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BackgroundDexmedetomidine (DEX) is a highly selective alpha 2 receptor agonist that has the advantage of causing less respiratory depression than other sedative agents. We evaluated the add-on effects of DEX on sedation among pediatric patients who received midazolam and pentazocine during cardiac catheterization.Methods120 cardiac catheterization procedures in 110 patients under deep sedation at Department of Pediatrics, Kanazawa University Hospital from January 2013 to August 2018: 63 procedures without DEX (i.e., non-DEX group) and 57 procedures with DEX (i.e., DEX group). Intravenous midazolam and pentazocine were used in both groups, and DEX without an initial loading dose (0.6 μg/kg/h) was used in the DEX group. We retrospectively investigated complications during catheterization, doses of sedative agents, and changes in vital signs.ResultsHypoxemia requiring oxygen administration during catheterization tended to be higher in the non-DEX group than in the DEX group (4.8% vs. 0%). Additional dose of midazolam was significantly lower in the DEX group (median [IQR]: 0.05 mg/kg [0–0.11]) than in the non-DEX group [0.09 mg/kg (0–0.23), p = 0.0288]. The additional dose of midazolam in the non-DEX group with hypoxemia was significantly higher than the dose used in the non-DEX group without hypoxemia. No case of bradycardia below the criteria for bradycardia occurred and no serious complications occurred in the DEX group.ConclusionThe use of intravenous DEX in combination with midazolam and pentazocine in pediatric cardiac catheterization may reduce the need for an additional dose of midazolam and may contribute to the prevention of airway complications associated with respiratory depression caused by sedative agents.

Mutations in the complement factor H (CFH) gene are associated with complement dysregulation and the development of atypical hemolytic uremic syndrome (aHUS). Several fusion genes that result from genomic structural variation in the CFH and complement factor H-related (CFHR) gene regions have been identified in aHUS. However, one allele has both CFHR gene duplication and CFH::CFHR1 fusion gene have not been reported. An 8-month-old girl (proband) presented with aHUS and was treated with ravulizumab. Her paternal grandfather developed aHUS previously and her paternal great grandmother presented with anti-neutrophil cytoplasmic antibody-associated vasculitis and thrombotic microangiopathy (TMA). However, the proband’s parents have no history of TMA. A genetic analysis revealed the presence of CFH::CFHR1 fusion gene and a CFHR3-1-4-2 gene duplication in the patient, her father, and her paternal grandfather. Although several fusion genes resulting from structural variations of the CFH–CFHR genes region have been identified, this is the first report of the combination of a CFH::CFHR1 fusion gene with CFHR gene duplication. Because the CFH–CFHR region is highly homologous, we hypothesized that CFHR gene duplication occurred. These findings indicate a novel pathogenic genomic structural variation associated with the development of aHUS.

Key Clinical Message. A 15‐year‐old girl developed inherited cardiomyopathy and macrothrombocytopenia revealing pathogenic variants of both MYH7 and MYH9 genes. This underlies the importance of repeated genetic testing in diagnosing and managing inherited disorders. Abstract The MYH7 and MYH9 genes encode for distinct myosin heavy chain proteins. Our case features a 15‐year‐old girl, presenting with inherited cardiomyopathy and macrothrombocytopenia, revealing distinct pathogenic variants of both MYH7 and MYH9 genes. This underlines the relevance of genetic testing and personalized medicine in diagnosing and managing inherited disorders.

Abstract Bloom syndrome patients often develop severe gastrointestinal symptoms mainly caused by gastric tumors due to DNA repair disorder. Here, we report 31‐year‐old Bloom syndrome patient suffering persistent abdominal pain due to refractory gastroduodenal ulcers which required gastroduodenectomy. Various causes should be considered, and the accumulation of their reports is warranted.

Review: Interleukin-18 (IL-18) is a proinflammatory cytokine that promotes various innate immune processes related to infection, inflammation, and autoimmunity. Patients with systemic juvenile idiopathic arthritis and adult-onset Still’s disease exhibit chronic excess of serum IL-18, which is associated with a high incidence of macrophage activation syndrome (MAS), although the mechanisms of IL-18 regulation in such diseases remain largely unknown. Similar elevation of serum IL-18 and susceptibility to MAS/hemophagocytic lymphohistiocytosis (HLH) have been reported in monogenic diseases such as X-linked inhibitor of apoptosis deficiency (i.e., X-linked lymphoproliferative syndrome type 2) and NLRC4-associated autoinflammatory disease. Recent advances in molecular and cellular biology allow the identification of other genetic defects such as defects in CDC42, PSTPIP1, and WDR1 that result in high serum IL-18 levels and hyperinflammation. Among these diseases, chronic excess of serum IL-18 appears to be linked with severe hyperinflammation and/or predisposition to MAS/HLH. In this review, we focus on recent findings in inflammatory diseases associated with and probably attributable to chronic excess of serum IL-18 and describe the clinical and therapeutical relevance of understanding the pathology of this group of diseases.

