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  • 251.
    Tavoosidana, Gholamreza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Darmanis, Spyros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yan, Junhong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wu, Di
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Conze, Tim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ek, Pia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Semjonow, Axel
    Prostate Center, Dept. of Urology, University Clinic, Muenster, Germany.
    Eltze, Elke
    Prostate Center, Gerhard-Domagk Institute of Pathology, University Clinic, Muenster, Germany.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Multiple recognition assay reveals prostasomes as promising plasma biomarkers for prostate cancer2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 21, p. 8809-8814Article in journal (Refereed)
    Abstract [en]

    Prostasomes are microvesicles (mean diameter, 150 nm) that are produced and secreted by normal and malignant prostate acinar cells. It has been hypothesized that invasive growth of malignant prostate cells may cause these microvesicles, normally released into seminal fluid, to appear in interstitial space and therewith into peripheral circulation. The suitability of prostasomes as blood biomarkers in patients with prostate cancer was tested by using an expanded variant of the proximity ligation assay (PLA). We developed an extremely sensitive and specific assay (4PLA) for detection of complex target structures such as microvesicles in which the target is first captured via an immobilized antibody and subsequently detected by using four other antibodies with attached DNA strands. The requirement for coincident binding by five antibodies to generate an amplifiable reporter results in both increased specificity and sensitivity. The assay successfully detected significantly elevated levels of prostasomes in blood samples from patients with prostate cancer before radical prostatectomy, compared with controls and men with benign biopsy results. The medians for prostasome levels in blood plasma of patients with prostate cancer were 2.5 to sevenfold higher compared with control samples in two independent studies, and the assay also distinguished patients with high and medium prostatectomy Gleason scores (8/9 and 7, respectively) from those with low score (<= 6), thus reflecting disease aggressiveness. This approach that enables detection of prostasomes in peripheral blood may be useful for early diagnosis and assessment of prognosis in organ-confined prostate cancer.

  • 252.
    Themudo, Raquel Espregueira
    et al.
    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. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Ebeling Barbier, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eggers, Kai M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bjerner, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Unrecognized myocardial scars detected by delayed-enhanced MRI are associated with increased levels of NT-proBNP2011In: Coronary Artery Disease, ISSN 0954-6928, E-ISSN 1473-5830, Vol. 22, no 3, p. 158-164Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Patients with unrecognized myocardial infarction (UMI) scars detected by delayed-enhanced magnetic resonance imaging (DE-MRI) have a decreased left ventricular ejection fraction and an increased left ventricular mass. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a marker of heart failure, and troponin I (TnI) is a marker of myocardial injury. The primary aim of this study was to investigate whether NT-proBNP plasma levels (in addition to ejection fraction) differed in patients with UMI scars compared with normal participants. The second aim was to compare whether the TnI levels differed in those two groups. METHODS: Data from the Prospective Investigation of Vasculature in Uppsala Seniors study were used. The participants who had undergone cardiac MRI were included in this study (n=248). Patients were divided into three groups depending on the existence of a myocardial infarction (MI) scar in DE-MRI and their earlier history of MI. In all the patients, a peripheral blood sample was collected and the plasma levels of NT-proBNP and TnI were determined. RESULTS: Patients with UMI had higher plasma levels of NT-proBNP (median 140.2 ng/l; 25th-75th percentiles: 79-225.5) than no-MI participants (median 94.9 ng/l; 25th-75th percentiles: 59.2-144.2; P=0.01) and lower levels than patients with recognized MI (median 310.4 ng/l; 25th-75th percentiles: 122.6-446.5; P=0.02). Plasma TnI values did not differ among the three groups. CONCLUSION: Patients with UMI scars detected by DE-MRI have increased plasma levels of NT-proBNP that is known to correlate with an increased risk of future cardiovascular adverse events.

  • 253.
    Trulson, Agneta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Byström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The functional heterogeneity of eosinophil cationic protein is determined by a gene polymorphism and post-translational modifications2007In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 37, no 2, p. 208-218Article in journal (Refereed)
    Abstract [en]

    Background

    The eosinophil is a cytotoxic cell and takes part in parasite killing and tissue-destructive processes by secretion of proteins such as eosinophil cationic protein (ECP). A polymorphism was demonstrated in the ECP gene, giving rise to a substitution of arginine at position 97 with threonine. This polymorphism is related to disease development.

    Objective

    To investigate the functional and molecular heterogeneity of native ECP and the functional consequences of the replacement of arginine with a threonine.

    Methods

    ECP was purified from healthy blood donors by gel filtration, ion-exchange chromatography and reversed-phase chromatography. Recombinant ECPs i.e. rECP 97arg and rECP 97thr were produced by the pFASTBAC baculovirus expression system. The cytotoxic activity was determined against an erythroleukaemia or a small cell lung cancer cell line.

    Results

    Native ECP was purified to apparent homogeneity and showed a considerable molecular heterogeneity and a corresponding functional heterogeneity with respect to cytotoxic activity. After reduction, the native cytotoxic ECP showed three bands on sodium dodecylsulphate polyacrylamide gel electrophoresis: one major band at 18-20 kDa and two minor bands at about 10 and 5 kDa, respectively. The 5 kDa contained two masses differing with 56.2 Da, which corresponds to the difference in molecular masses of arginine and threonine. rECP 97arg was cytotoxic in contrast to rECP97thr. Deglycosylation with N-glycosidase F did not affect the cytotoxic activity of native ECP to any measurable extent nor the activity of rECP 97arg, whereas rECP 97thr achieved cytotoxic activity. The RNase activities of the recombinant and native ECPs were similar.

    Conclusion

    We conclude that ECP is present in several molecular forms with varying biological activities. Some of this functional heterogeneity is based on the genetic polymorphism of the ECP gene and some on post-translational modifications. In subjects carrying the ECP 97thr variant, the cytotoxic activity may be disguised by N-linked glycosylation of the active site.

  • 254.
    Tsolakis, Apostolos V.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Molecular and Morphological Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Falkmer, Sture E.
    Waldum, Helge L.
    Saras, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Obestatin/ghrelin cells in normal mucosa and endocrine tumours of the stomach2009In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 160, no 6, p. 941-949Article in journal (Refereed)
    Abstract [en]

    Objective:

    Obestatin and ghrelin are derived from the same gene and co-expressed in the same endocrine cells. Vesicular monoamine transporter-2 (VMAT-2), a marker for enterochromaffin-like (ECL) cells, is considered to be expressed in ghrelin cells. The aim was to establish if the two peptides and the transporter are co-expressed, both in normal gastric mucosa and in gastric endocrine tumours.

    Design:

    An immunohistochemical study was performed on gastric biopsy material and on surgical specimens from 63 patients with gastric endocrine tumours and from individuals with normal gastric mucosa. Cells displaying obestatin immunoreactivity were examined regarding co-localization with ghrelin and VMAT-2. Both single- and double-immunostaining techniques were applied. Obestatin concentration in blood was measured in a subgroup of these patients. The results were correlated to various clinico-pathological parameters.

    Results:

    In the normal mucosa, obestatin/ghrelin-immunoreactive cells rarely co-expressed VMAT-2. In most tumour tissue specimens, only a fraction of neoplastic cells displayed immunoreactivity to obestatin, and these cells always co-expressed ghrelin. Neoplastic obestatin-/ ghrelin-IR cells invariably expressed VMAT-2, except for two ghrelinomas. The obestatin concentrations in blood were consistently low and did not correlate to clinico-pathological data.

    Conclusions:

    Obestatin and ghrelin immunoreactivity always occurred in the same endocrine cells in the gastric mucosa but these cells only occasionally co-expressed VMAT-2, opposite to the findings in tumours. These results indicate that endocrine cells expressing obestatin and ghrelin mainly differ from VMAT-2 expressing cells (ECL-cells) and can develop into pure ghrelinomas. Plasma concentrations of obestatin did not correlate to cellular expression.

  • 255. Uronen, Riikka-Liisa
    et al.
    Lundmark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Orho-Melander, Marju
    Jauhiainen, Matti
    Larsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Siegbahn, Agneta
    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, Clinical Chemistry.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Melander, Olle
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Ikonen, Elina
    Niemann-Pick C1 modulates hepatic triglyceride metabolism and its genetic variation contributes to serum triglyceride levels2010In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 30, no 8, p. 1614-1620Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To study how Niemann-Pick disease type C1 (NPC1) influences hepatic triacylglycerol (TG) metabolism and to determine whether this is reflected in circulating lipid levels.

    METHODS AND RESULTS:

     In Npc1−/− mice, the hepatic cholesterol content is increased but the TG content is decreased. We investigated lipid metabolism in Npc1−/− mouse hepatocytes and the association of NPC1 single-nucleotide polymorphisms with circulating TGs in humans. TGs were reduced in Npc1−/− mouse serum and hepatocytes. In Npc1−/− hepatocytes, the incorporation of [3H]oleic acid and [3H]acetate into TG was decreased, but shunting of oleic acid- or acetate-derived [3H]carbons into cholesterol was increased. Inhibition of cholesterol synthesis normalized TG synthesis, content, and secretion in Npc1−/− hepatocytes, suggesting increased hepatic cholesterol neogenesis as a cause for the reduced TG content and secretion. We found a significant association between serum TG levels and 5 common NPC1 single-nucleotide polymorphisms in a cohort of 1053 men, with the lowest P=8.7×10−4 for the single-nucleotide polymorphism rs1429934. The association between the rs1429934 A allele and higher TG levels was replicated in 2 additional cohorts, which included 8041 individuals.

