Development and Role in Therapy of Canakinumab in Adult-Onset Still's Disease

Adult-onset Still's disease (AOSD) is a rare inflammatory disease of unknown etiology typically characterized by episodes of spiking fever, evanescent rash, arthralgia, leukocytosis, and hyperferritinemia. The pivotal role of interleukin (IL)-1 and other pro-inflammatory cytokines gives rise to the development of new targeted therapies. Currently, AOSD patients can benefit from efficient and well tolerated biologic agents, such as IL-1, IL-6, and tumour necrosis factor (TNF)-\u3b1 antagonists. Canakinumab, a human monoclonal anti-IL-1\u3b2 antibody, is indicated for the treatment of different autoinflammatory syndromes in adults, adolescents, and children and it has recently been approved for AOSD treatment. In this article, we summarize the structural and biochemical data describing the molecular interactions between Canakinumab and its target antigen. Some special considerations of the pharmacological properties of Canakinumab are included. We also review the safety, efficacy and tolerability of this drug for the treatment of AOSD

Effect of integration time on the morphometric, densitometric and mechanical properties of the mouse tibia

Micro-Computed Tomography (microCT) images are used to measure morphometric and densitometric properties of bone, and to develop finite element (FE) models to estimate mechanical properties. However, there are concerns about the invasiveness of microCT imaging due to the X-rays ionising radiation induced by the repeated scans on the same animal. Therefore, the best compromise between radiation dose and image quality should be chosen for each preclinical application. In this study, we investigated the effect of integration time (time the bone is exposed to radiation at each rotation step during microCT imaging) on measurements performed on the mouse tibia. Four tibiae were scanned at 10.4 µm voxel size using four different procedures, characterized by decreasing integration time (from 200 ms to 50 ms) and therefore decreasing nominal radiation dose (from 513 mGy to 128 mGy). From each image, trabecular and cortical morphometric parameters, spatial distribution of bone mineral content (BMC) in the whole tibia and FE-based estimations of stiffness and strength were obtained. A high-resolution scan (4.3 µm voxel size) was used to quantify measurement errors. Integration time had the largest effect on trabecular morphometric parameters (7-28%). Lower effects were observed on cortical parameters (1-3%), BMC (1-10%) distribution, and FE-based estimations of mechanical properties (1-3%). In conclusion, the effect of integration time on image-based measurements has been quantified. This data should be considered when defining the in vivo microCT scanning protocols in order to find the best compromise between nominal radiation exposure and accuracy in the estimation of bone parameters

Histochemical detection of the lectin-binding carbohydrates in the zona pellucida during oocyte growth in the wild boar (Sus scrofa scrofa)

The changes that occur in the carbohydrate composition of zona pellucida glycoproteins during oocyte maturation in the wild-boar were studied using periodic-acid Schiff (PAS), High Iron Diamine (HID) and Low Iron Diamine (LID). Lectin staining was performed with a panel of 11 HRP-lectin conjugates combined with neuraminidase digestion and chemical treatments. There were few internal glucidic residues, such as N-acetylglucosamine, in the wild boar zona pellucida but there were many subterminal beta-N-acetylgalactosamine, alpha- and beta-galactose determinants masked by sialic acid. In addition, beta-N-acetylgalactosamine, beta-galactose-(1-3)-N-acetylgalactosamine and beta-galactose-(1-4)-N-acetylglucosamine were detected in the sulphated form in the terminal and/or subterminal position. Some differences in the lectin reactive sites occurred in the zona pellucida, depending on the stage of oocyte maturatio

Regional nanoindentation properties in different locations on the mouse tibia from C57BL/6 and Balb/C female mice

The local spatial heterogeneity of the material properties of the cortical and trabecular bone extracted from the mouse tibia is not well-known. Nevertheless, its characterization is fundamental to be able to study comprehensively the effect of interventions and to generate computational models to predict the bone strength preclinically. The goal of this study was to evaluate the nanoindentation properties of bone tissue extracted from two different mouse strains across the tibia length and in different sectors. Left tibiae were collected from four female mice, two C57BL/6, and two Balb/C mice. Nanoindentations with maximum 6 mN load were performed on different microstructures, regions along the axis of the tibiae, and sectors (379 in total). Reduced modulus (Er) and hardness (H) were computed for each indentation. Trabecular bone of Balb/C mice was 21% stiffer than that of C57BL/6 mice (20.8 ± 4.1 GPa vs. 16.5 ± 7.1 GPa). Moreover, the proximal regions of the bones were 13–36% less stiff than the mid-shaft and distal regions of the same bones. No significant differences were found for the different sectors for Er and H for Balb/C mice. The bone in the medial sector was found to be 8–14% harder and stiffer than the bone in the anterior or posterior sectors for C57BL/6 mice. In conclusion, this study showed that the nanoindentation properties of the mouse tibia are heterogeneous across the tibia length and the trabecular bone properties are different between Balb/C and C57BL/6 mice. These results will help the research community to identify regions where to characterize the mechanical properties of the bone during preclinical optimisation of treatments for skeletal diseases

