BMD and clinical risk factors predict hip and other osteoporotic fractures. The combination of clinical risk factors and BMD provide higher specificity and sensitivity than either alone. INTRODUCTION ...AND HYPOTHESES: To develop a risk assessment tool based on clinical risk factors (CRFs) with and without BMD.
Nine population-based studies were studied in which BMD and CRFs were documented at baseline. Poisson regression models were developed for hip fracture and other osteoporotic fractures, with and without hip BMD. Fracture risk was expressed as gradient of risk (GR, risk ratio/SD change in risk score).
CRFs alone predicted hip fracture with a GR of 2.1/SD at the age of 50 years and decreased with age. The use of BMD alone provided a higher GR (3.7/SD), and was improved further with the combined use of CRFs and BMD (4.2/SD). For other osteoporotic fractures, the GRs were lower than for hip fracture. The GR with CRFs alone was 1.4/SD at the age of 50 years, similar to that provided by BMD (GR = 1.4/SD) and was not markedly increased by the combination (GR = 1.4/SD). The performance characteristics of clinical risk factors with and without BMD were validated in eleven independent population-based cohorts.
The models developed provide the basis for the integrated use of validated clinical risk factors in men and women to aid in fracture risk prediction.
Although still early in clinical development, agonists of Toll-like receptor 9 (TLR9) have demonstrated potential for the treatment of cancer. TLR9 agonists directly induce activation and maturation ...of plasmacytoid dendritic cells and enhance differentiation of B cells into antibody-secreting plasma cells. Preclinical and early clinical data support the use of TLR9 agonists in patients with solid tumors and hematologic malignancies. In preclinical studies, TLR9 agonists have shown activity not only as monotherapy, but also in combination with multiple other therapies, including vaccines, antibodies, cellular therapies, other immunotherapies, antiangiogenic agents, radiotherapy, cryotherapy and some chemotherapies. Phase I and II clinical trials have indicated that these agents have antitumor activity as single agents and enhance the development of antitumor T-cell responses when used as therapeutic vaccine adjuvants. The activity and safety of these novel anticancer agents are being explored in a wide range of tumor types as part of a variety of therapeutic strategies with the goal of harnessing the immune response to fight cancer.
Summary
Meta-analysis of prospective studies shows that quantitative ultrasound of the heel using validated devices predicts risk of different types of fracture with similar performance across ...different devices and in elderly men and women. These predictions are independent of the risk estimates from hip DXA measures.
Introduction
Clinical utilisation of heel quantitative ultrasound (QUS) depends on its power to predict clinical fractures. This is particularly important in settings that have no access to DXA-derived bone density measurements. We aimed to assess the predictive power of heel QUS for fractures using a meta-analysis approach.
Methods
We conducted an inverse variance random effects meta-analysis of prospective studies with heel QUS measures at baseline and fracture outcomes in their follow-up. Relative risks (RR) per standard deviation (SD) of different QUS parameters (broadband ultrasound attenuation BUA, speed of sound SOS, stiffness index SI, and quantitative ultrasound index QUI) for various fracture outcomes (hip, vertebral, any clinical, any osteoporotic and major osteoporotic fractures) were reported based on study questions.
Results
Twenty-one studies including 55,164 women and 13,742 men were included in the meta-analysis with a total follow-up of 279,124 person-years. All four QUS parameters were associated with risk of different fracture. For instance, RR of hip fracture for 1 SD decrease of BUA was 1.69 (95% CI 1.43–2.00), SOS was 1.96 (95% CI 1.64–2.34), SI was 2.26 (95%CI 1.71–2.99) and QUI was 1.99 (95% CI 1.49–2.67). There was marked heterogeneity among studies on hip and any clinical fractures but no evidence of publication bias amongst them. Validated devices from different manufacturers predicted fracture risks with similar performance (meta-regression
p
values > 0.05 for difference of devices). QUS measures predicted fracture with a similar performance in men and women. Meta-analysis of studies with QUS measures adjusted for hip BMD showed a significant and independent association with fracture risk (RR/SD for BUA = 1.34 95%CI 1.22–1.49).
Conclusions
This study confirms that heel QUS, using validated devices, predicts risk of different fracture outcomes in elderly men and women. Further research is needed for more widespread utilisation of the heel QUS in clinical settings across the world.
Unmethylated CpG motifs are prevalent in bacterial but not vertebrate
genomic DNAs. Oligodeoxynucleotides (ODN) containing CpG motifs activate host
defense mechanisms leading to innate and acquired ...immune responses. The
recognition of CpG motifs requires Toll-like receptor (TLR) 9, which triggers
alterations in cellular redox balance and the induction of cell signaling
pathways including the mitogen activated protein kinases (MAPKs) and
NFκB. Cells that express TLR-9, which include plasmacytoid dendritic
cells (PDCs) and B cells, produce Th1-like proinflammatory cytokines,
interferons, and chemokines. Certain CpG motifs (CpG-A) are especially potent
at activating NK cells and inducing IFN-α production by PDCs, while other
motifs (CpG-B) are especially potent B cell activators. CpG-induced activation
of innate immunity protects against lethal challenge with a wide variety of
pathogens, and has therapeutic activity in murine models of cancer and allergy.
