ADAM-17 Activity and Its Relation to ACE2: Implications for Severe COVID-19.

There is a lack of studies aiming to assess cellular a disintegrin and metalloproteinase-17 (ADAM-17) activity in COVID-19 patients and the eventual associations with the shedding of membrane-bound angiotensin-converting enzyme 2 (mACE2). In addition, studies that investigate the relationship between ACE2 and ADAM-17 gene expressions in organs infected by SARS-CoV-2 are lacking. We used data from the Massachusetts general hospital COVID-19 study (306 COVID-19 patients and 78 symptomatic controls) to investigate the association between plasma levels of 33 different ADAM-17 substrates and COVID-19 severity and mortality. As a surrogate of cellular ADAM-17 activity, an ADAM-17 substrate score was calculated. The associations between soluble ACE2 (sACE2) and the ADAM-17 substrate score, renin, key inflammatory markers, and lung injury markers were investigated. Furthermore, we used data from the Genotype-Tissue Expression (GTEx) database to evaluate ADAM-17 and ACE2 gene expressions by age and sex in ages between 20-80 years. We found that increased ADAM-17 activity, as estimated by the ADAM-17 substrates score, was associated with COVID-19 severity (p = 0.001). ADAM-17 activity was also associated with increased mortality but did not reach statistical significance (p = 0.06). Soluble ACE2 showed the strongest positive correlation with the ADAM-17 substrate score, follow by renin, interleukin-6, and lung injury biomarkers. The ratio of ADAM-17 to ACE2 gene expression was highest in the lung. This study indicates that increased ADAM-17 activity is associated with severe COVID-19. Our findings also indicate that there may a bidirectional relationship between membrane-bound ACE2 shedding via increased ADAM-17 activity, dysregulated renin-angiotensin system (RAS) and immune signaling. Additionally, differences in ACE2 and ADAM-17 gene expressions between different tissues may be of importance in explaining why the lung is the organ most severely affected by COVID-19, but this requires further evaluation in prospective studies.

Genetic Predisposition to Elevated Levels of Circulating ADAM17 Is Associated with the Risk of Severe COVID-19.

High levels of ADAM17 activity have emerged as an important mediator in severe COVID-19. This study aims to characterize eventual causal relationships between ADAM17 and COVID-19. Using Mendelian randomization analyses, we examined the causal effects of circulating ADAM17 on COVID-19 outcomes using summary statistics from large, genome-wide association studies of ADAM17 (up to 35,559 individuals) from the Icelandic Cancer Project and deCODE genetics, as well as critically ill COVID-19 patients (cases: 13,769; controls: 1,072,442), hospitalized COVID-19 patients (cases: 32,519; controls: 2,062,805) and reported SARS-CoV-2 infections (cases: 122,616; controls: 2,475,240) from the COVID-19 Host Genetics Initiative. The Mendelian randomization (MR) analyses demonstrated that a 1 standard deviation increase in genetically determined circulating ADAM17 (extracellular domain) was associated with an increased risk of developing critical ill COVID-19 (odds ratio [OR] = 1.26, 95% confidence interval [CI]:1.03-1.55). The multivariable MR analysis suggested a direct causal role of circulating ADAM17 (extracellular domain) in the risk of developing critical COVID-19 (OR = 1.09; 95% CI:1.01-1.17) when accounting for body mass index. No causal effect for the cytoplasmic domain of ADAM17 on COVID-19 was observed. Our results suggest that an increased genetic susceptibility to elevated levels of circulating ADAM17 (extracellular domain) is associated with a higher risk of suffering from severe COVID-19, strengthening the idea that the timely selective inhibition of ADAM17 could be a potential therapeutic target worthy of investigation.

Quantification of chondroitin sulfate, hyaluronic acid and N-glycans in synovial fluid - A technical performance study.

