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  • 1. Aomori, Tohru
    et al.
    Yamamoto, Koujirou
    Oguchi-Katayama, Atsuko
    Kawai, Yuki
    Ishidao, Takefumi
    Mitani, Yasumasa
    Kogo, Yasushi
    Lezhava, Alexander
    Fujita, Yukiyoshi
    Obayashi, Kyoko
    Nakamura, Katsunori
    Kohnke, Hugo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Ekström, Lena
    Skogastierna, Cristine
    Rane, Anders
    Kurabayashi, Masahiko
    Murakami, Masami
    Cizdziel, Paul E.
    Hayashizaki, Yoshihide
    Horiuchi, Ryuya
    Rapid Single-Nucleotide Polymorphism Detection of Cytochrome P450 (CYP2C9) and Vitamin K Epoxide Reductase (VKORC1) Genes for the Warfarin Dose Adjustment by the SMart-Amplification Process Version 22009In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 55, no 4, p. 804-812Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Polymorphisms of the CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) gene (CYP2C9*2, CYP2C9*3) and the VKORC1 (vitamin K epoxide reductase complex, subunit 1) gene (-1639G>A) greatly impact the maintenance dose for the drug warfarin. Prescreening patients for their genotypes before prescribing the drug facilitates a faster individualized determination of the proper maintenance dose, minimizing the risk for adverse reaction and reoccurrence of thromboembolic episodes. With current methodologies, therapy can be delayed by several hours to 1 day if genotyping is to determine the loading dose. A simpler and more rapid genotyping method is required. METHODS: We developed a single-nucleotide polymorphism (SNP)-detection assay based on the SMart Amplification Process version 2 (SMAP 2) to analyze CYP2C9*2, CYP2C9*3, and VKORC1 -1639G>A polymorphisms. Blood from consenting participants was used directly in a closed-tube real-time assay without DNA purification to obtain results within 1 h of blood collection. RESULTS: We analyzed 125 blood samples by both SMAP 2 and PCR-RFLP methods. The results showed perfect concordance. CONCLUSIONS: The results validate the accuracy of the SMAP 2 for determination of SNPs critical to personalized warfarin therapy. SMAP 2 offers speed, simplicity of sample preparation, the convenience of isothermal amplification, and assay-design flexibility, which are significant advantages over conventional genotyping technologies. In this example and other clinical scenarios in which genetic testing is required for immediate and better-informed therapeutic decisions, SMAP 2-based diagnostics have key advantages.

  • 2.
    Darmanis, Spyros
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Gallant, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    PCR-Based Multiparametric Assays in Single Cells.2012In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 58, no 12, p. 1618-1619Article in journal (Refereed)
  • 3.
    Ebai, T
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Marques Souza de Oliviera, F
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Löf, L
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schweiger, C
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Keilholtz, U
    Haybaeck, J
    Kamali-Moghaddam, M
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sensitive protein detection by proximity ligation withrolling circle amplification in microtiter plates.2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561Article in journal (Refereed)
  • 4.
    Ebai, Tonge
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    de Oliveira, Felipe Marques Souza
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Löf, Liza
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wik, Lotta
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Schweiger, Caroline
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Keilholtz, Ulrich
    Haybaeck, Johannes
    Landegren, Ulf
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kamali-Moghaddam, Masood
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Analytically Sensitive Protein Detection in Microtiter Plates by Proximity Ligation with Rolling Circle Amplification.2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, article id clinchem.2017.271833Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Detecting proteins at low concentrations in plasma is crucial for early diagnosis. Current techniques in clinical routine, such as sandwich ELISA, provide sensitive protein detection because of a dependence on target recognition by pairs of antibodies, but detection of still lower protein concentrations is often called for. Proximity ligation assay with rolling circle amplification (PLARCA) is a modified proximity ligation assay (PLA) for analytically specific and sensitive protein detection via binding of target proteins by 3 antibodies, and signal amplification via rolling circle amplification (RCA) in microtiter wells, easily adapted to instrumentation in use in hospitals.

    METHODS: Proteins captured by immobilized antibodies were detected using a pair of oligonucleotide-conjugated antibodies. Upon target recognition, these PLA probes guided oligonucleotide ligation, followed by amplification via RCA of circular DNA strands that formed in the reaction. The RCA products were detected by horseradish peroxidase-labeled oligonucleotides to generate colorimetric reaction products with readout in an absorbance microplate reader.

    RESULTS: We compared detection of interleukin (IL)-4, IL-6, IL-8, p53, and growth differentiation factor-15 by PLARCA and conventional sandwich ELISA or immuno RCA. PLARCA detected lower concentrations of proteins and exhibited a broader dynamic range compared ELISA and iRCA using the same antibodies. IL-4 and IL-6 were detected in clinical samples at femtomolar concentrations, considerably lower than for ELISA.

    CONCLUSIONS: PLARCA offers detection of lower protein levels and increased dynamic ranges compared to ELISA. The PLARCA procedure may be adapted to routine instrumentation available in hospitals and research laboratories.

  • 5.
    Ebeling Barbier, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Themudo, Raquel
    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.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Cardiac Troponin I Associated with the Development of Unrecognized Myocardial Infarctions Detected with MRI2014In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 60, no 10, p. 1327-1335Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Late enhancement MRI (LE-MRI) and cardiac troponin I (cTnI) are sensitive methods to detect subclinical myocardial injury. We sought to investigate the relation between plasma concentrations of cTnI measured with a high-sensitivity assay (hs-cTnI) and the development of unrecognized myocardial infarctions (UMIs) detected with LE-MRI.

    METHODS:

    After approval from the ethics committee and written informed consent were obtained, LE-MRI was performed on 248 randomly selected community-living 70-year-old volunteers and hs-cTnI was determined with a highly sensitive premarket assay. Five years later these individuals were invited to a second LE-MRI, and 176 of them (82 women, 94 men), who did not have a hospital diagnosis of MI, constitute the present study population. LE-MR images were analyzed by 2 radiologists independently and in a consensus reading, blinded to any information on previous disease or assessments.

    RESULTS:

    New or larger UMIs were detected in 37 participants during follow-up. Plasma concentrations of hs-cTnI at 70 years of age, which were mainly within what is considered to be the reference interval, were related to new or larger UMIs at 75 years of age with an odds ratio of 1.98 per 1 unit increase in ln-transformed cTnI (95% CI, 1.17-3.35; P = 0.010). Plasma concentrations of hs-cTnI at 70 years of age were associated with the volumes of the UMIs detected at 75 years of age (P = 0.028).

    CONCLUSIONS:

    hs-cTnI in 70-year-old community-living women and men was associated with the development of MRI-detected UMIs within 5 years.

  • 6.
    Eggers, Kai
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Impact of Sex on Cardiac Troponin Concentrations-A Critical Appraisal2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 9, p. 1457-64Article in journal (Refereed)
  • 7.
    Eggers, Kai M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Serial Measurement of Biomarkers after Acute Coronary Syndrome: Which One to Choose?2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 7, p. 1181-1183Article in journal (Other academic)
  • 8.
    Eggers, Kai M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jaffe, Allan S.
    Lind, 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, Clinical Chemistry.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Value of cardiac troponin I cutoff concentrations below the 99th percentile for clinical decision-making2009In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 55, no 1, p. 85-92Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of this study was to evaluate factors influencing the 99th percentile for cardiac troponin I (cTnI) when this cutoff value is established on a highly sensitive assay, and to compare the value of this cutoff to that of lower cutoffs in the prognostic assessment of patients with coronary artery disease. METHODS: We used the recently refined Access AccuTnI assay (Beckman-Coulter) to assess the distribution of cTnI results in a community population of elderly individuals [PIVUS (Prospective Study of the Vasculature in Uppsala Seniors) study; n = 1005]. The utility of predefined cTnI cutoffs for risk stratification was then evaluated in 952 patients from the FRISC II (FRagmin and Fast Revascularization during InStability in Coronary artery disease) study at 6 months after these patients had suffered acute coronary syndrome. RESULTS: Selection of assay results from a subcohort of PIVUS participants without cardiovascular disease resulted in a decrease of the 99th percentile from 0.044 microg/L to 0.028 microg/L. Men had higher rates of cTnI elevation with respect to the tested thresholds. Whereas the 99th percentile cutoff was not found to be a useful prognostic indicator for 5-year mortality, both the 90th percentile (hazard ratio 3.1; 95% CI 1.9-5.1) and the 75th percentile (hazard ratio 2.8; 95% CI 1.7-4.7) provided useful prognostic information. Sex-specific cutoffs did not improve risk prediction. CONCLUSIONS: The 99th percentile of cTnI depends highly on the characteristics of the reference population from which it is determined. This dependence on the reference population may affect the appropriateness of clinical conclusions based on this threshold. However, cTnI cutoffs below the 99th percentile seem to provide better prognostic discrimination in stabilized acute coronary syndrome patients and therefore may be preferable for risk stratification.

  • 9.
    Eggers, Kai M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Kempf, Tibor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Anders
    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.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Wollert, Kai C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Evaluation of Temporal Changes in Cardiovascular Biomarker Concentrations Improves Risk Prediction in an Elderly Population from the Community2016In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 62, no 3, p. 485-493Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There is increasing interest in measurements of cardiovascular (CV) biomarker concentrations for risk prediction in the general population. We investigated the prognostic utility of a panel of novel CV biomarkers and their changes over time.

