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  • 1.
    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.

  • 2.
    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.

  • 3.
    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.

  • 4.
    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.

  • 5.
    Eriksson, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Håkansson, Lena Douhan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Karawajczyk, Malgorzata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Garwicz, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Neutrophil CD64 expression - comparison of two different flow cytometry protocols on EPICs MCL and the Leuko64 (TM) assay on a Celldyn Sapphire haematology analyser2015In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 75, no 5, p. 428-433Article in journal (Refereed)
    Abstract [en]

    Objective. To evaluate the Trillium Diagnostics Leuko64 (TM) assay on Abbott Celldyn Sapphire haematology analyser compared to two flow cytometry protocols on Beckman Coulter EPICS MCL flow cytometer. Materials and methods. CD64 expression on neutrophils was determined by two flow cytometry protocols and by a commercial assay on an automatic haematology analyser. The inclusion of study subjects was based on elevated procalcitonin (PCT) values, identifying patients where a systemic infection was suspected. Healthy blood donors were used as a reference group. Results. Statistically significant correlations between the Trillium Diagnostics Leuko64 (TM) assay and the flow cytometry methods were found when measuring neutrophil CD64 expression. Conclusions. The good correlation between a reference method and an automated haematology analyser method for CD64 expression on neutrophils supports introduction of the latter assay for routine use as an independent biomarker of bacterial infection and inflammation.

  • 6.
    Furebring, M
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    Håkansson, L
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
    Venge, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Klinisk kemi.
    Sjölin, J
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Infektion.
    C5a, interleukin-8 and tumour necrosis factor-alpha-induced changes in granulocyte and monocyte expression of complement receptors in whole blood and on isolated leukocytes.2006In: Scand J Immunol, ISSN 0300-9475, Vol. 63, no 3, p. 208-16Article in journal (Refereed)
  • 7.
    Furebring, Mia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Håkansson, Lena
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Differential expression of the C5a receptor and complement receptors 1 and 3 after LPS stimulation of neutrophils and monocytes2004In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 60, no 5, p. 494-499Article in journal (Refereed)
    Abstract [en]

    Animal experiments recently suggested that administration of anti-C5a, anti-C5a receptor or soluble complement receptor type-1 may be of value in the treatment of septic shock. Because results regarding C5a receptor expression (C5a-R, CD-88) have been found to differ between septic animals and patients, the aim of this study was to investigate the neutrophil and monocyte receptor expression of CD-88 and complement receptor-1 (CR-1, CD-35) after stimulation with lipopolysaccharide (LPS) ex vivo. Whole blood or isolated neutrophils and monocytes from healthy people were incubated with LPS in a dose range of 0.1-1000 ng/ml. The expressions of CD-88 and CD-35 were analysed by means of flow cytometry. For comparison, the expressions of complement receptor-3 (CR-3, CD-11b/CD-18), Fc-gamma receptor type-I (CD-64) and CEACAM-8 (CD-66b) were also investigated. In whole blood, CD-88 expression on neutrophils was reduced (P < 0.05). The expressions of CD-35 and CD-11b were increased both on neutrophils (P < 0.001; P < 0.05) and on monocytes (P < 0.001; P < 0.001). No effect was observed on isolated cells. In agreement with the findings in septic patients, LPS reduced the neutrophil C5a-R expression, whereas the expressions of CR-1 and CR-3 were increased. The effects of LPS were indirect and were mediated via factors in the blood. The clinical significance of this is not known, but may be associated with decreased chemotaxis.

