Akifumi Tokita

The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome

S phase progression. WINAC mediates the recruitment Hirochika Kitagawa,1,2 Ryoji Fujiki,1 Kimihiro Yoshimura,1 Yoshihiro Mezaki,1 Yoshikatsu Uematsu,1 Daisuke Matsui,1 Satoko Ogawa,1 Kiyoe Unno,1,3 Mataichi Okubo,3 Akifumi Tokita,3 Takeya Nakagawa,4 Takashi Ito,4 Yukio Ishimi,5 of unliganded VDR to VDR target sites in promoters, Hiromichi Nagasawa,6 Toshio Matsumoto,2 while subsequent binding of coregulators requires liJunn Yanagisawa,1,7 and Shigeaki Kato1,7,* gand binding. This recruitment order exemplifies that Institute of Molecular and Cellular Biosciences an interaction of a sequence-specific regulator with a University of Tokyo chromatin-remodeling complex can organize nucleo1-1-1 Yayoi somal arrays at specific local sites in order to make Bunkyo-ku promoters accessible for coregulators. Furthermore, Tokyo 113-0032 overexpression of WSTF could restore the impaired Japan recruitment of VDR to vitamin D regulated promoters 2 First Department of Internal Medicine in fibroblasts from Williams syndrome patients. This University of Tokushima School of Medicine suggests that WINAC dysfunction contributes to 3-18-15 Kuramoto-cho Williams syndrome, which could therefore be considTokushima 770-8503 ered, at least in part, a chromatin-remodeling factor Japan disease. 3 Department of Pediatrics

Association of gene polymorphisms and bone density in Japanese girls

Abstract. Although some studies have reported a relationship between several candidate polymorphic genes and bone mineral density (BMD), little is known concerning the genetic factors influencing BMD in children. This study examined this relationship in healthy Japanese girls (n = 125; age, 13.4 ± 0.89 years; range, 12–15 years). We investigated allelic variants of the vitamin D receptor (VDR) gene, the estrogen receptor (ER) gene, the parathyroid hormone (PTH) gene, the Ca-sensing receptor (CaSR) gene, and the β3-adrenergic receptor (β3-AR) gene. The genotype of the VDR gene (Fok I) correlated with lumbar spine, and femoral neck BMD. The PTH polymorphisms (BstB I, Dra II) were also associated with lumbar spine BMD. No relationship was found between genotypes of the ER gene, CaSR gene, or β3-AR gene and BMD. The age, height, weight, and body mass index did not differ significantly among girls with different VDR and PTH genotypes. These results suggest that the Fok I polymorphism of the VDR gene and the Dra II polymorphism of the PTH gene are risk factors for low bone density in Japanese girls.

Factors affecting peak bone density in Japanese women.

Abstract. Both genetic and environmental factors have been shown to contribute to the determination of bone density. To clarify the interaction between genetic and environmental factors affecting peak bone mass, we investigated the correlation between bone mineral density (BMD) and physical constitution, vitamin D receptor (VDR) genotype, age, age of menarche, history of menstrual dysfunction, and exercise in 157 healthy young Japanese women. History of exercise and menstrual dysfunction were significant independent predictors of BMD. The VDR genotype also affects peak bone density. Exercise has been shown to increase BMD in a similar way for each VDR genotype including those women who have the particular genotype associated with low bone density. This data indicate that there are complex gene-environmental interactions particularly in relation to menstrual history, exercise, and genetic factors during childhood/adolescence that may have implications for the development of adult BMD in women.

Analysis of the stable levels of messenger RNA derived from different polymorphic alleles in the vitamin D receptor gene

Abstract: The association between polymorphisms in the vitamin D receptor (VDR) gene and bone mineral density (BMD) has been studied by many investigators. However, the question of how polymorphisms in the gene modulate the function of the VDR remains to be answered. To address this issue, we examined the mRNA levels of the VDR in relation to polymorphisms. First, we compared the levels of mRNA between the allele with the polymorphic TaqI-digestive site (t) and nondigestive site (T) located at exon 9 of the VDR gene determined by reverse transcription-polymerase chain reaction (RT-PCR). Total RNA was extracted from peripheral mononuclear cells in volunteers whose genotype is Tt. After the amplification of cDNA by PCR, the amplified fragments were digested by TaqI. The digested (t) and undigested (T) fragments were visualized by ethidium bromide and semiquantified by an image analyzer. In 24 subjects, the mRNA levels of allele t were significantly higher than those of allele T (1.35 fold, P < 0.001). Second, the VDR mRNA levels were estimated by competitive RT-PCR in 60 healthy subjects (35 TT, 24 Tt, 1 tt). The competitive template was 47 bases shorter than the product of the wild-type gene. After RT-PCR, the mRNA level was determined by a comparison with the competitive fragments. No significant difference in the mRNA level was observed between two groups (1.75 ± 0.84 and 1.65 ± 0.99 10−13 mol/g total RNA in TT and Tt, respectively). In addition, no significant relationship was observed between the VDR mRNA levels and BMD in the 23 subjects whose BMD data were available. In conclusion, higher mRNA levels of allele t than T were detected, but the difference did not result in higher levels of VDR mRNA in subjects with the Tt genotype compared to those with the TT genotype.