    CONCLUSIONS:

    This study provides evidence of the following: (1) in mice, loss of NPC1 function reduces hepatocyte TG content and secretion by increasing the metabolic flux of carbons into cholesterol synthesis; and (2) common variation in NPC1 contributes to serum TG levels in humans.

  • 256. van Rooijen, Marianne
    et al.
    Hansson, L. O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Frostegård, J.
    Silveira, A.
    Hamsten, A.
    Bremme, K.
    Treatment with combined oral contraceptives induces a rise in serum C-reactive protein in the absence of a general inflammatory response2006In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 4, no 1, p. 77-82Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The role of inflammation in the pathogenesis of cardiovascular disease is well established. C-reactive protein (CRP) is the strongest independent predictor of myocardial infarction and stroke in women. Recent studies have indicated that CRP levels are raised during use of combined oral contraceptives (COCs). OBJECTIVES: The aim of the study was to investigate the effect of COCs on serum CRP levels and to indicate the underlying mechanisms of an expected increase. METHOD: In a prospective randomized cross over-study 35 women used two different preparations of COC, one second and one third generation. Serum levels of CRP, serum amyloid A (SAA), interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), antibodies against oxidized LDL, insulin and insulin-like growth factor-I (IGF-I) along with insulin-like growth factor binding protein-1 (IGFBP-1) and IGFBP-3 were analyzed before and during the two treatments. E-selectin, von Willebrand factor and factor VIII concentrations in plasma were also measured. RESULTS: A rise in serum CRP was observed during both treatments; the median level increased from 0.45 mg L(-1) at baseline to 1.48 mg L(-1) with second generation and to 2.02 mg L(-1) with third generation COC. The serum levels of SAA increased slightly during treatment with the third generation COC. IL-6 and TNFalpha were unaffected by treatment. Both preparations lowered IGF-I and raised IGFBP-1 and IGFBP-3 concentrations. CONCLUSION: The raised serum CRP concentration during treatment with COCs appears to be related to a direct effect on hepatocyte CRP synthesis and does not reflect IL-6 mediated inflammation, endothelial activation or induction of insulin resistance.

  • 257.
    Varenhorst, Christoph
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Koul, Sasha
    Department of Cardiology, Lund University.
    Erlinge, David
    Department of Cardiology, Lund University.
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. 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, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    James, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Relationship between Clopidogrel-Induced Platelet P2Y12 Inhibition and Stent Thrombosis or Myocardial Infarction after Percutaneous Coronary Intervention: A Case-Control Study2011In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 162, no 2, p. 363-371Article in journal (Refereed)
    Abstract [en]

    Aims: Platelet inhibition levels were investigated in patients with previous angiographically confirmed stent thrombosis (ST), myocardial infarction (MI) and controls.

    Methods and Results: Using The Swedish Coronary Angiography and Angioplasty Registry we identified patients with angiographically confirmed ST (n=48) or MI (n=30) while on dual antiplatelet therapy within 6 months of percutaneous coronary intervention (PCI) and matched control patients (n=78) with none of these events in the same setting. On-clopidogrel platelet reactivity was measured with VerifyNow™ P2Y12 and vasodilator stimulated phosphoprotein phosphorylation (VASP-P) assay.

    The mean P2Y12 reaction units (PRU) was higher (246.8 ± 75.9 vs. 200.0 ± 82.7, p=0.001) in ST patients compared to controls. The optimal cut-off for ST was ≥222 PRU (area under the curve 0.69, p<0.0001) in a receiver operating characteristics (ROC) analysis, which was identical to the cut-off level defined as the proportion of controls below the 30th percentile of P2Y12 inhibition distribution in patients with ST.  The cut-off level resulted in 70.2% sensitivity and 67.3% specificity. There was no significant difference in mean PRU but a higher device-reported % inhibition (45.1 ± 23.8 vs 32.1 ± 23.2, p=0.04) in patients with MI compared to controls. Results with the VASP-P assay were not related to the occurrence of ST or MI.

    Conclusion: Stent thrombosis was associated with high on-clopidogrel platelet reactivity measured with VerifyNow™. Spontaneous MI in stented patients on clopidogrel treatment was not. There was, however, a substantial overlap in clopidogrel platelet reactivity response between patients with and without on-treatment ST.

  • 258.
    Venge, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Johnston, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Wallentin, Lars
    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.
    Clinical and analytical performance of the liaison cardiac troponin I assay in unstable coronary artery disease, and the impact of age on the definition of reference limits: A FRISC-II substudy2003In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 49, no 6 Pt 1, p. 880-886Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Measurements of cardiac troponins are currently used as the standard for the detection of myocardial injury. None of the current assays complies with the new requirements on assay imprecision as proposed by the European Society of Cardiology/American College of Cardiology. Our aim was to evaluate the clinical and analytical performance of the Liaison cardiac troponin I (cTnI) assay.

    METHODS:

    EDTA-plasma was used, and cardiac troponins were assayed with the first-generation AxSYM assay, the second-generation AccuTnI assay, the third-generation Elecsys assay, and the first-generation Liaison assay.

    RESULTS:

    In a 6-day imprecision study, the Liaison cTnI assay had mean CV < or =10% at 0.027 microg/L and < or =20% at 0.015 microg/L. The 99th percentile of the upper reference limit (URL) of a reference population was 0.041 microg/L (age range, 41-76 years). Individuals <60 years had a significantly (P = 0.001) lower 99th percentile, 0.022 microg/L. The FRISC-II study participants with cTnI > or =0.041 microg/L had a poorer outcome relating to death/acute myocardial infarction than those with cTnI <0.041 microg/L (P <0.001). Treatment with low-molecular-weight heparin (dalteparin) or an invasive strategy reduced cardiac events only in patients with concentrations >0.041 microg/L (P = 0.002 and 0.02, respectively). Comparison with the AccuTnI assay showed that a large cohort of the patients with poor prognosis was identified by the AccuTnI assay but not by the Liaison cTnI assay.

    CONCLUSION:

    The Liaison cTnI assay is a sensitive assay with a CV < or =10% at the 99th percentile URL. The ability to detect age-related differences among apparently healthy individuals is unique among today's commercial assays. The results indicate that different assays seem to identify different patient cohorts for cardiac risk in the lower range of cTnI concentrations.

  • 259.
    Venge, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Seemingly healthy 71-year-old men with minor elevations of cardiac troponin I and at risk of premature death in CVD have elevated levels of NT-proBNP: report from the ULSAM study2009In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 69, no 3, p. 418-424Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hypersensitive cardiac troponin I (cTnI) assays detect even minor elevations of cTnI. Previous findings identifying a group of seemingly healthy elderly men with very minor elevations of cTnI have shown that these men were at risk of premature cardiovascular death. OBJECTIVES: To study the association between cTnI concentrations and cardiovascular risk factors and subclinical cardiac and renal target organ damage in a community-based sample of elderly men. METHODS: Biomarkers reflecting glucose and lipid metabolism, renal function, cardiac function and inflammation were measured in the ULSAM study (n = 1205, mean age 71 years). The participants were placed in three subgroups based on the cTnI concentrations: a low group with cTnI <0.02 microg/L, an intermediate group with cTnI between 0.02 and 0.039 microg/L and a high group with cTnI >0.039 microg/L. RESULTS: In the entire cohort of 71-year-old men, most markers of glucose and lipid metabolism, renal function, inflammation and NT-proBNP were significantly related to the concentrations of cTnI, and most obviously in the high-cTnI group. In subjects with no signs of CVD (cardiovascular disease), only levels of NT-proBNP related to cTnI, and with the highest NT-proBNP levels in the high-cTnI group (p<0.01). A multiple regression analysis showed that NT-proBNP was independently related to cTnI (p<0.001). CONCLUSIONS: Measurement of cardiac troponins with highly sensitive assays identifies those at risk of premature CVD death who have hitherto remained unrecognized. The associated elevations of NT-proBNP in these participants support the fact that these elevations reflect ongoing pathological processes in the myocardium.

  • 260.
    Venge, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Öhberg, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Flodin, Mats
    Uppsala University Hospital, Department of Clinical Chemistry and Pharmacology.
    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.
    Early and late outcome prediction of death in the emergency room setting by point-of-care and laboratory assays of cardiac troponin I2010In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 160, no 5, p. 835-841Article in journal (Refereed)
    Abstract [en]

    Background Point-of-care (POC) assays of cardiac troponins are common in the emergency department setting. The question raised was as follows: What is the clinical impact of the results of POC assays of cardiac troponins as compared with sensitive laboratory assays? Methods Patients admitted consecutively to the emergency department (N = 1,069) and on whom cardiac troponins were requested as part of their clinical work-up were included. Cardiac troponin I (cTnI) was measured by the POC assays-i-Stat (Abbott Diagnostics, Abbott Park, IL) and Stratus CS (Siemens Healthcare Diagnostics, Deerfield, IL)-and by the laboratory assays-Access AccuTnI (Beckman Coulter, Fullerton, CA) and Architect cTnI (Abbott Diagnostics). Results were related to early (14 days) and late outcome (median 3.3 months, range 0.1-35) as to death. Results The laboratory assays identified more patients (P<.001) with elevated levels than the two POC assays (39%-74% vs 20%-27%). Adopting the 99th percentiles upper reference limit, the Access AccuTnI identified 88% and Architect cTnI identified 81% of all patients who died of cardiovascular disease as compared with 50% and 54% for i-Stat and Stratus CS, respectively (P<.001). Negative predictive values for the laboratory assays were 97% as compared with 89% to 93% for the POC assays. Negative likelihood ratios were 0.25 (CI 0.15-0.041) and 0.59 to 0.68 (CI 0.47-0.79), respectively. Conclusions The current POC cTnI assays are less sensitive for outcome prediction of patients with myocardial injury. The clinical judgment of the patient with suspected myocardial ischemia should not solely rely on results from POC assays. If a clinical suspicion of myocardial injury remains despite negative cTnI results with the POC assays, such results should be complemented by results from sensitive laboratory assays.