    METHODS: We measured concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional proadrenomedullin, high-sensitivity cardiac troponin I, growth-differentiation factor-15 (GDF-15), soluble ST2 (sST2), and galectin-3 at baseline and 5 years later in 1016 elderly individuals participating in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Assessed outcomes included all-cause mortality and fatal and nonfatal CV events (in participants without CV disease at baseline) during 10 years of follow-up.

    RESULTS: GDF-15 exhibited the strongest association with all-cause mortality (n = 158) with a hazard ratio (HR) per 1-SD increase in standardized ln GDF-15 of 1.68 (95% CI, 1.44-1.96). NT-proBNP was the only biomarker to predict CV events (n = 163; HR 1.54 [95% CI, 1.30-1.84]). GDF-15 and NT-proBNP also improved metrics of discrimination and reclassification of the respective outcomes. Changes in GDF-15 concentrations between 70 and 75 years predicted all-cause mortality whereas changes in NT-proBNP predicted both outcomes. The other biomarkers and their temporal changes provided only moderate prognostic value apart from sST2 which had a neutral relationship with adverse events.

    CONCLUSIONS: Evaluation of temporal changes in GDF-15 and NT-proBNP concentrations improves risk prediction in an elderly population. These findings are of considerable interest given the emphasis on biomarkers as tools to identify and monitor at-risk individuals with preclinical and potentially modifiable stages of CV disease.

  • 10.
    Eggers, Kai M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Kempf, Tibor
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wollert, Kai C
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Change in Growth Differentiation Factor 15 Concentrations Over Time Independently Predicts Mortality in Community-Dwelling Elderly Individuals2013In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 59, no 7, p. 1091-1098Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Growth differentiation factor 15 (GDF-15) is emerging as a powerful risk indicator in both cardiovascular disease patients and community-dwelling individuals. We investigated GDF-15 concentrations and their changes over 5 years in elderly individuals from the community, together with the underlying conditions and prognostic implications of these measurements.

    METHODS:

    We analyzed GDF-15 concentrations using a sandwich immunoassay in participants from the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study. Measurements were performed at both 70 (n = 1004) and 75 (n = 813) years of age. Median follow-up was 8.0 years.

    RESULTS:

    Over time, GDF-15 concentrations increased by 11.0% (P < 0.001). These changes were related to male sex, hypertension, diabetes, heart failure, renal function, and concentrations of N-terminal pro–B-type natriuretic peptide (NT-proBNP). Significant relationships also emerged between changes in GDF-15 and NT-proBNP, C-reactive protein, and renal function between ages 70 and 75. The R2 value of this model was 0.20. GDF-15 concentrations independently predicted all-cause mortality [hazard ratio 4.0 (95% CI 2.7–6.0)] with results obtained at ages 70 and 75 as updated covariates. Baseline GDF-15 concentrations improved prognostic discrimination and reclassification [c-statistic 0.06 (P = 0.006); integrated discrimination improvement = 0.030 (P = 0.004); category-free net reclassification improvement = 0.281 (P = 0.006)]. Change in GDF-15 concentrations over time independently predicted even all-cause mortality occurring after age 75 [hazard ratio 3.6 (95% CI 2.2–6.0)].

    CONCLUSIONS:

    GDF-15 concentrations and their changes over time are powerful predictors of mortality in elderly community-dwelling individuals. GDF-15 concentrations increase with aging, and these changes are explained only partially by cardiovascular risk factors, indicators of neurohumoral activation and inflammation, and renal function. Thus GDF-15 reflects both cardiovascular and other biological processes closely related to longevity.

  • 11.
    Eggers, Kai M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    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, 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.
    Factors Influencing the 99th Percentile of Cardiac Troponin I Evaluated in Community-Dwelling Individuals at 70 and 75 Years of Age2013In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 59, no 7, p. 1068-1073Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    We aimed to investigate the effects of sex, prevalent cardiovascular disease (CVD), and ageing on the 99th percentile of cardiac troponin I (cTnI).

    METHODS:

    cTnI was measured using a high-sensitivity assay (Abbott Diagnostics) in 814 community-dwelling individuals at both 70 and 75 years of age. We determined the cTnI 99th percentiles separately using nonparametric methods in the total sample, in men and women, and in individuals with and without CVD.

    RESULTS:

    The cTnI 99th percentile at baseline was 55.2 ng/L for the total cohort. Higher 99th percentiles were noted in men (69.3 ng/L) and individuals with CVD (74.5 ng/L). The cTnI 99th percentile in individuals free from CVD at baseline (n = 498) increased by 51% from 38.4 to 58.0 ng/L during the 5-year observation period. Relative increases ranging from 44% to 83% were noted across all subgroups. Male sex [odds ratio, 5.3 (95% CI, 1.5-18.3)], log-transformed N-terminal pro-B-type natriuretic peptide [odds ratio, 1.9 (95% CI, 1.2-3.0)], and left-ventricular mass index [odds ratio, 1.3 (95% CI, 1.1-1.5)] predicted increases in cTnI concentrations from below the 99th percentile (i.e., 38.4 ng/L) at baseline to concentrations above the 99th percentile at the age of 75 years.

    CONCLUSIONS:

    cTnI concentration and its 99th percentile threshold depend strongly on the characteristics of the population being assessed. Among elderly community dwellers, higher concentrations were seen in men and individuals with prevalent CVD. Ageing contributes to increasing concentrations, given the pronounced changes seen with increasing age across all subgroups. These findings should be taken into consideration when applying cTnI decision thresholds in clinical settings.

  • 12.
    Eggers, Kai M.
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Application of Cardiac Troponin in Cardiovascular Diseases Other Than Acute Coronary Syndrome2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 1, p. 223-235Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND: Increased cardiac troponin concentrations in acute coronary syndrome (ACS) identify patients with ongoing cardiomyocyte necrosis who are at increased risk. However, with the use of more precise assays, cardiac troponin increases are commonly noted in other cardiovascular conditions as well. This has generated interest in the use of cardiac troponin for prognostic assessment and clinical management of these patients. In this review, we have summarized the data from studies investigating the implications of cardiac troponin concentrations in various acute and chronic conditions beyond ACS,, i.e., heart failure, myocarditis, Takotsubo cardiomyopathy, aortic dissection, supraventricular arrhythmias, valve disease, pulmonary arterial hypertension, stroke, and in the perioperative setting. CONTENT: Cardiac troponin concentrations are often detectable and frankly increased in non-ACS conditions, in particular when measured with high-sensitivity (hs) assays. With the exception of myocarditis and Takotsubo cardiomyopathy, cardiac troponin concentrations carry strong prognostic information, mainly with respect to mortality, or incipient and/or worsening heart failure. Studies investigating the prognostic benefit associated with cardiac troponin guided treatments however, are almost lacking and the potential role of cardiac troponin in the management of non-ACS conditions is not defined. SUMMARY: Increased cardiac troponin indicates increased risk for adverse outcome in patients with various cardiovascular conditions beyond ACS. Routine measurement of cardiac troponin concentrations can however, not be generally recommended unless there is a suspicion of ACS. Nonetheless, any finding of an increased cardiac troponin concentration in a patient without ACS should at least prompt the search for possible underlying conditions and these should be managed meticulously according to current guidelines to improve outcome.

  • 13.
    Eggers, Kai M.
    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.
    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.
    Carrero, Juan J.
    Karolinska Inst, Div Renal Med, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Evans, Marie
    Karolinska Inst, Div Renal Med, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Szummer, Karolina
    Karolinska Inst, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Jernberg, Tomas
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Cardiac Troponins and Their Prognostic Importance in Patients with Suspected Acute Coronary Syndrome and Renal Dysfunction2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 8, p. 1409-1417Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cardiac troponin (cTn) is important for risk assessment in patients with suspected acute coronary syndrome (ACS). cTn concentrations may, however, be affected by renal dysfunction, and the clinical importance of this interrelation is not well established. We investigated the association between cTnT and cTnI (measured with conventional assays and a more sensitive assay) with the estimated glomerular filtration rate (eGFR) and also assessed the ability of cTn to predict the 1-year all-cause mortality. METHODS: This retrospective registry-based study used data from 309454 admissions to Swedish coronary care units. cTn associations with eGFR and mortality were assessed using different regression models and by calculating multivariable-adjusted c-statistics. RESULTS: cTnT concentrations exhibited stronger associations with eGFR than cTnI concentrations (conventional cTnT assay: beta = -0.113; more sensitive cTnT assay: beta = -0.186; pooled conventional cTnI assays: beta = -0.098). Overall, cTnT provided greater prognostic accuracy than cTnI. This was most evident in non-ACS patients with normal or mildly reduced eGFR when using the more sensitive assay. Despite higher mortality rates, no consistent increases in the c-statistics of cTn were seen with severely reduced eGFR irrespective of the presence of ACS or non-ACS. CONCLUSIONS: cTnT concentrations exhibited stronger associations with reduced eGFR than cTnI concentrations in patients admitted because of suspected ACS. cTnT, particularly when measured using the more sensitive assay, also tended to be a stronger prognosticator. However, the relative significance of the obtained results must be considered in the context of the severity of renal dysfunction and whether ACS is present.

