Emergence of ciprofloxacin- and penicillin-resistant Neisseria meningitidis isolates in Japan between 2003 and 2020 and its genetic features.

Although we previously reported that some meningococcal isolates in Japan were resistant to penicillin (PCG) and ciprofloxacin (CIP), the antibiotic susceptibilities of Neisseria meningitidis isolates obtained in Japan remained unclear. In the present study, 290 N. meningitidis isolates in Japan between 2003 and 2020 were examined for the sensitivities to eight antibiotics (azithromycin, ceftriaxone, ciprofloxacin, chloramphenicol, meropenem, minocycline, penicillin, and rifampicin). All isolates were susceptible to chloramphenicol, ceftriaxone, meropenem, minocycline, and rifampicin while two were resistant to azithromycin. Penicillin- and ciprofloxacin-resistant and -intermediate isolates (PCGR, CIPR, PCGI and CIPI, respectively) were also identified. Based on our previous findings from whole genome sequence analysis, approximately 40% of PCGI were associated with ST-11026 and cc2057 meningococci, both of which were unique to Japan. Moreover, the majority of ST-11026 meningococci were CIPR or CIPI. Sensitivities to PCG and CIP were closely associated with genetic features, which indicated that, at least for Japanese meningococcal isolates, PCGR/I or CIPI/R would be less likely to be horizontally conferred from other neisserial genomes by transferring of the genes responsible (penA and gyrA genes, respectively), but rather that ancestral N. meningitidis strains conferring PCGR/I or CIPI/R phenotypes clonally disseminated in Japan.

Advantages and limitations of estrogen replacement therapy on hypogonadal survivors of childhood cancer.

BACKGROUND: Hypogonadism is a significant late complication in childhood cancer survivors (CCS). The aim of this study was to elucidate the advantages and limitations of estrogen replacement therapy (ERT) for CCS with hypogonadism. METHODS: Seventeen CCS were divided into two groups: gonadal hypogonadism (GH) group (n = 8) and central hypogonadism (CH) group (n = 9). Pearson correlation coefficients were used to investigate the impact of cancer management on final height, bone density, and uterine development. RESULTS: Seven of GH group had hematologic malignancies, and all of them underwent total body irradiation before bone marrow transplantation. The GH group showed significant positive correlations between the onset age of disease treatment and final height (p < 0.05, R = 0.712) and uterine size following ERT (p < 0.05, R = 0.775). All CCS in the CH group had brain tumors, and seven of them received chemotherapy. There were trends towards positive and negative correlations between the onset age of disease treatment and final height (p = 0.09, R = 0.598) or uterine size (p = 0.07, R = - 0.669), respectively. A negative correlation trend was observed between the age at ERT initiation and final height (p = 0.07, R = - 0.769) or bone density (p = 0.18, R = - 0.626) in six CH patients who received growth hormone therapy. Five CCS in both groups experienced osteoporosis, despite receiving ERT. CONCLUSION: Individualized management strategies beyond ERT are essential to reduce long-term complications in CCS with hypogonadism, considering the type and timing of cancer treatment.

Hyperemesis gravidarum followed by refeeding syndrome causes electrolyte abnormalities induced rhabdomyolysis and diabetes insipidus.