  • 8.
    Håkansson, L
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Carlson, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stålenheim, 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.
    Migratory responses of eosinophil and neutrophil granulocytes from patients with asthma1990In: Journal of Allergy and Clinical Immunology, ISSN 0091-6749, E-ISSN 1097-6825, Vol. 85, no 4, p. 743-750Article in journal (Refereed)
    Abstract [en]

    In the present study the migratory function of eosinophil and neutrophil granulocytes from patients with asthma were investigated. Fifty-seven patients with asthmatic disease of varying severity were included. Eosinophil and neutrophil chemotactic responses to 5% pooled normal human serum (NHS), 5% allergen-challenge serum, 2.5% zymosan-activated serum, N-formyl-methionyl-leucyl-phenylalanine (10 nmol/L), chemokinetic responses to albumin (2 gm/L) and 5% NHS, and the eosinophil and neutrophil chemotactic and chemokinetic activities of serum were investigated. Eosinophils from patients with asthma demonstrated significantly (p less than 0.02) increased chemotactic responses to allergen-challenge serum, zymosan-activated serum, and N-formyl-methionyl-leucyl-phenylalanine, compared with eosinophils from references. The chemokinetic responses to albumin and NHS were increased (p less than 0.01) by eosinophils from the patients who had blood eosinophilia (greater than 400 X 10(6)/L). Sera from the patients with asthma demonstrated raised eosinophil chemotactic activity (p less than 0.001) and raised eosinophil and neutrophil chemokinetic activity (p less than 0.001). The eosinophil chemokinetic activity of serum was correlated to the relative peak expiratory flow rate of the patients (r = -0.43; p less than 0.02). The increased migratory responses were specific for the eosinophils, since the migratory responses of their neutrophils were not altered compared with that of the references. These results suggest that the eosinophils from the patients with asthma had been exposed to a priming mechanism in vivo.

  • 9.
    Janson, Christer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ludviksdottir, Dora
    Gunnbjörnsdóttir, Mari­a
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Björnsson, Eythor H.
    Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Circulating adhesion molecules in allergic and non-allergic asthma2005In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 99, no 1, p. 45-51Article in journal (Refereed)
    Abstract [en]

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

  • 10.
    Jönsson, Ulla-Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Blom, Kristin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stålenheim, Gunnemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Douhan Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The production of the eosinophil proteins ECP and EPX/EDN are regulated in a reciprocal manner2014In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 122, no 4, p. 283-291Article in journal (Refereed)
    Abstract [en]

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

  • 11.
    Jönsson, Ulla-Britt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Douhan Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jõgi, Rain
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Associations of ECP (eosinophil cationic protein)-gene polymorphisms to allergy, asthma, smoke habits and lung function in two Estonian and Swedish sub cohorts of the ECRHS II study2010In: BMC Pulmonary Medicine, ISSN 1471-2466, E-ISSN 1471-2466, Vol. 10, p. 36-Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 12. Lampinen, Maria
    et al.
    Håkansson, Lena Douhan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Klinisk kemi.
    Venge, Per
    Klinisk kemi.
    Albumin stimulation of eosinophil migration involves PI3-kinases and is associated with diminished eosinophil CD49d and CD49f expression.2006In: Int Arch Allergy Immunol, ISSN 1018-2438, Vol. 140, no 2, p. 113-20Article in journal (Refereed)
  • 13.
    Manivel, Vivek Anand
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sohrabian, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wick, Marius C.
    Håkansson, Lena Douhan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Elshafie, Amir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Anti-type II collagen immune complex-induced granulocyte reactivity is associated with joint erosions in ra patients with anti-collagen antibodies2014In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 73, no S1, p. A5-A5Article in journal (Other academic)
  • 14.
    Manivel, Vivek Anand
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sohrabian, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wick, Marius C.
    Mullazehi, Mohammed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Håkansson, Lena Douhan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Anti-type II collagen immune complex-induced granulocyte reactivity is associated with joint erosions in RA patients with anti-collagen antibodies2015In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 17, article id 8Article in journal (Refereed)
    Abstract [en]

