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  • 101.
    James, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Flodin, Mats
    Johnston, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The antibody configurations of cardiac troponin I assays may determine their clinical performance2006In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 52, no 5, p. 832-837Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Previous studies have shown superior clinical performance of the cardiac troponin I (cTnI) assay from Beckman-Coulter Diagnostics. This assay had a unique combination of monoclonal antibodies with 2 monoclonal antibodies directed against epitopes near the NH(2) terminus of the heart-specific region of troponin I. The approach has been adopted by the new cTnI assay from Abbott Diagnostics. The aim of our study was to investigate whether this approach affects the clinical performance of cTnI assays. METHODS: Cardiac troponin concentrations were measured in a random sample of patients with unstable coronary artery disease included in the GUSTO IV trial (n = 696) by the AccuTnI (Beckman-Coulter Diagnostics), Architect cTnI (Abbott Diagnostics), Immulite 2500 cTnI (Diagnostics Products Corporation), and Elecsys 2010 cTnT (Roche Diagnostics) assays and related to the 1-year mortality. The primary cutoff concentrations were based on the 99th percentile upper reference limits and an imprecision (CV) < or =10%. RESULTS: The sensitivities of the AccuTnI and Architect cTnI assays in identifying patients who died within 1 year were equal and were significantly higher (P <0.05) than those of the Immulite 2500 cTnI and the Elecsys cTnT assays. The concordance between the AccuTnI and Architect cTnI assays was 97%, but concordances between the Architect cTnI and the Elecsys cTnT assays were 89%-92% with more at-risk patients (P <0.01 to P <0.001) identified by the Architect cTnI assay. CONCLUSIONS: The Architect cTnI assay has clinical performance similar to that of the AccuTnI, probably as a result of the inclusion of a monoclonal antibody against troponin I epitope 41-49 in the assay

  • 102.
    James, Stefan K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Armstrong, Paul
    Califf, Robert
    Simoons, Maarten L.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    A rapid troponin I assay is not optimal for determination of troponin status and prediction of subsequent cardiac events at suspicion of unstable coronary syndromes.2004In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 93, no 2-3, p. 113-120Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Troponin is a specific marker of myocardial damage. For early prediction of coronary events in patients with suspicion of acute coronary syndromes the assay also needs to be highly sensitive.

    METHODS AND RESULTS: A rapid troponin I assay was performed prior to inclusion in 4447 acute coronary syndrome patients in the GUSTO-IV trial. A quantitative troponin T analysis was later performed on blood samples obtained at randomization by a central laboratory. There was an agreement between the rapid troponin I assay and troponin T (< or =/>0.1 microg/l) in 3596 (80.9%) patients. A positive rapid troponin I was identifying any elevation of troponin T (>0.01 microg/l) in 1990 patients (90.4%) whereas a negative rapid troponin I was corresponding to negative troponin T (< or =0.01 microg/l) in only 1217 patients (54.2%). Patients with a positive versus negative rapid troponin I had an increased risk of death or myocardial infarction at 30 days (9.3 vs. 5.9%; odds ratio, O.R. 1.64; 95% confidence interval, 1.31-2.06). Troponin T elevation (>0.1 microg/l) provided a better (10.5 v. 4.9%, O.R. 2.26; C.I. 1.79-2.85) risk stratification. Regardless of a positive or a negative rapid troponin I, the troponin T result (>0.1 vs. < or =0.1 microg/l) stratified the patients into high and low risk of events at 30 days, (10.3 vs. 5.7%, P=0.002) and (11.5 vs. 4.8%, P<0.001), respectively.

    CONCLUSION: In a population with non-ST elevation acute coronary syndrome a positive rapid troponin I assay is a specific indicator of troponin elevation and a predictor of early outcome. However, a negative rapid troponin I is not a reliable indicator of the absence of myocardial damage and does not indicate a low risk of subsequent cardiac events. A rapid troponin I assay was performed prior to inclusion in 4447 acute coronary syndrome patients in the GUSTO-IV trial and related to a centrally analyzed quantitative troponin T test. A positive rapid troponin I was well corresponding to any elevation of troponin T (>0.01 microg/l) and predicted an unfavorable outcome at 30 days. However, a negative rapid troponin I was corresponding to troponin T < or =0.01 microg/l in only half of the patients. Troponin T >0.1 microg/l vs. < or =0.1 microg/l provided a better risk stratification than the rapid troponin I result. For patients with troponin T elevation (>0.1 microg/l) the 30 day event rate was high regardless of the rapid troponin I result.

  • 103.
    James, Stefan K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Tilly, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Armstrong, Paul
    Califf, Robert
    Simoons, Maarten L.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Troponin-T and N-terminal pro-B-type natriuretic peptide predict mortality benefit from coronary revascularization in acute coronary syndromes: a GUSTO-IV substudy2006In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 48, no 6, p. 1146-1154Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: This study was designed to evaluate biomarkers for selection of patients with non-ST-segment elevation acute coronary syndromes (ACS) that derive mortality benefit from revascularization. BACKGROUND: Biomarkers are essential for identification of patients at increased risk, which may be reduced by revascularization. METHODS: During the initial 30 days, 2,340 patients of 7,800 (30%) with non-ST-segment elevation ACS in the GUSTO (Global Utilization of Strategies To open Occluded arteries)-IV trial underwent coronary revascularization. The 1-year mortality was calculated in 30-day survivors stratified by status of revascularization and levels of biomarkers. A propensity score for receiving revascularization was constructed and included in a survival analysis that also included the time point of revascularization as a time-dependent covariate. RESULTS: Elevation of troponin-T or N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with a high mortality. In patients with either or both of these markers elevated, a lower mortality following revascularization was observed. In contrast, patients without elevation of these markers had low 1-year mortality without any reduction in mortality following revascularization. In fact, in patients with normal levels of both troponin-T and NT-proBNP, a significant increase in 1-year mortality after revascularization was observed. Elevation of C-reactive protein, interleukin-6, creatinine clearance, and ST-segment depression was also related to a higher mortality. However, independent of these markers, mortality was lower after revascularization. CONCLUSIONS: Markers of troponin-T and NT-proBNP not only assist in risk stratification of patients with non-ST-segment elevation ACS but also appear to identify patients who have a reduced mortality associated with early coronary revascularization.

  • 104.
    James, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Armstrong, P
    Barnathan, E
    Califf, R
    Topol, E
    Simoons, Maarten L
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    N-Terminal Pro–Brain Natriuretic Peptide and Other Risk Markers for the Separate Prediction of Mortality and Subsequent Myocardial Infarction in Patients With Unstable Coronary Artery Disease: A Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV Substudy2003In: Circulation, ISSN 0009-7322, E-ISSN 1524-4539, Vol. 108, no 3, p. 275-281Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Biochemical markers are useful for prediction of cardiac events in patients with non-ST-segment-elevation acute coronary syndrome (ACS). The associations between N-terminal pro-brain natriuretic peptide (NT-proBNP) and other biochemical and clinical risk indicators, as well as their prognostic value concerning the individual end points of death and myocardial infarction (MI), were elucidated in a large cohort of ACS patients. METHODS AND RESULTS: NT-proBNP, troponin T, and C-reactive protein (CRP) were analyzed in blood samples obtained at a median of 9.5 hours from symptom onset in 6809 of 7800 ACS patients in the Global Utilization of Strategies To Open occluded arteries-IV (GUSTO-IV) trial. Levels of NT-proBNP were correlated independently with age, female gender, low body weight, diabetes, renal dysfunction, history of MI, heart failure, heart rate, ongoing myocardial damage, and time since onset of ischemia. Increasing quartiles of NT-proBNP were related to short- and long-term mortality that reached 1.8%, 3.9%, 7.7%, and 19.2%, (P<0.001), respectively, at 1 year. Levels of troponin T, CRP, heart rate, and creatinine clearance, in addition to ST-segment depression, were also correlated independently with 1-year mortality, but NT-proBNP was the marker with the strongest relation. In contrast, only troponin T, creatinine clearance, and ST-segment depression were independently related to future MI. The combination of NT-proBNP and creatinine clearance provided the best prediction, with a 1-year mortality of 25.7% with both markers in the top quartile vs 0.3% with both markers in the bottom quartile. CONCLUSIONS: The use of NT-proBNP appears to add critical prognostic insight to the assessment of patients with ACS.

  • 105.
    James, Stefan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Bertil
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, Agneta
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Stridsberg, Mats
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Clinical Chemstry.
    Venge, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wallentin, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    [Prognosis in unstable coronary artery disease. Multimarker strategy is the best basis for the therapeutic choice]2004In: Lakartidningen, ISSN 0023-7205, Vol. 101, no 17, p. 1514-9, 1521Article in journal (Refereed)
  • 106.
    Janson, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ludviksdottir, Dora
    Gunnbjörnsdóttir, Mari­a
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Björnsson, Eythor H.
    Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Circulating adhesion molecules in allergic and non-allergic asthma2005In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 99, no 1, p. 45-51Article in journal (Refereed)
    Abstract [en]

    Circulating forms of adhesion molecules (intercellular-adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin ) are related to the turnover of these molecules on the cell surface. In contrast to the other molecules, the levels of E-selectin probably exclusively reflect the activity of endothelial cells. The aim of this study was to compare levels of circulating adhesion molecules in patients with allergic (AA) and non-allergic asthma (NA) and to relate the levels of soluble adhesion molecules to methacholine responsiveness and lung function. The study comprised 19 patients with AA, 15 patients with NA and 17 healthy subjects. Soluble adhesion molecules, spirometry, methacholine responsiveness and peak flow variability was measured. The group of patients with AA had higher levels of sE-selectin than the reference group (P=0.046). Serum levels of sE-selectin correlated significantly with bronchial responsiveness (r=0.76) and peak flow variability (r=0.75) (P<0.01) in the NA but not in the AA group. All adhesion molecules in AA (P<0.05-<0.001), but only sE-selectin in NA (P<0.05), were correlated to airway conductance. sVCAM-1 was reduced by inhaled steroids (P<0.01). Our results indicate that endothelial cells are activated in asthma and that this activity has a bearing on airflow variability and bronchial responsiveness in NA.

