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Gout is the most common inflammatory arthropathy caused by the deposition of monosodium urate (MSU) crystals. The burden of gout is substantial with increasing prevalence of gout globally. The prevalence of Gout in the United States has increased by over 7% in the last two decades. Initially, it was believed that MSU crystal deposits occur only in the joints with the involvement of the periarticular soft tissues, but recent studies have shown the presence of MSU crystal deposition in extra-articular sites as well. Human plasma becomes supersaturated with uric acid at 6.8 mg/dl, a state called hyperuricemia. Beyond this level, uric acid crystals precipitate out of the plasma and deposit in soft tissues, joints, kidneys, etc. If left untreated, hyperuricemia leads to chronic gout characterized by the deposition of tophi in soft tissues such as the joints, tendons, and bursae. With the advent of newer imaging techniques such as DECT, MSU crystals can be visualized in various extra-articular sites. Extra-articular deposition of MSU crystals is believed to be the causative factor for the development of multiple comorbidities in gout patients. Here, we review the literature on extra-articular deposition of urate crystals and the role of dual-energy computed tomography (DECT) in elucidating multi-organ involvement. DECT has emerged as an invaluable alternative for accurate and efficient MSU crystal deposition detection. Future studies using DECT can help determine the clinical consequences of extra-articular deposition of MSU in gout patients.
Osteoarthritis (OA) is a common cause of lameness in sport horses with a significant economic impact. The prevention of OA is crucial since no effective treatment is available. This study aimed to apply untargeted metabolomic analysis to investigate the differences in synovial fluid (SF) composition between healthy and OA-affected joints in horses. SF collected from healthy (n.8) and OA (n.11) horses was analyzed using H-NMR analysis. Metabolomic analysis allowed 55 different metabolites to be identified and quantified in SF samples. Nineteen metabolites were found to be differently concentrated in OA compared to control horses. Synovial fluids from the OC group were found to be higher in 1,3-dihydroxyacetone but lower in tryptophan, phenylalanine, tyrosine, uridine, creatinine, creatine, glycine, choline, asparagine, glutamine, arginine, 3-hydroxybutyrate, valine, 2-hydroxyisovalerate, α-ketoisovaleric acid, 3-methyl-2-oxovalerate, 3-hydroxyisobutyrate, isoleucine, and methionine compared to the controls. A variety of SF metabolites significantly changed following joint disease, demonstrating the complex mechanism underlying osteoarthritis in horses and highlighting the value of applying the metabolomic approach in clinical research.
The current understanding of hypermobility and its diagnostic criteria is still insufficient to create a complete and systematic clinical presentation of the disorder. The objective of this study was to assess the prevalence of joint hypermobility syndrome (JHS) amongst a cohort of jazz dancers, by analyzing its presence in accordance with a number of diagnostic criteria, and to verify potential risk factors for joint hypermobility in jazz dancers.
Since both the talocrural and subtalar joints can be involved in chronic ankle instability, the present study assessed the talar morphology as this bone is the key player between both joint levels. The 3D orientation and curvature of the superior and the posteroinferior facet between subjects with chronic ankle instability and healthy controls were compared. Hereto, the talus was segmented in the computed tomography images of a control group and a chronic ankle instability group, after which they were reconstructed to 3D surface models. A cylinder was fitted to the subchondral articulating surfaces. The axis of a cylinder represented the facet orientation, which was expressed by an inclination and deviation angle in a coordinate system based on the cylinder of the superior talar facet and the geometric principal axes of the subject's talus. The curvature of the surface was expressed as the radius of the cylinder. The results demonstrated no significant differences in the radius or deviation angle. However, the inclination angle of the posteroinferior talar facet was significantly more plantarly orientated (by 3.5°) in the chronic instability group (14.7 ± 3.1°) compared to the control group (11.2 ± 4.9°) (p < 0.05). In the coronal plane this corresponds to a valgus orientation of the posteroinferior talar facet relative to the talar dome. In conclusion, a more plantarly and valgus orientated posteroinferior talar facet may be associated to chronic ankle instability.
