A Pediatric Case of Graves' Hyperthyroidism with Associated Glucose Intolerance Detected by a Urine Glucose Screening Program at School.

We report here a 13-year-old female with Graves' disease, whose diagnostic clue was glycosuria, which was detected by a urine glucose screening program at school. She had had mild general malaise, and a physical examination revealed a slightly enlarged thyroid gland. Hyperthyroidism (thyroid-stimulating hormone (TSH) < 0.01 µU/ml, free triiodothyronine (fT3) 23.57 pg/ml, free thyroxine (fT4) 3.38 ng/dl) and anti-thyroid autoantibodies (TRAb 43.6%) were detected in laboratory tests, and her plasma glucose at 120 minutes was 142 mg/dl in a 75 g oral glucose tolerance test. She was diagnosed as having borderline diabetes. These findings revealed a diagnosis of Graves' hyperthyroidism with associated impaired glucose tolerance. Although it is reported that many adults with hyperthyroidism develop disorders of glucose metabolism, pediatric patients rarely have complications of glucose intolerance or diabetes mellitus, and there are no previous reports of Graves' disease diagnosed by a urine glucose screening program at school. This case suggests a possibility of abnormalities in glucose metabolism even in pediatric cases of Graves' disease. To avoid overlooking the diagnosis of glucose intolerance associated with hyperthyroidism, a careful medical interview and examination should be performed even if the clinical features are mild.

[Evaluation of Clinical Features and Growth Hormone Deficiency in Short Children Born Small For Gestational Age].

Growth hormone (GH) therapy for short children born small for gestational age (SGA) has been approved in Japan. It is important to evaluate GH secretion ability before the initiation of GH therapy because there are some differences in dose and medical expenses between short children born SGA and GH deficiency (GHD). This study was designed to elucidate the incidence of GHD and to find a useful marker for detecting it in short SGA children. We retrospectively reviewed medical records to analyze the clinical features of short children born SGA and with GHD who had started GH therapy before the age of 6 in the University Hospital of Occupational and Environmental Health and Kyushu Rousai Hospital. Nine of 22 SGA subjects (41%) had GHD. There were no significant differences between two groups of short SGA children (GHD, non-GHD) in the median of height and serum insulin-like growth factors (IGF)-1 levels at birth or at the start of GH therapy. The probability of GHD was higher if the height standard deviation scores (SD) of the SGA children were lower than -3.2 (odds ratio, 11.6; 95% confidence interval, 1.52 - 89.1, P = 0.013). This study showed that there is an approximately 40% incidence of GHD in short SGA children needing GH treatment. We should do GH stimulation tests for short SGA children whose height SD is lower than -3 to determine the appropriate GH therapy.

Sporadic pseudohypoparathyroidism type-1b with asymptomatic hypocalcemia.

Pseudohypoparathyroidism type 1b (PHP-1b) is usually diagnosed on various symptoms of hypocalcemia. Previous studies reported a few cases of autosomal dominant pattern PHP-1b identified on familial analysis with asymptomatic hypocalcemia. Herein we report the case of a 6-year-old male patient with sporadic PHP-1b incidentally detected on preoperative examination. He had neither characteristic findings of Albright hereditary osteodystrophy nor evidence of tetany. Sporadic PHP-1b was diagnosed on the basis of clinical observation and laboratory examination. In addition, genetic testing using methylation-specific multiplex ligation-dependent probe amplification indicated broad methylation abnormalities and confirmed the sporadic form of PHP-1b. Sporadic PHP-1b might often be overlooked when diagnosis is done simply on definitive clinical features. To avoid this, DNA sequencing and methylation analysis should be performed even in the absence of definitive clinical features.

Postnatal development of galanin-like peptide mRNA expression in rat hypothalamus.

We examined the developmental change of GALP mRNA in male and female rat hypothalamus during postnatal day 1 to 60, using in situ hybridization histochemistry. Neuropeptide Y (NPY) and proopiomelanocortin (POMC) mRNA in the hypothalamus were also examined because they are important in the regulation of food intake. GALP mRNA was first detected in the arcuate nucleus (ARC) on day 8. GALP mRNA was gradually increased between day 8 and 14 and markedly increased between day 14 and 40, which is the weaning and pubertal period in rats. After day 40, there were no significant differences in GALP mRNA. In contrast to GALP, NPY and POMC mRNAs were detected in the ARC from day 1 and lasted to day 60. There was no sexual dimorphism in GALP, NPY and POMC mRNAs during postnatal development. Next, we examined the effect of the milk deprivation for 24 h on GALP, NPY and POMC mRNA in pups. GALP mRNA did not change by milk deprivation on day 9 and 15, while milk deprivation had a significant effect on NPY and POMC mRNA on day 15. These results suggest that the development of GALP may be associated with developmental changes such as weaning, feeding and maturation of reproductive functions. The regulatory mechanism of GALP mRNA is different from that of the NPY and POMC genes during postnatal development.