  • 107. Jernberg, Tomas
    et al.
    Boman, Kurt
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Stridsberg, Mats
    Swedberg, Karl
    Venge, Per
    Kliniken för klinisk kemi och farmakologi, Akademiska sjukhuset, Uppsala, Sweden.
    BNP eller NT-proBNP bör analyseras vid misstänkt hjärtsvikt: Riktlinjer för analys och tolkning2006In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 103, no 17, p. 1289-1292, 1295Article in journal (Refereed)
    Abstract [en]

    Available data indicate that the use of B-type natriuretic peptide (BNP) or N-terminal-proBNP (NT-proBNP) improve the diagnostics of suspected heart failure as compared to the currently used clinical diagnosis. The increased use of these diagnostic aids is therefore desirable. Since the predictive values are less than 100 procent and the levels are affected by many other factors but heart failure, the results of such measurement should not be used in isolation, but together with a proper clinical judgement. BNP and NT-proBNP are strongly related to the prognosis of most heart diseases, but we are still missing sufficient scientific proof to recommend the measurement of these hormones routinely for monitoring and therapy control.

  • 108.
    Jernberg, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Johnston, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Natriuretic peptides in unstable coronary artery disease2004In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 25, no 17, p. 1486-1493Article in journal (Other academic)
    Abstract [en]

    Patients with unstable coronary artery disease (CAD), i.e., unstable angina or non-ST-elevation myocardial infarction, vary widely in clinical presentation, prognosis and response to treatment. To select appropriate therapy, early risk stratification has become increasingly important. This review focuses on the emerging role of natriuretic peptides in the early assessment of patients with unstable CAD. We conclude that levels of brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are strongly associated to mortality and the risk of future congestive heart failure, and carry important prognostic information independent from previously known risk factors in unstable CAD. There are some data indicating that these markers can also be helpful in the selection of appropriate therapy in these patients but further studies are needed. Before a routine use of BNP or NT-proBNP in unstable CAD can be recommended, the cost-effectiveness of adding these new markers to the currently routine markers and their impact on selection of treatment needs further evaluation.

  • 109.
    Jernberg, Tomas
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    James, Stefan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. dep of Medical sciences.
    Lindahl, Bertil
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Stridsberg, Mats
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Clinical Chemstry.
    Venge, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wallentin, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    NT-ProBNP in non-ST-elevation acute coronary syndrome.2005In: J Card Fail, ISSN 1071-9164, Vol. 11, no 5 Suppl, p. S54-8Article in journal (Other scientific)
  • 110.
    Jernberg, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    NT-proBNP in unstable coronary artery disease: experiences from the FAST, GUSTO IV and FRISC II trials2004In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844, Vol. 6, no 3, p. 319-325Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Risk stratification is important in patients with unstable coronary artery disease (CAD), i.e. unstable angina or non-ST-elevation myocardial infarction. This article focuses on the emerging role of N-terminal pro brain natriuretic peptide (NT-proBNP) and the results from the FAST, GUSTO IV and FRISC II trials.

    METHODS: In the FAST study, NT-proBNP was measured on admission in 755 patients admitted because of symptoms suggestive of unstable CAD. Follow up was performed after 40 months. The GUSTO IV and the FRISC II-trials included patients with unstable CAD and NT-proBNP was analyzed in 6806 and 2019 patients, with follow up after 1 and 2 years, respectively.

    RESULTS: In the FAST study, patients in the 2nd, 3rd, and 4th NT-proBNP quartile had a relative risk of subsequent death of 4.2 (1.6-11.1), 10.7 (4.2-26.8) and 26.6 (10.8-65.5), respectively. In the GUSTO IV trial, increasing quartiles of NT-proBNP were related to short and long term mortality which at 1 year was; 1.8%, 3.9%, 7.7% and 19.2% (P<0.001), respectively. In multivariable analyses including well-known predictors of outcome, NT-proBNP level was independently associated to mortality in all three studies. In the FRISC II trial, the NT-proBNP level, especially if combined with a marker of inflammation, identified those with the greatest benefit from an early invasive strategy.

    CONCLUSION: NT-proBNP is strongly associated with mortality in patients with suspected or confirmed unstable CAD and, combined with a marker of inflammation, seems helpful in identifying those with greatest benefit from an early invasive strategy.

  • 111. Jernberg, Tomas
    et al.
    Lindahl, Bertil
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, Agneta
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Andren, Bertil
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Frostfeldt, Gunnar
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lagerqvist, Bo
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Stridsberg, Mats
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Clinical Chemstry.
    Venge, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wallentin, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    N-terminal pro-brain natriuretic peptide in relation to inflammation, myocardial necrosis, and the effect of an invasive strategy in unstable coronary artery disease.2003In: J Am Coll Cardiol, ISSN 0735-1097, Vol. 42, no 11, p. 1909-16Article in journal (Refereed)
  • 112.
    Jernberg, Tomas
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Bertil
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, Agneta
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Andren, Bertil
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Frostfeldt, Gunnar
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lagerqvist, Bo
    Stridsberg, Mats
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Clinical Chemstry.
    Venge, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Wallentin, Lars
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Reply.2004Other (Other scientific)
  • 113.
    Jernberg, Tomas
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Bertil
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Comparison between second and third generation troponin T assay in patients with symptoms suggestive of an acute coronary syndrome but without ST segment elevation.2003In: Cardiology, ISSN 0008-6312, Vol. 100, no 1, p. 29-35Article in journal (Refereed)
  • 114.
    Johnston, Nina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Jernberg, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Biochemical indicators of cardiac and renal function in a healthy elderly population2004In: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 37, no 3, p. 210-216Article in journal (Refereed)
    Abstract [en]

    Objectives:

    To examine the distributions of NT-proBNP and cystatin C and their relation to age, gender, and other physiological factors in an apparently healthy elderly population.

    Method:

    NT-proBNP and cystatin C were analyzed in 407 and 408 healthy individuals, median age: 65 (range 40–76).

    Results:

    Increasing age, female gender and CRP were independently associated to higher NT-proBNP levels. Age, body mass index, and CRP level were independently associated to the cystatin C level. In women and men, ≤65 years, the 97.5th percentile value for NT-proBNP was 268 ng/l and 184 ng/l, in those older, 391 ng/l and 269 ng/l. For those ≤65 years the 97.5th percentile value for cystatin C was 1.12 mg/l, and for those older 1.21 mg/l.

    Conclusion:

    In a healthy elderly population, NT-proBNP is influenced by age and gender, whereas cystatin C is influenced by age but not by gender. Both markers seem to be associated to the CRP level.

  • 115.
    Jonsson, Niklas
    et al.
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden.
    Gille-Johnson, Patrik
    Karolinska Inst, Dept Med, S-17177 Stockholm, Sweden.
    Martling, Claes-Roland
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden.
    Xu, Shengyuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Mårtensson, Johan
    Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm, Sweden.
    Performance of plasma measurement of neutrophil gelatinase-associated lipocalin as a biomarker of bacterial infections in the intensive care unit2019In: Journal of critical care, ISSN 0883-9441, E-ISSN 1557-8615, Vol. 53, p. 264-270Article in journal (Refereed)
    Abstract [en]

    Purpose: To assess the value of dimeric neutrophil-gelatinase associated lipocalin (NGAL) as an early marker of bacterial infection and its response to antibiotic therapy in intensive care unit (ICU) patients.

    Materials & methods: We measured daily plasma dNGAL in 198 patients admitted to a mixed ICU. Likelihood of infection was determined with International Sepsis Forum criteria. Wemeasured dNGAL in 145 healthy controls to establish normal values.

    Results: ICU patients had higher dNGAL than healthy controls. A suspected or confirmed infection was independently associated with 90% (95% CI 15-215%) higher dNGAL than absence of infection. We observed no association between acute kidney injury and dNGAL. Diagnostic accuracy at antibiotic treatment initiation, assessed with area under the receiver-operating characteristics curve (AUC-ROC), for dNGAL was 0.70 (95% CI 0.60-0.79). AUC-ROC for dNGAL 24 h before antibiotic treatment initiation was 0.54 (95% CI 0.41-0.66). The mean (95% CI) change of dNGAL in the first 2 days after appropriate antibiotic therapy initiation was -31 (-49,-13)%.

    Conclusions: In our cohort of ICU patients, plasma dNGAL was associated with presence of bacterial infections independent of AKI but it performed poor as a predictor of infections. Following antibiotic therapy, dNGAL markedly decreased-supporting further exploration of dNGAL-guided antibiotic de-escalation.