The invention of DNA origami has expanded the geometric complexity and functionality of DNA nanostructures. Using DNA origami technology, we develop a flexible multi-joint ring motif as a novel self-assembling module. The motif can connect with each other through self-complementary sequences on its segments. The flexible joints can be fixed in a straightened position as desired, thereby allowing the motif to take various shapes. We can adjust the number of flexible joints and the number of connectable segments, thereby enabling programmable self-assembly of the motif. We successfully produced the motif and evaluated several self-assembly patterns. The proposed multi-joint ring motif can provide a novel method for creating functional molecular devices.
Dramatic increase in the prevalence of lumbar facet joint (LFJ) arthritis in women around the age of menopause indicates a protective role for estrogen in LFJ arthritis. To date, there is no evidence for this indication and the mechanism of such an effect remains poorly understood. In this study, ovariectomized (OVX) mice were used to mimic the estrogen-deficient status of post-menopausal women. Micro-CT and immunohistochemistry was employed to assess the morphological and molecular changes in ovariectomy-induced LFJ arthritis. The results show that the LFJ subchondral bone mass was significantly decreased in OVX mice, with increased cavities on the interface of the subchondral bone. Severe cartilage degradation was observed in ovariectomy-induced LFJ arthritis. Increased blood vessels and innervations were also found in degenerated LFJ, particularly in the subchondral bone area. 17β-Estradiol treatment efficiently suppressed LFJ subchondral bone turnover, markedly inhibited cartilage degradation, and increased blood vessel and nerve ending growth in degenerated LFJ in OVX mice. Our study reveals that estrogen is a key factor in regulating LFJ metabolism. Severe LFJ degeneration occurs when estrogen is absent in vivo. Collapsed subchondral bone may be the initiation of this process, and estrogen replacement therapy can effectively prevent degeneration of LFJ under estrogen-deficient conditions.
The impressive locomotion and manipulation capabilities of spiders have led to a host of bioinspired robotic designs aiming to reproduce their functionalities; however, current actuation mechanisms are deficient in either speed, force output, displacement, or efficiency. Here-using inspiration from the hydraulic mechanism used in spider legs-soft-actuated joints are developed that use electrostatic forces to locally pressurize a hydraulic fluid, and cause flexion of a segmented structure. The result is a lightweight, low-profile articulating mechanism capable of fast operation, high forces, and large displacement; these devices are termed spider-inspired electrohydraulic soft-actuated (SES) joints. SES joints with rotation angles up to 70°, blocked torques up to 70 mN m, and specific torques up to 21 N m kg-1 are demonstrated. SES joints demonstrate high speed operation, with measured roll-off frequencies up to 24 Hz and specific power as high as 230 W kg-1 -similar to human muscle. The versatility of these devices is illustrated by combining SES joints to create a bidirectional joint, an artificial limb with independently addressable joints, and a compliant gripper. The lightweight, low-profile design, and high performance of these devices, makes them well-suited toward the development of articulating robotic systems that can rapidly maneuver.
Intra-articular injections of local anaesthetics (LA), glucocorticoids (GC), or hyaluronic acid (HA) are used to treat osteoarthritis (OA). Contrast agents (CA) are needed to prove successful intra-articular injection or aspiration, or to visualize articular structures dynamically during fluoroscopy. Tranexamic acid (TA) is used to control haemostasis and prevent excessive intra-articular bleeding. Despite their common usage, little is known about the cytotoxicity of common drugs injected into joints. Thus, the aim of our study was to investigate the effects of LA, GC, HA, CA, and TA on the viability of primary human chondrocytes and tenocytes in vitro.
