Search Results (446)

Total knee arthroplasty is an increasingly common surgical intervention for degenerative knee disease, yet it carries a risk of prosthetic joint infection (PJI). While bacterial infections dominate the landscape of PJIs, fungal infections represent a rare but significant concern, especially in immunocompromised patients. This case report describes a 71-year-old patient who presented in October 2024 with left knee pain and swelling 7 months after total knee arthroplasty. A prosthetic joint infection due to Candida parapsilosis was diagnosed preoperatively by repetitive microbiological examination of synovial fluid and intraoperatively by tissue samples and sonication of prosthetic material. A two-stage revision surgery with a short 4-week interval was performed using an antifungal-impregnated spacer, followed by 6 months of systemic antifungal treatment with fluconazole and continued by fluconazole suppressive treatment for another 6 months. A favorable clinical and functional outcome was achieved after 11 months of follow-up. This is a rare case of fungal PJI treatment with a two-stage revision with a shorter interval, using an antifungal impregnated spacer combined with a prolonged antifungal therapy. Full article

Melioidosis is a multisystem disease caused by the sapronotic soil bacterium Burkholderia pseudomallei. Septic arthritis (SA) can occur as either a primary or secondary focus and requires surgical management with prolonged antimicrobial treatment. We used the Darwin Prospective Melioidosis Study to identify patients with melioidosis and SA, filtered by culture confirmation of B. pseudomallei, and subsequently collected synovial fluid analysis, laboratory, clinical, and risk factor data. We identified 68 patients in total with a label of SA, of which 46 patients supplied 69 synovial fluid samples which were culture-positive. These most commonly came from the knee (61%) and ankle (16%), though half (54%) of the specimens were clotted and unable to undergo cell count. We found a median white cell count (WCC) of 63,000 × 10⁶ cells/L in B. pseudomallei culture-positive samples. There was a numerical, but non-significant, difference in median synovial fluid WCC when stratified by preceding antimicrobial use (90,000 × 10⁶ cells/L prior versus 27,800 × 10⁶ cells/L in samples taken post antimicrobial initiation; p = 0.053). One sample was B. pseudomallei culture-positive 32 days following antimicrobial initiation. The presence/absence of contiguous osteomyelitis did not alter synovial fluid white cell counts. These findings suggest that in cases of suspected melioidosis SA, it is not necessary to withhold empirical antimicrobial therapy while awaiting joint aspiration. Further research is needed to define the role of non-culture-based diagnostics in suspected melioidosis SA. Full article

Objective: Monosodium urate (MSU) crystallization in human joints is poorly understood. This study aimed to investigate whether the length of MSU crystals varies in relation to organized ultrasound deposits, which may lead to longer crystals. Methods: Observational, cross-sectional study analyzing MSU crystals from synovial fluid samples of patients with crystal-proven gout. Using light microscopy, we measured crystal lengths (in µm) and noted the presence of long crystals, defined by cutoffs at the 66th, 75th, and 90th percentiles. We evaluated their association with two ultrasound-defined crystal deposition models: (1) grade 2–3 double-contour (DC) sign, tophi, and/or aggregates; and (2) grade 2–3 DC sign and/or tophi. Results: In a total of 1076 MSU crystals from 28 joints, median length was 23.3 µm (95% confidence interval 22.1–24.5). MSU crystal length was similar regardless of ultrasound deposition: in model 1 (20 joints, 71.4%), 22.5 µm in joints with deposits vs. 21.7 µm without; p = 0.42; in model 2 (15 joints, 53.6%), 22.8 µm vs. 21.2 µm, respectively; p = 0.12. Joints fulfilling model 2 criteria had more long crystals (>66th percentile), both in absolute and relative terms. Long crystals mildly correlated with serum urate levels and were numerically more frequent in patients with tophaceous gout. Conclusions: Most MSU crystals in synovial fluid gathered around a common length, regardless of ultrasound deposition. Long crystals were more common in joints with DC signs or tophi. Our finding is in keeping with two different mechanisms of MSU crystallization in humans. Full article