Objective: To validate a quantitative high performance liquid chromatography (HPLC) assay for chondroitin sulfate (CS) and hyaluronic acid (HA) in synovial fluid, and to analyze glycan-patterns in patient samples. Design: Synovial fluid from osteoarthritis (OA, n â€‹= â€‹25) and knee-injury (n â€‹= â€‹13) patients, a synovial fluid pool (SF-control) and purified aggrecan, were chondroitinase digested and together with CS- and HA-standards fluorophore labelled prior to quantitative HPLC analysis. N-glycan profiles of synovial fluid and aggrecan were assessed by mass spectrometry. Results: Unsaturated uronic acid and sulfated-N-acetylgalactosamine (ΔUA-GalNAc4S and ΔUA-GalNAc6S) contributed to 95% of the total CS-signal in the SF-control sample. For HA and the CS variants in SF-control the intra- and inter-experiment coefficient of variation was between 3-12% and 11-19%, respectively; tenfold dilution gave recoveries between 74 and 122%, and biofluid stability test (room temperature storage and freeze-thaw cycles) showed recoveries between 81 and 140%. Synovial fluid concentrations of the CS variants ΔUA-GalNAc6S and ΔUA2S-GalNAc6S were three times higher in the recent injury group compared to the OA group, while HA was four times lower. Sixty-one different N-glycans were detected in the synovial fluid samples, but there were no differences in levels of N-glycan classes between patient groups. The CS-profile (levels of ΔUA-GalNAc4S and ΔUA-GalNAc6S) in synovial fluid resembled that of purified aggrecan from corresponding samples; the contribution to the N-glycan profile in synovial fluid from aggrecan was low. Conclusions: The HPLC-assay is suitable for analyzing CS variants and HA in synovial fluid samples, and the GAG-pattern differs between OA and recently knee injured subjects.

Physical Activity in Late Prepuberty and Early Puberty Is Associated With High Bone Formation and Low Bone Resorption.

Background: Physical activity (PA) increases bone mass, especially in late prepuberty and early puberty, but it remains unclear if and how PA affects both bone formation and bone resorption. Materials and Methods: We included 191 boys and 158 girls aged 7.7 ± 0.6 (mean ± SD) in a population-based PA intervention study. The intervention group (123 boys and 94 girls) received daily physical education (PE) in school (40 min/day; 200 min/week) from study start and during the nine compulsory school years in Sweden. The controls (68 boys and 64 girls) received the national standard of 1-2 classes PE/week (60 min/week). During the intervention, blood samples were collected at ages 9.9 ± 0.6 (n = 172; all in Tanner stages 1-2) and 14.8 ± 0.8 (n = 146; all in Tanner stages 3-5) and after termination of the intervention at age 18.8 ± 0.3 (n = 93; all in Tanner stage 5) and 23.5 ± 0.7 (n = 152). In serum, we analyzed bone formation markers [bone-specific alkaline phosphatase (bALP), osteocalcin (OC), and N-terminal propeptide of collagen type 1 (PINP)] and bone resorption markers [C-terminal telopeptide cross links (CTX) and tartrate-resistant acid phosphatase (TRAcP 5b)]. Linear regression was used to compare age and sex-adjusted mean differences between intervention children and controls in these markers. Results: Two years after the intervention was initiated (at Tanner stages 1-2), we found higher serum levels of bALP and OC, and lower serum levels of TRAcP 5b in the intervention compared with the control group. The mean difference (95% CI) was for bALP: 13.7 (2.1, 25.3) µg/L, OC: 9.1 (0.1, 18.1) µg/L, and TRAcP 5b: -2.3 (-3.9, -0.7) U/L. At Tanner stages 3-5 and after the intervention was terminated, bone turnover markers were similar in the intervention and the control children. Conclusion: Daily school PA in the late prepubertal and early pubertal periods is associated with higher bone formation and lower bone resorption than school PA 1-2 times/week. In late pubertal and postpubertal periods, bone formation and resorption were similar. Termination of the intervention is not associated with adverse bone turnover, indicating that PA-induced bone mass benefits gained during growth may remain in adulthood.

Association between circulating furin levels, obesity and pro-inflammatory markers in children.

