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  • 151.
    Lindmark, Eva
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Leukocytes and Coronary Artery Disease: Experimental and Clinical Studies2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Tissue factor (TF) is the initiator of the coagulation cascade. Monocytes do not normally express TF, but can be induced to do so by certain stimuli. Aberrant TF expression is important in the thrombotic complications of bacterial sepsis, certain malignancies and coronary artery disease (CAD). In this thesis, regulation of monocyte TF by cytokines and by interactions with other vascular cells were studied, as well as the activation of blood cells, inflammation and coagulation in CAD patients and the association of the pro-inflammatory cytokine interleukin (IL)-6 with prognosis in unstable CAD.

    In a whole blood experimental system, the anti-inflammatory cytokine IL-10 was shown to suppress lipopolysaccharide-induced TF expression in monocytes, whereas IL-4 and IL-13 did not, contrary to previous in vitro findings. Activated platelets also induced monocyte TF in whole blood in a P-selectin-dependent manner, causing a rapid surface exposure of TF independent of mRNA formation. The differentiated monocytic cell line U-937 displayed different kinetics of platelet-stimulated TF induction.

    In co-culture with cytokine-activated human coronary artery endothelial cells, U-937 cells expressed TF, and also IL-6. The endothelial cells up-regulated their production of IL-10. Simvastatin, enalapril and dalteparin, all commonly used drugs in CAD treatment, suppressed TF induction but did not alter cytokine expression in co-cultures.

    In unstable CAD, there was an activation of both coagulation and inflammation compared to stable CAD that coincided with an increased activation of platelets and leukocytes. Women had different patterns of cellular activation than men, indicating differences in pathogenetic mechanisms.

    Plasma levels of IL-6 above 5 ng/L proved to be a strong, independent marker for increased risk of death in a 6-12 month perspective in patients with unstable CAD. This risk was significantly reduced by an early invasive strategy.

  • 152.
    Lindmark, Eva
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Diderholm, Erik
    Wallentin, Lars
    Siegbahn, Agneta
    Relationship between interleukin-6 and mortality in patients with unstable coronary artery disease: Effects of an early invasive or noninvasive strategy2001In: JAMA, Vol. 286, no 17, p. 2107-2113Article in journal (Refereed)
  • 153.
    Lindmark, Eva
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Siegbahn, Agneta
    Tissue factor regulation and cytokine expression in monocyte - endothelial cell co-cultures: Effects of a statin, an ACE-inhibitor and a low-molecular-weight heparinArticle in journal (Refereed)
  • 154.
    Lindmark, Eva
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wallentin, Lars
    Siegbahn, Agneta
    Blood cell activation, coagulation and inflammation in men and women with coronary artery disease2001In: Thromb Res, Vol. 103, p. 249-259Article in journal (Refereed)
  • 155.
    Lindqvist, Ulla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Westerberg, G
    Bergström, M
    Torsteindottir, I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Gustafson, S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Lööf, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. University Hospital, Uppsala, Sweden.
    Långström, Bengt
    [11C]Hyaluronan uptake with positron emission tomography in liver disease2000In: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 30, no 7, p. 600-607Article in journal (Other academic)
    Abstract [en]

    Background

    A hyaluronan-loading test has been developed for assessment of hyaluronan kinetics and applied in patients with liver and joint diseases. This test describes the metabolic process of hyaluronan but cannot define the specific contribution of different organs. A method for labelling of hyaluronan with the short-lived positron-emitting radionuclide 11C has been published and in this study applied in healthy subjects and liver diseases.

    Materials and methods

    Positron emission tomography (PET) was used for the regional assessment and quantification of [11C]hyaluronan uptake in three healthy subjects, four patients with alcoholic liver cirrhosis, one with alcoholic hepatitis and one with liver steatosis. After intravenous administration of 60 MBq of 11C-labelled hyaluronan, a 55-min PET scan was performed over the liver and plasma radioactivity was analysed. Rate constants describing the transport of the [11C]hyaluronan tracer from plasma to the liver were calculated.

    Results

    High uptake was observed in the liver combined with a rapid elimination of tracer from plasma. The liver uptake rate (k1) was significantly lower in patients (0.018 min−1) than in healthy subjects (0.043 min−1, P = 0.002). The rate constants seem to be related to the severity of the disease as defined by the Child–Pugh score.

    Conclusions

    The study suggests that PET with [11C]hyaluronan could be an accurate method by which to assess liver dysfunction, in conditions where endothelial cell function is impaired. The possibility of quantification over extended portions of the body also opens up possibilities to explore regional differences in liver function and to assess other elimination routes of hyaluronan.

