| 1. |
- Lundberg, Peter, et al.
(författare)
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1H NMR determination of urinary betaine in patients with premature vascular disease and mild homocysteinemia
- 1995
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Ingår i: Clinical Chemistry. - 0009-9147 .- 1530-8561. ; 41:2, s. 275-283
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Tidskriftsartikel (refereegranskat)abstract
- Urinary N,N,N-trimethylglycine (betaine) and N,N-dimethylglycine (DMG) have been identified and quantified for clinical purposes by proton nuclear magnetic resonance (1H NMR) measurement in previous studies. We have assessed these procedures by using both one-dimensional (1-D) and 2-D NMR spectroscopy, together with pH titration of urinary extracts to help assign 1H NMR spectral peaks. The betaine calibration curve linearity was excellent (r = 0.997, P = 0.0001) over the concentration range 0.2-1.2 mmol/L, and CVs for replicate betaine analyses ranged from 7% (n = 10) at the lowest concentration to 1% (n = 9) at the highest. The detection limit for betaine was < 15 mumol/L. Urinary DMG concentrations were substantially lower than those of betaine. Urinary betaine and DMG concentrations measured by 1H NMR spectroscopy from 13 patients with premature vascular disease and 17 normal controls provided clinically pertinent data. We conclude that 1H NMR provides unique advantages as a research tool for determination of urinary betaine and DMG concentrations.
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| 2. |
- Aakre, K. M., et al.
(författare)
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Analytical Considerations in Deriving 99th Percentile Upper Reference Limits for High-Sensitivity Cardiac Troponin Assays: Educational Recommendations from the IFCC Committee on Clinical Application of Cardiac Bio-Markers
- 2022
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Ingår i: Clinical chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 68:8, s. 1022-1030
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Tidskriftsartikel (refereegranskat)abstract
- The International Federation of Clinical Chemistry Committee on Clinical Application of Cardiac Bio-Markers provides evidence-based educational documents to facilitate uniform interpretation and utilization of cardiac biomarkers in clinical laboratories and practice. The committee's goals are to improve the understanding of certain key analytical and clinical aspects of cardiac biomarkers and how these may interplay in clinical practice. Measurement of high-sensitivity cardiac troponin (hs-cTn) assays is a cornerstone in the clinical evaluation of patients with symptoms and/or signs of acute cardiac ischemia. To define myocardial infarction, the Universal Definition of Myocardial Infarction requires patients who manifest with features suggestive of acute myocardial ischemia to have at least one cTn concentration above the sex-specific 99th percentile upper reference limit (URL) for hs-cTn assays and a dynamic pattern of cTn concentrations to fulfill the diagnostic criteria for MI. This special report provides an overview of how hs-cTn 99th percentile URLs should be established, including recommendations about prescreening and the number of individuals required in the reference cohort, how statistical analysis should be conducted, optimal preanalytical and analytical protocols, and analytical/biological interferences or confounds that can affect accurate determination of the 99th percentile URLs. This document also provides guidance and solutions to many of the issues posed.
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| 3. |
- Aakre, Kristin M, et al.
(författare)
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Lower Limits for Reporting High-Sensitivity Cardiac Troponin Assays and Impact of Analytical Performance on Patient Misclassification.
- 2024
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Ingår i: Clinical chemistry. - 0009-9147 .- 1530-8561. ; 70:3, s. 497-505
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Tidskriftsartikel (refereegranskat)abstract
- Cardiac troponin measurements are indispensable for the diagnosis of myocardial infarction and provide useful information for long-term risk prediction of cardiovascular disease. Accelerated diagnostic pathways prevent unnecessary hospital admission, but require reporting cardiac troponin concentrations at low concentrations that are sometimes below the limit of quantification. Whether analytical imprecision at these concentrations contributes to misclassification of patients is debated.The International Federation of Clinical Chemistry Committee on Clinical Application of Cardiac Bio-Markers (IFCC C-CB) provides evidence-based educational statements on analytical and clinical aspects of cardiac biomarkers. This mini-review discusses how the reporting of low concentrations of cardiac troponins impacts on whether or not assays are classified as high-sensitivity and how analytical performance at low concentrations influences the utility of troponins in accelerated diagnostic pathways. Practical suggestions are made for laboratories regarding analytical quality assessment of cardiac troponin results at low cutoffs, with a particular focus on accelerated diagnostic pathways. The review also discusses how future use of cardiac troponins for long-term prediction or management of cardiovascular disease may require improvements in analytical quality.Clinical guidelines recommend using cardiac troponin concentrations as low as the limit of detection of the assay to guide patient care. Laboratories, manufacturers, researchers, and external quality assessment providers should extend analytical performance monitoring of cardiac troponin assays to include the concentration ranges applicable in these pathways.
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| 4. |
- Ahlqvist, Emma, et al.
(författare)
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Genetics of type 2 diabetes
- 2011
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 57:2, s. 241-254
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Forskningsöversikt (refereegranskat)abstract
- Background: Type 2 diabetes (T2D) is a complex disorder that is affected by multiple genetic and environmental factors. Extensive efforts have been made to identify the disease-affecting genes to better understand the disease pathogenesis, find new targets for clinical therapy, and allow prediction of disease.Content: Our knowledge about the genes involved in disease pathogenesis has increased substantially in recent years, thanks to genomewide association studies and international collaborations joining efforts to collect the huge numbers of individuals needed to study complex diseases on a population level. We have summarized what we have learned so far about the genes that affect T2D risk and their functions. Although more than 40 loci associated with T2D or glycemic traits have been reported and reproduced, only a minor part of the genetic component of the disease has been explained, and the causative variants and affected genes are unknown for many of the loci.Summary: Great advances have recently occurred in our understanding of the genetics of T2D, but much remains to be learned about the disease etiology. The genetics of T2D has so far been driven by technology, and we now hope that next-generation sequencing will provide important information on rare variants with stronger effects. Even when variants are known, however, great effort will be required to discover how they affect disease risk.
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| 5. |
- Ahmad, Shafqat, et al.
