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  • 1. Altraja, Alan
    et al.
    Laitinen, Annika
    Virtanen, Ismo
    Kämpe, Mary
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Simonsson, Bo G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karlsson, Sven-Erik
    Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sillastu, Heinart
    Laitinen, Lauri A.
    Expression of laminins in the airways in various types of asthmatic patients: A morphometric study1996In: American Journal of Respiratory Cell and Molecular Biology, ISSN 1044-1549, E-ISSN 1535-4989, Vol. 15, no 4, p. 482-488Article in journal (Refereed)
    Abstract [en]

    Laminins (Ln) are crucial in airway morphogenesis. Because they are able to interact with inflammatory cells, they are likely to participate in inflammation accompanied by airway structural remodeling in asthma. Taking biopsies and using immunohistochemistry and quantitative image analysis, we characterized the distribution of Ln chains alpha 1, alpha 2, and beta 2 in the bronchial mucosa of patients with seasonal (n = 17), early occupational (n = 8), and chronic asthma (n = 16) for comparison with that of normal controls (n = 8). In all asthmatic patients, both Ln chains alpha 1 and beta 2 were confined to the superficial margin of the basement membrane (BM), blood vessels, and smooth muscle. The thickness of Ln beta 2 expression in BM was significantly greater in patients with chronic (1.9 +/- 0.1 microns; P < 0.001) and occupational asthma (1.7 +/- 0.1 microns; P < 0.05) than in controls (0.4 +/- 0.3 microns). Only in patients with occupational asthma was the thickness of the Ln alpha 1 layer (2.3 +/- 0.2 microns; mean +/- SEM) significantly different from that in controls (1.4 +/- 0.5 microns; P < 0.05). There was no immunoreactivity for the Ln alpha 2 chain in controls or patients with mild asthma, but in clinically severe chronic asthma we found a discontinuous staining along the epithelial margin of the BM. Since Ln chains alpha 2 and beta 2 appear to function only during morphogenesis, increased expression of these Ln chains in adult asthma patients suggests accelerated tissue turnover in the airways, possibly as a result of airway inflammation in asthma.

  • 2.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ekberg-Jansson, A.
    Löfdahl, C.G.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Relationship between inflammatory cells and structural changes in the lungs of asymptomatic and never smokers: a biopsy study2003In: Thorax, ISSN 0040-6376, E-ISSN 1468-3296, Vol. 58, no 2, p. 135-142Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A study was undertaken to investigate the relationship between inflammatory cells and structural changes in the mucosa of the airways in an epidemiological sample of a group of asymptomatic smokers (smokers who had never sought medical attention for respiratory problems) and in non-smoking subjects.

    METHODS: Bronchial biopsy specimens were taken from 29 smokers and 16 never smokers and stained with monoclonal antibodies HNL, EPO, AA1, CD68 in order to identify neutrophils, eosinophils, mast cells, and macrophages, respectively. The biopsy specimens were also stained with monoclonal antibodies to the cytokines interleukin (IL)-1beta and IL-8. Structural changes were identified by staining the biopsy specimens with antibodies to tenascin and laminin and by evaluating the condition of the epithelial layer.

    RESULTS: The numbers of all inflammatory cells and of cytokine staining cells were significantly increased in smokers. The thickness of the tenascin and laminin layers was increased in the smoking group and the integrity of the epithelial layer was significantly reduced. In smokers the epithelial integrity was negatively correlated with the number of eosinophils and macrophages. The thickness of the tenascin and laminin layers was positively correlated with AA1 and EPO positive cells only.

    CONCLUSION: High numbers of inflammatory cells are present in the bronchial mucosa of asymptomatic smokers which have a clear relationship with the impaired epithelial integrity. The increased thickness of the laminin and tenascin layers in these subjects was strongly related to the presence of eosinophils and mast cells, suggesting a role for these cells in tissue remodelling of the airways of smokers.

  • 3.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hurst, D. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Roomans, G. M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sevéus, L.
    Eosinophils and neutrophils in biopsies from the middle ear of atopic children with otitis media with effusion1999In: Inflammation Research, ISSN 1023-3830, E-ISSN 1420-908X, Vol. 48, no 12, p. 626-631Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE AND DESIGN: The majority of patients with otitis media with effusion (OME) and atopy have been shown to have elevated levels of eosinophil cationic protein (ECP) in their middle ear fluid. The mechanism underlying these elevated levels of ECP is not clear. The purpose of this study was to investigate the feasibility of a quantitative determination of eosinophils and neutrophils in the middle ear lining by specific immunocytochemical markers, in order to study the extent of the involvement of these cells in patients with OME.

    METHODS: Bilateral middle ear biopsies from five children with persistent OME and atopy confirmed by in vitro testing were evaluated for the presence of eosinophils and neutrophils with monoclonal antibodies against specific granule proteins. Five subjects who had no signs of effusion or infection but were undergoing routine tympanoplasty for dry perforations served as controls. The biopsies were embedded in a plastic resin to improve the structural preservation of the target cells and to increase the resolution in the light microscope. Dual markers were used to determine which marker was better for eosinophils and neutrophils, respectively. The following markers were used: eosinophil cationic protein (EG2), and eosinophil peroxidase (EPO) for eosinophils and myeloperoxidase (MPO) and human neutrophil lipocalin (HNL) for neutrophils.

    RESULTS: Antibodies against EPO gave a more localized and intense staining than antibodies against EG2. Antibodies against HNL appear more specific to neutrophils than antibodies against MPO that also recognize monocytes. The number of cells was determined both in the tissue and in the mucus covering the epithelium. Eosinophils and neutrophils were present in the subepithelial connective tissue and in the mucus blanket in the middle ear of patients with OME in significantly higher number than in the control group. In general, there were more inflammatory cells in the mucus than in the tissue itself, but the number of inflammatory cells in the mucus showed a significant positive correlation with the number of inflammatory cells in the tissue. There was a significant positive correlation between the number of neutrophils and the number of eosinophils in the tissue as well as in the mucus, irrespective of which marker was used.

    CONCLUSION: The results of this study show the feasibility of using specific antibodies to identify eosinophils and neutrophils in the middle ear. The initial data suggest that atopic children with OME have higher numbers of such cells as compared to non-OME controls.

  • 4.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Boman, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The extracellular deposition of mast cell products is increased in hypertrophic airways smooth muscles in allergic asthma but not in nonallergic asthma2005In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 60, no 10, p. 1241-1247Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bronchial asthma is characterized by airways smooth muscle hypertrophy and infiltration of mast cells in the bronchial mucosa. The aim of this investigation was to study the distribution of mast cells in different compartments in the bronchial mucosa of allergic and nonallergic asthma in relation to airways remodeling.

    METHODS: Bronchial biopsies were obtained from 29 subjects with allergic and nonallergic asthma and healthy controls. The biopsies were stained for mast cells by means of the tryptase specific antibody AA1. Extracellular deposition of mast cell products were judged on a semi-quantitative scale. Mast cells per mm(2) were counted in epithelium, lamina propria and the smooth muscle compartment. Smooth muscle was visualized by actin antibodies and the proportion of staining of the biopsy estimated. Laminin and tenascin layers were visualized by their respective antibodies.

    RESULTS: Airways smooth muscle thickness was greater in allergic vs nonallergic asthma (P < 0.001). Mast cells were increased in all three compartments in both allergic and nonallergic asthma, with significantly higher numbers in smooth muscles in allergic asthma (P < 0.03). The extracellular deposition of mast cell products was more common in allergic than nonallergic asthma in lamina propria and smooth muscles (P = 0.025; P = 0.002, respectively). In patients with allergic asthma the numbers of mast cells with extracellular deposition of mast cell products were significantly correlated to the thickness of the laminin and tenascin layers.

    CONCLUSION: Our results suggest that there are large differences between allergic and nonallergic asthmatics as to mast cell activation and airways smooth muscle thickness. Our data implies that mast cells are causally involved in structural alterations in allergic asthma.

  • 5.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Harvima, Ilkka
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nilsson, Gunnar
    CC chemokine receptors CCR1 and CCR4 are expressed on airway mast cells in allergic asthma2005In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 116, no 6, p. 1383-1386Article in journal (Other academic)
  • 6.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sevéus, Lahja
    Miyazaki, Kaoru
    Virtanen, Ismo
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Uncoordinated production of Laminin-5 chains in airways epithelium of allergic asthmatics2005In: Respiratory research (Online), ISSN 1465-9921, E-ISSN 1465-993X, Vol. 6, p. 110-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Laminins are a group of proteins largely responsible for the anchorage of cells to basement membranes. We hypothesized that altered Laminin chain production in the bronchial mucosa might explain the phenomenon of epithelial cell shedding in asthma. The aim was to characterize the presence of Laminin chains in the SEBM and epithelium in allergic and non-allergic asthmatics.

    PATIENTS AND METHODS: Biopsies were taken from the bronchi of 11 patients with allergic and 9 patients with non-allergic asthma and from 7 controls and stained with antibodies against the Laminin (ln) chains alpha1-alpha5, beta1-beta2 and gamma1-gamma2.

    RESULTS: Lns-2,-5 and -10 were the main Laminins of SEBM. The layer of ln-10 was thicker in the two asthmatic groups while an increased thickness of lns-2 and -5 was only seen in allergic asthmatics. The ln gamma2-chain, which is only found in ln 5, was exclusively expressed in epithelial cells in association with epithelial injury and in the columnar epithelium of allergic asthmatics.

    CONCLUSION: The uncoordinated production of chains of ln-5 in allergic asthma could have a bearing on the poor epithelial cell anchorage in these patients.

