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Morphometric analysis of synovial membrane blood vessels in rheumatoid arthritis: associations with the immunohistologic features, synovial fluid cytokine levels and the clinical course.

The morphologic characteristics of the endothelial cells lining postcapillary venules are cytokine dependent and critical in facilitating the infiltration of mononuclear cells into synovial membrane in rheumatoid arthritis (RA). We determined the relationships between endothelial cell (EC) tallness, mononuclear cell infiltration and synovial fluid levels of interleukin 1 beta (IL-1 beta) and interleukin 6 (IL-6) at different stages of RA. EC tallness was greatest in synovial tissues obtained by needle biopsy of the knee joints from 18 patients with active RA who had never received disease modifying drugs (Group 1) (p = 0.000001 versus controls). EC tallness in tissues obtained from 18 patients with advanced disease undergoing knee arthroplasty (Group 2) was greater than controls (p = 0.001) only when vessels located in focal lymphoid aggregates were considered. Vascular proliferation was noted in both groups. Synovial fluid IL-6 levels were greatest in Group 1. IL-1 beta levels were greatest in Group 2. The total numbers of infiltrating mononuclear cells and the clinical measures of disease activity were similar in both groups. The differences in EC characteristics at different stages of RA suggest changing pathogenic mechanisms as disease progresses. Disease modifying antirheumatic drugs may contribute to the findings observed.

Anti-Inflammatory Agents↗

Limulus assay for bacterial endotoxin in synovial fluid.

The limulus assay for the detection of bacterial endotoxin has been applied to the study of synovial fluid. Three of 5 patients (60%) with culture-positive gonococcal arthritis had positive SF limulus assay results; as did 2 of 11 (18%) with presumptive evidence of gonococcal arthritis, 3 of 6 (50%) with nongonococcal infectious arthritis, and none of 47 patients with noninfectious arthritis. Endotoxin levels ranged from 0.25 to 128.0 ng/ml. As at present applied to synovial fluid the commercial limulus assay appears to be specific for the infectious process but apparently lacks sensitivity.

Arthritis↗

[Substance P in synovial fluid in patients with temporomandibular joint dysfunction syndrome].

Radioimmunoassay technique was used to measure substance P levels in synovial fluid samples from thirty patients with temporomandibular joint dysfunction syndrome (TMJDS). Twenty-four samples (80%) were found to have substance P. Concentrations of substance P in the synovial fluid from patients with painful TMJDS were higher than those patients without pain (P < 0.05). The study supported the evidence for the secondary synovitis in painful TMJDS, and suggested that the nervous system play a role in the pathophysiology of TMJDS.

Adolescent↗

Relations among synovial membrane histopathologic findings, synovial fluid cytologic findings, and bacterial culture results in horses with suspected infectious arthritis: 64 cases (1979-1987).

A retrospective evaluation of 64 cases of suspected infectious arthritis in horses was undertaken to determine the relations among histopathologic findings in synovial membrane specimens, cytologic findings in synovial fluid samples, and bacterial culture results. Positive cultures were obtained from 55% of the joints, and 18 different bacterial organisms were cultured. Culturing of synovial fluid yielded bacterial growth more often than did culturing of synovial membrane. Histologic evaluation (H&E and Gram stain) of synovial membrane specimens provided little information to help distinguish infected from culture-negative joints. We do not advocate the routine use of closed synovial biopsy in suspected cases of equine septic arthritis.

Animals↗

Yersinia-specific antibodies in serum and synovial fluid in patients with Yersinia triggered reactive arthritis.

OBJECTIVES: To further evaluate the role of bacterial antigens in triggering inflammation in the joint in patients with reactive arthritis by studying local antibody synthesis in the joint. METHODS: Yersinia-specific antibodies in paired serum and synovial fluid samples from 29 patients with yersinia triggered reactive arthritis were studied using an enzyme linked immunosorbent assay (ELISA), an inhibition ELISA with six monoclonal antibodies against lipopolysaccharide or released proteins of yersinia and immunoblotting. Antibodies of IgM, IgG and IgA classes, as well as antibodies of IgA subclasses and those containing secretory component were measured against the lipopolysaccharide and the sodium dodecyl sulphate extract of whole Yersinia enterocolitica O:3 bacteria. RESULTS: It was shown that yersinia-specific antibodies, as well as antibodies against other microbial antigens (rubella, measles, Bordetella pertussis, tetanus toxoid and Candida albicans) in synovial fluid mirror those in serum by concentration, by specificity and by distribution in classes and subclasses. CONCLUSION: These results do not suggest any strong local antibody production, but indicate that the majority of yersinia antibodies in the synovial fluid are derived from the circulation.