Progressive vascular lesions in Williams-Beuren syndrome

SummaryWe report two patients with Williams-Beuren syndrome. The first patient showed no evidence of coarctation of the aorta at the first examination. Seven years later, she developed coarctation of the aorta. In the second patient, we found the progression of renal artery stenosis by serial angiography. We report that vascular lesions may be progressive in Williams-Beuren syndrome.

Ursodeoxycholic acid therapy in the treatment of biliary atresia.

The prognosis of operated biliary atresia in the cases with bile excretion chiefly depends upon the prevention of ascending cholangitis. An antibiotic is therefore intravenously administered during the early postoperative phase, but cannot be used over a long period. In the cases showing satisfactory bile excretion after operation, ascending cholangitis is rare because of rapid disappearance of jaundice. Regarding this, the authors prescribed ursodeoxycholic acid (UDCA) at 10-15 mg/kg/day to 6 infants with biliary atresia for several weeks after operation, and then determined the effects of UDCA in improving jaundice and bile excretion. As a result, serum bilirubin and serum total bile acid (STBA) levels were decreased in 4 of the 6 infants. In the remaining 2 infants, their STBA levels showed no decrease, but were rather increased; these infants subsequently died of hepatic failure. These results suggested that UDCA is useful in the treatment of cholestasis associated with biliary atresia in the cases attaining postoperative bile excretion. It was also suggested that the treatment with UDCA should be stopped when the STBA levels increased after the beginning of the treatment. Therefore, it was thought that STBA levels measured during UDCA therapy could serve as a good indicator of the choleretic effect of UDCA.

Prognostic value of serum procollagen III peptide and type IV collagen in patients with biliary atresia

BACKGROUND/PURPOSE Progressive hepatic fibrosis, in spite of a successful Kasai procedure, is a major problem in patients with biliary atresia (BA). Early identification of patients at risk would be of great value. N-terminal procollagen-III peptide (PIIIP) (which is a marker of fibrogenesis and, therefore, of on going inflammation), and type IV collagen (found in basement membrane extracellular matrix), were measured in patients with BA to determine their potential as prognostic markers. METHODS Thirty-three postoperative BA patients (11.0+/-3.7 years old) and 20 normal controls (10.5+/-2.8 years old) were studied. The BA patients were classified on the basis of their current liver function test results into three outcome groups. Group I (n = 9) had severe liver dysfunction, group II (n = 13) had moderate, and group III (n = 11) had good liver function. Serum P-III-P and type IV collagen values were determined by radioimmunoassays and one step sandwich enzyme immunoassay. RESULTS In group I, serum PIIIP (1.93+/-0.64 U/mL) and type IV collagen levels (363.5+/-69.5 ng/mL) were significantly higher than in group II (PIIIP [1.32+/-0.25 U/mL], type IV collagen [225.3+/-45.4 ng/mL]; P < .01). There were increased levels in serum PIIIP and serum type IV collagen in group II compared with group III (PIIIP [1.01+/-0.25 U/mL], type IV collagen [171.3+/-47.2 ng/mL]; P < .01). There were no significant differences in serum PIIIP and type IV collagen levels between group III and controls. CONCLUSION The authors conclude that serum levels of PIIIP and type IV collagen may be useful in the long-term follow-up of BA patients after Kasais portoenterostomy.

THE ROLE OF VITAMIN D METABOLITES IN THE TREATMENT OF OSTEOPOROSIS

The Second Symposium on Osteoporosis was organized in Tokyo, Japan on November 6, 1994, with the purpose of summarizing the current views on the biology of vitamin D, and the applications of vitamin D metabolites in osteoporosis. The Symposium was sponsored by Chugai Pharmaceuticals, Co., and Teijin Ltd., Tokyo, Japan. Dr. Etsuro Ogata (Cancer Research Institute, Tokyo, Japan) introduced the symposium observing that although vitamin D metabolites and analogs are currently being used in Japan and other countries for the treatment of osteoporosis, there is still controversy on their therapeutic role, especially in North America and Europe. Because the molecular aspects of vitamin D action on bone cells constitute the basis for understanding how vitamin D affects bone remodeling, and for the design of analogs with selective actions on bone, the first part of the symposium focused on the biologic action of vitamin D at the cellular level. The second part reviewed the role of vitamin D in the pathogenesis of osteoporosis, and in the last session the most important and controversial issues on the clinical application of active vitamin D analogs in osteoporosis were discussed.

Serum free T4 and thyroid stimulating hormone levels in preterm infants and relationship between these levels and respiratory distress syndrome.

Background: There have been few studies of the thyroid stimulating hormone (TSH) surge in extremely low‐birthweight (ELBW) infants, and the relationship between thyroid hormones and respiratory distress syndrome (RDS) has yet to be clarified. The present study sought to determine the serum levels of free T4 (fT4) and TSH in ELBW infants and to examine the relationship between these levels and the development of RDS.

Bone mineral density in children and adolescent girls with anorexia nervosa in Japan

Background: The correlation between reduced bone mineral density (BMD) and the disease anorexia nervosa (AN) has long been established. The aim of the present study was to examine the relationship in more detail, particularly focusing on the increasing incidence of the disease occurring in adolescent patients.