  • 156.
    Lipcsey, Miklos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Einarsson, Roland
    Abdul Qadhr, Goran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The brain is a source of S100B increase during endotoxemia in the pig2010In: Anesthesia and Analgesia, ISSN 0003-2999, E-ISSN 1526-7598, Vol. 110, no 1, p. 174-180Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Cerebral dysfunction frequently complicates septic shock. A marker of cerebral dysfunction could be of significant value in managing sedated septic patients. Plasma S100 (S100B) proteins increase in sepsis. S100B is present not only in the brain but also in other tissues. The source of this protein has not been investigated in sepsis. Our aim in this study was to determine whether the brain is an important source of S100B in an experimental sepsis model.

    METHODS:

    Twenty-seven pigs were anesthetized and randomized to either infusion of endotoxin at the rate of 1 µg · kg-1 · h-1 (n = 19) or saline (n = 8). Catheters were inserted into a cervical artery and the superior sagittal sinus. Blood samples were collected from both sites and physiologic data were registered before the start of the endotoxin infusion and hourly during the experiment. After 6 h, the animals were killed and brain tissue samples were taken from the left hemisphere. S100B in plasma was measured by enzyme-linked immunosorbent assay. Brain tissue samples were stained with biotinylated S100B antibodies.

    RESULTS:

    In the endotoxemic animals, the arterial S100B concentration increased to 442 ± 33 and 421 ± 24 ng/L at 1 and 2 h, respectively, vs 306 ± 28 and 261 ± 25 ng/L in controls (P = 0.018 and 0.00053, respectively). Mean superior sagittal sinus S100B concentrations were higher than mean arterial concentrations at all time points in the endotoxemic animals; however, significance was only reached at 2 h (P = 0.033). The focal glial S100B expression was more intense in the endotoxemic pigs than in controls (P = 0.0047).

    CONCLUSIONS:

    Our results support the hypothesis that the brain is an important source of S100B in endotoxemia even though there may be other sources. These findings make S100B a candidate as a marker of cerebral dysfunction in septic shock.

  • 157.
    Lipcsey, Miklós
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Carlsson, Markus
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Algotsson, Lars
    Eriksson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Lukinius, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Effect of a single dose of tobramycin on systemic inflammatory response-induced acute kidney injury in a 6-hour porcine model2009In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 10, p. 2782-2790Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To evaluate whether the addition of tobramycin further compromises renal function in inflammatory response-induced acute kidney injury. Effective antibiotic treatment in septic shock is crucial for the outcome. The combination of aminoglycosides with different beta-lactam antibiotics offers a broad antimicrobial coverage, rapid bacterial killing, synergistic effects, and low antibiotic-induced endotoxin release. However, aminoglycosides have nephrotoxic effects that may aggravate sepsis-induced acute kidney injury.

    DESIGN:

    Prospective, randomized, placebo-controlled experimental study.

    SETTING:

    University research unit.

    SUBJECTS:

    Twenty-four healthy pigs.

    INTERVENTIONS:

    The animals were anesthetized and randomized to four groups. Groups I (n = 8) and II (n = 8) received endotoxin infusion for 6 hrs, whereas groups III (n = 4) and IV (n = 4) received saline. Groups I and III received 7 mg/kg of tobramycin 20 mins after the initiation of the protocol, whereas groups II and IV received saline.

    MEASUREMENTS AND MAIN RESULTS:

    The renal elimination rate of a bolus dose of cefuroxime was chosen as the primary end point. Renal function was also evaluated by urine output, creatinine clearance, plasma cystatin C, plasma urea, and urine NAG (N-acetyl-beta-D-glucoaminidase). After 3 hrs, there were significantly lower cefuroxime elimination rates in the two endotoxin groups than in the nonendotoxin groups. No difference in cefuroxime elimination rates between groups I and II could be detected at any time point. Similarly, there were changes indicating acute kidney injury in urine output, creatinine clearance, and plasma cystatin C in the endotoxin groups with no differences between groups I and II. Plasma urea and urine NAG did not differ between any of the groups.

    CONCLUSIONS:

    The result of this study does not lend any support to the hypothesis that a single dose of tobramycin enhances the risk of acute renal failure in cases with systemic inflammatory response-induced acute kidney injury.

