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Mihoko Furuichi,1 Kaoru Goto,2 Nobuyuki Tetsuka,3 Katsushi Ishida,4 Isao Miyairi,3 Yoshiaki Cho,5 Masashi Kasai,6 Yukiya Kurahashi,7 Hideki Akeda,7 Yuho Horikoshi1 1Division of Infectious Diseases, Department of Pediatrics, 2Division of Microbiology, Department of Clinical Laboratory, Tokyo Metropolitan Children’s Medical Center, 3Division of Infectious Diseases, Department of Pediatrics, 4Division of Microbiology, Department of Clinical Laboratory, National Center for Child Health and Development, Tokyo, 5Department of Pediatrics, 6Division of Pediatric Critical Care Medicine and Infectious Disease, Nagano Children’s Hospital, Nagano, 7Department of General Pediatrics, Okinawa Prefectural Nanbu Medical Center & Children’s Medical Center, Okinawa, Japan Abstract: Group B streptococcus (GBS) is an important cause of serious bacterial infections (SBIs) in infants. Non-penicillin-susceptible GBS strains have been reported among adults, but little is known among children. We collected GBS isolates from 4 children’s hospitals in Japan, and performed serotyping of GBS strains and reviewed penicillin minimum inhibitory concentrations of GBS strains from both sterile and non-sterile sites. Our examination revealed 235 isolates including 41 isolates from SBIs and 194 isolates from colonization. Nine cases of GBS SBIs (21.9%) were early-onset, 19 (46.3%) were late-onset, and 13 (31.7%) were ultra-late-onset. Non-penicillin-susceptible GBS strains were not detected among either isolates. Serotypes Ia, Ib, and III were predominant among SBIs. In conclusion, at this time, we have no non-penicillin-susceptible GBS strains in Japanese children. Penicillin susceptibility should continue to be monitored carefully in each geographic area. Keywords: GBS, serotypes, penicillin, MIC, children

A patient with GATA2 deficiency developed corticosteroid-responsive sterile granulomatous lung disease despite monocytopenia. The presence of B-lymphopenia, autoimmunity, an elevated level of serum B-cell-activating factor, and pulmonary plasma cell infiltration, which together suggested an underlying mechanism similar to that of combined variable immunodeficiency lung disease., Competing Interests: Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (© 2024 The Authors.)

After the introduction of the seven-valent pneumococcal conjugate vaccine, the global spread of multidrug-resistant serotype 19A-sequence type 320 (ST320) strains of Streptococcus pneumoniae became a public health concern. In Japan, the main genotype of serotype 19A was ST3111, and the identification rate of ST320 was low. Although the isolates were sporadically detected in both adults and children, their origin remains unknown. Thus, by combining pneumococcal isolates collected in three nationwide pneumococcal surveillance studies conducted in Japan between 2008 and 2020, we analyzed 56 serotype 19A-ST320 isolates along with 931 global isolates, using whole-genome sequencing to uncover the transmission route of the globally distributed clone in Japan. The clone was frequently detected in Okinawa Prefecture, where the United States returned to Japan in 1972. Phylogenetic analysis demonstrated that the isolates from Japan were genetically related to those from the United States; therefore, the common ancestor may have originated in the United States. In addition, Bayesian analysis suggested that the time to the most recent common ancestor of the isolates from Japan and the U.S. was approximately the 1990s to 2000, suggesting the possibility that the common ancestor could have already spread in the United States before the Taiwan 19F-14 isolate was first identified in a Taiwanese hospital in 1997. The phylogeographical analysis supported the transmission of the clone from the United States to Japan, but the analysis could be influenced by sampling bias. These results suggested the possibility that the serotype 19A-ST320 clone had already spread in the United States before being imported into Japan.