  • 7.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lúdvíksdóttir, Dóra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nettelbladh, Otto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Björnsson, Eythór
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Roomans, Godfried M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Boman, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sevéus, Lahja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Inflammation and structural changes in the airways of patients with atopicand nonatopic asthma: BHR group2000In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 162, no 6, p. 2295-2301Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to compare the cellular pattern and structural changes in the airway walls of atopic and nonatopic patients with asthma. Bronchial biopsy specimens were obtained from 13 atopic subjects with asthma, nine nonatopic patients with asthma, and seven healthy control subjects and investigated using immunohistochemical methods. The number of eosinophils increased in both asthma groups, but significantly more in the atopic group. The number of mast cells increased similarly in the two asthma groups, whereas the number of neutrophils increased only in the nonatopic asthma group. The number of T-lymphocytes (CD3-, CD4-, CD8-, CD-25-positive cells) was higher in patients with atopic asthma compared with nonatopic asthma. Interleukin-4 (IL-4) and IL-5-positive cells were more frequently found in the atopic asthma group, whereas cells staining for IL-8 were more frequent in the nonatopic group. The degree of epithelial damage was significantly higher in the atopic asthma group compared with the control subjects and the nonatopic asthmatics. The tenascin and laminin layer was significantly thicker in the atopic group compared with the group of nonatopic asthmatics. In the atopic group, there was a significant negative correlation between epithelial integrity (defined as the relative length of intact epithelium) and the eosinophil count and also between the number of CD25-positive cells and epithelial integrity. The number of mast cells correlated positively with the thickness of tenascin- and laminin-positive layers. In conclusion, we provide evidence of different patterns of involvement of inflammatory cells in atopic and nonatopic patients with asthma. There were also structural differences in the bronchial mucous membrane between atopic asthma and nonatopic asthma. This suggests that there are differences in the extent of the immunopathologic response of these clinically distinct forms of asthma.

  • 8.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lúdvíksdóttir, Dóra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nettelbladt, O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gudbjörnsson, B.
    Valtysdóttir, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Björnsson, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Roomans, Godfried M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Boman, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sevéus, L.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Inflammation and structural changes in the airways of patients with primary Sjogren's syndrome2001In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 95, no 11, p. 904-910Article in journal (Refereed)
    Abstract [en]

    The present study aimed to compare the cellular pattern and structural changes in the airways of patients with primary Sjögren's syndrome (pSS) with healthy controls. Bronchial biopsy specimens were obtained from seven subjects with pSS and seven healthy controls. All the patients with pSS had increased bronchial responsiveness to methacholine. In the biopsies inflammatory cells, cytokine-producing cells, tenascin and laminin were visual zed by immunostaining. Patients with pSS had a higher number of neutrophils and mast cells than healthy controls, while the number of eosinophils was similar in the two groups. The number of IL-8-positive cells was higher in pSS butthe numbers of IL-4-and IL-5-positive cells were not significantly different between pSS and healthy controls. The numbers of T cells in patients with pSS were higher than in healthy controls, while the numbers of CD25-positive cells were similar to the healthy controls. The degree of epithelial integrity in patients with pSS was significantly lower than in the control group and the tenascin and laminin layers were significantly thicker in the pSS group. There was a correlation between the number of mast cells and the thickness of the tenascin and laminin layers in pSS. In conclusion, we found that the cellular pattern in the bronchial mucosa of patients with pSS displayed large numbers of neutrophils, mast cells and T-lymphocytes. These changes in inflammatory cell numbers seemed to relate to the observed increased epithelial damage and structural changes of the subepithelium. The structural findings, but not the pattern of inflammatory cells, are shared with atopic asthma and may relate to the increased bronchial hyper-responsiveness seen in both diseases.

  • 9.
    Amin, Kawa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Rinne, Juhani
    Haahtela, Tari
    Simola, Markku
    Peterson, Christer G. B.
    Roomans, Godfried M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Malmeberg, Henrik
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sevéus, Lahja
    Inflammatory cell and epithelial characteristics of perennial allergic and nonallergic rhinitis with a symptom history of 1 to 3 years' duration2001In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 107, no 2, p. 249-257Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Perennial rhinitis is an inflammatory condition of the mucosal lining of the nose that may be caused by allergic and nonallergic mechanisms.

    OBJECTIVE: We sought to characterize the cellular pattern and structural changes in the nasal mucous membrane of patients with perennial rhinitis and compare them with those of control subjects.

    METHODS: Biopsy specimens were obtained from 27 patients with perennial allergic rhinitis (PAR), from 12 patients with perennial nonallergic rhinitis (PNAR) with eosinophils present in the nasal smear, and from 6 control subjects without rhinitis. In 10 of 27 patients with PAR who were also allergic to pollen, biopsy specimens were taken within the respective season (PARseason). In the other 17 patients, the biopsy was taken outside the pollen season (PARoutside season). Inflammatory cells were identified by using mAbs to their unique granular proteins.

    RESULTS: The characteristic feature of perennial rhinitis was the accumulation of activated (degranulated) mast cells and eosinophils in the nasal mucosa. The tissue eosinophil/neutrophil ratio was higher, and the loss of epithelial integrity was greater in all patient groups compared with the control subjects. The extent of epithelial damage was significantly larger in patients in the PARseason group compared with that in the PARoutside season and PNAR groups, which did not significantly differ from each other in this respect. The number of eosinophils and mast cells was higher in the PNAR group compared with the PAR groups. In all patient groups, the number of eosinophils correlated with the loss of epithelial integrity. The number of mast cells did not correlate with the extent of epithelial damage nor did the number of neutrophils, except in patients in the PARseason group.

    CONCLUSION: The accumulation of eosinophils and mast cells, as well as loss of epithelial integrity, was characteristic for perennial rhinitis. Loss of epithelial integrity in the nasal mucosa may be a consequence of the activity of accumulated eosinophils.

  • 10. Bafadhel, Mona
    et al.
    McKenna, Susan
    Terry, Sarah
    Mistry, Vijay
    Pancholi, Mitesh
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lomas, David A.
    Barer, Michael R.
    Johnston, Sebastian L.
    Pavord, Ian D.
    Brightling, Christopher E.
    Blood Eosinophils to Direct Corticosteroid Treatment of Exacerbations of Chronic Obstructive Pulmonary Disease A Randomized Placebo-Controlled Trial2012In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 186, no 1, p. 48-55Article in journal (Refereed)
    Abstract [en]

    Rationale: Exacerbations of chronic obstructive pulmonary disease (COPD) and responses to treatment are heterogeneous. Objectives: Investigate the usefulness of blood eosinophils to direct corticosteroid therapy during exacerbations. Methods: Subjects with COPD exacerbations were entered into a randomized biomarker-directed double-blind corticosteroid versus standard therapy study. Subjects in the standard arm received prednisolone for 2 weeks, whereas in the biomarker-directed arm, prednisolone or matching placebo was given according to the blood eosinophil count biomarker. Both study groups received antibiotics. Blood eosinophils were measured in the biomarker-directed and standard therapy arms to define biomarker-positive and -negative exacerbations (blood eosinophil count > and <= 2%, respectively). The primary outcome was to determine noninferiority in health status using the chronic respiratory questionnaire (CRQ) and in the proportion of exacerbations associated with a treatment failure between subjects allocated to the biomarker-directed and standard therapy arms. Measurements and Main Results: There were 86 and 80 exacerbations in the biomarker-directed and standard treatment groups, respectively. In the biomarker-directed group, 49% of the exacerbations were not treated with prednisolone. CRQ improvement after treatment in the standard and biomarker-directed therapy groups was similar (0.8 vs. 1.1; mean difference, 0.3; 95% confidence interval, 0.0-0.6; P = 0.05). There was a greater improvement in CRQ in biomarker-negative exacerbations given placebo compared with those given prednisolone (mean difference, 0.45; 95% confidence interval, 0.01-0.90; P = 0.04). In biomarker-negative exacerbations, treatment failures occurred in 15% given prednisolone and 2% of those given placebo (P = 0.04). Conclusions: The peripheral blood eosinophil count is a promising biomarker to direct corticosteroid therapy during COPD exacerbations, but larger studies are required.

  • 11. Bell, Max
    et al.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Bellomo, Rinaldo
    Mårtensson, Johan
    Assessment of cell-cycle arrest biomarkers to predict early and delayed acute kidney injury2015In: Disease Markers, ISSN 0278-0240, E-ISSN 1875-8630, Vol. 2015, article id 158658Article in journal (Refereed)
    Abstract [en]

    Purpose. To assess urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein 7 ([TIMP-2]·[IGFBP7]), urinary neutrophil gelatinase-associated lipocalin (NGAL), and urinary cystatin-C as acute kidney injury predictors (AKI) exploring the association of nonrenal factors with elevated biomarker levels.

    Methods. We studied 94 patients with urine collected within 48 hours of ICU admission and no AKI at sampling. AKI was defined by the Kidney Disease: Improving Global Outcomes criteria. Predictive performance was assessed by the area under the receiver operating characteristics (ROC) curve. Associations between biomarkers and clinical factors were assessed by multivariate linear regression.

    Results. Overall, 19 patients (20%) developed AKI within 48 hours. [TIMP-2]·[IGFBP7], NGAL, or cystatin-C admission levels did not differ between patients without AKI and patients developing AKI. [TIMP-2]·[IGFBP7], NGAL, and cystatin-C were poor AKI predictors (ROC areas 0.34-0.51). Diabetes was independently associated with higher [TIMP-2]·[IGFBP7] levels (P = 0.02) but AKI was not (P = 0.24). Sepsis was independently associated with higher NGAL (P < 0.001) and cystatin-C (P = 0.003) levels.

    Conclusions. Urinary [TIMP-2]·[IGFBP7], NGAL, and cystatin-C should be used cautiously as AKI predictors in general ICU patients since urine levels of these biomarkers are affected by factors other than AKI and their performance can be poor.

