Exploratory use of romosozumab for osteoporosis in a patient with Hajdu-Cheney syndrome: a case report.

Hajdu-Cheney syndrome (HCS) is an inherited skeletal disorder caused by mutations in the Notch homolog protein 2 gene (NOTCH2). Treatment of this rare disease is challenging because there are no established guidelines worldwide. Previous case reports using bisphosphonates, denosumab, or teriparatide suggested that curative treatment for HCS did not exist yet in terms of preventing the disease progression. Therefore, the efficacy of romosozumab for osteoporosis in patients with HCS needs to be evaluated. Herein, we report the case of a 43-year-old woman who had progressive acro-osteolysis and repeated fractures since the age of 29 years. Next-generation sequencing confirmed HCS with a mutation at nucleotide 6758G>A, leading to Trp2253Ter replacement in NOTCH2. Romosozumab treatment was initiated because she had already received bisphosphonate for more than 10 years at other hospitals. After 1 year of romosozumab treatment, the bone mineral density (BMD) increased by 10.2%, 6.3%, and 1.3%, with Z scores of -2.9, -1.6, and -1.2 at the lumbar spine, femoral neck, and total hip, respectively. In addition, C-telopeptide was suppressed by 26.4% (0.121 to 0.089 ng/mL), and procollagen type I N-terminal propeptide increased by 18.7% (25.2 to 29.9 ng/mL). This was the first report of romosozumab treatment in patient with osteoporosis and HCS in Korea. One year of romosozumab treatment provided substantial gains in BMD with maintaining the last acro-osteolytic status without deteriorating, representing a possible treatment option for HCS.

Older American Women May Especially Benefit from Distributing and Consuming Protein for Decreasing Odds of Functional Limitations.

OBJECTIVES: Protein is a key macronutrient for preserving physical function, but the role of protein intake on functional status may differ in men and women. We sought to examine the associations of daily protein intake and distribution on functional limitations in older American men and women. DESIGN: Cross-sectional. SETTING: Population-based survey. PARTICIPANTS: The analytic sample included 3,976 men and 4,081 women aged ≥60-years from the 2007-2016 waves of the National Health and Nutrition Examination Survey. MEASUREMENTS: Participants reported their ability to perform basic activities of daily living, instrumental activities of daily living, leisure and social activities, lower extremity mobility activities, and general physical tasks. Those reporting difficulty or an inability in completing such functional tasks were considered as having a functional limitation. Protein intake was determined with dietary recalls and participants revealed functional limitations. Protein recommendations of ≥0.80, ≥1.00, and ≥1.50 g/kg/day were used. Based on these cut-points, we also investigated distribution of protein across 4 eating occasions at ≥0.20, ≥0.25, and ≥0.38 g/kg/meal, respectively. RESULTS: Older women meeting each recommendation had decreased odds for functional limitations: 0.55 (95% confidence interval (CI): 0.40-0.75) for ≥0.80 g/kg/day, 0.75 (CI: 0.58-0.97) for ≥1.00 g/kg/day, and 0.72 (CI: 0.55-0.94) for ≥1.5 g/kg/day. No significant associations were observed in older men. Further, older women with protein consumption ≥0.20 g/kg/meal had decreased odds for functional limitations: 0.24 (CI: 0.10-0.61) for 1 occasion, 0.20 (CI: 0.08-0.49) for 2 occasions, 0.16 (CI: 0.07-0.40) for 3 occasions, and 0.12 (CI: 0.04-0.32) for 4 occasions. A similar trend was observed for intake ≥0.25 g/kg/meal: 0.31 (CI: 0.16-0.62) for 2 occasions, 0.30 (CI: 0.14-0.61) for 3 occasions, and 0.31 (CI: 0.12-0.78) for 4 occasions. Women with 1 and 2 eating occasions at ≥0.38 g/kg/meal of protein had 0.66 (CI: 0.48-0.91) and 0.54 (CI: 0.37-0.79) decreased odds for functional limitations, respectively. CONCLUSION: Trials that are powered to detect the effects of protein on functional status in women will help to establish causality.