  • 14. Fredriksson, Simon
    et al.
    Horecka, Joe
    Brustugun, Odd Terje
    Schlingemann, Jörg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Koong, Albert C.
    Tibshirani, Rob
    Davis, Ronald W.
    Multiplexed proximity ligation assays to profile putative plasma biomarkers relevant to pancreatic and ovarian cancer2008In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 54, no 3, p. 582-589Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Sensitive methods are needed for biomarker discovery and validation. We tested one promising technology, multiplex proximity ligation assay (PLA), in a pilot study profiling plasma biomarkers in pancreatic and ovarian cancer. METHODS: We used 4 panels of 6- and 7-plex PLAs to detect biomarkers, with each assay consuming 1 mu L plasma and using either matched monoclonal antibody pairs or single batches of polyclonal antibody. Protein analytes were converted to unique DNA arnplicons by proximity ligation and subsequently detected by quantitative PCR. We profiled 18 pancreatic cancer cases and 19 controls and 19 ovarian cancer cases and 20 controls for the following proteins: a disintegrin and metalloprotease 8, CA-125, CA 19-9, carboxypeptidase A1, carcinoembryonic antigen, connective tissue growth factor, epidermal growth factor receptor, epithelial cell adhesion molecule, Her2, galectin-1, insulin-like growth factor 2, interleukin-1 alpha, interleukin-7, mesothelin, macrophage migration inhibitory factor, osteopontin, secretory leukocyte peptidase inhibitor, tumor necrosis factor a, vascular endothelial growth factor, and chitinase 3-like 1. Probes for CA-125 were present in 3 of the multiplex panels. We measured plasma concentrations of the CA-125-mesothelin complex by use of a triple-specific PLA with 2 ligation events among 3 probes. RESULTS: The assays displayed consistent measurements of CA-125 independent of which other markers were simultaneously detected and showed good correlation with Luminex data. In comparison to literature reports, we achieved expected results for other putative markers. CONCLUSION: Multiplex PLA using either matched monoclonal antibodies or single batches of polyclonal. antibody should prove useful for identifying and validating sets of putative disease biomarkers and finding. multimarker panels.

  • 15. Grubb, Anders
    et al.
    Horio, Masaru
    Hansson, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Björk, Jonas
    Nyman, Ulf
    Flodin, Mats
    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.
    Bökenkamp, Arend
    Yasuda, Yoshinari
    Blufpand, Hester
    Lindström, Veronica
    Zegers, Ingrid
    Althaus, Harald
    Blirup-Jensen, Søren
    Itoh, Yoshi
    Sjöström, Per
    Nordin, Gunnar
    Christensson, Anders
    Klima, Horst
    Sunde, Kathrin
    Hjort-Christensen, Per
    Armbruster, David
    Ferrero, Carlo
    Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator2014In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 60, no 7, p. 974-986Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Many different cystatin C-based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays.

    METHODS:

    Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C-based equation for estimation of GFR.

    RESULTS:

    We developed a simple cystatin C-based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, [Formula: see text] is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C.

    CONCLUSIONS:

    A virtually assay-independent simple cystatin C-based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.

  • 16.
    Gustafsdottir, Sigrun M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Nordengrahn, Ann
    Fredriksson, Simon
    Wallgren, Per
    Rivera, Esteban
    Schallmeiner, Edith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Merza, M.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Detection of individual microbial pathogens by proximity ligation2006In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 52, no 6, p. 1152-1160Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Nucleic acid amplification allows the detection of single infectious agents. Protein-based assays, although they provide information on ongoing infections, have substantially less detection sensitivity.

    METHODS: We used proximity ligation reactions to detect proteins on bacteria and virus particles via nucleic acid amplification. Antibodies recognizing viral or bacterial surface proteins were equipped with DNA strands that could be joined by ligation when several antibodies were bound in proximity to surface proteins of individual infectious agents.

    RESULTS: Detection sensitivities similar to those of nucleic acid-based detection reactions were achieved directly in infected samples for a parvovirus and an intracellular bacterium.

    CONCLUSIONS: This method enables detection of ligated DNA strands with good sensitivity by real-time PCR and could be of value for early diagnosis of infectious disease and in biodefense.

  • 17.
    Gustafsdottir, Sigrun M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wennström, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fredriksson, Simon
    Schallmeiner, Edith
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Hamilton, Andrew D
    Sebti, Said M
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Use of Proximity Ligation to Screen for Inhibitors of Interactions between Vascular Endothelial Growth Factor A and Its Receptors2008In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 54, no 7, p. 1218-1225Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Improved methods are required to screen drug candidates for their influences on protein interactions. There is also a compelling need for miniaturization of screening assays, with attendant reductions in reagent consumption and assay costs. METHODS: We used sensitive, miniaturized proximity ligation assays (PLAs) to monitor binding of vascular endothelial growth factor A (VEGF-A) to 2 of its receptors, VEGFR-1 and VEGFR-2. We measured the effects of proteins and low molecular weight compounds capable of disrupting these interactions and compared the results with those obtained by immunoblot analysis. We analyzed 6 different inhibitors: a DNA aptamer, a mixed DNA/RNA aptamer, a monoclonal VEGF-A neutralizing antibody, a monoclonal antibody directed against VEGFR-2, a recombinant competitive protein, and a low molecular weight synthetic molecule. RESULTS: The PLAs were successful for monitoring the formation and inhibition of VEGF-A-receptor complexes, and the results correlated well with those obtained by measuring receptor phosphorylation. The total PLA time is just 3 hours, with minimal manual work and reagent additions. The method allows evaluation of the apparent affinity [half-maximal inhibitory concentration (IC(50))] from a dose-response curve. CONCLUSIONS: The PLA may offer significant advantages over conventional methods for screening the interactions of ligands with their receptors. The assay may prove useful for parallel analyses of large numbers of samples in the screening of inhibitor libraries for promising agents. The technique provides dose-response curves, allowing IC(50) values to be calculated.

  • 18.
    Hagström, Emil
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Held, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Stewart, Ralph A H
    Aylward, Philip E
    Budaj, Andrzej
    Cannon, Christopher P
    Koenig, Wolfgang
    Krug-Gourley, Sue
    Mohler, Emile R
    Steg, Philippe Gabriel
    Tarka, Elizabeth
    Östlund, Ollie
    White, Harvey D
    Siegbahn, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Growth Differentiation Factor 15 Predicts All-Cause Morbidity and Mortality in Stable Coronary Heart Disease2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 1, p. 325-333Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Higher growth differentiation factor 15 (GDF-15) concentrations are associated with cardiovascular (CV) and non-CV morbidity and mortality. However, information on associations between GDF-15 and the risk of specific CV and non-CV events in stable coronary heart disease (CHD) patients is limited.

    METHODS: In 14 577 patients with stable CHD participating in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy Trial (STABILITY), GDF-15 and other prognostic biomarkers (N-terminal pro-B-type natriuretic peptide, high-sensitivity troponin T, cystatin C, and high-sensitivity C-reactive protein) were measured. In adjusted Cox regression models, the associations between GDF-15 and the composite CV end point [CV death, myocardial infarction (MI), and stroke], as well as other CV and non-CV events, were assessed.

    RESULTS: The median concentration (interquartile range) of GDF-15 at baseline was 1253 (915-1827) ng/L. The hazard ratio for the composite end point for the highest compared to the lowest quartile of GDF-15 was 1.8 (95% CI, 1.5-2.2); for CV death, 2.63 (1.9-3.6); for sudden death, 3.06 (1.9-4.8); for heart failure (HF) death, 4.3 (1.3-14); for cancer death, 2.5 (1.3-4.7); for hospitalization for HF, 5.8 (3.2-10); for MI 1.4 (95% CI, 1.1-1.9); and for stroke, 1.8 (95% CI, 1.1-2.8). After adjustment for other prognostic biomarkers, GDF-15 remained significantly associated with all outcomes except for MI.

    CONCLUSIONS: In stable CHD, GDF-15 was independently associated with CV, non-CV, and cancer mortality, as well as with MI and stroke. When also adjusting for other prognostic biomarkers, the associations to all fatal and nonfatal events were maintained except for MI. Information on GDF-15, therefore, might be helpful when assessing the risk of adverse outcomes in patients with stable CHD. ClinicalTrials.gov Identifier: NCT00799903.

