adeno is suitable as a diagnostic tool in the acute phase of HAdV infection.

Objective The main aims of the present study were to elucidate the systemic group A rotavirus (RVA) infection and to clarify the genetic changes of persistent virus in the X-linked severe combined immunodeficiency (SCID) patient. Methods RotaTeq vaccine (RV5) genotype-specific real-time reverse transcription polymerase chain reaction was used to monitor viral RNA load in serially collected serum and stool samples. Next-generation sequence analysis was used to determine the genotype of the virus by sequencing 11 gene segments. Polyacrylamide gel electrophoresis (PAGE) analysis was used to identify rearrangement of viral genes. The gene rearrangement was examined in NSP5 gene by using Sanger sequence. Results A 7-month-old boy demonstrated chronic diarrhea following the third administration of RV5 and failure to thrive. He was diagnosed with X-linked SCID and successfully underwent cord blood transplantation. High copy numbers of RV5 genotype G1 RNA were detected in serially collected stool and serum samples and the kinetics of viral RNA loads were correlated with the degree of clinical disease. Next-generation sequence analysis revealed genetic reassortment at least between the strains WI79-9/G1P7[5] and WI79-4/G6P1A[8] in the VP7 gene and the VP4 gene among the vaccine-derived rotavirus strains. In addition, PAGE analysis suggested genetic rearrangements in several genes, and it was confirmed in the NSP5 gene by sequence analysis. Conclusions The kinetics of RVA RNA load in serum and stool samples was consistent with the clinical course of the patient. Among five genotypes of RV5 vaccine, G1 genotype replicated well in this patient. Reassortment and rearrangements were demonstrated in persistently infected G1 genotype of RV5.

Background Immunoglobulin A nephropathy (IgAN) is a major cause of end-stage renal disease. Complement activation via the lectin pathway influences outcomes in IgAN. We examined the association of glomerular C4d deposition with clinicopathological severity at diagnosis and the disappearance of proteinuria in Japanese pediatric IgAN patients. Methods We retrospectively analyzed 25 children newly diagnosed with IgAN at Hokkaido University Hospital. We evaluated glomerular C4d immunofluorescent staining at diagnosis. We compared clinical findings, pathological findings (based on Oxford classification), and the disappearance of proteinuria within 24 months after renal biopsy between C4d-positive and C4d-negative patients. Results Glomerular C4d staining was observed in 14 patients (56.0%). C4d-positive patients had significantly higher proteinuria at diagnosis than C4d-negative patients (2.03 g/gCr vs 0.78 g/gCr; P = 0.005). The number of glomeruli with segmental glomerulosclerosis or adhesion (8.0% vs 0.0%; P = 0.046) and the extent of tubular atrophy/interstitial fibrosis (9.46% vs 2.86%; P = 0.031) were significantly increased in C4d-positive patients compared with C4d-negative patients. Further, the proportion of patients with modified T1 (>10%) was significantly higher in the C4d-positive group than the C4d-negative group. There was no significant difference, however, in the disappearance rate of proteinuria at 24 months after renal biopsy between groups (64% vs 82%; P = 0.149). Conclusions Glomerular C4d deposition was associated with clinicopathological severity at diagnosis in Japanese pediatric patients with IgAN. Glomerular C4d deposition, however, was not a predictor of the disappearance of proteinuria within 24 months after diagnosis in Japanese pediatric patients with IgAN.

Summary Background Genetic studies have indicated possible involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the pathogenesis of Kawasaki disease. We aimed to assess safety and efficacy of ciclosporin, an immunosuppressant targeting this pathway, for protection of patients with Kawasaki disease against coronary artery abnormalities. Methods We did a randomised, open-label, blinded endpoints trial involving 22 hospitals in Japan between May 29, 2014, and Dec 27, 2016. Eligible patients predicted to be at higher risk for intravenous immunoglobulin (IVIG) resistance were randomly assigned to IVIG plus ciclosporin (5 mg/kg per day for 5 days; study treatment) or IVIG (conventional treatment) groups, stratified by risk score, age, and sex. The primary endpoint was incidence of coronary artery abnormalities using Japanese criteria during the 12-week trial, assessed in participants who received at least one dose of study drug and who visited the study institution at least once during treatment. This trial is registered to Center for Clinical Trials, Japan Medical Association, number JMA-IIA00174. Findings We enrolled 175 participants. One patient withdrew consent after enrolment and was excluded and one patient (in the study treatment group) was excluded from analysis because of lost echocardiography data. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0·46; 95% CI 0·25–0·86; p=0·010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p=0·78). Interpretation Combined primary therapy with IVIG and ciclosporin was safe and effective for favourable coronary artery outcomes in Kawasaki disease patients who were predicted to be unresponsive to IVIG. Funding Japan Agency for Medical Research and Development (grant CCT-B-2503).