  • 12. Betsuyaku, Tomoko
    et al.
    Nishimura, Masaharu
    Takeyabu, Kimihiro
    Tanino, Mishie
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Xu, S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kawakami, Yoshikazu
    Evidence for neutrophil involvement in the development of subclinical emphysema2000In: Chest, ISSN 0012-3692, E-ISSN 1931-3543, Vol. 117, no 5 Suppl 1, p. 302S-303SArticle in journal (Refereed)
  • 13. Betsuyaku, Tomoko
    et al.
    Nishimura, Masaharu
    Takeyabu, Kimihiro
    Tanino, Mishie
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Xu, Shengyuan
    Kawakami, Yoshikazu
    Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with subclinical emphysema1999In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 159, no 6, p. 1985-1991Article in journal (Refereed)
    Abstract [en]

    Evidence for the contribution of neutrophils to the pathogenesis of pulmonary emphysema is not convincing. We evaluated neutrophil involvement in subclinical pulmonary emphysema by measuring human neutrophil lipocalin (HNL) and two matrix metalloproteinases, gelatinase B (MMP-9) and neutrophil collagenase (MMP-8), in bronchoalveolar lavage fluid (BALF) from 65 community-based older volunteers. HNL is a recently isolated 24-kD protein secreted from secondary granules of activated neutrophils. Despite no appreciable increase in the number of neutrophils, the level of HNL was significantly increased in BALF from subjects with emphysema evidenced by computed tomography regardless of current smoking, as compared with smokers without emphysema. The levels of MMP-9 and MMP-8 were also significantly higher in current smokers with emphysema than in those without emphysema. The appearance of a 130-kD HNL/MMP-9 complex on gelatin zymography and HNL immunoblot indicated neutrophils to be a significant source of MMP-9 in the subjects' BALF. In a 24-h culture medium of alveolar macrophages, only a latent form of MMP-9 was detected, and there was no difference in the level of MMP-9 between the groups. These data provide further evidence for neutrophil involvement in subclinical pulmonary emphysema.

  • 14. Bingisser, Roland
    et al.
    Cairns, Charles B.
    Christ, Michael
    Collinson, Paul
    Hausfater, Pierre
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Mair, Johannes
    Price, Christopher
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Measurement of natriuretic peptides at the point of care in the emergency and ambulatory setting: Current status and future perspectives2013In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 166, no 4, p. 614-+Article in journal (Refereed)
    Abstract [en]

    The measurement of natriuretic peptides (NPs), B-type NP or N-terminal pro-B-type NP, can be an important tool in the diagnosis of acute heart failure in patients presenting to an Emergency Department (ED) with acute dyspnea, according to international guidelines. Studies and subsequent meta-analyses are mixed on the absolute value of routine NP assessment of ED patients. However, levels of NPs are likely to be used also to guide treatment and to assess risk of adverse outcomes in other patients at risk of developing heart failure, including those with pulmonary embolism or diabetes, or receiving chemotherapy. Natriuretic peptide levels, like other biomarkers, can now be measured at the point of care (POC). We have reviewed the current status of NP measurement together with the potential contribution of POC measurement of NPs to clinical care delivery in the emergency and other settings. Several POC systems for measuring NP levels are now available: these produce test results within 15 minutes and appear sufficiently sensitive and robust to be used routinely in diagnostic evaluations. Point-of-care systems could be used to assess NP levels in the ED and community outpatient settings to monitor the risk of acute heart failure. Furthermore, the use of protocol-driven POC testing of NP within the time frame of a patient consultation in the ED may facilitate and accelerate the throughput and disposition of at-risk patients. Appropriately designed clinical trials will be needed to confirm these potential benefits. It is also important that processes of care delivery are redesigned to take full advantage of the faster turnaround times provided by POC technology.

  • 15. Bingisser, Roland
    et al.
    Cairns, Charles
    Christ, Michael
    Hausfater, Pierre
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Mair, Johannes
    Panteghini, Mauro
    Price, Christopher
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Cardiac troponin: a critical review of the case for point-of-care testing in the ED2012In: American Journal of Emergency Medicine, ISSN 0735-6757, E-ISSN 1532-8171, Vol. 30, no 8, p. 1639-1649Article, review/survey (Refereed)
    Abstract [en]

    The measurement of cardiac troponin concentrations in the blood is a key element in the evaluation of patients with suspected acute coronary syndromes, according to current guidelines, and contributes importantly to the ruling in or ruling out of acute myocardial infarction. The introduction of point-of-care testing for cardiac troponin has the potential to reduce turnaround time for assay results, compared with central laboratory testing, optimizing resource use. Although, in general, many point-of-care cardiac troponin tests are less sensitive than cardiac troponin tests developed for central laboratory-automated analyzers, point-of-care systems have been used successfully within accelerated protocols for the reliable ruling out of acute coronary syndromes, without increasing subsequent readmission rates for this condition. The impact of shortened assay turnaround times with point-of-care technology on length of stay in the emergency department has been limited to date, with most randomized evaluations of this technology having demonstrated little or no reduction in this outcome parameter. Accordingly, the point-of-care approach has not been shown to be cost-effective relative to central laboratory testing. Modeling studies suggest, however, that reengineering overall procedures within the emergency department setting, to take full advantage of reduced therapeutic turnaround time, has the potential to improve the flow of patients through the emergency department, to shorten discharge times, and to reduce cost. To properly evaluate the potential contribution of point-of-care technology in the emergency department, including its costeffectiveness, future evaluations of point-of-care platforms will need to be embedded completely within a local decision-making structure designed for its use.

  • 16.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hällgren, R.
    Killander, A.
    Strömberg, A.
    Venge, Per
    Wide, L.
    Serum ferritin during infection:  A longitudinal study1978In: Scandinavian journal of haematology, ISSN 0036-553X, Vol. 21, no 4, p. 333-340Article in journal (Refereed)
    Abstract [en]

    Serum ferritin, transferrin, iron and haptoglobin have been investigated in a longitudinal study in 18 patients hospitalized for various acute infections. Within a couple of days after the onset of an infection, a rise in serum ferritin was seen, the magnitude of which was not dependent on the type of infection (bacterial or viral). The serum ferritin level remained elevated for several weeks in some patients, and 7 out of the 18 patients still had abnormally high values 5 weeks after the onset of illness. The mean curves for serum ferritin and the acute phase reactant haptoglobin were parallel. Possible mechanisms causing the elevation in serum ferritin are discussed.

  • 17.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hällgren, R.
    Killander, A.
    Venge, Per
    Wide, L.
    Serum ferritin during infection:  A longitudinal study in renal transplant patients1979In: Acta medica Scandinavica, ISSN 0001-6101, Vol. 205, no 7, p. 641-645Article in journal (Refereed)
    Abstract [en]

    In order to follow the dynamics in the reaction of iron kinetic variables to acute infection, 8 renal transplantation patients were followed with test samples every second or third day for about two months. It was found that they just as previously shown in otherwise healthy subjects, responded to acute infection with a rise in serum ferritin levels, sometimes to very high values. In most cases the ferritin elevation started within two days after the onset of fever. The peak was reached within a week, except when very high values were obtained. The fall in serum ferritin after recovery from infection was much faster than in previously investigated groups of patients: the plasma half disappearance time for ferritin in one case was but 1.5 days. Transferrin did not change in response to infection. The expected fall in serum iron during infection was often absent and sometimes obscured by unexpected, sharp peaks in serum iron, which bore a temporal relationship to episodes of transplant rejection in 7 of 12 cases.

  • 18.
    Birgegård, Gunnar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hällgren, R.
    Venge, Per
    Wide, L.
    Serum ferritin during inflammation:  A study on myocardial infarction1979In: Acta medica scandinavica, ISSN 0001-6101, Vol. 206, no 5, p. 361-366Article in journal (Refereed)
    Abstract [en]

    The ferritin level in serum was investigated in 9 patients with myocardial infarction, all with a history of chest pain of less than 4 hours before admission. A significant rise in serum ferritin level was found in 8 patients. The rise was generally smaller than that seen in acute infection and not significantly correlated to the size of infarction, as estimated from changes in serum levels of myoglobin, ASAT and LDH. The rise started after a mean of 30 hours, the peak being reached within a week (M 4.3 days). Serum ferritin then fell to 120--300% (M 190) of the initial level, where it remained. An initial rise in serum iron levels was unexpectedly seen within 12 hours in 7 patients.

  • 19. Bjurman, Christian
    et al.
    Petzold, Max
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Farbemo, Julia
    Fu, Michael L. X.
    Hammarsten, Ola
    High-sensitive cardiac troponin, NT-proBNP, hFABP and copeptin levels in relation to glomerular filtration rates and a medical record of cardiovascular disease2015In: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 48, no 4-5, p. 302-307Article in journal (Refereed)
    Abstract [en]

    Background: Elevation of cardiac markers in patients with renal dysfunction has not been fully assessed reducing the diagnostic usefulness of these biomarkers. Objective: To examine the effects of renal function and a medical record of cardiovascular disease on levels of cardiac biomarkers. Methods: Serum samples were collected from 489 patients referred for GFR measurement using Cr51-EDTA or iohexol plasma clearance (measured GFR). The cardiac biomaiters Troponin T (hs-cTnT), Troponin I (hsTnI), N-Terminal pro Brain Natriuretic Peptide (NTproBNP), Copeptin, Human Fatty Acid Binding Protein (hFABP), as well as the kidney function biomarkers creatinine and cystatin C, were measured. Regression was used to analyse the relationship between biomarker levels and the glomerular filtration rate (GFR) between 15 and 90 mL/min/1.73 m(2). Results: Compared with normal kidney function, the estimated increases in the studied cardiac biomarkers at a CUR of 15 mL/mM/1.73 m(2) varied from 2-fold to 15 fold but were not very different between patients with or without a medical record of cardiovascular disease and were most prominent for cardiac biomarkers with low molecular weight. hs-cTnT levels correlated more strongly to measured CUR and increased more at low CUR compared to hs-cTnI. For hFABP and NT-proBNP increases at low kidney function were more correctly predicted by a local Cystatin C-based eGFR formula compared with creatinine-based eGFR (using the MDRD or CKD-EPI equations) Conclusion: The extent of the elevation of cardiac markers at low renal function is highly variable. For hFABP and NTproBNP Cystatin C-based eGFR provides better predictions of the extent of elevation compared to the MDRD or CKD-EPI equations. (C) 2015 The Authors. The Canadian Society of Clinical Chemists. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd,40/).