(författare)
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Adiposity and Genetic Factors in Relation to Triglycerides and Triglyceride-Rich Lipoproteins in the Women's Genome Health Study
- 2018
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 64:1, s. 231-241
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Previous results from Scandinavian cohorts have shown that obesity accentuates the effects of common genetic susceptibility variants on increased triglycerides (TG). Whether such interactions are present in the US population and further selective for particular TG-rich lipoprotein subfractions is unknown.METHODS: We examined these questions using body mass index (BMI) and waist circumference (WC) among women of European ancestry from the Women's Genome Health Study (WGHS) (n = 21840 for BMI; n = 19313 for WC). A weighted genetic risk score (TG-wGRS) based on 40 published TG-associated single-nucleotide polymorphisms was calculated using published effect estimates.RESULTS: Comparing overweight (BMI ≥ 25 kg/m2) and normal weight (BMI < 25 kg/m2) WGHS women, each unit increase of TG-wGRS was associated with TG increases of 1.013% and 1.011%, respectively, and this differential association was significant (Pinteraction = 0.014). Metaanalyses combining results for WGHS BMI with the 4 Scandinavian cohorts (INTER99, HEALTH2006, GLACIER, MDC) (total n = 40026) yielded a more significant interaction (Pinteraction = 0.001). Similarly, we observed differential association of the TG-wGRS with TG (Pinteraction = 0.006) in strata of WC (<80 cm vs ≥80 cm). Metaanalysis with 2 additional cohorts reporting WC (INTER99 and HEALTH2006) (total n = 27834) was significant with consistent effects (Pinteraction = 0.006). We also observed highly significant interactions of the TG-wGRS across the strata of BMI with very large, medium, and small TG-rich lipoprotein subfractions measured by nuclear magnetic resonance spectroscopy (all Pinteractions < 0.0001). The differential effects were strongest for very large TG-rich lipoprotein.CONCLUSIONS: Our results support the original findings and suggest that obese individuals may be more susceptible to aggregated genetic risk associated with common TG-raising alleles, with effects accentuated in the large TG-rich lipoprotein subfraction.
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| 6. |
- Alehagen, Urban, et al.
(författare)
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Prognostic Assessment of Elderly Patients with Symptoms of Heart Failure by Combining High-Sensitivity Troponin T and N-Terminal Pro-B-Type Natriuretic Peptide Measurements
- 2010
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Ingår i: CLINICAL CHEMISTRY. - : American Association for Clinical Chemistry; 1999. - 0009-9147 .- 1530-8561. ; 56:11, s. 1718-1724
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a useful biomarker in heart failure assessment, whereas measurement of cardiac troponin is central in the diagnosis of patients with acute coronary syndromes. This report examined the prognostic use of combining high-sensitivity cardiac troponin T (hs-cTnT) and NT-proBNP measurements in elderly patients presenting to a primary care center with symptoms associated with heart failure. METHODS: A total of 470 elderly patients (age range 65-86 years) presenting with symptoms of heart failure were recruited from primary healthcare. In addition to clinical examination and echocardiography, hs-cTnT and NT-proBNP plasma concentrations were measured. All patients were followed for 10 years, and cardiovascular mortality was registered. RESULTS: By use of the hs-cTnT assay, 80.4% of the population had plasma concentrations above the lower detection limit of the assay. Of those displaying a plasma concentration of hs-cTnT andgt;99th percentile of a healthy population, 43% also had an NT-proBNP concentration in the fourth quartile (andgt;507 ng/L). In the multivariate analysis, we observed a 2.5-fold increased risk for cardiovascular mortality in individuals with a plasma NT-proBNP concentration andgt;507 ng/L (P andlt; 0.0001). Conversely, patients with hs-cTnT andgt;99th percentile displayed an approximately 2-fold increased risk for cardiovascular mortality (P = 0.0002). Combining the 2 biomarkers, NT-proBNP concentrations andgt;507 ng/L with hs-cTnT andgt;99th percentile increased the risk 3-fold, even after adjustment for clinical variables such as age, sex, impaired estimated glomerular filtration rate, and anemia (P andlt; 0.0001). CONCLUSIONS: hs-cTnT and NT-proBNP measurements combined provide better prognostic information than using either biomarker separately in elderly patients with symptoms associated with heart failure.
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| 7. |
- Alehagen, Urban, 1951-, et al.
(författare)
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Utility of the amino-terminal fragment of pro-brain natriuretic peptide in plasma for the evaluation of cardiac dysfunction in elderly patients in primary health care
- 2003
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 49:8, s. 1337-1346
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aims of this study were to measure the N-terminal fragment of pro-brain natriuretic peptide (proBNP) in plasma in medical conditions commonly found in primary care and to evaluate the utility of these measurements in identifying impaired cardiac function in elderly patients with symptoms associated with heart failure.Methods: We studied 415 patients (221 men and 194 women; mean age, 72 years) who had contacted a primary healthcare center for dyspnea, fatigue, and/or peripheral edema. One cardiologist evaluated the patients in terms of history, physical examination, functional capacity, electrocardiography, and suspicion of heart failure. Plasma N-terminal proBNP was measured by an in-house RIA. An ejection fraction ≤40% by Doppler echocardiography was regarded as reduced cardiac function. Abnormal diastolic function was defined as an abnormal mitral inflow defined as reduced ratio of peak early diastolic filling velocity to peak filling velocity at atrial contraction (E/A ratio), or as abnormal pulmonary venous flow pattern.Results: Patients with impaired functional capacity, impaired systolic function, and/or impaired renal function had significantly increased N-terminal proBNP concentrations. By multiple regression analysis, N-terminal proBNP concentrations were also influenced by ischemic heart disease, cardiac enlargement, and certain medications but not by increased creatinine. No gender differences were observed. Patients with isolated diastolic dysfunction attributable to relaxation abnormali-ties had lower concentrations than those with normal cardiac function, whereas those with pseudonormal E/A ratios or restrictive filling patterns had higher concentrations.Conclusions: Plasma N-terminal proBNP concentrations increase as a result of impaired systolic function, age, impaired renal function, cardiac ischemia and enlargement, and certain medications. Values are high in diastolic dysfunction with pseudonormal patterns, but not in patients with relaxation abnormalities. An increase in plasma N-terminal proBNP might be an earlier sign of abnormal cardiac function than abnormalities identified by currently used echocardiographic measurements.
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| 8. |
- Aomori, Tohru, et al.
(författare)
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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 2
- 2009
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 55:4, s. 804-812
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 9. |
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| 10. |
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| 11. |
- Baxter, Douglas, et al.