  • 19. Hickman, Peter E.
    et al.
    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.
    Potter, Julia M.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Koerbin, Gus
    Eggers, Kai M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Is It Time to Do Away With the 99th Percentile for Cardiac Troponin in the Diagnosis of Acute Coronary Syndrome and the Assessment of Cardiac Risk?2014In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 60, no 5, p. 734-736Article in journal (Other academic)
  • 20. Hietala, M
    et al.
    Aula, P
    Syvänen, Ann-Christine
    Isoniemi, A
    Peltonen, L
    Palotie, A
    DNA-based carrier screening in primary healthcare: screening for aspartylglucosaminuria mutations in maternity health offices1996In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 42, no 9, p. 1398-1404Article in journal (Refereed)
    Abstract [en]

    Large-scale genetic screening programs are complex enterprises in which ethical, technical, medical, and socioeconomic aspects have to be handled with professional expertise. Establishment of automated, relatively robust, and inexpensive laboratory techniques is one step of this path. Here a pilot carrier-screening program for the mutations causing aspartylglucosaminuria was carried out for pregnant women in primary care maternity health offices. Women (1975) were tested before their 12th week of pregnancy, and 31 heterozygotes were detected. The sampling was based on dried blood strips, facilitating convenient handling and inexpensive mailing to the laboratory. The mutation detection technique, solid-phase mini-sequencing simplified by the use of scintillation microplates and automated equipment, proved to be rapid, simple, inexpensive, and reliable, with a low repeat rate (2.5%). In conclusion, we found that good collaboration between the primary healthcare unit, the laboratory, and counseling experts, combined with modern laboratory technology, facilitate reliable low-cost genetic testing.

  • 21.
    Hijazi, Ziad
    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.
    Oldgren, Jonas
    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.
    Siegbahn, Agneta
    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.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Application of Biomarkers for Risk Stratification in Patients with Atrial Fibrillation2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 11, p. 152-164Article, review/survey (Refereed)
    Abstract [en]

    BACKGROUND: Atrial fibrillation is the most common sustained arrhythmia and an important contributor to cardiovascular morbidity and mortality. Several strategies have been proposed for prediction of outcomes and individualization of treatments to better balance the benefits of stroke prevention and risks of bleeding during anticoagulation. CONTENT: The availability of analytically more specific and sensitive methods to measure circulating biomarkers of cellular and organ stress and dysfunction has led to testing of their utility in several cardiovascular conditions. In patients with atrial fibrillation, biomarkers of myocardial injury (troponin) and cardiovascular stress and dysfunction (natriuretic peptides, growth differentiation factor 15), myocardial fibrosis (galectin-3), renal dysfunction (creatinine, cystatin C), inflammation (C reactive protein, cytokines) and coagulation activity (D-dimer) have been found associated with underlying pathophysiology, clinical outcomes and effects of treatment. Measurements of these markers might therefore expand the understanding of the pathophysiology, improve risk assessment and optimize treatment in individual patients with atrial fibrillation. SUMMARY: Biomarkers for risk stratification have potential roles as tools for evaluation of patients with atrial fibrillation and for selection of the best treatment strategies to prevent stroke, major bleeding, and mortality.

  • 22.
    Hijazi, Ziad
    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.
    Siegbahn, Agneta
    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.
    Andersson, Ulrika
    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, 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.
    Granger, Christopher
    Duke Clinical Research Institute, Durham, NC, US.
    Alexander, John H
    Duke Clinical Research Institute, Durham, NC, US.
    Atar, Dan
    Department of Cardiology, Oslo University Hospital Ulleval and Faculty of Medicine, Institute for Clinical Medicine, University of Oslo, Norway.
    Gersh, Bernard
    Mayo Clinic College of Medicine, Rochester, MN, US.
    Hanna, Michael
    Bristol-Myers Squibb, Princeton, NJ, US.
    Harjola, Veli-Pekka
    Horowitz, John D
    Hylek, Elaine M
    Lopes, Renato D
    McMurray, John JV
    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.
    Comparison of Cardiac Troponins I and T Measured with High-Sensitivity Methods for Evaluation of Prognosis in Atrial Fibrillation: An ARISTOTLE Substudy2015In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 61, no 2, p. 368-378Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Although cardiac troponin is associated with outcomes in atrial fibrillation (AF), the complementary prognostic information provided by cardiac troponin I (cTnI) and cTnT is unknown. This study investigated the distribution, determinants, and prognostic value of cTnI and cTnT concentrations in patients with AF.

    METHODS:

    At the time of randomization, we analyzed cTnI and cTnT concentrations of 14 806 AF patients in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial using high-sensitivity assays. Correlations (Spearman), determinants (multiple analysis of variance), and outcomes (adjusted Cox models and c-statistics) were investigated.

    RESULTS:

    Concentrations of cTnI and cTnT were correlated (r = 0.70) and measurable in most participants [cTnI 98.5% (median 5.4 ng/L, ≥99th percentile in 9.2%) and cTnT 93.5% (median 10.9 ng/L, ≥99th percentile in 34.4%)]. Renal impairment was the most important factor affecting the concentrations of both troponins. cTnI increase was more associated with heart failure, vascular disease, and persistent/permanent AF, and cTnT with age, male sex, and diabetes. Over a median 1.9 years of follow-up, patients with both troponins above the median had significantly higher risk for stroke/systemic embolism [hazard ratio (HR) 1.72 (95% CI 1.31-2.27)], cardiac death [3.14 (2.35-4.20)], and myocardial infarction [2.99 (1.78-5.03)] than those with both troponins below median (all P < 0.005). Intermediate risks were observed when only 1 troponin was above the median. When combined with clinical information, each marker provided similar prognostication and had comparable c-statistics.

    CONCLUSIONS:

    cTnI and cTnT concentrations are moderately correlated and measurable in plasma of most AF patients. The risk of stroke and cardiovascular events is highest when both troponins are above median concentrations. Each troponin provides comparable prognostic information when combined with clinical risk factors.

  • 23. Ho, J. E.
    et al.
    Mahajan, A.
    Chen, M. -H
    Larson, M. G.
    McCabe, E. L.
    Ghorbani, A.
    Cheng, S.
    Johnson, A. D.
    Lindgren, C. M.
    Kempf, T.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ingelsson, E.
    Vasan, R. S.
    Januzzi, J.
    Wollert, K. C.
    Morris, A. P.
    Wang, T. J.
    Clinical and genetic correlates of growth differentiation factor 15 in the community2012In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 58, no 11, p. 1582-1591Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Growth differentiation factor 15(GDF15), a stress-responsive cytokine produced in cardiovascular cells under conditions of inflammation and oxidative stress, is emerging as an important prognostic marker in individuals with and without existing cardiovascular disease (CVD). We therefore examined the clinical and genetic correlates of circulating GDF15 concentrations, which have not been investigated collectively. METHODS: Plasma GDF15 concentrations were measured in 2991 participants in the Framingham Offspring Study who were free of clinically overt CVD (mean age, 59 years; 56% women). Clinical correlates of GDF15 were examined in multivariable analyses. We then conducted a genomewide association study of the GDF15 concentration that included participants in the Framingham Offspring Study and participants in the PIVUS (Prospective Investigation of the Vasculature in Uppsala Seniors) study. RESULTS: GDF15 was positively associated with age, smoking, antihypertensive treatment, diabetes, worse kidney function, and use of nonsteroidal antiinflammatory drugs (NSAIDs), but it was negatively associated with total cholesterol and HDL cholesterol. Clinical correlates accounted for 38% of interindividual variation in the circulating GDF15 concentration, whereas genetic factors accounted for up to 38% of the residual variability (h 2 = 0.38; P = 2.5 X 10 -11). We identified 1 locus of genomewide significance. This locus, which is on chromosome 19p13.11 and includes the GDF15 gene, is associated with GDF15 concentration (smallest P = 2.74 X 10 -32 for rs888663). Conditional analyses revealed 2 independent association signals at this locus (rs888663 and rs1054564), which were associated with altered cis gene expression in blood cell lines. CONCLUSIONS: In ambulatory individuals, both cardiometabolic risk factors and genetic factors play important roles in determining circulating GDF15 concentrations and contribute similarly to the overall variation.

  • 24. Jaffe, Allan S
    et al.
    Apple, Fred S
    Morrow, David A
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Katus, Hugo A
    Being rational about (im)precision: a statement from the Biochemistry Subcommittee of the Joint European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Heart Federation Task Force for the definition of myocardial infarction2010In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 56, no 6, p. 941-943Article in journal (Refereed)
  • 25. Jalanko, A
    et al.
    Kere, J
    Savilahti, E
    Schwartz, M
    Syvänen, Ann-Christine
    Ranki, M
    Söderlund, H
    Screening for defined cystic fibrosis mutations by solid-phase minisequencing1992In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 38, no 1, p. 39-43Article in journal (Refereed)
    Abstract [en]

    We have developed a rapid method for the quantitative detection of point mutations and deletions. In this minisequencing method, enzymatically amplified DNA, 5'-biotinylated in one strand, is bound to a solid phase and denatured. A detection primer, constructed to end immediately before the mutation, is annealed to the immobilized single-stranded template and elongated with a single, labeled deoxynucleoside residue. We have applied the solid-phase minisequencing method to the detection of the major mutation, delta F508, causing cystic fibrosis (CF). In the presence of the allele with the delta F508 mutation, [3H]dTTP is incorporated; with the nonmutated allele, [3H]dCTP is incorporated. Thus, samples from heterozygous individuals allow the incorporation of both labels. The method was evaluated by analyzing 59 coded DNA specimens collected from 20 Finnish CF patients and their parents. The ratio of [3H]C to [3H]T gave unambiguously the allele combination. The solid-phase minisequencing method was also applicable to the analysis of three CF mutations simultaneously, i.e., delta F508, G542X, and G551D. We conclude that the microtiter-plate-based minisequencing test is an accurate method for the screening of defined sequence alterations in the CF gene.