The diagnostic value of phase angle, an integrative bioelectrical marker, for identifying individuals with dysmobility syndrome: the Korean Urban-Rural Elderly study.

Low phase angle, a non-invasive bioimpedance marker, is associated with elevated odds of dysmobility syndrome and its components. Phase angle (estimated cutoffs: < 4.8° in men; < 4.5° in women) can be used to detect dysmobility syndrome in community-dwelling older adults as a simple, integrative screening tool. INTRODUCTION: Dysmobility syndrome uses a score-based approach to predict fracture risk that incorporates the concepts of osteoporosis, sarcopenia, and obesity. Low phase angle (PhA), a simple, non-invasive bioelectrical impedance marker, was associated with low lean mass, high fat mass, and poor muscle function. We aimed to investigate the association between PhA and dysmobility syndrome, with the exploration of the diagnostic cutoffs. METHODS: In a community-dwelling Korean older adult cohort, dysmobility syndrome was defined as the presence of ≥ 3 of the following components: osteoporosis, low lean mass, falls in the preceding year, low grip strength, high fat mass, and poor timed up and go performance. RESULTS: Among the 1825 participants (mean age 71.6, women 66.7%), subjects were classified into sex-stratified PhA tertiles. The prevalence of dysmobility syndrome increased from the highest PhA tertile group to the lowest (15.50 to 2.45% in men; 33.41 to 12.25% in women, P for trend < 0.001). The mean PhA values decreased as the dysmobility score increased (5.33° to 4.65° in men; 4.76° to 4.39° in women, P for trend < 0.001). Low PhA (cutoff: < 4.8° in men; < 4.5° in women) was associated with twofold elevated odds of dysmobility syndrome after adjusting for age, sex, and conventional risk factors. Low PhA improved the identification of individuals with dysmobility syndrome when added to the conventional risk model (area under the curve, 0.73 to 0.75, P = 0.002). CONCLUSION: Low PhA was associated with dysmobility syndrome and its components, independent of age, sex, body mass index, nutritional status, and inflammation.

Defining an international cut-off of two-legged countermovement jump power for sarcopenia and dysmobility syndrome.

We aimed to establish jump power cut-offs for the composite outcome of either sarcopenia (EWGSOP2) or dysmobility syndrome using Asian and Caucasian cohorts. Estimated cut-offs were sex specific (women: < 19.0 W/kg; men: < 23.8 W/kg) but not ethnicity specific. Jump power has potential to be used in definitions of poor musculoskeletal health. PURPOSE: Weight-corrected jump power measured during a countermovement jump may be a useful tool to identify individuals with poor musculoskeletal health, but no cut-off values exist. We aimed to establish jump power cut-offs for detecting individuals with either sarcopenia or dysmobility syndrome. METHODS: Age- and sex-matched community-dwelling older adults from two cohorts (University of Wisconsin-Madison [UW], Korean Urban Rural Elderly cohort [KURE], 1:2) were analyzed. Jump power cut-offs for the composite outcome of either sarcopenia defined by EWGSOP2 or dysmobility syndrome were determined. RESULTS: The UW (n = 95) and KURE (n = 190) cohorts were similar in age (mean 75 years) and sex distribution (68% women). Jump power was similar between KURE and UW women (19.7 vs. 18.6 W/kg, p = 0.096) and slightly higher in KURE than UW in men (26.9 vs. 24.8 W/kg, p = 0.050). In UW and KURE, the prevalence of sarcopenia (7.4% in both), dysmobility syndrome (31.6% and 27.9%), or composite of either sarcopenia or dysmobility syndrome (32.6% and 28.4%) were comparable. Low jump power cut-offs for the composite outcome differed by sex but not by ethnicity (< 19.0 W/kg in women; < 23.8 W/kg in men). Low jump power was associated with elevated odds of sarcopenia (adjusted odds ratio [aOR] 4.07), dysmobility syndrome (aOR 4.32), or the composite of sarcopenia or dysmobility syndrome (aOR 4.67, p < 0.01 for all) independent of age, sex, height, and ethnicity. CONCLUSION: Sex-specific jump power cut-offs were found to detect the presence of either sarcopenia or dysmobility syndrome in older adults independent of Asian or Caucasian ethnicity.