AIM: To, in children, investigate the associations between serum furin, obesity, overweight, body fat and circulating markers reflecting adipose tissue or systemic inflammation. METHODS: We analysed furin, leptin, adipocyte fatty acid-binding protein, triglycerides, interleukin (IL)-6, IL-8 and C-reactive protein in serum from 166 children in the Pediatric Osteoporosis Prevention (POP) study collected at mean age (SD) 9.9 (0.6) years. Children were classified as low-to-normal weight, overweight or obese. Total body fat mass (kg), trunk fat mass (kg) and total body lean mass (kg) were measured by dual-energy X-ray absorptiometry. Body fat percentage (%) was calculated. RESULTS: We found that circulating furin levels were higher in children with obesity and overweight compared with children with low-to-normal weight (p < 0.001 and p = 0.006, respectively). Also, there were positive correlations between circulating furin, total body fat mass, trunk fat mass, body fat percentage, triglycerides, adipokines and pro-inflammatory markers. CONCLUSION: This study indicates associations between furin, adiposity and a pro-inflammatory milieu in children. We suggest that future studies investigate the role of furin in fat tissue inflammation and associated increased risk of cardiometabolic diseases in children. Studies should also investigate whether higher furin levels could be a link between obesity and severe coronavirus disease 2019 in children.

Patterns of urinary albumin and IgM associate with markers of vascular ageing in young to middle-aged individuals in the Malmö offspring study.

BACKGROUND: Increased urinary excretion of IgM and low-grade albuminuria are associated with increased risk of cardiovascular morbidity and mortality. The objective of this study was to investigate the association between urinary IgM, albuminuria, and vascular parameters reflecting arterial structure and function. METHODS: Subjects of the present study were from the Malmö Offspring study (MOS) cohort, and included 1531 offspring (children and grand-children) to first-generation subjects that participated in the Malmö Diet Cancer-Cardiovascular Arm study cohort. At baseline, technical measurements of arterial stiffness (carotid-femoral pulse wave velocity; c-f PWV), carotid arterial morphology, 24-h ambulatory blood pressure recordings, ankle-brachial-index (ABI), and evaluation of endothelial function (reactive hyperemia index, RHI) were performed. Urinary (U) IgM, U-albumin, and U-creatinine were measured. Multivariate adjusted logistic regression was used to test whether U-IgM excretion and increasing urinary albumin excretion were related to vascular parameters. RESULTS: Detectable U-IgM was independently associated with higher systolic blood pressure, odds ratio (OR) 1.021, 95% confidence interval (CI, 1.003-1.039), p = 0.025 and lower ABI; ABI dx: OR 0.026, 95% CI (0.002-0.381), p = 0.008, ABI sin: OR 0.040, 95% CI (0.003-0.496), p = 0.012. Low-grade albuminuria was independently associated with systolic and diastolic blood pressure, aortic blood pressure, the c-f PWV and the number of carotid intima plaques (p < 0.05). CONCLUSIONS: In young to middle-aged, mostly healthy individuals, increased U-IgM excretion and low-grade albuminuria are associated with adverse vascular parameters. Increased U-IgM excretion may reflect subclinical peripheral atherosclerosis, whereas increased U-albumin excretion is associated with a wide range of cardiovascular abnormalities. This may reflect different pathophysiological mechanisms.

Osteoporosis in cirrhotics before and after liver transplantation: relation with malnutrition and inflammatory status.

Background: Liver cirrhosis is associated with osteoporosis and liver transplantation (LT) with increased bone loss. This study aimed to in LT candidates investigate the potential relation between bone mineral density (BMD) and BMD loss in those who undergo LT, with malnutrition, systemic inflammation, and hormonal status.Methods: We included 102 consecutively recruited cirrhotic LT candidates between May 2004 and April 2007. BMD was assessed by means of dual energy X-ray absorptiometry (DXA). Malnutrition was defined by means of anthropometry and assessment of recent weight loss. In 75/102 patients, serum-thyroid stimulating hormone (TSH), free triiodthyronine (T3) and free thyroxine (T4) and growth hormone (GH), cortisol, free testosterone, dehydroepiandrosterone sulfate, estradiol, interleukin-6, and tumor necrosis factor (TNF)-α was assessed. Overall 57/102 patients received a LT and 47/102 were followed for one year post-LT. At follow-up, nutritional status and BMD were assessed in all patients (n = 47) while 34/47 had available blood samples for analysis.Results: Forty (40%) LT- candidates had osteopenia or osteoporosis and 34 (38%) were malnourished. Malnutrition was associated with osteopenia/osteoporosis (odds ratio: 3.5, 95% CI 1.4, 9.9). Hip BMD Z-score decreased -0.25 (95% CI -0.41, -0.09) from baseline to one year post-LT. High baseline TNF-α correlated with a more marked decline in BMD (Partial correlation (r) = -0.47, p < .05) as did high baseline cortisol levels (r = -0.49, p < .05).Conclusion: Malnutrition in liver cirrhosis seems to be associated with osteopenia/osteoporosis, and systemic inflammation (higher TNF-α) and systemic stress (higher cortisol) to bone loss in patients who undergo LT.

