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Background Here, we genetically and antigenically analyzed influenza B viruses (IBVs) isolated in Japan during the 2017‐2018 and 2018‐2019 influenza seasons. Methods A total of 68 IBVs (61 B/Yamagata/16/88‐like [B/Yamagata]‐lineage and 7 B/Victoria/2/87‐like [B/Victoria]‐lineage) were antigenically and genetically characterized by using hemagglutination inhibition (HI) assays and phylogenetic analysis, respectively. The susceptibility of IBVs to neuraminidase (NA) inhibitors was assessed by using a fluorescence‐based NA inhibition assay. Results All 61 B/Yamagata‐lineage isolates were genetically closely related to B/Phuket/3073/2013, the vaccine strain for these two seasons. Eleven B/Yamagata‐lineage isolates tested were antigenically similar to B/Phuket/3073/2013 by the HI test. Seven B/Victoria‐lineage isolates were genetically closely related to B/Texas/02/2013, the WHO‐recommended vaccine strain for the 2017‐2018 season; however, they were antigenically distinct from B/Texas/02/2013 with an eightfold or 16‐fold difference in HI titer. Of these 7 isolates, 4 possessed a two‐amino‐acid deletion at positions 162 and 163 in hemagglutinin (HA) and the other 3 had a three‐amino‐acid deletion at positions 162‐164 in HA. Importantly, the variants with the three‐amino‐acid deletion appeared to be antigenically different from the B/Colorado/06/2017 virus with the two‐amino‐acid deletion, the vaccine strain for the 2018‐2019 season with a fourfold or eightfold difference in HI titer. One B/Yamagata‐lineage isolate carrying a G407S mutation in its NA showed a marked reduction in susceptibility to zanamivir, peramivir, and laninamivir. Conclusions These results highlight the need for continued monitoring for the prevalence of the antigenic variant with the three‐amino‐acid deletion and the variant with reduced NA inhibitor susceptibility.

Here we report the isolation of the influenza A/H1N1 2009 pandemic (A/H1N1pdm) and A/H3N2 viruses carrying an I38T mutation in the polymerase acidic protein-a mutation that confers reduced susceptibility to baloxavir marboxil-from patients before and after treatment with baloxavir marboxil in Japan. These variants showed replicative abilities and pathogenicity that is similar to those of wild-type isolates in hamsters; they also transmitted efficiently between ferrets by respiratory droplets.

When children around 2-year-old show leg bowing without lower-limb radiographic abnormalities for rickets, the leg bowing is classified as “physiologic” genu varum without conducting a blood test. However, it has recently been suggested that toddlers who are diagnosed with physiologic genu varum may in fact have some form of bone metabolic disorder. In this 1:2 case–control study, blood samples were obtained from 33 toddlers with genu varum without radiographic abnormalities for rickets and 66 age- and gender-matched healthy children. Serum alkaline phosphatase (sALP), intact parathyroid hormone (siPTH), 25-hydroxy vitamin D [s25(OH)D], calcium (sCa), and inorganic phosphate (sP) were measured. s25(OH)D of the subjects with genu varum (24.8 ng/ml) were significantly lower than those of the control (33.6 ng/ml) (p

Japan has been running a nationwide antenatal human T-cell leukemia virus type-1 (HTLV-1) antibody screening program since 2010 for the prevention of HTLV-1 mother-to-child transmission. As part of the program, pregnant women are invited to take an HTLV-1 antibody screening test, usually within the first 30 weeks of gestation, during regular pregnancy checkups. Pregnant women tested positive on the antibody screening test undergo a confirmatory test, either western blotting or line immunoassay. In indeterminate case, polymerase chain reaction (PCR) is used as a final test to diagnose infection. Pregnant women tested positive on a confirmatory or PCR test are identified as HTLV-1 carriers. As breastfeeding is a predominant route of postnatal HTLV-1 mother-to-child transmission, exclusive formula feeding is widely used as a postnatal preventive measure. Although there is insufficient evidence that short-term breastfeeding during ≤3 months does not increase the risk of mother-to-child transmission compared to exclusive formula feeding, this feeding method is considered if the mother is eager to breastfeed her child. However, it is important that mothers and family members fully understand that there is an increase in the risk of mother-to-child transmission when breastfeeding would be prolonged. As there are only a few clinical studies on the protective effect of frozen-thawed breastmilk feeding on mother-to-child transmission of HTLV-1, there is little evidence to recommend this feeding method. Further study on the protective effects of these feeding methods are needed. It is assumed that the risk of anxiety or depression may increase in the mothers who selected exclusive formula feeding or short-term breastfeeding. Thus, an adequate support and counseling for these mothers should be provided. In addition to raising public awareness of HTLV-1 infection, epidemiological data from the nationwide program needs to be collected and analyzed. In most cases, infected children are asymptomatic, and it is necessary to clarify how these children should be followed medically.

