Per Swärd

Risk factors for a contralateral anterior cruciate ligament injury.

Contralateral anterior cruciate ligament (ACL) injuries are together with the risk of developing osteoarthritis of the knee and the risk of re-rupture/graft failure important aspects to consider after an ACL injury. The aim of this review was to perform a critical analysis of the literature on the risk factors associated with a contralateral ACL injury. A better understanding of these risk factors will help in the treatment of patients with unilateral ACL injuries and in the development of interventions designed to prevent contralateral ACL injuries. A Medline search was conducted to find studies investigating risk factors for a contralateral ACL injury, as well as studies where a contralateral ACL injury was the outcome of the study. Twenty studies describing the risk of a contralateral ACL rupture, or specific risk factors for a contralateral ACL injury, were found and systematically reviewed. In 13 of these studies, patients were followed prospectively after a unilateral ACL injury. The evidence presented in the literature shows that the risk of sustaining a contralateral ACL injury is greater than the risk of sustaining a first time ACL injury. Return to a high activity level after a unilateral ACL injury was the most important risk factor of sustaining a contralateral ACL injury. There was inconclusive evidence of the relevance of factors such as female gender, family history of ACL injuries, and a narrow intercondylar notch, as risk factors for a contralateral ACL injury. Risk factors acquired secondary to the ACL injury, such as altered biomechanics and altered neuromuscular function, affecting both the injured and the contralateral leg, most likely, further increase the risk of a contralateral ACL injury. This literature review indicates that the increased risk of sustaining a contralateral ACL injury should be contemplated, when considering the return to a high level of activity after an ACL injury.

Acute and sustained actions of hyperglycaemia on endothelial and glomerular barrier permeability

Microalbuminuria is an established marker of systemic endothelial dysfunction, which for patients with diabetes signals an increased risk of both diabetic nephropathy and cardiovascular complications. A better understanding of the pathogenesis of microalbuminuria is important in the quest of finding new approaches to treat patients with diabetes. Direct acute effects of episodes of hyperglycaemia (HG) could have implications for the microalbuminuria seen in early diabetes before renal structural alterations have started, especially in those patients with poor glycaemic control. This review summarizes the literature evidence that acute or sustained HG may lead to an increased vascular or glomerular permeability. Special focus is on glomerular barrier permeability. There is evidence in the literature that HG increases systemic capillary and glomerular barrier permeability within 20–30 min in vivo in rats and mice. Furthermore, exposure of monolayers of cultured endothelial cells to HG has been shown to increase monolayer permeability rapidly and transiently (during 60–100 min). Instant cellular changes following F‐actin cytoskeleton rearrangements, which could be abrogated by Rho‐kinase (ROCK) inhibition, are implicated. Data in this review also suggest that activation of protein kinase C, the polyol pathway, and an increased release of reactive oxygen species (ROS) and cytokines could contribute to the increase in barrier permeability induced by HG. Recent in vitro data from cultured podocyte monolayers also designates a role of insulin in acute podocyte F‐actin remodelling, underpinning the complexity of the mechanisms leading to glomerular and endothelial barrier alterations in diabetes mellitus.

Effects of early endotoxemia and dextran-induced anaphylaxis on the size selectivity of the glomerular filtration barrier in rats