  • 116.
    Jönsson, Ulla-Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Blom, Kristin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stålenheim, Gunnemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Douhan Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The production of the eosinophil proteins ECP and EPX/EDN are regulated in a reciprocal manner2014In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 122, no 4, p. 283-291Article in journal (Refereed)
    Abstract [en]

    Previous studies showed that the biological activity and the eosinophil content of eosinophil cationic protein (ECP, RNase 3) are determined by single-nucleotide polymorphisms (SNPs) in the ECP (RNase3) gene. In this study, we report the prevalence of a common SNP in the eosinophil protein x/eosinophil-derived neurotoxin (EPX/EDN, RNase2) and the association with the cellular contents of EPX/EDN and ECP. The genes were sequenced and the EPX/EDN405(G>C) rs2013109 SNPs were also determined by TaqMan 5nuclease allelic discrimination assay. ECP and EPX/EDN in purified eosinophils or in whole blood extracts were analysed by sensitive immunoassays. The study included 379 non-allergic and allergic subjects. The genotype prevalence of the EPX/EDN405(G>C) polymorphism was GG 59%, GC 36% and CC 6%. The cellular contents of ECP and EPX/EDN were related in a reciprocal fashion with the sums of the protein contents being constant. The contents were associated with the ECP562(G>C) rs2233860 and EPX/EDN405(G>C) gene polymorphisms. The cellular content of eosinophil peroxidase (EPO) was not associated with the ECP and EPX/EDN genotypes. The prevalence of the EPX/EDN405(G>C) genotypes and the contents of the proteins were similar in non-allergic and allergic subjects. The production and storage of the two ancestral proteins, ECP and EPX/EDN likely share common regulatory mechanisms, which result in opposing productions of the two proteins.

  • 117.
    Jönsson, Ulla-Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Byström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Stålenheim, Gunnemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    A (G -> C) transversion in the 3 ' UTR of the human ECP (eosinophil cationic protein) gene correlates to the cellular content of ECP2006In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 79, no 4, p. 846-851Article in journal (Refereed)
    Abstract [en]

    Eosinophil cationic protein (ECP) is a cytotoxic protein produced by and secreted from human eosinophil granulocytes. ECP may be involved in the injury of epithelial cells in allergic diseases such as asthma. The objectives were to determine the prevalence of the ECP gene polymorphism 562(G > C) in apparently healthy subjects and subjects with allergy and relate the prevalence to clinical disease and to serum and cellular levels of ECP. The 562(G > C) ECP gene polymorphism was determined by gene sequencing of the ECP gene from DNA prepared from 163 apparently healthy subjects and 151 subjects with allergic and nonallergie asthma or other diseases. ECP was measured by a sensitive radioimmunoassay. A polymorphism was detected at position 562, which mapped to the 3' untranslated region (UTR) of the gene encoding the ECP (RNase 3). Sixty-nine percent of the population had the 562GG genotype and 4%, the 562CC genotype. The cellular content of ECP in peripheral blood cosinophid granulocytes was significantly lower in cells from subjects with the 562GC (4.6 +/- 1.5 mu g/10(6) eosinophils) and 562CC (3.2 +/- 0.7 mu g/10(6) eosinophils) genotypes as compared with those with the 562GG genotype (6. 0 +/- 1.9 mu g/10(6) eosinophils; P < 0.001). A close link was found to the 434(G > C) ECP gene polymorphism. Associations between the 562(G > C) polymorphism or haplotypes of the two polymorphisms to allergy were not found. The 562(G > C) polymorphism in the 3'-end of the UTR of the ECP gene may determine the ECP content in human eosinophils, but unlike the 434(G > C) polymorphism, the 562(G > C) polymorphism is not related to allergy.

  • 118.
    Jönsson, Ulla-Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Douhan Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jõgi, Rain
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Associations of ECP (eosinophil cationic protein)-gene polymorphisms to allergy, asthma, smoke habits and lung function in two Estonian and Swedish sub cohorts of the ECRHS II study2010In: BMC Pulmonary Medicine, ISSN 1471-2466, E-ISSN 1471-2466, Vol. 10, p. 36-Article in journal (Refereed)
    Abstract [en]

    Background: The Eosinophil Cationic Protein (ECP) is a potent multifunctional protein. Three common polymorphisms are present in the ECP gene, which determine the function and production of the protein. The aim was to study the relationship of these ECP gene polymorphisms to signs and symptoms of allergy and asthma in a community based cohort (The European Community Respiratory Health Survey (ECRHS)).

    Methods: Swedish and Estonian subjects (n = 757) were selected from the larger cohort of the ECRHS II study cohort. The prevalence of the gene polymorphisms ECP434(G>C) (rs2073342), ECP562(G>C) (rs2233860) and ECP c.-38(A>C) (rs2233859) were analysed by DNA sequencing and/or real-time PCR and related to questionnaire-based information of allergy, asthma, smoking habits and to lung functions.

    Results: Genotype prevalence showed both ethnic and gender differences. Close associations were found between the ECP434(G>C) and ECP562(G>C) genotypes and smoking habits, lung function and expression of allergic symptoms. Non-allergic asthma was associated with an increased prevalence of the ECP434GG genotype. The ECP c.-38(A>C) genotypes were independently associated to the subject being atopic.

    Conclusion: Our results show associations of symptoms of allergy and asthma to ECP-genotypes, but also to smoking habits. ECP may be involved in impairment of lung functions in disease. Gender, ethnicity and smoking habits are major confounders in the evaluations of genetic associations to allergy and asthma.

  • 119.
    Karawajczyk, Malgorzata
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Peterson, Christer G. B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Garcia, Rodolfo C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    An Extragranular Compartment of Blood Eosinophils Contains Eosinophil Protein X/Eosinophil-Derived Neurotoxin (EPX/EDN)2013In: Inflammation, ISSN 0360-3997, E-ISSN 1573-2576, Vol. 36, no 2, p. 320-329Article in journal (Refereed)
    Abstract [en]

    Serum and plasma profiles of eosinophil protein X (EPX/EDN) and those of other eosinophil proteins differ in various conditions, suggesting a different mobilisation from storage granules. This work studied the subcellular localisation of EPX/EDN in non-primed and in vivo primed blood eosinophils from healthy and allergic subjects, during and out of the pollen season. Primed eosinophils contain easily mobilisable secretory proteins. By fractionation on sucrose density gradients, EPX/EDN localised in the specific granules as well as in a cytoplasmic extra-granular compartment of low equilibrium density that partially overlapped with vesicular structures, cytosolic proteins and plasma membranes. This compartment was clearly separate from the low density peak of ECP that increases during the pollen season. There were no significant differences in the amounts of EPX/EDN present in the low density peak of healthy and allergic subjects. Immuno-gold labelling electron microscopy showed EPX/EDN in specific granules, cytoplasm and associated to plasma membranes. In conclusion, substantial amounts of EPX/EDN localise in an extra-granular, low equilibrium density compartment of human eosinophils.

  • 120.
    Kehoe, Kaat
    et al.
    Univ Antwerp, Dept Pharmaceut Sci, Lab Med Biochem, Antwerp, Belgium.
    Noels, Heidi
    Rhein Westfal TH Aachen, Inst Mol Cardiovasc Res, Aachen, Germany.
    Theelen, Wendy
    Rhein Westfal TH Aachen, Inst Mol Cardiovasc Res, Aachen, Germany.
    De Hert, Emilie
    Univ Antwerp, Dept Pharmaceut Sci, Lab Med Biochem, Antwerp, Belgium.
    Xu, Shenguan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Verrijken, An
    Antwerp Univ Hosp, Dept Endocrinol Diabetol & Metab, Edegem, Belgium;Univ Antwerp, Fac Med & Hlth Sci, LEMP, Antwerp, Belgium.
    Arnould, Thierry
    Univ Namur UNamur, Namur Res Inst Life Sci NARILIS, Lab Biochem & Cell Biol URBC, Namur, Belgium.
    Fransen, Erik
    Univ Antwerp, StatUa Ctr Stat, Antwerp, Belgium.
    Hermans, Nina
    Univ Antwerp, Dept Pharmaceut Sci, Nat Prod & Food Res & Anal Nat, Antwerp, Belgium.
    Lambeir, Anne-Marie
    Univ Antwerp, Dept Pharmaceut Sci, Lab Med Biochem, Antwerp, Belgium.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Van Gaal, Luc
    Antwerp Univ Hosp, Dept Endocrinol Diabetol & Metab, Edegem, Belgium;Univ Antwerp, Fac Med & Hlth Sci, LEMP, Antwerp, Belgium.
    De Meester, Ingrid
    Univ Antwerp, Dept Pharmaceut Sci, Lab Med Biochem, Antwerp, Belgium.
    Prolyl carboxypeptidase activity in the circulation and its correlation with body weight and adipose tissue in lean and obese subjects2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 5, article id e0197603Article in journal (Refereed)
    Abstract [en]

    Background Prolyl carboxypeptidase (PRCP) is involved in the regulation of body weight, likely by hydrolysing alpha-melanocyte-stimulating hormone and apelin in the hypothalamus and in the periphery. A link between PRCP protein concentrations in plasma and metabolic disorders has been reported. In this study, we investigated the distribution of circulating PRCP activity and assessed its relation with body weight and adipose tissue in obese patients and patients who significantly lost weight. Methods PRCP activity was measured using reversed-phase high-performance liquid chromatography in different isolated blood fractions and primary human cells to investigate the distribution of circulating PRCP. PRCP activity was measured in serum of individuals (n = 75) categorized based on their body mass index (BMI < 25.0; 25.0-29.9; 30.0-39.9; >= 40.0 kg/m(2)) and the diagnosis of metabolic syndrome. Differences in serum PRCP activity were determined before and six months after weight loss, either by diet (n = 45) or by bariatric surgery (n = 24). Potential correlations between serum PRCP activity and several metabolic and biochemical parameters were assessed. Additionally, plasma PRCP concentrations were quantified using a sensitive ELISA in the bariatric surgery group. Results White blood cells and plasma contributed the most to circulating PRCP activity. Serum PRCP activity in lean subjects was 0.83 +/- 0.04 U/L and increased significantly with a rising BMI (p<0.001) and decreased upon weight loss (diet, p<0.05; bariatric surgery, p<0.001). The serum PRCP activity alteration reflected body weight changes and was found to be positively correlated with several metabolic parameters, including: total, abdominal and visceral adipose tissue. Plasma PRCP concentration was found to be significantly correlated to serum PRCP activity (0.865; p<0.001). Additionally, a significant decrease (p<0.001) in plasma PRCP protein concentration (mean +/- SD) before (18.2 +/- 3.7 ng/mL) and 6 months after bariatric surgery (15.7 +/- 2.7 ng/mL) was found. Conclusion Our novel findings demonstrate that white blood cells and plasma contributed the most to circulating PRCP activity. Additionally, we have shown that there were significant correlations between serum PRCP activity and various metabolic parameters, and that plasma PRCP concentration was significantly correlated to serum PRCP activity. These novel findings on PRCP activity in serum support further investigation of its in vivo role and involvement in several metabolic diseases.