Pseudohypoparathyroidism type 1a (PHP1a) is a genetic disorder caused by heterozygous loss-of-function mutations on the maternal allele of the GNAS gene. Patients with PHP1a predominantly exhibit parathyroid hormone (PTH) resistance and physical features of Albright's hereditary osteodystrophy. We report two unrelated cases with PHP1a who developed tertiary hyperparathyroidism (HPT). Molecular analyses of the GNAS gene identified a previously known heterozygous 4-bp deletion (c. 565_568delGACT) in exon 7 in case 1 and a novel heterozygous missense mutation (p.Lys233Glu) in exon 9 in case 2. Both patients developed tertiary HPT associated with hyperfunctioning parathyroid glands during long-term treatment of hypocalcemia. Case 1 had severe osteoporosis and underwent parathyroidectomy. Case 2 was asymptomatic with no evidence of bone diseases associated with tertiary HPT. PHP1a patients are at risk of developing tertiary HPT and should be treated with sufficient doses of calcium and vitamin D to achieve serum PTH levels within the mid - normal to double the upper limit of the normal range, regardless of serum calcium levels.

Background Insulin-like growth factor-binding protein (IGFBP) 2 plays an important role in the regulation of cell adhesion, migration, growth, and apoptosis. This study aimed to investigate the clinical significance of serum IGFBP2 as a biomarker for disease activity and severity in hemolytic uremic syndrome (HUS) induced by enterohemorrhagic Escherichia coli (EHEC). Methods IGFBP2 production by human renal glomerular endothelial cells (RGECs) after exposure to Shiga toxin 2 (Stx-2) was investigated in vitro. Serum IGFBP2 levels in blood samples obtained from 22 patients with HUS and 10 healthy controls (HCs) were quantified using an enzyme-linked immunosorbent assay. The results were compared to the clinical features of HUS and serum tau and cytokine levels. Results Stx-2 induced the production of IGFBP2 in RGECs in a dose-dependent manner. Serum IGFBP2 levels were significantly higher in patients with HUS than in HCs and correlated with disease severity. Additionally, serum IGFBP2 levels were significantly higher in patients with encephalopathy than in those without encephalopathy. A serum IGFBP2 level above 3585 pg/mL was associated with a high risk of encephalopathy. Furthermore, serum IGFBP2 levels significantly correlated with serum levels of tau and inflammatory cytokines associated with the development of HUS. Conclusions Correlation of serum IGFBP2 level with disease activity in patients with HUS suggests that IGFBP2 may be considered as a possible indicator for disease activity and severity in HUS. Larger studies and additional experiments using various cells in central nervous system should elucidate the true value of IGFBP2 as a clinical diagnostic marker. Abbreviations IGFBP: insulin-like growth factor-binding protein; HUS: hemolytic uremic syndrome; EHEC: enterohemorrhagic Escherichia coli; RGECs: renal glomerular endothelial cells; STx-2: Shiga toxin 2; HCs: healthy controls; LPS: lipopolysaccharide; ROC: receiver operating characteristic; sTNFR: soluble tumor necrosis factor receptor.

Opportunistic infections are life-threatening conditions in immunocompromised patients including those with primary immunodeficiency. We describe a case of X-linked chronic granulomatous disease presenting with mesenteric abscess caused by a coinfection with Bacillus Calmette-Guérin (BCG) and Phialemonium sp. The patient received BCG vaccination at 5 months old. He developed left axillary BCG lymphadenitis at 17 months of age, and 3 months later mesenteric abscess occurred. Concomitant use of rifampicin and itraconazole at 17 months of age might have reduced serum itraconazole concentrations and led to superinfection with Phialemonium sp. in our patient, which was susceptible to itraconazole and voriconazole in vitro. The patient was successfully treated with a combination of isoniazid, rifampicin, streptomycin, ciprofloxacin, prednisolone, interferon-γ, and an increased dose of itraconazole, followed by hematopoietic stem cell transplantation. Our results suggest that clinician need to be aware of rifampicin drug interactions, and that precise detection and identification of pathogens are essential to appropriate treatment.