Versican is a large proteoglycan in the extracellular matrix. During embryonic stages, it plays a crucial role in the development of cartilage, heart, and dermis. Previously, we reported that Prx1-Vcan conditional knockout mice, lacking Vcan expression in mesenchymal condensation areas of the limb bud, show the impaired joint formation and delayed cartilage development. Here, we investigated their phenotype in adults and found that they develop swelling of the knee joint. Histologically, their newborn joint exhibited impaired formation of both anterior and posterior cruciate ligaments. Immunostaining revealed a decrease in scleraxis-positive cells in both articular cartilage and ligament of Prx1-Vcan knee joint, spotty patterns of type I collagen, and the presence of type II collagen concomitant with the absence of versican expression. These results suggest that versican expression during the perinatal period is required for cruciate ligaments' formation and that its depletion affects joint function in later ages.
Synovial joints are the lubricated connections between the bones of our body that are commonly affected in arthritis. It is assumed that synovial joints first evolved as vertebrates came to land, with ray-finned fishes lacking lubricated joints. Here, we examine the expression and function of a critical lubricating protein of mammalian synovial joints, Prg4/Lubricin, in diverse ray-finned fishes. We find that Prg4 homologs are specifically enriched at the jaw and pectoral fin joints of zebrafish, stickleback, and gar, with genetic deletion of the zebrafish prg4b gene resulting in the same age-related degeneration of joints as seen in lubricin-deficient mice and humans. Our data support lubricated synovial joints evolving much earlier than currently accepted, at least in the common ancestor of all bony vertebrates. Establishment of the first arthritis model in the highly regenerative zebrafish will offer unique opportunities to understand the aetiology and possible treatment of synovial joint disease.
The prevalence of osteoarthritis (OA) increases with obesity, with up to two thirds of the elderly obese population affected by OA of the knee. The metabolic syndrome (MetS), frequently associated with central obesity and characterised by elevated waist circumference, raised fasting plasma glucose concentration, raised triglycerides, reduced high-density lipoproteins, and/or hypertension, is implicated in the pathogenesis of OA. This narrative review discusses the mechanisms involved in the influence of MetS on OA, with a focus on the effects on macrophages and chondrocytes.
The ostrich is a highly cursorial bipedal land animal with a permanently elevated metatarsophalangeal joint supported by only two toes. Although locomotor kinematics in walking and running ostriches have been examined, these studies have been largely limited to above the metatarsophalangeal joint. In this study, kinematic data of all major toe joints were collected from gaits with double support (slow walking) to running during stance period in a semi-natural setup with two selected cooperative ostriches. Statistical analyses were conducted to investigate the effect of locomotor gait on toe joint kinematics. The MTP3 and MTP4 joints exhibit the largest range of motion whereas the first phalangeal joint of the 4th toe shows the largest motion variability. The interphalangeal joints of the 3rd and 4th toes present very similar motion patterns over stance phases of slow walking and running. However, the motion patterns of the MTP3 and MTP4 joints and the vertical displacement of the metatarsophalangeal joint are significantly different during running and slow walking. Because of the biomechanical requirements, osctriches are likely to select the inverted pendulum gait at low speeds and the bouncing gait at high speeds to improve movement performance and energy economy. Interestingly, the motions of the MTP3 and MTP4 joints are highly synchronized from slow to fast locomotion. This strongly suggests that the 3rd and 4th toes really work as an "integrated system" with the 3rd toe as the main load bearing element whilst the 4th toe as the complementary load sharing element with a primary role to ensure the lateral stability of the permanently elevated metatarsophalangeal joint.