  • 20.
    Björk, Anne
    et al.
    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.
    Peterson, C G B
    Pharmacia & Upjohn Diagnostics, Uppsala, Sweden .
    Measurements of ECP in serum and the impact of plasma coagulation2000In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 55, no 5, p. 442-448Article in journal (Refereed)
    Abstract [en]

    Serum measurement of ECP (eosinophil cationic protein) is used as an indication of eosinophil activation in diseases such as asthma. The levels are dependent on sample handling, since a certain amount of ECP is released during storage. The mechanisms that induce this in vitro release are not known, but are supposed to be related to the coagulation process. The aim of this study was to investigate this further. ECP was measured in EDTA plasma and serum at 22 and 37°C from healthy individuals and patients with asthma and allergy. The serum levels of ECP increased with temperature. Recalcification of citrated plasma in the presence of granulocytes with increasing concentrations of Ca2+ showed a dissociation between the levels of ECP and the occurrence of coagulation. Further experiments indicated that plasma coagulation is not of any importance for the degranulation of eosinophils, nor did the addition of platelets or mononuclear cells affect the ECP levels. Incubations of granulocytes with fresh or frozen plasma and Ca2+suggested the existence of a freezing labile factor in plasma, necessary for the degranulation of healthy eosinophils, but not for allergic/asthmatic eosinophils. Further experiments with pure eosinophils indicated the existence of factors in serum and plasma which facilitate ECP secretion of an active, temperature-dependent nature. We conclude that the raised ECP levels in serum, as compared to EDTA plasma, are unrelated to the coagulation process, but are due to the continuous secretion ex vivo of ECP from active eosinophils. This process is time and temperature dependent and may be facilitated by eosinophil-activating components in the extracellular environment.

  • 21.
    Björklund, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jernberg, T.
    Johanson, P.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dellborg, M.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    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.
    Admission N-terminal pro-brain natriuretic peptide and its interaction with admission troponin T and ST segment resolution for early risk stratification in ST elevation myocardial infarction2006In: Heart, ISSN 1355-6037, E-ISSN 1468-201X, Vol. 92, no 6, p. 735-740Article in journal (Refereed)
    Abstract [en]

    Objective: To assess the long term prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) on admission and its prognostic interaction with both admission troponin T (TnT) concentrations and resolution of ST segment elevation in fibrinolytic treated ST elevation myocardial infarction (STEMI).

    Design and setting: Substudy of the ASSENT (assessment of the safety and efficacy of a new thrombolytic) -2 and ASSENT-PLUS trials.

    Patients: NT-proBNP and TnT concentrations were determined on admission in 782 patients. According to NT-proBNP concentrations, patients were divided into three groups: normal concentration (for patients ≤ 65 years, ≤ 184 ng/l and ≤ 268 ng/l and for those > 65 years, ≤ 269 ng/l and ≤ 391 ng/l in men and women, respectively); higher than normal but less than the median concentration (742 ng/l); and above the median concentration. For TnT, a cut off of 0.1 μg/l was used. Of the 782 patients, 456 had ST segment resolution (< 50% or ≥ 50%) at 60 minutes calculated from ST monitoring.

    Main outcome measures: All cause one year mortality.

    Results: One year mortality increased stepwise according to increasing concentrations of NT-proBNP (3.4%, 6.5%, and 23.5%, respectively, p < 0.001). In receiver operating characteristic analysis, NT-proBNP strongly trended to be associated more with mortality than TnT and time to 50% ST resolution (area under the curve 0.81, 95% confidence interval (CI) 0.72 to 0.9, 0.67, 95% CI 0.56 to 0.79, and 0.66, 95% CI 0.56 to 0.77, respectively). In a multivariable analysis adjusted for baseline risk factors and TnT, both raised NT-proBNP and ST resolution < 50% were independently associated with higher one year mortality, whereas raised TnT contributed independently only before information on ST resolution was added to the model.

    Conclusion: Admission NT-proBNP is a strong independent predictor of mortality and gives, together with 50% ST resolution at 60 minutes, important prognostic information even after adjustment for TnT and baseline characteristics in STEMI.

  • 22.
    Björklund, Erik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Johanson, Per
    Jernberg, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Svensson, Ann-Marie
    Venge, Per
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Dellborg, Mikael
    Admission Troponin T and measurement of ST-segment resolution at 60 min improve early risk stratification in ST-elevation myocardial infarction2004In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 25, no 2, p. 113-120Article in journal (Refereed)
    Abstract [en]

    AIMS: The prognostic value of admission troponin T (tnT) levels and the resolution of the ST-segment elevation in ST-elevation myocardial infarction (STEMI) is well established. However, the combination of these two early available markers for predicting risk has not been evaluated.

    METHODS AND RESULTS: We evaluated 516 patients with fibrinolytic treated STEMI from the ASSENT-2 and ASSENT-PLUS studies, which had both admission tnT and ST-monitoring available. We used a prospectively defined cut-off value of tnT of 0.1microg/l. For ST-segment resolution, a cut-off of 50% measured after 60min was used. Both a tnT >/=0.1microg/l (n=116) and ST-segment resolution <50% (n=301) were related to higher one-year mortality, 13% vs 4% (P<0.001) and 8.4% vs 2.8% (P=0.009), respectively. In a multivariate analysis ST-segment resolution was and tnT showed a strong trend to be independently related to mortality. The combination of both further improved risk stratification. The one-year mortality in the group with elevation of tnT and without ST-segment resolution compared to the group without tnT elevation and with ST-segment resolution was 18.2% vs 2.8% (P<0.001).

    CONCLUSIONS: Both tnT on admission and ST-segment resolution after 60min are strong predictors of one-year mortality. The combination of both gives additive early information about prognosis and further improves risk stratification.

  • 23.
    Björklund, Erik
    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.
    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, P.
    Dellborg, M.
    Venge, Per
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Early risk stratification in ST-elevation myocardial infarction with admission Troponin T and ST-segment resolution2002Conference paper (Other academic)
  • 24.
    Björkqvist, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Källman, J
    Fjaertoft, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Xu, S
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Schollin, J
    Human neutrophil lipocalin: normal levels and use as a marker for invasive infection in the newborn2004In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 93, no 4, p. 534-539Article in journal (Refereed)
    Abstract [en]

    AIM: To evaluate human neutrophil lipocalin (HNL) as a marker of neonatal invasive infection and determine the normal serum levels of HNL in newborns.

    METHODS: HNL is released from neutrophil granulocytes and is regarded as a specific marker of neutrophil activity. In 81 newborns < or = 28 d of age with signs of infection on a total of 87 occasions, HNL and C-reactive protein (CRP) were measured at inclusion and on the three following days. As controls, term healthy newborns were recruited at birth (cord blood, n = 45) and at ages 3-5 d (n = 46). Serum HNL was measured by a radioimmunoassay.

    RESULTS: 25/87 episodes were classified as infection and 62 as non-proven infection. HNLmax was significantly higher in the infected group (mean 587.6 microg/l) than in the non-proven infected group (mean 217.7 microg/, p < 0.001). HNL peaked at inclusion, 1 d earlier than CRP. In the healthy controls. HNL was the same at 3-5 d of age as at birth (mean 82.4-81.7 microg/l) and similar to normal adult levels.

    CONCLUSIONS: The release of HNL is not increased in healthy newborns at birth, but neonatal neutrophils rapidly release HNL upon microbial stimulation in vivo. HNL might be useful as an early marker of neonatal infection.

  • 25.
    Björnsson, E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Håkansson, L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Enander, I.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Boman, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eosinophil peroxidase: a new serum marker of atopy and bronchial hyper-responsiveness1996In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 90, no 1, p. 39-46Article in journal (Refereed)
    Abstract [en]

    Do markers of eosinophil activation differ in their ability to detect subjects with atopy or bronchial hyper-responsiveness (BHR)? Comparisons of serum levels of eosinophil peroxidase (S-EPO), of eosinophil cationic protein (S-ECP) and the blood eosinophil count (B-Eos) have been made between 154 subjects aged 20-44 years, participating in the European Community Respiratory Health Survey in Uppsala, Sweden. Subjects with atopy had significantly higher levels of S-EPO and S-ECP than those without atopy (P <0 center dot 001). Subjects with BHR had significantly higher levels of S-EPO (P <0 center dot 001) and B-Eos (P <0 center dot 01) than subjects without BHR. Persons reporting asthma-related symptoms had significantly higher levels of S-EPO and B-Eos than subjects without such symptoms (P <0 center dot 001 and P <0 center dot 01, respectively). Asthma symptom score correlated significantly to S-EPO (r = 0 center dot 26, P <0 center dot 01), S-ECP (r = 0 center dot 20, P <0 center dot 05) and B-Eos (r = 0 center dot 18, P <0 center dot 05). Finally, S-EPO was significantly more sensitive than S-ECP for detecting subjects with BHR (P <0 center dot 05) and significantly more sensitive than B-Eos for detecting both subjects with BHR and subjects with a combination of atopy and BHR (P <0 center dot 05). It is concluded that S-EPO is a promising marker with a higher sensitivity for BHR than S-ECP or B-Eos. Further studies are needed to define the value of S-EPO when following disease activity.