An Arabidopsis mutant named defective repression of OLE3::LUC 1 (drol1) was originally isolated as a mutant with defects in the repression of OLEOSIN3 (OLE3) after seed germination. In this study, we show that DROL1 is an Arabidopsis homolog of yeast DIB1, a subunit of the U5 small nuclear ribonucleoprotein particle (snRNP) in the spliceosome. It is also part of a new subfamily that is specific to a certain class of eukaryotes. Comprehensive analysis of the intron splicing using RNA sequencing analysis of the drol1 mutants revealed that most of the minor introns with AT-AC dinucleotide termini had reduced levels of splicing. Only two nucleotide substitutions from AT-AC to GT-AG enabled AT-AC-type introns to be spliced in drol1 mutants. Forty-eight genes, including those having important roles in abiotic stress responses and cell proliferation, exhibited reduced splicing of AT-AC-type introns in the drol1 mutants. Additionally, drol1 mutant seedlings showed retarded growth, similar to that caused by the activation of abscisic acid signaling, possibly as a result of reduced AT-AC-type intron splicing in the endosomal Na + /H + antiporters and plant-specific histone deacetylases. These results indicate that DROL1 is specifically involved in the splicing of minor introns with AT-AC termini and that this plays an important role in plant growth and development., (© 2021 Society for Experimental Biology and John Wiley & Sons Ltd.)

In November 2013, a 13-valent pneumococcal conjugate vaccine (PCV13) for all infants aged younger than 5 years was incorporated into the Japan national immunization program. An annual survey of nasopharyngeal carriage rates was performed on healthy infants aged 2-24 months from Okinawa, Japan to evaluate the effect of PCV13 on pneumococcal colonization. Of 756 evaluable infants, 203 pneumococcal strains were detected in 193 infants. The overall nasopharyngeal carriage rate was 25.5%, which was not different from our previously reported isolation rate before the introduction of PCV13. The main serotypes of the Streptococcus pneumoniae strains are 15A (18.2%), non-typeable (14.8%), and 15B (11.8%). The carriage rates of pneumococcal strains with 7-valent pneumococcal conjugate vaccine serotypes and PCV13 serotypes were 3.0% and 9.9%, respectively. These values were significantly lower than we reported before the introduction of PCV13. However, the carriage rates of non-PCV13 serotypes have increased. Multivariate logistic regression analysis suggested that siblings and day care attendance are risk factors for pneumococcal carriage., Competing Interests: Declaration of Competing Interest None., (Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Haemophilus influenzae type b (Hib) vaccine was introduced as a voluntary vaccine in December 2008 and was included in the national routine immunization program in April 2013 in Japan. Currently, no nationwide data are available to evaluate the effectiveness of Hib vaccine in Japan., Methods: To evaluate the effectiveness of Hib vaccine in Japan, nationwide active population-based surveillance of culture-proven invasive infections caused by H. influenzae in children was performed in 2008-2017 in 10 prefectures in Japan (covering approximately 23% of the total Japanese population). Clinical data were recorded on a standardized case report form. Capsular type and antimicrobial susceptibility of the H. influenzae isolates were examined. The incidence rate ratio (IRR) and its confidence interval (CI) were calculated to compare data from 5 years before and that from after the introduction of the national routine Hib vaccine immunization program., Results: During the 10-year study period, 566 invasive H. influenzae disease cases including 336 meningitis cases were identified. The average number of invasive H. influenzae disease cases among children <5 years of age during 2013-2017 decreased by 93% (IRR: 0.07, 95%CI 0.05-0.10, p < 0.001) compared with those occurring during 2008-2012. Hib strains have not been isolated from invasive H. influenzae disease cases since 2014; however, non-typeable H. influenzae and H. influenzae type f isolates have been noted as causes of invasive H. influenzae diseases among children <5 years in the post-Hib vaccine era., Conclusions: After the governmental subsidization of the Hib vaccine, invasive Hib disease cases decreased dramatically in the study population, as per our surveillance. Continuous surveillance is necessary to monitor the effectiveness of Hib vaccine and for detecting any emerging invasive capsular types., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: In Japan, the seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2010. PCV13 has replaced PCV7 since November 2013., Methods: The effectiveness of PCV7 in protecting against invasive pneumococcal disease (IPD) in children aged <5 years was evaluated in a nationwide active population-based surveillance of IPD in 2008-2013 in 10 prefectures in Japan., Results: 1181 cases were identified; 711 pneumococcal strains were analyzed for serotyping and antimicrobial resistance. Compared with the baseline IPD incidence (25.0 per 100,000), a 98% decline in IPD caused by PCV7 serotypes was found after the introduction of PCV7. This was partially offset by an increased incidence of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes, resulting in a 57% decline in overall IPD incidence. Absolute increases in the incidence rates of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes were 2.1 and 2.8 per 100,000 during the study period, respectively. The proportion of meropenem-nonsusceptible strains, especially with serotypes 19A and 15A, increased significantly after PCV7 introduction., Conclusions: Our data confirmed a 98% decline in IPD incidence caused by PCV7 serotypes in children aged <5 years and serotype replacement after PCV7 introduction. This shows the importance of continuing surveillance of serotypes responsible for IPD and their antimicrobial resistance in Japan., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Group B Streptococcus (GBS) is one of the leading causes of neonatal bacterial infections. Population-based surveillance of GBS-related invasive diseases among newborns and infants from 10 prefectures in Japan was performed between 2007 and 2012. The characteristics of cases and isolated GBS are described in this study. The incidence rate of GBS-related invasive diseases was 0.13 per 1,000 live births. Analysis of GBS samples obtained from 60 invasive cases showed that the most frequent serotypes were III (48.3%), Ia (30.0%), and Ib (10.0%). All isolates were susceptible to penicillin G, ampicillin, cefotaxime, imipenem, and panipenem. However, 14, 2, and 7 isolates were resistant to erythromycin, clindamycin, and both erythromycin and clindamycin, respectively. Multilocus sequence typing revealed that GBS sequence type (ST) 23, ST17, and ST335 caused higher incidences of meningitis. These data show that serotypes III, Ia, and Ib together caused more than 80% of invasive infections in Japanese infants, and that GBS strains are still susceptible to β-lactam antibiotics.