Although hyperemesis gravidarum (HG), an extreme form of morning sickness, is a common complication during pregnancy, HG associated simultaneous onset of rhabdomyolysis and diabetes insipidus due to electrolyte abnormalities are rare. A 34-year-old woman with severe HG at 17 weeks of gestation complicated with appetite loss, weight reduction by 17 kg, general fatigue, myalgia, weakness and polyuria was identified to have simultaneous hypophosphatemia (1.6 mg/dL) and hypokalemia (2.0 mEq/L). Appetite recovery and the improvement of the hypophosphatemia (3.2 mg/dL) were observed prior to the first visit to our department. At the admission, she presented polyuria around 7,000~8,000 mL/day with impaired concentrating activity (U-Osm 185 mOsm/L), and abnormal creatine kinase elevation (4,505 U/L). The electrolyte disturbances and physio-metabolic abnormalities in undernourished state due to HG let us diagnose this case as refeeding syndrome (RFS). In this case, abnormal loss by vomiting, insufficient intake and previous inappropriate fluid infusion as well as the development of RFS may accelerate the severity of hypokalemia due to HG. Thus, as her abnormalities were considered as results of rhabdomyolysis and diabetes insipidus due to severe HG associated hypokalemia based on RFS, oral supplementation of potassium chloride was initiated. After 6 days of potassium supplementation, her symptoms and biochemical abnormalities were completely resolved. Severe HG followed by RFS can be causes of electrolyte abnormalities and subsequent complications, including rhabdomyolysis and renal diabetes insipidus. Appropriate diagnosis and prompt interventions including adequate nutrition are necessary to prevent electrolyte imbalance induced cardiac, neuromuscular and/or renal complications.

The clinical course and pathophysiological investigation of adolescent gestational diabetes insipidus: a case report.

BACKGROUND: Gestational diabetes insipidus (GDI) is a rare endocrine complication during pregnancy that is associated with vasopressinase overproduction from the placenta. Although increased vasopressinase is associated with placental volume, the regulation of placental growth in the later stage of pregnancy is not well known. CASE PRESENTATION: A 16-year-old pregnant woman was urgently transferred to our hospital because of threatened premature labor when the Kumamoto earthquakes hit the area where she lived. During her hospitalization, she complained of gradually increasing symptoms of polyuria and polydipsia. The serum level of arginine vasopressin (AVP) was 1.7 pg/mL, which is inconsistent with central DI. The challenge of diagnostic treatment using oral 1-deamino-8-D-AVP (DDAVP) successfully controlled her urine and allowed for normal delivery. DDAVP tablets were not necessary to control her polyuria thereafter. Based on these observations, clinical diagnosis of GDI was confirmed. Pathophysiological analyses revealed that vasopressinase expression was more abundant in the GDI patient's syncytiotrophoblast in placenta compared with that in a control subject. Serum vasopressinase was also observed during gestation and disappeared soon after delivery. Vasopressinase is reportedly identical to oxytocinase or insulin regulated aminopeptidase (IRAP), which is an abundant cargo protein associated with the glucose transporter 4 (GLUT4) storage vesicle. Interestingly, the expression and subcellular localization of GLUT4 appeared to occur in a vasopressinase (IRAP)-dependent manner. CONCLUSION: Because placental volume may be associated with vasopressinase overproduction in GDI, vasopressinase (IRAP)/GLUT4 association appears to contribute to the growth of placenta in this case.

Genomic characterization of Japanese meningococcal strains isolated over a 17-year period between 2003 and 2020 in Japan.

While invasive meningococcal disease (IMD) is a major public concern worldwide, IMD is categorized as a rare infectious disease in Japan and, thus, its causative agents and epidemiology have not yet been characterized in detail. In the present study, we used molecular methods to epidemiologically characterize 291 meningococcal strains isolated in Japan over a 17-year period between 2003 and 2020 by whole genome sequencing (WGS). Serogroup Y meningococci (MenY) were the most abundant, followed by B (MenB) and then C and W among meningococci from IMD patients, while non-groupable as well as MenY and MenB were the most abundant among isolates from healthy carriers. Sequence type (ST) defined by multilocus sequence typing (MLST) showed that ST-1655 and ST-23 belonging to clonal complex (cc) 23 were dominant among Japanese IMD isolates, while ST-11026 (cc32) unique to Japan as well as ST-23 were dominant among Japanese non-IMD isolates. Phylogenetic analyses of ST by MLST revealed that Japanese isolates were classified with 12 ccs, including recently reported cc2057. Phylogenic analyses by WGS showed that isolates of ST-11026 and of ST-1655 were genetically close, whereas ST-23 isolates appeared to be diverse. Moreover, comparisons with other cc11 isolates isolated worldwide indicated that some Japanese cc11 isolates were genetically close to those isolated in Europe and China. An in silico analysis suggested that 14.3 and 44.2% of Japanese MenB were cross-reactive with 4CMenB and rLP2086 MenB vaccines, respectively. The results in the present study revealed that some epidemiological features were unique to Japan.