Do Health Promoting Compounds of Flaxseed Attenuate Weight Gain Via Modulation of Obesity Gene Expression?

Diet-induced obesity (DIO) has been shown to increase DNA methyltransferases (DNMTs) expression and DNMTs binding at obesity-associated genes. Natural compounds have the potential to reverse obesity-associated gene expression via the regulation of DNA methylation. The objective of this study was to determine the effect of health promoting compounds of flaxseed on DNMTs and obesity-associated gene expression and weight gain. Sixty C57BL/6J male mice were randomly assigned into one of the following diet groups and fed for eight weeks: 45% kcal fat; 45% kcal fat+10% whole flaxseed; 45% kcal fat+6% defatted flaxseed; 45% kcal fat+4% flaxseed oil; and 16% kcal fat. DNMT1, DNMT3a, DNMT3b, leptin, and peroxisome proliferator-activated receptor (PPAR)-α expressions in adipose and muscle tissues were determined by real-time PCR. The health promoting compounds of flaxseed affected selected gene expression and attenuated weight gain. Further research is needed to identify the specific mechanisms modulating leptin or PPAR-α expression during DIO development.

Magnetized plasma implosion in a snail target driven by a moderate-intensity laser pulse.

Optical generation of compact magnetized plasma structures is studied in the moderate intensity domain. A sub-ns laser beam irradiated snail-shaped targets with the intensity of about 1016 W/cm2. With a neat optical diagnostics, a sub-megagauss magnetized plasmoid is traced inside the target. On the observed hydrodynamic time scale, the hot plasma formation achieves a theta-pinch-like density and magnetic field distribution, which implodes into the target interior. This simple and elegant plasma magnetization scheme in the moderate-intensity domain is of particular interest for fundamental astrophysical-related studies and for development of future technologies.

Clinical and laboratory features of patients with osteomalacia initially presenting with neurological manifestations.

Patients with osteomalacia often visit the neurology department with conditions mimicking other myopathies. We analyzed clinical features of osteomalacia patients who visited the neurology department. These patients frequently presented with hypocalcemia, hypovitaminosis D, and pain with less severe weakness. Osteomalacia should be considered when patients present with pain and weakness. INTRODUCTION: Osteomalacia is a disease of bone metabolism; however, some patients with osteomalacia initially visit the neurology department. As these patients often complain of weakness and gait disturbance, osteomalacia can be confused with other myopathies. We analyzed the clinical features of patients with osteomalacia who visited the neurology department. METHODS: We retrospectively reviewed the medical records. Osteomalacia was diagnosed based on symptoms, laboratory features, and imaging results. We compared the characteristics of patients with osteomalacia who visited the neurology department with (1) those who did not visit the neurology department and (2) patients with idiopathic inflammatory myopathy. RESULTS: Eighteen patients with osteomalacia visited the neurology department (NR group). The common etiologies in the NR group included tumors or antiepileptic medication, whereas antiviral medication was the most common in patients who did not visit the neurology department (non-NR group). The NR group showed lower serum calcium (p = 0.004) and 25-hydroxyvitamin D (p = 0.006) levels than the non-NR group. When compared with patients with inflammatory myopathy, both groups showed proximal dominant weakness. However, pain was more common in osteomalacia than in myopathy (p = 0.008), and patients with osteomalacia showed brisk deep tendon reflex more often (p = 0.017). Serum calcium (p = 0.003) and phosphate (p < 0.001) levels were lower in osteomalacia than in myopathy. CONCLUSIONS: It was not uncommon for patients with osteomalacia to visit the neurology department. The clinical presentation of these patients can be more complex owing the superimposed neurological disease and accompanying hypocalcemia. Osteomalacia should be considered when patients present with pain and weakness.

