SuPAR in major depression: Association with 26 weeks antidepressant response and 10-year depression outcomes.

Introduction: Inflammation has been associated with depression and differential antidepressant (AD) treatment response. Soluble urokinase plasminogen activator receptor (suPAR) is a novel measure of chronic inflammation. We investigated whether suPAR is associated with depression severity and AD response. Methods: We included 90 patients with major depressive disorder (MDD) who participated in a part-randomized clinical trial of 26 weeks of treatment with escitalopram or nortriptyline. suPAR levels were measured in serum samples collected at baseline and after 8, 12 and 26 weeks. Mixed effects models for the association between suPAR levels and AD response were performed. By merging with Danish nationwide registers, we included information on psychiatric hospital contacts during ten years after the GENDEP trial. Cox regression analyses calculated the hazard rate ratios between suPAR levels and subsequent hospitalizations. Results: At baseline, higher suPAR levels were not associated with overall depression severity but with greater severity of neurovegetative depressive symptoms, specifically appetite and weight changes. 57 (63.3%) patients responded positively to treatment. Among 57 (63.3%) patients who achieved response, those who responded had significantly higher baseline suPAR levels levels, and response was associated with a significant decrease in suPAR during AD treatment. Remitters decreased from 3.1 ng/ml at baseline to 2.8 ng/ml after 26 weeks (p = 0.003) and responders from 3.0 to 2.8 ng/ml (p = 0.02), whereas non-remitters and non-responders showed unchanged suPAR levels. We found no correlation between a change in suPAR and a change in MADRS, but a lowering of suPAR correlated with a decrease in neurovegetative symptoms. We found no association between suPAR levels and 10-year risk for hospitalizations. Discussion: The present study suggests that an elevated level of chronic inflammation, measured as the suPAR level, is associated with better response to AD treatment.

Inflammation and post-operative recovery in patients undergoing total knee arthroplasty-secondary analysis of a randomized controlled trial.

OBJECTIVE: Reduced function persists for many patients after total knee arthroplasty (TKA). Inflammation is part of osteoarthritis' pathophysiology, and surgery induces a marked inflammatory response. We therefore wanted to explore the role of inflammation in long-term recovery after TKA, and thus conducted this secondary analysis of our randomized controlled trial (RCT) of physical rehabilitation ± progressive strength training (PST). We aimed to investigate whether (1) inflammation is associated with functional performance, knee-extension strength, and knee pain before TKA; (2) PST affects inflammation, and the inflammatory state over time; (3) baseline or surgery-induced inflammation modifies the effect of rehabilitation ± PST on change in 6-min walk test (Δ6MWT); and (4) baseline or surgery-induced inflammation is associated with Δ6MWT following TKA. DESIGN: In the primary trial report's per-protocol analysis, 72/82 patients were included. Sixty had ≥1 blood sample before and after TKA, and were included in this secondary analysis. Inflammation was measured by interferon γ-inducible protein (IP)-10, soluble urokinase plasminogen activator receptor (suPAR), interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α at baseline; day 1, week 4, 8, and 26 after TKA. RESULTS: At baseline, suPAR (P = 006) was negatively associated with 6MWT. Neither baseline nor surgery-induced inflammation modified the response to rehabilitation ± PST. Only surgery-induced IL-10 was associated with Δ6MWT26 weeks-baseline (P = 0.001), also adjusted for 6MWTbaseline, age, sex and body mass index (BMI). CONCLUSION: In this secondary analysis, only increased surgery-induced IL-10 response was associated with decreased long-term functional performance after TKA. The importance of controlling the surgery-induced immune response remains to be investigated further. TRIAL IDENTIFICATION: NCT01351831.

Tuberculosis case finding and mortality prediction: added value of the clinical TBscore and biomarker suPAR.