  • 158.
    Lipcsey, Miklós
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Furebring, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Significant differences when using creatinine, modification of diet in renal disease, or cystatin C for estimating glomerular filtration rate in ICU patients2011In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 116, no 1, p. 39-46Article in journal (Refereed)
    Abstract [en]

    Background. Renal dysfunction is associated with increased morbidity and mortality in intensive care patients. In most cases the glomerular filtration rate (GFR) is estimated based on serum creatinine and the Modification of Diet in Renal Disease (MDRD) formula, but cystatin C-estimated GFR is being used increasingly. The aim of this study was to compare creatinine and MDRD and cystatin C-estimated GFR in intensive care patients. Methods. Retrospective observational study was performed, on patients treated within the general intensive care unit (ICU) during 2004-2006, in a Swedish university hospital. Results. GFR markers are frequently ordered in the ICU; 92% of the patient test results had cystatin C-estimated GFR (eGFR(cystatinC)) ≤ 80 mL/min/1.73 m(2), 75% had eGFR ≤ 50 mL/min/1.73 m(2), and 30% had eGFR ≤ 20 mL/min/1.73 m(2). In contrast, only 46% of the patients had reduced renal function assessed by plasma creatinine alone, and only 47% had eGFR(MDRD) ≤ 80 mL/min/1.73 m(2). The mean difference between eGFR(MDRD) and eGFR(cystatinC) was 39 mL/min/1.73 m(2) for eGFR(cystatinC) values ≤ 60 mL/min/1.73 m(2). Conclusions. GFR is commonly assessed in the ICU. Cystatin C-estimated GFR yields markedly lower GFR results than plasma creatinine and eGFR(MDRD). Many pharmaceuticals are eliminated by the kidney, and their dosage is adjusted for kidney function. Thus, the differences in GFR estimates by the methods used indicate that the GFR method used in the intensive care unit may influence the treatment.

  • 159.
    Lipcsey, Miklós
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Eriksson, Mats B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Inflammatory, coagulatory and circulatory responses to logarithmic increases in the endotoxin dose in the anaesthetised pig2006In: Journal of Endotoxin Research, ISSN 0968-0519, E-ISSN 1743-2839, Vol. 12, no 2, p. 99-112Article in journal (Other academic)
    Abstract [en]

    Although porcine intravenous endotoxin shock models are widely employed in experimental sepsis, endotoxin dose-effect studies are scarce. Our primary aim was to establish the dose response to increasing endotoxin doses in inflammatory, coagulatory and haemodynamic effect variables, as well as to determine the optimal time point for assessment in a pig model. A secondary aim was to study pathophysiological covariations between the different responses. Twenty anaesthetised piglets received endotoxin intravenously in doses of 0.063 (n = 3), 0.25 (n = 3), 1.0 (n = 3), 4.0 (n = 3), 8 (n = 3) and 16 microg/kg/h (n = 2). In addition, non-endotoxin piglets constituted a control group (n = 3). Physiological variables were registered and blood samples analysed for TNF-alpha, IL-6, leukocyte, platelet and haemoglobin concentrations hourly for 6 h. Increases in the endotoxin dose induced significant log-log cytokine responses as well as log-linear leukocyte and platelet responses. Significant log-linear responses were observed for circulatory parameters, plasma leakage, hypoperfusion and pulmonary compliance. Significant covariations in the responses were noted. In conclusion, there were log-log or log-linear responses to endotoxin suggesting a greater effect of a given dose at lower pre-existing endotoxin concentrations and lower doses of < or = 1 microg/kg/h may be of advantage in experiments designed to study potential anti-endotoxin effects of experimental drugs or measures.

  • 160.
    Lipcsey, Miklós
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Olovsson, Matts
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Eriksson, Mats B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Early endotoxin-mediated haemostatic and inflammatory responses in the clopidogrel-treated pig2005In: Platelets, ISSN 0953-7104, E-ISSN 1369-1635, Vol. 16, no 7, p. 408-414Article in journal (Refereed)
    Abstract [en]