  • 26.
    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

  • 27. Kempf, Tibor
    et al.
    Horn-Wichmann, Rüdiger
    Brabant, Georg
    Peter, Timo
    Allhoff, Tim
    Klein, Gunnar
    Drexler, Helmut
    Johnston, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wollert, Kai C.
    Circulating concentrations of growth-differentiation factor 15 in apparently healthy elderly individuals and patients with chronic heart failure as assessed by a new immunoradiometric sandwich assay2007In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 53, no 2, p. 284-291Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Growth-differentiation factor 15 (GDF15) is a member of the transforming growth factor beta (TGF-beta) cytokine superfamily. There has been increasing interest in using circulating GDF15 as a biomarker in patients, for example those with cardiovascular disease. METHODS: We developed an IRMA that uses a polyclonal, affinity chromatography-purified goat antihuman GDF15 IgG antibody, assessed the preanalytic characteristics of GDF15, and determined circulating GDF15 concentrations in 429 apparently healthy elderly individuals and 153 patients with chronic heart failure (CHF). RESULTS: The assay had a detection limit of 20 ng/L, an intraassay imprecision of < or =10.6%, and an interassay imprecision of < or =12.2%. Specificity was demonstrated with size-exclusion chromatography, parallel measurements with polyclonal and monoclonal anti-GDF15 antibody, and lack of cross-reactivity with TGF-beta. The assay was not appreciably influenced by the anticoagulant matrix or unrelated biological substances. GDF15 was stable at room temperature for 48 h and resistant to 4 freeze-thaw cycles. Apparently healthy, elderly individuals presented with a median GDF15 concentration of 762 ng/L (25th-75th percentiles, 600-959 ng/L). GDF15 concentrations were associated with age and with cystatin C and C-reactive protein concentrations. CHF patients had increased GDF15 concentrations that were closely related to disease severity. CONCLUSION: The IRMA can detect GDF15 in human serum and plasma with excellent sensitivity and specificity. The reference limits and confounding variables defined for apparently healthy elderly individuals and the favorable preanalytic characteristics of GDF15 are expected to facilitate future studies of GDF15 as a biomarker in various disease settings, including CHF.

  • 28. Kontula, K
    et al.
    Aalto-Setälä, K
    Kuusi, T
    Hämäläinen, L
    Syvänen, Ann-Christine
    Apolipoprotein E polymorphism determined by restriction enzyme analysis of DNA amplified by polymerase chain reaction: convenient alternative to phenotyping by isoelectric focusing1990In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 36, no 12, p. 2087-2092Article in journal (Refereed)
    Abstract [en]

    Three common alleles determine six apolipoprotein E (apo E) phenotypes that are associated with variations in serum cholesterol in the population. This genetic variation results from single nucleotide alterations at two DNA loci encoding the amino acid residues 112 and 158 of apo E. We compared results of apo E phenotyping carried out by isoelectric focusing with those of apo E genotyping accomplished by direct DNA analysis. In the latter, the target DNA was amplified by the polymerase chain reaction (PCR) and subsequently analyzed by digestion with the restriction enzyme Hha I, followed by polyacrylamide gel electrophoresis of the cleavage products. With one exception, these two techniques yielded similar results from all 40 samples tested. In addition, a rare variant form of apo E (phenotype E1) was analyzed separately and incorrectly diagnosed as E2 by the Hha I digestion method; the anticipated mutation in the codon 127 was, however, confirmed by demonstration of a new Taq I restriction site in this variant gene. These data confirm that the common isoforms of apo E usually arise from genetic variation of the codons 112 and 158 and demonstrate the feasibility of the PCR technique in apo E genotyping.

  • 29.
    Kushnir, Mark M
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Naessen, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Kirilovas, Dmitrijus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Chaika, Andrey
    Nosenko, Jelena
    Mogilevkina, Iryna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Rockwood, Alan L
    Carlström, Kjell
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry, Analytical Chemistry.
    Steroid profiles in ovarian follicular fluid from regularly menstruating women and women after ovarian stimulation2009In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 55, no 3, p. 519-526Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Information on the concentrations of steroids in ovarian follicular fluid (FF) from regularly menstruating (RM) women has been limited because of the absence of methods for the simultaneous quantification of multiple steroids in small volumes of FF. We studied steroid profiles in FF during the early follicular phase of the menstrual cycle and after ovarian stimulation for in vitro fertilization (IVF), and compared concentrations with published values obtained by immunoassay (IA). METHODS: We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure 13 steroids in 40-microL aliquots of FF samples from 21 RM women and from 5 women after ovarian stimulation for IVF. Relationships between concentrations of steroids and their ratios (representations of the enzyme activities) were evaluated within and between subgroups. RESULTS: The concentrations of testosterone (Te), androstenedione (A4), and estradiol (E2) measured by LC-MS/MS were lower than those previously reported in studies with IAs. In RM women, androgens were the most abundant class of steroids, with A4 being the major constituent. The concentrations of 17-hydroxyprogesterone (17OHP), total androgens, and estrogens were 200- to 1000-fold greater in FF than in serum. Compared with RM women, FF samples from women undergoing ovarian stimulation had significantly higher concentrations of E2 (P = 0.021), pregnenolone (P = 0.0022), 17OHP (P = 0.0007), and cortisol (F) (P = 0.0016), and significantly higher ratios of F to cortisone (P = 0.0006), E2 to estrone (P = 0.0008), and E2 to Te (P = 0.0013). CONCLUSIONS: The data provide the first MS-based concentration values for 13 steroids in ovarian FF from RM women, from estrogen- and androgen-dominant follicles, and from women after ovarian stimulation for IVF.

  • 30.
    Larsson, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hansson, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Flodin, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Katz, Ronit
    Shlipak, Michael G.
    Calibration of the Siemens Cystatin C Immunoassay Has Changed over Time2011In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 57, no 5, p. 777-778Article in journal (Refereed)
  • 31. Lempiäinen, Anna
    et al.
    Hotakainen, Kristina
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Alfthan, Henrik
    Stenman, Ulf-Håkan
    Increased human chorionic gonadotropin due to hypogonadism after treatment of a testicular seminoma2007In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 53, no 8, p. 1560-1561Article in journal (Refereed)
  • 32. Lempiäinen, Anna
    et al.
    Stenman, Ulf-Håkan
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Hotakainen, Kristina
    Free beta-subunit of human chorionic gonadotropin in serum is a diagnostically sensitive marker of seminomatous testicular cancer2008In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 54, no 11, p. 1840-3Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We studied whether measurement of the free beta subunit of human chorionic gonadotropin (hCGbeta) in serum offers additional diagnostic information compared to determination of intact hCG alone in testicular cancer. METHODS: We determined hCG and hCGbeta with ultrasensitive assays in 94 serum samples obtained preoperatively, 22 samples obtained during relapse, and 3687 samples obtained during routine follow-up of 351 patients with testicular tumors. RESULTS: In preoperative samples, isolated increases of hCGbeta were seen in 40% of the samples from seminoma patients (n = 42) and in 8% of those from patients with nonseminomatous testicular cancer (NSGCT) (n = 51). Both markers were increased in 12% of the seminoma and 71% of the NSGCT patients and were within reference intervals in 43% of the seminoma and 20% of the NSGCT patients. Specific determination of hCGbeta increased the frequency of marker-positive seminomas from 17% to 57% and of marker-positive relapses from 32% to 59% (n = 22). Theoretically, about 40% of marker-positive seminomas and relapses would have been missed with an assay measuring hCG and hCGbeta together. Preoperative hCG and hCGbeta concentrations correlated with stage, tumor histology, and disease-related mortality. Additionally, hCGbeta correlated with tumor size. CONCLUSIONS: hCGbeta is a diagnostically sensitive marker for testicular cancer. In patients with seminomatous testicular cancer, hCGbeta is superior to hCG, and in some NSGCT patients it provides additional information.

  • 33.
    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.
    Are there really biomarkers of vulnerable plaque?2012In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 58, no 1, p. 151-153Article in journal (Refereed)
  • 34.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Multimarker approach for diagnosis of acute myocardial infarction: better answers need better questions2009In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 55, no 1, p. 9-11Article in journal (Refereed)
  • 35.
    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.
    The Story of Growth Differentiation Factor 15: Another Piece of the Puzzle2013In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 59, no 11, p. 1550-1552Article in journal (Other academic)
  • 36.
    Lindholm, Daniel P
    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.
    James, Stefan K
    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.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Richard C
    Cannon, Christopher P
    Giannitsis, Evangelos
    Harrington, Robert A
    Himmelmann, Anders
    Kontny, Frederic
    Siegbahn, Agneta
    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.
    Steg, Philippe Gabriel
    Storey, Robert F
    Velders, Matthijs A
    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.
    Weaver, W Douglas
    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.
    Biomarkers and Coronary Lesions Predict Outcomes after Revascularization in Non-ST-Elevation Acute Coronary Syndrome2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 2, p. 573-584Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Risk stratification in non-ST-elevation acute coronary syndrome (NSTE-ACS) is currently mainly based on clinical characteristics. With routine invasive management, angiography findings and biomarkers are available and may improve prognostication. We aimed to assess if adding biomarkers [high-sensitivity cardiac troponin T (cTnT-hs), N-terminal probrain-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15)] and extent of coronary artery disease (CAD) might improve prognostication in revascularized patients with NSTE-ACS.

