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ABSTRACT: OBJECTIVE: 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 2 families) with NR5A1 mutations, showing psychiatric symptoms. DESIGN AND METHODS: We screened for NR5A1 mutations in a cohort of 34 patients with 46,XY DSD using PCR-based sequencing. Psychiatric symptoms were assessed using mental health assessment tools and structured clinical interviews. Functional properties of detected mutant NR5A1s were studied in silico and in vitro, including three-dimensional (3D) mutation models, subcellular NR5A1 protein localisation, and transactivation assays. RESULTS: We found 2 (46,XY) patients with NR5A1 heterozygous novel mutations (p.D257fs and p.V424del), which were transmitted from their respective mothers. The patients' clinical findings indicated DSD without adrenal insufficiency. Both mothers showed psychiatric symptoms, including excessive anxiety and/or depression. The mother and grandmother of one patient had premature ovarian insufficiency. Functional studies showed altered 3D models of p.V424del and normal subcellular NR5A1 localisation and impaired transcriptional activation without dominant negative effects in both mutations. CONCLUSIONS: We found 2 (46,XX) NR5A1 mutation carriers with excessive anxiety and/or depression. These results suggest that excessive anxiety and/or depression are possible clinical phenotypes of 46,XX NR5A1 mutations. © 2012 Blackwell Publishing Ltd.
Clinical Endocrinology 10/2012; · 3.17 Impact Factor
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ABSTRACT: 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.
Two siblings born from nonconsanguineous healthy parents exhibited IGHD. To elucidate the cause, GH1 in all family members was analysed.
Two novel mutations in GH1, a point mutation in intron 3 and a 16-bp deletion in exon 3, were identified by sequence analyses. The intronic mutation was present in both siblings and was predicted to cause aberrant splicing. The deletion was present in one of the siblings as well as the mother with normal stature and was predicted to cause rapid degradation of mRNA through nonsense-mediated mRNA decay. The point mutation was not identified in the parents' peripheral blood DNA; however, it was detected in the DNA extracted from the father's sperms. As a trace of the mutant allele was detected in the peripheral blood of the father using PCR-RFLP, the mutation is likely to have occurred de novo at an early developmental stage before differentiation of somatic cells and germline cells.
This is the first report of mosaicism for a mutation in GH1 in a family with IGHD. It is clear that the intronic mutation plays a dominant role in the pathogenesis of IGHD in this family, as one of the siblings who had only the point mutation was affected. On the other hand, the other sibling was a compound heterozygote for the point mutation and the 16-bp deletion and it may be arguable whether IGHD in this patient should be regarded as autosomal dominant or recessive.
Clinical Endocrinology 09/2011; 76(3):420-4. · 3.17 Impact Factor
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ABSTRACT: Corticosteroids therapy, classically the first-line treatment for ulcerative colitis (UC), often causes serious side-effects. Theoretically, pulse steroid therapy where high doses are given for a shorter period may have maximal beneficial effects and minimal side-effects as induction therapy for UC. We have therefore retrospectively compared induction therapy using pulse steroids with conventional steroid treatment for children and adolescents with moderate-to-severe UC.
We utilized conventional steroid treatment (prednisolone 1-1.5 mg/kg/day) as an induction treatment in 17 UC patients between 1985 and 2006. Alternatively we used a 3-day megadose pulse steroid therapy (methylprednisolone intravenously 20-30 mg/kg/day, max. 1000 mg/day) in 20 UC patients from 1993 to 2006.
Pulse steroid therapy successfully induced rapid remission in UC patients with moderate-to-severe disease compared with conventional treatment (13.2 days vs 25.1 days; P < 0.05). The amelioration of Pediatric Ulcerative Colitis Activity Index score between before and 1 week after pulse steroid therapy was significantly more than that of conventional treatment (P < 0.01). No serious adverse effects were observed in the patients treated with pulse steroid therapy. However, the rate of the relapse episodes during the next 12 months after pulse steroid therapy was not significantly different from that after conventional treatment.
These findings suggest that pulse steroid therapy is an option to be considered in children with moderate-to-severe UC.