Adolescent↗

A comparative study on the rate of de-esterification of dexamethasone phosphate and dexamethasone sulfate in synovial fluids.

Considering the importance of the 21-OH group in promoting the anti-inflammatory activity of the steroids, it is possible that differences in the rate of hydrolysis of steroid esters may influence the potency of pharmacological activity of the steroids (Polley and Mason, 1950, Goldfien, et al., 1955). In the present paper the rate of de-esterification of the steroid esters in human synovial fluids was studied in vitro. Hydrolytic rates of dexamethasone-21-sulfate (DS) and dexamethasone-21-phosphate (DP) in synovial fluids aspirated from the knee joint of 10 patients each with rheumatoid arthritis and osteoarthritis of the knee measured by radioimmunoassay. DP was hydrolyzed to the extent of 10%, 30%, 50%, 80% after incubation for 1, 3, 6, 24 hours respectively. On the other hand, DS was hydrolyzed to the extent of less than 10% even after incubation for 24 hours. The difference between the rate of de-esterification of DP and DS for each period was statistically highly significant (p less than 0.001). These results suggest that DP is hydrolyzed in synovial fluids much faster than DS and converted into free dexamethasone which may exhibit a powerful anti-inflammatory action.

Arthritis, Rheumatoid↗

Reduction of prostaglandin E2 concentrations in synovial fluid of patients suffering from rheumatoid arthritis following tiaprofenic acid or indomethacin treatment.

Prostaglandin E2 (PGE2) is a potent stimulator of inflammation, and the inhibition of its synthesis is one possible mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs). We have investigated patients suffering from rheumatoid arthritis to determine how synovial fluid levels of PGE2 are affected by tiaprofenic acid or indomethacin medication. Ten patients suffering from rheumatoid arthritis were studied, with 5 patients receiving tiaprofenic acid and 5 indomethacin for a 1-week period. Synovial fluid and serum samples were collected over an 8-hour period on days 1 and 8; these were then assayed for PGE2 and active drug concentrations. The concentration of PGE2 in the synovial fluid fell consistently as the concentration of each drug rose, and low levels of PGE2 persisted on continuation of the medication. Tiaprofenic acid appeared to cause a faster onset of inhibition of PGE2 synthesis than indomethacin.

Adult↗

Healing of ligaments in synovial fluid. An experimental study in rabbits.

To investigate the importance of nutritive environment in the healing of reconstructed ligaments, the morphology of sutured free patellar ligaments in synovial fluid of the contralateral knee joint, without re-establishment of microcirculation, was studied in rabbits. After two weeks (n = 6) and one (n = 6) and three (n = 5) months, the sutured ligament was removed from the joint and fibroblasts were seen growing into the suture gap. The ligaments were enveloped in a capsule of fibroblasts, which was more developed in those ligaments that were studied three months after operation. The collagen of the piece of ligament was disorganised at all time points, and tensile strength (n = 6) was low compared with non-sutured patellar ligament. Some ligaments disappeared or were partly attached to the synovial membrane and revascularised. The findings indicate that diffusion of nutrients may be important for the survival and healing of reconstructed ligaments, as the ligaments can heal in synovial fluid without re-establishment of the microcirculation.

Animals↗

Polyamine levels in synovial tissues and synovial fluids of patients with rheumatoid arthritis.