  • 121. Kelly, M. M.
    et al.
    Keatings, V.
    Leigh, R.
    Peterson, C.
    Shute, J.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Djukanovic, R.
    Analysis of fluid-phase mediators2002In: The European respiratory journal. Supplement, ISSN 0904-1850, Vol. 37, p. 24s-39sArticle in journal (Refereed)
  • 122.
    Kristjansson, Gudjon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Högman, Mariann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gut mucosal granulocyte activation precedes nitric oxide production: studies in coeliac patients challenged with gluten and corn2005In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 54, no 6, p. 769-774Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: To elucidate the dynamics of nitric oxide (NO) production induced by rectal gluten challenge and the relation between NO production and mucosal granulocyte activation. Subjects and

    METHODS: Release of rectal NO was measured in 13 patients with coeliac disease and in 18 controls before and after rectal wheat gluten challenge. Rectal gas was collected with a rectal balloon using a newly developed instrument/technique, the "mucosal patch technique". The instrument allows simultaneous measurements of concentrations of granulocyte mediators in the rectal mucosa. We measured myeloperoxidase (MPO), eosinophil cationic protein (ECP), and histamine. For comparison, we made similar measurements after corn (maize) gluten challenge.

    RESULTS: In all coeliac patients rectal NO concentration increased after gluten challenge and reached a peak after 15 hours (mean 9464 (SEM 2393) parts per billion (ppb); range 250-24982). The maximum MPO and ECP increase occurred five hours after challenge. A correlation was found between mucosal MPO and NO production at 15 hours. Six of the patients showed an increase in NO production 15 hours after rectal corn gluten challenge but this was much smaller than after gluten challenge. No increases were seen in the control group after either challenge.

    CONCLUSION: Mucosal activation of neutrophils and eosinophils precedes pronounced enhancement of mucosal NO production after rectal wheat gluten challenge in patients with coeliac disease. Some of our coeliac patients displayed signs of an inflammatory reaction, as measured by NO and granulocyte markers, after rectal corn gluten challenge.

  • 123.
    Kristjánsson, Gudjon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Högman, Marieann
    Venge, Per
    Hällgren, Roger
    Gut mucosal granulocyte activation precedes nitric oxide production:  studies in coeliac patients challenged with gluten and corn2005In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 54, no 6, p. 769-774Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: To elucidate the dynamics of nitric oxide (NO) production induced by rectal gluten challenge and the relation between NO production and mucosal granulocyte activation. Subjects and

    METHODS: Release of rectal NO was measured in 13 patients with coeliac disease and in 18 controls before and after rectal wheat gluten challenge. Rectal gas was collected with a rectal balloon using a newly developed instrument/technique, the "mucosal patch technique". The instrument allows simultaneous measurements of concentrations of granulocyte mediators in the rectal mucosa. We measured myeloperoxidase (MPO), eosinophil cationic protein (ECP), and histamine. For comparison, we made similar measurements after corn (maize) gluten challenge.

    RESULTS: In all coeliac patients rectal NO concentration increased after gluten challenge and reached a peak after 15 hours (mean 9464 (SEM 2393) parts per billion (ppb); range 250-24982). The maximum MPO and ECP increase occurred five hours after challenge. A correlation was found between mucosal MPO and NO production at 15 hours. Six of the patients showed an increase in NO production 15 hours after rectal corn gluten challenge but this was much smaller than after gluten challenge. No increases were seen in the control group after either challenge.

    CONCLUSION: Mucosal activation of neutrophils and eosinophils precedes pronounced enhancement of mucosal NO production after rectal wheat gluten challenge in patients with coeliac disease. Some of our coeliac patients displayed signs of an inflammatory reaction, as measured by NO and granulocyte markers, after rectal corn gluten challenge.

  • 124.
    Kristjánsson, Gudjon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Serra, Jordi
    Lööf, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kinetics of mucosal granulocyte activation after gluten challenge in coeliac disease2005In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 40, no 6, p. 662-669Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To elucidate the dynamics of the rectal inflammatory response to rectal gluten challenge in coeliac disease by measuring inflammatory mediators released by activated neutrophils, eosinophils and mast cells/basophils.

    MATERIAL AND METHODS: The release of myeloperoxidase (MPO), eosinophilic cationic protein (ECP) and histamine was measured continuously during the early challenge period (3-6 h after gluten challenge) in coeliac patients (n = 9) and healthy controls (n = 5). A segmental perfusion technique was used to carry out this part of the study. Another method, the mucosal patch technique, was used to enable studies of the late challenge period (5-48 h after gluten challenge) in coeliac patients (n = 10) and healthy controls (n = 15).

    RESULTS: During the early challenge period the MPO levels began to increase as early as 3 h after challenge and increased progressively (p < 0.001) during the next 3 h. A decline in MPO levels was seen 15 h after challenge and another phase of increasing levels at 24 h. The MPO values declined 48 h after challenge but still remained significantly increased (p < 0.05). The ECP levels started to increase 4 h after challenge and increased progressively during the next 2 h (p < 0.05). The ECP kinetics during the late challenge period was similar as for MPO but the relative increase in ECP was more modest. No increase in histamine was found except in one patient who had a transient, early increase of histamine (3-5 h after challenge). No signs of inflammatory reaction to gluten were seen in the controls.

    CONCLUSIONS: There is a pronounced neutrophil activation in coeliac patients after rectal gluten challenge. This activation is apparent 4 h after challenge and remains for at least 48 h. A more modest eosinophil activation defined by ECP levels starts 1-2 h later and also remains for at least 48 h. The biphasic pattern of MPO and ECP after challenge suggests a biphasic inflammatory reaction.

  • 125.
    Kristjánsson, Gudjon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Hällgren, Roger
    Cow's milk protein sensitivity is occuring frequently in coeliac diseaseArticle in journal (Refereed)
  • 126.
    Kristjánsson, Gudjon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mucosal reactivity to cow's milk protein in coeliac disease2007In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 147, no 3, p. 449-455Article in journal (Refereed)
    Abstract [en]

    Patients with coeliac disease (CD) on a gluten-free diet may still have gastrointestinal symptoms. On clinical grounds cow's milk (CM) protein sensitivity may be suspected. Here, using rectal protein challenge, we investigated the local inflammatory reaction to gluten and CM protein in adult patients with CD in remission. Rectal challenges with wheat gluten and dried CM powder were performed in 20 patients with CD and 15 healthy controls. Fifteen hours after challenge the mucosal reaction was recorded by the mucosal patch technique with measurements of local release of neutrophil and eosinophil granule constituents; myeloperoxidase (MPO) and eosinophil cationic protein (ECP). We measured the mucosal production of nitric oxide (NO) simultaneously. Six of the patients who reacted to CM were also challenged with alpha-lactalbumin and casein. In 18 of 20 patients gluten challenge induced neutrophil activation defined as increased MPO release and increased NO synthesis. Ten of these 20 patients showed a similarly strong inflammatory reaction to CM challenge. Six of the CM sensitive patients were challenged with specific CM proteins: casein and alpha-lactalbumin. Casein, in contrast to alpha-lactalbumin, induced an inflammatory response similar to that produced by CM. A mucosal inflammatory response similar to that elicited by gluten was produced by CM protein in about 50% of the patients with coeliac disease. Casein, in particular, seems to be involved in this reaction.

  • 127.
    Kristjánsson, Gudjon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wanders, Alkwin
    Lööf, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Hällgren, Roger
    Clinical and subclinical intestinal inflammation assessed by the mucosal patch technique: Studies of mucosal neutrophil and eosinophil activation in inflammatory bowel syndrome2004In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 53, no 12, p. 1806-1812Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: There is a clear need for a rapid, simple, safe, and sensitive method of determining the type and intensity of inflammation in the gut mucosa in clinical practice. In this study, we have evaluated the potential of a new method, the mucosal patch technique, in patients with and without apparent gut inflammation, as assessed by conventional diagnostic procedures. Subjects and

    METHODS: The technique tested is based on the idea that inflammatory mediators released from the rectal mucosa can be absorbed by and then extracted from cellulose patches brought into contact with the mucosa by use of an instrument with an inflatable balloon. Measurements were performed in healthy controls (n = 16) and in patients with active (n = 19) and inactive ulcerative colitis (UC, n = 8), collagen colitis (CC, n = 12), coeliac disease (n = 13), and irritable bowel syndrome (IBS, n = 13).