  • 261.
    Viberg, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Lannergård, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Cars, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Sandström, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    A population pharmacokinetic model for cefuroxime using cystatin C as a marker of renal function2006In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 62, no 3, p. 297-303Article in journal (Refereed)
    Abstract [en]

    Aims: Since cefuroxime mainly is excreted by renal filtration, dosing is currently based on serum creatinine (Scr) or creatinine clearance (CLcr). However, it has been suggested that cystatin C (CysC) is superior to Scr as a marker of renal function. The aim of this prospective study was to develop a population model that describes the pharmacokinetics of cefuroxime and to investigate the usefulness of CysC as a covariate of the model parameters.

    Methods: Ninety-seven patients were studied (CLcr range 6.5-115 ml min(-1)). Blood samples (n = 407) for the determination of cefuroxime were withdrawn according to a sparse data sampling schedule and analysed by liquid chromatography mass spectrometry. The population analysis was performed in NONMEM.

    Results: A two-compartment model described the data well. The biomarkers Scr, CLcr and CysC were evaluated as covariates on clearance (CL). The model that included CysC generated the best fit. In the final population model CL was a function of CysC and body weight, whereas V-1 was only a function of body weight. Final parameter estimates (relative standard errors) were 6.00 (3.2%) l h(-1), 11.4 (5.3%) l and 5.11 (11%) l for CL, V-1 and V-2, respectively.

    Conclusion: Based on the results of the present study, and because CysC is practical to use in the clinic, it is suggested that individual dosing of cefuroxime may be based on CysC rather than on Scr or CLcr. Furthermore, our final population model may be useful as a tool when designing new dosing schedules for cefuroxime.

  • 262. von Rooijen, Marianne
    et al.
    Silveira, Angela
    Thomassen, Stella
    Hansson, Lars-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Rosing, Jan
    Hamsten, Anders
    Bremme, Katarina
    Rapid activation of haemostasis after hormonal emergency contraception2007In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 97, no 1, p. 15-20Article in journal (Refereed)
    Abstract [en]

    Hormonal emergency contraception (EC) is a well established contraceptive method, recommended to all women, although the effects on haemostais are not fully evaluated. The aim of this study was to evaluate whether exposure to EC has effects on well established cardiovascular risk factors, and also to examine whether differences exist between two EC treatments. In a prospective randomized cross over design II women used two different EC methods, one with estrogen and levonorgestrel (EE-EC) and one with levonorgestrel only (LNG-EC). Plasma concentrations of haemostatic factors (APC resistance, antithrombin, fibrinogen, prothrombin fragment 1+2, free protein S, factor VII and PAI-I), sex-hormone-binding globulin (SHBG),the apolipoprotein (apo)B/apoAI ratio and C-reactive protein (CRP) were followed frequently during the following 48 hours.

  • 263.
    Wagner, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Peterson, Christer G. B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ridefelt, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Fecal markers of inflammation used as surrogate markers for treatment outcome in relapsing inflammatory bowel disease2008In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 14, no 36, p. 5584-5589Article in journal (Refereed)
    Abstract [en]

    Aims: To evaluate fecal calprotectin (FC) as a surrogate marker for treatment outcome of a relapse of inflammatory bowel disease (IBD) and, secondly, to compare FC to fecal myeloperoxidase (MPO) and fecal eosinophil protein X (EPX).

    Methods: Thirty-eight patients with IBD, whereof twenty-seven with ulcerative colitis (UC) and 11 with Crohn´s disease (CD) were studied before treatment (inclusion), and after four and eight weeks of treatment. Treatment outcome, based on clinical activity and endoscopy in UC patients, and clinical activity in CD patients, were evaluated together with fecal samples analysed for FC with ELISA and MPO and EPX with RIA.

    Results: At inclusion 37/38 (97%) patients had elevated FC levels (>94.7 µg/g). At the end of the study 31/38 (82%) patients fulfilled predefined criteria of a complete response [UC 21/27 (78%); CD 10/11 (91%)].  Overall, a normalised FC level at the end of the study predicted a complete response in 100% whereas elevated FC level predicted noncomplete response in 30%. Normalised MPO or EPX levels predicted a complete response in 100% and 90%, respectively. However, elevated MPO or EPX levels predicted noncomplete response in 23% and 22%, respectively.

    Conclusion: A normalised FC level poses the potential to be used as a surrogate marker for successful treatment outcome in IBD patients, but cases with persistent elevated FC levels needs further evaluation. FC and MPO appears to discriminate better than EPX to treatment outcome in IBD.

  • 264. Waldenström, Anders
    et al.
    Haney, M.
    Biber, B.
    Kavianipour, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Moritz, T.
    Strandén, P.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ischaemic preconditioning is related to decreasing levels of extracellular adenosine that may be metabolically useful in the at-risk myocardium: an experimental study in the pig2010In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 199, no 1, p. 1-9Article in journal (Refereed)
    Abstract [en]

    Aim: 'Pre-treatment' with short repetitive periods of ischaemia (ischaemic preconditioning) has proved to be a powerful mechanism for modification of the extent of myocardial damage following acute coronary artery occlusion. The exact mechanism of protection induced by ischaemic preconditioning is not known. We herewith put forward a contributing component for protection with preconditioning involving a shift in the adenylate kinase (AK) equilibrium reaction in favour of adenosine triphosphate (ATP) formation. Methods: A coronary artery was occluded in anaesthetized thoracotomized pigs to induce ischaemic preconditioning as well as a longer period of ischaemia. Microdialysis probes were inserted in ischaemic and control myocardium and were infused with (14)C- adenosine with two different specific activities. (14)C-lactate was identified and measured in the effluent. Results: (14)C-adenosine was taken up by non-preconditioned and preconditioned myocardium during ischaemia. Significantly increased levels of (14)C-lactate were recovered in preconditioned myocardium. (14)C-adenosine with high specific activity resulted in a specific activity of lactate that was 2.7 times higher than that of lactate after administration of (14)C-adenosine with low specific activity. Mass spectrography verified the identity of (14)C-lactate. Conclusions: Preconditioning up-regulates a new metabolic pathway (starting with 5'-nucleotidase and ending up with lactate) resulting in ATP formation in the micromolar range on top of another effect terminating in a useful shift in the AK equilibrium reaction in favour of ATP generation in the millimolar range. Although the up-regulation of the purine nucleoside phosphorylase pathway is clearly demonstrated, its biological relevance remains to be proved.

  • 265. Waldenström, Anders
    et al.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Aberg, Anna-Maja
    Ahlström, Katarina
    Hauck, Philip
    Abrahamsson, Pernilla
    Johansson, Göran
    Biber, Björn
    Haney, Michael F
    Ischaemic preconditioning reduces myocardial calcium overload in coronary-occluded pig hearts shown by continuous in vivo assessment using microdialysis2012In: Clinical Physiology and Functional Imaging, ISSN 1475-0961, E-ISSN 1475-097X, Vol. 32, no 2, p. 133-138Article in journal (Refereed)
    Abstract [en]

    During ischaemia, ATP depletion leads to insufficient fuelling for Na+/K+ ATPase, decreased electrochemical potential and increased influx of calcium ions. This study demonstrated a means to assess the effects of ischaemic preconditioning (IP) on the free intracellular Ca2+ pool during prolonged ischaemia. In a porcine myocardial ischaemia model, microdialysis (MD) was used for sampling of metabolic and injury markers in IP and non-IP (control) groups. 45Ca2+ was delivered in microperfusate locally to ischaemic myocardium, with distribution and uptake assessed by 45Ca2+ recovery in microdialysate. Cardiomyocytes in vitro were exposed to a Ca2+ ionophore and tested for 45Ca2+ uptake. An accentuated myocardial calcium ion influx (observed as an increased microdialysate 45Ca2+ recovery in the extracellular milieu) was noted in control pigs compared with IP pigs during ischaemia. Suspended cardiomyocytes preincubated with a Ca2+ ionophore to increase the intracellular calcium ion pool and subsequently incubated with 45Ca2+, displayed lower 45Ca2+ uptake in cells compared with control cells not exposed to the ionophore, corroborating the idea of a strong relationship between degree of intracellular calcium overload and microdialysate 45Ca2+ recovery. The ischaemic insult was differentially verified by metabolic and injury markers. We introduce an in vivo method for serial assessment of myocardial calcium overload during ischaemia, using a MD technique and 45Ca2+ inclusion. IP leads to relatively less calcium overload as assessed by this new method, and we interpret this to mean that reduction in calcium overload is an important part of the IP protective effect.