Flocked nylon swabs versus RODAC plates for detection of multidrug-resistant organisms on environmental surfaces in intensive care units.

To compare two culture methods [nylon fiber flocked swabs with broth enrichment versus RODAC ('replicate organism detection and counting') plates] for recovery of multidrug-resistant organisms, 780 environmental surfaces in 63 rooms of patients on contact precautions in four intensive care units at one hospital were examined. Among sites that had at least one positive culture, swab culture with broth enrichment detected the target organisms more frequently than RODAC plates (37.5% vs 26.0%, P = 0.06). There was moderate agreement between the two methods (κ = 0.44) with agreement better for small or flat surfaces compared to large or irregular surfaces.

Teriparatide therapy for severe, refractory osteoradionecrosis of the jaw.

Although osteoradionecrosis (ORN) is a serious complication of craniofacial radiotherapy, the current management methods remain suboptimal. Teriparatide (TPTD), a recombinant human parathyroid hormone (1-34), has shown beneficial effects on osseous regeneration in medication-related osteonecrosis of the jaw or periodontitis. However, TPTD therapy in irradiated bones has not been indicated yet because of the theoretical risk of osteosarcoma seen in rat models. Hence, we first report here two patients with tongue cancer with late-emerging ORN who were successfully treated with TPTD for 4-6 months with serum calcium and vitamin D supplementation. In contrast to the usual progress of ORN, the bone defect regenerated well and bone turnover markers including serum C-terminal telopeptide of type 1 collagen and osteocalcin were restored with TPTD therapy. Our experience might suggest that TPTD therapy with careful monitoring can provide an effective treatment option for patients with ORN in select refractory cases, with the benefits outweighing the potential risks.

PVX-tolerant potato development using a nucleic acid-hydrolyzing recombinant antibody.

3D8 scFv, a catalytic recombinant antibody developed in the MRL mouse, exhibits nucleic acid-hydrolyzing activity. Previous studies have demonstrated that tobacco plants harboring 3D8 scFv antibodies showed broad-spectrum resistance to infection by both DNA and RNA viruses. In this study, potatoes were transformed with the 3D8 scFv gene and screened by potato virus X (PVX) challenge. Starting with the T0 and T1 potato lines, PVX-tolerant T1 potatoes were identified in the field and characterized by ELISA and RT-PCR analysis. T2 potatoes were propagated for T3 generation and additional virus challenges in the field, and 44% of the 3D8 scFv T3 transgenic potatoes grown in GMO fields were found to be tolerant to PVX infection. Tubers from PVX-tolerant T3 lines were 60% bigger and 24% heavier, compared with tubers from PVX-susceptible transgenic lines and wild-type potatoes. Three-step virus challenge experiments and molecular characterization techniques were used for plants grown in growth chambers or fields to identify 3D8 scFv-transgenic, PVX-tolerant potatoes. These studies also revealed that the viral tolerance enabled by 3D8 scFv persisted during asexual propagation.

Association of circulating dipeptidyl-peptidase 4 levels with osteoporotic fracture in postmenopausal women.

Postmenopausal women with osteoporotic fracture (OF) had higher plasma dipeptidyl-peptidase 4 (DPP4) levels than those without. Furthermore, higher plasma DPP4 levels were significantly associated with higher bone turnover and a higher prevalence of OF. These results indicated that DPP4 may be associated with OF by mediating bone turnover rate. INTRODUCTION: Evidence indicates that dipeptidyl-peptidase 4 (DPP4) plays a distinct role in bone metabolism. However, there has been no report on the association, if any, between circulating DPP4 levels and osteoporosis-related phenotypes, including osteoporotic fracture (OF). Therefore, we performed a case-control study to investigate these associations in postmenopausal women. METHODS: This study was conducted in multiple centers in Korea. We enrolled 178 cases with OF and 178 age- and body mass index-matched controls. OF was assessed by an interviewer-assisted questionnaire and lateral thoracolumbar radiographs. Bone turnover markers (BTMs), bone mineral density (BMD), and plasma DPP4 levels were obtained in all subjects. RESULTS: After adjustment for potential confounders, subjects with OF had significantly higher DPP4 levels than those without (P = 0.021). Higher DPP4 levels were significantly positively associated with higher levels of all BTMs, but not with BMD at all measured sites. The differences in DPP4 levels according to OF status disappeared after an additional adjustment for each BTM, but not after adjustment for any BMD values. BTMs explained approximately half of the relationship between DPP4 and OF. The risk of OF was 3.80-fold (95% confidence interval = 1.53-9.42) higher in subjects in the highest DPP4 quartile than in those in the lowest quartile after adjustment for potential confounders, including femoral neck BMD. CONCLUSIONS: DPP4 may be associated with OF by at least partly mediating the bone turnover rate. Circulating DPP4 levels may be a potential biomarker that could increase the predictive power of current fracture risk assessment models.