This study was performed to investigate the glomerular permeability alterations responsible for the microalbuminuria occurring in endotoxemia and during anaphylactic shock. In anesthetized Wistar rats, the left ureter was catheterized for urine collection while, simultaneously, blood access was achieved. Endotoxemia was induced by lipopolysaccharide (LPS) from Escherichia coli, and glomerular permeability was assessed at 60 and 90 (n = 7) and 120 (n = 7) min. Anaphylaxis was induced by a bolus dose of Dextran-70, and glomerular permeability assessed at 5 min (n = 8) and 40 min (n = 9). Sham animals were followed for either 5 or 120 min. The glomerular sieving coefficients (theta) to fluorescein isothiocyanate-Ficoll (70/400) were determined from plasma and urine samples and assessed using size-exclusion chromatography (HPLC). After start of the LPS infusion (2 h), but not at 60 or 90 min, theta for Ficoll(70A) had increased markedly [from 2.91 x 10(-5) +/- 6.33 x 10(-6) to 7.78 x 10(-5) +/- 6.21 x 10(-6) (P < 0.001)]. In anaphylaxis, there was a large increase in theta for Ficolls >60 A in molecular radius already at 5 min, but the glomerular permeability was completely restored at 40 min. In conclusion, there was a transient, immediate increment of glomerular permeability in dextran-induced anaphylaxis, which was completely reversible within 40 min. By contrast, endotoxemia caused an increase in glomerular permeability that was manifest first after 2 h. In both cases, theta to large Ficoll molecules were markedly increased, reflecting an increase in the number of large pores in the glomerular filter.

Soft Tissue Knee Injury With Concomitant Osteochondral Fracture Is Associated With Higher Degree of Acute Joint Inflammation

Background: Osteochondral fractures are often seen on magnetic resonance imaging (MRI) of acutely injured knees, but their existence has gained little interest because of a lack of knowledge of their relation to treatment options and outcome. It is not clear whether acute phase synovial fluid (SF) concentrations of cartilage and bone markers and proinflammatory cytokines are different between traumatically injured knees with or without osteochondral fracture. Hypothesis: Acutely injured knees with an osteochondral fracture, particularly fractures with disrupted cortical bone, have higher concentrations of bone markers and cytokines than do knees without an osteochondral fracture. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Synovial fluid (hemarthrosis) was aspirated (median 1 day after injury) and 1.5-T MRI was performed (median 8 days after injury) in the acutely injured knee of 98 individuals (26% women; mean age, 23 years). As visualized on MRI, 39% knees had an osteochondral fracture with disrupted cortical bone, 30% had an osteochondral fracture with intact cortical bone, and 32% did not have an osteochondral fracture. Concentrations of sulfated glycosaminoglycan, ARGS aggrecan, cartilage oligomeric matrix protein, osteocalcin, secreted protein acidic and rich in cysteine (SPARC), osteopontin and proinflammatory cytokines (interleukin [IL]–1β, IL-6, IL-8, and tumor necrosis factor [TNF]–α) were analyzed. Results: After adjusting for days between injury and SF aspiration, age at injury, and sex, knees with any osteochondral fracture (with or without disrupted cortical bone) had significantly higher SF concentrations of TNF-α (median [interquartile range (IQR)] = 9 [7-12] pg/mL vs 7 [5-14] pg/mL; P = .013), whereas knees with an osteochondral fracture with disrupted cortical bone had significantly higher SF concentrations (medians [IQRs]) of SPARC (492 [328-754] ng/mL vs 407 [140-685] ng/mL; P = .030), IL-8 (278 [148-628] pg/mL vs 138 [67-413] pg/mL; P = .028), and TNF-α (11 [7-15] pg/mL vs 7 [5-14] pg/mL; P = .004) compared with knees without an osteochondral fracture. Conclusion: In acutely injured knees with hemarthrosis, a concomitant osteochondral fracture with disrupted cortical bone is associated with a higher degree of joint inflammation.

Type II collagen C2C epitope in human synovial fluid and serum after knee injury – associations with molecular and structural markers of injury