(författare)
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Methylmercury measurement in whole blood by isotope-dilution GC-ICPMS with 2 sample preparation methods
- 2007
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 53:1, s. 111-116
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Tidskriftsartikel (refereegranskat)abstract
- Background: Despite its known toxicity, methylmercury is rarely measured directly in clinical studies; instead, conclusions are based on total mercury measurements. We have developed isotope-dilution-based methods for methylmercury-specific analysis of whole blood by coupled gas chromatography-inductively coupled plasma mass spectrometry (GC-ICPMS). Methods: We analyzed animal and human blood samples after alkaline digestion or extraction of methylmercury into dichloromethane and back extraction into water. Methylmercury was converted to the volatile ethyl derivative, purged, and trapped on a solid-phase collection medium, and then introduced into the GC-ICPMS system. Results: Limits of quantification were 0.4 and 0.03 mu g/L at a signal-to-noise ratio of 10 with the alkaline digestion and extraction methods, respectively. Extraction met our selected acceptable total error criterion, with an SD of 0.58 mu g/L at the critical maternal blood concentration of 5.8 mu g/L.Results obtained with alkaline digestion indicated the need for improved random analytical uncertainty, which was achieved by increasing the enrichment of the isotope dilution. For 37 blood samples, the mean (SD) proportion of total mercury present as methylmercury was 60 (27)%, range 6%-100%.Conclusions: The combination of extraction and isotope-dilution GC-ICPMS meets the requirements for use as a reference method for measuring methylmercury in whole blood.
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| 12. |
- Beck, O., et al.
(författare)
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Potential of Mass Spectrometry in Developing Clinical Laboratory Biomarkers of Nonvolatiles in Exhaled Breath
- 2016
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 62:1, s. 84-91
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Exhaled breath contains nonvolatile substances that are part of aerosol particles of submicrometer size. These particles are formed and exhaled as a result of normal breathing and contain material from distal airways of the respiratory system. Exhaled breath can be used to monitor biomarkers of both endogenous and exogenous origin and constitutes an attractive specimen for medical investigations. CONTENT: This review summarizes the present status regarding potential biomarkers of nonvolatile compounds in exhaled breath. The field of exhaled breath condensate is briefly reviewed, together with more recent work on more selective collection procedures for exhaled particles. The relation of these particles to the surfactant in the terminal parts of the respiratory system is described. The literature on potential endogenous low molecular weight compounds as well as protein biomarkers is reviewed. The possibility to measure exposure to therapeutic and abused drugs is demonstrated. Finally, the potential future role and importance of mass spectrometry is discussed. SUMMARY: Nonvolatile compounds exit the lung as aerosol particles that can be sampled easily and selectively. The clinical applications of potential biomarkers in exhaled breath comprise diagnosis of disease, monitoring of disease progress, monitoring of drug therapy, and toxicological investigations. (C) 2015 American Association for Clinical Chemistry
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| 13. |
- Berg, Cecilia, 1969-, et al.
(författare)
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Direct solid-phase sequence analysis of the human p53 gene by use of multiplex polymerase chain reaction and alpha-thiotriphosphate nucleotides.
- 1995
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 41:10, s. 1461-6
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Tidskriftsartikel (refereegranskat)abstract
- Among the candidate cancer-prognostic genes is the p53 tumor suppressor gene, which, when mutated, plays an important role in the development of many types of cancers. To facilitate robust large-scale DNA analysis of microdissected tumor biopsies, we describe a multiplex/nested PCR approach for a simultaneous outer amplification of exons 4-9 of the human p53 gene with parallel amplification of the HLA-DQB1 locus, involving a total of 14 primers. This approach reduces the required number of cells for analysis and avoids any variation in the amplifications of the individual p53 exons during the common outer amplification step. The HLA sequencing allows sample identification because the DQB1 locus is highly polymorphic and is thereby patient-specific. The p53 and HLA amplicons are analyzed by solid-phase sequencing in a semiautomated format. To improve the DNA sequence quality, we used 2'-deoxyribonucleoside 5'-O-1-thiotriphosphates in the sequencing reactions.
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| 14. |
- Berois, Nora, et al.
(författare)
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ppGalNAc-TI3 : A new molecular marker of bone marrow involvement in neuroblastoma
- 2006
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 52:9, s. 1701-1712
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Tidskriftsartikel (refereegranskat)abstract
- Background: To identify new molecular markers of bone marrow dissemination in human neuroblastoma (NB), we studied the transcriptome profiles of malignant neuroblasts established from the human MYCN-amplified IGR-N-91 model. Methods: This experimental model includes human neuroblastoma cells derived from & subcutaneous stage 4 disease, myocardium (Myoc) and bone marrow (BM) metastatic cells. Results: Gene expression profiles obtained with Agilent oligo microarrays revealed a set of 107 differentially expressed genes in the metastatic neuroblasts. This set included up-regulated genes involved in chemoresistance, cell motility, neuronal structure/signaling, and the recently characterized GALNT13 gene encoding a glycosyltransferase that initiates mucin-type O-glycosylation. Because the glycosylation process is involved in the progression of primary tumor to metastatic disease, we investigated whether the most strongly upregulated gene, GALNT13, might be a marker of bone marrow involvement in stage 4 NB patients. Importantly, in the BM of healthy adults no GALNT13 transcript was detected with analysis by quantitative (n = 3) and nested reverse transcription-PCR (n = 4) assays. In contrast, GALNT13 transcripts were detected in 23/23 cytologically involved BM samples obtained at diagnosis of stage 4 NB patients and in 5/27 cytologically noninvolved BM samples obtained from patients with stage 1-4 and 4S and treated stage 4 NB. The quantitative measurements of tyrosine hydroxylase (TH), ganglioside D2 synthase, dopa decarboxylase, and GALNT13 transcript values were compared in the same NB patients, and the results showed that GALNT13 expression was most highly correlated to poor clinical outcome at diagnosis. Conclusion: We propose ppGalNAc-T13 as a new informative marker for the molecular diagnosis of BM involvement and the follow-up of minimal residual disease in NB patients. © 2006 American Association for Clinical Chemistry.
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| 15. |
- Bredberg, Anna, et al.
(författare)
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Exhaled Endogenous Particles Contain Lung Proteins.
- 2012
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 1530-8561 .- 0009-9147. ; 58:2, s. 431-440
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:We recently developed a novel, noninvasive method for sampling nonvolatile material from the distal airways. The method is based on the collection of endogenous particles in exhaled air (PEx). The aim of this study was to characterize the protein composition of PEx and to verify that the origin of PEx is respiratory tract lining fluid (RTLF).METHOD:Healthy individuals exhaled into the sampling device, which collected PEx onto a silicon plate inside a 3-stage impactor. After their extraction from the plates, PEx proteins were separated by SDS-PAGE and then analyzed by LC-MS. Proteins were identified by searching the International Protein Index human database with the Mascot search engine.RESULTS:Analysis of the pooled samples identified 124 proteins. A comparison of the identified PEx proteins with published bronchoalveolar lavage (BAL) proteomic data showed a high degree of overlap, with 103 (83%) of the PEx proteins having previously been detected in BAL. The relative abundances of the proteins were estimated according to the Mascot exponentially modified protein abundance index protocol and were in agreement with the expected protein composition of RTLF. No amylase was detected, indicating the absence of saliva protein contamination with our sampling technique.CONCLUSIONS:Our data strongly support that PEx originate from RTLF and reflect the composition of undiluted RTLF.