Chronic hemophilic synovitis (CHS), driven by hemosiderin-laden macrophages from recurrent hemarthrosis, is a major cause of joint damage in hemophilia. Platelet-rich plasma (PRP) is a promising regenerative therapy for joint diseases. This study investigated PRP’s ability to modulate macrophage polarization from a pro-inflammatory (M1) to a pro-resolving, tissue-repairing (M2) phenotype in CHS. We analyzed synovial fluid (SF) from CHS patients (N = 22), both pre- and post-PRP treatment. Ex vivo analysis revealed a predominant M1 profile with an increased proportion of CD11⁺CD14⁺CD64^hi compared with CD206⁺ or CD163⁺ M2 macrophages in CHS SF. In vitro experiments showed that CHS SF skewed monocyte-derived macrophages toward an M1 inflammatory program, evaluated by flow cytometry, qPCR, and ELISA. However, adding PRP significantly modulated the pro-inflammatory macrophage program, promoting an M2 tissue repair profile. Furthermore, a random forest machine learning algorithm, applied to public scRNAseq data, confirmed PRP’s macrophage reprogramming effect. Functional assays also showed increased TGF-β secretion and macrophage fusion when challenged with neutrophil extracellular traps (NETs). A small patient follow-up cohort treated with intra-articular PRP showed similar results, including normalization of cellular content and reduced CD64/CD206 expression. These findings indicate that PRP treatment effectively shifts SF-associated M1 macrophages to an M2-like phenotype, highlighting its potential as a therapeutic strategy for CHS. Full article

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by cartilage degradation, synovial inflammation, and subchondral bone remodeling, leading to chronic pain and reduced mobility. In early-stage OA, sustained oxidative stress and inflammation drive chondrocyte dysfunction and extracellular matrix (ECM) loss. Hyaluronic acid (HA), a key component of synovial fluid responsible for lubrication and viscoelasticity, is prone to enzymatic and oxidative degradation under inflammatory conditions, limiting its therapeutic effect. To address this, we developed an HA-based system incorporating the natural antioxidant and anti-inflammatory molecule carvacrol. The potential of this formulation was assessed in interleukin-1b-stimulated chondrocytes, which mimic the inflammatory environment of OA. The carvacrol-added HA combination upregulated antioxidant enzyme expression, attenuated pro-inflammatory signaling, and promoted ECM preservation by up regulating cartilage-specific markers and glycosaminoglycan production. In vivo efficacy was further evaluated in a rat model of monosodium iodoacetate-induced OA. HA-Carvacrol treatment alleviated pain-related behaviors and preserved cartilage structure, as confirmed by behavioral assessments and histological analyses. This dual-function formulation integrates the lubricating benefits of HA with the bioactivity of carvacrol, providing preclinical proof-of-concept evidence for its potential in early-stage OA. Full article

Osteoarthritis (OA) lacks disease-modifying therapies, in part because key features of the joint microenvironment remain underappreciated. One such feature is localized acidosis, characterized by sustained reductions in extracellular pH within the cartilage, meniscus, and the osteochondral interface despite near-neutral bulk synovial fluid. We synthesize current evidence on the origins, sensing, and consequences of joint acidosis in OA. Metabolic drivers include hypoxia-biased glycolysis in avascular cartilage, cytokine-driven reprogramming in the synovium, and limits in proton/lactate extrusion (e.g., monocarboxylate transporters (MCTs)), with additional contributions from fixed-charge matrix chemistry and osteoclast-mediated acidification at the osteochondral junction. Acidic niches shift proteolysis toward cathepsins, suppress anabolic control, and trigger chondrocyte stress responses (calcium overload, autophagy, senescence, apoptosis). In the nociceptive axis, protons engage ASIC3 and sensitize TRPV1, linking acidity to pain. Joint cells detect pH through two complementary sensor classes: proton-sensing GPCRs (GPR4, GPR65/TDAG8, GPR68/OGR1, GPR132/G2A), which couple to G_s, G_q/11, and G_12/13 pathways converging on MAPK, NF-κB, CREB, and RhoA/ROCK; and proton-gated ion channels (ASIC1a/3, TRPV1), which convert acidity into electrical and Ca²⁺ signals. Therapeutic implications include inhibition of acid-enabled proteases (e.g., cathepsin K), pharmacologic modulation of pH-sensing receptors (with emerging interest in GPR68 and GPR4), ASIC/TRPV1-targeted analgesia, metabolic control of lactate generation, and pH-responsive intra-articular delivery systems. We outline research priorities for pH-aware clinical phenotyping and imaging, cell-type-resolved signaling maps, and targeted interventions in ‘acidotic OA’ endotypes. Framing acidosis as an actionable component of OA pathogenesis provides a coherent basis for mechanism-anchored, locality-specific disease modification. Full article