A novel laser-collider used to produce monoenergetic 13.3 MeV (7)Li (d, n) neutrons.

Neutron energy is directly correlated with the energy of the incident ions in experiments involving laser-driven nuclear reactions. Using high-energy incident ions reduces the energy concentration of the generated neutrons. A novel "laser-collider" method was used at the Shenguang II laser facility to produce monoenergetic neutrons via (7)Li (d, n) nuclear reactions. The specially designed K-shaped target significantly increased the numbers of incident d and Li ions at the keV level. Ultimately, 13.3 MeV neutrons were obtained. Considering the time resolution of the neutron detector, we demonstrated that the produced neutrons were monoenergetic. Interferometry and a Multi hydro-dynamics simulation confirmed the monoenergetic nature of these neutrons.

Exopolysaccharide fraction from Pediococcus pentosaceus KFT18 induces immunostimulatory activity in macrophages and immunosuppressed mice.

AIMS: Exopolysaccharide fraction from Pediococcus pentosaceus KFT18 (PE-EPS), a lactic acid bacteria isolated from Kimchi (a Korean fermented vegetable product), was preliminary characterized and its immunostimulating effects were analysed. METHODS AND RESULTS: In this study, we used interferon-γ (IFN-γ)-primed RAW 264·7 macrophages and CD3/CD28-stimulated splenocytes to determine the immunotimulatory activities of PE-EPS. Upon exposure to PE-EPS, IFN-γ-primed RAW 264·7 macrophages showed significant increases in the expressions of inducible nitric oxide synthase (iNOS), tumour necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1ß. Molecular data using reporter gene assay and electrophoretic mobility shift assay (EMSA) revealed that PE-EPS upregulated transcriptional activity, DNA binding and the nuclear translocation of nuclear factor-κB (NF-κB). Furthermore, PE-EPS enhanced anti-CD3/CD28-specific proliferation and the productions of IL-2 and IFN-γ in primary splenocytes. In cyclophosphamide-induced immunosuppressed mice, pretreatment with PE-EPS (5, 15 or 45 mg kg(-1) day(-1), p.o.) increased thymus and spleen indices, and improved lymphocyte and neutrophil counts. CONCLUSION: PE-EPS stimulated the IFN-γ-primed macrophages and primary splenocytes to induce immune responses and improved the cyclophosphamide-induced immunosuppression in mice. SIGNIFICANCE AND IMPACT OF THE STUDY: The results in this study improved our understanding of immunostimulating activity of PE-EPS and supported its potential treatment option as a natural immunostimulant.

International study of the place of death of people with cancer: a population-level comparison of 14 countries across 4 continents using death certificate data.