  • 26.
    Björnsson, Eyþór
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm .
    Lúdviksdóttir, Dóra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm .
    Hedenström, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Eriksson, Britt-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Högman, Marieann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jansson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Airway hyperresponsiveness, peak flow variability and inflammatory markers in non-asthmatic subjects with respiratory infections2007In: Clinical Respiratory Journal, ISSN 1752-6981, Vol. 1, no 1, p. 42-50Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to characterise non-asthmatic subjects with asthma-like symptoms during a common cold, particularly in relation to airway hyperresponsiveness (AHR). Materials and Methods: Subjects with acute respiratory infections and a group of controls (n = 20 + 20), age 20-65 years, underwent bronchial provocations with methacholine, adenosine and cold air. All were non-smokers and had no history of asthma or heart disease. Those with infection had asthma-like symptoms (> , 2). Measurements of exhaled nitric oxide (eNO), serum levels of eosinophil cationic protein (ECP), eosinophil peroxidase, myeloperoxidase and human neutrophil lipocalin were made at each provocation. A 17-day symptom and peak flow diary was calculated. Results: No differences between the two groups were found, regarding responsiveness to methacholine, adenosine or cold air challenge, as well as the inflammatory markers measured. In the infected group, the mean (standard deviation) ECP was higher in those with AHR to methacholine or cold air [15.7 (6.5) and 11.4 (4.2) mg/L, respectively; P < , 0.05], furthermore, eNO was higher in the infected group [116 ( 54) and 88 ( 52) nL/min, respectively, P = 0.055]. The infected group had, at all times, more symptoms and higher peak flow, with a decrease in the symptoms (P = 0.02) and a tendency to change in peak flow variation (P = 0.06). Conclusion: AHR does not seem to be the main cause of asthma-like symptoms in adults with infectious wheezing. Peak flow variation and symptom prevalence during the post-infection period may imply airway pathology different from AHR.

  • 27.
    Blom, Kristin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    ElShafie, Amir Ibrahim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Alribat Univ Hosp, Dept Clin Pathol & Microbiol, Khartoum, Sudan.
    Jönsson, Ulla-Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Håkansson, Lena
    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 genetically determined production of the alarmin eosinophil-derived neurotoxin is reduced in visceral leishmaniasis2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 1, p. 85-91Article in journal (Refereed)
    Abstract [en]

    Visceral leishmaniasis (VL) is the most severe form of leishmaniasis. Recent findings indicate that dendritic cells have a key role in the defense against the Leishmania parasite and that the activity of this cell may be modified by the eosinophil secretory protein eosinophil-derived neurotoxin (EDN). We hypothesized that the interactions between dendritic cells and EDN might be of importance in the disease development. Cellular content of EDN was analyzed by ELISA. The single-nucleotide polymorphisms at positions 405, 416, and 1122 in the EDN gene were analyzed by real-time PCR with TaqMan((R)) reagents. The study cohorts comprised 239 Sudanese subjects (65 healthy controls and 174 with VL) and 300 healthy Swedish controls. The eosinophil content of EDN was lower in VL as compared with controls (p < 0.0001). The EDN405 (G>C) genotype distribution was similar among Swedish and Sudanese controls, whereas VL subjects had a higher prevalence of the EDN405-GG genotype (p < 0.0001). The content of EDN in the eosinophils was closely linked to the EDN405 polymorphism (p = 0.0002). Our findings suggest that the predisposition to acquire VL is related to the genetic polymorphism of the EDN gene and the reduced production by the eosinophil of this gene product.

  • 28.
    Blom, Kristin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Rubin, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Halfvarson, Jonas
    Torkvist, Leif
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Lordal, Mikael
    Jönsson, Ulla-Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Sjöqvist, Urban
    Håkansson, Lena Douhan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Carlson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Eosinophil associated genes in the inflammatory bowel disease 4 region: Correlation to inflammatory bowel disease revealed2012In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 18, no 44, p. 6409-6419Article in journal (Refereed)
    Abstract [en]

    AIM: To study the association between inflammatory bowel disease (IBD) and genetic variations in eosinophil protein X (EPX) and eosinophil cationic protein (ECP). METHODS: DNA was extracted from ethylene diamine tetraacetic acid blood of 587 patients with Crohn's disease (CD), 592 with ulcerative colitis (UC) and 300 healthy subjects. The EPX405 (G > C, rs2013109), ECP434 (G > C, rs2073342) and ECP562 (G > C, rs2233860) gene polymorphisms were analysed, by the 5'-nuclease allelic discrimination assay. For determination of intracellular content of EPX and ECP in granulocytes, 39 blood samples was collected and extracted with a buffer containing cetyltrimethylammonium bromide. The intracellular content of EPX was analysed using an enzyme-linked immunosorbent assay. The intracellular content of ECP was analysed with the UniCAP (R) system as described by the manufacturer. Statistical tests for calculations of results were chi(2) test, Fisher's exact test, ANOVA, Student-Newman-Keuls test, and Kaplan-Meier survival curve with Log-rank test for trend, the probability values of P < 0.05 were considered statistically significant. RESULTS: The genotype frequency for males with UC and with an age of disease onset of >= 45 years (n = 57) was for ECP434 and ECP562, GG = 37%, GC = 60%, CC = 4% and GG = 51%, GC = 49%, CC = 0% respectively. This was significantly different from the healthy subject's genotype frequencies of ECP434 (GG = 57%, GC = 38%, CC = 5%; P = 0.010) and ECP562 (GG = 68%, GC = 29 /0,CC = 3%; P = 0.009). The genotype frequencies for females, with an age of disease onset of >= 45 years with CD (n = 62), was for the ECP434 and ECP562 genotypes GG = 37%, GC = 52%, CC = 11% and GG = 48%, GC = 47% and CC = 5% respectively. This was also statistically different from healthy controls for both ECP434 (P = 0.010) and ECP562 (P = 0.013). The intracellular protein concentration of EPX and ECP was calculated in mu g/10(6) eosinophils and then correlated to the EPX 405 genotypes. The protein content of EPX was highest in the patients with the CC genotype of EPX405 (GG = 4.65, GC = 5.93, and CC = 6.57) and for ECP in the patients with the GG genotype of EPX405 (GG = 2.70, GC = 2.47 and CC = 1.90). ANOVA test demonstrated a difference in intracellular protein content for EPX (P = 0.009) and ECP (P = 0.022). The age of disease onset was linked to haplotypes of the EPX405, ECP434 and ECP562 genotypes. Kaplan Maier curve showed a difference between haplotype distributions for the females with CD (P = 0.003). The highest age of disease onset was seen in females with the EPX405CC, ECP434GC, ECP562CC haplotype (34 years) and the lowest in females with the EPX405GC, ECP434GC, ECP562GG haplotype (21 years). For males with UC there was also a difference between the highest and lowest age of the disease onset (EPX405CC, ECP434CC, ECP562CC, mean 24 years vs EPX405GC, ECP434GC, ECP562GG, mean 34 years, P = 0.0009). The relative risk for UC patients with ECP434 or ECP562-GC/CC genotypes to develop dysplasia/cancer was 2.5 (95%CI: 1.2-5.4, P = 0.01) and 2.5 (95%CI: 1.1-5.4, P = 0.02) respectively, compared to patients carrying the GG-genotypes. CONCLUSION: Polymorphisms of EPX and ECP are associated to IBD in an age and gender dependent manner, suggesting an essential role of eosinophils in the pathophysiology of IBD.

  • 29. Boner, A. L.
    et al.
    Comis, A.
    Schiassi, M.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Piacentini, G. L.
    Bronchial reactivity in asthmatic children at high and low altitude: Effect of budesonide1995In: American Journal of Respiratory and Critical Care Medicine, ISSN 1073-449X, E-ISSN 1535-4970, Vol. 151, no 4, p. 1194-1200Article in journal (Refereed)
    Abstract [en]

    Inhaled steroids may control bronchial inflammation in asthmatics exposed to allergens. In this study we evaluated whether prophylactic budesonide would prevent relapse of asthma in children re-exposed to offending allergens at sea level, after a period of antigen avoidance at high altitude. Thirty children received either budesonide (200 micrograms b.i.d.) or placebo (double-blind). Following a 4-wk baseline period and 2 wk of treatment at high altitude, children were treated for 3 mo at sea level. Methacholine challenge and pulmonary function studies were performed before and after baseline period, after the 2 wk of treatment in the mountain environment, and at the end of treatment. ECP serum levels were evaluated after the baseline period and at the end of treatment. PEFR and symptoms were recorded in a diary card during the study. The increase in methacholine provocative dosage was greater, although not significant (p = 0.096), in the budesonide than in the placebo group after the treatment at high altitude and remained higher at the end of the treatment (p = 0.04). ECP levels increased in both the groups with no significant difference. Our results confirm that budesonide, in addition to its efficacy in treating pre-existent airway inflammation, is effective in preventing the increase of reactivity in asthmatic children re-exposed to allergens.

  • 30.
    Borowiec, Jan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jaramillo, A.
    Venge, Per
    Nilsson, L.
    Thelin, S.
    Effects of heparin-coating of cardiopulmonary bypass circuits on leukocytes during simulated extracorporeal circulation1997In: Cardiovascular surgery, ISSN 0967-2109, E-ISSN 1479-0653, Vol. 5, no 6, p. 568-573Article, book review (Other academic)
    Abstract [en]

    Heparin-coated circuits used during extracorporeal circulation reduce many postoperative complications occurring after heart surgery. Such complications are partly related to leukocyte activation with subsequent release of active substances, e.g. oxygen free radicals, myeloperoxidase and lactoferrin. This experiment was performed to elucidate a possible influence of heparin-coating on leukocytes. A 2-h-long simulated extracorporeal circulation was performed on two groups of five extracorporeal circulation circuits, primed with heparinized, fresh whole human blood and Ringer's solution. Heparin-coated circuits (HC group) were compared with uncoated circuits (NC group). Oxygen free radical production was estimated by determination of malonyldialdehyde in plasma and erythrocyte suspension. Granulocyte activation was measured in terms of myeloperoxidase and lactoferrin release. Time-related changes in leukocyte subset counts were analysed. Heparin-coating diminished myeloperoxidase and lactoferrin release. There were significant inter-group differences after 90 and 120 min of extracorporeal circulation for myeloperoxidase (101 (12) microg/l and 107(12) microg/l in the HC group versus 154(20) microg/l and 174(23) microg/l in the NC group), and after 120 min of extracorporeal circulation for lactoferrin (78(5) microg/l in the HC group versus 212(49) microg/l in the NC group). No significant changes of MDA concentration were observed in plasma or erythrocytes; however, a tendency towards lower MDA levels was seen after 90 and 120 min of extracorporeal circulation in the NC group. Neutrophil, monocyte and eosinophil numbers decreased significantly in the NC group but were unchanged in the HC group, as were lymphocyte counts. Heparin-coated extracorporeal circulation circuits significantly reduce granulocyte activation and better preserve the number of circulating neutrophils, eosinophils and monocytes, but do not change oxygen free radical production during simulated extracorporeal circulation.