    RESULTS: Inflammatory mediators from neutrophils (myeloperoxidase (MPO)) and eosinophils (eosinophil cationic protein (ECP)) were increased on average 300- and 10-fold, respectively, in patients with active UC compared with healthy controls and were correlated with the endoscopic score. Patients with inactive UC, CC, coeliac disease, and IBS exhibited no endoscopic signs of inflammation. These patient groups had significantly lower levels of MPO and ECP than the active UC group but showed on average a four- to sevenfold increase in MPO compared with healthy controls.

    CONCLUSION: The mucosal patch technique was well tolerated by patients and easily applied by the investigator. Pronounced neutrophil and eosinophil involvement in UC was demonstrated. With the high sensitivity of the technique, low degree mucosal neutrophil activation could also be quantified in patients with CC and UC in clinical remission. The finding of increased neutrophil involvement in patients with IBS contributes to the pathophysiological ideas of this disease.

  • 128. Kulander, Lena
    et al.
    Pauksens, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Soluble adhesion molecules, cytokines and cellular markers in serum in patients with acute infections2001In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 33, no 4, p. 290-300Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to evaluate the diagnostic capacity of a number of blood components such as soluble adhesion molecules, interleukin-6 (IL-6), myeloperoxidase (MPO) and lysozyme in the distinction of acute bacterial and viral infections. Blood was taken from 115 acutely infected patients at admission before any treatment and in some cases on several consecutive days. 35 of the patients had a definite viral cause for their infection and 66 a bacterial cause. All variables were raised in patients with acute bacterial infections. Soluble vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin, lysozyme and MPO were also raised in acute viral infections, but for sE-selectin and MPO less so than in bacterial infections. Evaluation of the diagnostic power showed that for MPO and IL-6 at cut-offs of 1300 microg/l and 100 ng/l, respectively, the positive predictive value was 97% and 100% and the negative predictive value 78% and 76%, respectively, in the classification of acute bacterial infections. In the distinction between viral or bacterial causes of acute infections in otherwise healthy subjects serum measurements of MPO and IL-6 are valuable tools and should be considered as diagnostic aids in the routine setting. The soluble adhesion molecules did not offer any further information in this respect.

  • 129.
    Lagerqvist, B
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Diderholm, E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Husted, S
    Kontny, F
    Ståhle, E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Swahn, E
    Venge, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wallentin, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    FRISC score for selection of patients for an early invasive treatment strategy in unstable coronary artery disease2005In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 91, no 8, p. 1047-1052Article in journal (Refereed)
    Abstract [en]

    Objective: To develop a scoring system for risk stratification and evaluation of the effect of an early invasive strategy for treatment of unstable coronary artery disease (CAD).

    Design: Retrospective analysis of a randomised study (FRISC II; fast revascularisation in instability in coronary disease).

    Setting: 58 Scandinavian hospitals.

    Patients: 2457 patients with unstable CAD from the FRISC II study.

    Main outcome measures: One year rates of mortality and death/myocardial infarction (MI).

    Methods: Patients were randomly assigned to an early invasive or a non-invasive strategy. From the non-invasive cohort independent variables of death or death/MI were identified.

    Results: Seven factors, age > 70 years, male sex, diabetes, previous MI, ST depression, and increased concentrations of troponins and markers of inflammation (interleukin 6 or C reactive protein), were associated with an independent increased risk for death or death/MI. In patients with ≥ 5 of these factors the invasive strategy reduced mortality from 15.4% (20 of 130) to 5.2% (7 of 134) (risk ratio (RR) 0.34, 95% confidence interval (CI) 0.15 to 0.78, p  =  0.006). Death/MI was also reduced in patients with 3–4 factors from 15.7% (80 of 511) to 10.8% (58 of 538) (RR 0.69, 95% CI 0.50 to 0.94, p  =  0.02). Neither death nor death/MI was reduced in patients with 0–2 risk factors.

    Conclusion: In unstable CAD, this scoring system based on factors independently associated with an adverse outcome can be used shortly after admission to the hospital for risk stratification and for selection of patients to an early invasive treatment strategy.

  • 130.
    Lahtinen, Mika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Borowiec, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Henze, P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Stiernström, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nitric oxide increases leukocyte granule release during simulated extracorporeal circulation2000In: The thoracic and cardiovascular surgeon, ISSN 0171-6425, E-ISSN 1439-1902, Vol. 48, no 3, p. 151-156Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Nitric Oxide (NO) is reported to possess anti-inflammatory properties. The aim of this study was to investigate if nitric oxide affects leukocyte response during simulated extracorporeal circulation (SECC).

    METHODS: Human blood was circulated for 23 hours through SECC circuit. Control group C (n = 5) was ventilated with an oxygen/air mixture, and NO was added in the study group (n = 5). Leukocyte response was determined by release of myeloperoxidase (MPO) and human neutrophil lipocalin (HNL) and by oxygen free radical production, estimated using chemiluminescence.

    RESULTS: Addition of NO significantly increased MPO at 30 minutes and 120 minutes of SECC and HNL at 120 minutes of SECC. Oxygen free radical production in whole blood was generally not affected by NO. Similarly, no significant differences were observed between the groups with regard to the chemiluminescence in isolated granulocytes.

    CONCLUSIONS: Nitric oxide increased release of leukocyte granule derived proteins; MPO and HNL at an early stage of simulated extracorporeal circulation. At the same time, nitric oxide did not affect the whole blood and leukocyte capacity to produce oxygen free radicals.

  • 131. Laitinen, Lauri A.
    et al.
    Laitinen, Annika
    Altraja, Alan
    Virtanen, Ismo
    Kämpe, Mary
    Simonsson, Bo G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, Sven-Erik
    Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sillastu, Heinart
    Bronchial biopsy findings in intermittent or "early" asthma1996In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 98, no 5 Pt 2, p. S3-6, discussion S33-40Article in journal (Refereed)
    Abstract [en]

    Bronchial biopsy specimens from subjects with intermittent or "early" asthma were compared with specimens taken from healthy subjects. Patients with early asthma included those with seasonal asthma and occupational asthma. There was a small but statistically significant increase in the thickness of the subepithelial extracellular matrix protein tenascin in subjects with seasonal and occupational asthma compared with control subjects. Collagen types IV and VII were increased only in patients with occupational asthma. Eosinophils were the only inflammatory cells that were significantly increased in subjects with seasonal asthma compared with control subjects. These data show that inflammation is present in the airways of patients with early asthma, and the increase in tenascin expression in the basement membrane zone suggests that structural changes are also initiated at an early stage of the disease.

  • 132.
    Lampinen, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Douhan-Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cytokine-regulated accumulation of eosinophils in inflammatory disease2004In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 59, no 8, p. 793-805Article in journal (Refereed)
    Abstract [en]

    The role of cytokines in the accumulation of eosinophil granulocytes in inflamed tissue has been studied extensively during recent years, and these molecules have been found to participate throughout the whole process of eosinophil recruitment. Haematopoietic cytokines such as IL-3, IL-5 and GM-CSF stimulate the proliferation and differentiation of eosinophils in the bone marrow, and the release of mature eosinophils from the bone marrow into the blood is probably promoted by IL-5. Priming of eosinophils in the blood following, for example, allergen challenge is performed mainly by IL-3, IL-5 and GM-CSF. An important step in the extravasation of eosinophils is their adhesion to the vascular endothelium. Adhesion molecules are upregulated by, e.g. IL-1, IL-4, TNF-alpha and IFN-gamma and the same cytokines may also increase the affinity of adhesion molecules both on eosinophils and endothelial cells. Finally, a number of cytokines have been shown to act as eosinophil chemotactic factors, attracting the cells to the inflammatory focus in the tissue. Some of the most important eosinophil chemoattractant cytokines are IL-5, IL-8, RANTES, eotaxin, eotaxin-2, eotaxin-3, MCP-3, MCP-4 and TNF-alpha. Th2 cells, mast cells and epithelial cells are important sources of proinflammatory cytokines, but in recent years, the eosinophils have also been recognized as cytokine-producing and thereby immunoregulatory cells. The aim of this paper is to review the role of cytokines in the process of eosinophil recruitment in asthma, allergy and ulcerative colitis.

  • 133. Lampinen, Maria
    et al.
    Håkansson, Lena Douhan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Klinisk kemi.
    Venge, Per
    Klinisk kemi.
    Albumin stimulation of eosinophil migration involves PI3-kinases and is associated with diminished eosinophil CD49d and CD49f expression.2006In: Int Arch Allergy Immunol, ISSN 1018-2438, Vol. 140, no 2, p. 113-20Article in journal (Refereed)
  • 134.
    Lampinen, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Selective priming of peripheral blood eosinophils in patients with idiopathic hypereosinophilic syndrome2006In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 114, no 11, p. 757-763Article in journal (Refereed)
    Abstract [en]

    The idiopathic hypereosinophilic syndrome (HES) is characterised by blood eosinophilia associated with organ involvement. Elevated numbers of blood neutrophils have been observed during episodes of active HES. However, an increased responsiveness of eosinophils to chemotactic and chemokinetic stimuli may explain the selective eosinophil infiltration of the tissue. We have studied the migratory responses of blood eosinophils and neutrophils from 9 patients with HES and from 13 healthy control subjects. Chemokinetic and chemotactic responses to factors acting on both cell types were analysed by means of a modification of the Boyden chamber technique. We found increased migratory responses of the eosinophils, but not of the neutrophils, from the patients with HES. Increased blood neutrophil counts in three of the patients did not coincide with alterations of the neutrophil migratory responses. Our finding of increased migratory responses of eosinophils from patients with HES towards non-specific chemoattractants suggests selective priming of eosinophils in this disease. Interleukin (IL)-5 has previously been shown to prime eosinophils for migratory responses, and successful anti-IL-5 therapy of patients with HES indicates an important role for this cytokine in the development of hypereosinophilia.

