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.
Tsunami warning centres face the challenging task of rapidly forecasting tsunami threat immediately after an earthquake, when there is high uncertainty due to data deficiency. Here we introduce ...Probabilistic Tsunami Forecasting (PTF) for tsunami early warning. PTF explicitly treats data- and forecast-uncertainties, enabling alert level definitions according to any predefined level of conservatism, which is connected to the average balance of missed-vs-false-alarms. Impact forecasts and resulting recommendations become progressively less uncertain as new data become available. Here we report an implementation for near-source early warning and test it systematically by hindcasting the great 2010 M8.8 Maule (Chile) and the well-studied 2003 M6.8 Zemmouri-Boumerdes (Algeria) tsunamis, as well as all the Mediterranean earthquakes that triggered alert messages at the Italian Tsunami Warning Centre since its inception in 2015, demonstrating forecasting accuracy over a wide range of magnitudes and earthquake types.
•AgNPs decrease the viability of EA.hy926 cells.•AgNPs modify the expression of miR-126, 146 and 155 and endothelial markers as VCAM-1.•AgNPs induce a hypermethylation state of genomic DNA.
The aim ...of this study was to determine the effect of AgNPs on the epigenome of endothelial cells EA.hy926, including the levels of expression of microRNAs (miRNAs) and global DNA methylation patterns. In addition, evaluation of the expression of inflammatory genes and the levels of VCAM-1 protein (miRNA-126 target) was performed. The expression levels of analyzed miRNAs (microRNAs-126, 155 and 146) were reduced significantly and there were not observed changes in inflammatory gene expression. Regarding the levels of protein vascular cell adhesion molecule 1 (VCAM-1), they increase significantly to 0.5 μM AgNPs at 24 h of exposure. As far as DNA methylation is concerned, we found that AgNPs induce a state of global hyper-methylation. In conclusion, it was demonstrated that direct contact between AgNPs and endothelial cells resulted in the dysregulation of highly enriched and vastly functional miRNAs and DNA hypermethylation, that may have multiple effects on endothelium function and integrity.
Summary
Vitamin D insufficiency is very common among Spanish community-dwelling adult subjects. A threshold of serum 25(OH)D around 30 ng/ml would be necessary for the prevention of secondary ...hyperparathyroidism and hip bone loss in our population, regardless of the dairy calcium ingestion.
Introduction
This study aims to assess 25-hydroxyvitamin D—25(OH)D—status in Spanish adult subjects and to analyze its relationships with serum PTH levels, calcium intake, and bone mineral density (BMD).
Methods
A total of 1811 individuals (1154 postmenopausal women and 657 men) aged 44–93 years participated in the study. Serum 25(OH)D, intact parathyroid hormone (PTH), aminoterminal propeptide of type I collagen (P1NP), and C-terminal telopeptide of type I collagen (β-CTX) levels were measured by electrochemiluminescence. BMD was determined by dual x-ray absorptiometry (DXA) at lumbar spine, femoral neck, and total hip.
Results
Serum 25(OH)D levels were below 10, 20, and 30 ng/ml in 5, 40, and 83 % of participants, respectively. There was a significant seasonal difference in mean serum 25(OH)D, with higher levels in summer–autumn. In multivariate analysis, 25(OH)D levels were negatively correlated with age, serum PTH and creatinine, body mass index, smoking, alcohol intake, and a number of chronic diseases, but positively with dairy calcium intake. The magnitude of the difference in serum PTH according to 25(OH)D quartiles was not influenced by calcium intake. A threshold of serum 25(OH)D around 30 ng/ml was observed for serum PTH and hip BMD.
Conclusions
Vitamin D insufficiency is very common among Spanish community-dwelling adult subjects. A threshold of serum 25(OH)D around 30 ng/ml would be necessary for the prevention of secondary hyperparathyroidism and hip bone loss in our population, regardless of the dairy calcium ingestion. Programs to improve vitamin D status may be required in our country.
Abstract
Many functional aspects of the protein kinase p38α have been illustrated by more than three hundred structures determined in the presence of reducing agents. These structures correspond to ...free forms and complexes with activators, substrates, and inhibitors. Here we report the conformation of an oxidized state with an intramolecular disulfide bond between Cys119 and Cys162 that is conserved in vertebrates. The structure of the oxidized state does not affect the conformation of the catalytic site, but alters the docking groove by partially unwinding and displacing the short αD helix due to the movement of Cys119 towards Cys162. The transition between oxidized and reduced conformations provides a mechanism for fine-tuning p38α activity as a function of redox conditions, beyond its activation loop phosphorylation. Moreover, the conformational equilibrium between these redox forms reveals an unexplored cleft for p38α inhibitor design that we describe in detail.