CpG ODN also enhance the development of acquired immune responses for
prophylactic and therapeutic vaccination.
The use of bacteria and bacterial extracts for immunotherapy has a checkered past. Recent developments in immunology reveal that these nonspecific immune activators actually work by triggering ...specific receptors that are expressed by subsets of immune cells. Identification of these receptors and the molecular signaling pathways that they activate has enabled a new era of specific targeted immunotherapy using chemically synthesized mimics of pathogen molecules.
Summary
We evaluated the longitudinal effects of anti-resorptive agents (534 treated women vs. 1,150 untreated) on lumbar spine bone mineral density (BMD) and trabecular bone score (TBS). TBS was ...responsive to treatment in women over age 50. The treatment-related increase in TBS was less than the increase in BMD, which is consistent with bone texture preservation.
Introduction
In addition to inducing an increase in BMD, anti-resorptive agents also help to preserve bone architecture. TBS, a new gray-level texture measurement, correlates with 3D parameters of bone micro-architecture independent of BMD. Our objective was to evaluate the longitudinal effects of anti-resorptive agents on lumbar spine BMD and TBS.
Methods
Women (≥50 years), from the BMD program database for the province of Manitoba, Canada, who had not received any anti-resorptive drug prior to their initial dual X-ray absorptiometry (DXA) exam were divided into two groups:
untreated
, those without any anti-resorptive drug over the course of follow-up, and
treated
, those with a non-estrogen anti-resorptive drug (86 % bisphosphonates, 10 % raloxifene, and 4 % calcitonin). Lumbar spine TBS was calculated for each lumbar spine DXA examination. Changes in TBS and BMD between baseline and follow-up (mean follow-up 3.7 years), expressed in percentage per year, were compared between the two groups.
Results
A total of 1,150 untreated women and 534 treated women met the inclusion criteria. Only a weak correlation was seen between BMD and TBS in either group. Significant intergroup differences in BMD change and TBS change were observed over the course of follow-up (
p
< 0.001). Similar mean decreases in BMD and TBS (−0.36 %/year and −0.31 %/year, respectively) were seen for untreated subjects (both
p
< 0.001). Conversely, treated subjects exhibited a significant mean increase in BMD (+1.86 %/year,
p
< 0.002) and TBS (+0.20 %/year,
p
< 0.001).
Conclusion
TBS is responsive to treatment with non-estrogen anti-resorptive drug therapy in women over age 50. The treatment-related increase in TBS is less than the increase in BMD, which is consistent with bone texture preservation.
The hemochorial placenta develops from the coordinated multi-lineage differentiation of trophoblast stem (TS) cells. An invasive trophoblast cell lineage remodels uterine spiral arteries, ...facilitating nutrient flow, failure of which is associated with pathological conditions such as preeclampsia, intrauterine growth restriction, and preterm birth. Hypoxia plays an instructive role in influencing trophoblast cell differentiation and regulating placental organization. Key downstream hypoxia-activated events were delineated using rat TS cells and tested in vivo, using trophoblast-specific lentiviral gene delivery and genome editing. DNA microarray analyses performed on rat TS cells exposed to ambient or low oxygen and pregnant rats exposed to ambient or hypoxic conditions showed up-regulation of genes characteristic of an invasive/vascular remodeling/inflammatory phenotype. Among the shared up-regulated genes was matrix metallopeptidase 12 (MMP12). To explore the functional importance of MMP12 in trophoblast cell-directed spiral artery remodeling, we generated an Mmp12 mutant rat model using transcription activator-like nucleases-mediated genome editing. Homozygous mutant placentation sites showed decreased hypoxia-dependent endovascular trophoblast invasion and impaired trophoblast-directed spiral artery remodeling. A link was established between hypoxia/HIF and MMP12; however, evidence did not support Mmp12 as a direct target of HIF action. Lysine demethylase 3A (KDM3A) was identified as mediator of hypoxia/HIF regulation of Mmp12. Knockdown of KDM3A in rat TS cells inhibited the expression of a subset of the hypoxia–hypoxia inducible factor (HIF)-dependent transcripts, including Mmp12, altered H3K9 methylation status, and decreased hypoxia-induced trophoblast cell invasion in vitro and in vivo. The hypoxia-HIF-KDM3A-MMP12 regulatory circuit is conserved and facilitates placental adaptations to environmental challenges.