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| 16. |
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| 17. |
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| 18. |
- Carlsson, Sigrid, 1982, et al.
(författare)
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Perspective on prostate cancer screening
- 2019
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 65:1, s. 24-27
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Tidskriftsartikel (refereegranskat)
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| 19. |
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| 20. |
- Ceder, Gunnel, et al.
(författare)
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Concentration ratios of morphine to codeine in blood of impaired drivers as evidence of heroin use and not medication with codeine
- 2001
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Ingår i: Clinical Chemistry. - 0009-9147 .- 1530-8561. ; 47:11, s. 1980-1984
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Tidskriftsartikel (refereegranskat)abstract
- Background: Both the illicit drug heroin and the prescription drug codeine are metabolized to morphine, which tends to complicate interpretation of opiate-positive samples. We report here the concentrations of morphine and codeine, the morphine/codeine ratios, and 6-acetylmorphine (6-AM) in blood specimens from individuals arrested for driving under the influence of drugs (DUID) in Sweden. The results were compared with positive findings of 6-AM in urine as evidence of heroin intake. Methods: In 339 DUID suspects, both blood and urine specimens were available for toxicologic analysis. In another 882 cases, only blood was available. All specimens were initially analyzed by immunoassay, and the positive results were verified by isotope-dilution gas chromatography-mass spectrometry. In routine casework, the limits of quantification (LOQs) for unconjugated opiates were 5 ng/g for blood and 20 ╡g/L for urine. Results: The median concentration of morphine in blood was 30 ng/g with 2.5 and 97.5 percentiles of 5 and 230 ng/g, respectively (n = 979). This compares with a median codeine concentration of 20 ng/g and 2.5 and 97.5 percentiles of 5 and 592 ng/g, respectively (n = 784). The specific metabolite of heroin, 6-AM, was identified in only 16 of 675 blood specimens (2.3%). This compares with positive findings of 6-AM in 212 of 339 urine samples (62%) from the same population of DUID suspects. When 6-AM was identified in urine, the morphine/codeine ratio in blood was always greater than unity (median, 6.0, range, 1-66). In 18 instances, 6-AM was present in urine, although morphine and codeine were below the LOQ in blood. The morphine/codeine ratio in blood was greater than unity in 85% of DUID cases when urine was not available (n = 506), and the median morphine and codeine concentrations were 70 ng/g and 10 ng/g, respectively. When morphine/codeine ratios in blood were less than unity (n = 76), the median morphine and codeine concentrations were 10 ng/g and 180 ng/g, respectively. Conclusions: Only 2.3% of opiate-positive DUID suspects were verified as heroin users on the basis of positive findings of 6-AM in blood. A much higher proportion (62%) were verified heroin users from 6-AM identified in urine. When urine was not available for analysis, finding a morphine/codeine concentration ratio in blood above unity suggests heroin use and not medication with codeine. This biomarker indicated that 85% of opiate-positive DUID blood samples were from heroin users. ⌐ 2001 American Association for Clinical Chemistry.
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| 21. |
- Chalbot, Sonia, et al.
(författare)
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Cerebrospinal fluid secretory Ca2+-dependent phospholipase A2 activity is increased in Alzheimer disease.
- 2009
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Ingår i: Clinical chemistry. - : Oxford University Press (OUP). - 1530-8561 .- 0009-9147. ; 55:12, s. 2171-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The phospholipase A(2) (PLA2) family comprises multiple isoenzymes that vary in their physicochemical properties, cellular localizations, calcium sensitivities, and substrate specificities. Despite these differences, PLA2s share the ability to catalyze the synthesis of the precursors of the proinflammatory mediators. To investigate the potential of PLA2 as a biomarker in screening neuroinflammatory disorders in both clinical and research settings, we developed a PLA2 assay and determined the predominant types of PLA2 activity in cerebrospinal fluid (CSF). METHODS: We used liposomes composed of a fluorescent probe (bis-Bodipy FL C11-PC [1,2-bis-(4,4- difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-undecanoyl)-sn-glycero-3-phosphocholine]) and 1,2-dioleoyl-l-alpha-phosphatidylcholine as a substrate to measure CSF PLA2 activity in a 96-well microtiter plate format. We established the type of CSF PLA2 activity using type-specific inhibitors of PLA2. RESULTS: Using 5 microL CSF per assay, our PLA2 activity assay was reproducible with CVs <15% in 2 CSF samples and for recombinant secretory Ca(2+)-dependent PLA2 (sPLA2) in concentrations ranging from 0.25 to 1 micromol/L. This PLA2 assay allowed identification of sPLA2 activity in lumbar CSF from healthy individuals 20-77 years old that did not depend on either sex or age. Additionally, CSF sPLA2 activity was found to be increased (P = 0.0008) in patients with Alzheimer disease. CONCLUSIONS: Adult human CSF has sPLA2 activity that can be measured reliably with the assay described. This enzyme activity in the CSF is independent of both sex and age and might serve as a valuable biomarker of neuroinflammation, as we demonstrated in Alzheimer disease.
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| 22. |
- Chan, Mark Y., et al.