  • 135.
    Lidén, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Kristjánsson, Gudjón
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Valtysdóttir, Sigridur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Self-reported food intolerance and mucosal reactivity after rectal food protein challenge in patients with rheumatoid arthritis2010In: Scandinavian Journal of Rheumatology, ISSN 0300-9742, E-ISSN 1502-7732, Vol. 39, no 4, p. 292-298Article in journal (Refereed)
    Abstract [en]

    Objectives: A dietary link to rheumatoid arthritis (RA) has been suspected and an influence on arthritic symptoms by different diets has been reported. Our primary aim was to record the self-experienced adverse food reactions in patients with RA. A secondary aim was to relate self-experienced adverse reactions to dairy produce and wheat to the local mucosal reactivity observed after rectal challenge with cow's milk protein (CM) and wheat gluten. Methods: A questionnaire about self-experienced adverse reaction to food was sent to 347 RA patients. Rectal challenge with CM and gluten was performed in 27 of these patients and in healthy controls (n = 18). After a 15-h challenge the mucosal production of nitric oxide (NO) and the mucosal release of myeloperoxidase (MPO) and eosinophil cationic protein (ECP) were measured by using the mucosal patch technique. Results: Twenty-seven per cent of the RA patients reported food intolerance (FI) to various foods, and in particular to CM, meat, and wheat gluten. Strong mucosal reactivity to CM was observed in 11% of the patients. Moderately increased mucosal reactivity to CM and gluten was found in 22% and 33%, respectively, of the patients. No relationship was found between self-experienced adverse reactions to CM or gluten and mucosal reactivity to these proteins. Conclusions: Perceived FI is reported frequently by RA patients, with a prevalence similar to that reported previously in the general population. Mucosal reactivity to CM and gluten is seen in a minor fraction of RA patients and is not related to the frequently perceived intolerance to these proteins.

  • 136.
    Lindahl, Bertil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Diderholm, Erik
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mechanisms behind the prognostic value of troponin T in unstable coronary artery disease: a FRISC II substudy2001In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 38, no 4, p. 979-986Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: This study was designed to elucidate possible mechanisms for the prognostic value of troponin T (tnT).

    BACKGROUND: The reasons for the adverse prognosis associated with elevation of troponins in unstable coronary artery disease are poorly understood.

    METHODS: Patients enrolled in the Fast Revascularization during InStability in CAD (FRISC-II) trial were included. Clinical characteristics, findings at echocardiography and coronary angiography, and prognosis were evaluated in relation to different tnT levels.

    RESULTS: Absence of significant coronary stenosis was more frequent and three-vessel disease or left main stem stenosis was less frequent in patients without, compared with, detectable tnT. The occurrence of visible thrombus increased with rising levels of tnT. In the group with the highest levels of tnT, occlusion of the left circumflex artery was more common than in the three other tnT groups, as was a left ventricular ejection fraction below 0.45. The one-year risk of death in the noninvasive arm of the study increased by increasing levels of tnT (1.6% to 4.6%), whereas the risk of myocardial infarction showed an inverted U-shaped curve and was lower in the lowest (5.5%) and highest (8.4%) tnT groups than in the two intermediate groups (17.5% and 16.2%).

    CONCLUSIONS: Any detectable elevation of tnT raises the probability of significant coronary stenosis and thrombus formation and is associated with an increased risk of reinfarction and death. However, at a more pronounced elevation of troponin, a higher proportion of patients has a persistent occlusion of the culprit vessel and reduced left ventricular function, associated with a high mortality but a modest risk of reinfarction.

  • 137.
    Lindahl, Bertil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Eggers, Kai M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Evaluation of four sensitive troponin assays for risk assessment in acute coronary syndromes using a new clinically oriented approach for comparison of assays2013In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 51, no 9, p. 1859-1864Article in journal (Refereed)
    Abstract [en]

    Background:

    Measurement of cardiac troponin T or I (cTnT; cTnI) is useful for risk prediction in acute coronary syndromes. The objective of the present study was to compare the prognostic capacity of four sensitive cardiac troponin assays using a new method for comparison.

    Methods:

    Cardiac troponin was analyzed in serum samples from 1335 patients with acute coronary syndrome using the Elecsys high sensitivity TnT (hs-cTnT), ARCHITECT STAT high sensitivity TnI (hs-cTnI), Access AccuTnI (Acc-cTnI) and Architect cTnI (Arc-cTnI) assays. All patients were followed for 30 days regarding death and acute myocardial infarction (AMI), and for 1 year regarding mortality.

    Results:

    By receiver operating characteristic (ROC) curve analyses, there were only minor differences in the area under the curves (AUC) between the assays. At a given sensitivity of 85% the hs-cTnT, Arc-cTnI and Acc-cTnI assays showed comparable specificities, while 90% or higher sensitivity was only possible to achieve with the hs-cTnT, hs-cTnI and Acc-cTnI assays. The highest odds ratios for death/AMI at 30 days and death at 1 year, respectively, were reached by cut-off levels yielding 95% sensitivity; these cut-off levels were below the respective 99th percentile levels.

    Conclusions:

    By the adoption of a new method for the comparison of cardiac troponin assays we showed that the hs-cTnT, hs-cTnI and Acc-cTnI assays had comparable prognostic properties, while the Arc-cTnI assay had inferior prognostic sensitivity.

  • 138.
    Lindahl, Bertil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindbäck, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Jernberg, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Johnston, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Serial analyses of N-terminal pro-B-type natriuretic peptide in patients with non-ST-segment elevation acute coronary syndromes: a Fragmin and fast Revascularisation during In Stability in Coronary artery disease (FRISC)-II substudy2005In: Journal of the American College of Cardiology, ISSN 0735-1097, E-ISSN 1558-3597, Vol. 45, no 4, p. 533-541Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    The aim of this research was to describe N-terminal part of the pro-B-type natriuretic peptide (NT-proBNP) levels over time in non-ST-segment elevation acute coronary syndromes (NSTEACS), to elucidate factors associated with changes of NT-proBNP levels, and to examine association with long-term mortality.

    BACKGROUND:

    The NT-proBNP levels are associated with mortality. Long-term temporal changes of NT-proBNP levels and their relation to other factors have not been examined.

    METHODS:

    The NT-proBNP was analyzed at randomization and at 48 h, after 6 weeks, 3 and 6 months in NSTEACS patients enrolled in the Fragmin and fast Revascularisation during InStability in Coronary artery disease (FRISC)-II trial. The NT-proB-type natriuretic peptide was analyzed at least three time points in 1,216 patients.

    RESULTS:

    The median NT-proBNP level, which at randomization was 529 ng/l, decreased throughout the whole sampling period to 238 ng/l at six months. Elevated troponin T, C-reactive protein, and female gender were associated with higher reduction rates, and high age, diabetes, previous myocardial infarction, treatment with diuretics, and nitrates on admission with lower reduction rates. At each time point, the NT-proBNP level was predictive of the two-year mortality. However, the adjusted odds ratio increased for each time point.

    CONCLUSIONS:

    The initial rise of NT-proBNP in NSTEACS is mainly reversible. Factors associated with less reversibility are related to chronically impaired left ventricular function, and factors associated with greater reversibility are related to the acute myocardial damage. The NT-proBNP level measured during a chronic, relatively stable phase is a better predictor of mortality than during an acute unstable phase. The clinical setting and timing of measurement will be important to consider when using NT-proBNP for risk assessment.

  • 139.
    Martensson, J.
    et al.
    Austin Hosp, Dept Intens Care, Melbourne, Vic 3084, Australia.;Karolinska Inst, Sect Anesthesia & Intens Care Med, Dept Physiol & Pharmacol, Stockholm, Sweden..
    Glassford, N. J.
    Austin Hosp, Dept Intens Care, Melbourne, Vic 3084, Australia.;Monash Univ, Sch Prevent Med & Publ Hlth, Australian & New Zealand Intens Care Res Ctr, Melbourne, Vic 3004, Australia..
    Jones, S.
    Austin Hosp, Dept Intens Care, Melbourne, Vic 3084, Australia..
    Eastwood, G. M.
    Austin Hosp, Dept Intens Care, Melbourne, Vic 3084, Australia.;Deakin Univ, Sch Nursing & Midwifery, Melbourne, Vic 3004, Australia..
    Young, H.
    Austin Hosp, Dept Intens Care, Melbourne, Vic 3084, Australia..
    Peck, L.
    Austin Hosp, Dept Intens Care, Melbourne, Vic 3084, Australia..
    Ostland, V.
    Intrins LifeSci LLC, La Jolla, CA USA..
    Westerman, M.
    Intrins LifeSci LLC, La Jolla, CA USA..
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Bellomo, R.
    Austin Hosp, Dept Intens Care, Melbourne, Vic 3084, Australia.;Monash Univ, Sch Prevent Med & Publ Hlth, Australian & New Zealand Intens Care Res Ctr, Melbourne, Vic 3004, Australia..
    Urinary neutrophil gelatinase-associated lipocalin to hepcidin ratio as a biomarker of acute kidney injury in intensive care unit patients2015In: Minerva Anestesiologica, ISSN 0375-9393, E-ISSN 1827-1596, Vol. 81, no 11, p. 1192-1200Article in journal (Refereed)
    Abstract [en]