Background/Objectives: Osteoarthritis (OA) is a prevalent age-related degenerative joint disease causing cartilage damage, leading to a debilitating lifestyle. However, there are currently no drugs on the market that promote cartilage repair, and advanced cases often require arthroplasty. Increasing evidence suggests that exosomes, the smallest extracellular vesicles (30–150 nm) secreted by all cell types, are involved in the pathological process of OA and play a crucial and complex role in its progression. This review aims to provide in-depth insights into exosome biology, isolation techniques, their role in OA pathophysiology, and their clinical therapeutic potential. Methods: We systematically reviewed studies published since 2020 on exosomes in OA, focusing on their biological properties, isolation techniques, pathological roles, and therapeutic applications. Results: Exosomes derived from synovial fluid, chondrocytes, synoviocytes, and mesenchymal stem cells regulate key processes in OA progression, including inflammation, apoptosis, extracellular matrix degradation, and regeneration. Various cell-derived exosomes show therapeutic potential for cartilage damage/OA. However, their mechanisms of action have not been fully investigated. Moreover, emerging methodologies, such as utilizing novel materials for exosome delivery, potentially facilitate the development of more effective and personalized therapeutic interventions. Conclusions: Exosomes exert dual roles in OA pathogenesis and therapy. Although challenges remain regarding their sources, dosage, delivery, and standardization, exosome-based strategies represent a promising cell-free therapeutic approach with potential applications in personalized and precision medicine. Full article

Musculoskeletal disorders are a major cause of lameness in horses, often necessitating innovative regenerative strategies to restore joint function and improve quality of life. This study investigated the effects of platelet-rich plasma (PRP), ozonized PRP, hyaluronic acid, paracetamol, and polyacrylamide hydrogel (NOLTREX^®) on the behavior of mesenchymal stem cells (MSCs) derived from equine synovial fluid. Synovial fluid samples were collected under strict cytological criteria to ensure viability, followed by in vitro expansion and phenotypic characterization of MSCs. Cultures were supplemented with the tested preparations, and cellular proliferation and viability were evaluated at 24 h, 72 h, and 7 days. PRP significantly promoted MSC proliferation in a time- and dose-dependent manner, with maximal effect at 10%. Hyaluronic acid stimulated growth, most pronounced at 1 mg/mL, while paracetamol induced a concentration-dependent proliferative response, strongest at 100 μg/mL. NOLTREX displayed a biphasic effect, initially inhibitory at high concentrations but stimulatory at 7 days. Ozonized PRP showed concentration-dependent redox activity, with lower doses maintaining viability and higher doses producing an initial suppression followed by delayed stimulation. Collectively, these findings support the therapeutic potential of PRP and related biologic preparations as intra-articular regenerative therapies in equine medicine, while underscoring the importance of dose optimization and standardized protocols to facilitate clinical translation. Full article

Osteoarthritis (OA) is one of the most common forms of arthritis and is commonly characterized by the breakdown of the hyaline cartilage and synovial fluid in joints. The body naturally responds by releasing proteins with specific functions to combat the degradation of the joint. The objective of the research undertaken in this study was to simulate a selection of these proteins from previous work in the literature to gather data on their energies. This was accomplished using the molecular dynamics software NAMD and VMD, in which each protein was simulated for 5 ps in water at three different temperatures. The simulations showed that at body temperature, orosomucoid-1 and complement component 4B had energies that stabilized significantly faster than the other proteins simulated, and alpha-2-macroglobulin had energies that stabilized significantly slower than the others. These outliers were further investigated by simulating them for 1 ns to reveal their molecular dynamics. Based on the data collected, it was proposed that the proteins that had faster stabilization times would be more stable biomarkers overall. Despite any limitations of the research performed, the novel work performed here provides a foundation for future work that could give clinical insight into the diagnosis and prognosis of individuals experiencing symptoms associated with osteoarthritis. Full article