Genetic characterization of clonal complex sequence type 2057 (cc2057) serogroup B Neisseria meningitidis strains unique to Japan and identification of a capsular-switched serogroup Y isolate cc2057.

Introduction. Only approximately 40 cases of invasive meningococcal diseases are reported annually in Japan, and the dominant strains are serogroup Y meningococci (MenY) followed by serogroup B meningococci (MenB). Within the last 10 years, Neisseria meningitidis strains belonging to clonal complex (cc)2057 have become dominant among Japanese MenB and have not been identified in countries other than Japan.Hypothesis/Gap Statement. The uniqueness of cc2057 N. meningitidis strains was considered to be epidemiologically of importance, and some genetic features could be hidden in the genome of cc2057 meningococci.Method. We investigated 22 cc2057 MenB and one cc2057 MenY using whole genome sequencing (WGS) and also predicted the potential coverage of 4CMenB and bivalent rLP2086 vaccines in silico.Results. cc2057 N. meningitidis strains were phylogenetically assigned to two clades. Three hypothetical genes homologous to those in Neisseria lactamica and sequences related to a new CRISPR Cas9 system were found only in the genome of cc2057 strains. Moreover, one cc2057 MenY strain was presumed to be capsular-switched at the capsule synthesis (cps) locus. The potential coverage of 4CMenB and rLP2086 for cc2057 MenB strains was estimated to be very low.Conclusion. To the best of our knowledge, this is the first study to provide genetic insights from epidemiologically unique N. meningitidis cc2057 strains isolated only in Japan, an island country.

Severe encephalopathy associated with SARS-CoV-2 Omicron BA.1 variant infection in a neonate.

INTRODUCTION: The coronavirus disease 2019 (COVID-19), including the Omicron variant, is less severe in children than in adults. To date, there has been no detailed description of COVID-19-associated severe encephalopathy due to the Omicron variant during the neonatal and early infantile periods. CASE PRESENTATION: During the outbreak of the Omicron variant, a 29-day-old male presented with a pale and ill appearance. The patient was intubated for mechanical ventilation owing to recurrent apnea, which subsequently turned out to be a breath-holding that may have been caused by seizure. In addition, nonconvulsive status epilepticus was observed. Total duration of repetitive seizure activities was approximately 30 min per hour when seizures were most severe. Brain magnetic resonance imaging (MRI) on day 14 revealed extensive hyperintensity in the T2 sequence, hypointensity in the fluid-attenuated inversion recovery (FLAIR) sequence in the deep and subcortical white matter, and diffusion restriction in the corpus callosum. The Omicron BA.1 variant of the severe acute respiratory syndrome coronavirus 2 was detected in his respiratory sample. Follow-up MRI on day 45 revealed multiple cystic cavitations. CONCLUSION: Although COVID-19 is not severe in most children, life-threatening conditions such as COVID-19-associated severe encephalopathy can occur during the neonatal and early infantile periods.

Vasovagal reactions after COVID-19 vaccination in Japan.

Coronavirus disease 2019 (COVID-19) vaccine administration started in February 2021 in Japan. As of December 2021, approximately 75% of the population aged ≥12 years had received two doses of vaccine. We conducted a study to investigate vasovagal reactions (VVR) after COVID-19 vaccination using data on adverse events following immunization. The crude reporting rate of VVR (cases/1,000,000 doses) after vaccination was 9.6 in all age groups combined, and was more frequent in the younger age groups: 28.6 and 37.2 in individuals aged 10-19 years and 20-29 years, respectively. In individuals aged 10-29 years, the rate was similar in males and females (33.0 and 34.2, respectively, p = 0.53); but was higher after dose 1 than after dose 2 (57.4 and 8.8, respectively, p < 0.001). Based on these results, caution needs to be exercised when vaccinating adolescents and young adults, especially with dose 1 of COVID-19 vaccines.