(författare)
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Temporal biomarker profiling reveals longitudinal changes in risk of death or myocardial infarction in Non-ST-segment elevation acute coronary syndrome
- 2017
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 63:7, s. 1214-1226
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There are conflicting data on whether changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity C-reactive protein (hs-CRP) concentrations between time points (delta NT-proBNP and hs-CRP) are associated with a change in prognosis. METHODS: We measured NT-proBNP and hs-CRP at 3 time points in 1665 patients with non-ST-segment elevation acute coronary syndrome (NSTEACS). Cox proportional hazards was applied to the delta between temporal measurements to determine the continuous association with cardiovascular events. Effect estimates for delta NT-proBNP and hs-CRP are presented per 40% increase as the basic unit of temporal change. RESULTS: Median NT-proBNP was 370.0 (25th, 75th percentiles, 130.0, 996.0), 340.0 (135.0, 875.0), and 267.0 (111.0, 684.0) ng/L; and median hs-CRP was 4.6 (1.7, 13.1), 1.9 (0.8, 4.5), and 1.8 (0.8, 4.4) mg/L at baseline, 30 days, and 6 months, respectively. The deltas between baseline and 6 months were the most prognostically informative. Every 40% increase of delta NTproBNP (baseline to 6 months) was associated with a 14% greater risk of cardiovascular death (adjusted hazard ratio (HR) 1.14, 95% CI, 1.03-1.27) and with a 14% greater risk of all-cause death (adjusted HR 1.14, 95% CI, 1.04 -1.26), while every 40% increase of delta hs- CRP (baseline to 6 months) was associated with a 9% greater risk of the composite end point (adjusted HR 1.09, 95% CI, 1.02-1.17) and a 10% greater risk of myocardial infarction (adjusted HR 1.10, 95%, CI 1.00 -1.20). CONCLUSIONS: Temporal changes in NT-proBNP and hs-CRP are quantitatively associated with future cardiovascular events, supporting their role in dynamic risk stratification of NSTEACS.
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| 23. |
- Chinnasamy, Thiruppathiraja, et al.
(författare)
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Point-of-Care Vertical Flow Allergen Microarray Assay : Proof of Concept
- 2014
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 60:9, s. 1209-1216
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sophisticated equipment, lengthy protocols, and skilled operators are required to perform protein microarray-based affinity assays. Consequently, novel tools are needed to bring biomarkers and biomarker panels into clinical use in different settings. Here, we describe a novel paper-based vertical flow microarray (VFM) system with a multiplexing capacity of at least 1480 microspot binding sites, colorimetric readout, high sensitivity, and assay time of < 10 min before imaging and data analysis. METHOD: Affinity binders were deposited on nitrocellulose membranes by conventional microarray printing. Buffers and reagents were applied vertically by use of a flow controlled syringe pump. As a clinical model system, we analyzed 31 precharacterized human serum samples using the array system with 10 allergen components to detect specific IgE reactivities. We detected bound analytes using gold nanoparticle conjugates with assay time of <= 10 min. Microarray images were captured by a consumer-grade flatbed scanner. RESULTS: A sensitivity of 1 ng/mL was demonstrated with the VFM assay with colorimetric readout. The reproducibility (CV) of the system was < 14%. The observed concordance with a clinical assay, Immuno-CAP, was R-2 = 0.89 (n = 31). CONCLUSIONS: In this proof-of-concept study, we demonstrated that the VFM assay, which combines features from protein microarrays and paper-based colorimetric systems, could offer an interesting alternative for future highly multiplexed affinity point-of-care testing.
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| 24. |
- Clarke, Robert, et al.
(författare)
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Detection of vitamin B12 deficiency in older people by measuring vitamin B12 or the active fraction of vitamin B12, holotranscobalamin.
- 2007
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 53:5, s. 963-970
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Impaired vitamin B(12) function and decreased vitamin B(12) status have been associated with neurological and cognitive impairment. Current assays analyze total vitamin B(12) concentration, only a small percentage of which is metabolically active. Concentrations of this active component, carried on holotranscobalamin (holoTC), may be of greater relevance than total vitamin B(12). METHODS: We compared the utility of serum holoTC with conventional vitamin B(12) for detection of vitamin B(12) deficiency in a population-based study of older people, using increased methylmalonic acid (MMA) concentrations as a marker of metabolic vitamin B(12) deficiency in the overall population (n = 2403) and in subsets with normal (n = 1651) and abnormal (n = 752) renal function. RESULTS: Among all participants, 6% had definite (MMA >0.75 micromol/L) and 16% had probable (MMA >0.45 micromol/L) metabolic vitamin B(12) deficiency. In receiver operating characteristic curves for detection of definite vitamin B(12) deficiency, holoTC had a greater area under the curve (AUC) compared with vitamin B(12) in all participants (0.85 vs 0.76; P <0.001) and in subsets with normal (AUC: 0.87 vs 0.79; P <0.001) and abnormal (AUC: 0.85 vs 0.74; P = 0.002) renal function. Similar findings were observed for detection of moderate vitamin B(12) deficiency. Whereas the positive predictive value for both holoTC and vitamin B(12) was greater for detection of probable than definite vitamin B(12) deficiency, both tests were associated with more false-positive than true-positive test results. CONCLUSIONS: HoloTC has a modestly superior diagnostic accuracy compared with conventional vitamin B(12) for the detection of vitamin B(12) deficiency, but neither test can be recommended to screen asymptomatic populations.
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| 25. |
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| 26. |
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| 27. |
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| 28. |
- Dizdar (Dizdar Segrell), Nil, et al.
(författare)
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Human pharmacokinetics of L-3,4-dihydroxyphenylalanine studied with microdialysis
- 1999
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Ingår i: Clinical Chemistry. - 0009-9147 .- 1530-8561. ; 45:10, s. 1813-1820
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Tidskriftsartikel (refereegranskat)abstract
- Background: Intravenous and subcutaneous microdialysis was performedto compare the free concentrations and pharmacokinetics of L-3,4-dihyroxyphenylalanine(L-dopa) in blood and tissue in healthy subjects and in patientswith Parkinson disease.Methods: Nine healthy volunteers and 10 patients with Parkinson disease, stage 1.5–2 according to the Hoehn-Yahr rating scale, took part of the study. In the patient group subcutaneous microdialysis and ordinary blood sampling were performed, whereas in the control group intravenous microdialysis was also performed. Microdialysis samples were collected in fractions of 15 min. The first two fractions were collected for analysis of basal concentrations. A blood sample was also taken. The patients were then given one tablet of Madopar® (100 mg of L-dopa and 25 mg of benserazide),and the microdialysis was continued for another 210 min. Bloodsamples were obtained at 30-min intervals.Results: The serum samples gave a significantly higher meanarea under the curve (AUC; 491 ± 139 µmol ·min/L) than that for intravenous dialysates (235 ± 55.3µmol · min/L), suggesting a protein binding of50%. The L-dopa concentrations from the subcutaneous dialysatesmatched those from the intravenous dialysates, indicating rapiddistribution of L-dopa to the tissues.Conclusions: Parkinsonian patients in early stages of the disease have a pharmacokinetic pattern of free L-dopa similar to that of healthy subjects. Comparison of AUCs from microdialysis with ordinary serum analysis revealed data indicating significant protein binding. Microdialysis is a suitable and easily applied tool in pharmacokinetic studies.
