Knee osteoarthritis (OA) is one of the leading causes of disability within the adult population. Current treatment options for OA of the knee include intra-articular (IA) hyaluronic acid (HA), a ...molecule found intrinsically within the knee joint that provides viscoelastic properties to the synovial fluid. A variety of mechanisms in which HA is thought to combat knee OA are reported in the current basic literature.
We conducted a comprehensive literature search to identify currently available primary non-clinical basic science articles focussing on the mechanism of action of IA-HA treatment. Included articles were assessed and categorized based on the mechanism of action described within them. The key findings and conclusions from each included article were obtained and analyzed in aggregate with studies of the same categorical assignment.
Chondroprotection was the most frequent mechanism reported within the included articles, followed by proteoglycan and glycosaminoglycan synthesis, anti-inflammatory, mechanical, subchondral, and analgesic actions. HA-cluster of differentiation 44 (CD44) receptor binding was the most frequently reported biological cause of the mechanisms presented. High molecular weight HA was seen to be superior to lower molecular weight HA products. HA derived through a biological fermentation process is also described as having favorable safety outcomes over avian-derived HA products.
The non-clinical basic science literature provides evidence for numerous mechanisms in which HA acts on joint structures and function. These actions provide support for the purported clinical benefit of IA-HA in OA of the knee. Future research should not only focus on the pain relief provided by IA-HA treatment, but the disease modification properties that this treatment modality possesses as well.
Abstract Objectives Hyaluronic acid and corticosteroids are common intra-articular (IA) therapies widely used for the management of mild to moderate knee osteoarthritis (OA). Many trials evaluating ...the efficacy of IA administered therapies commonly use IA saline injections as a placebo comparator arm. Using a systematic review and meta-analysis, our objective was to assess the clinical benefit associated with use of IA saline in trials of IA therapies in the treatment of patients with painful knee OA. Methods MEDLINE and Embase databases were searched for articles published up to and including August 14th , 2014. Two reviewers assessed the eligibility of potential reports and the risk of bias of included trials. We analyzed short (≤3 months) and long-term (6–12 months) pain reduction of the saline arm of included trials using standardized mean differences (SMDs; estimated assuming a null-effect in a comparator group) that were combined and weighted using a random-effects model. Treatment-related adverse events (AEs) were tabulated and presented using descriptive statistics. Results From 40 randomized controlled trials (RCTs) eligible for inclusion only 38 provided sufficient data to be included in the meta-analysis. Based on data with moderate inconsistency IA saline was found to significantly improve short-term knee pain in 32 studies involving 1,705 patients (SMD −0.68, 95% CI −0.78 to −0.57; P <.001; I2 =50%). Long-term knee pain was significantly decreased following IA injection with saline in 19 studies involving 1445 patients (SMD −0.61, 95% CI −0.76 to −0.45; P < .001) with a substantial degree of inconsistency (I2 =74%). Twenty-nine of the included trials reported on adverse events, none of which found any serious treatment-related AEs following IA injection with saline. Conclusions Pain relief observed with IA saline should prompt health care providers to consider the additional effectiveness of current IA treatments that use saline comparators in clinical studies, and challenges of identifying IA saline injection as a “placebo”.
To assess the use of combined color Doppler ultrasonography (US), power Doppler US, and spectral wave analysis (SWA) in differentiating malignant and benign musculoskeletal tumors.
Seventy-nine ...musculoskeletal tumors (34 malignant, 45 benign) were examined with color and power Doppler US and SWA. Two radiologists independently assessed US images and SWA findings. Echotexture and vessel characteristics such as stenoses, occlusions, loops, shunts, trifurcations, vascular pattern, and resistive index were evaluated. All tumors were subject to US-guided or open biopsy for histologic correlation.
Combined color and power Doppler US and SWA revealed four major (stenosis, occlusion, trifurcation, vascular pattern) and three minor (shunt, self loop, resistive index) vessel characteristics, which proved helpful in differentiating benign from malignant lesions. Echotexture showed moderate sensitivity (82% 28 of 34 tumors) and low specificity (38% 17 of 45 tumors). When comparing several combinations of vessel characteristics, a combination of any two major characteristics demonstrated the best results (sensitivity, 94% 33 of 39 tumors; specificity, 93% three of 45 tumors). Combining more than two characteristics resulted in lower sensitivity.