PURPOSE Investigate in a cross-sectional study time-dependent changes of synovial fluid type II collagen epitope C2C concentrations after knee injury and correlate to other joint injury biomarkers. METHODS Synovial fluid samples were aspirated between 0 days and 7 years after injury (n = 235). Serum was collected from 71 of the knee injured patients. Synovial fluid from 8 knee-healthy subjects was used as reference. C2C was quantified by immunoassay and structural injury was determined from magnetic resonance images (MRI) of the injured knee acquired 1-38 days after injury (n = 98). Additional joint injury biomarker results were from earlier investigations of the same samples. RESULTS Synovial fluid C2C concentrations were higher in injured knees than in knees of reference subjects from 1 day up to 7 years after injury. C2C concentrations in synovial fluid and serum were correlated (r = 0.403, P < 0.001). In synovial fluid from subjects early after injury (0-33 days), C2C concentrations were correlated with cross-linked C-telopeptide of type II collagen (r = 0.444, P = 0.003), ARGS-aggrecan (r = 0.337, P < 0.001), osteocalcin (r = 0.345, P < 0.001), osteopontin (r = 0.371, P < 0.001) and IL-8 (r = -0.385, P < 0.001), but not with structural joint injury as visualized on MRI. CONCLUSION The increased levels of synovial fluid C2C after injury, together with the associations seen with several other injury-related biomarkers, suggest that an acute knee injury is associated with an immediate and sustained local degradation of type II collagen.

The complement system is activated in synovial fluid from subjects with knee injury and from patients with osteoarthritis.

BackgroundThe complement system is suggested to be involved in the pathogenesis of osteoarthritis (OA), and proinflammatory cytokines may play a role in OA development by inducing proteases. The association between complement factors, cytokines and OA has not been investigated. The aim of the present study was to explore the involvement of the complement system after knee trauma and in OA.MethodsC4d, C3bBbP and soluble terminal complement complex (sTCC) resulting from complement activation were immunoassayed in synovial fluid from subjects with healthy knees (reference), OA, rheumatoid arthritis (RA; positive control), pyrophosphate arthritis (PPA; positive control) and knee injury; other biomarkers were previously assessed. Magnetic resonance imaging was used to assess joint injuries.ResultsCompared with levels in the reference group, the median concentrations of C4d, C3bBbP and sTCC in the OA, RA, PPA and knee injury groups were 2- to 34-fold increased (p < 0.001 to p = 0.044). For the knee injury group, the median concentrations of C4d, C3bBbP and sTCC were 5- to 12-fold increased (p < 0.001) at the day of injury; after 3–12 weeks, C3bBbP and sTCC concentrations were similar to reference levels; and C4d was still increased several years after injury. In the 0–12 weeks period after injury, the concentrations of C4d, C3bBbP and sTCC correlated positively with levels of interleukin (IL)-1β, IL-6 and tumour necrosis factor α (rs range 0.232–0.547); none of the measured complement factors correlated with proteolytic fragments of aggrecan or cartilage oligomeric matrix protein. Knees with osteochondral fracture, with or without disrupted cortical bone, had higher concentrations of C4d (p = 0.014, p = 0.004) and sTCC (p = 0.004, p < 0.001) compared with knees without fractures.ConclusionsThe complement system is activated in OA and after knee injury. Following knee injury, this activation is instant and associated with inflammation as well as with the presence of osteochondral fractures.

Imaging following acute knee trauma.

Joint injury has been recognized as a potent risk factor for the onset of osteoarthritis. The vast majority of studies using imaging technology for longitudinal assessment of patients following joint injury have focused on the injured knee joint, specifically in patients with anterior cruciate ligament injury and meniscus tears where a high risk for rapid onset of post-traumatic osteoarthritis is well known. Although there are many imaging modalities under constant development, magnetic resonance (MR) imaging is the most important instrument for longitudinal monitoring after joint injury. MR imaging is sensitive for detecting early cartilage degeneration and can evaluate other joint structures including the menisci, bone marrow, tendons, and ligaments which can be sources of pain following acute injury. In this review, focusing on imaging following acute knee trauma, several studies were identified with promising short-term results of osseous and soft tissue changes after joint injury. However, studies connecting these promising short-term results to the development of osteoarthritis were limited which is likely due to the long follow-up periods needed to document the radiographic and clinical onset of the disease. Thus, it is recommended that additional high quality longitudinal studies with extended follow-up periods be performed to further investigate the long-term consequences of the early osseous and soft tissue changes identified on MR imaging after acute knee trauma.