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| 29. |
- DOrazio, Paul, et al.
(författare)
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Approved IFCC recommendation on reporting results for blood glucose (abbreviated)
- 2005
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 51:9, s. 1573-1576
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Tidskriftsartikel (refereegranskat)abstract
- In current clinical practice, plasma and blood glucose are used interchangeably with a consequent risk of clinical misinterpretation. In human blood, glucose, like water, is distributed between erythrocytes and plasma. The molality of glucose (amount of glucose per unit of water mass) is the same throughout the sample, but the concentration is higher in plasma because the concentration of water and, therefore, glucose is higher in plasma than in erythrocytes. Different devices for the measurement of glucose may detect and report fundamentally different quantities. Different water concentrations in calibrators, plasma, and erythrocyte fluid can explain some of the differences. Results of glucose measurements depend on sample type and on whether methods require sample dilution or use biosensors in undiluted samples. If the results are mixed up or used indiscriminately, the differences may exceed the maximum allowable error of glucose determinations for diagnosing and monitoring diabetes mellitus, and complicate the treatment. The goal of the IFCC Scientific Division Working Group on Selective Electrodes and Point of Care Testing (IFCC-SD, WG-SEPOCT) is to reach a global consensus on reporting results. The document recommends reporting the concentration of glucose in plasma (with the unit mmol/L), irrespective of sample type or measurement technique. A constant factor of 1.11 is used to convert concentration in whole blood to the equivalent concentration in the pertinent plasma. The conversion will provide harmonized results, facilitating the classification and care of patients and leading to fewer therapeutic misjudgments. © 2005 American Association for Clinical Chemistry.
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| 30. |
- Drogan, Dagmar, et al.
(författare)
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Untargeted Metabolic Profiling Identifies Altered Serum Metabolites of Type 2 Diabetes Mellitus in a Prospective, Nested Case Control Study
- 2015
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 61:3, s. 487-497
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Application of metabolite profiling could expand the etiological knowledge of type 2 diabetes mellitus (T2D). However, few prospective studies apply broad untargeted metabolite profiling to reveal the comprehensive metabolic alterations preceding the onset of T2D. METHODS: We applied untargeted metabolite profiling in serum samples obtained from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort comprising 300 individuals who developed T2D after a median follow-up time of 6 years and 300 matched controls. For that purpose, we used ultraperformance LC-MS with a protocol specifically designed for large-scale metabolomics studies with regard to robustness and repeatability. After multivariate classification to select metabolites with the strongest contribution to disease classification, we applied multivariable-adjusted conditional logistic regression to assess the association of these metabolites with T2D.RESULTS: Among several alterations in lipid metabolism, there was an inverse association with T2D for metabolites chemically annotated as lysophosphatidylcholine(dm16:0) and phosphatidylcholine(O-20:0/O-20:0). Hexose sugars were positively associated with T2D, whereas higher concentrations of a sugar alcohol and a deoxyhexose sugar reduced the odds of diabetes by approximately 60% and 70%, respectively. Furthermore, there was suggestive evidence for a positive association of the circulating purine nucleotide isopentenyladenosine-5' -monophosphate with incident T2D.CONCLUSIONS: This study constitutes one of the largest metabolite profiling approaches of T2D biomarkers in a prospective study population. The findings might help generate new hypotheses about diabetes etiology and develop further targeted studies of a smaller number of potentially important metabolites. (C) 2014 American Association for Clinical Chemistry
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| 31. |
- Ebai, Tonge, et al.
(författare)
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Analytically Sensitive Protein Detection in Microtiter Plates by Proximity Ligation with Rolling Circle Amplification
- 2017
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 63:9, s. 1497-1505
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 32. |
- Ebeling Barbier, Charlotte, et al.
(författare)
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Cardiac Troponin I Associated with the Development of Unrecognized Myocardial Infarctions Detected with MRI
- 2014
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 60:10, s. 1327-1335
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 33. |
- Eggers, Kai, 1962-, et al.
(författare)
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Impact of sex on cardiac troponin concentrations – A critical appraisal.
- 2017
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 63:9, s. 1457-1464
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND:The use of sex-specific cutoffs for cardiac troponin (cTn) is currently debated. Although endorsed by scientific working groups, concerns have been raised that sex-specific cutoffs may have only a small clinical effect at the cost of increased complexity in decision-making.METHODS:We reviewed studies investigating the interrelations between high-sensitivity (hs) cTn results and sex, diagnoses, and outcome. Investigated populations included community-dwelling subjects and patients with stable angina, congestive heart failure, or acute chest pain including those with acute coronary syndromes.RESULTS:Men usually have higher hs-cTn concentrations compared with women, regardless of the assessed population or the applied assay. The distribution and prognostic implications of hs-cTn concentrations indicate that women have a broader cardiovascular risk panorama compared with men, particularly at lower hs-cTn concentrations. At higher concentrations, particularly above the 99th percentile, this variation is often attenuated. Sex-specific hs-cTn 99th percentiles have so far shown clinical net benefit in only 1 study assessing patients with chest pain. However, several methodological aspects need to be considered when interpreting study results, e.g., issues related to the determination of the 99th percentiles, the selection bias, and the lack of prospective and sufficiently powered analyses.CONCLUSIONS:Available studies do not show a consistent clinical superiority of sex-specific hs-cTn 99th percentiles. This may reflect methodological aspects. However, from a pathobiological perspective, the use of sex-specific hs-cTn 99th percentiles makes sense for the ruling in of myocardial infarction. We propose a new approach to hs-cTn 99th cutoffs taking into account the analytical properties of the used assays.
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| 34. |
- Eggers, Kai M., 1962-, et al.
(författare)
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Application of Cardiac Troponin in Cardiovascular Diseases Other Than Acute Coronary Syndrome
- 2017
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Ingår i: Clinical Chemistry. - : AMER ASSOC CLINICAL CHEMISTRY. - 0009-9147 .- 1530-8561. ; 63:1, s. 223-235
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Forskningsöversikt (refereegranskat)abstract
- 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.
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| 35. |
- Eggers, Kai M., 1962-, et al.
(författare)
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Cardiac Troponins and Their Prognostic Importance in Patients with Suspected Acute Coronary Syndrome and Renal Dysfunction
- 2017
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 63:8, s. 1409-1417
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 36. |
- Eggers, Kai M, et al.
(författare)
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Change in Growth Differentiation Factor 15 Concentrations Over Time Independently Predicts Mortality in Community-Dwelling Elderly Individuals
- 2013
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 59:7, s. 1091-1098
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 37. |
- Eggers, Kai M, et al.