Solitary metastasis of a clear cell ovarian adenocarcinoma to the small bowel mucosa.

Metastasis of ovarian carcinoma to the small bowel parenchyma without peritoneal dissemination is uncommon. A 63-year-old woman underwent surgery for a clear cell adenocarcinoma of the ovary and received adjuvant chemotherapy. Eighteen months after the operation, she presented with recurrent occult bowel hemorrhage without evidence of an abdominal mass. Nine months later, a rapidly growing abdominal mass was detected. Laparoscopy revealed a solitary tumor of the ileum covered with an intact serosal layer. Partial ileectomy was performed for tumor resection. Histological examination revealed cells resembling the primary ovarian tumor in the mucosal surface of the small bowel along with an intact serosa. The tumor cells were positive for cytokeratin 7 and negative for cytokeratin 20, suggesting an ovarian origin. This is the first report of solitary metastasis of an ovarian carcinoma to the small bowel parenchyma without peritoneal dissemination. Metastasis to the small bowel should be considered in ovarian carcinoma patients with occult gastrointestinal hemorrhage.

Preventing peripheral intravenous catheter failure by reducing mechanical irritation.

Peripheral intravenous catheter failure is a significant concern in the clinical setting. We investigated the effectiveness of care protocols, including an ultrasonographic "pre-scan" for selecting a large-diameter vein before catheterization, a "post-scan" for confirming the catheter tip position after catheterization with ultrasonography, and the use of a flexible polyurethane catheter to reduce the mechanical irritation that contributes to the incidence of catheter failure. This intervention study was a non-randomized controlled trial to investigate the effectiveness of the abovementioned care protocols, the effects of which were compared to the outcomes in the control group, which received conventional care. For both groups, participants were selected from patients in two wards at the University of Tokyo in Japan between July and November 2017. Inverse probability score-based weighted methods (IPW) using propensity score were used to estimate the effectiveness of care protocols. The primary outcome was catheter failure, which was defined as accidental and unplanned catheter removal. We used Kaplan-Meier survival curves to compare rates of time until catheter failure. We analysed 189 and 233 catheters in the intervention and control groups, respectively. In the control group, 68 catheters (29.2%) were determined to have failed, whereas, in the intervention group, only 21 catheters (11.1%) failed. There was a significant difference between each group regarding the ratio of catheter failure adjusted according to IPW (p = 0.003). The relative risk reduction of the intervention for catheter failure was 0.60 (95% CI: 0.47-0.71). Care protocols, including assessment of vein diameter, vein depth, and catheter tip location using ultrasound examination for reducing mechanical irritation is a promising method to reduce catheter failure incidence.

Emx2 and Pax6 function in cooperation with Otx2 and Otx1 to develop caudal forebrain primordium that includes future archipallium.

One of the central issues in developmental neurobiology is how the forebrain is organized ontogenetically. The traditional view is that the anterior neuroectoderm first develops into mesencephalic and prosencephalic vesicles; the latter vesicle subsequently develops into the diencephalon and secondary prosencephalon, of which dorsal parts protrude to generate the telencephalon. The diencephalon yields the pretectum, thalamus, and prethalamus, and the telencephalon produces the archipallium, neopallium, and ganglionic eminences. By identifying cell descendants that once expressed Emx2 with use of the Cre knock-in mutant into the Emx2 locus and analyzing phenotypes of double mutants between Emx2 and Otx2/Otx1 and between Emx2 and Pax6, we propose that at the 3-6 somite stage, the anterior neuroectoderm develops into three primordia: midbrain, caudal forebrain, and rostral forebrain. The caudal forebrain primordium generates not only the pretectum, thalamus, and prethalamus but also the archipallium, cortical hem, choroid plexus, choroidal roof, and eminentia thalami. The primordium corresponds to the Emx2- or Pax6-positive region at the 3-6 somite stage that most probably does not include the future neopallium or commissural plate. Otx2 and Otx1 that are expressed in the entire future forebrain and midbrain cooperate with this Emx2 and Pax6 expression in the development of the caudal forebrain primordium; Emx2 and Pax6 functions are redundant. In the embryonic day 9.5 Emx2-/-Pax6-/- double mutant, the caudal forebrain remained unspecified and subsequently transformed into tectum in a mirror image of the endogenous one.

cfm is a novel gene uniquely expressed in developing forebrain and midbrain, but its null mutant exhibits no obvious phenotype.