  • 266.
    Wallentin, Lars
    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.
    Varenhorst, Christoph
    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.
    James, Stefan
    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.
    Erlinge, David
    Braun, Oscar O.
    Jakubowski, Joseph A.
    Sugidachi, Atsuhiro
    Winters, Kenneth J.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease2008In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 29, no 1, p. 21-30Article in journal (Refereed)
    Abstract [en]

    AIMS: P2Y(12) receptor antagonism and platelet inhibition by prasugrel vs. clopidogrel were investigated in patients with stable coronary artery disease. METHODS AND RESULTS: One hundred and ten aspirin treated subjects were randomized to double-blind treatment with clopidogrel (n = 55) 600 mg loading dose (LD) and 75 mg maintenance dose (MD) or prasugrel (n = 55) 60 mg LD and 10 mg MD for 28 days. Concentrations of prasugrel and clopidogrel active metabolites were determined. Platelet aggregation to 20 microM adenosine diphosphate, measured by light transmission aggregometry, was reported as maximal platelet aggregation (MPA). P2Y(12) function was assessed by the vasodilator-stimulated phosphoprotein assay and reported as platelet reactivity index (PRI). The same pharmacodynamic measurements were performed after ex vivo addition of clopidogrel's active metabolite. At 2 h post-LD, mean MPA was 31 vs. 55%, and mean PRI 8.3 vs. 55.9% for prasugrel and clopidogrel, respectively (P < 0.001). During MD on day 14 and 28, mean MPA was 42 vs. 54% and mean PRI was 25 vs. 51%, respectively (P < 0.001). Peak level of the active metabolite and P2Y(12) inhibition occurred earlier and was greater with prasugrel (P < 0.001). Mean area under the time-concentration curve (AUC; microM.h) of the respective active metabolite was higher with prasugrel vs. clopidogrel post-LD (1.11 vs. 0.24) and post-MD (0.16 vs. 0.062). Ex vivo addition of clopidogrel's active metabolite further reduced PRI in all patients whose platelets were not already maximally inhibited. CONCLUSION: In aspirin-treated subjects with coronary artery disease, prasugrel 60/10 mg provides faster onset and greater inhibition of P2Y(12) receptor-mediated platelet aggregation than clopidogrel 600/75 mg, because of greater and more efficient generation of the active metabolite.

  • 267.
    Weitoft, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Serum levels of sex steroid hormones and matrix metalloproteinases after intra-articular glucocorticoid treatment in female patients with rheumatoid arthritis2008In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 67, no 3, p. 422-424Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To study metalloproteinase activity and sex steroid hormone production in serum after intra-articular glucocorticoid treatment for knee synovitis. METHODS: A total of 18 female patients with rheumatoid arthritis (RA) and synovitis of the knee with need for intra-articular glucocorticoid treatment were included in this study. Serum samples of matrix metalloproteinases (MMP-1/TIMP complex and MMP-3), dehydroepiandrosterone sulphate (DHEAS), testosterone, estradiol, steroid hormone binding globulin (SHBG), follicle stimulating hormone (FSH) and luteinizing hormone(LH) were collected before injection with 20 mg triamcinolone hexacetonide, and 24 hours, 48 hours, one week and two weeks after injection, respectively. RESULTS: Serum levels of MMP-3 were significantly decreased, but MMP-1/TIMP complex was unaffected. DHEAS, testosterone and estradiol levels all decreased and tended to return to baseline levels during the observation period. SHBG, FSH and LH levels were unchanged. CONCLUSION: Intra-articular glucocorticoid treatment causes a temporary, but considerable suppression of sex steroid hormone secretion. The reduction of MMP-3 indicates an inhibition of the inflammatory, but probably also the cartilage destructive processes within the treated joint.

  • 268.
    Welin, Staffan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Elevated Plasma Chromogranin A is the First Indication of Recurrence in Radically Operated Midgut Carcinoid Tumours2009In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 89, no 3, p. 302-307Article in journal (Refereed)
    Abstract [en]

    Background:

    Patients with malignant midgut carcinoids are occasionally diagnosed with limited tumor spread, and surgery with radical intention is performed. Despite curative intent, recurrences occur frequently, motivating long-term biochemical and radiological follow-up. This study aimed to compare the usefulness of various methods in detecting such recurrences.

    Methods:

    This retrospective study included 56 patients with radically operated midgut carcinoids referred to our University Hospital for evaluation and follow-up between 1985 and 2004. Patients were monitored 1-3 times per year using plasma-chromogranin A (P-CgA), urinary 5-hydroxyindoleacetic acid (U-5HIAA) concentrations as well as radiological examinations, including ultrasonography, computerized tomography or magnetic resonance investigation. In a subset of cases, somatostatin receptor scintigraphy and/or positron emission tomography with 5-hydroxytryptophan was performed. Time from operation until established recurrence was recorded.

    Results:

    Tumor recurrence was established in 33 of 56 patients after a median of 32 months (range 6-217). Elevated P-CgA was the first marker to become pathologically elevated in 28 of these 33 patients (85%). In 3 of these 28 patients, radiology was simultaneously positive for a recurrence.

    Conclusion:

    P-CgA was the first marker to indicate tumor recurrence in the majority of radically operated midgut carcinoid patients. To avoid unnecessary and costly examinations in asymptomatic patients, we suggest that follow-up should comprise measurements of P-CgA twice a year and annual ultrasonography until P-CgA is elevated or clinical symptoms occur, at which time all efforts should be made to identify recurrent tumor lesions in order to give the patient the best possible treatment which, if possible, should be surgical removal of the recurrence.

  • 269.
    Wide, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Eriksson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Sluss, Patrick M.
    Hall, Janet E.
    Serum half-life of pituitary gonadotropins is decreased by sulfonation and increased by sialylation in women2009In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 94, no 3, p. 958-64Article in journal (Refereed)
    Abstract [en]

    CONTEXT: The gonadotropins are secreted from the human pituitary as spectra of isoforms with different degrees of sulfonation and sialylation of the oligosaccharides, modifications suspected to determine their half-lives in the circulation. OBJECTIVES: Our objectives were to determine the isoform composition of the serum gonadotropins during GnRH receptor blockade, and to estimate the half-lives in circulation of isoforms with 0-1-2-3 sulfonated N-acetylgalactosamine (SO(3)-GalNAc) residues. DESIGN/PARTICIPANTS: Serum samples were collected in seven healthy women before and up to 20 h after administration of the NAL-GLU GnRH antagonist. MAIN OUTCOME MEASURES: The number of sialic acid and SO(3)-GalNAc residues per LH and FSH molecule and the distribution of molecules with 0-1-2-3 sulfonated residues were measured. The half-lives were estimated by monoexponential decay. RESULTS: More sialylated and less sulfonated gonadotropin isoforms remain longer in circulation during GnRH receptor blockade. LH isoforms with two and three sulfonated residues per molecule had shorter half-lives compared with those with zero and one (109 and 80 vs. 196 and 188 min; P < 0.01). FSH isoforms with one and two sulfonated residues had shorter half-lives than those with zero (485 and 358 vs. 988 min; P < 0.01). CONCLUSIONS: The decline in LH and FSH during GnRH receptor blockade is associated with a decrease in sulfonated and increase in sialylated residues. The rapid disappearance of LH isoforms with two and three SO(3)-GalNAc residues suggests their removal by hepatic SO(3)-GalNAc-receptors similar to those in rodents. Episodical secretion of spectra of isoforms with different half-lives is expected to lead to continuous changes in gonadotropin isoform compositions in blood.

  • 270.
    Wide, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Eriksson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Sluss, Patrick M.
    Hall, Janet E.
    The common genetic variant of luteinizing hormone has a longer serum half-life than the wild type in heterozygous women2010In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 95, no 1, p. 383-389Article in journal (Refereed)
    Abstract [en]

    CONTEXT: The common genetic variant of human LH has two mutations and an extra N-linked oligosaccharide chain, a modification expected to affect the half-life in the circulation. OBJECTIVES: Our objectives were to determine the half-lives of variant and wild-type forms of LH during GnRH receptor blockade in heterozygous women and to determine the time-related changes in isoform composition. DESIGN AND PARTICIPANTS: Serum samples were obtained from three healthy women heterozygous for variant LH before and up to 20 h after administration of the NAL-GLU GnRH antagonist. MAIN OUTCOME MEASURES: The half-lives were estimated by monoexponential decay. The number of sialic acid and sulfonated N-acetylgalactosamine residues per wild-type and variant LH molecule and the distribution of molecules with zero, one, two, or three sulfonated residues were measured. RESULTS: The variant LH had a half-life that was approximately 40% longer than the corresponding forms of wild-type LH (148 vs. 108 min; P < 0.001). Variant LH had more sialic acid residues per molecule than wild type (3.6 vs. 2.4; P < 0.05), whereas the number of sulfonated residues was similar (1.0 vs. 0.98). The decline in the variant LH during GnRH receptor blockade was associated with a decrease in sulfonated and an increase in sialic acid residues similar to that for in wild-type LH. Isoforms of either variant or wild-type LH with two to three sulfonate groups per molecule had the shortest half-life. CONCLUSION: Variant LH remains longer in circulation than wild type during GnRH receptor blockade in heterozygous women, in accord with its higher content of sialic acid.

