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Summary: Romosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. Among high-risk postmenopausal East Asian women, romosozumab followed by alendronate was associated with lower incidences of fractures vs alendronate alone. Romosozumab demonstrates potential to address an unmet need in osteoporosis management in Asia. Introduction: Romosozumab, a sclerostin antibody, exerts dual effect to increase bone formation and decrease bone resorption. The global ARCH study demonstrated superiority of romosozumab followed by alendronate in reducing fracture risk in high-risk postmenopausal osteoporotic women vs alendronate alone. We report outcomes among ARCH East Asian patients. Methods: In ARCH, 4093 postmenopausal osteoporotic women with fragility fracture were randomized 1:1 to monthly romosozumab 210 mg or weekly alendronate 70 mg for 12 months, both followed by open-label alendronate. Primary endpoints were incidence of new vertebral fracture (VF) at 24 months and clinical fracture at primary analysis (confirmed fractures in ≥ 330 patients and all patients had opportunity to attend month 24 visit). This post hoc analysis was not powered to detect fracture-rate differences. Results: This analysis included 275 patients from Hong Kong, Korea, and Taiwan. Romosozumab followed by alendronate reduced risk of new VFs at 24 months by 60% (P = 0.11) and clinical fractures at primary analysis by 44% (P = 0.15) vs alendronate alone. Romosozumab followed by alendronate significantly increased mean bone mineral density at 24 months from baseline by a further 9.0%, 3.3%, and 3.0% at the lumbar spine, total hip, and femoral neck vs alendronate alone. Adverse event (AE) rates, including positively adjudicated serious cardiovascular AEs (1.6% vs 1.4% at 12 months for romosozumab vs alendronate), were similar across treatment groups. Conclusions: Consistent with the global analysis, romosozumab followed by alendronate was associated with lower incidences of new vertebral, clinical, non-vertebral, and hip fractures vs alendronate alone among East Asian patients. [ABSTRACT FROM AUTHOR]

Summary: In aged population, the association of thyroid hormones on physical performance, especially within their normal range, has yet to be elucidated. In this study, individuals with low serum free T3/free T4 were likely to have low muscle mass and impaired physical performance. Purpose: We aimed to evaluate the associations of muscle mass, strength, and physical performance with thyroid hormone in an aged euthyroid population from a community-based cohort. Methods: We examined 918 men aged over 60 years and 1215 postmenopausal women from the Ansung cohort study. Appendicular skeletal muscle mass divided by square of height (ASM/ht2) was used as the muscle mass index. Hand grip strength was measured using a hydraulic dynamometer. Physical performance was assessed using the short physical performance battery (SPPB). Results: Participants with higher tertiles of free T3 and free T3/free T4 were younger and had higher ASM/ht2, stronger hand grip strength, and higher SPPB scores than those in the lower tertiles. In adjusted models, men within higher tertiles of free T3 had higher ASM/ht2 compared with those within lower tertiles (p = 0.033), whereas subjects with higher tertiles of free T4 had lower ASM/ht2 compared with those within lower tertiles (p = 0.043). Subjects within higher tertiles of free T3/free T4 had higher ASM/ht2 (p < 0.001) and better physical performance (p = 0.048) than those within lower tertiles after adjustments. However, free T3, free T4, or free T3/free T4 was not related to hand grip strength after adjustment for covariates. Conclusion: Our results thus indicate that in an aged euthyroid population, low serum free T3/free T4 was a better index for low muscle mass and impaired physical performance than serum free T3 or free T4 alone. [ABSTRACT FROM AUTHOR]

Summary: We determined the incidence of second hip fracture and evaluated whether compliant and persistent users of bisphosphonate had a lower incidence of second hip fracture after prior hip fracture, from a national claim registry. Introduction: Bisphosphonate is prescribed worldwide for the primary prevention of osteoporotic fracture. However, the association between adherent use of bisphosphonate and prevention of second hip fracture is unclear. Our purpose was to determine whether the adherent use of bisphosphonate was associated with a decreased risk of second hip fracture in South Korea, using a nationwide database. Methods: From 2007 to 2011, first and second hip fractures were identified using the ICD-10 and procedure code form from the nationwide database of the Health Insurance Review and Assessment Service. Compliant use of bisphosphonate was defined as a patient medication possession ratio of 80 or more. Persistent users were defined patients with a refill gap of 30 days or less. We compared the incidence of second hip fracture in compliant and persistent users and non-users. Results: Among 59,782 patients with first hip fracture, in this study, 1,336 second hip fracture occurred after the initial hip fracture during the study period. The mean age at the first hip fracture was 75.4 years (range, 50 to 100 years). The cumulative 1-year, 2-year, and 3-year incidence of second hip fracture was 1.0 % (552/59,782), 1.9 % (1,123/59,782), and 2.2 % (1,336/59,782), respectively. After multivariate analysis, compliant and persistent use of bisphosphonate was significantly independent protectors for second hip fracture (HR, 0.595; 95 % CI, 0.400–0.885; HR, 0.433; 95 % CI, 0.327–0.573, respectively). Conclusions: Compliant and persistent use of bisphosphonate decreases the risk of second hip fracture, in terms of secondary prevention. [ABSTRACT FROM AUTHOR]