Viral carrier transport efficiency of gene delivery is high, depending on the type of vector. However, viral delivery poses significant safety concerns such as inefficient/unpredictable reprogramming outcomes, genomic integration, as well as unwarranted immune responses and toxicity. Thus, non-viral gene delivery methods are more feasible for translation as these allow safer delivery of genes and can modulate gene expression transiently both in vivo, ex vivo, and in vitro. Based on current studies, the efficiency of these technologies appears to be more limited, but they are appealing for clinical translation. This review presents a summary of recent advancements in orthopedics, where primarily bone and joints from the musculoskeletal apparatus were targeted. In connective tissues, which are known to have a poor healing capacity, and have a relatively low cell-density, i.e., articular cartilage, bone, and the intervertebral disk (IVD) several approaches have recently been undertaken. We provide a brief overview of the existing technologies, using nano-spheres/engineered vesicles, lipofection, and in vivo electroporation. Here, delivery for microRNA (miRNA), and silencing RNA (siRNA) and DNA plasmids will be discussed. Recent studies will be summarized that aimed to improve regeneration of these tissues, involving the delivery of bone morphogenic proteins (BMPs), such as BMP2 for improvement of bone healing. For articular cartilage/osteochondral junction, non-viral methods concentrate on targeted delivery to chondrocytes or MSCs for tissue engineering-based approaches. For the IVD, growth factors such as GDF5 or GDF6 or developmental transcription factors such as Brachyury or FOXF1 seem to be of high clinical interest. However, the most efficient method of gene transfer is still elusive, as several preclinical studies have reported many different non-viral methods and clinical translation of these techniques still needs to be validated. Here we discuss the non-viral methods applied for bone and joint and propose methods that can be promising in clinical use.
Chromosome segregation is a mechanical process that requires assembly of the mitotic spindle - a dynamic microtubule-based force-generating machine. Connections to this spindle are mediated by sister kinetochore pairs, that form dynamic end-on attachments to microtubules emanating from opposite spindle poles. This bi-orientation generates forces that have been reported to stretch the kinetochore itself, which has been suggested to stabilise attachment and silence the spindle checkpoint. We reveal using three dimensional tracking that the outer kinetochore domain can swivel around the inner kinetochore/centromere, which results in large reductions in intra-kinetochore distance (delta) when viewed in lower dimensions. We show that swivel provides a mechanical flexibility that enables kinetochores at the periphery of the spindle to engage microtubules. Swivel reduces as cells approach anaphase, suggesting an organisational change linked to checkpoint satisfaction and/or obligatory changes in kinetochore mechanochemistry may occur before dissolution of sister chromatid cohesion.
Abstract: This paper firstly reveals that when assessing if a bonded joint meets the certification requirements inherent in MIL-STD-1530D and the US Joint Services Standard JSSG2006 it is necessary to ensure that: (a) There is no yielding at all in the adhesive layer at 115% of design limit load (DLL), and (b) that the joint must be able to withstand design ultimate load (DUL). Secondly, it is revealed that fatigue crack growth in both nano-reinforced epoxies, and structural adhesives can be captured using the Hartman-Schijve crack growth equation, and that the scatter in crack growth in adhesives can be modelled by allowing for variability in the fatigue threshold. Thirdly, a methodology was established for estimating a valid upper-bound curve, for cohesive failure in the adhesive, which encompasses all the experimental data and provides a conservative fatigue crack growth curve. Finally, it is shown that this upper-bound curve can be used to (a) compare and characterise structural adhesives, (b) determine/assess a "no growth" design (if required), (c) assess if a disbond in an in-service aircraft will grow and (d) to design and life in-service adhesively-bonded joints in accordance with the slow-growth approach contained in the United States Air Force (USAF) certification standard MIL-STD-1530D.