When children around 2 years of age show leg bowing and diseases are ruled out based on radiographic findings without conducting blood tests, they are classified as "physiologic" genu varum. Since whether or not physiologic genu varum is associated with bone metabolism is unclear, this study was conducted to clarify the association between genu varum and bone metabolism in children. Thirty-five pediatric patients with genu varm who visited our out-patient clinic were enrolled. While two of the 35 children had nutritional rickets, showing abnormalities on both blood test (ALP, ≥1000 IU/L; iPTH, >65 pg/mL and 25(OH)D, ≤20 ng/mL) and radiographs (such as cupping, fraying or splaying), five of 35 children showed abnormalities on blood tests but not radiographs. While metaphyseal-diaphyseal angle (MDA) correlated with serum 25-hydroxy vitamin D (r = -0.35, p = 0.04) and magnesium (r = -0.36, p = 0.04), MDA and femorotibial angle (FTA) correlated with alkaline phosphatase (r = 0.43, p = 0.01 and r = 0.51, p = 0.006, respectively). A ridge regression analysis adjusted for age and body mass index indicated that ALP was associated with MDA and FTA. A logistic regression analysis adjusted for age and BMI indicated that higher ALP influenced an MDA >11°, which indicates the risk for the progression of genu varum (odds ratio 1.002, 95% confidence interval 1.0003-1.003, p = 0.021). The higher ALP (+100 IU), the higher risk of an MDA >11° (odds ratio 1.22). In conclusion, genu varum is associated with the alkaline phosphatase level regardless of the presence of radiographic abnormalities in the growth plate in children.

Here we report the isolation of the influenza A/H1N1 2009 pandemic (A/H1N1pdm) and A/H3N2 viruses carrying an I38T mutation in the polymerase acidic protein-a mutation that confers reduced susceptibility to baloxavir marboxil-from patients before and after treatment with baloxavir marboxil in Japan. These variants showed replicative abilities and pathogenicity that is similar to those of wild-type isolates in hamsters; they also transmitted efficiently between ferrets by respiratory droplets.

Objectives: To examine the factors associated with increase in lumbar spine bone mineral density (LS-BMD) by bisphosphonates (BPs) with active vitamin D analog (aVD). Methods: Two independent postmenopausal osteoporotic patients treated by BPs with aVD for 24 months (Study 1: n = 93, Study 2: n = 99) were retrospectively analyzed. Results: In Study 1, LS-BMD of the patients significantly increased for 24 m (5.4%, p r2: 0.088, p = .02). While average sCa of the patients was 9.2 mg/dL before treatment, it increased time-dependently to 9.6 mg/dL for 24 m by treatment. As each patient had their LS-BMD five times during the study, there were four instances of %LS-BMD in each patient, resulting in 372 instances of %LS-BMD in Study 1. The smallest Akaike’s information criterion value for the most appropriate cut-off levels of sCa for %LS-BMD by treatment every 6 m was 9.3 mg/dL. The %LS-BMD by treatment for 6 m during 24 m period in patients with sCa ≥9.3 mg/dL (1.5%) was significantly higher than that in patients with sCa p = .038). The results of Study 2 were similar to those of Study 1, confirming the phenomena observed. Conclusion: sCa was associated with an increased LS-BMD by BPs with aVD.