    Introduction: Rheumatoid arthritis (RA) patients with autoantibodies against collagen type II (CII) are characterized by acute RA onset with elevated inflammatory measures and early joint erosions as well as increased production of tumor necrosis factor-alpha (TNF-alpha) by peripheral blood mononuclear cells (PBMC) stimulated by anti-CII immune complexes (IC) in vitro. Polymorphonuclear granulocytes (PMN) are abundant in RA synovial fluids, where they might interact directly with anti-CII IC in the articular cartilage, but no studies have investigated PMN responses towards anti-CII IC. The aim was to investigate whether PMN react towards anti-CII IC, and to what extent such reactivity might relate to the clinical acute onset RA phenotype associated with elevated levels of anti-CII. Methods: PMN and PBMC isolated from healthy donors were stimulated with IC made with a set of 72 baseline patient sera (24 anti-CII positive, 48 anti-CII negative) chosen from a clinically well-characterized RA cohort with two-year radiological follow-up with Larsen scoring. PMN expression of cluster of differentiation (CD) 11b, CD66b, CD16 and CD32 was measured by flow cytometry, whereas PMN production of myeloperoxidase (MPO) and interleukin (IL)-17, and PBMC production of TNF-alpha was measured with enzyme linked immunosorbent assay. Results: PMN expression of CD11b, CD66b and MPO, and PBMC production of TNF-alpha were upregulated whereas PMN expression of CD16 and CD32 were downregulated by anti-CII IC. CD16, CD66b, and MPO production correlated to serum anti-CII levels (Spearman's rho = 0.315, 0.675 and 0.253, respectively). CD16 was associated with early joint erosions (P = 0.024, 0.034, 0.046 at baseline, one and two years) and CD66b was associated with changes in joint erosions (P = 0.017 and 0.016, at one and two years compared to baseline, respectively). CD66b was associated with baseline C-reactive protein and PBMC production of TNF-alpha was associated with baseline erythrocyte sedimentation rate, in accordance with our earlier findings. No clinical associations were observed for MPO or IL-17. Conclusion: PMN responses against anti-CII IC are more closely associated with early joint erosions than are PBMC cytokine responses. PMN reactivity against anti-CII IC may contribute to joint destruction in newly diagnosed RA patients with high levels of anti-CII.

  • 15.
    Manivel, Vivek Anand
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sohrabian, Azita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wick, Maurius C.
    Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Granulocyte Reactivity is Associated with Cartilage Destruction in Patients with Anti-collagen Antibodies2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 424-424Article in journal (Other academic)
  • 16.
    Melki, Vilyam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Håkansson, Lena Douhan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Borowiec, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Effect of simulated extracorporeal circulation and glyceryl-tri-nitrate on leukocyte activation.2014In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 48, no 1, p. 59-64Article in journal (Refereed)
    Abstract [en]

    Objectives. During extracorporeal circulation (ECC), a mechanical pump and an oxygenator replace the functions of the heart and lungs. The aim of this study is to test the effect of the nitric oxide donor glyceryl-tri-nitrate on activation markers of the innate immune system during simulated ECC. Design. Whole blood concentrations of selected leukocyte adhesion molecules, complement system components and myeloperoxidase (MPO) were measured in an in vitro system of simulated ECC. Results. Simulated ECC stimulated the expression of monocyte LPS-receptor CD14 and C3b-receptor CD35. Glyceryl-tri-nitrate significantly reduced the expression of leukocyte Fcγ receptor CD32 over time, compared to control. Simulated ECC increased the concentrations of MPO, terminal complement complex, and complement component C3a. Addition of glyceryl-tri-nitrate did not significantly affect these changes. Conclusions. Simulated ECC induces the increased expression of some leukocyte markers. Glyceryl-tri-nitrate addition significantly reduces the expression of some leukocyte activation markers.

  • 17.
    Ridefelt, Peter
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Klinisk kemi.
    Håkansson, Lena D
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences. Klinisk kemi.
    Lactose intolerance: lactose tolerance test versus genotyping2005In: Scand J Gastroenterol, ISSN 0036-5521, Vol. 40, no 7, p. 822-6Article in journal (Refereed)
  • 18.
    Stålhammar, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Douhan Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sindelar, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Under Agarose Migration Assay: a Method to Study Graded Chemotactic Activity of Leukocytes in Newborn Infants2010In: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447, Vol. 68, no suppl. 1, p. 427-427Article in journal (Refereed)
  • 19.
    Stålhammar, Maria E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Douhan Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Sindelar, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Bacterial N-formyl Peptides Reduce PMA and Escherichia coli-Induced Neutrophil Respiratory Burst in Term Neonates and Adults2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 85, no 5, p. 365-371Article in journal (Refereed)
    Abstract [en]