An unusual rotavirus strain, Ryukyu-1120, with G5P[6] genotypes (RVA/Human-wt/JPN/Ryukyu-1120/2011/G5P[6]) was identified in a stool specimen from a hospitalized child aged 4 years who showed diarrhoea and encephalopathy. In this study, we sequenced and characterized the complete genome of strain Ryukyu-1120. On whole genomic analysis, this strain was found to have a unique genotype constellation: G5-P[6]-I5-R1-C1-M1-A8-N1-T1-E1-H1. The VP6 and NSP1 genotypes I5 and A8 are those commonly found in porcine strains. Furthermore, phylogenetic analysis indicated that each of the 11 genes of strain Ryukyu-1120 appeared to be of porcine origin. Thus, strain Ryukyu-1120 was found to have a porcine rotavirus genetic backbone and is likely to be of porcine origin. To our knowledge, this is the first report of whole-genome-based characterization of the emerging G5P[6] strains in Asian countries. Our observations will provide important insights into the origin of G5P[6] strains and the dynamic interactions between human and porcine rotavirus strains.

We report a case of mild encephalopathy with a reversible splenial lesion (MERS) associated with acute gastroenteritis caused by rotavirus (RV) infection. The patient (male, 4 years and 3 months old) was admitted to our hospital for diarrhea and afebrile seizures. Head MRI revealed a hyperintense signal in the splenium of the corpus callosum on DWI and a hypointense signal on the ADC-map. After awakening from sedation, the patient's disturbance of consciousness improved. On day 5 after admission of the illness, the patient was discharged from the hospital in a good condition. Electroencephalography on day 2 after admission was normal. On day 8 of admission, head MRI revealed that the splenial lesion had disappeared. RV antigen-positive stools suggested that RV had caused MERS. This RV genotype was considered to be G5P[6]; it may have spread to humans as a strain reassortment through substitution of porcine RV into human RV gene segments. This extremely rare genotype was detected first in Japan and is not covered by existing vaccines; this is the first sample isolated from encephalopathy patients. Few reports have investigated RV genotypes in encephalopathy; we believe that this case is valuable for studying the relationship between genotypes and clinical symptoms.