  • 271.
    Wide, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Eriksson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Effects of 17 beta-oestradiol and norethisterone acetate on sulfonation and sialylation of gonadotrophins in post-menopausal women2010In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 2, p. 97-106Article in journal (Refereed)
    Abstract [en]

    Background. The number of terminal sialic acid and sulfonated N-acetylgalactosamine (SO3-GalNAc) on gonadotrophins in serum varies during the menstrual cycle and changes at menopause, suggesting that gonadal steroids modify their oligosaccharide synthesis. Our objective was to determine the effects of 17 beta-oestradiol (E-2) and a progestogen, norethisterone acetate (NETA), on the sulfonation and sialylation of gonadotrophins in post-menopausal women. Methods. Serum samples were obtained from eight post-menopausal women treated with 20 mg E-2 implants every 6 months, from four women who in addition were treated daily with 5 mg NETA orally for a 2-week period, and from four women who got this NETA treatment during a 4-week period. Sera from 11 non-treated post-menopausal women served as a reference group. The gonadotrophin serum concentrations, the number of SO3-GalNAc and sialic acid residues per serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) molecule, and the distributions of molecules with 0-1-2-3-4 sulfonated residues were measured. Results. The E-2-treated post-menopausal women had considerably less (P < 0.001) sialic acid and slightly more (P < 0.01) SO3-GalNAc per serum LH and FSH molecule than the non-treated. Two weeks of NETA treatment increased the sulfonation of LH (P < 0.01) and FSH (P < 0.05) concomitantly with decreased (P < 0.05) sialylation of LH. Conclusion. The primary effect of E-2 treatment was a decrease in sialylation and, due to competition for the same substrate, a secondary and consequentially minor increase in sulfonation of LH and FSH. The primary effect of the NETA therapy was an increase in the sulfonation of LH and FSH concomitantly with secondary and consequentially decreases in sialylation of LH.

  • 272.
    Wieslander, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Norbäck, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Changes of symptoms, tear film stability and eosinophilic cationic protein in nasal lavage fluid after re-exposure to a damp office building with a history of flooding2007In: Indoor Air, ISSN 0905-6947, E-ISSN 1600-0668, Vol. 17, no 1, p. 19-27Article in journal (Refereed)
    Abstract [en]

    The aim was to study health effects in office workers (N = 18) in a medical case book archive with dampness caused by flooding. They were first investigated in a building without dampness (exposure free for 10 days). Then all returned to the damp building, and were re-investigated after 2 days. We measured tear film break up time (BUT), nasal patency, biomarkers in nasal lavage (NAL), and dynamic spirometry. Both buildings had low CO2 (380-600 ppm), low levels of respirable particles (8-10 μg/m3), and formaldehyde (5-7 μg/m3). The flooded building had slightly higher (149 ng/m3 vs. 94 ng/m3) levels of microbial volatile organic compounds (MVOC). After 2 days of re-exposure, there was an increase of ocular (P < 0.001), nasal (P = 0.002), and throat symptoms (P < 0.001), dyspnea (P = 0.006), headache (P = 0.002), nausea (P = 0.04), and tiredness (P = 0.01). The median BUT decreased from 16 to 8 s (P = 0.003), and eosinophilic cationic protein (ECP) in NAL increased slightly (P = 0.04). A separate test of the weekday effect showed slight improvements, or no change of symptoms and signs from Monday to Wednesday. In conclusion, subjects previously exposed to building dampness had an increase of symptoms, reduced tear film stability, and signs of eosinophilic inflammation in the nasal mucosa after 2 days of re-exposure.

  • 273.
    Wikström, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Eriksson, Ulf J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Nash, Peppi
    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.
    Olovsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Early postpartum changes in circulating pro- and anti-angiogenic factors in early-onset and late-onset pre-eclampsia2008In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 87, no 2, p. 146-153Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Pre-eclampsia is associated with altered plasma concentrations of the pro- and anti-angiogenic factors placental growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A) and soluble fms-like tyrosine kinase 1 (sFlt1). However, there is insufficient knowledge about how these concentrations change after delivery, and whether the changes differ between early-onset and late-onset pre-eclampsia. METHODS: Plasma concentrations of sFlt1, PlGF and VEGF-A were measured before delivery and on days 1, 3 and 7 postpartum in women with early-onset (24-32 weeks' gestation) (n=18) and late-onset pre-eclampsia (35-42 weeks' gestation) (n=20) and in control groups delivered in corresponding weeks of gestation. RESULTS: All groups showed a rapid decrease in median sFlt1 concentration postpartum. Women with late-onset pre-eclampsia did not differ in sFlt1 concentration from controls on day 1 postpartum, whereas women with early-onset pre-eclampsia displayed a persistently elevated sFlt1 concentration on day 7 postpartum compared with controls. PlGF concentrations did not change from before delivery to any time point postpartum in the pre-eclampsia groups. VEGF-A concentrations were slightly increased on day 7 postpartum in both pre-eclampsia and control groups compared to concentrations prior to delivery. CONCLUSION: Median sFlt1 concentrations decreased rapidly postpartum in all groups, but remained higher in early-onset pre-eclampsia than controls on day 7. Postpartum, the median PlGF concentrations were similar to the concentrations measured before delivery in women with pre-eclampsia.

  • 274.
    Wikström, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Eriksson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Nash, Peppi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Nordén-Lindeberg, Solveig
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Placental growth factor and soluble fms-like tyrosine kinase-1 in early-onset and late-onset preeclampsia2007In: Obstetrics and Gynecology, ISSN 0029-7844, E-ISSN 1873-233X, Vol. 109, no 6, p. 1368-1374Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To estimate whether alterations in plasma levels of the proangiogenic proteins placental growth factor (PlGF) and vascular endothelial growth factor-A (VEGF-A), and the antiangiogenic protein soluble fms-like tyrosine kinase-1 (sFlt1) were more pronounced in early-onset than in late-onset preeclampsia. METHODS: A cross-sectional study was conducted to estimate the levels of sFlt1, PlGF, and VEGF-A in plasma in a control group of nonpregnant women, in an early control group of women at 24-32 weeks of gestation, in a late control group of women at 36-42 weeks of gestation, and in cases of women with early-onset (before 32 weeks of gestation) and late-onset (after 35 weeks of gestation) preeclampsia. RESULTS: Women with early-onset preeclampsia had a 43 times higher median plasma sFlt1 level than early controls (P<.001). Women with late-onset preeclampsia had a three times higher median plasma sFlt1 level than late controls (P<.001). Women with early-onset preeclampsia had a 21 times lower median plasma PlGF level than early controls (P<.001). Women with late-onset preeclampsia had a five times lower median plasma PlGF level than late controls (P=.01). The median level of VEGF-A in plasma was less than 15 pg/mL in all groups of pregnant women. CONCLUSION: Both early- and late-onset preeclampsia are associated with altered plasma levels of sFlt1 and PlGF. The alterations are more pronounced in early-onset rather than in late-onset disease.

  • 275.
    Wikström, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Increased circulating levels of the antiangiogenic factor endostatin in early-onset but not late-onset preeclampsia2009In: Reproductive Sciences, ISSN 1933-7191, Vol. 16, no 10, p. 995-1000Article in journal (Refereed)
    Abstract [en]

    Changes in circulating angiogenic factors seem to play a key role in the pathogenesis of preeclampsia and it seems as if these changes are of greater importance in the pathogenesis of early-onset than of late-onset disease. Endostatin is a potent, broad spectrum antagonist of angiogenesis whose role in preeclampsia is poorly investigated. The aim of this study was to estimate whether circulating endostatin levels are altered in preeclampsia, and whether women with early-onset (before 32 weeks of gestation; n = 16) and late-onset (after 35 weeks of gestation; n = 19) preeclampsia differ in this regard. Women with early-onset, but not of late-onset preeclampsia had higher levels of endostatin than healthy pregnant women in corresponding lengths of gestation. The results of the study support the hypothesis that there is heterogeneity between early- and late-onset preeclampsia, with a stronger association between an altered angiogenic balance and early-onset than late-onset disease.

  • 276.
    Wikström, Anna-Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Random albumin/creatinine ratio for quantification of proteinuria in manifest pre-eclampsia2006In: BJOG, ISSN 1470-0328, Vol. 113, no 8, p. 930-934Article in journal (Refereed)
  • 277.
    Woschnagg, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Forsberg, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Engström, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Odreman, Federico
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Garcia, Rodolfo C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The Human Eosinophil Proteome. Changes Induced by Birch Pollen Allergy2009In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 8, no 6, p. 2720-2732Article in journal (Refereed)
    Abstract [en]

    Proteins from human eosinophils were separated bidimensionally and identified by mass spectrometry (336 spots/bands, 98 different proteins). Of these, 24.7% belonged to the cytoskeleton/migration group. Highly basic proteins (11.3%) were concentrated in the granule-containing cell fraction. We detected novel hyperacidic forms of cofilin-1, profilin-1 and adenylyl cyclase-associated protein, and hyperbasic forms of eosinophil-derived neurotoxin/eosinophil protein X and major basic protein homologue. We also found evidence of the triglycosylation of the heavy chain of eosinophil peroxidase. In addition, through comparative 2D image analysis, spot quantification and MS, it was found that hsc70, actin-capping protein and hyperacidic forms of eosinophil peroxidase heavy chain are overexpressed in cells from birch pollen allergic subjects, at the peak of a season. The link between these findings and an increased cellular antigen-presenting capacity and motility are discussed.

  • 278.
    Xu, Shengyuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Cai, Linjun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Zhao, Linshu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Douhan-Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Kristjansson, Gudjon
    Pauksen, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Tissue localization and the establishment of a sensitive immunoassay of the newly discovered human phospholipase B-precursor (PLB-P)2010In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 353, no 1-2, p. 71-77Article in journal (Refereed)
    Abstract [en]

    Human phospholipase B-precursor (PLB-P) is a newly identified and purified protein from human neutrophils. The precise function of PLB-P in vivo is not yet known. Its existence in neutrophils and the enzymatic activity against phospholipids imply a role in the defence against invading microorganisms and in the generation of lipid mediators of inflammation. We describe here the generation of specific antibodies against PLB-P, the tissue localizations of PLB-P and the establishment of an accurate, specific, and reproducible radioimmunoassay (RIA). A survey of normal and malignant tissues showed strong immunostaining of PLB-P in neuronal and myeloid cells and in adrenal glands. Elevated levels were found in sera of patients with influenza A infection i.e. > 1 mu g/L and in gut fluids of patients with inflammatory bowel disease i.e. > 20 mu g/L. The levels correlated to markets of neutrophil activation, suggesting a neutrophil origin of PLB-P in these conditions. The antibodies and the assay will be useful in the future basic and clinical investigations of PLB-P.