Combined color and power Doppler US and SWA may enable assessment of vascular architecture and altered flow of musculoskeletal tumors. Vascular architecture analysis enables differentiation of benign and malignant lesions and evaluation of musculoskeletal tumors.
Stress fractures are common injuries frequently overlooked on first radiographs, especially in the early course. The gold standard for accurate diagnosis is MRI and scintigraphy. We report six cases ...of stress fractures of the lower limb diagnosed with sonography and describe typical sonographic features.
Currently, there are no in vivo techniques for quantifying healing within fractures involving mainly trabecular bone. Methods for quantitatively assessing healing would aid the investigation of new ...treatment regimes, and might also be useful for predicting whether a patient may be undergoing delayed union. Using CT and automated image registration, we have developed an image processing technique for measuring changes in CT image intensity at fracture sites. The technique focuses on quantifying the formation of new mineralised tissue within fracture gaps, while ignoring loss of bone mineral due to disuse osteoporosis. Seven patients with fractures of the distal radius were examined for 12 weeks following fracture. To assess reproducibility of measurements of change in CT intensity at the fracture line, measurements were performed on two separate occasions, by each of two independent readers. Reproducibility was compared to rates of change over time, to determine detectable differences in individual progression. Scans were scored qualitatively for features of healing and scores compared to the quantitative measurements. The mean (SD) change in CT intensity was +128 (65) Hounsfield Units (HU) over the 12 week follow-up. Inter- and intra-observer reproducibilities were both similar (±17 HU), 1/7 of the change seen during the study. In this small patient cohort, a significant increase in CT intensity was seen 2 weeks post-fracture. Large early increases in CT intensity were associated with early visual appearance of sclerosis and blurring of the fracture line. In this preliminary, prospective study, we have developed a reproducible quantitative technique for measuring changes in CT intensity of trabecular bone at the fracture line in the distal radius. Further work is required to determine whether it can be used to identify, or monitor patients who are undergoing delayed fracture repair. The technique appears sensitive for measuring changes immediately post-fracture, and could have a role in examining potential effects of new therapies in patient cohorts.
Development of new agents to induce fracture healing requires more sensitive methods to detect early changes in fracture repair. The aims of this study were to determine quantitative and qualitative ...features of fracture healing using volumetric computed tomography (CT) and to compare them with conventional radiography during the weeks following uncomplicated fractures of the appendicular skeleton.
39 otherwise healthy men and women with acute, closed fractures of the distal radius, tibial and/or fibular malleoli, or tibial shaft, were enrolled and underwent CT and X-ray imaging at 1, 2, 4, 8, 12, and 16 (tibial shaft only) weeks post fracture. Qualitative assessment included fracture line/margins, fracture gap, external callus appearance, callus-to-cortex ratio, bridging, and radiologic union. Quantitative assessment of CT density changes (Hounsfield units HU) in the fracture gap was performed in a subset of 8 fracture patients using MEDx multimodality image analysis software (Sterling,VA). The analysis was performed by drawing free form regions of interest (ROI) covering the fracture gap on baseline (week 1) images and by automated registration of the follow-up images to the baseline co-ordinate system.
The mean time to achieve radiologic union on CT was slightly shorter than on X-rays for radial and tibial shaft fractures (7.3 vs. 8.0 weeks, P = .1). Blurring of the fracture margins and reactive sclerosis were the earliest signs of healing in both modalities. External callus formation was evident in 11 cases and was detected earlier with CT technique. Overall, CT images allowed for more complete and detailed visualization of healing compared with conventional X-rays, which were limited by cast and fixation hardware superimposition, especially in subjects with malleolar and distal radial fractures. Quantitative evaluation showed good intraobserver and interobserver reproducibility and a statistically significant correlation to qualitative changes.
Our methods of fracture healing assessment are reliable tools that are able to detect early changes in normal bone healing and may serve as useful additions to subjective image analysis in monitoring fracture healing in clinical trials. CT shows some advantages over conventional X-rays in evaluation of early fracture healing.