Hyper-IgE syndrome (HIES) is a primary immunodeficiency disease characterized by recurrent infections and marked immunoglobulin (Ig)E elevation. To assess the proper T-cell defects of HIES, the cytokine profile of naturally activated T cells was compared between HIES, atopic dermatitis and chronic granulomatous disease (CGD). Intracellular flow cytometric analysis after in vitro stimulation showed no difference in the proportion of interferon (IFN)gamma- or interleukin 4 (IL-4)-producing T cells among these diseases. Quantitative polymerase chain reaction (PCR) for the cytokine genes was performed using circulating highly fractionated HLA-DR+ and HLA-DR- T cells. The IFNgamma/IL-4 or IFNgamma/IL-10 ratios were lower in HLA-DR+ T cells of HIES than in CGD (P = 0.0106, 0.0445), but did not differ between HIES and atopy. The transforming growth factor-beta (TGFbeta)/IL-4 ratio in HLA-DR+ T cells of HIES was lower than that of atopy (0.0106) or CGD (0.0062). The TGFbeta/IL-4 ratio in HLA-DR- T cells of HIES was also lower than that of atopy (0.0285). Stepwise logistic regression analysis identified TGFbeta/IL-4 ratios in HLA-DR+ (0.0001) or HLA-DR- (0.0086) T cells as the most powerful parameters to distinguish HIES from atopy and/or CGD. Serum IgE levels negatively correlated with IFNgamma/IL-4 (0.0108), IFNgamma/IL-10 (0.0254), or TGFbeta/IL-4 (0.0163) ratios in HLA-DR+, but not HLA-DR-, T cells. These results suggested that the in vivo activated T cells of HIES did not sufficiently express the IFNgamma and TGFbeta genes, which could affect IL-4-dependent IgE production. The reduced TGFbeta expression may involve the indigenous T-cell defects of HIES.

Background: Therapeutic modalities in acute metabolic decompensation in maple syrup urine disease (MSUD) are variable, and outcomes of each therapeutic measure have been known only individually. Factors that affect neurological outcome are not clear., Methods: A questionnaire was sent throughout Japan to each pediatrician treating any of the 42 MSUD patients., Results: Necessary information was available for 13 patients through the questionnaire, and through a publication for one patient. In nine of the 14 patients episodes of metabolic decompensation developed in the neonatal period. In the other five, the onset of disease was delayed until infancy or later. In the nine patients with neonatal onset, a pretreatment level of plasma leucine greater than 40 mg/100 mL or a duration of altered level of alertness longer than 10 days was associated with a poor neurological outcome. The therapeutic measures employed included intravenous infusion of glucose and electrolyte solution or hypertonic glucose and electrolyte solution, exchange transfusion, peritoneal dialysis, a large dose of thiamine and intravenous hyperalimentation. All patients had survived the episodes and were alive at the time of the survey. Five of the nine patients with neonatal onset have developed neurological sequelae to varying degrees. Episodes of metabolic decompensation in infancy or thereafter did not affect, or only minimally affected, the neurological outcome., Conclusion: Therapeutic goals to improve neurological outcome are to shorten the duration of the altered level of consciousness, and to minimize the peak plasma leucine level as much as possible.

In 1991, in Fukuoka, Japan, a measles outbreak occurred in which we observed 15 cases of measles vaccine failure (MVF). We examined these patients both clinically and serologically. Seven of them, with a response pattern of an early rise in and attainment of a high hemagglutination inhibition (HI) antibody titre, were considered to be secondary vaccine failures (EH group). Eight others showed a normal (relatively late rise and low titre) HI antibody response pattern and were considered to be primary vaccine failures (LL group). In both MVF groups, measles-specific IgM antibody was detected by enzyme immunoassay. The EH group had a milder rash than did the LL group and unvaccinated controls. We believe they had an immunological memory that modified the clinical manifestations of measles. Two cases of encephalitis were observed in the EH group; both patients recovered without sequelae. These data suggest that the mere presence or absence of IgM antibody is not sufficient to differentiate primary from secondary MVFs. A two-dose measles vaccination scheme should be recommended to secure a booster effect, because immunity is waning in the population in which the measles vaccination rate is not high enough and in which natural measles still exists.

Macrophage colony-stimulating factor (M-CSF) levels in the cerebrospinal fluid of 14 patients with meningitis and of 14 patients suffering from a disease other than meningitis were measured using an enzyme-linked immunosorbent assay. All four bacterial meningitis patients had M-CSF levels in the cerebrospinal fluid which exceeded 1540 U/ml, and the mean value was 3333 +/- 1481 U/ml. The mean M-CSF level in the cerebrospinal fluid of the ten aseptic meningitis patients was 393 +/- 175 U/ml, which was higher than that of patients who suffered from a disease other than meningitis (179 +/- 90 U/ml) (P < 0.01). There was no clear correlation between the M-CSF levels and the numbers of white blood cells, granulocytes, or monocytes in the cerebrospinal fluid. These elevated M-CSF levels were thought to be of a local origin, since most patients with high M-CSF levels in the cerebrospinal fluid had relatively low M-CSF levels in the serum.