SETTING: A suburban area of Bissau, the capital of Guinea-Bissau; the study was conducted among presumptive pulmonary tuberculosis (prePTB) patients seeking medical care for signs and symptoms suggestive of PTB. OBJECTIVE: To determine if a clinical TB score and a biomarker suPAR (soluble urokinase plasminogen activator receptor) have separate and composite ability to predict PTB diagnosis and mortality in prePTB patients. DESIGN: Observational prospective follow-up study conducted from August 2010 to August 2012. RESULTS: We included 1011 prePTB patients (mean age 34 years, 95%CI 33-35); 55% (n = 559) were female and 161 (16%) had human immunodeficiency virus (HIV) infection. Of all included patients, 10% (n = 101) were diagnosed with PTB. Mortality during follow-up was 5% (n = 48), with a mean survival time of 158 days (95%CI 27-289) in prePTB patients diagnosed with PTB vs. 144 days (95%CI 109-178) in those not diagnosed with PTB (P = 0.774). After adjusting for HIV status and age, the best separate predictor was suPAR 5 ng/ml, with a hazard ratio (HR) of 4.6 (95%CI 2.1-9.9) for mortality and 6.7 (95%CI 4.0-11.2) for TB diagnosis. All patients who died had a TBscore II + suPAR 7; the HR of the composite score for subsequent PTB diagnosis was 33.0 (95%CI 4.6-236.6). CONCLUSION: The proposed composite score of suPAR + TBscore II 7 can improve TB case finding and clinical monitoring.

Impact of lifestyle intervention for obese women during pregnancy on maternal metabolic and inflammatory markers.

BACKGROUND: Offspring of obese mothers have increased risk of developing obesity and related short- and long-term disease. The cause is multifactorial and may partly be explained by the unfavorable intrauterine environment. Intervention during pregnancy leading to a healthier lifestyle among obese may alter this. OBJECTIVE: To assess the effect of lifestyle intervention on markers of maternal metabolism and inflammation in 'the TOP (Treatment of Obese Pregnant Women) study', a randomized controlled trial. METHODS: In the TOP-study 425 participants with body mass index ⩾30 kg/m2 were randomized to intervention with dietary advices and physical activity assessed by pedometer (PA+D), physical activity assessed by pedometer (PA) or control (C). Of 389 participants completing the study 376 had available blood samples. Serum was analyzed for insulin, c-peptide, lipid profile, leptin, high-sensitivity CRP (hsCRP) and Soluble urokinase Plasminogen Activator Receptor (suPAR), in week 18-20 and 28-30, and simultaneously a 2-h oral glucose-tolerance-test was performed. Diet was assessed in gestational week 11-14 and 36-37 using a validated 360-item Food Frequency Questionnaire. RESULTS: Median levels of hsCRP in gestational week 28-30 were lower in each of the intervention groups (8.3 mg/l in PA+D group, P=0.03; and 8.8 mg/l in PA group, P=0.02) versus the control group (11.5 mg/l). Obtaining 11 000 steps per day as aimed for resulted in a 21% lower hsCRP compared to non-compliant women. Women reporting high carbohydrate intake had around 30% higher hsCRP concentrations in late gestation than women reporting the lowest intake. There were no differences in lipid profile or any of the metabolic markers in gestational week 28-30 when comparing the intervention and control groups. CONCLUSIONS: Lifestyle intervention in obese women can reduce hsCRP representing a marker of inflammation during pregnancy. The effect may partly be mediated by more physical activity and partly by changes in intake of carbohydrates and the glycaemic load.

Soluble urokinase plasminogen activator receptor (suPAR) is a novel, independent predictive marker of myocardial infarction in HIV-1-infected patients: a nested case-control study.

OBJECTIVES: Patients infected with HIV are at increased risk of myocardial infarction (MI). Increased plasma levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) have been associated with increased risk of cardiovascular diseases (CVD), including MI in the general population. We tested suPAR as a predictive biomarker of MI in HIV-1-infected individuals. METHODS: suPAR levels were investigated in a nested case-control study of 55 HIV-1-infected cases with verified first-time MI and 182 HIV-1-infected controls with no known CVD. Controls were matched for age, gender, duration of antiretroviral therapy (ART), smoking and no known CVD. suPAR was measured in the four plasma samples available for each patient at different time-points; 1, Before initiation of ART; 2, 3 months after initiation of ART; 3, 1 year before the case's MI; and 4, The last sample available before the case's MI. RESULTS: In unadjusted conditional regression analysis, higher levels of suPAR were associated with a significant increase in risk of MI at all time-points. Patients in the third and fourth suPAR quartiles had a three- to 10-fold higher risk of MI compared to patients in the lowest suPAR quartile at all time-points. suPAR remained a strong significant predictor of MI, when adjusting for HIV-1 RNA, total cholesterol, triglycerides and high-density lipoprotein. CONCLUSION: Elevated suPAR levels were associated with increased risk of MI in HIV-infected patients, suggesting that suPAR could be a useful biomarker for prediction of first-time MI in this patient group, even years before the event.