  • 31.
    Borowiec, Jan
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences. Thoracic Surgery.
    Stiernström, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences. Anaesthesiology and Intensive Care.
    Lahtinen, M
    Venge, P
    Department of Medical Sciences.
    Henze, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences. Thoracic Surgery.
    Inflammatory response during simulated extracorporeal circulation with addition of nitric oxide1998In: J Cardiovasc Surg, Vol. 41, p. 207-Article in journal (Refereed)
  • 32.
    Borowiec, Jan W.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Bozdayi, Mithat
    Jaramillo, Alfonso
    Nilsson, Leif
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Henze, Axel
    Influence of two blood conservation techniques (cardiotomy reservoir versus cell-saver) on biocompatibility of the heparin coated cardiopulmonary bypass circuit during coronary revascularization surgery1997In: Journal of cardiac surgery, ISSN 0886-0440, E-ISSN 1540-8191, Vol. 12, no 3, p. 190-197Article in journal (Refereed)
    Abstract [en]

    Blood conservation during cardiac surgery is critically important because of the inherent risks in homologous blood transfusions. Two techniques for the intraoperative conservation of blood--retransfusion of the red cells using a cell-saver (CS), or retransfusion of the blood using a cardiotomy suction (CTR) system--were compared using biocompatibility markers, granulocyte activation, and production of oxygen-free radicals (OFR). In the CTR group, heparin coated circuits with an uncoated cardiotomy reservoir were used. For the CS group, identical heparin coated cardiopulmonary bypass (CPB) sets, without a cardiotomy reservoir but with a CS, were used. In each group, eight patients had coronary artery bypass grafting performed. The capacity of the whole blood and the granulocytes to produce OFR was estimated by a chemiluminescence, and granulocyte activation was measured as release of the granulocyte granule proteins myeloperoxidase (MPO) and lactoferrin. A significantly reduced capacity to produce OFR by the whole blood was noted at 45 minutes of CPB in the CTR group (68% +/- 17% vs 94% +/- 16% in the CS group). MPO release was higher after 3 hours (p = 0.05) and 20 hours (p < 0.05), postoperatively, in the CTR group (417 +/- 77 micrograms/L and 257 +/- 31 micrograms/L vs 246 +/- 25 micrograms/L and 164 +/- 12 micrograms/L, respectively, in the CS group). We conclude that the heparin coated CPB circuit with the uncoated cardiotomy reservoir may be less biocompatible than the identical CPB set used together with the CS.

  • 33.
    Borowiec, Jan W.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Henze, Axel
    Nilsson, B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Stiernström, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Biomaterial-dependent blood activation during simulated extracorporeal circulation: a study of heparin-coated and uncoated circuits1997In: The thoracic and cardiovascular surgeon, ISSN 0171-6425, E-ISSN 1439-1902, Vol. 45, no 6, p. 295-301Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Blood activation during extracorporeal circulation is associated with morbidity and mortality in cardiac surgery. This activation can be diminished by usage of heparin-coated circuits. Nitric oxide has also been reported to influence humoral and cellular components of blood. This study was performed to determine biomaterial-dependent part of blood activation.

    DESIGN: Fresh, whole human blood mixed with Ringer's solution was circulated through a heart-lung machine for two and half hours. Five circuits were heparin-coated (group HC), whilst five other circuits were uncoated (group NC). During the last half hour NO was added to the oxygen/air mixture.

    METHODS: Blood activation was estimated by measuring following parameters: interluekin 6, complement activation products C3a and terminal complement complex, and oxygen free radicals (OFR) production capacity, which was determined using chemiluminescence enhanced by serum opsonized zymosan (SOZ) and phorbol myristate acetate (PMA). Granulocyte activation was measured as release of myeloperoxidase (MPO) and human neutrophil lipocalin (HNL).

    RESULTS: OFR in granulocyte suspension stimulated by SOZ and PMA were significantly lower in the NC group, mostly later during ECC. Similarly, lower neutrophil and monocyte counts were observed in this group. NO increased superoxide production in the whole blood in heparin-coated circuits, but did not change OFR in isolated granulocytes. MPO was also affected by heparin-coating. NO supply seemed to increase release of MPO and HNL. It is concluded that heparin-coating contributed to reduction of biomaterial-dependent blood activation. An addition of NO at late stage of ECC tended to influence this activation.

  • 34.
    Byström, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Garcia, R. C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Håkansson, L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Karawajczyk, Malgorzata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Moberg, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Soukka, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eosinophil cationic protein is stored in, but not produced by, peripheral blood neutrophils2002In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 32, no 7, p. 1082-1091Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Eosinophil cationic protein (ECP) is an eosinophil-derived protein, which has been shown to be present in circulating neutrophils.

    OBJECTIVE: To establish whether ECP is produced or internalized by peripheral blood neutrophils.

    METHODS: This was done using microscopy, flow cytometry, fractionation of cells and RT-PCR techniques.

    RESULTS: No ECP mRNA was detected after extensive cell purification to eliminate all traces of contaminating eosinophils. Examination of immunostained neutrophils by light, confocal, electron microscopy together with cell fraction experiments, established that ECP is present intracellularly and is mostly associated to cell granules. Uptake studies by flow cytometry and by using both cold and radiolabelled ECP showed that it is internalized by neutrophils and stored in some proportion in their primary granules. Upon stimulation with serum-treated Sephadex particles, the internalized ECP was partially released from cells.

    CONCLUSION: ECP is not produced but can be internalized by circulating neutrophils, which take it from the environment and partially store it in their primary granules.

  • 35.
    Carlson, M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Peterson, C G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Human eosinophil peroxidase: purification and characterization1985In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 134, no 3, p. 1875-1879Article in journal (Refereed)
    Abstract [en]

    Human eosinophil peroxidase (EPO) was isolated from granules from granulocytes of a patient with hypereosinophilia. The granules were extracted by means of 0.2 M NaAc, pH 4.0. The purification steps included gel filtration chromatography on Sephadex G-75 superfine and ion-exchange chromatography on CM-Sephadex G-50. The purified protein showed one band on agarose-electrophoresis, a high peroxidase activity, and a 415-nm/280 nm ratio of 1.15. After reduction, EPO showed two bands on SDS-PAGE of m.w. 52,000 and 15,000, respectively. On gel filtration, the unreduced protein had a m.w. of approximately 77,000. Amino acid analyses showed a high content of arginine and aspartic acid. Monospecific antibodies to EPO were prepared in rabbits, and a specific radioimmunoassay was developed. There was an almost linear correlation between the content of EPO measured by the radioimmunoassay and the number of eosinophils in a mixed cell extract from reference material, indicating the eosinophil origin of EPO. The content of EPO was estimated to be 15.0 micrograms/10(6) eosinophils.

  • 36.
    Carlson, M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Peterson, C
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The influence of IL-3, IL-5, and GM-CSF on normal human eosinophil and neutrophil C3b-induced degranulation1993In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 48, no 6, p. 437-442Article in journal (Refereed)
    Abstract [en]

    The priming effect of interleukin-3 (IL-3), interleukin-5 (IL-5), and granulocyte/macrophage-colony stimulating factor (GM-CSF) on eosinophil and neutrophil degranulation was studied. Granulocytes were obtained from normal donors, and degranulation was induced by incubation with serum-opsonized Sephadex particles. The released amounts of eosinophil cationic protein (ECP), eosinophil protein X (EPX), myeloperoxidase (MPO), and lactoferrin (LF) were measured by radioimmunoassay (RIA). The effect of IL-5 was dose- and time-dependent, with a maximal enhancement of ECP and EPX release of 71% (P < 0.03) and 66% (P < 0.03), respectively. Neutrophil degranulation, however, was unaffected. IL-3 was marginally effective, whereas GM-CSF seemed to act as a secretagogue for both eosinophil and neutrophil degranulation. We conclude that IL-5 selectively primes eosinophil degranulation, whereas IL-3 and GM-CSF seem to act as secretagogues for eosinophils and neutrophils. The results indicate that IL-5 may be involved in the priming of eosinophils as observed in patients with asthma and hypereosinophilic syndrome (HES).

  • 37.
    Carlson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kämpe, Mary
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Stålenheim, Gunnemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Peterson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Degranulation of eosinophils from pollen-atopic patients with asthma is increased during pollen season1992In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 89, no 1 Pt 1, p. 131-139Article in journal (Refereed)
    Abstract [en]

    The secretion of granule proteins from eosinophils and neutrophils was studied in isolated cells, obtained from 11 pollen-atopic patients with asthma, twice during and twice outside pollen season. Granulocytes were stimulated with serum-opsonized Sephadex particles, and the released amount of eosinophil cationic protein (ECP), eosinophil protein X (EPX), and myeloperoxidase (MPO) were measured by means of specific radioimmunoassay (RIA). Eosinophils from the pollen-atopic patients obtained during pollen season released significantly more (p less than 0.02) ECP and EPX than cells from the same patients obtained before pollen season. The released amount of ECP and EPX was correlated (r = 0.54; p less than 0.003) to the total pollen count. The release of MPO from neutrophils was only raised (p less than 0.01) at the end of the pollen season. Serum concentrations of ECP and EPX and blood eosinophil counts were significantly raised (p less than 0.002, p less than 0.001, and p less than 0.009, respectively) before pollen season and increased further at the end of the pollen season. There were no changes in lung function during pollen season and consequently no discernible relationships to eosinophil and neutrophil degranulation. We conclude that eosinophils and, to some extent, neutrophils from birch pollen-atopic subjects have an increased propensity to secrete their granule proteins during a pollen season. We suggest that these cells have been primed as a consequence of allergen exposure.