A novel gene, cfm, that is expressed uniquely during early forebrain and midbrain development was isolated, and its null mutant was generated. cfm does not have any known functional domains, but is conserved in human, chick, Xenopus and zebrafish; a site of phosphorylation by MAP kinase exists in one of the domains conserved among them. Its expression was initially found at the 5-somite stage in the future midbrain and caudal forebrain region. The expression in mesencephalon subsequently decreased, was found in a stripe in the mid mesencephalon at E9.0. The expression in diencephalon was restricted to the dorsal thalamic region by E9.5 and to epiphysis at E12.5. In mouse a cognate, cfm2, exists that is expressed uniquely in the somite just formed and the presomite to be segmented, but not in forebrain or midbrain during early development. However, the cfm null mutant was live-born without any apparent defects.

Emx1 and Emx2 cooperate in initial phase of archipallium development.

Emx1 and Emx2 are mouse cognates of the Drosophila head gap gene, ems. Previously we have reported that the dentate gyrus is affected in Emx2 single mutants, and defects are subtle in Emx1 single mutants. In most of the cortical region Emx1 and Emx2 functions would be redundant. To test this assumption here we examined the Emx1 and Emx2 double mutant phenotype. In the double mutants the archipallium was transformed into the roof without establishing the signaling center at the cortical hem and without developing the choroid plexus. We propose that Emx1 and Emx2 cooperate in generation of the boundary between the roof and archipallium; these genes develop the archipallium against the roof. This process probably occurs immediately after the neural tube closure concomitant with the Emx1 expression.

ang is a novel gene expressed in early neuroectoderm, but its null mutant exhibits no obvious phenotype.

To find genes that play roles in initial regionalization of anterior neuroectoderm, 15 novel genes were isolated that are expressed in anterior neuroectoderm at E8.0-E8.5. Moreover, to assess their functions by generation of mutant mice a conventional targeting strategy was designed, exploiting the availability of accurate long amplification PCR and BAC library that is coupled with genome information, in C57BL/6 strain. The ang is one of such genes; it has no known functional domains or no cognates, but is conserved not only in vertebrates, but also in Drosophila. Its expression was initially found throughout neuroectoderm at E7.5; subsequently the expression became high in rostral brain and caudal neuropore regions and low in hindbrain and spinal cord regions. At E12.5 the expression was found in undifferentiated neuroepithelium in ventricular zone, dorsal root ganglia and several non-neural tissues. However, ang null mutant was live-born without any apparent defects.

A dimethoxytriazine type glycosyl donor enables a facile chemo-enzymatic route toward α-linked N-acetylglucosaminyl-galactose disaccharide unit from gastric mucin.

An efficient chemo-enzymatic process for construction of the α-linked disaccharide unit (GlcNAcα1-4Gal) found in gastric mucin has been developed. The process consists of a one-step preparation of a novel triazine type glycosyl donor in water and the subsequent transglycosylation to a galactose derivative catalysed by α-N-acetylglucosaminidase.

Specific binding of GM1-binding peptides to high-density GM1 in lipid membranes.