Hydroxymethylglutaryl--CoA reductase inhibitor inhibits induction of nitric oxide synthase in 3T3--L1 preadipocytes.

Preadipocytes are considered to play a role in adipose tissue inflammation in obesity. The purpose of this study was to determine whether hydroxymethylglutaryl-CoA reductase inhibitor (statin) modulates the nitric oxide (NO) production via inducible NO synthase (iNOS) in preadipocytes. Undifferentiated 3T3-L1 cells, a model of preadipocytes, significantly produced NO by the treatment with the combination of lipopolysaccharide (L), tumor necrosis factor-alpha (T) and interferon-gamma (I). Pre-incubation with simvastatin, a lipophilic statin, or pravastatin, a hydrophilic one, dose-dependently inhibited the NO production in the LTI-treated cells. The effect of simvastatin was offset by mevalonate or geranylgeranyl pyrophosphate (GGPP) but not by squalene. The mRNA level for iNOS paralleled the NO production. The nuclear factor-kappaB (NF-kappaB) was activated by the LTI-treatment, and was inhibited by addition of simvastatin or pravastatin. Mevalonate or GGPP completely offset the effect of simvastatin. Simvastatin or pravastatin also decreased the LTI-stimulated interleukin-6 (IL-6) secretion. These effects of pravastatin were relatively weak compared with those of simvastatin. Y27632, an inhibitor of Rho kinase, also inhibited the LTI-induced NF-kappaB activation and iNOS expression, and decreased the production of NO and IL-6 in 3T3-L1 preadipocytes. These results suggest that statins, especially lipophilic types, inhibit induction of iNOS by inhibiting the small GTP-binding protein signal in preadipocytes.

[Prevalence of 'obesity disease' and 'metabolic syndrome' in obese pediatric outpatients at the University Hospital of Occupational and Environmental Health, Japan].

'Obesity Disease for Japanese Children' was defined in 2002, and very recently 'Metabolic Syndrome (MS) for Japanese Children' was also defined. We therefore aimed to determine the prevalence of these two among the obese pediatric outpatients at our university hospital. The subjects were 97 children, 58 boys and 39 girls, ranging in age from 5 to 15 years. A child was considered to be obese when the body weight exceeded 120% of the standard body weight. All the subjects exceeded 120% overweight, and 58 children (35 boys and 23 girls) were over 150% overweight. Eighty five children (53 boys and 32 girls) were diagnosed with obesity disease (87.6%). Sixteen children (12 boys and 4 girls) were diagnosed with metabolic syndrome, which was 16.5% of all the subjects and 18.8% of the children with obesity disease. Fourteen of the 16 children with MS were over 10 years old. Obesity disease is diagnosed when the child has an obesity disease score of more than 6. The obesity disease score was significantly correlated with the waist circumference and the visceral adipose tissue area measured by computed tomography. The mean score of the children with MS was significantly higher than that of the non-MS group (30.2 vs. 12.3 points). In this study, it was clear that about 90% of our clinic patients are in the obesity disease group, and need therapeutic interventions. The prevalence of MS in the pediatric age is very low compared with that of adults, but MS is a high-risk category of obesity disease.

N-acetylcysteine inhibits induction of nitric oxide synthase in 3T3-L1 adipocytes.

The present study was designed to determine whether N-acetylcysteine (NAC), a potent antioxidant, modulates nitric oxide (NO) production stimulated by lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha) in adipocytes. Stimulation by the combination of 5 microg/ml of LPS and 100 ng/ml of TNF-alpha (LT) significantly enhanced NO production in 3T3-L1 adipocytes. Preincubation of the cells with NAC (5-20 mM) for 24 h suppressed the increased NO production in a dose-dependent manner. The production of NO was decreased by 49% at the concentration of 20 mM of NAC. The decrease in NO production by NAC was accompanied by a decrease in inducible nitric oxide synthase (iNOS) protein, detected by immunoblot analysis, and iNOS mRNA, determined by real-time reverse-transcriptase coupled polymerase chain reaction analysis. Nuclear factor-kappa B (NF-kappa B) was significantly activated by LT-treatment, while the pretreatment with 20 mM of NAC prevented the activity by 42%. Pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, also inhibited the LT-mediated NO production dose-dependently. One hundred microM of PDTC inhibited the NO production by 46%. We also investigated the effect of NAC and PDTC on the production of interleukein-6 (IL-6), which is regulated transcriptionally by NF-kappa B in 3T3-L1 adipocytes. IL-6 production was markedly increased by LT stimulus, and the enhanced secretion of IL-6 was suppressed in a dose-dependent manner by pretreatment with NAC or PDTC. These results suggest that NAC regulates iNOS expression and NO production in adipocytes through the modulating activation of NF-kappa B.

Plasma but not serum brain-derived neurotrophic factor concentration is decreased by oral glucose tolerance test-induced hyperglycemia in children.