We determined the polyamine contents of the synovial tissues from 11 patients with rheumatoid arthritis (RA), and the free putrescine levels in the synovial fluids (SF) from 10 patients with RA, 7 with osteoarthritis (OA), 5 with posttraumatic arthritis, and 3 with infectious arthritis. Putrescine levels in the synovial tissues correlated with serum C reactive protein concentration in patients with RA. Free putrescine levels in SF were significantly elevated in patients with infectious arthritis, compared with those found in RA, OA, and posttraumatic arthritis. Free putrescine levels in SF from patients with RA were significantly higher than in those with OA. Our findings suggest that polyamines may play an important role in RA.

Adult↗

Type II collagen-immune complex arthritis in sheep: collagen antibodies in serum, synovial fluid and afferent lymph.

Type II native bovine collagen was used to induce arthritis in sheep. The sheep received a subcutaneous injection of collagen in Freund's adjuvant, and some sheep also received an intra-articular injection of collagen. The response to the collagen injections was monitored by measurement of antibody levels to bovine and ovine collagen in serum, synovial fluid and afferent lymph samples. There were antibodies in the normal sheep serum which reacted with native and denatured type II collagen, but there was a marked rise in serum and synovial fluid reactivity after subcutaneous injection of native collagen. In these sensitised sheep there was a further rise in antibody levels in the synovial fluid and afferent lymph samples after an intra-articular injection of collagen. There was little effect on antibody levels in the non-injected contralateral limb. Histological and immunohistochemical studies showed that the rise in antibody levels was associated with pathological changes to the synovium which were consistent with the development of arthritis. These changes were most severe in those joints of sensitized sheep which had received an intra-articular injection of collagen and were characterized by increased numbers of T cells in the synovial tissue, mainly of the CD4 phenotype. There was a marked increase in B cell expression by cells on the surface of the synovial intima, and accumulations of B and T cells were seen in the subsynovial tissues. Collagen-immune complex arthritis in sheep appears to be a useful large animal model of arthritis, with significant similarities to the arthropathies of other species, including man.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

The natural history of the anterior cruciate ligament-deficient knee. Changes in synovial fluid cytokine and keratan sulfate concentrations.

Restoring knee stability through reconstruction, while providing symptomatic relief, has not been shown to decrease the incidence of degenerative changes after rupture of the anterior cruciate ligament. This suggests that posttraumatic osteoarthritis may not be purely biomechanical in origin, but also biochemical. To test this, we measured the levels of seven cytokine modulators of cartilage metabolism in knee joint synovial fluid after anterior cruciate ligament rupture. We also measured keratan sulfate, a product of articular cartilage catabolism. The sample population consisted of patients with uninjured knee joints (N = 10), and patients with acute (N = 60), subacute (N = 18), and chronic (N = 8) anterior cruciate ligament-deficient knees. Synovial fluid samples were analyzed by enzyme-linked immunosorbent assays. Normal synovial fluids contained high levels of the interleukin-1 receptor antagonist but low concentrations of other cytokines. Immediately after ligament rupture there were large increases in interleukins 6 and 8, tumor necrosis factor alpha, and keratan sulfate. Interleukin-1 levels remained low throughout the course. As the injury became subacute and then chronic, interleukin-6, tumor necrosis factor-alpha, and keratan sulfate levels fell but remained considerably elevated 3 months after injury. Concentrations of interleukin-1Ra fell dramatically. Granulocyte-macrophage colony-stimulating factor concentrations were normal acutely and subacutely but by 3 months after injury were elevated 10-fold. Our data reveal a persistent and evolving disturbance in cytokine and keratan sulfate profiles within the anterior cruciate ligament-deficient knee, suggesting an important biochemical dimension to the development of osteoarthritis there.

Adolescent↗

Quantification of hemostatic proteins and activation products in synovial fluids from arthritic joints prior to and after induction of chemical synoviorthesis.

