Hidenori Haruna

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.

Studies of anti-inflammatory effects of Rooibos tea in rats.

Background:  Rooibos tea is known to be caffeine free with abundant flavonoids. Aspalathin and nothofagin, the main flavonoids contained in Rooibos tea, have stronger anti‐oxidative activity than other flavonoids.

Neonatal transient eosinophilic colitis causes lower gastrointestinal bleeding in early infancy.

Background: Lower gastrointestinal bleeding (LGB), particularly in newborns, is of serious concern and requires urgent investigation and hospital care. Whereas allergic proctocolitis caused by food protein is a significant cause of LGB in infants with eosinophilia, there are several cases of diseases with symptoms similar to those of allergic proctocolitis but without an apparent allergic reaction influence. Patients and Methods: We examined 2 neonates using rectosigmoidoscopy who showed eosinophilia and experienced fresh LGB soon after birth and before their first feedings. Serum eosinic cationic protein (ECP) and platelet activating factor (PAF) levels were also examined in the second case to confirm the involvement of eosinophils for its pathogenesis. Results: Both patients were in a clinically stable condition, and their abdomens were soft. The results of their blood analyses, abdominal radiographs, and stool cultures were normal, but they had gross eosinophilia: the eosinophil counts were 9014/mm3 (patient 1) and 1955/mm3 (patient 2). Rectosigmoidoscopy with colonic mucosal biopsy revealed nodular lymphoid hyperplasia with a pale mucosal surface and massive oozing with diffuse eosinophilic infiltration in the lamina propria. In patient 2 the serum ECP and PAF levels were elevated to 123 μg/L (normal, <14.7) and 13.1 μmol/L/min (normal, <6). A few days after intravenous hydration therapy, LGB was no longer detected, and the serum ECP and PAF levels returned to normal. Conclusions: Inasmuch as these infants had LGB similar to allergic proctocolitis without any allergic reactions, we suggest that infiltrated eosinophils in the colonic mucosa could be involved in the pathogenesis of LGB in early infancy.

Cytokines in the gastric mucosa of children with Helicobacter pylori infection

Aim: Few studies have looked at the cytokine profile in gastric mucosa in children with Helicobacter pylori infection. This study investigated cytokines and their effects on histological abnormalities in the gastric mucosa of children with H. pylori infection. Methods: The levels of interferon‐γ (IFN‐γ), interleukin‐4 (IL‐4) and IL‐8 proteins were measured in biopsy specimens from the gastric antrum and corpus of children with H. pylori infection, and related to inflammatory cell infiltrations. Results: The antral and corporal mucosal levels of IFN‐γ and IL‐8 proteins were significantly higher in children with H. pylori infection than in uninfected children, but there was no such difference in the levels of IL‐4 protein. The antral mucosal level of IL‐8 protein was significantly higher than the corporal mucosal level of IL‐8 protein in the infected children. Inflammatory cell infiltration was significantly higher in the infected children than in the uninfected children, but there were no significant correlations between mucosal cytokine levels and inflammatory cell infiltrations.

Urine-based enzyme-linked immunosorbent assay for the detection of Helicobacter pylori antibodies in children

Objective:  Recent studies of urine‐based enzyme‐linked immunosorbent assays (ELISA) for detection of antibody to Helicobacter pylori (H. pylori) have already shown high sensitivity and specificity in adults. The diagnostic accuracy of these assays in children was investigated.

Changes in the presence of urine Helicobacter pylori antibody in Japanese children in three different age groups

Background: The rates of acquisition and spontaneous eradication of Helicobacter pylori infection in children has yet to be established. To determine these rates in children living in an urban region of Japan, the levels of urine H. pylori antibodies in children of three different age groups were measured.

A report of two novel NR5A1 mutation families: Possible clinical phenotype of psychiatric symptoms of anxiety and/or depression

NR5A1 or steroidogenic factor 1 is a nuclear receptor that plays important roles in the hypothalamus–pituitary–steroidogenic axis. The clinical phenotype of most 46,XY mutation carriers includes disorders of sex development (DSD) without adrenal insufficiency, whereas 46,XX mutation carriers have phenotypes ranging from no symptoms to ovarian insufficiency. Although genetically engineered ventromedial hypothalamus‐specific Nr5a1 knockout mice show anxiety behaviour, no psychiatric symptoms have been reported in human NR5A1 mutation carriers. We report clinical and molecular findings for individuals (from two families) with NR5A1 mutations, showing psychiatric symptoms.

Expression of COX‐1, COX‐2, and PPAR‐γ in the gastric mucosa of children with Helicobacter pylori infection

Background: Gastric inflammation in patients with Helicobacter pylori infection is considered to be regulated by many kinds of inflammatory and cytoprotective factors. The present study examined the effects of cyclo‐oxygenase (COX)‐1, ‐2, and peroxisome proliferator‐activated receptor‐γ (PPAR‐γ) on gastric mucosal injury in children with H. pylori infection.

Effects of stool dilution on the faecal Helicobacter pylori antigen test

Objective:  To examine the effects of stool dilution on the results of the faecal Helicobacter pylori antigen test.

Isolated growth hormone deficiency in two siblings because of paternal mosaicism for a mutation in the GH1 gene

Context  Mutations in the GH1 gene have been identified in patients with isolated growth hormone deficiency (IGHD). Mutations causing aberrant splicing of exon 3 of GH1 that have been identified in IGHD are inherited in an autosomal dominant manner, whereas other mutations in GH1 that have been identified in IGHD are inherited in an autosomal recessive manner.