N⁶-methyladenosine (m⁶A) has recently emerged as a post-transcriptional modulator governing cell-specific gene expression in innate immune cells, particularly in monocytes. Disruptions in m⁶A homeostasis, manifested as the altered expression of m⁶A-related proteins and m⁶A levels, have been implicated in autoimmune disorders. Perturbations in m⁶A dynamics within total Peripheral blood mononuclear cells (PBMCs) have shown strong correlations with disease severity in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It remains unclear in which specific cell type(s) m⁶A homeostasis is disturbed, and also whether other rheumatic diseases such as juvenile idiopathic arthritis (JIA) show similar features. Here, we assess the involvement of m⁶A and m⁶A-regulatory proteins in JIA monocytes. Notably, the diminished expression of m⁶A-eraser proteins FTO and ALKBH5 was observed in JIA monocytes extracted from the inflamed joint. This resulted in increased m⁶A-methylated transcripts in monocytes from these patients. Correspondingly, we observed that culturing monocytes in the presence of synovial fluid from JIA inflamed joints reduced the expression of both FTO and ALKBH5. The knock-out of FTO in human monocytes of healthy controls increased monocyte activation, indicating the relevance of FTO and m⁶A in the context of JIA. These findings underscore the potential of ALKBH5 and FTO expression as a biomarker in JIA and identify the m⁶A machinery as a potential therapeutic target for the treatment of JIA and possibly other autoimmune diseases in the future. Full article

Total joint arthroplasty (TJA) and total joint replacement (TJR) are effective treatments for end-stage osteoarthritis, but prosthetic joint infections (PJIs) remain a significant complication. These infections are often associated with bacteria that form biofilms, which contribute to their persistence and resistance to treatment. The aim of this study was to investigate the biofilm-forming ability, cyclic diguanylic acid (c-di-GMP) production, and the presence of biofilm-associated genes in Staphylococcus aureus and coagulase-negative Staphylococci (CoNS) isolates obtained from synovial fluid samples of patients with PJIs following TJA and TJR. A total of 198 samples were analyzed, with bacterial growth detected in 33 samples (16.7%). Among these, 10 strains of S. aureus and 22 strains of CoNS were identified. Biofilm formation was evaluated using the crystal violet assay, and c-di-GMP levels were measured. A statistically significant linear regression was found between biofilm formation and c-di-GMP production (p = 0.016, R² = 0.18). Genetic analysis revealed the presence of biofilm-associated genes, including icaA, clfA, fnbA in S. aureus, and atlE, fbe in CoNS. Furthermore, there was a statistically significant difference in c-di-GMP production between strains harboring the icaA gene and strains without icaA (p = 0.016), while oxacillin resistance was detected more frequently in strains carrying fbe gene (p = 0.031). The study emphasizes the variability in antibiotic resistance profiles among staphylococcal isolates, underscoring the complexity of managing these infections. Full article

Objective: Platelet-rich plasma (PRP) therapy has become a popular treatment for knee osteoarthritis. We aimed to determine the outcomes of knee osteoarthritis patients following PRP therapy using magnetic resonance imaging (MRI) findings and patient-reported outcome measures (PROMs). Design: In this retrospective observational cohort study, we enrolled 161 patients (221 knees) with varus knee osteoarthritis who received multiple PRP injections at our hospital from June 2017 to June 2019. Patients underwent whole-body MRI before and 6 months after treatment. Whole-organ MRI score (WORMS) cartilage integrity and synovial fluid volume were assessed for the medial femorotibial (MFTJ), lateral femorotibial (LFTJ), and patellofemoral joints (PFJ). Pain visual analog scale and Knee Injury and Osteoarthritis Outcome scores were used as PROMs. In addition, a historical control group of 30 patients with medial knee osteoarthritis who did not receive intra-articular injections was evaluated by MRI over the same period for comparison. Results: After 6 months of PRP therapy, the mean WORMS cartilage score of the LFTJ and PFJ and the total WORMS cartilage score for all three joints improved significantly, and synovial fluid volume reduced significantly. Moreover, a reduction in synovial fluid volume correlated with improvements in several KOOS subscales but not with VAS, which may explain the lack of association with responder status. These results suggest that synovial fluid reduction reflects functional improvement but is not a direct surrogate for pain relief. In addition, the change score of WORMS PFJ cartilage correlated positively with clinical outcomes in responders. By contrast, in the control group, no compartment demonstrated improvement in WORMS cartilage scores, and several compartments showed a trend toward deterioration. Conclusions: In this retrospective observational study, PRP therapy was associated with improvements in WORMS cartilage integrity scores and reductions in synovial fluid volume, with partial correlations to patient-reported outcomes. The inclusion of a historical control group strengthens the interpretation of these findings, although definitive conclusions cannot be drawn. Further randomized controlled trials are needed to confirm these preliminary observations. Full article