Synovial fluids drawn from joints of patients suffering from rheumatoid arthritis were investigated for their concentrations of proteins and activation markers of the complement, coagulation and fibrinolytic systems. A broad spectrum of plasmatic inhibitors and other hemostatic proteins were detectable by immunologic assays. Compared to normal plasma concentration ranges, levels of alpha 2-antiplasmin, antithrombin III, heparin-cofactor II, factor H, alpha 2-macroglobulin, inter-alpha-trypsin inhibitor, fibrinogen and particularly high molecular weight kininogen were found to be decreased when corrected for total protein content. However, highly elevated levels of C-reactive protein, factor XIII, PMN-elastase, prothrombin fragment F1+2, thrombin-antithrombin III, plasmin-antiplasmin and terminal complement-complexes as well as C5a were determined. Eight and 24 hours after induction of chemical synoviorthesis, a general increase in most of the parameters was observed. Statistically significant alterations were found for C1-inhibitor, factor H, alpha 1-antitrypsin, inter-alpha-trypsin inhibitor, factor XIII, protein C, thrombin-antithrombin III complexes and C5a.

Arthritis, Rheumatoid↗

Surface fissures in articular cartilage: effect of pathological changes in synovial fluid.

OBJECTIVE: A unified mathematical model of two different modes of inception of fissures at the surface of articular cartilage in healthy and pathological joints. DESIGN: The superficial tangential zone of articular cartilage is modeled as a three-phase medium consisting of collagen fibers, matrix, and of infiltrated thin constituent of synovial fluid. BACKGROUND: The author's general mesomechanical concept is applied to the analysis of deterioration of articular cartilage. METHODS: Theoretical analysis based on the results of the author's preceding paper. RESULTS: The presented analysis shows that superficial fissures in articular cartilage can also be caused by pathological thinning of synovial fluid. CONCLUSIONS: Whereas in healthy joints the probable cause of creation of fissures at the surface of cartilage was shown to be fast impact loading, in joints with inflammatory synovial fluid the fissures can be caused by plain walking. RELEVANCE: Appearance of surface fissures in articular cartilage is a serious, still not fully clarified problem that deserves attention.

Cartilage, Articular↗

Septic arthritis caused by Granulicatella adiacens: diagnosis by inoculation of synovial fluid into blood culture bottles.

Granulicatella species, formerly known as nutritionally variant streptococci, cause a variety of infections, primarily endocarditis. We report the first culture-proven case of a Granulicatella species causing septic arthritis. A 68-year-old female presented with knee pain and swelling. She was initially evaluated with arthrocentesis and arthroscopy, but no organism was identified. Her pain improved after a brief course of antibiotics but recurred 3 months later. She underwent repeat arthrocentesis, with direct inoculation of synovial fluid into blood culture bottles. Granulicatella adiacens was recovered from both bottles. She was treated with cefazolin for 4 weeks combined with gentamicin for the first 2 weeks. Her knee pain and swelling resolved without evidence of recurrence. Granulicatella should be considered in cases of septic arthritis with initially negative synovial fluid cultures. Inoculation of blood cultures bottles with synovial fluid may increase the diagnostic yield for these species.

Aged↗

Concentration and molecular weight of sodium hyaluronate in synovial fluid from patients with rheumatoid arthritis and other arthropathies.

The molecular weight distribution of hyaluronate (HA) in synovial fluid (SF) from 10 patients with rheumatoid arthritis (RA), from six patients with other joint disorders, and from five recently deceased persons without joint affections was investigated by a gel chromatographic procedure. A new and highly specific radioassay was used for determination of the HA concentration in the effluent from the chromatographic column, and this allowed analyses on 0.5 ml or less of untreated synovial fluid. The results confirmed the findings by others that the weight-average molecular weight (Mw) of HA in SF from patients with RA (4.8 X 10(6)) was similar to that in other joint diseases (5.0 X 10(6)) and moderately but significantly (p less than 0.001) lower than that of normal SF (7.0 X 10(6)). Furthermore, the molecular weight distribution of HA in the pathological SF was generally broad and varied considerably between individuals. The HA concentration in the pathological SF varied between 0.17 and 1.32 g/l, which is in accordance with previous reports and considerably lower than that of normal SF. Neither the nature of the arthropathy and the extent of the inflammatory process nor the pharmacological treatment had a tendency to influence the HA concentration in the SF, the mean molecular weight of HA, or its molecular weight distribution. Although the concentration of HA in SF drops in joint disease, the total amount of the polysaccharide is greatly enhanced. Also the amount of high molecular weight polysaccharide (Mw greater than 6 X 10(6)) is in excess in joint disease. The pathological state is therefore characterised not by lack of high molecular weight hyaluronate but by a dilution of it.

