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Yasuo Mashio, Mutsuo Beniko, Akemi Ikota, Hiroaki Mizumoto and Haruhiko Kunita

Abstract. A prospective randomized trial with the conventional divided doses (10 mg 3 times daily, N = 29) and a small single daily dose (15 mg once daily, N = 25) of methimazole for the treatment of Graves' hyperthyroidism was performed. Within 8 weeks, almost 80% of the patients in both groups became euthyroid. The mean time required to achieve the euthyroid state was 6.0 ± 2.8 and 6.0 ± 3.8 weeks, respectively. TSH binding inhibitor immunoglobulin was found in about 90% of the patients in both groups before methimazole treatment. However, a gradual fall of its levels was observed in nearly all patients after treatment. There was no difference in the mean levels of TSH binding inhibitor immunoglobulin between the two groups during therapy. We conclude that the single daily dose regimen of 15 mg of methimazole will control Graves' hyperthyroidism in most patients, and TSH binding inhibitor immunoglobulin levels decrease in this regimen in the same way as with the conventional divided dose regimen (10 mg 3 times daily).

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Yasuo Mashio, Mitsuo Inada, Kiyoshi Tanaka, Hitoshi Ishii, Koichi Naito, Mitsushige Nishikawa, Kiyoyuki Takahashi and Hiroo Imura

Abstract. Previous studies have shown the existence of specific high affinity T3 binding sites in rat cerebrocortical synaptosomes. In this study, to define the localization of the binding sites, T3 binding to disrupted synaptic membrane fractions was compared with the binding to intact synaptosomes obtained from the rat cerebral cortex. Scatchard analysis revealed two orders of T3 binding sites with almost identical apparent dissociation constant (Kd) in synaptosomes and synaptic membrane fractions. However, the maximal binding capacity (MBC) of the higher affinity binding sites for synaptic membrane fractions was significantly greater than that for intact synaptosomes (4.2 ± 0.2 vs 3.0 ± 0.3 pg T3/mg protein).

Regional distribution of the synaptosomal T3 binding sites in various areas of the rat brain was also studied. The Kd values were not significantly different in discrete brain regions. On the other hand, the MBCs of the higher affinity binding sites were greater in the cerebral cortex and hypothalamus (72.8 ± 1.4 and 64.8 ± 9.5 pg T3/g tissue) than in the cerebellum (22.1 ± 1.6 pg T3/g tissue). Similar difference was also observed in the lower affinity sites.

These results indicate that the specific T3 binding sites in brain synaptosomes are localized mainly on synaptic membranes and that the MBC is different in discrete brain regions.

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Kiyoshi Tanaka, Mitsuo Inada, Yasuo Mashio, Hitoshi Ishii, Koichi Naito, Mitsushige Nishikawa, Kiyoyuki Takahashi and Hiroo Imura

Abstract.

The present study revealed the existence and some characteristics of rT3 5'-deiodinase in rat brain by measuring the production of 3,3'-T2 from rT3 by radioimmunoassay. The conversion of rT3 to 3,3'-T2 was dependent on the duration of the incubation, tissue amount, temperature and pH (the optimal pH was 8.0), suggesting its enzymatic nature. Apparent Km was estimated to be 0.16 μm and the Vmax was 139.3 fmol/mg protein/min. The converting activity was dependent on the concentration of dithiothreitol (DTT). In contrast to T4 or T3 5-deiodinase, rT3 5'-deiodinase activity in the rat brain was the highest in cerebellum and the activity was low in the neonatal rat brain. Moreover, the 5'-deiodinase activity was inhibited by propylthiouracil (PTU). These differences between rT3 5'-deiodinase and T4 or T3 5-deiodinase suggest that different deiodinases are present in rat brain, and that local conversion of thyroid hormone is important for its action in the central nervous system.

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Akiko Yuno, Takeshi Usui, Yuko Yambe, Kiichiro Higashi, Satoshi Ugi, Junji Shinoda, Yasuo Mashio and Akira Shimatsu

Context

Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare disorder resulting from genetic and epigenetic aberrations in the GNAS complex. PHP-Ib, usually defined by renal resistance to parathyroid hormone, is due to a maternal loss of GNAS exon A/B methylation and leads to decreased expression of the stimulatory G protein α (Gsα) in specific tissues.

Objective

To clarify the usefulness of methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), we evaluated genetic and epigenetic changes of the GNAS locus in Japanese PHP-Ib patients.

Design

Retrospective case series.

Patients

We studied 13 subjects with PHP-Ib (three families with eight affected members and one unaffected member and four sporadic cases).

Measurements

The methylation status of GNAS differentially methylated regions (DMRs) was evaluated using MS-MLPA. The main outcome measure was the presence of deletion mutations in the GNAS locus and STX16, which were assessed using MLPA.

Results

In all familial PHP-Ib cases, a ∼3 kb deletion of STX16 and demethylation of the A/B domain were identified. In contrast, no deletion was detected throughout the entire GNAS locus region in the sporadic cases. Broad methylation abnormalities were observed in the GNAS DMRs.

Conclusions

MS-MLPA allows for precise and rapid analysis of the methylation status in GNAS DMRs as well as the detection of microdeletion mutations in PHP-Ib. Results confirm the previous findings in this disorder and demonstrate that this method is valuable for the genetic evaluation and visualizing the methylation status. The MS-MLPA assay is a useful tool that may facilitate making the molecular diagnosis of PHP-Ib.