The ganglioside Galbeta1-3GalNAcbeta1-4(Neu5Acalpha2-3)Galbeta1-4Glcbeta1-1'Cer (GM1) is an important receptor. We have previously identified GM1-binding peptides based on affinity selection from a random peptide library. In the present study, we determined the amino acids essential for binding GM1 and investigated the specific interaction with GM1 in the lipid membrane. Arginines and aromatic amino acids in the consensus sequence (W/F)RxL(xP/Px)xFxx(Rx/xR)xP contributed to the ability of the peptides to bind GM1. The peptide p3, VWRLLAPPFSNRLLP, having the consensus sequence, showed high affinity for GM1 with a dissociation constant of 1.2 microM. Furthermore, the density-dependent binding of p3 was investigated using mixed monolayers of GM1 and Glcbeta1-1'Cer (GlcCer). p3 binds preferentially to high-density GM1, and its interaction with GM1 was found to be cooperative based on a Hill plot. These results indicated that a lateral assembly of GM1 molecules was required for the recognition of carbohydrates by p3. The GM1-binding peptide played a role as a unique anti-GM1 probe differing from the cholera toxin B subunit or antibodies.

Prevention of ventilatory disturbance while in the face-down position after macular hole surgery.

The aim of the present study was to assess the effects of the face-down position on ventilatory function after macular hole surgery. The transcutaneous carbon dioxide tensions (tcPCO2) were measured in five patients who had undergone intraocular tamponade and in 17 normal subjects. The tcPCO2 measurements were done in patients following vitrectomy in the sitting position and in the prone position with their faces down over the semi-closed spaces of the conventional mats. In normal subjects, minute ventilatory volumes (V.E) were measured simultaneously with tcPCO2 in the sitting position and prone position. The newly introduced face-down mats (new mats) for the prone position were also tested in the normal subjects. In normal subjects, VE in the prone position with the conventional mats was significantly lower than that found in the sitting position (5.06 +/- 1.55 vs 6.06 +/- 1.64 L/min; P < 0.002). The tcPCO2 in the prone position was significantly higher than that in the sitting position (41.7 +/- 2.1 vs 38.0 +/- 1.9 mmHg; P < 0.0001). In post-vitrectomy patients, tcPCO2 in the prone position with the conventional mats was significantly higher than that in the sitting position (41.4 +/- 1.7 vs 38.6 +/- 2.2 mmHg; P < 0.02). The tcPCO2 in the prone position in normal subjects was significantly lower using new mats than that when using conventional mats. The use of conventional mats during a prone position, increased the tcPCO2 values when compared to the tcPCO2 values obtained during the sitting position in patients following vitrectomy. This could be due to either a decrease of the VE caused by limited thoracic movement or rebreathing of the exhaled gas over the semi-closed space, or both. The new mats might be useful in alleviating the increase of tcPCO2 by eliminating the rebreathing of the exhaled gas.

Identification of transcriptional targets for Six5: implication for the pathogenesis of myotonic dystrophy type 1.

Myotonic dystrophy 1 (DM1) is the most common inherited neuromuscular disease in adults. The disorder, characterized by myotonia, muscle wasting and weakness, cataract, insulin resistance, and mental impairment, is caused by the expansion of an unstable CTG repeat located in the 3' untranslated region of DMPK. The repeat expansion suppresses the expression of the homeobox gene SIX5. We describe here an experimental system to identify downstream transcriptional targets of mouse Six5 in order to elucidate the role of SIX5 in the pathogenesis of DM1 and development. By overexpressing a constitutively active Six5 (VP16-Six5wt) using adenovirus-mediated gene transfer in P19 cells and subsequent expression profiling using cDNA arrays, 21 genes, whose expression level increased by the treatment, were identified as potential target genes. Genes expressed in the somites, skeletal muscles, brain and meninges comprised the majority, suggesting the role of Six5 in the development and function of mesodermal tissues and brain. We provide evidence that Igfbp5 encoding a component of IGF signaling is a direct Six5-target. Moreover, the overall expression level of Igfbp5 was decreased in Six5-deficient mouse fibroblasts, and the response of human IGFBP5 to MyoD-induced muscle conversion was altered in cells of DM1 patients. Our results not only identify Six5 as an activator that directs Igfbp5 expression but also suggest that reduced SIX5 expression in DM1 might contribute to specific aspects of the DM1 phenotype.