    Background. Labile iron is important in the pathogenesis of acute kidney injury (AKI). Neutrophil gelatinase-associated lipocalin (NGAL) and hepcidin control iron metabolism and are upregulated during renal stress. However, higher levels of urinary NGAL are associated with AKI severity whereas higher urinary hepcidin levels are associated with absence of AKI. We aimed to investigate the value of combining both biomarkers to estimate the severity and progression of AKI in intensive care unit (ICU) patients. Methods. Urinary NGAL and hepcidin were quantified within 48 hours of ICU admission in patients with the systemic inflammatory response syndrome and early kidney dysfunction (oliguria for >= 2 hours and/or a 25 mu mol/L creatinine rise from baseline). Diagnostic and prognostic characteristics were assessed by logistic regression and receiver operating characteristics (ROC) analysis. Results. Of 102 patients, 26 had mild AKI and 28 patients had severe AKI on admission. Sepsis (21%), cardiac surgery (17%) and liver failure (9%) were primary admission diagnoses. NGAL increased (P=0.03) whereas hepcidin decreased (P=0.01) with increasing AKI severity. The value of NGAL/hepcidin ratio to detect severe AKI was higher than when NGAL and hepcidin were used individually and persisted after adjusting for potential confounders (adjusted OR 2.40, 95% CI 1.20-4.78). The ROC areas for predicting worsening AKI were 0.50, 0.52 and 0.48 for NGAL, 1/hepcidin and the NGAL/hepcidin ratio. Conclusion. The NGAL/hepcidin ratio is more strongly associated with severe AKI than the single biomarkers alone. NGAL and hepcidin, alone or combined as a ratio, were unable to predict progressive AKI in this selected ICU cohort.

  • 140. Martensson, Johan
    et al.
    Bell, Max
    Xu, Shengyuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Bottai, Matteo
    Ravn, Bo
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Martling, Claes-Roland
    Association of plasma neutrophil gelatinase-associated lipocalin (NGAL) with sepsis and acute kidney dysfunction2013In: Biomarkers, ISSN 1354-750X, E-ISSN 1366-5804, Vol. 18, no 4, p. 349-356Article in journal (Refereed)
    Abstract [en]

    Objective: Neutrophil gelatinase-associated lipocalin (NGAL) is secreted by injured kidney cells as well as by activated neutrophils in response to bacterial infections. We assessed the influence of acute renal dysfunction on the association between plasma NGAL and sepsis. Methods: NGAL was measured daily in 138 critically ill patients. Simultaneous recordings of sepsis status and fluctuations in renal function were made. Results: Elevated NGAL was associated with sepsis independent of level of acute renal dysfunction. A cut-off value of 98 ng/mL distinguished sepsis from systemic inflammation with high sensitivity (0.77) and specificity (0.79). Conclusions: Plasma NGAL can help clinicians to identify bacterial infections in critically ill patients.

  • 141. Martensson, Johan
    et al.
    Xu, Shengyuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Bell, Max
    Martling, Claes-Roland
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Immunoassays distinguishing between HNL/NGAL released in urine from kidney epithelial cells and neutrophils2012In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 413, no 19-20, p. 1661-1667Article in journal (Refereed)
    Abstract [en]

    Background: The distinction between monomeric human neutrophil lipocalin/neutrophil gelatinase-associated lipocalin (HNL/NGAL), secreted by injured kidney tubular cells, and dimeric HNL/NGAL, released by activated neutrophils, is important to accurately diagnose acute kidney injury (AKI).

    Methods: 132 urine samples from 44 intensive care unit (ICU) patients and five urine samples from non-ICU patients with urinary tract infections (UTIs) were analyzed by two monoclonal enzyme-linked immunosorbent assays (ELISA-1 and ELISA-2). The presence of monomeric and/or dimeric HNL/NGAL in each sample was visualized by Western blotting.

    Results: The ELISA-1 detected both monomeric and dimeric HNL/NGAL whereas the ELISA-2 almost exclusively detected dimeric HNL/NGAL with an area under the receiver-operating characteristics curve (AuROC) of 0.90. The ELISA-1/ELISA-2 ratio detected the monomeric form with an AuROC of 0.92. In 32 AKI patients, dimer-specific EUSA-2 levels decreased pre-AKI whereas the monomer-specific ELISA-1/ELISA-2 ratio gradually increased beyond AKI diagnosis. High EUSA-2 levels and/or low ELISA-1/ELISA-2 ratios detected a predominance of dimeric HNL/NGAL in urine from the patients with tills.

    Conclusions: In combination, our two ELISAs distinguish monomeric HNL/NGAL, produced by the kidney epithelium, from dimeric HNL/NGAL, released by neutrophils during AKI development, as well as reduce the confounding effect of neutrophil involvement when bacteriuria is present.

  • 142.
    Mogensen, Ida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Alving, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Dahlen, Sven-Erik
    James, Anna
    Forsberg, Bertil
    Ono, Junya
    Ohta, Shoichiro
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Borres, Magnus P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Izuhara, Kenji
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Malinovschi, Andrei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Fixed airflow obstruction relates to eosinophil activation in asthmatics2019In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 49, no 2, p. 155-162Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Some asthmatics develop irreversible chronic airflow obstruction, for example, fixed airflow obstruction (fixed-AO). This is probably a consequence of airway remodelling, but neither its relation to inflammation nor which asthma biomarkers can be clinically useful are elucidated. We hypothesized that the presence of type 2 inflammation relates to fixed-AO.

    OBJECTIVES: To evaluate the presence of four markers for type 2 inflammation in fixed airflow obstruction among asthmatics.

    METHODS: This was a cross-sectional study of 403 participants with asthma, aged 17-75 years, from three Swedish centres. Fixed airflow obstruction was defined as forced expiratory volume during the first second (FEV1 ) over forced vital capacity (FVC) being below the lower limit of normal (LLN). The following type 2 inflammation markers were assessed: exhaled nitric oxide (FeNO), serum periostin, serum eosinophil cationic protein (S-ECP), and urinary eosinophil-derived neurotoxin (U-EDN).

    RESULTS: Elevated U-EDN (values in the highest tertile, ≥65.95 mg/mol creatinine) was more common in subjects with fixed-AO vs. subjects without fixed-AO: 55% vs. 29%, P < 0.001. Elevated U-EDN related to increased likelihood of having fixed-AO in both all subjects and never-smoking subjects, with adjusted (adjusted for sex, age group, use of inhaled corticosteroids last week, atopy, early-onset asthma, smoking history, and packyears) odds ratios (aOR) of 2.38 (1.28-4.41) and 2.51 (1.04-6.07), respectively. In a separate analysis, having both elevated S-ECP (>20 μg/L) and U-EDN was related to having the highest likelihood of fixed-AO (aOR (95% CI) 6.06 (2.32-15.75)). Elevated serum periostin or FeNO did not relate to fixed-AO.

    CONCLUSIONS AND CLINICAL RELEVANCE: These findings support that type 2 inflammation, and in particular eosinophil inflammation, is found in asthma with fixed-AO. This could indicate a benefit from eosinophil-directed therapies. Further longitudinal studies are warranted to investigate causality and relation to lung function decline.

  • 143. Nordenskjold, A. M.
    et al.
    Hammar, P.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Bjerner, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Duvernoy, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eggers, Kai M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Frobert, P.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Cardiac troponin I, NT-proBNP and galactin-3 are elevated in patients with unrecognized myocardial infarction detected by cardiac magnetic resonance imaging2014In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 35, p. 1002-1003Article in journal (Refereed)
  • 144. Nordenskjöld, Anna M
    et al.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eggers, Kai M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Fröbert, Ole
    Jaffe, Allan S
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Short- and Long-term Individual Variation in Cardiac Troponin in Patients with Stable Coronary Artery Disease2013In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 59, no 2, p. 401-409Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    A rise or fall of cardiac troponin is a prerequisite for the diagnosis of acute myocardial infarction. Defining significant changes requires knowledge of both biological and analytical variation. The short-term biological variation of cardiac troponin in healthy individuals is 3%-48%. However, healthy individuals may not be representative for patients in whom cardiac troponin measurement is often of clinical importance. Therefore, we studied the individual variation of cardiac troponin in patients with symptoms of stable coronary artery disease.

    METHODS:

    Twenty-four patients scheduled for elective coronary angiography were included. Blood samples were drawn once at enrollment and serially at six 4-h intervals on the day before coronary angiography. Cardiac troponin was measured with hs-cTn assays from Abbott Laboratories (premarket cTnI assay) and Roche Diagnostics (Elecsys® cTnT assay with two different lots).

    RESULTS:

    The short-term individual variation in cardiac troponin I (cTnI) was 14%, the reference change value (RCV) 49%, and RCV-log-normal (rise/fall) 54%/-35%. The corresponding values for cTnT were 7%, 23%, and 26%/-21%. The long-term variation for cTnI was 24%, RCV 69%, and RCV-log-normal (rise/fall) 97%/-49%. The corresponding values for cTnT were 11%, 32%, and 37%/-27%.

    CONCLUSIONS:

    The short-term individual variation of cardiac troponin in patients with symptoms of stable coronary artery disease is similar to the biological variation previously demonstrated in healthy individuals. Our results suggest that a change in cardiac troponin concentrations of >50% can be used in attempting to diagnose acute myocardial injury. To detect significant long-term changes in cardiac troponin concentrations, larger changes will be required.