Sulfotransferase 1E1 (SULT1E1) catalyze estrogen into sulfate conjugation and is involved in the metabolism of phytoestrogen. A community-based cross-sectional study was conducted on 397 Korean women, to evaluate the association between genetic polymorphisms of SULT1E1 and bone mineral density (BMD) and the combined effect of the genetic polymorphism and phytoestrogen intake for BMD in Korean women. BMDs of the distal radius and the calcaneus were measured by dual-energy X-ray absorptiometry. Genotypes of SULT1E1 IVS1-447 C>A, IVS4-1653 T>C, and *959 G>A were determined by the 5'-nuclease assay (TaqMan). Phytoestrogen intake was estimated by a food-frequency questionnaire validated against multiple 24-hour recalls. Women with the SULT1E1 *959 GG genotype had a 4.5% lower BMD at the distal radius (Ptrend = 0.05) and a 7.9% lower BMD at the calcaneus compared to those with AA genotype (Ptrend < 0.01), whereas the SULT1E1 IVS1-447 CC genotype and IVS4-1653 TT genotype were not associated with BMD. There was no significant trend of BMD with the numbers of CTG-containing haplotypes, but calcaneal BMDs significantly differed between SULT1E1 CTA-CTA haplotype and CTG-CCA haplotype (P < 0.05). When stratified by SULT1E1 genotype, the correlation between phytoestrogen consumption and BMD at the calcaneus was noteworthy in women with SULT1E1 *959 GG genotype (r = 0.25, P = 0.01) or SULT1E1 IVS 4-1653 TT genotype (r = 0.15, P = 0.02). This trend remained significant only in postmenopausal women (r = 0.36, P = 0.01) after multiple testing was corrected by the false discovery rate method. In conclusion, the genetic polymorphism of SULT1E1 *959 G > A was associated with BMD at the distal radius and calcaneus, and the association between phytoestrogen consumption and calcaneal BMD might be modified by this genetic polymorphism. [ABSTRACT FROM AUTHOR]

Bone morphogenetic proteins (BMPs) play critical roles in osteoblast differentiation. To investigate the association between common single-nucleotide polymorphisms (SNPs) of BMPs and bone mineral density (BMD), a cross-sectional study was conducted in healthy Korean men ( n = 237) and women ( n = 276) aged 20–39 years. Calcaneus and distal radius BMD were measured by dual energy X-ray absorptiometry. SNPs of BMP2 (-1103C>A, c.584G>A, IVS1-2744A>G, c.893T>A), BMP4 (c.712T>C, IVS1-160C>T), and BMP6 (c.1283C>G, IVS4-6838A>G, IVS5 + 24C>T) were determined using the 5′-nuclease assay. Significant associations were observed between BMP2 c.584G>A, c.893T>A genotypes and male calcaneus as well as female distal radius BMD. Men with the BMP2 c.893 AA genotype had a 16% higher BMD at the calcaneus ( P for trend = 0.014), whereas women with this genotype had a 7% lower BMD at the distal radius than the other genotypes ( P for trend = 0.010). A significant association was also observed between BMP4 IVS1-160C>T and male calcaneus BMD ( P for trend = 0.024). When the association between haplotypes and BMD was investigated, the AAGA haplotype of BMP2 was significantly associated with low bone mass in female distal radius ( P for trend = 0.013). These results suggested that one or more SNPs of BMP2 and BMP4 are associated with peripheral BMD in Korean men and women. However, this association is dependent on anatomical sites and gender. Thus, larger studies with complete coverage of SNPs are needed in the future. [ABSTRACT FROM AUTHOR]

To evaluate the effects of genetic polymorphisms of OPG, RANK, and ESR1, which regulate osteoclastogenesis, on bone mineral density (BMD), a cross-sectional study was conducted in 650 Korean postmenopausal women. BMDs of the distal radius and the calcaneus were measured by dual energy X-ray absorptiometry (DXA). Genetic polymorphisms of OPG 163 A > G, 1181 G > C; RANK 421 C > T, 575 T > C; and ESR1 1335 C > T, 2142 G > A were determined by matrix-assisted laser desorption/ionization—time of flight (MALDI-ToF) mass spectrometry. The differences between the BMDs of the genotypes of OPG, RANK, and ESR1 were analyzed by multiple linear regression model adjusted for age and body mass index. Women with the OPG 1181 CC genotype had higher BMDs at the distal radius (7%) and calcaneus (10%) than those with the GG genotype; and these differences were statistically significant ( P = 0.001 and P = 0.007, respectively). A significant association was also observed between RANK 575 T > C and calcaneus BMD ( P for trend = 0.017). No significant association was observed between BMDs and the polymorphisms of ESR1. The association between OPG 1181 G > C and BMD was profound in subjects with the RANK 575 TT or ESR1 2142 GG genotypes; women with OPG 1181 CC had higher BMDs at the distal radius (11%) and calcaneus (11%) than those with OPG 1181 GG only in women with RANK 575 TT genotype ( P = 0.002 and P = 0.021, respectively). These results suggest that OPG genetic polymorphisms, especially with the RANK 575 TT or ESR1 2142 GG genotypes, are related to low BMD in postmenopausal Korean women. [ABSTRACT FROM AUTHOR]