The aim of our study is to clarify the association of myositis-specific autoantibodies (MSAs) with clinical and laboratory features in Japanese patients with juvenile idiopathic inflammatory myopathies (JIIMs).We retrospectively analyzed the frequency of MSAs and their association with clinical or laboratory findings in 25 Japanese patients with JIIMs in Hokkaido district.Eighteen of the 25 patients (72%) were positive for MSAs; seven with anti-melanoma differentiation associated gene (MDA) 5 (28%), five with anti-transcriptional intermediary factor (TIF)-1γ (20%), four with anti-MJ/nuclear matrix protein (NXP)-2 (16%), two with anti-Jo-1 (8%), one with anti- HMG-CoA reductase, one with anti-signal recognition peptide (SRP) antibodies (4% each), including co-existence and transition of MSAs in one patient each. Anti-MDA5 antibodies were related to interstitial lung disease (ILD) and arthritis but not to amyopathic juvenile dermatomyositis. Drug-free remission was achieved, once ILD was overcome in this group. Anti-TIF-1γ antibodies were associated with typical rashes and mild myositis. Anti-MJ/NXP2 and anti-SRP antibodies were associated with severe muscle weakness. No patient was complicated with malignancy.Anti-MDA5 antibodies are prevalent and closely associated with ILD in our series compared with other countries. There was no apparent difference in clinical features associated with other MSAs among races.

Background/Aims: De novo expression of CD44 is considered as a marker of parietal epithelial cell (PEC) activation. The aim of our study was to explore CD74 expression, which can form a complex with CD44, in PECs during the progression of focal segmental glomerulosclerosis (FSGS). To clarify the role of CD74 expression and of its interaction with CD44, we generated a new mouse model with enhanced PEC activation through lipopolysaccharide (LPS) application to adriamycin (ADR)-induced nephropathy mice (LPS-treated ADR mice). Methods: As a new model, LPS was intraperitoneally injected into the mice 3 weeks after ADR injection. The mice were divided into 3 categories: control mice, ADR mice and LPS-treated ADR mice. Renal function parameters, histologic changes and immunohistochemical expression of CD74 and other PEC activation markers were analyzed after LPS application. Results: After LPS stimulation, the glomeruli were characterized by enlarged epithelial cells with strong CD74 expression, followed by pseudo-crescent formation. By double staining, CD74-positive enlarged cells showed co-expression of classical PEC markers, but not of Lotus tetragonolobus lectin (marker of proximal tubular cells), suggesting amplification of PEC activation. Time-course analysis displayed marked upregulation of CD74 expression during rapid PEC activation compared with CD44. Additionally, the time-dependent change in ERK phosphorylation showed a similar pattern to CD74. Conclusion: Our results indicate that CD74 can be a marker for PEC activation in FSGS. By modifying the ADR mouse model through LPS treatment, we found that CD74 upregulation better reflects a rapid amplification of PEC activation than CD44 expression.

Recently, macrolide-resistant (MR) Mycoplasma pneumonia appeared, and prevalence of macrolide resistance among M. pneumoniae infections varies by country. However, reports on regional differences in the prevalence of MR M. pneumonia within a country are scarce. In this study, 617 nasopharyngeal swab samples were collected from 617 pediatric patients, and DNA of M. pneumoniae was identified in 95 samples. In 51 of the 95 M. pneumonia positive samples, we detected the presence of mutation A2063G mutation (conferring macrolide resistance) in the 23S rRNA gene. The overall macrolide resistance rate was 53.7%, but there were regional differences: 0.0% in Muroran, 5.3% in Asahikawa, 55.3% in Sapporo, and 100.0% in Kushiro. Statistically significant pairwise differences in the prevalence of MR M. pneumoniae were observed among these cities except for the pair of Muroran and Asahikawa. After exclusion (in order to avoid the influence of macrolides) of patients who were prescribed macrolides before collection of nasopharyngeal swab samples, statistically significant differences persisted: 0.0% in Muroran, 5.6% in Asahikawa, 38.5% in Sapporo, and 100.0% in Kushiro.

The aims of this research are to investigate the effects of Ni on the physical properties of Sn58Bi–xNi lead-free solder, and to examine its interfacial reaction with the copper substrate. In the experiments, four concentrations of Ni (i.e. 0.05, 0.1, 0.5 and 1.0 wt.%) were individually added into Sn58Bi and their respective microstructure, tensile strength, elongation, melting temperature, wettability and electrical resistivity of Sn58Bi–xNi were subsequently measured. The results indicated that Ni refined the microstructure of the solder matrix and induced the formation of Ni3Sn4 intermetallic phase, and that the size and volume fraction of Ni3Sn4 were positively correlated to the Ni content. The optimal concentration of Ni to enhance the tensile strength of the alloy was 0.1 wt.%, but the elongation of the alloy was inversely correlated to the Ni content. The addition of Ni contributed positively to the melting temperature and wetting behavior of the alloy, whereas no significant change in the electrical resistivity of Sn58Bi–xNi was detected. In addition, Ni increased the thickness of the intermetallic layer at the interface, and only monoclinic η′-Cu6Sn5 phase was present at the intermetallic layer. Nevertheless, the intermetallic phase of this research was dissimilar from the findings of existing literature. Keywords: Lead-free solder, Alloying element, Intermetallic compound

Palindromic rheumatism (PR), a rare disease in children, is characterized by recurrent arthritis or periarthritis and asymptomatic interval. We report evolution of PR to juvenile idiopathic arthritis in a Japanese girl with heterozygous complex L110P-E148Q allele of MEFV gene. Poor response to colchicine alone suggests that the MEFV substitution could increase the susceptibility to arthritis rather than caused arthritis associated with atypical Familial Mediterranean Fever. Weekly methotrexate is a choice for such cases.