Soluble urokinase plasminogen activator receptor levels are elevated and associated with complications in patients with type 1 diabetes.

OBJECTIVES: Soluble urokinase plasminogen activator receptor (suPAR) is a marker of inflammation and endothelial dysfunction. We investigated the associations between suPAR and diabetes, including diabetes duration and complications, in patients with type 1 diabetes. DESIGN, SETTING AND SUBJECTS: From 2009 to 2011, 667 patients with type 1 diabetes and 51 nondiabetic control subjects were included in a cross-sectional study at Steno Diabetes Center, Gentofte, Denmark. suPAR levels were measured with an enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: The investigated diabetic complications were cardiovascular disease (CVD: previous myocardial infarction, revascularisation, peripheral arterial disease and stroke), autonomic dysfunction (heart rate variability during deep breathing <11 beats min(-1) ), albuminuria [urinary albumin excretion rate (UAER) ≥30 mg/24 h] or a high degree of arterial stiffness (pulse wave velocity ≥10 m s(-1) ). Analyses were adjusted for gender, age, systolic blood pressure, estimated glomerular filtration rate, UAER, glycated haemoglobin (HbA1c ), total cholesterol, body mass index, C-reactive protein, antihypertensive treatment and smoking. RESULTS: Soluble urokinase plasminogen activator receptor levels were lower in control subjects versus all patients, in control subjects versus normoalbuminuric patients (UAER <30 mg/24 h), in normoalbuminuric patients with short (<10 years) versus long diabetes duration and were increased with degree of albuminuria (adjusted P < 0.001 for all). Furthermore, suPAR levels were higher in patients with versus without CVD (n = 144; 21.3%), autonomic dysfunction (n = 369; 59.2%), albuminuria (n = 357; 53.1%) and a high degree of arterial stiffness (n = 298; 47.2%) (adjusted P ≤ 0.024). The adjusted odds ratio (95% confidence interval) values per 1 ln unit increase in suPAR were as follows: 2.5 (1.1-5.7) for CVD: 2.7 (1.2-6.2) for autonomic dysfunction; 3.8 (1.3-10.9) for albuminuria and 2.5 (1.1-6.1) for a high degree of arterial stiffness (P ≤ 0.039). CONCLUSION: The suPAR level is higher in patients with type 1 diabetes and is associated with diabetes duration and complications independent of other risk factors. suPAR is a potential novel risk marker for the management of diabetes.

Can tuberculosis case finding among health-care seeking adults be improved? Observations from Bissau.

SETTING: The Bandim Health Project study area in Bissau, Guinea-Bissau. OBJECTIVE: To assess the potential usefulness of predictors (elsewhere applied) and clinical scores (TBscore and TBscore II) based on signs and symptoms typical of tuberculosis (TB) in case finding. DESIGN: Observational prospective cohort study of patients with signs and symptoms suggestive of pulmonary TB (PTB) from 2010 to 2012. RESULTS: We included 1089 PTB suspects with a mean age of 34 years (95%CI 33-35); human immunodeficiency virus (HIV) prevalence was 15.1%. PTB was diagnosed in 107 suspects (76.4% sputum smear-positive, 25.2% HIV-infected). Cough > 2 weeks had the highest diagnostic ability (area under the receiver operating characteristic curve [AUC] 0.66, 95%CI 0.62-0.71), while TBscore < 3 best excluded PTB (negative likelihood ratio [LR-] 0.3) when HIV status was not known. TBscore II ≥ 3 had the highest diagnostic ability in HIV-infected PTB suspects (AUC 0.62, 95%CI 0.53-0.72), while the absence of self-reported weight loss best excluded PTB (LR- 0.2). Cough > 2 weeks as a trigger for smear microscopy missed 32.1% of smear-positive PTB cases. CONCLUSION: Case finding could be improved by screening symptomatic adults for cough and/or weight loss using TBscore II as the trigger for smear microscopy. To suspect PTB only in patients with cough > 2 weeks (non-HIV-infected) or with current cough, fever, weight loss or night sweats (HIV-infected) was not effective in patients whose HIV status was unknown at first visit.