Adult↗

Limited heterogeneity of rearranged T cell receptor V alpha and V beta transcripts in synovial fluid T cells in early stages of rheumatoid arthritis.

OBJECTIVE: The identification of activated T cells in synovial fluid and synovium, and the association of rheumatoid arthritis (RA) with specific HLA-DR restriction elements, strongly suggest that these T cells play a critical role in the etiology and pathogenesis of RA. Analysis of the T cell receptor (TCR) repertoire in the early stages of RA might be an approach to identify those T cells involved in the initiation and/or perpetuation of the disease. METHODS: TCR V alpha and V beta transcripts of synovial T cells, sampled at the early stages of RA, were amplified by reverse transcriptase-polymerase chain reaction. HLA-DR subtyping was determined by serologic analysis and dot-blot hybridization of polymerase chain reaction amplification products using digoxigenin-labeled, sequence-specific oligonucleotide probes. RESULTS: Our findings showed a limited heterogeneity of V alpha and V beta TCRs in synovial fluid T cells, and a preferential usage of TCR V alpha 17 in early RA. In contrast, in the later stages of RA, a more polyclonal TCR V alpha and V beta gene usage was observed. CONCLUSION: Our results support the view that induction of RA is driven by an oligoclonal immune response to an unknown antigen. These findings also suggest a pathogenetic role for V alpha 17 T cells in the early stages of RA.

Adult↗

Quantification of protease activities in synovial fluid from rheumatoid and osteoarthritis cases: comparison with antioxidant and free radical damage markers.

We have compared (using the same series of experimental samples) the levels of activity of a comprehensive range of cytoplasmic, lysosomal and matrix protease types, together with the levels of free radical-induced protein damage (determined as protein carbonyl derivative) in synovial fluid from rheumatoid (RA) and osteoarthritis (OA) cases. Many protease types showed significantly increased activity (typically by a factor of 2-3-fold) in RA compared to OA cases. Protease activity levels (including those enzyme types putatively involved in the immune response, such as dipeptidyl aminopeptidase IV) in plasma were not significantly different in RA and control cases. The level of free radical induced damage to synovial fluid proteins was approximately 2-fold higher in RA compared to OA, although there was no significant difference in total antioxidant status in synovial fluid or plasma between RA, OA or control cases. We conclude from the above that activation of proteolytic enzymes and free radicals (occurring specifically within synovial tissues) are likely to be of equal potential importance as protein damaging agents in the pathogenesis of RA, and the development of novel therapeutic strategies for the latter disorder should include both protease inhibitory and free radical scavenging elements. In addition, the protease inhibitory element should be designed to inhibit the action of a broad range of enzymic mechanistic types (cysteine, serine, metallo proteinases and peptidases).

Antioxidants↗

[The role of Salmonella and Yersinia in the pathogenesis of spondyloarthropathies and rheumatoid arthritis. I. Detection of bacteria, bacterial DNA, lipopolysaccharide and ECA antigen in synovial fluid or blood].

To investigate the role of Salmonella and Yersinia in the pathogenesis of spondyloarthropathies and rheumatoid arthritis synovial specimens from 92 patients were analysed for the presence of bacterial DNA with the use of polymerase chain reaction and for the presence of lipopolysaccharide and enterobacterial common antigen (ECA) with the use of Dot-ELISA. In addition, peripheral blood samples were available for PCR analysis from 68 patients. Salmonella and Yersinia chromosomal DNA was not found in any of the synovial specimens and blood samples from the patients. All of the synovial fluids were also culture-negative. Salmonella LPS antigens were observed in 8 (8.6%), Yersinia in 20 (21.7%) and ECA antigens in 32 (34.9%) synovial specimens. Our findings revealed the presence of bacterial degradation products, but not bacteria from the genus Salmonella and Yersinia or their DNA in the synovial fluid or blood of patients with spondyloarthropathies and rheumatoid arthritis.

Antigens, Bacterial↗