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T Ogata, M Inokuchi and M Ogawa

OBJECTIVE: To report on growth pattern and body proportion in the combination of short stature homeobox-containing gene (SHOX) overdosage and gonadal estrogen deficiency. DESIGN: Auxological studies in a 20-year-old Japanese female with 45,X[28]/46,X,psu idic(X)(q28)[72], gonadal estrogen deficiency, and SHOX duplication on the idic(X) chromosome, who received sex steroid replacement therapy from 16 years 8 months of age. METHODS: Growth pattern and body proportion were assessed by the age-matched standards for Japanese females. RESULTS: She continued to grow with a mean height velocity of 5.0 cm/year between 8 and 12 years of age and 4.4 cm/year between 12 and 16 years 8 months of age, and ceased to grow shortly after the replacement therapy. The standard deviation score (SDS) for height was -0.9, -1.4, +0.7 and +0.8 at 8, 12, 16 years 8 months and 20 years of age respectively. She showed a unique change in body proportion in her middle teens. At 8, 12, 16 years 8 months and 20 years of age, the SDS for sitting height (SH) was -0.8, -1.1, -0.9 and -0.6 respectively, the SDS for leg length (LL) was -1.2, -1.4, +1.1 and +1.4 respectively, and the SDS for SH/LL ratio was +0.6, +0.4, -1.6 and -1.7 respectively. CONCLUSIONS: The results provide further support for the notion that the combination of SHOX overdosage and gonadal estrogen deficiency permits continued growth with a roughly constant height velocity throughout the pubertal period of normal children, and suggest that the height gain in that period is primarily ascribed to the LL increase, as expected from SHOX expression in the distal limb bones.

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H Machida, K Ogawa, M Funaba, T Mizutani and M Tsujimoto

OBJECTIVE: Intracellular signaling of activin and transforming growth factor-beta (TGF-beta) is thought to be mediated by the same molecules (Smad2/3 and Smad4). Although differentiation of murine erythroleukemia F5-5.fl cells is induced by activin, it is not induced by TGF-beta, suggesting that at some point TGF-beta signaling is defective. The aim of this study was to investigate the unresponsiveness of F5-5.fl cells to TGF-beta. DESIGN: mRNA expression of ligands, receptors, and signal mediators for the TGF-beta family was examined in F5-5.fl cells using RT-PCR. RESULTS: Activin induced erythrodifferentiation of F5-5.fl cells in a dose-dependent manner. Neither TGF-beta1 nor bone morphogenetic protein (BMP)-4 affected the differentiation of F5-5.fl cells in the presence or absence of activin. Although mRNAs of TGF-betas (TGF-beta1, TGF-beta2 and TGF-beta3) were detected, those of inhibin/activin (alpha-, betaA- and betaB-subunits) and BMPs (BMP-2, BMP-4 and BMP-7) could not be detected in the cells, suggesting that neither activins nor BMPs are produced in F5-5.fl cells. The expression of both type I (ALK-4/ActRIB) and type II (ActRII) receptors for activin was detected in F5-5.fl cells. In contrast, while the expression of type I receptor for TGF-beta (ALK-5/TbetaRI) was detected, that of type II receptor (TbetaRII) was not. The mRNA of all Smads examined was detected in F5-5.fl cells. CONCLUSIONS: A defect in the type II receptor might cause unresponsiveness to TGF-beta in F5-5.fl cells. An erythrodifferentiation assay using F5-5.fl cells would be useful for measuring net activin activity because it would not be necessary to consider endogenous activins and BMPs.

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H Yamashita, S Noguchi, S Uchino, S Watanabe, T Murakami, T Ogawa, T Masatsugu, Y Takamatsu, E Miyatake and H Yamashita

OBJECTIVE: Disturbed renal function may play an important role in the clinico-pathological presentation of primary hyperparathyroidism (pHPT). We studied the influence of renal function on the clinico-pathological characteristics of 141 patients (123 women and 18 men) with surgically proven pHPT. METHODS: The 141 patients were assigned to one of two groups based on creatinine clearance (C(cr)) level: a renal insufficiency group (n=37) in which C(cr) of patients was <70 ml/min and a normal renal function group (n=104) in which C(cr) was > or =70 ml/min. Clinical presentation and biochemical indices were evaluated and compared between the two groups. RESULTS: Age, and frequency of hypertension and of diabetes mellitus were significantly (P<0.001, P<0.05 and P<0.05 respectively) higher in the renal insufficiency group than in the normal renal function group. Serum levels of calcium, intact parathyroid hormone and bone Gla protein were significantly (P<0.05) higher and the excised parathyroid weighed significantly more (P<0.05) in the renal insufficiency group than in the normal renal function group; however, serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and 24 h urinary calcium excretion were significantly (P<0.001 and P<0.05 respectively) lower in the former than in the latter group. There was a significant inverse correlation between C(cr) level and serum calcium (r=0.315, P<0.001) and a significant positive correlation between C(cr) level, 1,25(OH)(2)D (r=0.315, P<0.001), and 24 h calcium excretion (r=0.458, P<0.0001). CONCLUSIONS: Clinico-pathological features of pHPT were notably influenced by even moderate renal insufficiency. Urinary calcium excretion decreased according to the decrease in glomerular filtration rate. Therefore, endocrinologists need to appraise urinary calcium excretion and renal function of pHPT patients when considering surgery or in discriminating familial hypocalciuric hypercalcemia.