    METHODS: In the PLATO (Platelet Inhibition and Patient Outcomes) trial, 5174 NSTE-ACS patients underwent initial angiography and revascularization and had cTnT-hs, NT-proBNP, and GDF-15 measured. Cox models were developed adding extent of CAD and biomarker levels to established clinical risk variables for the composite of cardiovascular death (CVD)/spontaneous myocardial infarction (MI), and CVD alone. Models were compared using c-statistic and net reclassification improvement (NRI).

    RESULTS: For the composite end point and CVD, prognostication improved when adding extent of CAD, NT-proBNP, and GDF-15 to clinical variables (c-statistic 0.685 and 0.805, respectively, for full model vs 0.649 and 0.760 for clinical model). cTnT-hs did not contribute to prognostication. In the full model (clinical variables, extent of CAD, all biomarkers), hazard ratios (95% CI) per standard deviation increase were for cTnT-hs 0.93(0.81-1.05), NT-proBNP 1.32(1.13-1.53), GDF-15 1.20(1.07-1.36) for the composite end point, driven by prediction of CVD by NT-proBNP and GDF-15. For spontaneous MI, there was an association with NT-proBNP or GDF-15, but not with cTnT-hs.

    CONCLUSIONS: In revascularized patients with NSTE-ACS, the extent of CAD and concentrations of NT-proBNP and GDF-15 independently improve prognostication of CVD/spontaneous MI and CVD alone. This information may be useful for selection of patients who might benefit from more intense and/or prolonged antithrombotic treatment.

  • 37.
    Lindqvist, Ulla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Chichibu, Kenji
    Delpech, Bertrand
    Goldberg, Ronald L.
    Knudson, Warren
    Poole, A. Robin
    Laurent, Torvald C.
    Seven different assays of hyaluronan compared for clinical utility1992In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 38, no 1, p. 127-132Article in journal (Refereed)
    Abstract [en]

    To compare six assays of hyaluronan (hyaluronic acid; HYA) in serum, developed in different laboratories, we analyzed 10 samples from each of three groups: healthy persons, patients with primary biliary cirrhosis, and patients with rheumatoid arthritis. All the assays are based on the use of affinity proteins specific for HYA, prepared from cartilage or brain tissue, and are analogous to RIA or enzyme immunoassay techniques. The assay results were of the same magnitude. Although statistical analysis indicated that the methods in some cases deviated significantly from one another, this variation was less than the physiological variation in the healthy population. Therefore, the results of clinical investigations in which the various methods have been used are comparable. The analyses have high specificity and sensitivity for primary biliary cirrhosis but are somewhat less suitable for detecting rheumatoid arthritis. A seventh laboratory, which obtained antibodies to HYA, used these in an RIA to analyze a separate series of serum specimens. Results were in agreement with those obtained by one of the other assays.

  • 38.
    Mueller-Hennessen, Matthias
    et al.
    Univ Heidelberg Hosp, Dept Internal Med 3, Cardiol Angiol & Pulmonol, Heidelberg, Germany..
    Mueller, Christian
    Univ Basel Hosp, Cardiol &Cardiovasc Res Inst Basel, Basel, Switzerland..
    Giannitsis, Evangelos
    Univ Heidelberg Hosp, Dept Internal Med 3, Cardiol Angiol & Pulmonol, Heidelberg, Germany..
    Biener, Moritz
    Univ Heidelberg Hosp, Dept Internal Med 3, Cardiol Angiol & Pulmonol, Heidelberg, Germany..
    Vafaie, Mehrshad
    Univ Heidelberg Hosp, Dept Internal Med 3, Cardiol Angiol & Pulmonol, Heidelberg, Germany..
    deFilippi, Christopher R.
    Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA..
    Christ, Michael
    Community Hosp, Dept Emergency & Crit Care Med, Nurnberg, Germany.;Paracelsus Med Univ, Nurnberg, Germany..
    Ordonez-Llanos, Jorge
    Inst Invest Biomed St Pau, Dept Clin Biochem, Barcelona, Spain..
    Panteghini, Mauro
    Univ Milan, Sch Med, Dept Biomed & Clin Sci Luigi Sacco, Milan, Italy..
    Plebani, Mario
    Univ Hosp Padova, Dept Lab Med, Padua, Italy..
    Verschuren, Franck
    Clin Univ St Luc, Dept Acute Med, Brussels, Belgium.;Catholic Univ Louvain, Brussels, Belgium..
    Melki, Dina
    Karolinska Inst, Dept Med, Huddinge, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    French, John K.
    Liverpool Hosp, Sydney, NSW, Australia.;Univ New South Wales, Sydney, NSW, Australia..
    Christenson, Robert H.
    Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA..
    Body, Richard
    Cent Manchester Univ Hosp NHS Fdn Trust, Manchester, Lancs, England..
    McCord, James
    Henry Ford Hlth Syst, Henry Ford Heart & Vasc Inst, Detroit, MI USA..
    Dinkel, Carina
    Roche Diagnost Germany, Penzberg, Germany..
    Katus, Hugo A.
    Univ Heidelberg Hosp, Dept Internal Med 3, Cardiol Angiol & Pulmonol, Heidelberg, Germany..
    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.
    Serial Sampling of High-Sensitivity Cardiac Troponin T May Not Be Required for Prediction of Acute Myocardial Infarction Diagnosis in Chest Pain Patients with Highly Abnormal Concentrations at Presentation2017In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 63, no 2, p. 542-551Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Guidelines for diagnosing acute myocardial infarction (AMI) recommend adding kinetic changes to the initial cardiac troponin (cTn) blood concentration to improve AMI diagnosis. We hypothesized that kinetic changes may not be required in patients presenting with highly abnormal cTn.

    METHODS: Patients presenting with suspected AMI to the emergency department were enrolled in a prospective diagnostic study. We assessed the positive predictive value (PPV) of initial high-sensitivity cardiac troponin T (hs-cTnT) blood concentrations alone and in combination with kinetic changes for AMI. Predefined relative changes (delta change of >= 20%) and absolute changes (Delta change 9.2 >= ng/L) within different time intervals (1 h, 2 h, and 4-14 h after presentation) were assessed. The final diagnosis was adjudicated by 2 independent cardiologists.

    RESULTS: Among 1282 patients, 213 (16.6%) patients had a final diagnosis of AMI. For AMI prediction, PPVs increased from 48.8% for an initial hs-cTnT >14 ng/L to 87.2% for >60 ng/L, whereas PPVs remained unchanged for higher hs-cTnT concentrations at baseline (87.1% for both >80 ng/L and >100 ng/L). With addition of 20% relative Delta change, PPVs were not further improved in patients with baseline hs-cTnT >80 ng/L using the 1-h (84.0%) and 2-h (88.9%) intervals, and only minimally when extending the interval to 4-14 h (91.2% for >80 ng/L and 90.4% for >100 ng/L, respectively). Similar findings were observed when applying absolute changes.

    CONCLUSIONS: In chest pain patients with highly abnormal hs-cTnT concentrations at presentation, subsequent blood draws may not be required, as they do not provide incremental diagnostic value for prediction of AMI diagnosis.

  • 39.
    Myhre, Peder L.
    et al.
    Akershus Univ Hosp, Div Med, Sykehusveien 25, N-1478 Lorenskog, Norway.;Univ Oslo, Ctr Heart Failure Res, Oslo, Norway..
    Ottesen, Anett H.
    Akershus Univ Hosp, Div Med, Sykehusveien 25, N-1478 Lorenskog, Norway.;Univ Oslo, Ctr Heart Failure Res, Oslo, Norway..
    Okkonen, Marjatta
    Oslo Univ Hosp Ulleval, Ctr Clin Heart Res, Oslo, Norway.;Univ Helsinki, Intens Care & Pain Med, Dept Anesthesiol, Div Intens Care Med, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Linko, Rita
    Oslo Univ Hosp Ulleval, Ctr Clin Heart Res, Oslo, Norway.;Univ Helsinki, Intens Care & Pain Med, Dept Anesthesiol, Div Intens Care Med, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland..
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Nygård, Ståle
    Oslo Univ Hosp, Bioinformat Core Facil, Oslo, Norway.;Univ Oslo, Oslo, Norway..
    Christensen, Geir
    Univ Oslo, Ctr Heart Failure Res, Oslo, Norway.;Oslo Univ Hosp, Expt Med Res Inst, Oslo, Norway..
    Pettilä, Ville
    Oslo Univ Hosp Ulleval, Ctr Clin Heart Res, Oslo, Norway.;Univ Helsinki, Intens Care & Pain Med, Dept Anesthesiol, Div Intens Care Med, Helsinki, Finland.;Helsinki Univ Hosp, Helsinki, Finland.;Univ Bern, Univ Hosp Bern, Dept Intens Care Med, Bern, Switzerland..
    Omland, Torbjörn
    Akershus Univ Hosp, Div Med, Sykehusveien 25, N-1478 Lorenskog, Norway.;Univ Oslo, Ctr Heart Failure Res, Oslo, Norway..
    Rösjö, Helge
    Akershus Univ Hosp, Div Med, Sykehusveien 25, N-1478 Lorenskog, Norway.;Univ Oslo, Ctr Heart Failure Res, Oslo, Norway..
    Prognostic Value of Secretoneurin in Patients with Acute Respiratory Failure: Data from the FINNALI Study2016In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 62, no 10, p. 1380-1389Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We examined whether secretoneurin (SN), a biomarker associated with cardiomyocyte Ca2+ handling, provides prognostic information in patients with acute respiratory failure (ARF).