  • 279.
    Xu, Shengyuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zhao, Linshu
    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, Clinical Chemistry.
    Smeds, Emanuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kusche-Gullberg, Marion
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Purification of a 75 kDa protein from the organelle matrix of human neutrophils and identification as N-acetylglucosamine-6-sulphatase2005In: Biochemical Journal, ISSN 0264-6021, E-ISSN 1470-8728, Vol. 387, no Pt 3, p. 841-7Article in journal (Refereed)
    Abstract [en]

    A 75 kDa protein was purified to homogeneity from granule extracts of normal human granulocytes using Sephadex G-75 chromatography, Mono-S cation exchange chromatography and chromatofocusing. The protein consisted of one chain with a molecular mass of 75 kDa, as determined by SDS/PAGE. Tryptic peptide analysis by MALDI-TOF (matrix-assisted laser-desorption ionization-time-of-flight) MS and sequence analysis by MS/MS identified the protein to be N-acetylglucosamine-6-sulphatase (EC 3.1.6.14). The identity of the protein was confirmed by demostrating enzymatic activity towards the substrate N-acetylglucosamine 6-sulphate. The enzyme was active over a broad pH range with an optimum of pH 7.0, and showed a Km value of 13.0 mM and a Vmax value of ~1.8 µM/min per mg. The enzyme also showed O-desulphation activity towards heparan sulphate-derived saccharides. Subcellular fractionation of neutrophil organelles showed the presence of enzymatic activity mainly in the same fractions as primary granules. Furthermore, PMA treatment of the neutrophils induced release of the enzyme, indicating its matrix protein nature. The presence of N-acetylglucosamine-6-sulphatase in human neutrophils implies that neutrophils may play a role in the modulation of cell surface molecules and extracellular matrix by O-desulphation.

  • 280.
    Xu, Shengyuan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Zhao, Linshu
    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.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The identification of a phospholipase B precursor in human neutrophils2009In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 276, no 1, p. 175-186Article in journal (Refereed)
    Abstract [en]

    A phospholipase B (PLB) precursor was purified from normal human granulocytes using Sephadex G-75, Mono-S cation-exchange and hydroxyapatite columns. The molecular mass of the protein was estimated to be approximately 130 kDa by gel filtration and 22 and 42 kDa by SDS/PAGE. Tryptic peptide and sequence analyses by MALDI-TOF and tandem mass spectrometry (MS/MS) identified the protein as a FLJ22662 (Homo sapiens) gene product, a homologue of the amoeba Dictyostelium discoideum PLB. The native protein needed modifications to acquire deacylation activity against phospholipids including phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine and lysophospholipids. Enzyme activity was associated with fragments derived from the 42 kDa fragment. The enzyme revealed a PLB nature by removing fatty acids from both the sn-1 and sn-2 positions of phospholipids. The enzyme is active at a broad pH range with an optimum of 7.4. Immunoblotting of neutrophil postnuclear supernatant using antibodies against the 42 kDa fragment detected a band at a molecular mass of 42 kDa, indicating a neutrophil origin of the novel PLB precursor. The existence of the PLB precursor in neutrophils and its enzymatic activity against phospholipids suggest a role in the defence against invading microorganisms and in the generation of lipid mediators of inflammation.

  • 281. Zagai, Ulrika
    et al.
    Dadfar, Elham
    Lundahl, Joachim
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Sköld, C Magnus
    Eosinophil Cationic Protein Stimulates TGF-β1 Release by Human Lung Fibroblasts In Vitro2007In: Inflammation, ISSN 0360-3997, E-ISSN 1573-2576, Vol. 30, no 5, p. 153-160Article in journal (Refereed)
    Abstract [en]

    Eosinophilic inflammation and airway remodeling are features of asthma. Eosinophil cationic protein ( ECP) is released by activated eosinophils and transforming growth factor ( TGF)beta(1) has major functions in the fibrotic process. We therefore hypothesized that ECP stimulates TGF-beta(1) release by human lung fibroblasts. Fibroblasts in monolayer displayed a constitutive release of TGF-beta(1), which increased in presence of ECP ( 436 +/- 60 vs. 365 +/- 48 pg/ ml at 48 h; P< 0.01). mRNA expression of TGF-beta(1) was almost twofold in ECP- stimulated fibroblasts. ECP in threedimensional cultures stimulated both TGF-beta(1) release ( 180 +/- 61 vs. 137 +/- 54 pg/ ml; P< 0.01) and fibroblast- mediated collagen gel contraction ( 28 vs. 39% of initial gel area at 48 h; P< 0.001). ECP stimulates TGF-beta(1) release by human lung fibroblasts, suggesting a potential mechanism for eosinophils in the fibrotic response. This may be an important mechanism by which ECP promotes remodeling of extra cellular matrix leading to airway fibrosis in asthmatics.

  • 282. Zagai, Ulrika
    et al.
    Lundahl, J.
    Klominek, J.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Sköld, C. M.
    Eosinophil cationic protein stimulates migration of human lung fibroblasts in vitro2009In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 69, no 4, p. 381-386Article in journal (Refereed)
    Abstract [en]

    Asthma is characterized by eosinophilic inflammation and remodelling of the airways. Eosinophil cationic protein (ECP) is a protein released by activated eosinophils and the hypothesis that ECP contributes to the development of structural changes in the airways of asthmatics has been posed. Fibroblast recruitment is an important step in the remodelling process, and we therefore put the question whether ECP stimulates migration of human lung fibroblasts. Human peripheral eosinophils isolated from buffycoats from healthy individuals were cultured and conditioned media (CM) were collected. Native ECP was extracted from human peripheral eosinophils by gel filtration, ion-exchange and chelating chromatography. The ability of eosinophil CM and ECP to stimulate fibroblast migration was determined using the 48-well Boyden chamber. ECP concentrations in CM were assayed by ECP-CAP-FEIA. Both CM and ECP significantly stimulated fibroblast migration (48.4+/-cells/field versus 33+/-2 and 36+/-6 versus 25+/-4; P<0.001 and 0.05 respectively) in a time- and concentration-dependent manner. Adding neutralizing ECP antibodies attenuated fibroblast migration induced by both ECP as well as CM. ECP stimulates migration of human lung fibroblasts, suggesting a potential mechanism for eosinophils in the fibrotic response. This may be an important mechanism by which ECP promotes remodelling of extracellular matrix leading to airway fibrosis in asthmatics.

  • 283. Zhang, Kuixing
    et al.
    Rao, Fangwen
    Rana, Brinda K.
    Gayen, Jiaur R.
    Calegari, Federico
    King, Angus
    Rosa, Patrizia
    Huttner, Wieland B.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Mahata, Manjula
    Vaingankar, Sucheta
    Mahboubi, Vafa
    Salem, Rany M.
    Rodriguez-Flores, Juan L.
    Fung, Maple M.
    Smith, Douglas W.
    Schork, Nicholas J.
    Ziegler, Michael G.
    Taupenot, Laurent
    Mahata, Sushil K.
    OConnor, Daniel T.
    Autonomic function in hypertension; role of genetic variation at the catecholamine storage vesicle protein chromogranin B2009In: Circulation: Cardiovascular Genetics, ISSN 1942-3268, Vol. 2, no 1, p. 46-56Article in journal (Refereed)
    Abstract [en]

    Background: Hypertension is a complex trait, with deranged autonomic control of circulation. Chromogranin B (CHGB) is the most abundant core protein in human catecholamine secretory vesicles, playing an important role in their biogenesis. Does common interindividual variation at the CHGB locus contribute to phenotypic variation in CHGB and catecholamine secretion, autonomic stability of circulation, or blood pressure (BP) in the population? Methods and Results: To probe interindividual variability in CHGB, we systematically studied polymorphism across the locus by resequencing CHGB (≈6 kbp footprint spanning the promoter, 5 exons, exon/intron borders, untranslated regions) in 160 subjects (2n=320 chromosomes) of diverse biogeographic ancestries. We identified 53 single-nucleotide polymorphisms, of which 22 were common. We then studied 1182 subjects drawn from the most extreme BP values in the population (highest and lowest 5th percentiles), typing 4 common polymorphisms spanning the ≈14 kbp locus. Sliding-window haplotype analysis indicated BP associations peaking in the 5'/promoter region, most prominent in men, and a peak effect in the proximal promoter at variant A-261T (A>T), accounting for ≈8/≈6 mm Hg BP in males. The promoter allele (A-261) that was a predictor of higher diastolic BP and systolic BP was also associated with lower circulating/plasma CHGB concentration (CHGB439to451 epitope) in twin pairs. In twins, the same CHGB variants that were predictors of lower basal CHGB secretion were also associated with exaggerated catecholamine secretion and BP response to environmental (cold) stress; likewise, women displayed increased plasma CHGB439to451 but decreased catecholamine secretion as well as BP response to environmental stress. The effect of A-261T on CHGB expression was confirmed in chromaffin cells by site-directed mutagenesis on transfected CHGB promoter/luciferase reporter activity, and the allelic effects of A-261T on gene expression were directionally coordinate in cella and in vivo. To confirm these clinical associations experimentally, we undertook targeted homozygous (-/-) ablation of the mouse CHGB gene; knockout mice displayed substantially increased BP, by ≈20/≈18 mm Hg, confirming the mechanistic basis of our findings in humans. Conclusion-Common genetic variation at the CHGB locus, especially in the proximal promoter, influences CHGB expression and later catecholamine secretion and the early heritable responses to environmental stress, eventuating in changes in resting/basal BP in the population. Both the early (gene expression) and late (population BP) consequences of CHGB variation are sex dependent. These results point to new molecular strategies for probing autonomic control of circulation and, ultimately, the susceptibility to and pathogenesis of cardiovascular disease states such as hypertension.