Vitamin D insufficiency and deficiency are common in the elderly. Most previous studies using alendronate have used vitamin D supplementation regardless of individual vitamin D status. However, the minimum required vitamin D levels for the efficacy of alendronate treatment of osteoporosis remain unclear. Fifty-two postmenopausal women, diagnosed with osteoporosis, were enrolled in this prospective study, in which they took 5 mg of alendronate daily for 6 months without any supplements. Associations between baseline factors and their changes during the treatment and the change in the lumbar spine bone mineral density (LS-BMD) were examined. The most appropriate cut-off level of 25-hydroxyvitamin D (25[OH]D) for the optimal increase in LS-BMD with alendronate was determined using the Akaike information criterion statistical criterion. Overall, alendronate treatment significantly increased LS-BMD by 4.7%. The basal serum 25(OH)D and change in urinary NTX were significantly associated with the increase in LS-BMD. The increase in LS-BMD between the two groups was not different when comparing those with baseline 25(OH)D above vs. below 30 ng/ml. However, 25(OH)D of 25 ng/ml was determined to be the minimum required vitamin D level for an adequate effect of alendronate. Vitamin D status may affect the increase in LS-BMD with alendronate treatment in individuals being treated for osteoporosis, and a 25(OH)D level >25 ng/ml appears to be required for an optimal LS-BMD response.

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. Methods: The authors measured serum fT4 and TSH levels soon after birth in 449 preterm infants, who were born at 22–36 weeks of gestation, and determined the associations between these levels, the incidence of RDS, and the recognized clinical factors associated with RDS. Results: Serum fT4 and TSH levels, and the fT4/TSH ratio, in the group at 22–24 weeks of gestation were significantly lower than those in the group at 28–36 weeks. The levels and ratio increased significantly with increasing gestational age. There were significant correlations between the serum fT4 level and the birthweight, Apgar score, and gender, and between the serum TSH level and the gestational age, mode of delivery, and birthweight. No significant relationship between the incidence of RDS and the serum levels of fT4 and TSH was observed. Conclusion: The authors’ results suggest that the serum levels of fT4 and TSH in ELBW infants are very low, and that these levels are not correlated with the occurrence of RDS.

TBP-free TAF II-containing-type HAT complex subclasses, which contain hGCN5 HAT and TRRAP, appear to act as common coactivator complexes for nuclear receptors. However, their physiological significance with respect to each nuclear receptor remains to be established. To address this issue, we used hepatic cell lines (HepG2) with reduced endogenous TRRAP expression through antisense RNA expression or with overexpressed TRRAP or other major coactivators. The ligand-induced transactivation function of liver X receptor alpha (LXRalpha) and farnesoid X receptor/bile acid receptor reflected TRRAP expression levels, while that of PPARgamma did not. A GST pull-down assay indicated that TRRAP contains two potential LXRalpha-interacting domains in the C-terminal and central domains. Expression of antisense TRRAP RNA in HepG2 cells abolished the ligand-induced expression of LXRalpha target genes. These results suggested that TRRAP plays an important role as a coactivator, presumably part of a complex, in lipid metabolism through regulation of the LXRalpha-mediated gene cascade in hepatic cells.

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 beta3-adrenergic receptor (beta3-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 beta3-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.

A highly sensitive single-stranded conformation polymorphism method for analysis of Vitamin D receptor (VDR) gene polymorphism was developed employing laser-induced fluorescence capillary electrophoresis (LIF-CE). LIF-CE was conducted utilizing a linear polyacrylamide solution as entangled polymer and acridine orange as a fluorescent dye of single-stranded DNA. Effect of acridine orange, size of PCR product and running temperature were investigated by LIF-CE in order to analyze the two polymorphisms of the allelic variation of the Bsm I and Taq I sites in intron 8 and exon 9, respectively, of the VDR gene. The developed method was simple, rapid (

We developed a sensitive and rapid PCR-RFLP ELISA using acetate kinase (AK) and firefly luciferase as a detection system. AK used as a label enzyme could sensitively be detected by bioluminescent assay using the firefly luciferase reac-tion. The detection limit was 10-20 mol/assay and the luminescence was stable for 48 h. FITC-labeled sense primer and biotin labeled anti sense primer were used for PCR amplification of the vitamin D receptor gene. After PCR, the products were digested with Taq I or Apa I enzyme. The reaction products were diluted with assay buffer and transferred to a plate coated with anti FITC IgG. After incubation for 2 h at 37°C, the plate was washed and reacted with avidin/biotinylated AK, the AK activity was detected by bioluminescence assay using the firefly luciferin/luciferase system. DNA polymorphism types (AA, Aa, aa, TT, Tt, tt) of the vitamin D receptor gene (VDR) could be clearly determined by measuring the bioluminescent intensity or by using photon imaging with a CCD camera.

