Small Oscillatory Accelerations, Independent of Matrix Deformations, Increase Osteoblast Activity and Enhance Bone Morphology

A range of tissues have the capacity to adapt to mechanical challenges, an attribute presumed to be regulated through deformation of the cell and/or surrounding matrix. In contrast, it is shown here that extremely small oscillatory accelerations, applied as unconstrained motion and inducing negligible deformation, serve as an anabolic stimulus to osteoblasts in vivo. Habitual background loading was removed from the tibiae of 18 female adult mice by hindlimb-unloading. For 20 min/d, 5 d/wk, the left tibia of each mouse was subjected to oscillatory 0.6 g accelerations at 45 Hz while the right tibia served as control. Sham-loaded (n = 9) and normal age-matched control (n = 18) mice provided additional comparisons. Oscillatory accelerations, applied in the absence of weight bearing, resulted in 70% greater bone formation rates in the trabeculae of the metaphysis, but similar levels of bone resorption, when compared to contralateral controls. Quantity and quality of trabecular bone also improved as a result of the acceleration stimulus, as evidenced by a significantly greater bone volume fraction (17%) and connectivity density (33%), and significantly smaller trabecular spacing (−6%) and structural model index (−11%). These in vivo data indicate that mechanosensory elements of resident bone cell populations can perceive and respond to acceleratory signals, and point to an efficient means of introducing intense physical signals into a biologic system without putting the matrix at risk of overloading. In retrospect, acceleration, as opposed to direct mechanical distortion, represents a more generic and safe, and perhaps more fundamental means of transducing physical challenges to the cells and tissues of an organism

Combining estimates of interest in prognostic modelling studies after multiple imputation: current practice and guidelines

Background: Multiple imputation (MI) provides an effective approach to handle missing covariate data within prognostic modelling studies, as it can properly account for the missing data uncertainty. The multiply imputed datasets are each analysed using standard prognostic modelling techniques to obtain the estimates of interest. The estimates from each imputed dataset are then combined into one overall estimate and variance, incorporating both the within and between imputation variability. Rubin's rules for combining these multiply imputed estimates are based on asymptotic theory. The resulting combined estimates may be more accurate if the posterior distribution of the population parameter of interest is better approximated by the normal distribution. However, the normality assumption may not be appropriate for all the parameters of interest when analysing prognostic modelling studies, such as predicted survival probabilities and model performance measures. Methods: Guidelines for combining the estimates of interest when analysing prognostic modelling studies are provided. A literature review is performed to identify current practice for combining such estimates in prognostic modelling studies. Results: Methods for combining all reported estimates after MI were not well reported in the current literature. Rubin's rules without applying any transformations were the standard approach used, when any method was stated. Conclusion: The proposed simple guidelines for combining estimates after MI may lead to a wider and more appropriate use of MI in future prognostic modelling studies

Quantum states made to measure

Recent progress in manipulating quantum states of light and matter brings quantum-enhanced measurements closer to prospective applications. The current challenge is to make quantum metrologic strategies robust against imperfections.Comment: 4 pages, 3 figures, Commentary for Nature Photonic

W Plus Multiple Jets at the LHC with High Energy Jets

We study the production of a W boson in association with n hard QCD jets (for n>=2), with a particular emphasis on results relevant for the Large Hadron Collider (7 TeV and 8 TeV). We present predictions for this process from High Energy Jets, a framework for all-order resummation of the dominant contributions from wide-angle QCD emissions. We first compare predictions against recent ATLAS data and then shift focus to observables and regions of phase space where effects beyond NLO are expected to be large.Comment: 19 pages, 9 figure

Late weaning and maternal closeness, associated with advanced motor and visual maturation, reinforce autonomy in healthy, 2-year-old children.