Serum Renin Levels Increase With Age in Boys Resulting in Higher Renin Levels in Young Men Compared to Young Women, and Soluble Angiotensin-Converting Enzyme 2 Correlates With Renin and Body Mass Index.

Background: Age, sex, and body constitution may affect the shedding of membrane bound angiotensin-converting enzyme 2 (mACE2) and lead to a relative mACE2 deficiency. However, it is unclear if differences, reflected by serum renin levels, exist in the basal renin-angiotensin-system (RAS) between children and adults, boys, and girls as well as young women and young men. Furthermore, it remains to be investigated if renin and soluble ACE2 (sACE2) levels are correlated with body mass index (BMI) in children and young adults. The aim of this observational study was to assess age-and sex differences in serum renin, and the relationship between renin, soluble angiotensin-converting enzyme 2, and body mass index in a prospectively followed population-based cohort of children which were followed into young adulthood. Study Design: We analyzed renin and sACE2 in serum in a prospectively followed population-based cohort at 9.9 (0.6) [mean (SD)] (n = 173), 11.7 (0.6) (n = 156), 14.8 (0.8) (n = 149), 18.8 (0.3) (n = 93), and 23.5 (0.7) (n = 152) years of age. Height (cm) and weight (kg) was measured and body mass index (BMI) was calculated as weight (kg)/height (m)2. Sex-related differences in renin levels were calculated using analysis of covariance, adjusted for age. Correlations were assessed by calculating the correlation coefficient (R 2) using a multivariable linear mixed model. Results: Both sexes had low renin levels up to 12 years of age. Thereafter renin levels increased more in boys than in girls. Males from the age of 15 had significantly higher levels than females (p < 0.001). There was a positive linear relationship between renin and sACE2 levels in male and female subjects (p < 0.001), and between sACE2 levels and BMI in males (p < 0.001). Conclusion: Renin levels increase with age, are higher in men than in women since around puberty, and are correlated with sACE2 levels. Furthermore, sACE2 levels are correlated with body mass index in males. These findings indicate that high renin levels in males and females and a high BMI in males may activate pathways which increase the shedding of mACE2, with possible implications for the risk of severe coronavirus disease 2019.

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

BACKGROUND: A 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. METHODS: Bovine 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. RESULTS: Aggrecanase 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. CONCLUSIONS: Indicative 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.

Microproteinuria Predicts Organ Failure in Patients Presenting with Acute Pancreatitis.

BACKGROUND AND AIMS: The disease course of acute pancreatitis (AP) ranges from mild and self-limiting to severe inflammation, associated with significant morbidity and mortality. At present, there are no universally accepted and reliable predictors for severity. Microproteinuria has been associated with the presence of systemic inflammatory response syndrome as well as trauma, although its association with AP is not well understood. The aim of this study was to investigate the value of microproteinuria to predict development of organ failure in AP. METHODS: Consecutive AP patients were prospectively enrolled. Urine samples were collected upon admission, 12-24 h after admission, and 3 months post-discharge for calculation of urine α1-microglobulin-, albumin-, IgG-, and IgM/creatinine ratios. Data regarding AP etiology, severity, and development of organ failure were registered. RESULTS: Overall, 92 AP patients were included (14 % with organ failure; 6 % with severe AP). The α1-microglobulin-, albumin-, and IgG/creatinine ratios correlated with high-sensitivity C-reactive protein 48 h after admission (r = 0.47-0.61, p < 0.001 for all). They were also significantly higher in patients with versus without organ failure (p < 0.05 for all). The α1-microglobulin/creatinine ratio upon admission predicted organ failure [adjusted odds ratio 1.286, 95 % confidence interval (CI) 1.024-1.614] with similar accuracy (AUROC 0.81, 95 % CI 0.69-0.94) as the more complex APACHE II score (AUROC 0.86, 95 % CI 0.70-1.00). CONCLUSION: The α1-microglobulin/creatinine ratio upon presentation with AP is related to inflammation and predicts development of organ failure. Further studies are warranted to evaluate its potential usefulness in predicting outcome for AP patients.