  • 284.
    Zhang, Yanyu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Valsala Madhavan Unnithan, Ragaseema
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Saupe, Falk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Siegbahn, Agneta
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cedervall, Jessica
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    TBK1, an NF-κB activating kinase, is required for platelet-induced EMTManuscript (preprint) (Other academic)
    Abstract [en]

    Platelets can promote several steps during the metastatic process, and hence

    contribute to malignant progression. During early stages of metastasis, platelets

    promote invasive properties of tumor cells by induction of epithelial to mesenchymal transition (EMT). In this study we show that TANK binding kinase-1 (TBK1) is a previously unknown mediator of platelet-induced EMT - a finding that suggests a possible role of TBK1 as a potential driver of metastatic disease. Using the two mammary epithelial cell lines Ep5 and MCF10A (M2), we show that co-culture with isolated platelets induced morphological as well as molecular features indicative of EMT, and that this is paralleled with activation of TBK1. Inhibiting TBK1 using siRNA suppressed platelet induced EMT in both Ep5 and MCF10A (M2) cells. Furthermore, platelet induced NF-κB signaling was suppressed after TBK1 knock down, suggesting that TBK1 is a crucial mediator of platelet-induced NF-κB signaling and subsequent EMT. Altogether, these results suggest that TBK1 contribute to tumor invasiveness and may hence be a driver of metastatic spread in mammary epithelial tumors.

  • 285.
    Zhao, Linshu
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    CarcinoEmbryonic Antigen-related Cell Adhesion Molecule 8 (CEACAM8): Purification, Characterization, Cellular and Clinical Studies2004Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A 95-kDa protein was purified from normal human granulocytes. The protein reacted with a monoclonal antibody against CEACAM8. MALDI-Tof and MS/MS analyses revealed the protein to be a CGM6 gene product. Thus, the protein was proved to be identical to CEACAM8.

    An ELISA for CEACAM8 was developed with detection range of 1-64μg/L. Data are presented on the levels of CEACAM8 in the blood of healthy individuals and patients undergoing surgery, as well as in patients with acute infection. The highly elevated levels of CEACAM8 in the blood of these patients were significantly correlated with the surface expression of CEACAM8 on neutrophils and the number of circulating neutrophils, which suggests that CEACAM8 could serve as a biological marker for granulocyte activitiy in vivo.

    The cellular content of CEACAM8 in neutrophils was estimated to be 82.4 ± 8.9 ng/106 cells. Subcellular localisation and mobilisation studies showed that the majority of CEACAM8 is present in the secondary granules of human neutrophils, with a small amount on the plasma membranes. Upon stimulation, CEACAM8 translocated to the plasma membranes from the secondary granules and was also released extracellularly (5.5 ± 0.7% of the total content of CEACAM8).

    In eosinophils, the cellular content of CEACAM8 was estimated to be 73.8 ± 6.0 ng/106 cells. In these cells, CEACAM8 is mainly stored in secretory vesicles. Upon activation, eosinophils released 5.1 ± 1.1% of the total content of CEACAM8.

    Administration of granulocyte colony-stimulating factor (G-CSF) to healthy individuals resulted in an increased content of CEACAM8 in neutrophils on day 1, and decreased on day 4. However, the content of CEACAM8 in light membrane fractions was increased on day 4. The translocation of CEACAM8 observed in vivo after G-CSF administration is probably not directly related to this cytokine but to other cytokines such as TNF-a.

  • 286.
    Zhao, Linshu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Furebring, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Xu, Shengyuan
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Subcellular localization and mobolization of carcinoembryonic antigen-related cell adhesion molecule 8 in human neutrophils2004In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 125, no 5, p. 666-673Article in journal (Refereed)
    Abstract [en]

    The subcellular localization and mobilization of carcinoembryonic antigen-related cell adhesion molecule 8 (CEACAM8) was investigated quantitatively in human neutrophils. In resting neutrophils the majority of CEACAM8 was present in the secondary granules, and a small amount of CEACAM8 was present in a light membrane fraction. Stimulation of the neutrophils with phorbol 12-myristate 13-acetate caused a dramatic increase in the content of CEACAM8 in the light membrane fraction, suggesting a translocation of CEACAM8 to the plasma membrane from intracellular pools. The cellular content of CEACAM8 in the neutrophils was estimated to be 82.4 +/- 8.9 ng/10(6) cells (mean +/- SE, n = 10). Administration of granulocyte colony-stimulating factor (G-CSF) to healthy individuals resulted in an increased content of CEACAM8 in neutrophils on day 1, which decreased on day 4. However, the content of CEACAM8 in the light membrane fraction was increased on day 4, possibly due to the stimulation by induced secondary cytokines, such as tumour necrosis factor-alpha (TNF-alpha). This study establishes the secondary granules as the major intracellular pools of CEACAM8 in human neutrophils, from which it may translocate to the plasma membranes upon stimulation of the cells. The translocation of CEACAM8 seen in vivo after G-CSF administration is probably indirect and caused by cytokines such as TNF-alpha.

  • 287.
    Zhao, Linshu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Xu, Shengyuan
    Fjaertoft, Gustaf
    Pauksen, PerKarlis
    Håkansson, Lena
    Venge, Per
    An enzyme linked immunosorbent assay for human carcinoembryonic antigen-related cell adhesion 8, a biological marker of granulocytes in vivo2004In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 293, no 1-2, p. 201-214Article in journal (Refereed)
    Abstract [en]

    Carcinoembryonic antigen-related cell adhesion molecule 8 (CEACAM8), also known as CD66b, NCA-95 and CD67, is a highly glycosylated protein expressed only in neutrophils and eosinophils in humans. The precise function of CEACAM8 remains unclear. As a member of the family of carcinoembryonic antigen (CEA), it may play a role in the interaction between granulocytes or between granulocytes and epithelial cells. We describe here an accurate, specific and reproducible enzyme-linked immunosorbent assay (ELISA) using purified native CEACAM8 as standard for the measurement of CEACAM8 with a detection range of 1-64 microg/l. We also present data on the levels of CEACAM8 in the blood of healthy individuals and patients undergoing surgery, as well as in patients with acute infections. The highly elevated levels of CEACAM8 in the blood of these patients, which are significantly correlated with the surface expression of CEACAM8 on neutrophils and the number of circulating neutrophils, suggest that CEACAM8 could serve as a biological marker for granulocyte activities in vivo.

  • 288.
    Zhao, Linshu
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Xu, Shengyuan
    Håkansson, Lena
    Karawajczyk, Malgorzata
    Subcellular localization of carcinoembryonic antigen-related cell adhesion molecular 8 (CEACAM8) in human eosinophils: CEACAM8 in human eosinophilsManuscript (Other academic)
  • 289.
    Zhao, Linshu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Xu, Shengyuan
    Peterson, Christer
    Kuroki, Motomu
    Kuroki, Masahide
    Venge, Per
    Purification and characterization of a 95 kDa protein: from normal human granulocytes2002In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 270, no 1, p. 27-35Article in journal (Refereed)
    Abstract [en]

    A 95-kDa protein was purified to homogeneity from granule extracts of normal human granulocytes. The column procedure consisted of Sephadex G-75, Mono-S cation exchange and Superdex HR 75 chromatography. The purified protein showed only one broad band at a molecular weight of 95 kDa when analyzed by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE). It reacted with polyclonal antibodies against carcinoembryonic antigen (CEA) and a specific monoclonal antibody against CD66b, but did not react with monoclonal antibodies against CD66acde and CD66c when analyzed by immunoblotting. The molecular weight of the protein shifted from 95 to 40 kDa on SDS-PAGE after deglycosylation. Tryptic peptide analysis by MALDI-Tof identified four peptides with spectra of m/z matching the expected tryptic peptides from a CGM6 gene product. Furthermore, the nanoelectrospray mass spectrometry (MS/MS) analysis of the two selected tryptic peptides of the protein revealed two amino acid sequences corresponding to residues 79-98 and 199-207 of the CGM6 gene product. Based on this, and also on the immunochemical data, it is concluded that the purified 95 kDa is identical to carcinoembryonic antigen-related cell adhesion molecule 8 (CEACAM8) (nonspecific cross-reacting antigen (NCA)-95, CD67 and CD66b) and is a product of the CGM6 (W272) gene. We present, for the first time, a method for the purification of CEACAM8 from normal human granulocytes, which should be useful for further studies on its structure and functions. We also confirmed at the protein level that CEACAM8 is a product of the CGM6 (NCA-W272) gene.