A permanent electric dipole moment (EDM) of a particle or system is a separation of charge along its angular momentum axis and is a direct signal of T violation and, assuming CPT symmetry, CP ...violation. For over 60 years EDMs have been studied, first as a signal of a parity-symmetry violation and then as a signal of CP violation that would clarify its role in nature and in theory. Contemporary motivations include the role that CP violation plays in explaining the cosmological matter-antimatter asymmetry and the search for new physics. Experiments on a variety of systems have become ever-more sensitive, but provide only upper limits on EDMs, and theory at several scales is crucial to interpret these limits. Nuclear theory provides connections from standard-model and beyond-standard-model physics to the observable EDMs, and atomic and molecular theory reveal how CP violation is manifest in these systems. EDM results in hadronic systems require that the standard-model QCD parameter of θ¯ must be exceptionally small, which could be explained by the existence of axions, also a candidate dark-matter particle. Theoretical results on electroweak baryogenesis show that new physics is needed to explain the dominance of matter in the Universe. Experimental and theoretical efforts continue to expand with new ideas and new questions, and this review provides a broad overview of theoretical motivations and interpretations as well as details about experimental techniques, experiments, and prospects. The intent is to provide specifics and context as this exciting field moves forward.
Stellar winds and supernova (SN) explosions of massive stars (‘stellar feedback’) create bubbles in the interstellar medium (ISM) and insert newly produced heavy elements and kinetic energy into ...their surroundings, possibly driving turbulence. Most of this energy is thermalized and immediately removed from the ISM by radiative cooling. The rest is available for driving ISM dynamics. In this work we estimate the amount of feedback energy retained as kinetic energy when the bubble walls have decelerated to the sound speed of the ambient medium. We show that the feedback of the most massive star outweighs the feedback from less massive stars. For a giant molecular cloud (GMC) mass of 105 M⊙ (as e.g. found in the Orion GMCs) and a star formation efficiency of 8 per cent the initial mass function predicts a most massive star of approximately 60 M⊙. For this stellar evolution model we test the dependence of the retained kinetic energy of the cold GMC gas on the inclusion of stellar winds. In our model winds insert 2.34 times the energy of an SN and create stellar wind bubbles serving as pressure reservoirs. We find that during the pressure-driven phases of the bubble evolution radiative losses peak near the contact discontinuity (CD), and thus the retained energy depends critically on the scales of the mixing processes across the CD. Taking into account the winds of massive stars increases the amount of kinetic energy deposited in the cold ISM from 0.1 per cent to a few per cent of the feedback energy.
Context. Large-scale shocks formed by clustered feedback of young OB stars are considered an important source of mechanical energy for the interstellar medium (ISM) and a trigger of molecular cloud ...formation. Their interaction sites are locations where kinetic energy and magnetic fields are redistributed between ISM phases. Aims. In this work we address two questions, both involving the role of galactic magnetic fields in the dynamics of supershells and their interactions. On the one hand, we study the effect of the magnetic field on the expansion and fragmentation of supershells and, on the other hand, we look for the signatures of supershell collisions on dense structures and on the kinetic and magnetic energy distribution of the ISM. Methods. We performed a series of high-resolution, three-dimensional simulations of colliding supershells. The shocks are created by time-dependent feedback and evolve in a diffuse turbulent environment that is either unmagnetized or has different initial magnetic field configurations. Results. In the hydrodynamical situation, the expansion law of the superbubbles is consistent with the radius-time relation R ∝ t3/5 that is theoretically predicted for wind-blown bubbles. The supershells fragment over their entire surface into small dense clumps that carry more than half of the total kinetic energy in the volume. However, this is not the case when a magnetic field is introduced, either in the direction of the collision or perpendicular to the collision. In both situations, the shell surfaces are more stable to dynamical instabilities. When the magnetic field opposes the collision, the expansion law of the supershells also becomes significantly flatter than in the hydrodynamical case. Although a two-phase medium arises in all cases, in the magnetohydrodynamical (MHD) simulations the cold phase is limited to lower densities and the cold clumps are located further away from the shocks with respect to the hydrodynamical simulations. Conclusions. For the parameters we explored, self-gravity has no effect on either the superbubble expansion or the shock fragmentation. In contrast, a magnetic field, whether mostly parallel or mostly perpendicular to the collision axis, causes a deceleration of the shocks, deforms them significantly, and largely suppresses the formation of the dense gas on their surface. The result is a multi-phase medium in which the cold clumps are not spatially correlated with the supershells.
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