CPG 7909, a 24-mer B-Class CpG oligodeoxynucleotide (ODN), was tested for safety, tolerability and its ability to augment the immunogenicity of a commercial trivalent killed split influenza vaccine ...(Fluarix
® containing A/Beijing/262/95, A/Sydney/5/97 and B/Harbin/7/94; SmithKline Beecham) in a phase Ib blinded, randomized, controlled clinical trial. Sixty healthy volunteers were recruited in two consecutive cohorts of 30 subjects, who were randomly assigned to receive Fluarix plus 1
mg CPG 7909 or Fluarix plus saline control (15 subjects each). Vaccines were administered by intramuscular injection on a single occasion with subjects in the first cohort receiving a 1/10th dose of Fluarix and those in the second cohort receiving the full-dose. All safety measures including physical evaluation, laboratory blood assays, and assays for DNA autoimmunity were within normal values except for transient and clinically inconsequential decreases in total white blood cell counts in groups receiving CPG 7909. All vaccines were found to be generally well tolerated with similar frequency and intensity for most adverse reactions for groups receiving CPG 7909 as controls. Exceptions were injection site pain and headache, which were reduced in frequency in subjects receiving the 1/10th Fluarix dose without CpG, compared to the frequency in all other groups. There was a lack of pre-existing immunity, defined as hemagglutinin inhibition (HI) activity ≤20, for all subjects to the influenza strains A/Beijing/262/95 and B/Harbin/7/94 and for some subjects to A/Sydney/5/97. Post-vaccination humoral immune responses, as determined 2 and 4 weeks later by assay of HI activity and ELISA to detect antibodies against hemagglutinin (anti-HA) were similar for both full and reduced Fluarix doses but the cellular immune responses (measured as PBMC antigen-specific IFN-γ secretion) were reduced in the 1/10th Fluarix dose group. Humoral responses were not significantly enhanced by the addition of CPG 7909, except in individuals with pre-existing immunity to A/Sydney/5/97 strain (baseline HI activity titre >20), where there was a trend to higher HI activity with CPG 7909 (
P=0.06). The addition of CPG 7909 to the 1/10th dose of Fluarix did however result in significantly higher levels of IFN-γ secretion from peripheral blood mononuclear cells recovered at 4 weeks and restimulated ex vivo with A/Beijing/262/95 (
P=0.048) and B/Harbin/7/94 (
P=0.0057), restoring these to the level seen with full-dose vaccine. These results suggest that addition of CPG 7909 to Fluarix may allow the use of reduced vaccine doses without reduced immunogenicity.
Summary
The relationship between bone quantitative ultrasound (QUS) and fracture risk was estimated in an individual level data meta-analysis of 9 prospective studies of 46,124 individuals and 3018 ...incident fractures. Low QUS is associated with an increase in fracture risk, including hip fracture. The association with osteoporotic fracture decreases with time.
Introduction
The aim of this meta-analysis was to investigate the association between parameters of QUS and risk of fracture.
Methods
In an individual-level analysis, we studied participants in nine prospective cohorts from Asia, Europe and North America. Heel broadband ultrasonic attenuation (BUA dB/MHz) and speed of sound (SOS m/s) were measured at baseline. Fractures during follow-up were collected by self-report and in some cohorts confirmed by radiography. An extension of Poisson regression was used to examine the gradient of risk (GR, hazard ratio per 1 SD decrease) between QUS and fracture risk adjusted for age and time since baseline in each cohort. Interactions between QUS and age and time since baseline were explored.
Results
Baseline measurements were available in 46,124 men and women, mean age 70 years (range 20–100). Three thousand and eighteen osteoporotic fractures (787 hip fractures) occurred during follow-up of 214,000 person-years. The summary GR for osteoporotic fracture was similar for both BUA (1.45, 95 % confidence intervals (CI) 1.40–1.51) and SOS (1.42, 95 % CI 1.36–1.47). For hip fracture, the respective GRs were 1.69 (95 % CI, 1.56–1.82) and 1.60 (95 % CI, 1.48–1.72). However, the GR was significantly higher for both fracture outcomes at lower baseline BUA and SOS (
p
< 0.001). The predictive value of QUS was the same for men and women and for all ages (
p
> 0.20), but the predictive value of both BUA and SOS for osteoporotic fracture decreased with time (
p
= 0.018 and
p
= 0.010, respectively). For example, the GR of BUA for osteoporotic fracture, adjusted for age, was 1.51 (95 % CI 1.42–1.61) at 1 year after baseline, but at 5 years, it was 1.36 (95 % CI 1.27–1.46).
Conclusions
Our results confirm that quantitative ultrasound is an independent predictor of fracture for men and women particularly at low QUS values.
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