Pediatric multisystem inflammatory syndrome (MIS-C) is a disease that presents mainly in older children after coronavirus disease 2019 (COVID-19) and is associated with Kawasaki-like symptoms and multiple-organ failure. The number of cases of MIS-C has increased since April 2020, with reports mainly from Europe and the United States. The reason is unclear, but few cases of MIS-C have been reported in Asian countries, including Japan. No treatment has been established for MIS-C. In this study, we report the case of a young boy treated with IVIg for MIS-C by measuring the cytokine profile over time. A 4-year-old boy presented with Kawasaki disease-like symptoms 28 days after a positive result from polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), meeting the World Health Organization criteria for MIS-C diagnosis. Blood tests showed lower levels of C-reactive protein and ferritin, and no decrease in lymphocyte count (

Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) causes hospital- and community-acquired infections. It is not clear whether genetic characteristics of the bacteria contribute to disease pathogenesis in MRSA infection. We hypothesized that whole genome analysis of MRSA strains could reveal the key gene loci and/or the gene mutations that affect clinical manifestations of MRSA infection. Methods: Whole genome sequences (WGS) of MRSA of 154 strains were analyzed with respect to clinical manifestations and data. Further, we evaluated the association between clinical manifestations in MRSA infection and genomic information. Results: WGS revealed gene mutations that correlated with clinical manifestations of MRSA infection. Moreover, 12 mutations were selected as important mutations by Random Forest analysis. Cluster analysis revealed strains associated with a high frequency of bloodstream infection (BSI). Twenty seven out of 34 strains in this cluster caused BSI. These strains were all positive for collagen adhesion gene (cna) and have mutations in the locus, those were selected by Random Forest analysis. Univariate and multivariate analysis revealed that these gene mutations were the predictor for the incidence of BSI. Interestingly, mutant CNA protein showed lower attachment ability to collagen, suggesting that the mutant protein might contribute to the dissemination of bacteria. Conclusions: These findings suggest that the bacterial genotype affects the clinical characteristics of MRSA infection. Keywords: MRSA, Bloodstream infection, Cna, Whole genome sequencing

Reversion mosaicism has been reported in an increasing number of genetic disorders including primary immunodeficiency diseases. Several mechanisms can mediate somatic reversion of inherited mutations. Back mutations restore wild-type sequences, whereas second-site mutations result in compensatory changes. In addition, intragenic recombination, chromosomal deletions, and copy-neutral loss of heterozygosity have been demonstrated in mosaic individuals. Revertant cells that have regained wild-type function may be associated with milder disease phenotypes in some immunodeficient patients with reversion mosaicism. Revertant cells can also be responsible for immune dysregulation. Studies identifying a large variety of genetic changes in the same individual further support a frequent occurrence of reversion mosaicism in primary immunodeficiency diseases. This phenomenon also provides unique opportunities to evaluate the biological effects of restored gene expression in different cell lineages. In this paper, we review the recent findings of reversion mosaicism in primary immunodeficiency diseases and discuss its clinical implications.

Abstract Pneumocystis jirovecii pneumonia associated with primary immunodeficiency should be considered in infants with slowly progressing cyanosis, even without fever or respiratory symptoms. Genetic counseling is crucial for incontinentia pigmenti families in advance of pregnancy because lethal infections can occur before the diagnosis of X‐linked anhidrotic ectodermal dysplasia with immunodeficiency.

Ambient polycyclic aromatic hydrocarbons’ (PAHs) specific components are likely involved in respiratory disease development and exacerbation in children and adults. Airborne PAH exposure’s effects on cough symptoms in children and adults with chronic coughs in Kanazawa and Fukuoka, Japan, were investigated in this longitudinal study. A total of 98 patients with chronic coughs were enrolled and followed up between 1 April and 31 May 2020. The enrolled patients were non-smoking adults and children aged 3–83 years. Cough diaries were used to record and collect daily cough symptoms. High-performance liquid chromatography coupled with a fluorescence detector was used to determine the particulate PAH content in daily total suspended particles collected on quartz fiber filters. Ambient concentrations of fine particulate matter, nitrogen dioxide, and sulfur dioxide were obtained from local monitoring sites. Generalized estimated equations were used to estimate the association between daily PAHs and cough symptoms. Among nine PAHs measured, benz[a]anthracene (BaA) was significantly associated with cough symptoms for both lag4 and lag5 PAH exposure. These findings suggest that airborne specific PAHs, especially BaA, affect cough symptoms in children and adults with chronic cough. Further studies are needed to develop effective measures to prevent respiratory diseases against specific PAHs.