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, P0.001). Second, the VDR mRNA levels were estimated by competitive RT-PCR in 60 healthy subjects (35TT, 24Tt, 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.

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.

Ribavirin-related anemia is a serious side-effect of the pegylated interferon and ribavirin therapy used for hepatitis C, and may be cause for a reduction in ribavirin dose or even cessation of treatment. The aim of this study was to evaluate the prophylactic effects of oral eicosapentaenoic acid (EPA) supplementation on ribavirin-induced hemolytic anemia in pediatric and young adult patients.Twelve chronic hepatitis C patients ranging in age from 3 to 21 years (mean, 13.9 ± 5.1 years) who received pegylated interferon α-2b and ribavirin combination therapy were randomized to either the control group (n = 6) or EPA group (n = 6). Blood samples were collected before, and at 4, 8, and 16 weeks after treatment to measure clinical laboratory parameters.The reduction in hemoglobin levels of the EPA group was significantly ameliorated at 8 and 16 weeks when compared to the control group (P0.05). There was no significant difference in plasma ribavirin concentrations between the two groups during the treatment. However, one patient in the control group had a reduction in ribavirin dose.EPA supplementation prevented ribavirin-induced hemolytic anemia during combination therapy with pegylated interferon α-2b and ribavirin in pediatric and young adult patients.

Circulating osteocalcin, a marker of bone formation, is under strong genetic influence, and this effect is related to the genetic influence on bone density. To examine genetic influences on bone turnover further, other markers of bone formation (serum carboxyterminal propeptide of type I procollagen, PICP), bone resorption (serum pyridinoline cross-linked carboxyterminal telopeptide of type I collagen, ICTP), and nonosseous connective tissue synthesis (serum aminoterminal propeptide of type III procollagen, PIIINP) were studied in 82 female twin pairs: 42 monozygotic (MZ) and 40 dizygotic (DZ) twin pairs (mean age, MZ; 48.4 yr; DZ; 45.6 yr). The intraclass correlation coefficients of MZ twin pairs, rMZ, for serum PICP (0.78) and serum ICTP (0.68) were significantly greater than the corresponding rDZ (0.31 and 0.36, respectively), but a genetic effect on serum PIIINP was not demonstrable. Within DZ twin pair differences in serum PICP predicted differences in lumbar spine bone density (r = -0.37); higher serum PICP levels indicating the twin with the lower lumbar spine bone density. Also within pair differences in serum ICTP and PICP predicted differences in bone density at the lumbar spine independent of serum osteocalcin. These data indicate that both synthesis and degradation of type I collagen are genetically determined and that this phenomenon is related to the genetic regulation of bone density.

Bone density achieved in early adulthood is the major determinant of risk of osteoporotic fracture. Up to 60% of women suffer osteoporotic fractures as a result of low bone density, which is under strong genetic control acting through effects on bone turnover. Here we show that common allelic variants in the gene encoding the vitamin D receptor can be used to predict differences in bone density, accounting for up to 75% of the total genetic effect on bone density in healthy individuals. The genotype associated with lower bone density was overrepresented in postmenopausal women with bone densities more than 2 standard deviations below values in young normal women. The molecular mechanisms by which bone density is regulated by the vitamin D receptor gene are not certain, although allelic differences in the 3' untranslated region may alter messenger RNA levels. These findings could open new avenues to the development and targeting of prophylactic interventions. It follows that other pathophysiological processes considered to be subject to complex multifactorial genetic regulation may also be modulated by a single gene with pleiotropic transcriptional actions.