The pro-inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is associated with incident type 2 diabetes among overweight but not obese individuals with impaired glucose regulation: effect modification by smoking and body weight status.

AIMS/HYPOTHESIS: Recent evidence links the soluble urokinase plasminogen activator receptor (suPAR), a stable biomarker of systemic immune activation, to several chronic diseases, including type 2 diabetes. suPAR is also associated with adiposity and smoking. We hypothesised that this biomarker would be linked to incident type 2 diabetes in individuals with impaired glucose regulation and that this association would be modified by smoking and body weight status. METHODS: The study included 1,933 participants with impaired glucose regulation, who were drawn from the Danish arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care (ADDITION) and for whom data on suPAR, BMI and smoking were available. Logistic regression analysis was used to estimate the odds for incident type 2 diabetes per twofold increase in suPAR levels. Interactions between both smoking and body weight status and suPAR were tested. RESULTS: During a 3-year follow-up (599 incident diabetes cases), there was a 48% overall increase in the odds of developing type 2 diabetes per twofold increase in suPAR (p = 0.006). This association was modified by body weight status in overweight, but not in obese individuals (OR 2.36, 95% CI 1.48, 3.76 in overweight group), and by smoking status (OR 2.05, 95% CI 1.20, 3.51 in non-smokers). After adjustment for other diabetes risk factors, the association between suPAR and type 2 diabetes was attenuated in the whole sample and among non-smokers, but remained robust among overweight participants. CONCLUSIONS/INTERPRETATION: suPAR may be a good novel biomarker for systemic sub-clinical inflammation and immune activation linked to incident type 2 diabetes risk in overweight individuals and non-smokers. The observed interactions with adiposity and smoking should be investigated further.

Elevated soluble urokinase receptor values in CSF, age and bacterial meningitis infection are independent and additive risk factors of fatal outcome.

The aim of the present study was to evaluate the potential role of cerebrospinal fluid soluble urokinase receptor (suPAR) level, infection and age as risk factors for fatal outcome in patients suspected of having meningitis and/or bacteraemia on admission to hospital. A total of 545 cerebrospinal fluid samples from patients with clinically suspected meningitis were sent to the Hellenic National Meningitis Reference Laboratory. Ten of 545 (1.83%) patients died. Analysis by receiver operating characteristics (ROC) curve revealed that both suPAR and age were significant for prediction of fatal outcome. Patients with levels of suPAR above the cut-off values and age ≥ 51 years, or patients in which either Neisseria meningitis or Streptococcus pneumoniae were detected were categorized as high risk patients. The combination of the above three predictors (suPAR, age and infectious agent) in a logistic regression model with outcome of infection as the dependent variable yielded an overall odds ratio (OR = 85.7, 95% CI 10.6-690.2) with both sensitivity and specificity being equal to the value of 0.9. In conclusion, suPAR, age and type of infection have an additive effect in predicting mortality among patients suspected of meningitis.

The immune marker soluble urokinase plasminogen activator receptor is associated with new-onset diabetes in non-smoking women and men.

AIM: To explore the putative association of new-onset diabetes and the soluble urokinase plasminogen activator receptor (suPAR), which is a new and stable plasma marker of immune function and low-grade inflammation. This association has been previously suggested by using the less sensitive International Classification of Disease system to detect incident diabetes in the Danish MONICA 10 cohort. METHODS: The Danish National Diabetes Register enabled more accurate identification of incident diabetes during a median follow-up of 13.8 years in the Danish MONICA 10 cohort (n = 2353 generally healthy individuals). The soluble urokinase plasminogen activator receptor was measured by the ELISA method. To fulfil model assumptions, outcome analyses were stratified by age, and further by smoking, owing to the interaction between the soluble urokinase plasminogen activator receptor and smoking on new-onset diabetes (P < 0.0001). RESULTS: New-onset diabetes (n = 182) was associated with increased soluble urokinase plasminogen activator receptor levels (P = 0.013). Among 699 middle-aged (41 and 51 years) and 564 older (61 and 71 years) non-smokers, participants in the upper soluble urokinase plasminogen activator receptor quartile had a sex- and age-adjusted relative risk of 6.01 (95% CI 2.17-16.6, P < 0.0006) and relative risk of 3.25 (95% CI 1.51-6.98, P = 0.0025), respectively, for new-onset diabetes compared with participants in the lowest quartile. This relationship remained significant after additional adjustments for C-reactive protein and leukocytes or fasting glucose and insulin or BMI (P < 0.05). The soluble urokinase plasminogen activator receptor was not related to incident diabetes among smokers (P ≥ 0.85). CONCLUSIONS: In these explorative analyses, the soluble urokinase plasminogen activator receptor associated independently with incident diabetes in non-smokers, supporting an immune origin of Type 2 diabetes. Competing disease risk may explain lack of association among smokers.