  • 145. Nordenskjöld, Anna M.
    et al.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eggers, Kai M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Fröbert, Ole
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Short-and long-term individual variation in NT-proBNP levels in patients with stable coronary artery disease2013In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 422, p. 15-20Article in journal (Refereed)
    Abstract [en]

    Background: In addition to diagnosis of heart failure (HF) natriuretic peptides (BNP and NT-proBNP) may be used for risk prediction in stable and acute coronary artery disease. The aim of the study was to evaluate the short- and long-term individual variation of NT-proBNP in patients with stable coronary artery disease. Methods: Twenty-four patients with suspected stable coronary artery disease and scheduled for elective coronary angiography were included. Blood samples were drawn at enrolment and, on average 3 weeks later, serially the day prior to coronary angiography. NT-proBNP was determined using Elecsys proBNP sandwich immunoassay (Roche Diagnostics). Results: The individual variation in NT-proBNP over 4 h was 11.8%, over 20 h 12.4% and over 3 weeks 20.4%. The corresponding positive and negative lognormal reference change values (RCV) were +41/-29%, +42/-30% and + 76/-43%, respectively. No significant circadian variation was found. Conclusions: Our results suggest that an increase in NT-proBNP levels of >42% or a decrease of >30% is needed to indicate a reliable short-term change; and for a long-term change an increase of >76% or a decrease of >43% is required. This should be considered when interpreting changes in NT-proBNP levels. 

  • 146.
    Nylander, Ruta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Arnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Relation between Cardiovascular Disease Risk Markers and Brain Infarcts Detected by Magnetic Resonance Imaging in an Elderly Population2015In: Journal of Stroke & Cerebrovascular Diseases, ISSN 1052-3057, E-ISSN 1532-8511, Vol. 24, no 2, p. 312-318Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Established cardiovascular risk markers, such as hypertension, are associated with increased risk of brain infarcts. The newer markers N-terminal pro-brain natriuretic peptide, troponin I, C-reactive protein, and cystatin C may affect the risk of cardiovascular events and potentially, thereby, also stroke. We investigated the association between established and new risk markers for cardiovascular disease and brain infarcts detected by magnetic resonance imaging (MRI) at age 75.

    METHODS:

    Four hundred six randomly selected subjects from the Prospective Investigation of the Vasculature in Uppsala Seniors study were examined with MRI of the brain at age 75. Blood samples, measurements, and dedicated questionnaires at age 70 were used for analysis of risk markers. A history of diseases had been obtained at age 70 and 75. MRI was evaluated regarding lacunar and cortical infarcts. Univariate associations between outcomes and risk markers were assessed with logistic regression models.

    RESULTS:

    One or more infarcts were seen in 23% of the subjects (20% had only lacunar infarcts, 1% had only cortical infarcts, and 2% had both). Hypertension (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.4, 4.7) and obesity (OR 1.3; CI 1.0, 1.8) were significantly associated with increased risk of brain infarction. The newer risk markers were not significantly associated with the brain infarcts.

    CONCLUSIONS:

    The new markers were not associated with the predominantly lacunar infarcts in our 75-year-old population, why troponin I and NT-proBNP may be associated mainly with cardioembolic infarcts as shown recently.

  • 147.
    Olsson, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Haldén, Eric
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Thelin, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    No benefit of reduced heparinization in thoracic aortic operation with heparin-coated bypass circuits2000In: Annals of Thoracic Surgery, ISSN 0003-4975, E-ISSN 1552-6259, Vol. 69, no 3, p. 743-749Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Heparin coating of the cardiopulmonary bypass circuit attenuates inflammatory response and confer clinical benefits in cardiac operations. The positive effects may be amplified with reduced systemic heparin dosage. We studied markers of inflammation and coagulation in thoracic aortic operations with heparin-coated circuits and standard vs reduced systemic heparinization.

    METHODS: Thirty patients were randomized to standard (group S; 300 IU/kg initially; activated clotting times [ACT] > 480 seconds; 5,000 IU in prime; n = 16) or reduced (group R; 100 IU/kg initially; ACT > 250 seconds; 2,500 IU in prime; n = 14) dose systemic heparin. The following markers were analyzed perioperatively: (a) inflammatory response; acute phase cytokine interleukin-6, and granulocytic proteins myeloperoxidase and lactoferrin; (b) complement activation; factor C3a and the C5a-9 terminal complement complex [TCC]; and (c) coagulation; thrombin-antithrombin III complex.

    RESULTS: The clinical outcome did not differ between groups. Four (29%) patients in group R had a perioperative thromboembolic event. All studied markers were significantly elevated during and throughout cardiopulmonary bypass in both groups. Maximal values were higher in group R for all variables except for TCC. There were no statistically significant intergroup differences regarding markers of inflammation, complement activation, or coagulation activation.

    CONCLUSIONS: The blood trauma in thoracic aortic operation is extensive, as reflected by the elevation of the studied biochemical markers, even when heparin-coated cardiopulmonary bypass circuits are used. In this study, we did not detect any benefits, either biochemical or clinical, of reducing the dose of systemic heparin.

  • 148.
    Olsson, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Henze, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Joachimsson, Per-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Thelin, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Heparin-coated cardiopulmonary bypass circuits reduce circulating complement factors and interleukin-6 in paediatric heart surgery2000In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 34, no 1, p. 33-40Article in journal (Refereed)
    Abstract [en]

    Children are sensitive to the inflammatory side effects of cardiopulmonary bypass (CPB). Our intention was to investigate if the biocompatibility benefits of heparin-coated CPB circuits apply to children. In 20 operations, 19 children were randomized to heparin-coated (group HC, n = 10) or standard (group C, n = 10) bypass circuits. Plasma levels of acute phase reactants, interleukins, granulocytic proteins and complement factors were measured. All were significantly elevated after CPB. Levels of complement factor C3a (851 (791-959)ng/ml [median with quartiles] in group C, 497 (476-573)ng/ml in group HC, p < 0.001), Terminal Complement Complex (114 (71-130) AU/ml in group C, 35.5 (28.9-51.4) AU/ml in group HC, p < 0.001), and interleukin-6 (570 (203-743) pg/ml in group C, 168 (111-206)pg/ml in group HC, p = 0.005), were significantly reduced in group HC. Heparin-coated CPB circuits improve the biocompatibility of CPB during heart surgery in the paediatric patient population, as reflected by significantly reduced levels of circulating complement factors and interleukin-6.

  • 149.
    Rubin, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Asparagine-linked glycans determine the cytotoxic capacity of eosinophil cationic protein (ECP)2013In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 55, no 3-4, p. 372-380Article in journal (Refereed)
    Abstract [en]

    Eosinophil cationic protein (ECP) is a toxic, granule-stored protein of the eosinophil granulocyte. It is a heterogeneous protein; molecular weights can differ from 15 to 22 kDa, due to glycosylations. We purified high molecular weight ECP from blood donors with the ECP434GG (rs2073342) genotype, with the aim of examining whether removal of carbohydrates could enhance the cytotoxic capacity. The cytotoxic activity of the ECP pools was tested against the NCI-H69 cell line, before and after enzymatic deglycosylation. ECP was also analysed by SELDI-TOF MS to monitor the changes in molecular mass after deglycosylation. Five high molecular weight pools of ECP (HMW-ECP I-V) with decreasing degrees of glycosylation were tested at concentrations ranging from 0.02 to 0.6 mu M. The activity ranged from EC50 of >0.6 mu M to 0.04 mu M; HMW-ECP II had the lowest activity and HMW-ECP V the highest. After deglycosylation with N-glycosidase F, pools HMW-ECP I-III were reduced to the same molecular weight of 15.78 kDa and acquired potent cytotoxic activities. HMW-ECP IV and V with molecular species at 163 and 16.1 kDa were highly cytotoxic as such and were only partially deglycosylated, with slight enhancement of the toxic properties. The results suggest the presence of several HMW-ECP molecular species with differences in their post-translational modifications and cytotoxic properties. We conclude that a fraction of native ECP is stored in a non-cytotoxic form, which can be converted into a cytotoxic form by N-deglycosylation, whereas another fraction is stored as a highly cytotoxic form carrying different post-translational modifications.

  • 150.
    Rundström, Gerd
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Surface Biotechnology.
    Jonsson, Ann
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Surface Biotechnology, Centre for Surface Biotechnology.
    Mårtensson, Ola
    Mendel-Hartvig, Ib
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lateral Flow Immunoassay Using Europium (III) Chelate Microparticles and Time-Resolved Fluorescence for Eosinophils and Neutrophils in Whole Blood2007In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 53, no 2, p. 342-348Article in journal (Refereed)
    Abstract [en]

    Background: A simple point-of-care method for measuring leukocyte counts in a doctor’s office or emergency room could be of great importance. We developed a protocol for measuring cell count by disrupting the cell membrane and analyzing specific proteins within the cells and used it to analyze proteins from eosinophils and neutrophils.

    Methods: Lateral immunochromatographic (ICR) assays have been developed for eosinophil protein X (EPX) and human neutrophil lipocalin (HNL) as measures of the concentration of eosinophils and neutrophils. The correlation between the lateral ICR assays and cell counting of eosinophils and neutrophils was performed manually and with an automated cell counter. RIA assays measuring the same analytes were also compared with the results from cell counting and lateral ICR assays.

    Results: The optimized assays showed analytical detection limits below the clinical ranges of 3.36 µg/L and 2.05 µg/L for EPX and HNL, respectively. The recovery was 114.8%–122.8% for EPX and 94.5%–96.9% for HNL. The imprecision was 3%–17% CV for EPX over the whole range and 5%–16% CV for HNL. The correlation coefficients between manually counted cells and lateral ICR assays were 0.9 and 0.83 for EPX and HNL, respectively.

    Conclusion: The numbers of eosinophils and neutrophils in small amounts of blood can be estimated in the point-of-care setting by means of fast lateral ICR assays of EPX and HNL.

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