Angiogenesis is involved in the pathogenesis of inflammatory arthritis, but little is known about the role of lymphangiogenesis in this setting. Here, we examined whether tumor necrosis factor (TNF) stimulates osteoclast precursors (OCPs) to produce the lymphatic growth factor, vascular endothelial growth factor-C (VEGF-C), and induce lymphangiogenesis. We used TNF-transgenic (Tg) mice and mice with serum-induced arthritis. OCPs were purified by fluorescence-activated cell sorting of CD11b+/Gr-1-/lo blood or bone marrow cells and subjected to microarray analysis or were generated from spleen or joint cells and treated with TNF. Expression of VEGFs was analyzed and examined by real-time reverse transcription-polymerase chain reaction and Western blotting. Immunostaining and magnetic resonance imaging were used to quantify lymphatic vessels and volumes of synovium and draining lymph nodes. TNF stimulated VEGF-C expression by OCPs and increased nuclear factor-kappa B (NF-kappaB) binding to an NF-kappaB sequence in the VEGF-C promoter. OCPs from joints of TNF-Tg mice express high levels of VEGF-C. Lymphatic vessel numbers and size were markedly increased in joint sections of TNF-Tg mice and mice with serum-induced arthritis. The severity of synovitis correlated with draining lymph node size. In summary, TNF induces OCPs to produce VEGF-C through NF-kappaB, leading to significantly increased lymphangiogenesis in joints of arthritic mice. The lymphatic system may play an important role in the pathogenesis of inflammatory arthritis.
In spite of numerous investigations of regenerating salamander limbs, little attention has been paid to the details of how joints are reformed. An understanding of the process and mechanisms of joint regeneration in this model system for tetrapod limb regeneration would provide insights into developing novel therapies for inducing joint regeneration in humans. To this end, we have used the axolotl (Mexican Salamander) model of limb regeneration to describe the morphology and the expression patterns of marker genes during joint regeneration in response to limb amputation. These data are consistent with the hypothesis that the mechanisms of joint formation whether it be development or regeneration are conserved. We also have determined that defects in the epiphyseal region of both forelimbs and hind limbs in the axolotl are regenerated only when the defect is small. As is the case with defects in the diaphysis, there is a critical size above which the endogenous regenerative response is not sufficient to regenerate the joint. This non-regenerative response in an animal that has the ability to regenerate perfectly provides the opportunity to screen for the signaling pathways to induce regeneration of articular cartilage and joints.
The occurrence of amyloid in capsular tissue and cartilage from human hip joints were studied by the macroscopic iodine/sulphuric acid test, by light and polarization microscopy, and finally by electron microscopy. It is concluded that the congophilic substance with green dichroism, which in an earlier light and polarization microscopic study was found in a large percentage of hip joints of elderly persons, is amyloid.
Osteoarthritis (OA) is one of most common skeletal disorders and can affect synovial joints such as knee and ankle joints. α5 integrin, a major fibronectin receptor, is expressed in articular cartilage and has been demonstrated to play roles in synovial joint development and in the regulation of chondrocyte survival and matrix degradation in articular cartilage. We hypothesized that α5 integrin signaling is involved in pathogenesis of OA. To test this, we generated compound mice that conditionally ablate α5 integrin in the synovial joints using the Gdf5Cre system. The compound mice were born normally and had an overall appearance similar to the control mice. However, when the mutant mice received the OA surgery, they showed stronger resistance to osteoarthritic changes than the control. Specifically the mutant knee joints presented lower levels of cartilage matrix and structure loss and synovial changes and showed stronger biomechanical properties than the control knee joints. These findings indicate that α5 integrin may not be essential for synovial joint development but play a causative role in induction of osteoarthritic changes.
The auto-cleaning system in digging forelegs of the Congo rose chafer Pachnoda marginata femoro-tibial joint is described. The cleaning system consists of four subsystems: three external ones represented by microsetal pad, hairy brush and scraper and one internal one. They work proactively not only removing contaminants, but also preventing them from entering the joint. The principle of functioning of the cleaning system is based on the sliding of the contacting surfaces of the joint, equipped with hairs, bristles and scrapers. The mutual movement of such surfaces leads to the shift of contaminating particles and, ultimately, to their removal from surfaces of the joint. The key feature of the joint cleaning system is its complete autonomy, in which cleaning is performed constantly with each movement of the femoro-tibial joint without special actions required from the insect. The difference between the auto-cleaning system and self-cleaning and active grooming is also discussed.
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