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

BACKGROUND: The 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. METHODS: C4d, 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. RESULTS: Compared 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)-1ß, IL-6 and tumour necrosis factor α (r s 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. CONCLUSIONS: The 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.

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.

Factors That Affect Disease Progression After First Attack of Acute Pancreatitis.

BACKGROUND & AIMS: Little is known about recurrence of pancreatitis after an initial episode, and little is known about how the disease progresses or what factors affect progression. We performed a population-based study of patients with acute pancreatitis (AP) to determine their outcomes and associated factors. METHODS: We performed a retrospective study of patients with first-time AP from 2003 through 2012 in a well-defined area of Sweden. Data were collected from medical records on disease etiology, severity (according to the Atlanta classification), recurrence of AP, subsequent chronic pancreatitis, and mortality. Patients were followed up for a median time of 4.6 years, until death or the end of 2013. RESULTS: We identified 1457 patients with first-time AP (48% biliary disease, 17% alcohol-associated, 9.9% severe); 23% of patients had 1 or more recurrences. Risk for recurrence was significantly higher among smokers (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.03-1.95; P = .03), patients with alcohol-associated AP (HR, 1.58; 95% CI, 1.25-2.23; P < .01), after organ failure (HR, 1.46; 95% CI 1.05-2.03; P = .02), and in patients with systemic complications (HR, 1.88; 95% CI, 1.27-2.79; P < .01) or local complications (HR, 1.66; 95% CI, 1.22-2.27; P < .01). AP of all etiologies progressed to chronic pancreatitis, although alcohol-associated AP progressed most frequently (2.8/100 patient-years). Patients with recurrent AP were at the highest risk for chronic pancreatitis (HR, 6.74; 95% CI, 4.02-11.3; P < .01), followed by alcohol-associated AP (HR, 3.10; 95% CI, 2.05-5.87; P < .01), smoking (HR, 2.26; 95% CI, 1.12-4.58; P = .02), systemic complications (HR, 1.37; 95% CI, 1.06-4.62; P = .03), and peripancreatic necrosis (HR, 2.74; 95% CI, 1.7-4.43; P < .01). In-hospital mortality was 2.8%, and independently associated only with organ failure (odds ratio, 71.17; 95% CI, 21.14-239.60; P < .01). Fifty-three percent of patients who died during disease recurrence had biliary AP; a higher percentage of these patients died upon first recurrence (5.9%) than upon first attack of AP (2%; P = .01). CONCLUSIONS: The severity of first-time AP, smoking, and alcohol abuse are related to recurrence and subsequent chronic pancreatitis. Recurrence increases the risk for progression to chronic pancreatitis. Most patients who die upon disease recurrence have biliary AP.

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]-1ß, 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.

Increased urinary IgM excretion in patients with chest pain due to coronary artery disease.