BACKGROUND: Where people die can influence a number of indicators of the quality of dying. We aimed to describe the place of death of people with cancer and its associations with clinical, socio-demographic and healthcare supply characteristics in 14 countries. METHODS: Cross-sectional study using death certificate data for all deaths from cancer (ICD-10 codes C00-C97) in 2008 in Belgium, Canada, Czech Republic, England, France, Hungary, Italy, Mexico, the Netherlands, New Zealand, South Korea, Spain (2010), USA (2007) and Wales (N=1,355,910). Multivariable logistic regression analyses evaluated factors associated with home death within countries and differences across countries. RESULTS: Between 12% (South Korea) and 57% (Mexico) of cancer deaths occurred at home; between 26% (Netherlands, New Zealand) and 87% (South Korea) occurred in hospital. The large between-country differences in home or hospital deaths were partly explained by differences in availability of hospital- and long-term care beds and general practitioners. Haematologic rather than solid cancer (odds ratios (ORs) 1.29-3.17) and being married rather than divorced (ORs 1.17-2.54) were most consistently associated with home death across countries. CONCLUSIONS: A large country variation in the place of death can partly be explained by countries' healthcare resources. Country-specific choices regarding the organisation of end-of-life cancer care likely explain an additional part. These findings indicate the further challenge to evaluate how different specific policies can influence place of death patterns.

Neutron yield enhancement in laser-induced deuterium-deuterium fusion using a novel shaped target.

Neutron yields have direct correlation with the energy of incident deuterons in experiments of laser deuterated target interaction [Roth et al., Phys. Rev. Lett. 110, 044802 (2013) and Higginson et al., Phys. Plasmas 18, 100703 (2011)], while deuterated plasma density is also an important parameter. Experiments at the Shenguang II laser facility have produced neutrons with energy of 2.45 MeV using d (d, n) He reaction. Deuterated foil target and K-shaped target were employed to study the influence of plasma density on neutron yields. Neutron yield generated by K-shaped target (nearly 10(6)) was two times higher than by foil target because the K-shaped target results in higher density plasma. Interferometry and multi hydro-dynamics simulation confirmed the importance of plasma density for enhancement of neutron yields.

Exercise capacity independently predicts bone mineral density and proximal femoral geometry in patients with acute decompensated heart failure.

UNLABELLED: Heart failure is associated with increased risk of osteoporosis. We evaluated the prevalence and predictors of osteoporosis in hospitalized patients with ADHF using quantitative computed tomography. Osteoporosis and vertebral fracture are prevalent in patients with ADHF and exercise capacity independently predicts bone mass and femoral bone geometry. INTRODUCTION: Heart failure is associated with reduced bone mass and increased risk of osteoporotic fractures. However, the prevalence and predictors of osteoporosis in hospitalized patients with acute decompensated heart failure (ADHF) are not well understood. METHODS: Sixty-five patients (15 postmenopausal females and 50 males) with ADHF were prospectively and consecutively enrolled. After stabilization of heart failure symptoms, quantitative computed tomography for bone mineral density (BMD) and femoral geometry as well as biochemical, echocardiographic, and cardiopulmonary exercise tests were performed. RESULTS: Fifteen postmenopausal female showed a high prevalence of osteoporosis (40%) and vertebral fracture (53%). Among 50 male patients, 12% had osteoporosis and 32% had osteopenia, while vertebral fracture was found in 12%. Lumbar volumetric BMD (vBMD) was significantly lower in ischemic patients than non-ischemic patients (107.9 ± 47.5 vs. 145.4 ± 40.9 mg/cm(3), p = 0.005) in male. Exercise capacity, indicated by peak oxygen consumption (VO2), was significantly associated with lumbar vBMD (r = 0.576, p < 0.001) and total hip areal BMD (aBMD) (r = 0.512, p = 0.001) and cortical thickness of the femur neck (r = 0.544, p = 0.001). When controlled for age, body mass index, N-terminal proBrain natriuretic protein (NT-proBNP), etiology of heart failure, hemoglobin, and thigh circumference, multivariate regression analysis revealed peak VO2 independently predicted lumbar vBMD (ß = 0.448, p = 0.031), total hip aBMD (ß = 0.547, p = 0.021), and cortical thickness of the femur neck (ß = 0.590, p = 0.011). CONCLUSION: In male patients with ADHF, osteoporosis and vertebral fracture are prevalent, and exercise capacity independently predicts bone mass and geometry. Given that heart failure patients with reduced exercise capacity carry a substantial increased risk of fracture, proper osteoporosis evaluation is important in these patients.