BACKGROUND: Little is known regarding the relationships among circulating brain-derived neurotrophic factor (BDNF) levels and glucose or insulin in children and adolescents. The objective of this study was to investigate whether circulating BDNF levels would change during the oral glucose tolerance test (OGTT). METHODS: We performed the OGTT and measured the serial changes in BDNF levels in both plasma and serum. RESULTS: There were 22 subjects in the normal type (N) group and 20 in the borderline/diabetic type (B/D) group, defined by the results of the OGTT. Serum levels of BDNF were almost five times higher and plasma levels gradually decreased during the OGTT, whereas serum levels showed no significant change. The reduction of plasma BDNF level changes from baseline to 120 min were significantly different between the N and B/D groups (36.3% vs. 20.8%, p=0.023). CONCLUSIONS: Our results showed that plasma levels of BDNF are more sensitive to acute changes in glucose or insulin levels than serum.

Tamoxifen treatment for pubertal gynecomastia in two siblings with partial androgen insensitivity syndrome.

BACKGROUND: Although tamoxifen has been shown to be fairly safe and effective for idiopathic pubertal gynecomastia, it remains unknown whether it is also beneficial for gynecomastia associated with endocrine disorders. Here, we report the effect of tamoxifen on pubertal gynecomastia in 2 siblings with partial androgen insensitivity syndrome (PAIS). CASE REPORTS: Cases 1 and 2 presented with persistent pubertal gynecomastia at 13 and 16 years of age, respectively. Physical examinations revealed breast of Tanner stage 3 and normal male-type external genitalia in both cases. Clinical features such as female-type pubic hair and borderline small testis indicated mildly impaired masculinization. RESULTS: Molecular analysis identified a previously reported p.Arg789Ser mutation in the androgen receptor gene (AR) in the 2 cases. Two months of oral administration of tamoxifen ameliorated gynecomastia to Tanner stage 2 with no adverse events. Additional treatment with testosterone enanthate showed negligible effects on body hair and penile length. Hormone values of the 2 cases during tamoxifen treatment remained similar to those in previously reported untreated patients with PAIS. CONCLUSION: The results indicate that tamoxifen was effective in treating pubertal gynecomastia in these 2 patients with PAIS and may be considered as a therapeutic option in this situation pending further studies.

An Infantile Case of Transient, Severe Hypercholesterolemia with Normalization after Complete Weaning from Breast-feeding.

A 20-d-old boy was referred to our department because of hyperthyrotropinemia at neonatal mass screening and diagnosed with neonatal transient hyperthyrotropinemia. A follow-up examination when the patient was 5 mo old revealed severe hypercholesterolemia. Familial hypercholesterolemia was first suspected because of the patient's significantly high levels of total and low-density lipoprotein cholesterol. The parent's serum lipid profiles were examined and found to be normal. He was completely breast-fed until 6 mo of age. Breast milk was still the main source of food for a period following weaning. At 14 mo old, the patient was weaned completely from breast milk, and his serum cholesterol levels decreased dramatically. According to the normal lipid profiles of the patient's parents and the spontaneous normalization of serum cholesterol levels after complete weaning from breast milk, breast-feeding was suggested to be responsible for his transient severe hypercholesterolemia. It is well documented that breast-fed infants have higher serum cholesterol levels than formula-fed infants. However, there is no reported case with severe hypercholesterolemia equivalent to or higher than the levels observed in the case of familial hypercholesterolemia. Although the exact mechanism is unknown, it is necessary to consider that a small number of cases develop severe hypercholesterolemia related to breast-feeding.

Plasma visfatin concentration as a surrogate marker for visceral fat accumulation in obese children.

OBJECTIVE: This study was designed to elucidate whether the plasma visfatin level reflects visceral or subcutaneous fat accumulation and metabolic derangement in obese children. METHODS AND PROCEDURES: Fifty-six obese Japanese children, including 37 boys and 19 girls were enrolled in the study. The age of the subjects ranged from 5 to 15 (10.2 +/- 0.3; mean +/- s.e.m.) years. The age-matched control group for measuring visfatin consisted of 20 non-obese children. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) areas were measured by computed tomography. The plasma concentrations for visfatin and leptin were assayed by enzyme-linked immunosorbent assay kits. RESULTS: The plasma visfatin level was higher in the obese (14.7 +/- 0.9 ng/ml) than in the control children (8.6 +/- 0.6 ng/ml). In a univariate analysis, the visfatin correlated significantly with age, height, body weight, waist circumference, VAT and SAT area, triglyceride (TG), insulin, and the homeostasis model assessment for insulin resistance (HOMA-R). After being adjusted for age and sex, only the VAT area retained significant partial correlation with visfatin, and in contrast the body weight, BMI-s.d., and SAT area with leptin. The plasma visfatin concentration was not correlated with leptin. The plasma visfatin levels in the control, non-metabolic syndrome (MS) (n = 49), and MS groups (n = 7) were significantly different from each other. DISCUSSION: These results suggest that plasma visfatin level is a specific marker for visceral fat accumulation in obese children. As a good surrogate marker, plasma visfatin level can predict the VAT area in obese children.