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K Takano, M Ogawa, T Tanaka, K Tachibana, K Fujita and N Hizuka

Clinical trials of human GH (hGH) therapy in Turner's syndrome were started in 1986. Between 1986 and 1990. 362 patients were enrolled; 115 were treated for more than 6 years. The age at the start of treatment ranged from 5 to 18 years (mean 10 years). Fifty-one patients received hGH at a weekly dosage of 0.5 IU/kg and 64 received 1.0 IU/kg by daily s.c. injection. Both treatment groups showed a statistically significant growth increase during the initial 4 years of treatment. The rate of increase in height was significantly greater for the initial 2 years with the high dose than with the low dose. The increases in height over 6 years of treatment (expressed by S.D. score for chronological age) were 1.48 +/- 0.8 with 0.5 IU/kg per week and 1.80 +/- 1.0 with 1.0 IU/kg per week. To date, 260 patients have stopped GH therapy. In 32% of them, the height attained was above the -2 S.D. value for normal girls. In 27%, the growth rate was not sufficient when they stopped treatment. The mean final height (growth rate < or = 1.0 cm/year) of patients treated for more than 6 years was 142.2 +/- 6.5 cm (n = 15) with 0.5 IU/kg per week, and 144.3 +/- 3.9 cm (n = 15) with 1.0 IU/kg per week. The adult height was improved by GH treatment, although final height did not differ statistically between the two dose regimens. No remarkable adverse events occurred during the treatment. These results indicate that hGH treatment improves the final height in patients with Turner's syndrome.

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K Ogawa, O Hashimoto, M Kurohmaru, T Mizutani, H Sugino and Y Hayashi

Immunohistochemistry using an antiserum raised against the synthetic follistatin peptide (residues 123-134) was used, in the present study, to detect the stage-specific appearance of immunoreactive follistatin in the rat testis. Follistatin immunoreactivity was not found in Sertoli and Leydig cells, while it was clearly detected in spermatogenic cells. Follistatin-like immunoreactivity was detected in the cytoplasm and nucleus of late pachytene spermatocytes. Although the reaction in the cytoplasm disappeared after meiosis, it continued to be intense in the nucleus from pachytene spermatocytes to round spermatids. This finding indicated that follistatin or its closely related peptide produced in late pachytene spermatocytes migrates from the cytoplasm to the nucleus. We subjected rat testis homogenate to affinity chromatography on a sulfate-cellulofine and anti-follistatin Cys (123-134)-Affi-Gel Hz column followed by reverse-phase HPLC and analyzed the resulting fractions by Western blotting using follistatin antiserum. Three major bands at 57, 45 and 39 kDa or four bands at 52, 44, 39 and 34 kDa were detected in crude preparations from rat testis homogenate, under reducing or non-reducing SDS-PAGE respectively. The protein from rat testis, which was recognized by anti-follistatin (123-134) antiserum, exhibited a characteristic pattern for follistatin on SDS-PAGE, i.e. slower migration under reducing conditions than under non-reducing conditions, suggesting that it was follistatin or its closely related protein. Follistatin or its closely related protein may be a stage-specific modulator of spermatogenesis. Since follistatin-like immunoreactivity was not found in oocytes in any stage of development from embryonic to adult rats, it may act in an event specific to spermatogenesis, such as nuclear condensation.

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M Shigemoto, S Nishi, Y Ogawa, N Isse, N Matsuoka, T Tanaka, N Azuma, H Masuzaki, H Nishimura, Y Yoshimasa, K Hosoda and K Nakao

OBJECTIVE: Although the molecular mechanism of obesity has been poorly understood, recent studies indicate that leptin plays a critical role in regulating both food intake and body weight. Because obesity decreases the sensitivity to insulin, the human ob gene is presumed to be one of the candidate genes for non-insulin-dependent diabetes mellitus (NIDDM) associated with obesity. Although the protein coding region in the ob gene has been screened for mutations, the promoter region and the non-coding first exon have not yet been studied. We investigated the involvement of the human ob gene, especially mutations at the promoter region and the non-coding first exon, in the development of NIDDM associated with obesity. SUBJECTS: The study group comprised 60 Japanese obese subjects with NIDDM (body mass index (BMI) 43.6 > or = BMI > or = 26.4, 29.0+/-0.41 (mean+/-S.E.M.)) and 24 obese individuals with impaired glucose tolerance (IGT) (30 > or = BMI > or = 26.4, 27.1+/-0.22). METHODS: Mutations at both the promoter region and all three exons in the human ob gene were screened by the single-stranded conformational polymorphism analysis. When aberrantly migrated bands were recognized, the PCR-amplified DNA fragment was directly sequenced. RESULTS: In the protein coding region a silent mutation in the second exon was detected. The non-coding first exon and the about 100 bp 5'-flanking region of the gene which contains a proximal CCAAT/enhancer-binding protein site were screened, but no mutations were found. CONCLUSION: These results suggest that no mutations in either the promoter region at the about 100 bp 5'-flanking region of the gene, or in any of the three exons, are involved in the development of NIDDM or IGT associated with obesity.