Soluble urokinase plasminogen activator receptor is associated with subclinical organ damage and cardiovascular events.

OBJECTIVE: The soluble urokinase plasminogen activator receptor (suPAR) is a plasma marker of low grade inflammation and has been associated with cardiovascular risk. We wanted to investigate whether suPAR was associated with markers of subclinical organ damage. METHODS: In a population sample of 2038 individuals, aged 41, 51, 61 and 71 years, without diabetes, prior stroke or myocardial infarction, not receiving any cardiovascular, anti-diabetic or lipid-lowering medications, we measured urine albumin/creatinine ratio (UACR), carotid atherosclerotic plaques and carotid/femoral pulse wave-velocity (PWV) together with traditional cardiovascular risk factors and high sensitivity C-reactive protein (hsCRP). RESULTS: suPAR was significantly associated with the presence of plaques (P = 0.003) and UACR (P < 0.001), but not PWV (P = 0.17) when adjusting for age, gender, systolic blood pressure, cholesterol, plasma glucose, waist/hip ratio, smoking and hsCRP. However, suPAR explained only a small part of the variation in the markers of subclinical organ damage (R(2) 0.02-0.04). During a median follow-up of 12.7 years (5th-95th percentile 5.1-13.4 years) a total of 174 composite endpoints (CEP) of cardiovascular death, non-fatal myocardial infarction and stroke occurred. suPAR was associated with CEP independent of plaques, PWV, UACR, and hsCRP as well as age, gender, systolic blood pressure, cholesterol, plasma glucose, waist/hip ratio and smoking with a standardized hazard ratio of 1.16 (95% confidence interval 1.04-1.28, P = 0.006). CONCLUSION: suPAR was associated with subclinical organ damage, but predicted cardiovascular events independent of subclinical organ damage, traditional risk factors and hsCRP. Further studies must investigate whether suPAR plays an independent role in the pathogenesis of cardiovascular disease.

Twelve potential fibrosis markers to differentiate mild liver fibrosis from cirrhosis in patients infected with chronic hepatitis C genotype 1.

Information about the stage of liver fibrosis is important for managing patients with chronic hepatitis C (CHC). The aim of this study was to evaluate 12 plasma markers for differentiating no/mild liver fibrosis from cirrhosis among patients with CHC genotype 1. Transient elastography was used to assess the stage of fibrosis for the patients included in the study. Forty patients were included (21 cirrhotic). Plasma levels of tumor necrosis factor-α (TNF-α), interleukin 8 (IL-8), interferon-γ inducible protein-10 (IP-10), monocyte chemotactic protein-1 (MCP-1), soluble urokinase-type plasminogen activator (suPAR), monokine induced by γ-interferon (MIG), human hepatocyte growth factor (HGF), insulin, interleukin 6 (IL-6), interleukin 1-ß (IL-1ß), leptin, and nerve growth factor (NGF) were analyzed. Concentrations of TNF-α (median 15.0 vs. 25.1 pg/ml, area under the receiver operating characteristic curve [AUC] 0.91), IL-8 (48.7 vs. 103.3 pg/ml, AUC 0.85), IP-10 (176 vs. 566 pg/ml, AUC 0.83), MCP-1 (449 vs. 735 pg/ml, AUC 0.78), suPAR (3.5 vs. 5.2 ng/ml, AUC 0.78), MIG (100 vs. 152 pg/ml, AUC 0.75), and HGF (3.69 vs. 5.58 ng/ml, AUC 0.71) were significantly higher in patients with cirrhosis. In conclusion, several of the investigated markers showed promise for differentiating cirrhosis from no/mild fibrosis among patients with CHC genotype 1.

Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population.

BACKGROUND: Low-grade inflammation is thought to contribute to the development of cardiovascular disease (CVD), type-2 diabetes mellitus (T2D), cancer and mortality. Biomarkers of inflammation may aid in risk prediction and enable early intervention and prevention of disease. OBJECTIVE: The aim of this study was to investigate whether plasma levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) are predictive of disease and mortality in the general population. DESIGN: This was an observational prospective cohort study. Cohort participants were included from June 1993 to December 1994 and followed until the end of 2006. SETTING: General adult Caucasian population. PARTICIPANTS: The MONICA10 study, a population-based cohort recruited from Copenhagen, Denmark, included 2602 individuals aged 41, 51, 61 or 71 years. MEASUREMENTS: Blood samples were analysed for suPAR levels using a commercially available enzyme-linked immunosorbent assay. Risk of cancer (n = 308), CVD (n = 301), T2D (n = 59) and mortality (n = 411) was assessed with a multivariate proportional hazards model using Cox regression. RESULTS: Elevated baseline suPAR level was associated with an increased risk of cancer, CVD, T2D and mortality during follow-up. suPAR was more strongly associated with cancer, CVD and mortality in men than in women, and in younger compared with older individuals. suPAR remained significantly associated with the risk of negative outcome after adjustment for a number of relevant risk factors including C-reactive protein levels. LIMITATION: Further validation in ethnic populations other than Caucasians is needed. CONCLUSION: The stable plasma protein suPAR may be a promising biomarker because of its independent association with incident cancer, CVD, T2D and mortality in the general population.

Evaluating the potential of IP-10 and MCP-2 as biomarkers for the diagnosis of tuberculosis.

The aim of the present study was to evaluate the potential of diagnostic tests based on interferon-gamma inducible protein (IP)-10 and monocyte chemotactic protein (MCP)-2, and compare the performance with the QuantiFERON TB Gold In-Tube (QFT-IT; Cellestis, Carnagie, Australia) test. IP-10 and MCP-2 were determined in supernatants from whole blood stimulated with Mycobacterium tuberculosis-specific antigens. Samples were obtained from 80 patients with culture- and/or PCR-proven tuberculosis (TB), and 124 unexposed healthy controls: 86 high school students and 38 high school staff. IP-10 and MCP-2 test cut-offs were established based on receiver operating characteristic curve analysis. TB patients produced significantly higher levels (median) of IP-10 (2158 pg x mL(-1)) and MCP-2 (379 pg x mL(-1)) compared with interferon (IFN)-gamma (215 pg x mL(-1)). The QFT-IT, IP-10 and MCP-2 tests detected 81, 83 and 71% of the TB patients; 0, 3 and 0% of the high school students and 0, 16 and 3% of the staff, respectively. Agreement between tests was high (>89%). By combining IP-10 and IFN-gamma tests, the detection rate increased among TB patients to 90% without a significant increase in positive responders among the students. In conclusion, interferon-gamma inducible protein-10 and monocyte chemotactic protein-2 responses to Mycobacterium tuberculosis-specific antigens could be used to diagnose infection. Combining interferon-gamma inducible protein-10 and interferon-gamma may be a simple approach to increase the detection rate of the Mycobacterium tuberculosis-specific in vitro tests.

Predicting mortality in patients with systemic inflammatory response syndrome: an evaluation of two prognostic models, two soluble receptors, and a macrophage migration inhibitory factor.

