Osteoclasts degrade bone matrix by secretion of hydrochloric acid and proteases. We studied the processes involved in the degradation of the organic matrix of bone in detail and found that lysosomal acidification is involved in this process and that MMPs are capable of degrading the organic matrix in the absence of cathepsin K.

Purpose Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart containing two additional excipients: niacinamide, to increase early absorption, and L-arginine, to optimize stability. The aim of this study was to evaluate the impact of niacinamide on insulin aspart absorption and to investigate the mechanism of action underlying the accelerated absorption. Methods The impact of niacinamide was assessed in pharmacokinetic analyses in pigs and humans, small angle X-ray scattering experiments, trans-endothelial transport assays, vascular tension measurements, and subcutaneous blood flow imaging. Results Niacinamide increased the rate of early insulin aspart absorption in pigs, and pharmacokinetic modelling revealed this effect to be most pronounced up to ~30–40 min after injection in humans. Niacinamide increased the relative monomer fraction of insulin aspart by ~35%, and the apparent permeability of insulin aspart across an endothelial cell barrier by ~27%. Niacinamide also induced a concentration-dependent vasorelaxation of porcine arteries, and increased skin perfusion in pigs. Conclusion Niacinamide mediates the acceleration of initial insulin aspart absorption, and the mechanism of action appears to be multifaceted. Niacinamide increases the initial abundance of insulin aspart monomers and transport of insulin aspart after subcutaneous administration, and also mediates a transient, local vasodilatory effect. Electronic supplementary material The online version of this article (10.1007/s11095-019-2578-7) contains supplementary material, which is available to authorized users.

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SummaryAs anti-inflammatory treatments used in rheumatoid arthritis, such as glucocorticoids, often result in secondary detrimental effects on bone health, the objective of this study was to investigate the effects of oestrogen therapy (ET) on the development and activity of collagen-induced arthritis (CIA) in rats, with a focus on assessment of chondroprotective effects using biomarkers of type II collagen degradation. Forty female Lewis rats were allocated into four intervention groups: (i) control + vehicle; (ii) CIA + vehicle; (iii) CIA + ET; and (iv) CIA + prednisolone. During the 28-day intervention period we monitored body weight, time-point of disease onset, incidence of manifest disease and paw volume. Levels of the type II collagen degradation marker (CTX-II) were measured in serum. At euthanasia, hind paws were isolated, extracted for proteins and measured for the concentration of CTX-II. Matrix metalloproteinase (MMP) activity was evaluated using gelatinase zymography. Oestrogen treatment delayed the time-point of disease onset and reduced the incidence and degree of manifest immunoarthritis significantly, assessed by macroscopic evaluation of hind paw inflammation and paw volume. Measures of serum or tissue levels of CTX-II showed significantly reduced type II collagen degradation elicited by oestrogen treatment. In alignment, a decreased activity of MMP-2 and MMP-9 was found in the paw protein extracts. We have demonstrated that the anti-inflammatory effect of ET is linked to chondroprotective effects in an animal model of systemic immunoarthritis. As ET has positive rather than negative effects on bone health in contrast to prednisolone, these observations may be important for potential combination therapy.

These data indicate that the age of the bone plays an important role in controlling osteoclast-mediated resorption, with significantly higher levels of osteoclast differentiation and resorption on aged bones when compared to young bones.

Abstract. Weather radar has become an invaluable tool for monitoring rainfall and studying its link to hydrological response. However, when it comes to accurately measuring small-scale rainfall extremes responsible for urban flooding, many challenges remain. The most important of them is that radar tends to underestimate rainfall compared to gauges. The hope is that by measuring at higher resolutions and making use of dual-polarization radar, these mismatches can be reduced. Each country has developed its own strategy for addressing this issue. However, since there is no common benchmark, improvements are hard to quantify objectively. This study sheds new light on current performances by conducting a multinational assessment of radar's ability to capture heavy rain events at scales of 5 min up to 2 h. The work is performed within the context of the joint experiment framework of project MUFFIN (Multiscale Urban Flood Forecasting), which aims at better understanding the link between rainfall and urban pluvial flooding across scales. In total, six different radar products in Denmark, the Netherlands, Finland and Sweden were considered. The top 50 events in a 10-year database of radar data were used to quantify the overall agreement between radar and gauges as well as the bias affecting the peaks. Results show that the overall agreement in heavy rain is fair (correlation coefficient 0.7–0.9), with apparent multiplicative biases on the order of 1.2–1.8 (17  %–44  % underestimation). However, after taking into account the different sampling volumes of radar and gauges, actual biases could be as low as 10 %. Differences in sampling volumes between radar and gauges play an important role in explaining the bias but are hard to quantify precisely due to the many post-processing steps applied to radar. Despite being adjusted for bias by gauges, five out of six radar products still exhibited a clear conditional bias, with intensities of about 1 %–2 % per mmh−1. As a result, peak rainfall intensities were severely underestimated (factor 1.8–3.0 or 44 %–67 %). The most likely reason for this is the use of a fixed Z–R relationship when estimating rainfall rates (R) from reflectivity (Z), which fails to account for natural variations in raindrop size distribution with intensity. Based on our findings, the easiest way to mitigate the bias in times of heavy rain is to perform frequent (e.g., hourly) bias adjustments with the help of rain gauges, as demonstrated by the Dutch C-band product. An even more promising strategy that does not require any gauge adjustments is to estimate rainfall rates using a combination of reflectivity (Z) and differential phase shift (Kdp), as done in the Finnish OSAPOL product. Both approaches lead to approximately similar performances, with an average bias (at 10 min resolution) of about 30 % and a peak intensity bias of about 45 %.

Addition of ovariectomy augmented site-specific traumatic OA pathology, which was reduced by oral salmon calcitonin treatment. Treatments for OA might ideally affect both bone and cartilage.

sCT over-expressing mice had higher bone volume, and were protected against cartilage erosion. These data suggest that increased levels of sCT may hamper the pathogenesis of osteoarthritis (OA). However more studies are necessary to confirm these preliminary results.