    Neutrophil migration and respiratory burst is the prerequisite for efficient first line defense against invading microorganisms. However, migration and respiratory burst can be compromised in adults and especially in newborn infants, where sustained neutrophil accumulation, uncontrolled burst and reduced scavenging of ROS might cause inadvertent tissue damage due to uncontrolled inflammation. The aim of this study was to investigate the modulatory effect of the chemoattractants formyl-methionyl-leucyl-phenylalanine (fMLP) and IL-8 on respiratory burst in neutrophils from term newborn infants and adults. Whole blood from the umbilical cord of 17 healthy term newborn infants delivered by caesarean section and from 17 healthy adults as reference was preincubated with fMLP or IL-8 and stimulated with PMA or E.coli bacteria. Respiratory burst was quantified by flow cytometry analysis of dihydrorhodamine 123 fluorescence. fMLP reduced the PMA-induced respiratory burst of neutrophils from newborn infants and adults by 12% and 21% respectively (p<0.05). E.coli-induced burst was also reduced by fMLP in neutrophils from newborn infants (10%; p<0.01) and adults (6%; p<0.05). No such changes were observed with IL-8. Similar respiratory burst in response to single stimulus with PMA or E.coli were observed in both newborn infants and adults. fMLP reduced PMA- and E.coli-induced respiratory burst of neutrophils in whole blood from term newborn infants as well as in adults. The reduced respiratory burst by fMLP might be a mechanism to reduce the detrimental effects of uncontrolled inflammation during neutrophil migration

  • 20.
    Stålhammar, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Håkansson, Lena Douhan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jonzon, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Sindelar, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Differential Neutrophil Chemotactic Response towards IL-8 and Bacterial N-formyl Peptides in Term Newborn Infants2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 35-42Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A prerequisite for an effective innate immunity is the migrative ability of neutrophils to respond to inflammatory and infectious agents such as the intermediate interleukin (IL)-8 and the end-target formyl-methionyl-leucyl-phenylalanine (fMLP) chemoattractants. The aim was to study the chemotactic capacity of neutrophils from newborn infants and adults in response to IL-8 and the bacterial peptide fMLP.

    METHODS: In the under-agarose cell migration assay, isolated leukocytes from healthy adults and from cord blood of healthy term newborn infants were studied with dose responses towards IL-8 and fMLP. The same number of leukocytes (1 × 10(5) cells), with the same distribution of neutrophils and monocytes, were analyzed in neonates and adults. Chemotaxis was distinguished from randomly migrating neutrophils, and the neutrophil pattern of migration, i.e. the migration distance and the number of migrating neutrophils per distance, was evaluated.

    RESULTS: In comparison to adults, fewer neutrophils from newborn infants migrated towards IL-8 and for a shorter distance (P < .01, respectively). The number of neutrophils migrating to different gradients of fMLP, the distance they migrated, and the correlation between the number and the distance were the same for neonates and adults. Random migration did not differ in any instance.

    CONCLUSION: Chemotaxis of neutrophils from newborn infants was as co-ordinated as neutrophils from adults in response to fMLP, whereas the response to IL-8 was reduced. The differential response of neutrophils from neonates to intermediate and end-target chemoattractants could indicate a reduced infectious response.