Pediatrics International 05/2011; 53(6):974-9. · 0.63 Impact Factor
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Pediatrics International 12/2010; 52(6):891-2. · 0.63 Impact Factor
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ABSTRACT: In Japan, there is as yet no report on growth retardation in children with IBD. We therefore investigated the cause of growth retardation in Japanese children with IBD. We investigated the height, body weight, serum levels of albumin, IGF-I, CRP, and cytokines, and the amount of corticosteroid administered in children with Crohn's disease (CD, n = 15) and ulcerative colitis (UC, n = 18). Our results suggest that growth retardation is already present before the initial visit in children with CD, and chronic inflammation may be responsible this growth disturbance. Moreover, the amount of PSL used may contribute to growth retardation by decreasing the serum levels of IGF-I in children with IBD.
International Journal of Pediatrics 01/2010; 2010:958915.
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Maki Fukami,
Gen Nishimura,
Keiko Homma,
Toshiro Nagai,
Keiichi Hanaki,
Ayumi Uematsu,
Tomohiro Ishii,
Chikahiko Numakura,
Hirotake Sawada,
Mariko Nakacho, [......], Hidenori Haruna,
Mihoko Nakamura,
Akira Ohishi,
Masanori Adachi,
Toshihiro Tajima,
Yukihiro Hasegawa,
Tomonobu Hasegawa,
Reiko Horikawa,
Kenji Fujieda,
Tsutomu Ogata
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ABSTRACT: 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.
The objective of the study was to examine such unresolved matters by detailed molecular studies and genotype-phenotype correlations.
Thirty-five Japanese patients with POR deficiency participated in the study.
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.
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.
The Journal of clinical endocrinology and metabolism 04/2009; 94(5):1723-31. · 6.50 Impact Factor
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ABSTRACT: 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. As oxidative stress can induce inflammation, the anti-inflammatory effects of Rooibos tea were investigated using a rat colitis model.
Seven-week-old Wister rats were divided into two groups: one group given Rooibos tea, and one given water. After four weeks of breeding, serum superoxide dismutase (SOD) levels were determined using the Electron Spin Resonance analysis. Urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) concentrations were also determined as reflections of DNA damage using enzyme-linked immunosorbent assay. Furthermore, rats were administrated dextran sodium sulfate (DSS), which is known to induce colitis in rodents, with or without Rooibos tea to evaluate its anti-inflammatory activity. Clinical symptoms, hemoglobin, serum iron and SOD levels were compared between the groups.
There were no significant differences in bodyweight gain or laboratory data between the groups. The serum SOD levels were significantly increased, and urine 8-hydroxy-2'-deoxyguanosine levels were significantly decreased in the Rooibos group compared with the controls (P < 0.05 in each). After DSS administration, the serum SOD levels were significantly higher in the Rooibos group compared to the controls (P < 0.05). As a result, a decreased hemoglobin level, observed in the control group, was prevented in the Rooibos group after the DSS challenge.
Rooibos tea may prevent DNA damage and inflammation by its anti-oxidative activity in vivo. As Rooibos tea is free from caffeine, routine intake may be safe and useful in reducing oxidative stress in children.
Pediatrics International 03/2009; 51(5):700-4. · 0.63 Impact Factor
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ABSTRACT: Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] have been implicated in tissue injury and remodeling in many organs. The objective of this study was to evaluate the expression of MMP-3 and -9, and TIMP-1, -2, and -3 and their relationship to liver fibrosis in infants with biliary atresia.
The expression of MMP-3 and-9 and TIMP-1, -2 and -3 was investigated in liver tissue samples of nine patients with biliary atresia. In addition, the expression of CCR-4 and CCR-5 was analyzed to investigate the activation of Th1 and Th2 cells. The mRNA levels were measured by semiquantitative reverse transcriptase polymerase chain reaction.
The expression of MMP-3 was higher than that of MMP-9 in all samples (P < 0.01). The expression of TIMP-1 was higher than that of TIMP-2 and -3 in all samples (P < 0.01). The expression of CCR-5 was higher than that of CCR-4 (P < 0.05), which implied higher activation of Th1 cells relative to Th2 cells.