  • 290. Åberg, A. M.
    et al.
    Ahlström, K.
    Abrahamsson, P.
    Waldenström, A.
    Ronquist, G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hauck, P.
    Johansson, G.
    Biber, B.
    Haney, M.
    Ischaemic pre-conditioning means an increased adenosine metabolism with decreased glycolytic flow in ischaemic pig myocardium2010In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 54, no 10, p. 1257-1264Article in journal (Refereed)
    Abstract [en]

    Background Ischaemic pre-conditioning (IP) is a potent protective mechanism for limiting the myocardial damage due to ischaemia. It is not fully known as to how IP protects. The metabolism of adenosine may be an important mechanistic component. We study the role of adenosine turnover together with glycolytic flow in ischaemic myocardium subjected to IP. Methods An acute myocardial ischaemia pig model was used, with microdialysis sampling of some metabolites (lactate, adenosine, glucose, glycerol, taurine) of ischaemic myocardium. An IP group was compared with a control group before and during a prolonged ischaemia. 14C-labelled adenosine and glucose were infused through microdialysis probes, and lactate, 14C-labelled lactate, glucose, taurine and glycerol were analysed in the effluent. The glycogen content in myocardial biopsies was determined. Results The 14C-adenosine metabolism was higher as there was a higher production of 14C-lactate in IP animals compared with the controls. The glycolytic flow, measured as myocardial lactate formation, was retarded during prolonged ischaemia in IP animals. Myocardial free glucose and glycogen content decreased during the prolonged ischaemia in both groups, with higher free glucose in the IP group. We confirmed the protective effects of IP with lower myocardial concentrations of markers for cellular damage (glycerol). Conclusions This association between increased adenosine turnover and decreased glycolytic flow during prolonged ischaemia in response to IP can possibly be explained by the competitive effect for the metabolites from both glucose and adenosine metabolism for entering glycolysis. We conclude that this study provides support for an energy-metabolic explanation for the protective mechanisms of IP.

  • 291. Åberg, Anna-Maja
    et al.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Haney, Michael
    Waldenström, Anders
    Effects of some modulators on purine nucleoside phosphorylase activity in myocardial tissue2010In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 70, no 1, p. 8-14Article in journal (Refereed)
    Abstract [en]

    Purine nucleoside phosphorylase (PNP) in mammalian tissue is an enzyme responsible for formation of purine bases in DNA. It is also believed that PNP is crucial under energy-deprived conditions for the cell to metabolise adenosine during ATP degradation. This work describes a new method for determination of PNP activity in myocardial tissue using a commercially available substrate, 2-amino-6-mercapto-7-methylpurine riboside (MESG). The method involves the photometric assessment of the reaction between PNP (extracted from myocardial tissue) and MESG. Quantification as well as temperature- and pH-dependency for myocardial PNP activity is described. Also, the effect of some modulators has been studied. We have established the presence of PNP activity in pig myocardial tissue. Further, the results indicate a pH tolerance under slightly acid conditions and a calcium ion dependence of the enzyme.

  • 292.
    Åberg, Mikael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Johnell, Matilda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wickström, Malin
    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, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Tissue Factor/ FVIIa prevents the extrinsic pathway of apoptosis by regulation of the tumor suppressor Death-Associated Protein Kinase 1 (DAPK1)2011In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 127, no 2, p. 141-148Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: This study determines the impact of tissue factor (TF)-signaling on the extrinsic pathway of apoptosis in cancer cells and propose death associated protein kinase-1 (DAPK1) as a novel key regulator. MATERIALS AND METHODS: In MDA-MB-231 breast and PC3 prostate cancer cells, mRNA levels were analyzed by real-time PCR and protein expressions were assessed by flow cytometry or western blot. Caspase-8 and -3 levels, cell size, and changes in nuclear morphology were recorded using the ArrayScan microscope and 84 apoptosis-related genes were screened with the RT2 Profiler™ PCR Array. RESULTS: In serum starved MDA-MB-231 cells, a TF/FVIIa-sensitive upregulation of apoptosis markers was recorded. Similarly, TRAIL-induced apoptosis was negatively regulated by TF/FVIIa (10 and 100nM) and TF/FVIIa/FXa but not by active-site inhibited FVIIa. FVIIa, moreover, decreased the transcription of DAPK1 and thereby diminished the association between DAPK1 and FADD in the caspase-8 activating death-inducing signaling complex (DISC). TF/FVIIa regulation of caspase-8 and DAPK1 was dependent on PI3-kinase/AKT and independent of the protease activated receptors (PAR) 1 and 2. Despite of receptor expression and functional signaling, both PAR-agonist treatment and PAR-blocking antibodies in combination with FVIIa failed to influence the anti-apoptotic signal. CONCLUSIONS: We hereby report that TF/FVIIa-induced signaling governs the extrinsic pathway of apoptosis by reducing the levels of DAPK1 in the DISC independently of PAR1 and PAR2. This implies the conceivable involvement of cell surface components other than the PARs and entails the search for TF-dependent regulators of DAPK1 transcription.

  • 293.
    Åkerblom, Axel
    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.
    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.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Becker, Richard C.
    Duke Clinical Research Institute, Durham, NC, USA.
    Budaj, Andrzej
    Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland.
    Himmelmann, Anders
    AstraZeneca Research and Development, Mölndal, Sweden.
    Horrow, Jay
    AstraZeneca Research and Development, Wilmington, USA.
    Husted, Steen
    Department of Cardiology, Århus University Hospital, Århus, Denmark.
    Storey, Robert F.
    Department of Cardiovascular Science, University of Sheffield, Sheffield, UK.
    Åsenblad, Nils
    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.
    Cystatin C- and Creatinine-based Estimates of Renal Function and Their Value for Risk Prediction in Patients with Acute Coronary Syndrome: Results from the PLATelet Inhibition and Patient Outcomes (PLATO) Study2013In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 59, no 9, p. 1369-1375Article in journal (Refereed)
    Abstract [en]

    Background: The estimated glomerular filtration rate (eGFR) independently predicts cardiovascular (CV) death or myocardial infarction (MI), and can be estimated by creatinine and cystatin C concentrations. We evaluated two different cystatin C assays, alone or combined with creatinine, in patients with acute coronary syndromes.

    Methods: Plasma cystatin C, measured with assays from Gentian and Roche, and serum creatinine was analyzed in 16279 patients from the PLATelet inhibition and patient Outcomes trial. Pearson’s correlation and agreement (Bland–Altman) between methods was evaluated. Prognostic value in relation to CV death or MI during one year of follow up was evaluated by multivariable logistic regression analysis including clinical variables and biomarkers, c-statistics and relative Integrated Discrimination Improvement (IDI).

    Results: Median cystatin C concentrations (interquartile intervals) were 0.83 (0.68 - 1.01) mg/L (Gentian) and 0.94 (0.80 - 1.14) mg/L (Roche). Overall correlation was 0.86 (95% confidence interval 0.85-0.86). The level of agreement was ±0.39mg/L (±2 standard deviations) (n=16279).

    The area under curve (AUC) in the multivariable risk prediction model with cystatin C (Gentian, Roche) or Chronic Kidney Disease - Epidemiology (CKD-EPI) added was 0.6914, 0.6913 and 0.6932. Corresponding relative IDIs were 2.96%, 3.86% and 4.68%, respectively (n=13050). Addition of eGFR by the combined creatinine-cystatin C equation yielded AUC of 0.6923(Gentian) and 0.6924(Roche) with relative IDIs of 3.54% and 3.24% respectively.

    Conclusions: Despite differences in cystatin C concentrations, overall correlation between the Gentian and Roche assays was good while agreement was moderate.  The combined creatinine-cystatin C equation did not outperform risk prediction compared to CKD-EPI.

  • 294.
    Åkerfeldt, Torbjörn
    et al.
    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.
    Inflammatory response is associated with increased cathepsin B and decreased cathepsin S concentrations in the circulation2011In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 71, no 3, p. 203-207Article in journal (Refereed)
    Abstract [en]

    Abstract Objective. Extracellular matrix remodeling by cathepsins play an important role in many conditions associated with inflammation. The aim of this study was to study the effect of inflammation on circulating levels of human cathepsin B and S. Materials and methods. Blood sampling was carried out prior to surgery and 4 and 30 days after surgery, respectively. Two patient groups were included: (1) patients undergoing orthopedic surgery (n = 29) and coronary bypass patients (n = 21). Serum cathepsin B and S levels were measured using sandwich ELISAs. C-reactive protein (CRP) was analysed by turbidimetry. Results. Serum cathepsin B showed significantly higher values 4 days after surgery in comparison with samples collected prior to surgery. Serum cathepsin S instead showed significantly lower values 4 days after surgery. Similar results were found in both patient groups. Conclusions. Inflammation has different effects on circulating levels of cathepsin B and S.

  • 295.
    Öhman, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Åkerfeldt, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Ingela
    Rosen, Christer
    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.
    Biochemical effects of consumption of eggs containing omega-3 polyunsaturated fatty acids2008In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 113, no 3, p. 315-323Article in journal (Refereed)
    Abstract [en]

    Today, eggs with an increased content of -3 fatty acids are available but there are few publications on the effects of consumption of such eggs on the lipoproteins and acute phase markers in humans. The aim of the present study was to evaluate the effects of consumption of standard eggs and -3 enriched eggs on lipoproteins, glucose and inflammation markers. Nineteen healthy volunteers consumed one extra egg per day of either standard eggs or omega-3 enriched eggs in a double-blind, cross-over study. The duration of each period was 1 month. The effects of the different egg diets on apolipoprotein A1 and B (Apo A1 and B), lipoprotein (a), creatinine, cystatin C, C-reactive protein, serum amyloid protein A, interleukin 6, triglycerides, glucose, total-, high-density lipoprotein and low-density lipo-protein cholesterol concentrations were analyzed. Addition of one regular egg per day to the normal diet had no negative impact on blood lipids or inflammation markers. Consumption of omega-3 enriched eggs resulted in higher levels of ApoA1, lower ApoB/ApoA1 ratio and lower plasma glucose. These effects have been associated in previous studies with a reduced risk for cardiovascular mortality and diabetes.

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