  • 38.
    Carlson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Peterson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stålenheim, Gunnemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Secretion of granule proteins from eosinophils and neutrophils is increased in asthma1991In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 87, no 1 Pt 1, p. 27-33Article in journal (Refereed)
    Abstract [en]

    The activity of eosinophil and neutrophil granulocytes with respect to secretion of granule proteins was studied in 30 patients with asthma and with varying severity of their disease. Granulocytes were stimulated with serum-opsonized Sephadex particles, and the released amount of eosinophil cationic protein (ECP), eosinophil protein X (EPX), and myeloperoxidase was measured by means of specific radioimmunoassays. Eosinophils from patients with asthma released significantly more (p less than 0.001) ECP and EPX after 20 minutes of incubation than cells from control subjects without asthma. The release of myeloperoxidase from neutrophils was also somewhat higher (p less than 0.03). The serum concentrations of ECP and EPX were also significantly increased (p less than 0.001) in the group with asthma. No significant relationships were found between clinical variables and the secretory activity of either eosinophils or neutrophils. We conclude that eosinophils and, to some extent, neutrophils from subjects with asthma have an increased propensity to release their granule proteins, which we suggest is a consequence of priming of these cells.

  • 39.
    Carlson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Raab, Y.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sevéus, L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Xu, Shengyuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Human neutrophil lipocalin is a unique marker of neutrophil inflammation in ulcerative colitis and proctitis2002In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 50, no 4, p. 501-506Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIM: Accumulation and infiltration by neutrophil granulocytes is a prominent feature in the local inflammatory process in ulcerative colitis (UC). The present study was performed to evaluate human neutrophil lipocalin (HNL) as a specific neutrophil marker in the inflamed lesions of the colon and rectum in patients with colitis and proctitis.

    METHODS: The activity of intestinal neutrophils with respect to release of granule proteins was studied in 18 patients with UC (10 with colitis and eight with isolated proctitis) and in 18 healthy controls using perfusion fluid and biopsies from the sigmoid colon and rectum. The released amounts of the neutrophil granule proteins HNL and myeloperoxidase (MPO) were determined by radioimmunoassays, and the location of HNL and MPO in biopsies from colonic mucosa was examined by immunohistochemistry.

    RESULTS: Mucosal release of HNL and MPO was increased 10-55-fold in patients with colitis and proctitis compared with controls. Their bowel biopsies demonstrated that only neutrophils were stained with anti-HNL. We also found correlations between HNL and levels of granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 8 (IL-8) in perfusion fluids from the sigmoidal segments of patients with proctitis, between HNL and GM-CSF in rectal segments in patients with proctitis, and in sigmoidal segments in patients with colitis.

    CONCLUSION: We conclude that the increased release of HNL and MPO in colorectal perfusion fluids indicates neutrophil involvement in the local inflammatory process, and suggest that HNL may serve as a specific marker of intestinal neutrophil activation in UC. GM-CSF, and to some extent IL-8, may play a role in neutrophil accumulation and priming in this disease.

  • 40.
    Carlson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Raab, Yngve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Peterson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Increased intraluminal release of eosinophil granule proteins EPO, ECP, EPX, and cytokines in ulcerative colitis and proctitis in segmental perfusion1999In: American Journal of Gastroenterology, ISSN 0002-9270, E-ISSN 1572-0241, Vol. 94, no 7, p. 1876-1883Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The role of the eosinophil granulocyte in bowel mucosa in inflammatory bowel disease still remains obscure. The present study was performed in order to elucidate the local eosinophil activity and activating cytokines in the inflamed lesions of colon and rectum in patients with ulcerative colitis and proctitis. METHODS: The activity of intestinal eosinophils with respect to the release of granule proteins was studied in 18 patients (10 with colitis and 8 with isolated proctitis) and 18 healthy controls, using intraluminal segmental perfusion of the sigmoid colon and rectum. The released amounts of eosinophil granule proteins: eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophil protein X (EPX) to perfusion fluid were determined by radioimmunoassays. The intraluminal release of possible eosinophil priming cytokines granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 8 (IL-8), were analyzed by immunoassays. RESULTS: The mucosal release of ECP, EPO, and EPX was increased 10- to 20-fold in patients with colitis and proctitis compared with controls. The intraluminal release of GM-CSF and IL-8, was several-fold enhanced in patients with colitis and proctitis. We also found a correlation between all three eosinophil granule proteins and the levels of IL-8/GM-CSF in the sigmoidal segments of patients with colitis. CONCLUSIONS: We conclude that the increased release of ECP, EPO, and EPX to colorectal perfusion fluid indicate eosinophil involvement in the local disease in patients with colitis and proctitis. IL-8 and GM-CSF may play a role in eosinophil accumulation and priming in colitis.

  • 41.
    Carlson, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Öberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Peterson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Releasability of human hypereosinophilic eosinophils is related to the density of the cells1994In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 86, no 1, p. 41-47Article in journal (Refereed)
    Abstract [en]

    The activity of eosinophils and neutrophils with respect to the release of granule proteins was studied in 11 patients with the hypereosinophilic syndrome (HES). Granulocytes or purified eosinophils were stimulated with serum-opsonized Sephadex particles (C3b-induced release), and the released amounts of eosinophil cationic protein (ECP), eosinophils protein-X (EPX) and myeloperoxidase (MPO) were measured by means of specific radioimmunoassays (RIA). Eosinophils obtained from patients with HES released significantly more ECP (P<0·002) and EPX (P<0·01) after 20 min of incubation than cells from the control group. The cellular content of ECP and EPX in eosinophils obtained from the patients with HES was significantly reduced to 50% and 62%, respectively, of the content of these granule proteins of eosinophils from the control group. In separated eosinophils light-density eosinophils released more of both ECP and EPX than normal density eosinophils. There was no difference in MPO release between the patients and the control group. We conclude that the eosinophils from patients with HES have an increased propensity to release their granule proteins and the releasability seems to be related to the density of the cells.

  • 42.
    Cooray, Ruby
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Waller, Karin Persson
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Haptoglobin comprises about 10% of granule protein extracted from bovine granulocytes isolated from healthy cattle2007In: Veterinary Immunology and Immunopathology, ISSN 0165-2427, E-ISSN 1873-2534, Vol. 119, no 3-4, p. 310-315Article in journal (Refereed)
    Abstract [en]

    Haptoglobin (Hp) is a plasma protein with haemoglobin binding capacity important in maintaining the iron homeostasis and in disease processes influenced by iron metabolism. In cattle Hp is one of the major acute phase proteins, and increases rapidly during infectious disease. At acute clinical mastitis in dairy cows the Hp concentration increases markedly both in blood and milk. Hepatocytes are considered to be the main origin of Hp, but expression of Hp mRNA has also been found in the mammary gland and leukocytes in healthy cattle. In the present study we show that bovine granulocytes, isolated from peripheral blood of healthy cattle, contain abundant amounts of Hp within the granules. As shown by two-dimensional gel electrophoresis (2-DE) in combination with matrix assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-ToF-MS) bovine granulocyte Hp consists of two sets of peptides ca. 20 kDa (a-chains) and ca. 40 kDa ((3-chains) with multiple iso-forms.

  • 43. Dahl, R.
    et al.
    Larsen, B. B.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Effect of long-term treatment with inhaled budesonide or theophylline on lung function, airway reactivity and asthma symptoms2002In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 96, no 6, p. 432-438Article in journal (Refereed)
    Abstract [en]

    Asthma is characterized by inflammation of the airways and long-term treatment with inhaled glucocorticosteroids improve clinical control in patients previously treated with inhaled rescue beta-2 agonist. We investigated whether the dose of inhaled glucocorticosteroid was related to outcome compared with oral theophylline. Budesonide 800 microg bd, budesonide 200 microg bd, or theophylline (Theo-Dur 300 mg bd was given double-blind, double-dummy and randomized, in a parallel group design for 9 months; when therapy was stopped patients were followed for an additional 3 months. Forced expiratory volume in 1 sec (FEV1), bronchial reactivity and asthma symptom scores were assessed before entering the study and after 1, 2, 3, 5, 7, and 9 months of treatment and monthly after treatment was stopped. Eighty-five patients (38 females and 47 males) were enrolled in the study during 1 1/2 year. Withdrawal from the study due to exacerbations during the treatment period was significantly increased (P <0.01) in the theophylline group. After treatment was stopped more patients withdrew in the budesonide group. In the budesonide 800 microg bd group, FEV1 improved significantly after 1 months treatment (P <0.01) and persisted throughout the study period. In the budesonide 200 microg bd group, FEV1 improved slightly and reached significance (P=0.05) after 5 months of treatment. In the theophylline group, FEV1 was unchanged during the 9 months of treatment. In both budesonide groups, FEV1 deteriorated significantly (P<0.01 and P<0.02, respectively) after termination of study medication and reached pretreatment values during the first month. In the budesonide 800 microg bd group, the concentration of histamine causing a 20% fall in FEV1 (PC20) increased significantly (P<0.01) after 1 months treatment and increased further after 9 months (P<0.0001), equivalent to two doubling dilutions. In the budesonide 200 microg bd, group PC20 histamine significantly increased (P <0.005) after 2 months of treatment and remained constant; theophylline was unchanged. After treatment with budesonide 800 microg bd and 200 microg bd were stopped, PC20 decreased significantly (P<0.002 and P=0.05, respectively) within the first month. PC20 remained unchanged after theophylline was stopped. After budesonide 800 microg bd and 200 microg bd treatment, symptom severity decreased in a dose-related and highly significant manner (P < 0.00001 and P < 0.0001, respectively). With theophylline, asthma symptoms decreased slightly after 1 and 2 months treatment (P < 0.01 and P < 0.02, respectively) and when treatment was stopped no increase in asthma symptoms was evident. Oral theophylline slightly reduced airways symptoms and had no influence on FEV1 and PC20 histamine. Maintenance treatment with inhaled budesonide gave a dose-related reduction in airways obstruction, bronchial reactivity and asthma symptom severity. The efficacy of inhaled corticosteroid was superior to oral theophylline.