ObjectivesHuman parechovirus (HPeV), especially HPeV A3 (HPeV3), causes sepsis-like diseases and sudden infant death syndrome in neonates and young infants. Development of rapid and easier diagnostic laboratory tests for HPeVs is desired.MethodsOriginal inner primers, outer primers, and loop-primers were designed on the 5' untranslated region of HPeV3. HPeV3 ribonucleic acids (RNAs), other viral RNAs, and clinical stool samples were used to confirm whether the designed primers would allow the detection of HPeV3 with the reverse transcription loop-mediated isothermal amplification (RT-LAMP) technique.ResultsThree combinations of primers were created and it was confirmed that all primer sets allowed the detection of HPeV3 RNAs. The primer sets had cross-reactivity with HPeV type 1 (HPeV1), but all sets showed negative results when applied to coxsackievirus, echovirus, enterovirus, norovirus, and adenovirus genomes. Four of six stool samples, obtained from newborn and infant patients with sepsis-like symptoms, showed positive results with our RT-LAMP technique.ConclusionsThis manuscript is the first description of an RT-LAMP for the diagnosis of HPeVs, allowing a faster, easier, and cheaper diagnosis. This technique is clinically useful for newborns and infants who have sepsis-like symptoms.

Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs. Flow cytometry can evaluate specific cell populations and subpopulations, cell surface, intracellular and intranuclear proteins, biologic effects associated with specific immune defects, and certain functional immune characteristics, each being useful for the diagnosis and evaluation of PIDs. Flow cytometry effectively identifies major forms of PIDs, including severe combined immunodeficiency, X-linked agammaglobulinemia, hyper IgM syndromes, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, familial hemophagocytic lymphohistiocytosis, autoimmune lymphoproliferative syndrome, IPEX syndrome, CTLA 4 haploinsufficiency and LRBA deficiency, IRAK4 and MyD88 deficiencies, Mendelian susceptibility to mycobacterial disease, chronic mucocuneous candidiasis, and chronic granulomatous disease. While genetic analysis is the definitive approach to establish specific diagnoses of PIDs, flow cytometry provides a tool to effectively evaluate patients with PIDs at relatively low cost.

Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency characterized by recurrent respiratory tract infections, lymphoproliferation, and defective IgG production. Heterozygous mutations in PIK3CD, PIK3R1, or PTEN, which are related to the hyperactive phosphoinositide 3-kinase (PI3K) signaling, were recently presented to cause APDS1 or APDS2 (APDSs), or APDS-like (APDS-L) disorder. In this study, we examined the AKT phosphorylation of peripheral blood lymphocytes and monocytes in patients with APDSs and APDS-L by using flow cytometry. CD19+ B cells of peripheral blood in APDS2 patients showed the enhanced phosphorylation of AKT at Ser473 (pAKT) without any specific stimulation. The enhanced pAKT in CD19+ B cells was normalized by the addition of a p110δ inhibitor. In contrast, CD3+ T cells and CD14+ monocytes did not show the enhanced pAKT in the absence of stimulation. These findings were similarly observed in patients with APDS1 and APDS-L. Among CD19+ B cells, enhanced pAKT was prominently detected in CD10+ immature B cells compared to CD10- mature B cells. Enhanced pAKT was not observed in B cells of healthy controls, patients with common variable immunodeficiency (CVID), and hyper IgM syndrome (HIGM) due to CD40L deficiency. These results suggest that the enhanced pAKT in circulating B cells may be useful for the discrimination of APDS1, APDS2, and APDS-L from other antibody deficiencies.