Enhanced relativistic-electron-beam energy loss in warm dense aluminum.

Energy loss in the transport of a beam of relativistic electrons in warm dense aluminum is measured in the regime of ultrahigh electron beam current density over 2×10^{11} A/cm^{2} (time averaged). The samples are heated by shock compression. Comparing to undriven cold solid targets, the roles of the different initial resistivity and of the transient resistivity (upon target heating during electron transport) are directly observable in the experimental data, and are reproduced by a comprehensive set of simulations describing the hydrodynamics of the shock compression and electron beam generation and transport. We measured a 19% increase in electron resistive energy loss in warm dense compared to cold solid samples of identical areal mass.

In vitro and in vivo immunostimulatory activity of an exopolysaccharide-enriched fraction from Bacillus subtilis.

AIMS: The aim of this study was to investigate the immunostimulatory effects of an exopolysaccharide-enriched fraction obtained from Bacillus subtilis J92 (B-EPS). METHODS AND RESULTS: To determine the immunostimulatory activities of B-EPS, we used IFN-γ-primed RAW 264.7 macrophages and CD3/CD28-stimulated splenocytes. Increases in the levels of NO and many cytokines, such as, TNF-α, IL-6, and IL-1ß, were observed in IFN-γ-primed RAW 264.7 macrophages by Griess reaction and ELISAs respectively. Using Western blotting and qRT-PCR, we found that B-EPS increased the protein and mRNA expressions of iNOS and the mRNA expressions of TNF-α, IL-6, and IL-1ß. A reporter gene assay and EMSA revealed that B-EPS up-regulated the transcriptional activity of NF-κB by increasing its DNA binding and nuclear translocation. Pretreatment with NF-κB inhibitors, that is, BAY11-7082 and PDTC, decreased NO production in IFN-γ-primed RAW 264.7 macrophages by B-EPS. Furthermore, B-EPS increased the proliferation of and cytokine (IL-2 and IFN-γ) production by CD3/CD28-stimulated splenocytes. In a cyclophosphamide-induced immunosuppressed mouse model, B-EPS (5, 15 or 45 mg kg(-1) , p.o.) restored thymus and spleen indices. B-EPS also inhibited cyclophosphamide-induced reductions in neutrophil and lymphocyte numbers. CONCLUSIONS: B-EPS improves immune function by regulating immunological parameters in IFN-γ-primed macrophages, CD3/CD28-stimulated splenocytes, and in cyclophosphamide-induced immunosuppressed mice. SIGNIFICANCE AND IMPACT OF THE STUDY: This study suggests that the exopolysaccharides secreted by B. subtilis J92 could be used as immune stimulants.

CXXC5 is a negative-feedback regulator of the Wnt/ß-catenin pathway involved in osteoblast differentiation.

The positive roles of the Wnt/ß-catenin pathway in osteoblast differentiation and bone mineral density (BMD) maintenance have been clearly demonstrated in both animal experiments and clinical investigations. CXXC finger protein 5 (CXXC5), a recently identified negative regulator of the Wnt/ß-catenin pathway, showed altered cellular localization and function, which were dependent on the cell type in previous studies. However, the in vivo function of CXXC5 has not been clearly investigated yet. Here, we characterized CXXC5 as a negative regulator of osteoblast differentiation and bone formation. Deficiency of CXXC5 resulted in elevated BMD in mice without any severe gross developmental abnormalities. CXXC5 exerted a negative-feedback effect on the Wnt/ß-catenin pathway via Wnt-dependent binding to Dishevelled (Dvl) during osteoblast differentiation. Suppression of the Dvl-CXXC5 interaction using a competitor peptide resulted in the activation of the Wnt/ß-catenin pathway and osteoblast differentiation, and accelerated thickness growth of ex vivo-cultured calvariae. Overall, CXXC5 is a negative-feedback regulator induced by Wnt/ß-catenin signaling that inhibits osteoblast differentiation and bone formation via interaction with Dvl.