Better outcomes in patients suspected of community-acquired infections requires the optimal and timely assessment of disease severity at the point of first contact with the health care system, which is typically in the emergency department. This study was conducted using a previously described, prospectively collected cohort of patients with systemic inflammatory response syndrome (SIRS) that were admitted to an emergency department and a department of infectious diseases at a university hospital. Plasma samples were collected and disease severity scores calculated upon admission. A multiplex immunoassay and a newly developed enzyme-linked immunosorbent assay (ELISA)-based assay were used to measure the soluble urokinase-type plasminogen activator receptor, soluble triggering receptor expressed on myeloid cells-1, and macrophage migration inhibitory factor. The area under the receiver operating characteristic (ROC) curve for the prediction of 30- and 180-day mortality was used to compare the performance of the markers and the models. A total of 151 patients were eligible for analysis. Of these, nine died before day 30 and 19 died before day 180 post-admission. Admission-soluble urokinase-type plasminogen activator receptor levels were significantly higher in both day 30 and day 180 non-survivors. There was a non-significant trend towards higher macrophage migration inhibitory factor concentrations in day 30 non-survivors. Soluble triggering receptor expressed on myeloid cells-1 levels were significantly lower in non-survivors at both time points. The simplified acute physiology score II (SAPS II) and sequential organ failure assessment (SOFA) scores were significantly higher in non-survivors at both time points, indicating that these models intended for use in intensive care units might also be useful in an emergency department setting.

Chemokine receptor CCR5 in interferon-treated multiple sclerosis.

OBJECTIVE: To study the relationship between CC chemokine receptor CCR5 expression and disease activity in multiple sclerosis (MS) patients treated with beta-interferon (IFN-beta). METHODS: The CCR5 Delta32 allele and a CCR5 promoter polymorphism associated with cell surface expression of CCR5 were analyzed in 109 patients with relapsing-remitting MS treated with IFN-beta who were followed clinically for 1 year. Cellular CCR5 expression was measured by flow cytometry. RESULTS: Patients with MS had a higher percentage of CCR5-positive monocytes than healthy controls. Increased monocyte expression of CCR5 correlated weakly with an increased short-term relapse risk but there was no relationship between CCR5 Delta32 allele and CCR5 promoter polymorphism genotypes and relapse risk. CONCLUSIONS: The results do not support a major role of CCR5 in the pathogenesis of relapses in MS patients treated with IFN-beta, but it is possible that monocyte CCR5 expression may be used as a marker of disease activity.

Excretion patterns of human metapneumovirus and respiratory syncytial virus among young children.

BACKGROUND: As respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) cause serious respiratory tract infections, the routes of transmission of these viruses are important to elucidate. We examined the modes of virus shedding and shedding duration of RSV and hMPV in young children. METHODS: From each child in a group of 44 children (37 RSV-positive, 6 hMPV-positive, and 1 co-infected child), aged between 0.5-38 months, hospitalised at Hvidovre Hospital, Copenhagen, Denmark, one nasopharyngeal aspirate (NPA), saliva, urine, and faeces sample were collected at inclusion and weekly in a three-week period. Sweat and blood samples were obtained at inclusion. The presence of RSV and hMPV RNA was detected using real-time RT-PCR. RESULTS: We detected RSV RNA in 28 saliva specimens, 5 stool samples, and 3 sweat samples. hMPV RNA was detected in one saliva specimen and two sweat samples. Four of the five children shedding RNA in faeces had diarrhoea and children shedding RNA in sweat were either less than five weeks of age or had a chronic lung disease. RSV and hMPV RNA was shed in nasal secretions for a median of 11.5 and 5.0 days respectively (p = 0.001). More than 75% of the family members of the infected children showed to have an upper respiratory tract infection when following up. CONCLUSION: Viral RNA was present in nasal secretions, saliva, sweat, and faeces, but whether or not the virions were infectious and constitute a potential mode of transmission remains to be shown in future studies.

Predictive value of soluble haemoglobin scavenger receptor CD163 serum levels for survival in verified tuberculosis patients.