A novel intracellular glucosyltransferase (GTase) was isolated from cells of Actinoplanes sp. CKD485-16—acarbose-producing cells. The enzyme was purified by DEAE-cellulose and G75-40 Sephadex chromatography. The molecular mass of the enzyme was estimated to be 62 kDa by SDS-polyacrylamide gel electrophoresis, and its isoelectric point (pI) was pH 4.3. The N-terminal sequence of the GTase consisted of NH2-Ser-Val-Pro-Leu-Ser-Leu-Pro-Ala-Glu-Trp. The optimum pH and temperature were 7.5 and 30show $132#°show $132#C. The enzyme was stable in a pH range of 5.5–9.0 and below 40show $132#°show $132#C. Enzymatic reactions were performed by incubating the GTase with various substrates. The GTase converted acarbose into component C, maltose into trehalose, and maltooligosaccharides into maltooligosyl trehaloses. The reactions were reversible. Various acarbose analogs were tested as inhibitors against the GTase as a means to suppress component C formation. Valienamine was the most potent, with an IC50 value of 2.4×10-3 mM and showed a competitive inhibition mode. [ABSTRACT FROM AUTHOR]

Enhancement of monascus pigment production in a co-culture of Monascus sp. J101 with Saccharomyces cerevisiae was accomplished using chitinase in the feeding of a S. cerevisiae culture filtrate. Batch fermentations were carried out at constant chitinase activity levels of 0.8 U and 0.5 U after 24 h of cultivation. Monascus red pigment concentrations obtained at the end of fermentation were 182.4 OD units and 147.3 OD units, respectively, for chitinase activity levels of 0.8 U and 0.5 U. The cell mass was higher at 0.8 U than at 0.5 U, whereas pigment production per unit cell mass was higher at 0.5 U than at 0.8 U. Kinetic equations involving cell growth rate, cell activity and chitinase activity levels were analyzed. Cell activity was expressed as a function of mean cell age. The optimum time for reduction of the chitinase activity level from 0.8 U to 0.5 U for maximization of monascus pigment production was numerically estimated to be 60 h. Based on this result, a batch fermentation was performed where the chitinase activity level was maintained at 0.8 U from 24 h to 60 h, then the level was lowered to 0.5 U after 60 h. This scheme resulted in a monascus pigment production of 198.3 OD units. [ABSTRACT FROM AUTHOR]

Yarrowia lipolytica KCCM50506, which transforms isobutyric acid to L- β-hydroxy isobutyric acid (L- β-HIBA), was screened. Chemostat cultures were carried out in jar fermentors at dilution rates of 0.02 h−1 to 0.12 h−1. L- β-HIBA fermentation-regulating factors were determined to be specific growth rate, and concentrations of glucose and isobutyric acid in fermentor from analysis of steady-state data. The specific productivity of L- β-HIBA increased as the specific growth rate increased, apparently as a growth-associated type of product formation. A fed-batch culture was carried out under optimum conditions where the concentrations of glucose and isobutyric acid in the fermentor were maintained at 23 g l−1 and 9 g l−1, respectively. The concentrations of cells and L- β-HIBA obtained at the end of fermentation were 20 g l−1 and 49 g l−1, respectively, corresponding to 2.0 and 2.7 times more than concentrations in batch culture. [ABSTRACT FROM AUTHOR]

Synthesis of two recombinant proteins (human glucagon and human growth hormone) was investigated in fed-batch cultures at high cell concentrations of recombinant Escherichia coli. The glucose-limited growth was achieved without accumulation of metabolic by-products and hence the cellular environment is presumed invariable during growth and recombinant protein synthesis. Via exponential feeding in the two-phase fed-batch operation, the specific cell growth rate was successfully controlled at the desired rates and the fed-batch mode employed is considered appropriate for examining the correlation between the specific growth rate and the efficiency of recombinant product formation in the recombinant E. coli strains. The two recombinant proteins were expressed as fusion proteins and the concentration in the culture broth was increased to 15 g fusion growth hormone l−1 and 7 g fusion glucagon l−1. The fusion growth hormone was initially expressed as soluble protein but seemed to be gradually aggregated into inclusion bodies as the expression level increased, whereas the synthesized fusion glucagon existed as a cytoplasmic soluble protein during the whole induction period. The stressful conditions of cultivation employed (i.e. high-cell-density cultivation at low growth rate) may induce the increased production of various host-derived chaperones and thereby enhance the folding efficiency of synthesized heterologous proteins. The synthesis of the recombinant fusion proteins was strongly growth-dependent and more efficient at a higher specific growth rate. The mechanism linking specific growth rate with recombinant protein productivity is likely to be related to the change in cellular ribosomal content. [ABSTRACT FROM AUTHOR]