Acetabular dysplasia (AD) contributes to the development of osteoarthritis of the hip. A rotational acetabular osteotomy (RAO) is one of the methods of pelvic osteotomy to prevent or treat secondary osteoarthritis of the hip. Although most of the patients that undergo RAO show satisfactory results, some have poor results. This study investigated whether gene polymorphisms of both the vitamin D receptor (VDR) and oestrogen receptor (ER) are involved in both AD and the postoperative results following RAOs. Sixty-four Japanese patients with AD who were treated by an RAO were enrolled in this study (59 women and 5 men, aged 13–59, with an average age of 40.3). Gene polymorphisms of the VDR [ApaI and TaqI restriction fragment length polymorphisms (RFLPs)] and ER (PvuII and XbaI RFLPs) were determined in these patients. The relationship between both the AD and radiographic postoperative changes of the hip joint after an RAO with these gene polymorphisms were examined. The frequencies of ER gene polymorphism coded as pp (RFLP/PvuII) in patients with AD were statistically significantly different (p = .011) from those coded as both PP and Pp. The joint space width narrowed even after RAO in 90% of the patients with the pp gene polymorphism, while it narrowed in only 35% of the patients with either PP or Pp seven years or longer after an RAO. The PvuII polymorphism in the ER gene was associated with the postoperative result of an RAO, while no association was observed between the AD with VDR and ER gene polymorphisms.

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. Method: Twenty-four girls diagnosed with AN were enrolled in the study. All subjects ranged in age from 11.1 to 15.5 years, with an average age of 13.5 years. The BMD of lumbar spines and femoral necks were measured. All the values for BMD at admission were expressed as means ± SD and patients with and without menarche were separately investigated. Results: The average BMD of lumbar spines at the time of admission was −0.51 SD in total. However, the average BMD of patients without menarche was −1.28 SD, which was significantly lower than the −0.16 SD on average in patients with menarche. As a whole the BMD of femoral necks at admission tended to be lower than that of lumbar spines. Similarly, it was lower in patients without menarche (−1.7 SD on average) than in those with menarche (−0.77 SD on average). Conclusions: BMD was lower in children and adolescent AN patients without menarche, and such a tendency was more significant at the femoral neck region. In child AN cases without menarche, the BMD, especially at the femoral neck, needs to be measured, and later recovery should be monitored closely over a long period.

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.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.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.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 Kasai's portoenterostomy.

The fundamental role of vitamin D receptor (VDR) gene polymorphisms have been reviewed. The VDR gene polymorphisms are associated with the intestinal calcium absorption , rate of bone gain and loss. The observed variability in younger and elderly people in the response of bone mass to calcium intake and supplementation may be explained partly by the interaction between environmental and genetic factors.

We identified a human multiprotein complex (WINAC) that directly interacts with the vitamin D receptor (VDR) through the Williams syndrome transcription factor (WSTF). WINAC has ATP-dependent chromatin-remodeling activity and contains both SWI/SNF components and DNA replication-related factors. The latter might explain a WINAC requirement for normal S phase progression. WINAC mediates the recruitment of unliganded VDR to VDR target sites in promoters, while subsequent binding of coregulators requires ligand binding. This recruitment order exemplifies that an interaction of a sequence-specific regulator with a chromatin-remodeling complex can organize nucleosomal arrays at specific local sites in order to make promoters accessible for coregulators. Furthermore, overexpression of WSTF could restore the impaired recruitment of VDR to vitamin D regulated promoters in fibroblasts from Williams syndrome patients. This suggests that WINAC dysfunction contributes to Williams syndrome, which could therefore be considered, at least in part, a chromatin-remodeling factor disease.

In humans, the vitamin D receptor (VDR) gene has been localized to the chromosomal locus 12q13-14. The gene is composed of a minimum of nine exons. Hereditary 1,25-dihydroxyvitamin D resistant rickets (HVDRR) known as vitamin D dependent rickets type II is a rare autosomal recessive disease that arises as a result of mutations in the gene encoding the VDR. Genetic factors play a key role in determining bone mass, which is an important predictor of osteoporosis. Recently, polymorphism at the VDR locus has been implicated as a genetic marker for bone mineral density. Vitamin D receptor gene start codon polymorphisms, and 3'-end region polymorphisms may modulate bone density.