    We have previously shown that the thrombin inhibiting agent melagatran markedly prolongs aPTT and counteracts creatinine increase in endotoxemic pigs. Against this background the effects of the platelet-inhibiting agent, clopidogrel on basic haemostatic, inflammatory and physiological variables were evaluated during porcine endotoxemia. Clopidogrel (10 mg/kg) or saline was randomly injected i.v. 30 min before start of a 6-h continuous infusion of endotoxin in 12 anaesthetised pigs. Another three pigs were given clopidogrel but not endotoxin. Clopidogrel did not affect physiological variables, formation of activated platelet microparticles, PK, aPTT, platelet count, plasma fibrinogen, TNF-alpha, or IL-6 during porcine endotoxemia. Although renal function, as evaluated by creatinine clearance (CLcr) deteriorated significantly (P = 0.01) in the saline-endotoxin, but not in the clopidogrel-endotoxin group, there was no significant difference between the saline-endotoxin and the clopidogrel-endotoxin groups. Renal biopsies were marked with a FITC-labelled chicken anti-fibrinogen antibody detecting fibrinogen and platelet bound fibrinogen, as a marker of porcine platelet activation, and examined by light microscopy. Evaluation of these immunohistochemical slides did not indicate that clopidogrel, significantly reduced the amount of intrarenal fibrin or fibrinogen depositions. Besides a trend to preserve renal function, clopidogrel did not affect haemodynamics or the coagulatory and inflammatory responses in porcine endotoxemia.

  • 161.
    Lipcsey, Miklós
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Söderberg, Ewa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Aström, Mikael
    Eriksson, Mats B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    F2-isoprostane, inflammation, cardiac function and oxygenation in the endotoxaemic pig2008In: Prostaglandins, Leukotrienes and Essential Fatty Acids, ISSN 0952-3278, E-ISSN 1532-2823, Vol. 78, no 3, p. 209-217Article in journal (Refereed)
    Abstract [en]

    Prostaglandins are profoundly involved in endotoxaemic shock. Twenty pigs were given endotoxin at various doses (0.063-16 microg kg(-1) h(-1)). Three non-endotoxaemic pigs served as controls. Two eicosanoids were measured in plasma (8-iso-PGF(2alpha), a free radical-mediated lipid peroxidation product, and 15-keto-dihydro-PGF(2alpha) a major metabolite of COX activity) and evaluated against the pathophysiological responses that occur during endotoxaemic shock. Endotoxin mediates an increase in both 8-iso-PGF(2alpha) and 15-keto-dihydro-PGF(2alpha). An increase in the endotoxin dose induced significant log-linear responses in 8-iso-PGF(2alpha) and 15-keto-dihydro-PGF(2alpha). Oxidative injury correlated to the TNF-alpha, IL-6, reductions in cardiac performance and to oxygen delivery and utilisation. COX-mediated inflammatory responses correlated to TNF-alpha, IL-6 and to reductions in arterial oxygen tension. Thus, oxidative injury and COX-mediated inflammation play a central role in the manifestation of endotoxaemic shock. Furthermore, formation of these eicosanoids on endotoxin-mediated alterations in pulmonary hypertension, oxygen delivery and oxygen utilisation seems to be independent of the administered endotoxin dose.

  • 162. Ljungvall, I.
    et al.
    Höglund, K.
    Tidholm, A.
    Olsen, L. H.
    Borgarelli, M.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Haggström, J.
    Cardiac Troponin I Is Associated with Severity of Myxomatous Mitral Valve Disease, Age, and C-Reactive Protein in Dogs2010In: Journal of Veterinary Internal Medicine, ISSN 0891-6640, E-ISSN 1939-1676, Vol. 24, no 1, p. 153-159Article in journal (Refereed)
    Abstract [en]

    Background Concentrations of cardiac troponin I (cTnI) and C-reactive protein (CRP) might be associated with cardiac remodeling in dogs with myxomatous mitral valve disease (MMVD). Age- and sex-dependent variations in cTnI concentration have been described. Objective To investigate whether plasma concentrations of cTnI and CRP are associated with severity of MMVD, and investigate potential associations of dog characteristics on cTnI and CRP concentrations. Animals Eighty-one client-owned dogs with MMVD of varying severity. Methods Dogs were prospectively recruited for the study. Dogs were classified according to severity of MMVD. Plasma cTnI was analyzed by a high sensitivity cTnI assay with a lower limit of detection of 0.001 ng/mL, and plasma CRP was analyzed by a canine-specific CRP ELISA. Results Higher cTnI concentrations were detected in dogs with moderate (0.014 [interquartile range 0.008-0.029] ng/mL, P = .0011) and severe (0.043 [0.031-0.087] ng/mL, P < .0001) MMVD, compared with healthy dogs (0.001 [0.001-0.004] ng/mL). Dogs with severe MMVD also had higher cTnI concentrations than dogs with mild (0.003 [0.001-0.024] ng/mL, P < .0001) and moderate (P = .0019) MMVD. There were significant associations of age, CRP, heart rate, and left ventricular end-diastolic diameter, on cTnI concentration C-reactive protein did not differ among severity groups, but was significantly associated with cTnI, breed, and systolic blood pressure on CRP concentration. Conclusions and Clinical Importance Analysis of cTnI concentration has potential to increase knowledge of overall cardiac remodeling in dogs with MMVD. However, effect of age on cTnI needs consideration when assessing cTnI.

