Clinical characteristics of pediatric febrile urinary tract infection in Japan.

BACKGROUND: Febrile urinary tract infection (fUTI) is the most common serious bacterial infection in children. Despite this, there have been no studies examining the clinical features of pediatric fUTI in Japan. The purpose of this study was to describe the clinical characteristics of fUTI in Japanese children. METHODS: A multicenter, retrospective, observational study was conducted at 21 hospitals in Japan. Children under the age of 15 years who were diagnosed with fUTI between 2008 and 2017 were included. The diagnostic criteria were a temperature over 38 °C and the presence of a single bacterial pathogen in urine culture. Patient characteristics were obtained from medical records. RESULTS: In total, 2,049 children were included in the study. The median age was 5 months, and 59.3% were male. It was found that 87.0% of the males and 53.2% of the females were under 1 year of age. The main causative pathogens identified were Escherichia coli and Enterococcus spp., accounting for 76.6% and 9.8% of infections, respectively. CONCLUSIONS: There was a male predominance of fUTI in Japanese children, particularly in infants. Enterococcus spp. were the second most frequent causative pathogen; therefore, Gram staining of urine samples is strongly recommended before initiating antibiotic therapy.

Cytochrome P450 oxidoreductase deficiency: identification and characterization of biallelic mutations and genotype-phenotype correlations in 35 Japanese patients.

CONTEXT: Cytochrome P450 oxidoreductase (POR) deficiency is a rare autosomal recessive disorder characterized by skeletal dysplasia, adrenal dysfunction, disorders of sex development (DSD), and maternal virilization during pregnancy. Although multiple studies have been performed for this condition, several matters remain to be clarified, including the presence of manifesting heterozygosity and the underlying factors for clinical variability. OBJECTIVE: The objective of the study was to examine such unresolved matters by detailed molecular studies and genotype-phenotype correlations. PATIENTS: Thirty-five Japanese patients with POR deficiency participated in the study. RESULTS: Mutation analysis revealed homozygosity for R457H in cases 1-14 (group A), compound heterozygosity for R457H and one apparently null mutation in cases 15-28 (group B), and other combinations of mutations in cases 29-35 (group C). In particular, FISH and RT-PCR sequencing analyses revealed an intragenic microdeletion in one apparent R457H homozygote, transcription failure of apparently normal alleles in three R457H heterozygotes, and nonsense mediated mRNA decay in two frameshift mutation-positive cases examined. Genotype-phenotype correlations indicated that skeletal features were definitely more severe, and adrenal dysfunction, 46,XY DSD, and pubertal failure were somewhat more severe in group B than group A, whereas 46,XX DSD and maternal virilization during pregnancy were similar between two groups. Notable findings also included the contrast between infrequent occurrence of 46,XY DSD and invariable occurrence of 46,XX DSD and pubertal growth pattern in group A mimicking that of aromatase deficiency. CONCLUSIONS: The results argue against the heterozygote manifestation and suggest that the residual POR activity reflected by the R457H dosage constitutes the underlying factor for clinical variability in some features but not other features, probably due to the simplicity and complexity of POR-dependent metabolic pathways relevant to each phenotype.

Estrogen enhances gonadotropin-releasing hormone-stimulated transcription of the luteinizing hormone subunit promoters via altered expression of stimulatory and suppressive transcription factors.

Transcription of the LH subunit genes is stimulated by GnRH and may be modulated physiologically by steroids such as 17beta-estradiol (E). We found that E treatment amplified GnRH stimulation of the rat LHbeta and alpha-subunit promoters, and expression of the endogenous mRNA, in LbetaT2 gonadotrope cells 2- to 5-fold above GnRH alone. We examined gene expression in LbetaT2 cells after E and/or GnRH treatment, and found that E suppressed expression of transcription factor Zfhx1a, and enhanced GnRH stimulation of Egr-1 mRNA and protein. E effects were abolished in the presence of antiestrogen. Egr-1 is critical for LHbeta expression; however, the role of Zfhx1a, which binds to E-box sequences, was untested. We found E-box motifs in both the rat LHbeta (-381, -182, and -15 bp) and alpha-subunit (-292, -64, -58 bp) promoters. Zfhx1a overexpression suppressed basal and GnRH-stimulated activity of both promoters. Mutation of the alpha-subunit promoter E boxes at either -64 or -58 bp eliminated Zfhx1a suppression, whereas mutation of the -292 bp E box had no effect. Gel shift assays demonstrated that Zfhx1a bound to the -64 and -58, but not -292, bp E-box DNA. Similarly, mutation of LHbeta promoter E boxes at either -381 or -182, but not -15, bp reduced Zfhx1a suppression, correlating with binding of Zfhx1a. The -381 bp LHbeta E box overlaps with an Sp1 binding site in the distal GnRH-stimulatory region, and increased Sp1 expression overcame Zfhx1a suppression. Thus, one mechanism by which E may enhance GnRH-stimulated LH subunit promoter activity is through regulation of both activators and suppressors of transcription.

Immunohistochemical localization of growth factor-regulated channel (GRC) in human tissues.

Insulin-like growth factor-I activates a calcium-permeable cation channel GRC (growth factor-regulated channel). In the present study, we investigated the immunohistochemical localization of GRC in human tissues using a polyclonal anti-GRC antibody. Immunoreactive GRC was detected in the stomach, duodenum, large intestine and prostate. In these tissues, GRC-expressing cells were distributed solitarily in the epithelium and coexpressed chromogranin-A, a marker of neuroendocrine cells. GRC was also expressed in the epithelium of the pancreatic duct, mammary gland, parotid gland, and submandibular gland. Epithelial cells of the renal tubule and the tracheal gland were also stained with anti-GRC antibody. In the lung, alveolar macrophages expressed GRC. In the brain, Purkinje cells of the cerebellum and arachnoid cells of the meningitis expressed GRC. These results indicate that GRC is expressed in restricted types of cells in particular tissues, and that GRC may modulate calcium entry in these cells.