We studied neurodevelopmental outcomes and behaviours in healthy 2-year old children (N = 1306) from Brazil, India, Italy, Kenya and the UK participating in the INTERGROWTH-21st Project. There was a positive independent relationship of duration of exclusive breastfeeding (EBF) and age at weaning with gross motor development, vision and autonomic physical activities, most evident if children were exclusively breastfed for ≥7 months or weaned at ≥7 months. There was no association with cognition, language or behaviour. Children exclusively breastfed from birth to 6 months had, in a dose-effect pattern, adjusting for confounding factors, higher scores for "emotional reactivity". The positive effect of EBF and age at weaning on gross motor, running and climbing scores was strongest among children with the highest scores in maternal closeness proxy indicators. EBF, late weaning and maternal closeness, associated with advanced motor and vision maturation, independently influence autonomous behaviours in healthy children

Transforming growth factor beta-1 (TGFB1) and peak bone mass: association between intragenic polymorphisms and quantitative ultrasound of the heel

BACKGROUND: Variance of peak bone mass has a substantial genetic component, as has been shown with twin studies examining quantitative measures such as bone mineral density (BMD) and quantitative ultrasound (QUS). Evidence implicating single nucleotide polymorphisms (SNPs) of the transforming growth factor beta-1 (TGFB1) gene is steadily accumulating. However, a comprehensive look at multiple SNPs at this locus for their association with indices of peak bone mass has not been reported. METHODS: A cohort of 653 healthy Caucasian females 18 to 35 years old was genotyped for seven TGFB1 SNPs. Polymorphisms were detected by restriction endonuclease digestion of amplified DNA segments. RESULTS: The frequencies of the least common allele at G-800A, C-509T, codon 10 (L10P), codon 25 (R25P), codon 263 (T263I), C861-20T, and 713-8 delC loci were 0.07, 0.33, 0.41, 0.08, 0.04, 0.25 and 0.01, respectively. A significant association was seen between QUS Stiffness Index (QUS-SI) and the SNP at codon 10 and the linked promoter SNP, C-509T. This association remained significant after multiple regression was used to incorporate important clinical covariates – age, BMI, level of activity, family history, and caffeine intake – into the model. CONCLUSION: The association of QUS-SI with -509T is consistent with a gene-dose effect, while only individuals homozygous for the codon 10P allele showed a significant increase. In this cohort of young healthy Caucasian females, the T allele at position -509 is associated with greater bone mass as measured by calcaneal ultrasound

Assessing the impact of prescribed medicines on health outcomes

This paper reviews methods that can be used to assess the impact of medicine use on population health outcomes. In the absence of a gold standard, we argue that a convergence of evidence from different types of studies using multiple methods of independent imperfection provides the best bases for attributing improvements in health outcomes to the use of medicines. The major requirements are: good evidence that a safe and effective medicine is being appropriately prescribed; covariation between medicine use and improved health outcomes; and being able to discount alternative explanations of the covariation (via covariate adjustment, propensity analyses and sensitivity analyses), so that medicine use is the most plausible explanation of the improved health outcomes. The strongest possible evidence would be provided by the coherence of the following types of evidence: (1) individual linked data showing that patients are prescribed the medicine, there are reasonable levels of patient compliance, and there is a relationship between medicine use and health improvements that is not explained by other factors; (2) ecological evidence of improvements in these health outcomes in the population in which the medicine is used. Confidence in these inferences would be increased by: the replication of these results in comparable countries and consistent trends in population vital statistics in countries that have introduced the medicine; and epidemiological modelling indicating that changes observed in population health outcomes are plausible given the epidemiology of the condition being treated

Acute inhalation of hypertonic saline does not improve mucociliary clearance in all children with cystic fibrosis

<p>Abstract</p> <p>Background</p> <p>Little is known of how mucociliary clearance (MCC) in children with cystic fibrosis (CF) and normal pulmonary function compares with healthy adults, or how an acute inhalation of 7% hypertonic saline (HS) aerosol affects MCC in these same children.</p> <p>Methods</p> <p>We compared MCC in 12 children with CF and normal pulmonary function after an acute inhalation of 0.12% saline (placebo), or HS, admixed with the radioisotope ^{99 m}technetium sulfur colloid in a double-blind, randomized, cross-over study. Mucociliary clearance on the placebo day in the children was also compared to MCC in 10 healthy, non-CF adults. Mucociliary clearance was quantified over a 90 min period, using gamma scintigraphy, and is reported as MCC at 60 min (MCC60) and 90 min (MCC90).</p> <p>Results</p> <p>Median [interquartile range] MCC60 and MCC90 in the children on the placebo visit were 15.4 [12.4-24.5]% and 19.3 [17.3-27.8%]%, respectively, which were similar to the adults with 17.8 [6.4-28.7]% and 29.6 [16.1-43.5]%, respectively. There was no significant improvement in MCC60 (2.2 [-6.2-11.8]%) or MCC90 (2.3 [-1.2-10.5]%) with HS, compared to placebo. In addition, 5/12 and 4/12 of the children showed a decrease in MCC60 and MCC90, respectively, after inhalation of HS. A <it>post hoc </it>subgroup analysis of the change in MCC90 after HS showed a significantly greater improvement in MCC in children with lower placebo MCC90 compared to those with higher placebo MCC90 (p = 0.045).</p> <p>Conclusions</p> <p>These data suggest that percent MCC varies significantly between children with CF lung disease and normal pulmonary functions, with some children demonstrating MCC values within the normal range and others showing MCC values that are below normal values. In addition, although MCC did not improve in all children after inhalation of HS, improvement did occur in children with relatively low MCC values after placebo. This finding suggests that acute inhalation of hypertonic saline may benefit a subset of children with low MCC values.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01293084">NCT01293084</a></p