Severe congenital neutropenia (SCN) is a rare disease that involves a heterogeneous group of hereditary diseases. Mutations in the HAX1 gene can cause an autosomal recessive form of SCN-characterized low blood neutrophil count from birth, increased susceptibility to recurrent and life-threatening infections, and preleukemia predisposition. A 7-year-old boy was admitted due to life-threatening infections, mental retardation, and severe neutropenia. He had early-onset bacterial infections, and his serial complete blood count showed persistent severe neutropenia. One older sister and one older brother of the patient died at the age of 6 months and 5 months, respectively, because of severe infection. Bone marrow analysis revealed a maturation arrest at the promyelocyte/myelocyte stage with few mature neutrophils. In direct DNA sequencing analysis, we found a novel homozygous frameshift mutation (c.423_424insG, p.Gly143fs) in the HAX1 gene, confirming the diagnosis of SCN. The patient was successfully treated with granulocyte colony-stimulating factor (G-CSF) and antibiotics. A child with early-onset recurrent infections and neutropenia should be considered to be affected with SCN. Genetic analysis is useful to confirm diagnosis. Timely diagnosis and suitable treatment with G-CSF and antibiotics are important to prevent further complication.

For the treatment of monogenetic hematological disorders, restoration of transgene expression in affected cell populations is generally considered to have beneficial effects. However, X-linked chronic granulomatous disease (XCGD) is unique since the appearance of functional neutrophils in the peripheral blood following hematopoietic stem cell gene therapy is transient only. One contributing factor could be the occurrence of detrimental effects secondary to ectopic gp91phox expression in neutrophils, which has not been formally demonstrated previously. This study uses iPSCs to model XCGD, which allows the process of differentiation to be studied intensely in vitro. Alpharetroviral vectors carrying a ubiquitous promoter were used to drive the âectopicâ expression of codon optimized gp91phox cDNA. In the mature fraction of neutrophils differentiated from transduced XCGD-iPSCs, cellular recovery in terms of gp91phox expression and reactive oxygen species production was abruptly lost before cells had fully differentiated. Most critically, ectopic gp91phox expression could be identified clearly in the developing fraction of the transduced groups, which appeared to correspond with reduced cell viability. It is possible that this impedes further differentiation of developing neutrophils. Therefore, affording cellular protection from the detrimental effects of ectopic gp91phox expression may improve XCGD clinical outcomes.

Mutations in the complement factor H (CFH) gene are associated with complement dysregulation and the development of atypical hemolytic uremic syndrome (aHUS). Several fusion genes that result from genomic structural variation in the CFH and complement factor H-related (CFHR) gene regions have been identified in aHUS. However, one allele has both CFHR gene duplication and CFH::CFHR1 fusion gene have not been reported. An 8-month-old girl (proband) presented with aHUS and was treated with ravulizumab. Her paternal grandfather developed aHUS previously and her paternal great grandmother presented with anti-neutrophil cytoplasmic antibody-associated vasculitis and thrombotic microangiopathy (TMA). However, the proband's parents have no history of TMA. A genetic analysis revealed the presence of CFH::CFHR1 fusion gene and a CFHR3-1-4-2 gene duplication in the patient, her father, and her paternal grandfather. Although several fusion genes resulting from structural variations of the CFH-CFHR genes region have been identified, this is the first report of the combination of a CFH:: CFHR1 fusion gene with CFHR gene duplication. Because the CFH-CFHR region is highly homologous, we hypothesized that CFHR gene duplication occurred. These findings indicate a novel pathogenic genomic structural variation associated with the development of aHUS. [ABSTRACT FROM AUTHOR]

Background: Social activity has long been recognized as an essential component of active aging. How- ever, an overlooked dimension is cross-national comparison within Asia on social activity and its relationship to the functional decline. This study examined functional decline among older Thai and Japanese adults over a two-year period and compared associated social and other factors. Methods: We collected data from two waves of a longitudinal cohort survey administered in Nakhon Pathom, Thailand and the city of Tosa, Japan, covering community-dwelling adults aged ≤ 65. The data cover basic activities of daily living (ADL), sociodemographic traits, health status, depression, and social activities. A total of 338 Thai and 869 Japanese participants with no functional limitations participated at baseline, and 216 Thai and 480 Japanese participants completed the follow-up study after two years. Results: At follow-up, Thai participants reported a higher percentage of functional decline than Japanese participants (22.2% vs. 13.5%). Risk factors associated with functional decline in Thai participants were increased age, female gender, low economic satisfaction, and low social activity levels. Functional decline among Japanese participants was associated with increased age, low social activity levels, and arthropathy. Low social activity was a strong predictor of decline in ADL, and the association was significant even after adjusting for related factors in Thai and Japanese individuals. Conclusion: Although there were differences in the variables associated with ADL decline between Thai and Japanese participants, our results support the promotion of social activities for older adults to preserve a healthy functional status. [ABSTRACT FROM AUTHOR]