  • 21.
    Stålhammar, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Sindelar, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Douhan Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Neutrophil Receptor Response to Bacterial N-formyl Peptides is Similar in Term Newborn Infants and Adults in Contrast to IL-82016In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 84, no 6, p. 332-337Article in journal (Refereed)
    Abstract [en]

    We have previously observed that neutrophils from neonates exhibit different migratory responses to intermediate and end-target chemoattractants compared to adults. The aim of the present study was to investigate the effect of the chemoattractants IL-8 (intermediate) and formyl-methionine-leucyl-phenylalanine (fMLP; end-target) on cell surface receptor expression involved in adhesion, migration and granule release of neutrophils from term newborn infants and adults. Heparinized cord blood from 16 healthy term infants delivered by caesarean section and peripheral blood from 17 healthy adults were incubated with 1 μM IL-8 or 0.01 μM fMLP, previously defined as optimal inducers of neutrophil migration. The leukocytes were labelled with antibodies to cell surface receptors (CD11b, CD15S, CD18, CD35, CD44, CD64, CD65, CD88, CD162, CD181 and CD182). Receptor expression was quantified by flow cytometry analysis. Up regulation of CD11b and down regulation of CD88 and CD182 after stimulation with IL-8, was more pronounced in adults than in neonates (p<0.05, p<0.05 and p≤0.001 respectively), whereas fMLP induced changes in receptor expression that were of the same magnitude in neutrophils from neonates as from adults. We observed similar expression of receptors that mediate adhesion, migration, granule activation, and phagocytosis induced by fMLP in neutrophils from neonates and adults. In contrast, differences between neonates and adults, induced by IL-8, suggest that the neutrophil response to intermediate chemoattractants might lead to a compromised infectious response in newborn infants.

  • 22.
    Vahlquist, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Håkansson, Lena Douhan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Karawajczyk, Malgorzata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Fasth, Anders
    van Gijn, Marielle E.
    Roos, Dirk
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Recurrent Pyoderma Gangrenosum and Cystic Acne Associated with Leucocyte Adhesion Deficiency due to Novel Mutations in ITGB2: Successful Treatment with Infliximab and Adalimumab2015In: Acta Dermato-Venereologica, ISSN 0001-5555, E-ISSN 1651-2057, Vol. 95, no 3, p. 349-351Article in journal (Refereed)
  • 23.
    Venge, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Douhan Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Garwicz, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Peterson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Xu, Shengyuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Pauksen, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Human Neutrophil Lipocalin as a Superior Diagnostic Means To Distinguish between Acute Bacterial and Viral Infections2015In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 22, no 9, p. 1025-1032Article in journal (Refereed)
    Abstract [en]

    The distinction between causes of acute infections is a major clinical challenge. Current biomarkers, however, are not sufficiently accurate. Human neutrophil lipocalin (HNL) concentrations in serum or whole blood activated by formyl-methionine-leucine-phenylalanine (fMLP) were shown to distinguish acute infections of bacterial or viral cause with high accuracy. The aim was therefore to compare the clinical performance of HNL with currently used biomarkers. Seven hundred twenty-five subjects (144 healthy controls and 581 patients with signs and symptoms of acute infections) were included in the study. C-reactive protein (CRP), the expression of CD64 on neutrophils, procalcitonin (PCT), and blood neutrophil counts were measured by established techniques, and HNL concentrations were measured in whole-blood samples after activation with fMLP. All tested biomarkers were elevated in bacterial as opposed to viral infections (P<0.001). CRP, PCT, and CD64 expression in neutrophils was elevated in viral infections compared to healthy controls (P<0.001). In the distinction between healthy controls and patients with bacterial infections, the areas under the receiver operating characteristic (ROC) curves were >0.85 for all biomarkers, whereas for the distinction between bacterial and viral infections, only HNL concentration in fMLP-activated whole blood showed an area under the ROC curve (AUROC) of >0.90 and superior clinical performance. The clinical performance of HNL in fMLP-activated whole blood was superior to current biomarkers and similar to previous results of HNL in serum. The procedure can be adopted for point-of-care testing with response times of <15 min.