  • 163.
    Ludvigsen, Eva
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Janson, Eva T.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Altered Expression of Somatostatin Receptors in Pancreatic Islets from NOD Mice Cultured at Different Glucose Concentrations In Vitro and in Islets Transplanted to Diabetic NOD Mice In Vivo2011In: Experimental Diabetes Research, ISSN 1687-5214, E-ISSN 1687-5303, Vol. 2011, p. 623472-Article in journal (Refereed)
    Abstract [en]

    Somatostatin acts via five receptors (sst1-5). We investigated if the changes in pancreatic islet sst expression in diabetic NOD mice compared to normoglycemic mice are a consequence of hyperglycemia or the ongoing immune reaction in the pancreas. Pancreatic islets were isolated from NOD mice precultured for 5 days and further cultured for 3 days at high or low glucose before examined. Islets were also isolated from NOD mice and transplanted to normal or diabetic mice in a number not sufficient to cure hyperglycemia. After three days, the transplants were removed and stained for sst1-5 and islet hormones. Overall, changes in sst islet cell expression were more common in islets cultured in high glucose concentration in vitro as compared to the islet transplantation in vivo to diabetic mice. The beta and PP cells exhibited more frequent changes in sst expression, while the alpha and delta cells were relatively unaffected by the high glucose condition. Our findings suggest that the glucose level may alter sst expressed in islets cells; however, immune mechanisms may counteract such changes in islet sst expression.

  • 164.
    Marklund, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Sihver, Sven
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Hovda, David
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Watanabe, Yasuyoshi
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Bergström, Mats
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Increased Cerebral Uptake of [18F]Fluoro-Deoxyglucose but not [1-14C]Glucose Early following Traumatic Brain Injury in Rats2009In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 26, no 8, p. 1281-1293Article in journal (Refereed)
    Abstract [en]

    Following experimental and clinical traumatic brain injury (TBI), the local cerebral metabolic rate of glucose (lCMRGlc) is commonly estimated using the 2-[18F]fluoro-2-deoxy-D-glucose (FDG) method. The adequate estimation of lCMRGlc using FDG requires a correction factor, the lumped constant (LC), to convert FDG net uptake into lCMRGlc. The LC, and thus lCMRGlc calculations, requires a "steady state" that may be disrupted following TBI. In the present report, we hypothesized that [1-14C]glucose uptake would accurately reflect glucose dynamics early post-injury and was compared to the regional uptake of FDG in 44 rats subjected to moderate (2.4-2.6 atm) lateral fluid percussion brain injury (FPI) or sham injury. Cortical energy state and adenylate (ATP, ADP, AMP) levels were also measured. Early (7-42 min) after FPI, FDG uptake was increased in the ipsilateral cortex and hippocampus (p<0.05). In contrast, no change in [1-14C]glucose uptake (7 and 17 min) or cortical adenylate content (42 min post-injury) was observed. At 12 hours following FPI, the ipsilateral FDG and [1-14C]glucose uptake was decreased in the cortex and hippocampus and the ipsilateral cortical ATP concentration was decreased in comparison to sham-injured controls (p<0.05). Under the present experimental conditions, the rate of cerebral uptake of FDG and of [1-14C]glucose differs, and indicate that following TBI, regional changes in the LC may occur in the immediate, but not in the late, post-injury phase. These results should be considered when interpreting results obtained using FDG for the estimation of lCMRGlc early following experimental TBI.

  • 165. Martensson, Johan
    et al.
    Bell, Max
    Oldner, Anders
    Xu, Shengyuan
    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.
    Martling, Claes-Roland
    Neutrophil gelatinase-associated lipocalin in adult septic patients with and without acute kidney injury2010In: Intensive Care Medicine, ISSN 0342-4642, E-ISSN 1432-1238, Vol. 36, no 8, p. 1333-1340Article in journal (Refereed)
    Abstract [en]