We reported a case of salmonellosis treated with ofloxacin (OFLX) which showed excellent clinical and bacteriological effect in a 22 year-old Japanese male with Salmonellosis paratyphi A. He had stayed in India from Sept. 6, 1990 to Oct. 13, 1990. On Oct. 25, 1990, he complained of a high fever and headache. On Oct. 29, he was admitted to our hospital and was diagnosed as Salmonellosis paratyphi A by the blood culture. He was treated with 2.0 g/day of chloramphenicol (CP) for 7 days, but the clinical efficacy was not sufficient. Therefore, we added 900 mg/day of OFLX for 10 days. He was treated successfully with them, the temperature became on the 2nd day. No side effect and no changes of laboratory data were observed and no recurrence was observed clinically and bacteriologically for three months after his discharge.

We reported a rare case of Plasmodium vivax malaria who showed findings of disseminated intravascular coagulation (DIC). A 50-year-old Japanese male was sent to our hospital with the diagnosis of Plasmodium vivax malaria on the 26th of April, 1990. He had stayed in the Solomon Islands from Oct. 1987 to Dec. 1989, and had febrile episodes during his stay in the island. On April 18, 1990, he complained of a high fever with chills, and showed the same episodes on the 20th, 22th and was diagnosed as malaria. He was treated successfully with the sulfadoxine 500 mg and pyrimethamine 25mg (Fansidar), following the normal temperature on the 4th day and disappearance of malarial parasites in the peripheral blood smear on the 6th day. Interestingly, he had thrombocytopenia and a high titer serum level of fibrin degradation product (FDP) supporting the questionable diagnosis of DIC. Even on the 12th day after improved thrombocytopenia by treatment with Gabexate (FOY), the serum level of FDP, D-dimer and thrombin-nati-thrombin (TAT)III complex still remained at high titer levels. One month later he was readmitted for a relapse of Plasmodium vivax malaria, when he showed thrombocytopenia but the serum level of FDP, D-dimer, TAT III complex and PM.alpha 2 PI complex were normal levels. We concluded that the thrombocytopenia and the high titer of FDP at his first admission was a manifestation of DIC.

The level of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the cerebrospinal fluid from 14 infants and children with meningitis and 6 patients who suffered other diseases besides meningitis was measured by our sensitive enzyme linked immunosorbent assay for GM-CSF. The minimal detection level of GM-CSF was 40 pg/ml. Six of 9 patients (67%) with aseptic meningitis had detectable GM-CSF in cerebrospinal fluid and the concentrations of GM-CSF ranged from 49 to 114 pg/ml (mean 72 pg/ml), whereas none of 5 patients with bacterial meningitis or 6 patients with other diseases besides meningitis had detectable GM-CSF levels. There was no clear correlation between the GM-CSF levels in cerebrospinal fluid and the leukocyte count in either peripheral blood or cerebrospinal fluid, or the concentration of protein or glucose in cerebrospinal fluid.

The contribution of phagocytes and antibody to protection against Salmonella typhimurium during the early phase of infection in mice was analysed. Following intravenous injection, most of the bacteria were trapped in the liver and spleen within 10 to 60 min and killed within 6 h; surviving organisms began to multiply in these tissues after 24 h and reached a maximum at 5 to 7 d. The transient killing phase was abrogated by treatment with carrageenan, a macrophage blocker, but not by whole-body X-irradiation. These observations suggest that carrageenan-sensitive, but radio-resistant macrophages play an important role in the early phase of the infection. Actively immunized mice showed accelerated trapping and killing; the protection observed at the early stage of infection in immunized mice could be passively transferred to normal mice, whereas carrageenan-treated mice did not kill the bacterial even after receiving immune serum. It seems that the synergistic action of macrophages and antibody provided the main initial primary defence in immune animals.