Background Among neonates with Down syndrome (DS) and transient leukemia (TL), hyperleukocytosis (white blood cell [WBC] count >100 × 109/L) is associated with increased blood viscosity, respiratory failure due to pulmonary hypertension, multiorgan failure, and increased risk of early death. There have been no previous studies focusing on the effects of exchange transfusion (ExT) on WBC count, respiratory status, and other parameters in TL patients with hyperleukocytosis. Methods An observational retrospective study was carried out at a single center of all five DS neonates with TL, GATA1 mutations, and hyperleukocytosis, born at a median gestational age of 34 weeks (range, 30–38 weeks) with birthweight 2556 g (range, 1756–3268 g) during a 24 month study period between September 2011 and August 2013. All five neonates underwent ExT at a median age of 2 days (range, 0–5 days) before initiation of other cytoreductive therapy with cytarabine, which was carried out in two patients. Results All patients required respiratory support before ExT. After ExT, respiration status improved in all five patients: WBC count (mean) decreased by 85% from 143 × 109/L to 21 × 109/L. None developed tumor lysis syndrome. Three survived and two died: one hydrops fetalis neonate born at gestational week 30 died at age 5 days, and another died eventually from acute gastroenteritis 40 days after leaving hospital at the age of 155 days with complete remission. Two of the three surviving neonates developed acute megakaryocytic leukemia at age 90 days and 222 days. Conclusion ExT was very effective in improving hyperleukocytosis and may have had favorable effects on respiration.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease that is characterized by susceptibility to bacterial and fungal infections. Various mutations in CYBB encoding the gp91(phox) subunit of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase impair the respiratory burst of all types of phagocytic cells and result in X-linked CGD (X-CGD). We here sought to evaluate the underlying cause in an attenuated phenotype in an X-CGD patient. The patient is a 31-year-old male who had been diagnosed as having X-CGD based on the absence of nitroblue tetrazolium reduction and the presence of a CYBB mutation at the age of 1 year. He has been in good health after overcoming recurrent bacterial infections in infancy. We investigated genomic DNA analysis of CYBB gene, residual activity of NADPH oxidase, and expression of gp91(phox) in both polymorphonuclear leukocytes (PMNs) and monocytes/macrophages in the present patient. Although his underlying germline mutation, c.1016C > A (p.P339H) in the CYBB gene, was identified in both PMNs and monocytes, the expression and functional activity of gp91(phox) retained in monocytes/macrophages, in stark contrast to markedly reduced PMNs. Our results indicate that residual reactive oxygen intermediates (ROI) production in PMNs plays an important role in infantile stage in X-CGD, but thereafter retained function of monocytes/macrophages might compensate for the function of NADPH oxidase deficient PMNs and might be an important parameter for predicting the prognosis of X-CGD patients.

Phosphoinositide 3-kinase (PI3K) signaling promotes diverse intracellular responses including proliferation, survival and differentiation. Class IA PI3K is a heterodimer, composed of p110 (catalytic) and p85 (regulatory) subunits. One of the p110 catalytic subunits, p110δ, is encoded by PIK3CD, and its expression is restricted to leukocytes. Activated phosphoinositide 3-kinase δ syndrome (APDS) 1 is a primary immunodeficiency disease (PID) caused by gain-of-function mutations of PIK3CD and is associated with various infections, autoimmunity, lymphoproliferative disease (LPD), and malignancy.1 Recently, APDS2 caused by heterozygous mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene, affecting all of the three subunits, p85α, p55α and p50α, was reported. Patients with APDS2 also have increased PI3K/Akt/mTOR (mammalian target of rapamycin) signals and clinical features observed in APDS1.2, 3, 4, 5, 6, 7 Haematopoietic stem cell transplantation (HSCT) is one of available treatments to achieve long-term immune reconstitution and to prevent malignancy. Here, we report successful HSCT in two sisters with APDS2 suffering from EBV-associated lymphoproliferation.

This paper describes an investigation of cadmium-free silver brazing filler metals, the ternary Ag–Cu–Sn alloys. The influences of tin content on solidus and liquidus temperatures and gap filling ability of Ag–Cu–Sn alloys on copper were investigated. Microstructures of the joint and the shear strength were examined. Investigation on gap filling ability test procedure was performed according to ISO 5179-1983. The result from differential thermal analysis showed that the solidus and liquidus temperatures of the filler metals decreased with the increment of tin content in Ag–Cu–Sn. The results from the shear test showed that the brazed joint exhibited the highest strength at 10 wt-% tin content in the filler metal. The joint gaps of less than 0·10 mm were proposed when designing the brazed joint for Ag–Cu–Sn filler metals.