    METHODS: We included 490 patients with ARF, defined as ventilatory support >6 h, with blood samples available on admission to the intensive care unit (ICU). SN concentrations were measured by RIA.

    RESULTS: A total of 209 patients (43%) were hospitalized with cardiovascular (CV)-related ARF, and 90-day mortality rates were comparable between CV- and non CV-related ARF (n = 281): 31% vs 24%, P = 0.11. Admission SN concentrations were higher in nonsurvivors than in survivors in both CV -related (median 148 [quartile 1-3, 117-203] vs 108 [87-143] pmol/L, P < 0.001) and non CV-related ARF (139 [115-184] vs 113 [91-139] pmol/L, P < 0.001). In patients with CV -related ARF, SN concentrations on ICU admission were associated with 90-day mortality [odds ratio (OR) 1.97 (95% CI, 1.04-3.73, P = 0.04)] after adjusting for established risk indices, including N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentrations. SN also improved patient classification in CV -related ARF as assessed by the net reclassification index: 0.32 (95% CI, 0.04-0.59), P = 0.03. The area under the curve (AUC) of SN to predict mortality in patients with CV -related ARF was 0.72 (95% CI, 0.65-0.79), and the AUC of NT-proBNP was 0.64 (0.56-0.73). In contrast, SN concentrations on ICU admission did not provide incremental prognostic value to established risk indices in patients with non CV-related ARF, and the AUC was 0.67 (0.60-0.75).

    CONCLUSIONS: SN concentrations measured on ICU admission provided incremental prognostic information to established risk indices in patients with CV -related ARF, but not in patients with non CV-related ARF.

  • 40.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Unraveling the Transcriptional Heterogeneity in Human Colon Cancer: Potential New Insights regarding Pathobiology and Treatment2012In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 58, no 6, p. 966-967Article in journal (Other academic)
  • 41. 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.

  • 42. Pastinen, T
    et al.
    Partanen, J
    Syvänen, Ann-Christine
    Multiplex, fluorescent, solid-phase minisequencing for efficient screening of DNA sequence variation1996In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 42, no 9, p. 1391-1397Article in journal (Refereed)
    Abstract [en]

    We developed a multiplex, solid-phase minisequencing method to detect multiple single-nucleotide polymorphisms in an undivided sample. The amplified DNA templates are first captured on a manifold. Then, with multiple minisequencing primers of various sizes, single-nucleotide extension reactions are carried out simultaneously with fluorescently labeled dideoxynucleotides. The size of the extended product, determined by using a DNA sequencing instrument, defines the site of the polymorphisms, and the incorporated nucleotide gives the identity of the nucleotide at each site. HLA-DQA1 typing was used as a model system to evaluate the method. The DR2 subgroup of the HLA-DRB1 gene was typed along with the DQA1 gene to demonstrate the feasibility of the method in analyzing multiple genes at multiple sites simultaneously. The method is generally applicable for screening any single-nucleotide polymorphisms or point mutations, and its manifold format allows practical handling of large numbers of samples.

  • 43.
    Paulmichl, Katharina
    et al.
    Paracelsus Med Univ, Dept Pediat, Div Pediat Gastroenterol Hepatol & Nutr, Mullner Hauptstr 48, A-5020 Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria..
    Hatunic, Mensud
    Mater Misericordiae Univ Hosp, Dublin, Ireland..
    Hojlund, Kurt
    Odense Univ Hosp, Dept Endocrinol, Odense, Denmark.;Univ Southern Denmark, Dept Clin Res, Odense, Denmark.;Univ Southern Denmark, Inst Mol Med, Odense, Denmark..
    Jotic, Aleksandra
    Univ Belgrade, Fac Med, Clin Ctr Serbia, Clin Endocrinol Diabet & Metab Disorders, Belgrade, Serbia..
    Krebs, Michael
    Med Univ Vienna, Div Endocrinol & Metab, Dept Internal Med 3, Wahringer Gurtel 18-20, A-1090 Vienna, Austria..
    Mitrakou, Asimina
    Univ Athens, Sch Med, Dept Clin Therapeut, Alexandra Hosp, Athens, Greece..
    Porcellati, Francesca
    Univ Perugia, Dept Internal Med, Perugia, Italy..
    Tura, Andrea
    CNR, IN, Metab Unit, Padua, Italy..
    Bergsten, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Forslund, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Manell, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Widhalm, Kurt
    Paracelsus Med Univ, Dept Pediat, Div Pediat Gastroenterol Hepatol & Nutr, Mullner Hauptstr 48, A-5020 Salzburg, Austria..
    Weghuber, Daniel
    Paracelsus Med Univ, Dept Pediat, Div Pediat Gastroenterol Hepatol & Nutr, Mullner Hauptstr 48, A-5020 Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria..
    Anderwald, Christian-Heinz
    Paracelsus Med Univ, Dept Pediat, Div Pediat Gastroenterol Hepatol & Nutr, Mullner Hauptstr 48, A-5020 Salzburg, Austria.;Med Univ Vienna, Div Endocrinol & Metab, Dept Internal Med 3, Wahringer Gurtel 18-20, A-1090 Vienna, Austria.;CNR, IN, Metab Unit, Padua, Italy.;Mariahilf Community Pharm, Arnoldstein, Austria..
    Modification and Validation of the Triglyceride-to-HDL Cholesterol Ratio as a Surrogate of Insulin Sensitivity in White Juveniles and Adults without Diabetes Mellitus: The Single Point Insulin Sensitivity Estimator (SPISE)2016In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 62, no 9, p. 1211-1219Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The triglyceride-to-HDL cholesterol (TG/HDL-C) ratio was introduced as a tool to estimate insulin resistance; because circulating lipid measurements are available in routine settings. Insulin, C-peptide, and free fatty acids are components of other insulin-sensitivity indices but their measurement is expensive. Easier and more affordable tools are of interest for both pediatric and adult patients. METHODS: Study participants from the Relationship Between Insulin Sensitivity and Cardiovascular Disease [43.9 (8.3) years, n = 1260] as well as the Beta-Cell Function in Juvenile Diabetes and Obesity study cohorts [15 (1.9) years, n = 29] underwent oral-glucose-tolerance tests and euglycemic clamp tests for estimation of whole-body insulin sensitivity and calculation of insulin sensitivity indices. To refine the TG/HDL ratio, mathematical modeling was applied including body mass index (BMI), fasting TG, and HDL cholesterol and compared to the clamp-derived M-value as an estimate of insulin sensitivity. Each modeling result was scored by identifying insulin resistance and correlation coefficient. The Single Point Insulin Sensitivity Estimator (SPISE) was compared to traditional insulin sensitivity indices using area under the ROC curve (aROC) analysis and chi(2) test. RESULTS: The novel formula for SPISE was computed as follows: SPISE = 600 X HDL-C-0.185/(TG(0.2) X BMI1.338), with fasting HDL-C (mg/dL), fasting TG concentrations (mg/dL), and BMI (kg/m(2)). A cutoff value of 6.61 corresponds to an M-value smaller than 4.7 mg . kg(-1) . min(-1) (aROC, M:0.797). SPISE showed a significantly better aROC than the TG/HDL-C ratio. SPISE aROC was comparable to the Matsuda ISI (insulin sensitivity index) and equal to the QUICKI (quantitative insulin sensitivity check index) and HOMA-IR (homeostasis model assessment insulin resistance) when calculated with M-values. CONCLUSIONS: The SPISE seems well suited to surrogate whole-body insulin sensitivity from inexpensive fasting single-point blood draw and BMI in white adolescents and adults.

  • 44. Paunio, T
    et al.
    Reima, I
    Syvänen, Ann-Christine
    Preimplantation diagnosis by whole-genome amplification, PCR amplification, and solid-phase minisequencing of blastomere DNA1996In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 42, no 9, p. 1382-1390Article in journal (Refereed)
    Abstract [en]

    We have developed a new method for preimplantation diagnosis of inherited diseases. Our procedure for the identification of point mutations in single cells combines whole-genome amplification using 15-mer random primers (primer extension preamplification, PEP) with a single locus-specific PCR amplification, followed by detection of the mutation by solid-phase minisequencing. The procedure was evaluated by detecting three disease-causing mutations and seven polymorphic nucleotides located on different human chromosomes from single granuloma and blastomere cells. The correct genotype of the cell was identified at 96% of the nucleotide positions analyzed, showing that a representative part of the genome is amplified during PEP. We estimate that PEP yielded at least 1000 copies of the genome. The quantitative nature of the solid-phase minisequencing method allowed us to notice that preferential amplification of one allele occurs at heterozygous loci during PEP, which is a potential problem in preimplantation diagnosis.