RNA framework: An all-in-one toolkit for the analysis of RNA structures and post-transcriptional modifications

RNA is emerging as a key regulator of a plethora of biological processes. While its study has remained elusive for decades, the recent advent of high-throughput sequencing technologies provided the unique opportunity to develop novel techniques for the study of RNA structure and post-transcriptional modifications. Nonetheless, most of the required downstream bioinformatics analyses steps are not easily reproducible, thus making the application of these techniques a prerogative of few laboratories. Here we introduce RNA Framework, an all-in-one toolkit for the analysis of most NGS-based RNA structure probing and post-transcriptional modification mapping experiments. To prove the extreme versatility of RNA Framework, we applied it to both an in-house generated DMS-MaPseq dataset, and to a series of literature available experiments. Notably, when starting from publicly available datasets, our software easily allows replicating authors' findings. Collectively, RNA Framework provides the most complete and versatile toolkit to date for a rapid and streamlined analysis of the RNA epistructurome. RNA Framework is available for download at: http://www.rnaframework.com

Late gestation diet supplementation of resin acid-enriched composition increases sow colostrum immunoglobulin G content, piglet colostrum intake and improve sow gut microbiota

Resin acid-enriched composition (RAC) mainly containing tall oil fatty acid with an active component of resin acid (RA) can improve the microbial population in the digestive system, change the microbial fermentation, and improve the feed conversion ratio. We investigated the effects of dietary supplementation of RAC on sow colostrum yield (CY), colostrum composition and gut microbiota. Tall oil fatty acid and RA are commonly termed RAC and CLA, pinolenic, abietic, dehydrobiotic acids are characteristic components of RAC. The experiment was conducted in three trials in three respective herds. Sows were fed with a control diet and the same diet supplemented with 5 g RAC/day per sow during the last week of gestation. The 16S ribosomal RNA gene sequencing technique was used to assess sows' faecal microbiota populations at farrowing. Colostrum nutritional composition, acute phase proteins (APPs) and immunoglobulin (Ig) content were also assessed. Individual piglets were weighed at birth and 24 h after the birth of first piglets in order to calculate CY and later at 3 to 4 weeks to calculate average daily gain. The RAC-fed sows had significantly higher IgG levels (P0.05), but those fed RAC had higher levels of colostrum serum amyloid A. Colostrum yield was significantly higher in RAC-fed sows in herds 2 and 3 with heavier piglets between 3 and 4 weeks of age (P0.05). Resin acid-enriched composition supplementation significantly increased some beneficial and fermentative bacteria (Romboutsia and Clostridium sensu stricto) than the control diet (PPeer reviewe

Heterogeneous strain distribution in the subchondral bone of human osteoarthritic femoral heads, measured with digital volume correlation

Osteoarthritis (OA) is a chronic disease, affecting approximately one third of people over the age of 45. Whilst the etiology and pathogenesis of the disease are still not well understood, mechanics play an important role in both the initiation and progression of osteoarthritis. In this study, we demonstrate the application of stepwise compression, combined with microCT imaging and digital volume correlation (DVC) to measure and evaluate full-field strain distributions within osteoarthritic femoral heads under uniaxial compression. A comprehensive analysis showed that the microstructural features inherent in OA bone did not affect the level of uncertainties associated with the applied methods. The results illustrate the localization of strains at the loading surface as well as in areas of low bone volume fraction and subchondral cysts. Trabecular thickness and connectivity density were identified as the only microstructural parameters with any association to the magnitude of local strain measured at apparent yield strain or the volume of bone exceeding yield strain. This work demonstrates a novel approach to evaluating the mechanical properties of the whole human femoral head in case of severe OA