A Novel Solid-Phase Site-Specific PEGylation Enhances the In Vitro and In Vivo Biostabilty of Recombinant Human Keratinocyte Growth Factor 1

Keratinocyte growth factor 1 (KGF-1) has proven useful in the treatment of pathologies associated with dermal adnexae, liver, lung, and the gastrointestinal tract diseases. However, poor stability and short plasma half-life of the protein have restricted its therapeutic applications. While it is possible to improve the stability and extend the circulating half-life of recombinant human KGF-1 (rhKGF-1) using solution-phase PEGylation, such preparations have heterogeneous structures and often low specific activities due to multiple and/or uncontrolled PEGylation. In the present study, a novel solid-phase PEGylation strategy was employed to produce homogenous mono-PEGylated rhKGF-1. RhKGF-1 protein was immobilized on a Heparin-Sepharose column and then a site-selective PEGylation reaction was carried out by a reductive alkylation at the N-terminal amino acid of the protein. The mono-PEGylated rhKGF-1, which accounted for over 40% of the total rhKGF-1 used in the PEGylation reaction, was purified to homogeneity by SP Sepharose ion-exchange chromatography. Our biophysical and biochemical studies demonstrated that the solid-phase PEGylation significantly enhanced the in vitro and in vivo biostability without affecting the over all structure of the protein. Furthermore, pharmacokinetic analysis showed that modified rhKGF-1 had considerably longer plasma half-life than its intact counterpart. Our cell-based analysis showed that, similar to rhKGF-1, PEGylated rhKGF-1 induced proliferation in NIH 3T3 cells through the activation of MAPK/Erk pathway. Notably, PEGylated rhKGF-1 exhibited a greater hepatoprotection against CCl4-induced injury in rats compared to rhKGF-1

Awareness, attitudes, and practices related to the swine influenza pandemic among the Saudi public

<p>Abstract</p> <p>Background</p> <p>During an infectious disease outbreak, it is critical to learn as much as possible about the concerns, knowledge, attitudes, and behavior of the public. Such information can be crucial to the improvement of communication efforts by public health officials and clinicians. The aim of this study was to identify awareness, attitudes, and practices related to influenza A (H1N1) among the Saudi public.</p> <p>Methods</p> <p>A cross-sectional study of 1,548 adult subjects recruited from various shopping malls in Riyadh and Jeddah was conducted. All of the subjects were interviewed using a questionnaire that tested their knowledge, attitudes, and use of precautionary measures in relation to the H1N1 influenza pandemic.</p> <p>Results</p> <p>More than half (54.3%, 840/1548) of the participants showed high concern, 43.7%(677/1548) showed a low level of knowledge, and 60.8%(941/1548) had taken minimal or no precautionary measures. After adjusting for other variables, education level was the only significant predictor of the level of concern (p < 0.001), while greater precautionary measures were taken by participants who were male (p < 0.001), older (p = 0.047), better educated (p = 0.04), and more knowledgeable (p < 0.001). More than one-third (38.3%) of participants were not convinced that the MOH reports about the disease were true, and only 16.1% of the participants reported receiving information from health providers.</p> <p>Conclusions</p> <p>High concern did not translate into a higher compliance with precautionary recommendations, possibly due to the low level of knowledge about the disease among the public. Frequent communication between physicians and the public is recommended to help dispel myths about the disease and to spread better information about the role that the public can play in limiting the spread of the disease.</p