BACKGROUND: Micro-albuminuria is a recognized predictor of cardiovascular morbidity and mortality in patients with coronary artery disease. We have previously reported, in diabetic and non-diabetic patients, that an increased urinary excretion of IgM is associated with higher cardiovascular mortality. The purpose of this study was to investigate the pattern of urinary IgM excretion in patients with acute coronary syndrome (ACS) and its correlation to cardiovascular outcome. METHODS: Urine albumin, and IgM to creatinine concentration ratios were determined in 178 consecutive patients presenting with chest pain to the Department of Emergency Medicine (ED) at the University Hospital of Lund. Fifty eight (23 female) patients had ACS, 55 (19 female) patients had stable angina (SA), and 65 (35 female) patients were diagnosed as non-specific chest pain (NS). RESULTS: Urine albumin and IgM excretions were significantly higher in patients with ACS (p = 0.001, and p = 0.029, respectively) compared to patients with NS-chest pain. During the 2 years follow-up time, 40 (19 female) patients suffered a new major cardiovascular event (ACS, acute heart failure, stroke) and 5 (4 male/1 female) patients died of cardiovascular cause. A high degree of albuminuria and IgM-uria significantly predicted cardiovascular mortality and morbidity (HR = 2.89, 95% CI: 1.48 - 5.66, p = 0.002). Microalbuminuric patients (≥3 mg/mmol) with high IgM-uria (≥0.005 mg/mmol) had a 3-fold higher risk for cardiovascular new events compared to patients with low IgM-uria (RR = 3.3, 95% CI: 1.1 - 9.9, p = 0.001). CONCLUSION: In patients with chest pain, an increased urine IgM excretion, is associated with coronary artery disease and long-term cardiovascular complications. Measuring urine IgM concentration could have a clinical value in risk stratification of patients with ACS.

Association between varus alignment and post-traumatic osteoarthritis after anterior cruciate ligament injury.

PURPOSE: To investigate the association between varus alignment and post-traumatic osteoarthritis (OA) after an anterior cruciate ligament (ACL) injury. METHODS: One hundred subjects with an acute complete ACL tear were followed for 15 years. Anterior-posterior radiographs of the tibiofemoral joint were obtained with a knee flexion of 20°, and the patellofemoral joint was examined with skyline view at 50° knee flexion. Joint space narrowing and osteophytes were graded in the tibiofemoral and patellofemoral joints in the injured (ACL) and uninjured knee according to the radiographic atlas of the Osteoarthritis Research Society International. The alignment of the uninjured, contralateral knee was measured at follow-up, using full-limb radiographs of leg with the knee in full extension. Alignment was expressed as the hip-knee-ankle (HKA) angle. Alignment was defined as valgus (HKA ≤178°), neutral (179°-181°) or varus (≥182°). RESULTS: Data from 68 subjects were included in the analysis. Varus alignment of the uninjured knee at follow-up appeared to be associated with OA of the injured knee 15 years after an ACL injury (odds ratio (95% confidence interval) 3.9 (1.0-15.8, p = 0.052)). CONCLUSIONS: Varus alignment of the uninjured knee at follow-up may be associated with OA of the injured knee 15 years after an ACL injury. LEVEL OF EVIDENCE: II.

The influence of posterior-inferior tibial slope in ACL injury.

PURPOSE: To explore the effect of different posterior-inferior tibial slope (PITS) angles on ACL injury at non-contact sports, knee laxity and the need for ACL reconstruction. METHODS: One hundred patients with an acute, arthroscopically verified total ACL rupture were followed prospectively with the intention of treating the injury without reconstruction. Knee laxity was assessed with the Lachman and pivot shift tests with the patients under general anesthesia within 10 days of injury. After 15 years, 22 patients of 94 available for follow-up had undergone reconstruction a mean of 4 years after injury. Reconstruction was performed in case of repeated giving-way episodes (n = 16) or meniscus lesions suitable for fixation (n = 6). Knee radiographs were available from 82 patients. Two independent readers determined the PITS angle. RESULTS: Patients injured in contact sports had a greater mean PITS angle than those injured in non-contact sports (10.5° and 9.3°, respectively, P = 0.03). The mean PITS angle was 10.1 (SD = 2.3) for non-reconstructed knees and 9.1 (SD = 3.0) for reconstructed knees (P = NS). Eight of 17 reconstructed knees showed a PITS angle of less than 7.6° (P = 0.006), and the odds ratio of need for reconstruction was 3.9 (CI 1.26-12.3, P = 0.02). No significant difference in PITS angle was found between patients with low- and high-grade instability. CONCLUSION: The main finding of the study was that reconstructed knees were overrepresented in knees with extremely low PITS angles. Additionally, patients injured in contact sports had higher PITS angles than those injured in non-contact sports, and PITS angle did not influence knee laxity.