(författare)
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Evaluation of Temporal Changes in Cardiovascular Biomarker Concentrations Improves Risk Prediction in an Elderly Population from the Community
- 2016
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 62:3, s. 485-493
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 38. |
- Eggers, Kai M, et al.
(författare)
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Factors Influencing the 99th Percentile of Cardiac Troponin I Evaluated in Community-Dwelling Individuals at 70 and 75 Years of Age
- 2013
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 59:7, s. 1068-1073
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 39. |
- Eggers, Kai M., 1962-, et al.
(författare)
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High-Sensitivity Cardiac Troponin-Based Strategies for the Assessment of Chest Pain Patients : A Review of Validation and Clinical Implementation Studies
- 2018
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Ingår i: Clinical Chemistry. - : American Association for Clinical Chemistry. - 0009-9147 .- 1530-8561. ; 64:11, s. 1572-1585
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: The introduction of high-sensitivity cardiac troponin (hs-cTn) assays has improved the early assessment of chest pain patients. A number of hs-cTn-based algorithms and accelerated diagnostic protocols (ADPs) have been developed and tested subsequently. In this review, we summarize the data on the performance and clinical utility of these strategies. CONTENT: We reviewed studies investigating the diagnostic and prognostic performance of hs-cTn algorithms [level of detection (LoD) strategy, 0/1-h, 0/2-h, and 0/3-h algorithms) and of hs-cTn-based ADPs, together with the implications of these strategies when implemented as clinical routine. The LoD strategy, when combined with a nonischemic electrocardiogram, is best suited for safe rule-out of myocardial infarction and the identification of patients eligible for early discharge from the emergency department. The 0/1-h algorithms appear to identify most patients as being eligible for rule-out. The hs-cTn-based ADPs mainly focus on prognostic assessment, which is in contrast with the hs-cTn algorithms. They identify smaller proportions of rule-out patients, but there is increasing evidence from prospective studies on their successful clinical implementation. Such information is currently lacking for hs-cTn algorithms. CONCLUSIONS: There is a trade-off between safety and efficacy for different hs-cTn-based strategies. This trade-off should be considered for the intended strategy, along with its user-friendliness and evidence from clinical implementation studies. However, several gaps in knowledge remain. At present, we suggest the use of an ADP in conjunction with serial hs-cTn results to optimize the early assessment of chest pain patients. (C) 2018 American Association for Clinical Chemistry
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| 40. |
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| 41. |
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| 42. |
- Eggers, Kai M., 1962-, et al.
(författare)
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Value of cardiac troponin I cutoff concentrations below the 99th percentile for clinical decision-making
- 2009
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 55:1, s. 85-92
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 43. |
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| 44. |
- Eisen, A., et al.
(författare)
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High-Sensitivity Troponin I in Stable Patients with Atherosclerotic Disease in the TRA 2 degrees P - TIMI 50 Trial
- 2017
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 63:1, s. 307-315
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cardiac troponin I, measured with a high-sensitivity assay (hs-TnI), is well-established for risk prediction in acute coronary syndromes. However, its prognostic role in stable atherosclerotic disease, particularly for future myocardial infarction (MI), is less well defined. METHODS: We measured hs-TnI (Abbott ARCHITECT) in 15 833 patients with prior MI, ischemic stroke, or peripheral arterial disease from the placebo controlled Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P) Thrombolysis in Myocardial Infarction (TIMI) 50 trial of the platelet inhibitor vorapaxar, excluding patients with recent MI (<30 days). hs-TnI was categorized into 5 groups based on the detection limit (1.9 ng/L), 99th percentile reference limit (26 ng/L), and tertiles in between (1.9-26 ng/L), as well as sex-specific reference limits. RESULTS: Higher hs-TnI concentration was associated with older age, male sex, and increased atherosclerosis burden. hs-TnI identified a graded 3-year risk of cardiovascular death, MI, or stroke from 5.0% to 18.6% (P < 0.001), driven by cardiovascular death and MI (P < 0.001). This risk was independent of established clinical risk indicators, B-type natriuretic peptide and C-reactive protein [adjusted hazard ratio 2.70 (95% CI, 1.96-3.71), P < 0.001 for hs-TnI >26 ng/L vs <1.9 ng/L]. In patients with prior MI, there was a pattern of greater absolute benefit with vorapaxar in patients with an increased hs-TnI (absolute risk difference 1.9% with hs-TnI >26 ng/L vs 0.3% with hs-TnI <1.9 ng/L; P interaction = 0.82). CONCLUSIONS: In stable patients with established atherosclerosis, hs-TnI concentrations effectively stratified the risk of new or recurrent cardiovascular (CV) events, in particular CV death and MI. High-risk patients with prior MI identified by increased hs-TnI had a substantial absolute improvement in net clinical outcome with vorapaxar. (C) 2016 American Association for Clinical Chemistry
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| 45. |
- El-Heliebi, Amin, et al.
(författare)
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In Situ Detection and Quantification of AR-V7, AR-FL, PSA, and KRAS Point Mutations in Circulating Tumor Cells
- 2018
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 64:3, s. 536-546
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Liquid biopsies can be used in castration-resistant prostate cancer (CRPC) to detect androgen receptor splice variant 7 (AR-V7), a splicing product of the androgen receptor. Patients with AR-V7-positive circulating tumor cells (CTCs) have greater benefit of taxane chemotherapy compared with novel hormonal therapies, indicating a treatment-selection biomarker. Likewise, in those with pancreatic cancer (PaCa), KRAS mutations act as prognostic biomarkers. Thus, there is an urgent need for technology investigating the expression and mutation status of CTCs. Here, we report an approach that adds AR-V7 or KRAS status to CTC enumeration, compatible with multiple CTC-isolation platforms.METHODS: We studied 3 independent CTC-isolation devices (CellCollector, Parsortix, CellSearch) for the evaluation of AR-V7 or KRAS status of CTCs with in situ padlock probe technology. Padlock probes allow highly specific detection and visualization of transcripts on a cellular level. We applied padlock probes for detecting AR-V7, androgen receptor full length (AR-FL), and prostate-specific antigen (PSA) in CRPC and KRAS wildtype (wt) and mutant (mut) transcripts in PaCa in CTCs from 46 patients.RESULTS: In situ analysis showed that 71% (22 of 31) of CRPC patients had detectable AR-V7 expression ranging from low to high expression [1-76 rolling circle products (RCPs)/CTC]. In PaCa patients, 40% (6 of 15) had KRAS mut expressing CTCs with 1 to 8 RCPs/CTC. In situ padlock probe analysis revealed CTCs with no detectable cytokeratin expression but positivity for AR-V7 or KRAS mut transcripts.CONCLUSIONS: Padlock probe technology enables quantification of AR-V7, AR-FL, PSA, and KRAS mut/wt transcripts in CTCs. The technology is easily applicable in routine laboratories and compatible with multiple CTC-isolation devices.