  • 24.
    Venge, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Douhan, Lena Håkansson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Garwicz, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Peterson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Xu, Shengyuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Pauksen, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Human neutrophil lipocalin in fMLP-activated whole blood as a diagnostic means to distinguish between acute bacterial and viral infections2015In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 424, p. 85-90Article in journal (Refereed)
    Abstract [en]

    The distinction between causes of acute infections is a major clinical challenge. Current biomarkers, however, are not sufficiently accurate. Human neutrophil lipocalin (HNL) in serum distinguishes acute infections with high accuracy, but in the emergency setting the assay time should be <15-20 min, which excludes the use of serum samples. The aim was therefore to develop a novel rapid assay principle and test its clinical performance. Methods: Serum and neutrophils obtained from 84 infected and 20 healthy subjects were used in the experimental study. 725 subjects (144 healthy controls and 581 patients with signs and symptoms of acute infections) were included in the clinical study. HNL was measured in EDTA-plasma by ELISA or in heparinized whole blood after fMLP activation by a prototype point-of-care assay. Results: Increased release of HNL from neutrophils after activation with fMLP was seen already after 5 min incubation. The release of HNL from purified neutrophils after 15 min incubation with fMLP was significantly correlated to the HNL concentrations in serum obtained from the same patient (r = 0.74, p < 0.001). In the distinction between healthy controls and patients with bacterial infections, the areas under the ROC-curves were 0.95 (95% CI 0.91-0.97) and 0.88 (95% CI 0.84-0.91) for HNL in fMLP-activated whole blood and EDTA-plasma, respectively, (p <0.001) and in the distinction between bacterial and viral infections 0.91 (95% CI 0.86-0.95) and 0.76 (95% CI 0.70-0.81), respectively (p <0.001). Conclusion: The clinical performance of HNL in fMLP-activated whole blood was superior to HNL in EDTA-plasma and similar to HNL in serum. The procedure can be adopted for point-of-care testing with response times of <15 min.

  • 25.
    Venge, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Diagnostics Development, Uppsala, Sweden..
    Eriksson, Ann-Katrin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Diagnostics Development, Uppsala, Sweden..
    Douhan Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Pauksen, Karlis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Human Neutrophil Lipocalin in Activated Whole Blood Is a Specific and Rapid Diagnostic Biomarker of Bacterial Infections in the Respiratory Tract2017In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 24, no 7, article id UNSP e00064Article in journal (Refereed)
    Abstract [en]

    The distinction between bacterial and viral causes of infections of the respiratory tract is a major but important clinical challenge. We investigated the diagnostic performance of human neutrophil lipocalin (HNL) in respiratory tract infections compared to those of C-reactive protein (CRP) and procalcitonin (PCT). Patients were recruited from the emergency department and from a primary care unit (n = 162). The clinical diagnosis with regard to bacterial or viral cause of infection was complemented with objective microbiological/serological testing. HNL was measured in whole blood after preactivation with the neutrophil activator formyl-methionine-leucine-phenylalanine (fMLP) (B-HNL), and CRP and PCT were measured in plasma. Head-to-head comparisons of the three biomarkers showed that B-HNL was a superior diagnostic means to distinguish between causes of infections, with areas under the concentration-time curve (AUCs) of receiver operating characteristic (ROC) analysis for HNL of 0.91 (95% confidence interval [CI], 0.83 to 0.96) and 0.92 (95% CI, 0.82 to 0.97) for all respiratory infections and for upper respiratory infections, respectively, compared to 0.72 (95% CI, 0.63 to 0.80) and 0.68 (95% CI, 0.56 to 0.79) for CRP, respectively (P = 0.001). In relation to major clinical symptoms of respiratory tract infections (cough, sore throat, stuffy nose, and signs of sinusitis), AUCs varied between 0.88 and 0.93 in those patients with likely etiology (i.e., etiology is likely determined) of infection, compared to 0.63 and 0.71 for CRP, respectively, and nonsignificant AUCs for PCT. The diagnostic performance of B-HNL is superior to that of plasma CRP (P-CRP) and plasma PCT (P-PCT) in respiratory tract infections, and the activity specifically reflects bacterial challenge in the body. The rapid and accurate analysis of HNL by point-of-care technologies should be a major advancement in the diagnosis and management of respiratory infections with respect to antibiotic treatment.

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