Plasma pro-inflammatory cytokines, IgM-uria and cardiovascular events in patients with chest pain: A comparative study.

Background. Risk stratification of patients presenting with acute chest pain is crucial for immediate and long-term management. Traditional predictors are suboptimal; therefore inflammatory biomarkers are studied for clinical assessment of patients at risk. Recently, we reported the association of IgM-uria with worse cardiovascular outcome in patients with acute chest pain. In this study, in the same cohort of patients with chest pain, we compared the value of IgM-uria to pro-inflammatory cytokines in predicting the occurrence of subsequent cardiovascular events. Methods. A total of 178 consecutive patients presenting with acute chest pain to the emergency department at the University Hospital of Lund, were recruited. Twenty-seven of 57 patients with acute coronary syndrome (ACS), and 18 of 118 patients with non-specific chest pain at baseline developed a subsequent major cardiovascular event during the 18 months follow-up. Urinary proteins (IgM-uria and Microalbuminuria) and plasma inflammatory markers (IL-6, Il-8, IL-10, IFN-γ and TNF-α) were measured at time of admission. Results. Using the receiver operating characteristic curves, the area under the curve for predicting cardiovascular events was 0.71 (95%CI 0.61–0.81) for IgM-uria, 0.61 (95%CI 0.51–0.71) for IL-6, 0.63 (95%CI 0.53–0.72) for IL-8, 0.65 (95%CI 0.56–0.74) for IL-10, and 0.64 (95% CI 0.54–0.74) for TNF-α. In multivariate Cox-regression analysis adjusted for age, microalbuminuria, IgM-uria, IL-10, TNF-α, troponin T, hsCRP and ACS at baseline; IgM-uria was the only biomarker that remained an independent predictor of outcome (HR = 4.2, 95%CI 2.2–7.8, p < 0.001). Conclusion. In patients with chest pain with or without acute coronary syndrome, IgM-uria could better predict the occurrence of cardiovascular events than plasma pro-inflammatory cytokines.

Coculture of bovine cartilage with synovium and fibrous joint capsule increases aggrecanase and matrix metalloproteinase activity

BackgroundA hallmark of osteoarthritis is increased proteolytic cleavage of aggrecan. Cross talk between cartilage and the synovium + joint capsule (SJC) can drive cartilage degradation by activating proteases in both tissues. We investigated aggrecan proteolysis patterns in cartilage explants using a physiologically relevant explant model of joint injury combining cartilage mechanical compression and coincubation with SJC.MethodsBovine cartilage explants were untreated; coincubated with SJC; or subjected to mechanical injury and coincubated with SJC, mechanical injury alone, or mechanical injury and incubated with tumor necrosis factor-α (TNF-α). To compare the patterns of aggrecan proteolysis between 6 h and 16 days, release of sulfated glycosaminoglycans and specific proteolytic aggrecan fragments into medium or remaining in cartilage explants was measured by dimethylmethylene blue and Western blot analysis.ResultsAggrecanase activity toward aggrecan was observed in all conditions, but it was directed toward the TEGE↓ARGS interglobular domain (IGD) site only when cartilage was coincubated with SJC or TNF-α. Matrix metalloproteinase (MMP) activity at the aggrecan IGD site (IPES↓FFGV) was not detected when cartilage was exposed to TNF-α (up to 6 days), but it was in all other conditions. Compared with when bovine cartilage was left untreated or subjected to mechanical injury alone, additional aggrecan fragment types were released into medium and proteolysis of aggrecan started at an earlier time when SJC was present.ConclusionsIndicative of different proteolytic pathways for aggrecan degradation, the SJC increases both aggrecanase and MMP activity toward aggrecan, whereas TNF-α inhibits MMP activity against the IGD of aggrecan.