Osteoarthritis (OA) is a multifactorial chronic musculoskeletal disorder characterised by cartilage degradation, synovial inflammation, and subchondral bone remodelling. Conventional diagnostic modalities, including radiographic imaging and symptom-based assessments, primarily detect disease in its later stages, limiting the potential for timely intervention. Inflammatory biomarkers, particularly Interleukin-6 (IL-6), Tumour Necrosis Factor-alpha (TNF-α), and Myeloperoxidase (MPO), have emerged as biologically relevant indicators of disease activity, with potential applications as companion diagnostics in precision medicine. This review examines the diagnostic and prognostic relevance of IL-6, TNF-α, and MPO in OA, focusing on their mechanistic roles in inflammation and joint degeneration, particularly through the activity of fibroblast-like synoviocytes (FLSs). The influence of sample type (serum, plasma, synovial fluid) and analytical performance, including enzyme-linked immunosorbent assay (ELISA), is discussed in the context of biomarker detectability. Advanced statistical and computational methodologies, including rank-based analysis of covariance (ANCOVA), discriminant function analysis (DFA), and Cox proportional hazards modelling, are explored for their capacity to validate biomarker associations, adjust for demographic variability, and stratify patient risk. Further, the utility of synthetic data generation, hierarchical clustering, and dimensionality reduction techniques (e.g., t-distributed stochastic neighbour embedding) in addressing inter-individual variability and enhancing model generalisability is also examined. Collectively, this synthesis supports the integration of biomarker profiling with advanced analytical modelling to improve early OA detection, enable patient-specific classification, and inform the development of targeted therapeutic strategies. Full article

Synovitis resolution is critical for joint homeostasis and prevents the progression of osteoarthritis (OA). Treatments like NSAIDs and intra-articular corticosteroids relieve symptoms by blocking pro-inflammatory mediators, but also impair the production of pro-resolving mediators, contributing to the likelihood of chronic synovitis. PPARγ signaling is an essential mechanism of synovitis resolution, which is decreased in OA tissues. To evaluate the potential of PPARγ agonists to promote pro-resolving pathways, equine macrophages cultured in autologous, normal, or inflamed synovial fluid (n = 10 horses) were treated with pioglitazone, geraniol, or both. Treatments modulated patterns of gene expression, increasing the expression of early drivers of resolution RELB and IL6, followed by increased NRF2 and PPARGC1A expression. Concentrations of TNF-α in conditioned synovial fluid significantly decreased as an early response to treatment, while IL10 concentrations also declined over time, suggesting increased tolerance to inflammatory stimuli and decreased compensatory feedback. Using an equine model of synovitis, intra-articular delivery of pioglitazone (n = 3 horses) or geraniol (n = 4 horses) was associated with decreased markers of synovium inflammation (geraniol) and enhanced cartilage proteoglycan preservation (geraniol and pioglitazone). In this small cohort of horses, no systemic or articular side effects were observed. Further studies optimizing treatment doses and regimens for intra-articular PPARγ agonism as a pro-resolving OA therapy are warranted. Full article

Background and Objectives: Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, and progressive arthritis is its primary clinical manifestation. The role of human parvovirus B19 (B19V) infection in the progression of RA remains unclear. This study aims to investigate the association between B19V infection and viral genetic distribution in Vietnamese RA patients. Materials and Methods: 115 Vietnamese RA patients and 86 healthy controls (HCs) were enrolled in this observational study at the Thai Nguyen National Hospital from January 2019 to December 2021. B19V DNA was examined in serum and synovial fluid samples from RA patients using nested PCR and real-time PCR. B19V antibodies were detected in serum samples using ELISA. Results: B19V DNA was detected in the serum of 2 out of 115 (1.74%) RA patients but not in any HCs. Interestingly, B19V DNA was present in 12 out of 68 (17.65%) RA patients with knee effusion in their synovial fluid. Anti-B19V-IgG and anti-B19V-IgM were detected in the serum of 42.61% and 2.61% of RA patients, respectively, and in 24.42% and 12.79% of HCs, respectively. Anti-B19V-IgG levels were significantly higher in the serum of RA patients than in the serum of HCs (p = 0.007). However, anti-B19V-IgM was more commonly detected in HC serum than in RA patient serum (p = 0.006). Phylogenetic analysis showed that all B19V strains belonged to genotype 1 and subgenotype 1A. Conclusions: B19V infection is frequent in RA patients and suggests a contribution of B19V to the progression of RA, particularly in a B19V genotype-1- and subgenotype-1A-dependent manner and emphasises the need for early detection and management of B19V infection in RA patients. Full article