Sex steroids, particularly estrogen, play an important role in increasing and maintaining bone mineral density (BMD) during puberty; sex steroids also promote bone maturation. 1-3 To assess the relation between bone maturation and bone mineralization during exposure to excessive estrogen, we evaluated the BMD of patients with precocious puberty associated with advanced bone age. Patients and Methods . We measured spinal BMD in 7 untreated girls with central precocious puberty (age range, 6.0-11.3 years), all with a history of breast development before 8 years of age. The patients' breast development was Tanner stage II through IV. Bone age, assessed by means of the TW2 RUS method for Japanese, 4 was found to be advanced (bone age–chronological age ratio, 1.11-1.62). Bone mineral density was measured using dual-energy x-ray absorptiometry (Hologic QDR-2000, Hologic Inc, Waltham, Mass) at the lumbar spine (L2-4). Normal BMD values for Japanese 5 to 15 years of age were

Familial occurrence of extrahepatic biliary atresia (EHBA) or biliary dilatation has been reported; however, the genetic influences on these disorders are still obscure. The authors previously reported the occurrence of biliary dilatation and EHBA in sisters, which is extremely rare. Recently, a similar pair of sisters was treated; one had pancreaticobiliary maljunction with minimal dilatation of the common bile duct, and the other also had EHBA. The authors' investigations suggest that there may be common etiologic factors for EHBA and biliary dilatation, such as pancreaticobiliary maljunction; however, other factors are required to complete the process and cause biliary atresia.

Recent studies have shown that genetic effects on bone mineral density (BMD) and bone turnover are related to allelic variation in the vitamin D receptor (VDR) gene. We examined allelic influences of the VDR gene on bone turnover and density in 202 normal healthy premenopausal Japanese women (age 30.1 +/- 1.2, mean +/- SEM). The VDR effect on BMD and turnover is similar to that observed in Caucasian women; however, there are major differences in allele frequency. The B allele by BsmI restriction fragment length polymorphisms (RFLPs), associated with low BMD and high bone turnover, is found in only 12% of Japanese women (1.4% homozygote BB), compared with 41% of Caucasians (16.7% homozygote BB). In comparing the two most frequent genotypes, Bb heterozygotes (21.5%) and bb homozygotes (77.1%), BMD is 5.3% lower in Bb heterozygotes, and levels of bone formation markers including osteocalcin and bone-specific alkaline phosphatase are 20-32% higher with lower serum calcium (2.30 +/- 0.02 vs 2.35 +/- 0.01 mmol/l) and higher 1,25-dihydroxyvitamin D (95 +/- 4.8 vs. 76 +/- 3.8 pmol/l). Further discrimination of the genotype was achieved using two additional RFLPs (ApaI, A and TaqI, T); the lumbar spine BMD of the common genotype BbAATt was 9.3% (0.94 SD) lower than in the bbaaTT genotype in premenopausal Japanese women. These data confirm that VDR RFLPs affect bone mineral metabolism regardless of racial differences. Moreover, the VDR genotypes based on haplotype analysis should yield useful insights into the potential prevention of osteoporosis.

Nature 367, 284-287 (1994) .... In order to expand our original observations of a relationship between bone density and vitamin D receptor (VDR) genotype and to examine other genes potentially involved in bone biology, we set out to recruit a larger set of identical and non-identical twins. On re-analysis of these newly collected and re-genotyped samples, we found reduced correlation of the VDR genotype with bone density in this larger sample of twin pairs.

We describe a 16-year-old boy with idiopathic hypogonadotropic hypogonadism associated with osteoporosis. Osteoporotic lesions of the hands, skull and spine were shown by routine radiography. Single-photon absorptiometry at the distal radius confirmed a significant reduction of bone mineral density. The parathyroid hormone-vitamin D axis and calcitonin secretion showed no derangement. Reduced bone mineral density in association with relatively elevated levels of serum osteocalcin and alkaline phosphatase suggested an increased bone turnover (so-called high-turnover osteoporosis). Tetosterone therapy for 3 months significantly increased the radial bone mineral density.

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.