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| 46. |
- El-Khoury, Joe M., et al.
(författare)
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Time to Reevaluate the 95% Inclusion Criteria for Defining Reference Intervals?
- 2024
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Ingår i: Clinical Chemistry. - : OXFORD UNIV PRESS INC. - 0009-9147 .- 1530-8561.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- When test results fall outside the reference intervals in healthy individuals, it often leads to frustration and unnecessary investigations for potential diseases. These anomalies can be attributed to matrix effects or lack of selectivity but more commonly are due to the strict criteria we use when designing reference intervals that ultimately could be narrow for some tests (1–3).The central question we raise here is whether it is time to reevaluate and redesign our approach to creating reference intervals to reduce the occurrence of false positives while minimizing false negatives. Here we provide a condensed overview of the history, theory, and practical considerations regarding reference intervals and why we firmly believe we need to update our approach for some tests.
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| 47. |
- Estampador, Angela C., et al.
(författare)
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Precision Medicine in Obesity and Type 2 Diabetes : The Relevance of Early-Life Exposures
- 2018
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 64:1, s. 130-141
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: Type 2 diabetes is highly prevalent and devastating. Obesity is a diabetogenic factor, driving insulin resistance and a compensatory demand for increased insulin secretion from the pancreatic β cells; a failure to address this demand results in diabetes. Accordingly, primary and secondary prevention of obesity are at the core of diabetes prevention programs. The development of obesity and declining β-cell function often span many years or decades before diabetes is clinically manifest. Thus, characterizing the early-life process and risk factors that set disease trajectories may yield novel targets for early intervention and help improve the accuracy of prediction algorithms, factors germane to the emerging field of precision medicine.CONTENT: Here, we overview the concepts of precision medicine and fetal programming. We discuss the barriers to preventing obesity and type 2 diabetes in adulthood and present the rationale for considering early-life events in this context. In so doing, we discuss proof-of-concept studies and cutting-edge technological developments that are likely to transform current thinking on the etiology and pathogenesis of obesity and type 2 diabetes. We also review the factors hampering progress, including the success and failures of pregnancy intervention trials.SUMMARY: Obesity and type 2 diabetes are among the major health and economic burdens of our time. Defeating these diseases is likely to require life-course approaches, which may include aggressive interventions informed by biomarker profiling undertaken during early life.
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| 48. |
- Filges, Stefan, 1991, et al.
(författare)
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Digital Quantification of Chemical Oligonucleotide Synthesis Errors
- 2021
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 67:10, s. 1384-1394
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Chemically synthesized oligonucleotides are vital to most nucleic acids-based technologies and several applications are sensitive to oligonucleotide sequence errors. However, it is challenging to identify and quantify the types and amount of errors in synthetic oligonucleotides. METHODS: We applied a digital sequencing approach using unique molecular identifiers to quantify errors in chemically synthesized oligonucleotides from multiple manufacturers with different synthesis strategies, purity grades, batches, and sequence context. RESULTS: We detected both deletions and substitutions in chemical oligonucleotide synthesis, but deletions were 7 times more common. We found that 97.2% of all analyzed oligonucleotide molecules were intact across all manufacturers and purity grades, although the number of oligonucleotide molecules with deletions ranged between 0.2% and 11.7% for different types. Different batches of otherwise identical oligonucleotide types also varied significantly, and batch effect can impact oligonucleotide quality more than purification. We observed a bias of increased deletion rates in chemically synthesized oligonucleotides toward the 5'-end for 1 out of 2 sequence configurations. We also demonstrated that the performance of sequencing assays depends on oligonucleotide quality. CONCLUSIONS: Our data demonstrate that manufacturer, synthesis strategy, purity, batch, and sequence context all contribute to errors in chemically synthesized oligonucleotides and need to be considered when choosing and evaluating oligonucleotides. High-performance oligonucleotides are essential in numerous molecular applications, including clinical diagnostics.
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| 49. |
- Floderus, Y, et al.
(författare)
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Variations in porphobilinogen and 5-aminolevulinic acid concentrations in plasma and urine from asymptomatic carriers of the acute intermittent porphyria gene with increased porphyrin precursor excretion
- 2006
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Ingår i: Clinical chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 52:4, s. 701-707
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Tidskriftsartikel (refereegranskat)abstract
- Background: The heme precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA) accumulate during overt crises of acute intermittent porphyria (AIP), and high excretion of these metabolites often continues in the asymptomatic phase.Methods: We measured concentrations of PBG and ALA and investigated the correlation between these metabolites in plasma and urine in 10 asymptomatic AIP carriers with high excretion and in 5 healthy individuals. We quantified plasma concentrations with an HPLC–mass spectrometric method and urine concentrations with ion-exchange chromatography.Results: The mean (SD) plasma concentrations of PBG and ALA in the AIP carriers were 3.1 (1.0) and 1.7 (0.7) μmol/L, respectively. The mean 8-h urinary excretion amounts of PBG and ALA in the AIP carriers were 102 (25) and 56 (18) μmol, respectively, whereas the corresponding values for healthy individuals were 2.9 (0.7) and 9.3 (1.2) μmol. The correlations between PBG and ALA values in plasma and urine of the AIP carriers were 0.678 and 0.856, respectively. The mean PBG/ALA ratio was ∼2.0 in both plasma and urine for the AIP carriers and 0.3 in urine for the healthy individuals. The renal clearance rates for PBG and ALA were 71 (15) and 70 (13) mL/min, respectively.Conclusions: The described HPLC-mass spectrometric method enabled characterization of variations in plasma PBG and ALA in AIP carriers during an 8-h period. The renal clearances were similar for both metabolites. This method could be used to monitor AIP patients during treatment.
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| 50. |
- Fredriksson, Simon, et al.
(författare)
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Multiplexed proximity ligation assays to profile putative plasma biomarkers relevant to pancreatic and ovarian cancer
- 2008
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Ingår i: Clinical Chemistry. - : Oxford University Press (OUP). - 0009-9147 .- 1530-8561. ; 54:3, s. 582-589
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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