  • 44.
    Dahlén, Inger
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Björnsson, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stålenheim, Gunnemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Peterson, C. G. B.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Changes in inflammatory markers following treatment of acute exacerbationsof obstructive pulmonary disease2001In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 95, no 11, p. 891-897Article in journal (Refereed)
    Abstract [en]

    The aim ofthe study was to investigate changes in inflammatory markers following emergency treatment of obstructive pulmonary disease. The study comprised 43 patients. After acute treatment, they were given either 30 mg of prednisolone p.o. or 1600 microg of inhaled budeson de daily for 1 week. Over the following 3 weeks, all the patients were given 1600 microg of inhaled budesonide daily. Blood samples for measurements of eosinophil cationic protein (S-ECP), eosinophil peroxidase (S-EPO), total eos nophil count (B-Eos), myeloperoxidase (S-MPO) and human neutrophil lipocaline (HNL) were taken and spirometry was performed before emergency treatment and after 1 and 4 weeks. There was no difference in the improvement in forced expiratory volume in 1 sec (FEV1) between patients given prednisolone or budesonide. Patients with an improvement in FEV1 of >20% of baseline after 1 and 4 weeks displayed a larger decrease in eosinophil markers. The correlation between deltaFEV1 and deltaS-ECP was r= -0.37, P < 0.05, deltaS-EPO -0.40, P < 0.01 and deltaB-Eos -0.44, P < 0.01, after 4 weeks. This correlation was highly significant in patients who had smoked < or = 5 pack-years, while the correlation was not significant in patients with a longer smoking history and chronic airflow limitation (best FEV <80% of predicted). We conclude that the change in eosinophil markers is correlated to the improvement in lung function in non-smokers or short-term smokers following the emergency treatment of obstructive pulmonary disease. This study indicates that following eosinophil markers is more useful in patients with asthma than patients with COPD.

  • 45.
    Dahlén, Inger
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Björnsson, E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stålenheim, Gunnemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Peterson, C. G. B.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Inflammatory markers in acute exacerbations of obstructive pulmonary disease: predictive value in relation to smoking history1999In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 93, no 10, p. 744-751Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the relationship between the effect of emergency treatment and inflammatory markers in patients with acute exacerbations of obstructive pulmonary disease, especially with respect to smoking history. We investigated 50 unselected patients with acute bronchial obstruction. Blood, urine and sputum samples were taken and analysed for eosinophil and neutrophil markers. The patients were observed for at least 2 h and recordings of forced expiratory volume in 1 s (FEV1) were taken. They were re-examined after 1 and 4 weeks. The absolute levels of inflammatory markers did not differ significantly between non- or short-term smokers (< or = 5 pack-years) and long-term smokers (> 5 pack-years) with the exception of myeloperoxidase in serum (S-MPO), which was higher in long-term smokers. The patients with higher levels of eosinophil markers before emergency treatment experienced a greater improvement in lung function. In non- or short-term smokers this relationship was found in blood and urine, whereas in long-term smokers it was seen in sputum. No correlation was found between neutrophil markers and changes in lung function. We conclude that patients with obstructive pulmonary disease with acute exacerbations and high levels of eosinophil markers respond well to treatment.

  • 46. Diderholm, Erik
    et al.
    Andrén, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Frostfeldt, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Genberg, Margareta
    Jernberg, Tomas
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The prognostic and therapeutic implications of increased troponin T levels and ST depression in unstable coronary artery disease: the FRISC II invasive troponin T electrocardiogram substudy2002In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 143, no 5, p. 760-767Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In unstable coronary artery disease, both increased troponin T level and occurrence of ST-segment depression are associated with a worse prognosis. In the Fast Revascularisation in InStability in Coronary disease trial II invasive study, we evaluated whether the troponin T level, alone and combined with ST depression, identified more severe coronary artery disease or a greater efficacy of an early invasive strategy.

    METHODS: In the study, 2457 patients with unstable coronary artery disease were randomized to early invasive or noninvasive strategy. Troponin T value and admission electrocardiogram results were available in 2286 patients.

    RESULTS: In the noninvasive cohort, death or myocardial infarction occurred in 16.6% with troponin T level > or =0.03 microg/L versus 8.5% with troponin T level < 0.03 microg/L (P <.001). In the invasive group, 49% of patients with both ST depression and troponin T level > or =0.03 microg/L had 3-vessel or left main disease compared with 17% if neither finding was present (P <.001). The invasive strategy reduced death/myocardial infarction at 12 months in the cohort with both ST depression and troponin T level > or =0.03 microg/L from 22.1% to 13.2% (risk ratio, 0.60; 95% confidence interval, 0.43 to 0.82; P =.001). In the cohort with either ST depression or troponin T level > or =0.03 microg/L or neither of these findings, the absolute gain of the invasive strategy was smaller and more uncertain.

    CONCLUSION: Patients with unstable coronary artery disease with the combination of troponin T level > or =0.03 microg/L and ST depression have a poor prognosis and, in half of the cases, 3-vessel or left main disease. In these patients, an early invasive strategy will substantially reduce death/myocardial infarction.

  • 47.
    Ebeling Barbier, Charlotte
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Themudo, Raquel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Bjerner, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Cardiac Troponin I Associated with the Development of Unrecognized Myocardial Infarctions Detected with MRI2014In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 60, no 10, p. 1327-1335Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

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

    METHODS:

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

    RESULTS:

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

    CONCLUSIONS:

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

  • 48. Edelstam, Greta
    et al.
    Löwbeer, C.
    Kral, G.
    Gustafsson, S. A.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    New reference values for routine blood samples and human neutrophilic lipocalin during third-trimester pregnancy2001In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 61, no 8, p. 583-592Article in journal (Refereed)
    Abstract [en]

    Reference values are usually based on blood samples from healthy men or non-pregnant women. Blood samples from pregnant women may be compared with these reference values. Correct references for pregnancy can be extremely important for clinical decisions such as ablatio placentae, appendicitis, premature rupture of membranes and preeclampsia. Previous studies of normal variations during third-trimester pregnancy are incomplete. Blood samples during pregnancy weeks 33, 36 and 39 as well as 1-3 h postpartum were collected from pregnant women with dietary iron supplement and at least one previous pregancy without a history of hypertension or preeclampsia. When the sampled values were compared with the present reference values from men and non-pregnant women, the following differences were found during normal pregnancy: Haemoglobin and ferritin were reduced, CRP was slightly elevated, WBC (white blood cell count) and HNL (human neutrophilic lipocalin) were elevated during pregnancy and significantly increased postpartum. Albumin was reduced. ALT and AST were slightly elevated and GGT was unchanged during pregnancy. ALP, D-dimer and fibrinogen were elevated. Uric acid increased during the third trimester and thrombocyte count decreased. Separate reference values for pregnant women are essential for correct diagnostic decisions during third-trimester pregnancy. Elevated levels of D-dimer do not necessarily indicate ablatio placentae. A diagnosis of progressive preeclampsia cannot be based on increasing uric acid levels and reduced platelet count in a stable clinical condition. HNL signals activation of neutrophilic granulocytes and can thereby offer a helpful tool for diagnosing infection during pregnancy and postpartum.

  • 49.
    Eggers, Kai M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Armstrong, Paul W.
    Califf, Robert M.
    Johnston, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Simoons, Maarten L.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    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.
    Clinical and prognostic implications of circulating pentraxin 3 levels in non ST-elevation acute coronary syndrome2013In: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 46, no 16-17, p. 1655-1659Article in journal (Refereed)
    Abstract [en]

    Objectives: Pentraxin 3 (PTX3) is the prototype of the long pentraxin family. PTX3 is involved in inflammatory processes affecting the cardiovascular system, and PTX3 levels have been shown to be elevated and independently prognostic in ST-elevation myocardial infarction. Data on PTX3 levels in non-ST-elevation acute coronary syndrome (NSTE-ACS), in contrast, are limited. The aim of the present analysis was to investigate the implications of PTX3 levels in a fairly large sample of NSTE-ACS patients and in comparison to levels of C-reactive protein (CRP). Design and methods: We measured levels of PTX3 and CRP in both 82 healthy controls and 401 NSTE-ACS patients from the GUSTO IV study, and studied the associations of these biomarkers to clinical data and 1-year mortality. Results: NSTE-ACS patients had significantly higher median PTX3 levels compared to healthy controls (3.8 vs. 1.9 mu g/L; p < 0.001). PTX3 levels in patients with NSTE-ACS were independently related to female sex and cardiac troponin T levels, but not to age or cardiovascular risk factors. PTX3 levels were higher in patients who died within 1 year but did not emerge as an independent predictor of 1-year mortality (adjusted OR 1,2 [95% Cl 0.6-2.31). This was in contrast to CRP (adjusted OR 1.5 [95% Cl 1.1-2.3]). Neither PTX3 nor CRP yielded significant discriminative value regarding mortality prediction. Conclusions: PTX3 levels are elevated in NSTE-ACS. However, the prognostic information provided by PTX3 levels is limited and inferior compared to CRP. Our data, thus, do not support the measurement of PTX3 in patients with NSTE-ACS.

  • 50.
    Eggers, Kai M.
    et al.
    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, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Prognostic implications of changes in cardiac troponin I levels in patients with non-ST elevation acute coronary syndrome2013In: Biomarkers, ISSN 1354-750X, E-ISSN 1366-5804, Vol. 18, no 8, p. 668-672Article in journal (Refereed)
    Abstract [en]

    Objective: Information is limited on the prognostic implications of cardiac troponin I (cTnI) changes during the first days of non-ST elevation acute coronary syndrome (NSTE-ACS). Methods: High-sensitivity cTnI levels were measured at study inclusion and after 48 h in 1615 conservatively managed NSTE-ACS patients from the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO) IV trial. Results: Patients with moderately increased cTnI levels and without a relevant decrease over time had a significantly raised mortality at 30 days and 1 year. No relevant associations between cTnI changes and recurrent myocardial infarction were seen. Conclusion: The cTnI change is predictive for subsequent mortality in selected conservatively managed NSTE-ACS patients.

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