  • 45. Rosenling, Therese
    et al.
    Stoop, Marcel P
    Smolinska, Agnieszka
    Muilwijk, Bas
    Coulier, Leon
    Shi, Shanna
    Dane, Adrie
    Christin, Christin
    Suits, Frank
    Horvatovich, Peter L
    Wijmenga, Sybren S
    Buydens, Lutgarde M C
    Vreeken, Rob
    Hankemeier, Thomas
    van Gool, Alain J
    Luider, Theo M
    Bischoff, Rainer
    The Impact of Delayed Storage on the Measured Proteome and Metabolome of Human Cerebrospinal Fluid2011In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 57, no 12, p. 1703-1711Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Because cerebrospinal fluid (CSF) is in close contact with diseased areas in neurological disorders, it is an important source of material in the search for molecular biomarkers. However, sample handling for CSF collected from patients in a clinical setting might not always be adequate for use in proteomics and metabolomics studies. METHODS: We left CSF for 0, 30, and 120 min at room temperature immediately after sample collection and centrifugation/removal of cells. After tryptic digestion at 2 laboratories by nanoLC Orbitrap-MS and chipLC QTOF-MS, CSF proteomes were analyzed. Metabolome analysis was performed at 3 laboratories by NMR, GC-MS, and LC-MS. Targeted analyses of cystatin C and albumin were performed by LC-MS/MS in the selected reaction monitoring mode. RESULTS: We did not find significant changes in the measured proteome and metabolome of CSF stored at room temperature after centrifugation, except for 2 peptides and 1 metabolite, 2,3,4-trihydrobutanoic acid, of 5780 identified peptides and 93 identified metabolites. A sensitive protein stability marker, cystatin C, was not affected. CONCLUSIONS: The measured proteome and metabolome of centrifuged, human CSF is stable at room temperature for up to 2 hours. We cannot exclude, however, that changes undetectable with our current methodology, such as denaturation or proteolysis, might occur due to sample handling conditions. The stability we observed gives laboratory personnel at the collection site sufficient time to aliquot samples before freezing and storage at -80 °C.

  • 46.
    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.

  • 47. Savukoski, Tanja
    et al.
    Engstrom, Emilia
    Engblom, Janne
    Ristiniemi, Noora
    Wittfooth, Saara
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    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.
    Pettersson, Kim
    Troponin-Specific Autoantibody Interference in Different Cardiac Troponin I Assay Configurations2012In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 58, no 6, p. 1040-1048Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Autoantibodies to cardiac troponins (cTnAAb) can interfere with the measurement of cardiac troponin I (cTnI) by immunoassays. The aim of this study was to explore the degree of cTnAAb interference in different cTnI assay configurations. METHODS: Ternary troponin complex was added into samples (serum or plasma, n = 132, 68% cTnAAb positive) from individuals without known cardiac conditions. The recovery of cTnI was then measured with 6 investigational cTnI assays (2, 3, or 4 antibodies per assay). Three of these assays were then selected for further comparison by use of samples (plasma, n = 210, 33% cTnAAb positive) from non-ST-elevation acute coronary syndrome patients in the FRISC-II (FRagmin/Fast Revascularisation during InStability in Coronary artery disease) cohort. Finally, these results were compared to those obtained with 3 commercial cTnI assays. RESULTS: Analytical recoveries varied widely among the 6 investigational assays. Notably the low recoveries (median 9%) of the midfragment-targeting reference assay were normalized (median 103%) with the use of the 4-antibody assay construct (3 capture, 1 tracer antibody) with only 1 antibody against a midfragment epitope. Reduced analytical recoveries correlated closely with measured autoantibody amounts. cTnI concentrations from cTnAAb-positive patient samples determined with 3 investigational assays confirmed the reduced concentrations expected from the low analytical recoveries. The results from the commercial cTnI assays with antibody selections representative for contemporary assay constructs revealed a similar underestimation (up to 20-fold) of cTnI in cTnAAb-positive samples. CONCLUSIONS: A novel cTnI assay deviating from the conventional IFCC-recommended midfragment approach substantially improves cTnI detection in samples containing cTnAAbs.

  • 48. Shlipak, Michael G.
    et al.
    Weekley, Cristin C.
    Li, Yongmei
    Hansson, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Whooley, Mary
    Comparison of Cardiovascular Prognosis by 3 Serum Cystatin C Methods in the Heart and Soul Study2011In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 57, no 5, p. 737-745Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cystatin C is a promising new biomarker to estimate glomerular filtration (eGFR). However, the Siemens' cystatin C assay (Siemens), used in many longitudinal studies, has had limited clinical applicability because it requires a specific, dedicated instrument. Other companies, including Gentian and Roche, have developed cystatin C assays that can be used with most routine clinical chemistry analyzers. METHODS: We compared the agreement of Gentian and Roche with Siemens in 948 participants at the baseline visit of the Heart and Soul Study, a cohort of participants with established coronary artery disease who were followed for an average of 8 years. We then compared associations of all 3 cystatin C measures and eGFR-Modification of Diet in Renal Disease (MDRD) with clinical outcomes. RESULTS: The Gentian assay had higher correlation with Siemens (r = 0.96) than did Roche (r = 0.93, P < 0.001). After cross-tabulating quartiles of each cystatin C measure, agreements (κ statistic) were higher for Siemens and Gentian (0.73, 95% CI 0.72-0.75) than for Roche and Siemens (0.64, 0.63-0.66) or for Roche and Gentian (0.69, 0.65-0.71). These differences in agreement had minimal impact on associations with clinical outcomes; the hazard ratios (HRs) for mortality comparing the high vs low quartiles were 3.2 (95% CI 2.1-4.8) for Siemens, 3.1 (CI 2.1-4.7) for Gentian, 3.1 (CI 2.1-4.7) for Roche, and 1.6 (CI 1.1-2.3) for eGFR-MDRD, after multivariate adjustment. CONCLUSIONS: In summary, agreement with the Siemens' assay was modestly higher for the Gentian compared with the Roche assay, although all 3 methods for cystatin C measurement had similar utility as predictors of clinical outcomes.

  • 49. Soletormos, Gyorgy
    et al.
    Duffy, Michael J.
    Hayes, Daniel F.
    Sturgeon, Catharine M.
    Barak, Vivian
    Bossuyt, Patrick M.
    Diamandis, Eleftherios P.
    Gion, Massimo
    Hyltoft-Petersen, Per
    Lamerz, Rolf M.
    Nielsen, Dorte L.
    Sibley, Paul
    Tholander, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Tuxen, Malgorzata K.
    Bonfrer, Johannes M. G.
    Design of Tumor Biomarker-Monitoring Trials: A Proposal by the European Group on Tumor Markers2013In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 59, no 1, p. 52-59Article in journal (Refereed)
    Abstract [en]

    A major application of tumor biomarkers is in serial monitoring of cancer patients, but there are no published guidelines on how to evaluate biomarkers for this purpose. The European Group on Tumor Markers has convened a multidisciplinary panel of scientists to develop guidance on the design of such monitoring trials. The panel proposes a 4-phase model for biomarker-monitoring trials analogous to that in use for the investigation of new drugs. In phase I, biomarker kinetics and correlation with tumor burden are assessed. Phase II evaluates the ability of the biomarker to identify, exclude, and/or predict a change in disease status. In phase III, the effectiveness of tumor biomarker guided intervention is assessed by measuring patient outcome in randomized trials. Phase IV consists of an audit of the long-term effects after biomarker monitoring has been included into standard patient care. Systematic well-designed evaluations of biomarkers for monitoring may provide a stronger evidence base that might enable their earlier use in evaluating responses to cancer therapy.

  • 50. Starnberg, Karin
    et al.
    Jeppsson, Anders
    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.
    Hammarsten, Ola
    Revision of the Troponin T Release Mechanism from Damaged Human Myocardium2014In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 60, no 8, p. 1098-1104Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cardiac troponin T (cTnT) is released from damaged heart tissue in patients with acute myocardial infarction. It is presumed that most cTnT is tightly bound and released following the degradation of myofibrils in necrotic cardiomyocytes, resulting in sustained increases in circulating cTnT. Evidence of a large irreversibly bound fraction is based on the inability to extract most cTnT from cardiac tissue in cold low-salt extraction buffers. METHODS: Here we examined in vitro extraction of cTnT from human cardiac tissue in serum at 37 degrees C. RESULTS: We found that over 80% of the cTnT can be extracted from human cardiac tissue in 90 min using large volumes of human serum at 37 degrees C. The release ratio was highly dependent on the extraction volume and was only 3% if an equal volume of serum and heart tissue was used. In contrast, extraction of the cytoplasmic cardiac damage markers myoglobin and creatinine kinase was much less affected by changing these conditions. Purified cTnT was poorly soluble in a low-salt extraction buffer at 0 degrees C, previously used to define the free cTnT fraction. CONCLUSIONS: Our data indicate that the diffusible fraction of cTnT is likely substantially larger in vivo than previously reported and likely is not fixed but dependent on local plasma flow. It is therefore possible that the sustained increase in circulating cTnT after myocardial infarction is at least in part due to a slow washout of cTnT that interacts reversibly with tropomyosin in myofibrils.

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