Our findings suggest that MMP-3, possibly induced by Th1 cytokines, and its balance with TIMP-1, may be one of the factors involved in the pathogenesis of biliary atresia.
Pediatric Surgery International 12/2008; 25(2):157-62. · 1.25 Impact Factor
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ABSTRACT: 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 urine-based enzyme-linked immunosorbent assay (ELISA) was used to detect H. pylori antibodies twice within a 12 month interval over 2 years in 452 healthy children living in Tokyo. The subjects were divided into three groups: ages 4, 7, and 10 years.
The prevalence of H. pylori infection was not different among the groups, being between 4.0% and 6.7%. The rate of turn to positivity for H. pylori infection was 1.5% per year and the rate of turn to negativity was 1.1%, but in the 10 year age group the rates were markedly lower than in the younger children. CONCLUSIOn: The prevalence of H. pylori infection in Tokyo was 4.0-6.7% and was not different among 4, 7, and 10 year age groups.
Pediatrics International 07/2008; 50(3):291-4. · 0.63 Impact Factor
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ABSTRACT: 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-gamma (PPAR-gamma) on gastric mucosal injury in children with H. pylori infection.
The subjects were 24 children who underwent endoscopy for the evaluation of anemia or gastrointestinal symptoms, and they were divided into two groups: a H. pylori-positive group and -negative group. The numbers of neutrophils in the gastric mucosa of children with and without H. pylori infection and expression of COX-1, -2, and PPAR-gamma were examined, using reverse transcription-polymerase chain reaction.
The numbers of neutrophils were significantly higher in the H. pylori-positive group than in the H. pylori-negative group. The ratio of COX-1 mRNA to COX-2 mRNA in the H. pylori-positive group was significantly lower than that in the H. pylori-negative group. The ratio of PPAR-gamma m-RNA to beta-actin mRNA was significantly higher in the H. pylori-positive group than the H. pylori-negative group.
Enhanced production of COX-2 and PPAR-gamma in the gastric mucosa has cytoprotective and anti-inflammatory effects, although the relationship to the carcinogenic activity of COX-2 and PPAR-gamma should be clarified.
Pediatrics International 03/2008; 50(1):1-6. · 0.63 Impact Factor
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ABSTRACT: 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- (PPAR-) on gastric mucosal injury in children with H. pylori infection.Methods: The subjects were 24 children who underwent endoscopy for the evaluation of anemia or gastrointestinal symptoms, and they were divided into two groups: a H. pylori-positive group and -negative group. The numbers of neutrophils in the gastric mucosa of children with and without H. pylori infection and expression of COX-1, -2, and PPAR- were examined, using reverse transcription–polymerase chain reaction.Results: The numbers of neutrophils were significantly higher in the H. pylori-positive group than in the H. pylori-negative group. The ratio of COX-1 mRNA to COX-2 mRNA in the H. pylori-positive group was significantly lower than that in the H. pylori-negative group. The ratio of PPAR- m-RNA to β-actin mRNA was significantly higher in the H. pylori-positive group than the H. pylori-negative group.Conclusions: Enhanced production of COX-2 and PPAR- in the gastric mucosa has cytoprotective and anti-inflammatory effects, although the relationship to the carcinogenic activity of COX-2 and PPAR- should be clarified.
Pediatrics International 02/2008; 50(1):1 - 6. · 0.63 Impact Factor
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Yoshikazu Ohtsuka,
Toshiaki Shimizu,
Hiromichi Shoji,
Takahiro Kudo,
Tohru Fujii,
Mariko Wada,
Hiroaki Sato,
Yo Aoyagi, Hidenori Haruna,
Satoru Nagata,
Yuichiro Yamashiro
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ABSTRACT: 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.
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.
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 microg/L (normal, <14.7) and 13.1 micromol/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.
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.
Journal of pediatric gastroenterology and nutrition 04/2007; 44(4):501-5. · 2.18 Impact Factor
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Journal of Antimicrobial Chemotherapy 11/2002; 50(4):617-8. · 5.07 Impact Factor
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Gastroenterology 07/2002; 122(7):2091. · 11.68 Impact Factor