Pre-treatment serum levels of sCD163 were measured in a cohort of 236 suspected tuberculosis (TB) cases from Guinea-Bissau, with a median follow-up period of 3.3 years (range 0-6.4 years). In 113 cases, the diagnosis of TB was verified by positive sputum microscopy and/or culture. Among the verified TB cases, a decreased survival rate was found in 27 patients with sCD163 levels above the upper reference limit (3.95 microg/mL). The difference in survival was significant during TB treatment (log rank, p<0.02) and after long-term follow-up (log rank, p<0.001). The decrease in survival rate during TB treatment remained significant in a multivariate Cox model controlling for human immunodeficiency virus (HIV) status, age and gender, with a mortality increase of 1.19 (95% CI, 1.04-1.36) per microg of sCD163, and a hazard ratio (HR) for sCD163 levels above the upper reference limit of 4.18 (95% CI, 1.06-16.4). The difference was not significant after excluding patients with concomitant HIV-1 and HIV-2 infection in Kaplan-Meier analyses (log rank, p 0.11). In contrast, the difference in survival remained significant in Kaplan-Meier analyses after long-term follow-up, even after excluding patients with concomitant HIV-1 and HIV-2 infection (log rank, p 0.002). In the Cox model, the mortality increase per microg of sCD163 was 1.27 (95% CI, 1.14-1.40), with an HR for elevated sCD163 levels of 2.85 (95% CI, 1.44-5.63). The HRs for concomitant HIV-1 and HIV-2 infection were 6.92 (95% CI, 3.28-14.58) and 2.48 (95% CI, 1.09-5.67), respectively. Thus, sCD163 levels appeared to be an independent predictor of survival in verified TB patients.

Activation of nuclear factor kappaB in colonic mucosa from patients with collagenous and ulcerative colitis.

BACKGROUND AND AIMS: Expression of inducible nitric oxide synthase (iNOS) is greatly upregulated in the colonic mucosa of patients with collagenous and ulcerative colitis. As the transcription factor nuclear factor kappaB (NFkappaB) is a major inducer of iNOS gene expression, we compared activation and transcriptional activity of NFkappaB in colonic mucosal biopsies from these patients. PATIENTS: Eight patients with collagenous colitis, six with relapsing ulcerative colitis, and eight with uninflamed bowel were studied. METHODS: NFkappaB DNA binding activity was assessed by electrophoretic mobility shift assay and inhibitor of NFkappaB (IkappaB) kinase (IKK) activity by immunocomplex kinase assay. In vivo recruitment of NFkappaB to the iNOS promoter was determined by chromatin immunoprecipitation analysis and transcriptional activity by NFkappaB gene expression profiling arrays. Cells showing NFkappaB activation were identified by immunohistochemistry. RESULTS: In collagenous and ulcerative colitis, as opposed to uninflamed bowel, IKKbeta activity and strong NFkappaB DNA binding gave rise to activation of identical NFkappaB subunits and recruitment of transcriptionally active p65 to the iNOS promoter. In collagenous colitis, activated NFkappaB was observed only in epithelial cells while up to 10% of lamina propria macrophages showed activation in ulcerative colitis. CONCLUSIONS: In collagenous and ulcerative colitis, colonic mucosal NFkappaB is activated and recruited to the iNOS promoter in vivo via an IKKbeta mediated pathway. As collagenous colitis is not associated with tissue injury, these data challenge the prevailing view that activation of NFkappaB per se mediates tissue injury. Our results suggest that downstream inflammatory reactions leading to tissue damage originate in lamina propria immune cells, as increased NFkappaB activity in collagenous colitis was localised solely in epithelial cells, but present also in macrophages in ulcerative colitis.

Characterization of rotavirus strains in a Danish population: high frequency of mixed infections and diversity within the VP4 gene of P[8] strains.

We characterized the G and P types from 162 rotavirus-positive stool specimens collected from 162 persons in Denmark (134 children and 28 adults) with acute diarrhea in 1998, 2000, and 2002. Samples were obtained during outpatient consultations (73%) and from hospitalized patients (27%). Although more than 20 different G-P combinations were identified, only 52% represented the globally most common types G1P[8], G2P[4], and G4P[8]. The G9 genotype, which is emerging worldwide, was identified in 12% of all samples. Twenty-one percent of the samples were of mixed genotypic origin, which is the highest frequency reported in any European population. The standard reverse transcription-PCR methods initially failed to identify a considerable fraction of the rotavirus P strains due to mutations at the VP4 primer-binding sites of P[8] strains. The application of a degenerate P[8] primer resulted in typing of most VP4 strains. There was considerable year-to-year variation among the circulating G-P types, and whereas G1P[8] was predominant in 1998 (42% of samples) and 2002 (26%), G2P[4] was the strain that was most frequently detected in 2000 (26% of samples). Our findings might implicate challenges for rotavirus vaccine implementation in a European population and underscore the importance of extensive strain surveillance prior to, during, and after introduction of any vaccine candidate.