p38α is a versatile protein kinase that can control numerous processes and plays important roles in the cellular responses to stress. Dysregulation of p38α signaling has been linked to several ...diseases including inflammation, immune disorders and cancer, suggesting that targeting p38α could be therapeutically beneficial. Over the last two decades, numerous p38α inhibitors have been developed, which showed promising effects in pre-clinical studies but results from clinical trials have been disappointing, fueling the interest in the generation of alternative mechanisms of p38α modulation. Here, we report the in silico identification of compounds that we refer to as non-canonical p38α inhibitors (NC-p38i). By combining biochemical and structural analyses, we show that NC-p38i efficiently inhibit p38α autophosphorylation but weakly affect the activity of the canonical pathway. Our results demonstrate how the structural plasticity of p38α can be leveraged to develop therapeutic opportunities targeting a subset of the functions regulated by this pathway.
Introduction
Osteoporosis has been said to be associated with increased mortality. On the other hand, it is debated whether treatment with bisphosphonates may reduce mortality in osteoporotic ...patients. To contribute to the clarification of these issues, we have studied in a prospective cohort the mortality in people without osteoporosis and in patients with osteoporosis, untreated or treated with bisphosphonates
Material and Methods
At their inclusion in the cohort, four groups of participants were identified: (a) people without osteoporosis (group 1); (b) osteoporotic patients treated with bisphosphonates (group 2); (c) osteoporotic patients who refused to be treated (group 3); and (d) patients who met osteoporosis diagnostic criteria but were not treated because their risk of fracture was considered to be low (group 4). To compare all four groups, unadjusted Kaplan–Meier estimates of survivorship were obtained and they were compared using log-rank test. Hazard ratios were then estimated via Cox regression adjusting for the main confounders. A comparison among the osteoporotic groups was made by means of a Cox regression analysis performed using only these three groups, adjusting for propensity scores.
Results
Two thousand six hundred and sixty-five people were included. In the unadjusted analysis, mortality in group 3 was higher than in the other groups (
p
< 0.001). Taking group 1 as a reference, Cox regression analysis showed the following mortality HRs for groups 2, 3, and 4 after adjusting for confounding factors: 0.82 (0.41–1.63), 1.37 (0.90–2.10), and 0.69 (0.46–1.02). In the analysis of the osteoporotic groups with the PS generated for them, and taking group 2 as a reference, the HRs were as follows: group 3, 2.38 (1.34–4.22); group 4, 1.45 (0.61–3.43).
Conclusion
Mortality in osteoporotic patients who refused treatment is higher than in osteoporotic patients treated with bisphosphonates. In unadjusted analysis, it was also higher than in non-osteoporotic people; however, this difference disappeared after adjustment for confounding factors.
Ulcerative colitis and Crohn's disease are forms of inflammatory bowel disease whose incidence and prevalence are increasing worldwide. These diseases lead to chronic inflammation of the ...gastrointestinal tract as a result of an abnormal response of the immune system. Recent studies positioned Cortistatin, which shows low stability in plasma, as a candidate for IBD treatment. Here, using NMR structural information, we design five Cortistatin analogues adopting selected native Cortistatin conformations in solution. One of them, A5, preserves the anti-inflammatory and immunomodulatory activities of Cortistatin in vitro and in mouse models of the disease. Additionally, A5 displays an increased half-life in serum and a unique receptor binding profile, thereby overcoming the limitations of the native Cortistatin as a therapeutic agent. This study provides an efficient approach to the rational design of Cortistatin analogues and opens up new possibilities for the treatment of patients that fail to respond to other therapies.
Treatment failure in osteoporosis Diez-Perez, A.; Adachi, J. D.; Agnusdei, D. ...
Osteoporosis international,
12/2012, Letnik:
23, Številka:
12
Journal Article
Recenzirano
Odprti dostop
Summary
Guidelines concerning the definition of failure of therapies used to reduce the risk of fracture are provided.
Introduction
This study aims to provide guidelines concerning the definition of ...failure of therapies used to reduce the risk of fracture.
Methods
A working group of the Committee of Scientific Advisors of the International Osteoporosis Foundation was convened to define outcome variables that may assist clinicians in decision making.
Results
In the face of limited evidence, failure of treatment may be inferred when two or more incident fractures have occurred during treatment, when serial measurements of bone remodelling markers are not suppressed by anti-resorptive therapy and where bone mineral density continues to decrease.
Conclusion
The provision of pragmatic criteria to define failure to respond to treatment provides an unmet clinical need and may stimulate research into an important issue.
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