    To study the impact of inflammation/sepsis on the concentrations of neutrophil gelatinase-associated lipocalin (NGAL) in plasma and urine in adult intensive care unit (ICU) patients and to estimate the predictive properties of NGAL in plasma and urine for early detection of acute kidney injury (AKI) in patients with septic shock. Sixty-five patients admitted to the general ICU at the Karolinska University Hospital Solna, Sweden, with normal plasma creatinine were assessed for eligibility. Twenty-seven patients with systemic inflammatory response syndrome (SIRS), severe sepsis, or septic shock without AKI and 18 patients with septic shock and concomitant AKI were included in the final analysis. Plasma and urine were analyzed twice daily for plasma NGAL (pNGAL), C-reactive protein (CRP), procalcitonin, myeloperoxidase, plasma cystatin C, plasma creatinine, urine NGAL (uNGAL), urine cystatin C, and urine alpha 1-microglobulin. Of the 45 patients, 40 had elevated peak levels of pNGAL. Peak levels of pNGAL were not significantly different between septic shock patients with and without AKI. Peak levels of uNGAL were below the upper reference limit in all but four patients without AKI. uNGAL was a good predictor (area under ROC 0.86) whereas pNGAL was a poor predictor (area under ROC 0.67) for AKI within the next 12 h in patients with septic shock. pNGAL is raised in patients with SIRS, severe sepsis, and septic shock and should be used with caution as a marker of AKI in ICU patients with septic shock. uNGAL is more useful in predicting AKI as the levels are not elevated in septic patients without AKI.

  • 166.
    Matsson, H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Davey, Eva J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Fröjmark, Anne-Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Miyake, K.
    Utsugisawa, T.
    Flygare, J.
    Zahou, E.
    Byman, I.
    Landin, B.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Karlsson, S.
    Dahl, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Erythropoiesis in the Rps19 disrupted mouse: Analysis of erythropoietin response and biochemical markers for Diamond-Blackfan anemia2006In: Blood Cells, Molecules & Diseases, ISSN 1079-9796, E-ISSN 1096-0961, Vol. 36, no 2, p. 259-64Article in journal (Refereed)
    Abstract [en]

    The human ribosomal protein S19 gene (RPS19) is mutated in approximately 20% of patients with Diamond-Blackfan anemia (DBA), a congenital disease with a specific defect in erythropoiesis. The clinical expression of DBA is highly variable, and subclinical phenotypes may be revealed by elevated erythrocyte deaminase (eADA) activity only. In mice, complete loss of Rps19 results in early embryonic lethality whereas Rps19+/- mice are viable and without major abnormalities including the hematopoietic system. We have performed a detailed analysis of the Rps19+/- mice. We estimated the Rps19 levels in hematopoietic tissues and we analyzed erythrocyte deaminase activity and globin isoforms which are used as markers for DBA. The effect of a disrupted Rps19 allele on a different genetic background was investigated as well as the response to erythropoietin (EPO). From our results, we argue that the loss of one Rps19 allele in mice is fully compensated for at the transcriptional level with preservation of erythropoiesis.

  • 167. Mattsson, Niklas
    et al.
    Johansson, Per
    Hansson, Oskar
    Wallin, Anders
    Johansson, Jan-Ove
    Andreasson, Ulf
    Andersen, Oluf
    Haghighi, Sara
    Olsson, Maria
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Svensson, Johan
    Blennow, Kaj
    Zetterberg, Henrik
    Converging Pathways of Chromogranin and Amyloid Metabolism in the Brain2010In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 20, no 4, p. 1039-1049Article in journal (Refereed)
    Abstract [en]

    Much is unknown regarding the regulation of Alzheimer-related amyloid-beta protein precursor (AbetaPP)-processing in the human central nervous system. It has been hypothesized that amyloidogenic AbetaPP-processing preferentially occurs in the regulated secretory pathway of neurons. To test this hypothesis we looked for correlations of AbetaPP-derived molecules in cerebrospinal fluid (CSF) with chromogranin (Cg) derived peptides, representing the regulated secretion. Patients with Alzheimer's disease (AD, N=32), multiple sclerosis (MS, N=50), and healthy controls (N= 70) were enrolled. CSF was analyzed for the amyloid peptides Abeta{1-42}, Abeta{x-42}, Abeta{x-40}, Abeta{x-38}, alpha-cleaved soluble AbetaPP (sAbetaPPalpha), beta-cleaved soluble AbetaPP (sAbetaPPbeta), and peptides derived from CgB and SgII (Secretogranin-II, CgC). We investigated CSF levels of the protease BACE1, which processes AbetaPP into Abeta, in relation to Cg-levels. Finally, we measured Cg levels in cell media from untreated and BACE1-inhibited SH-SY5Y human neuroblastoma cells. CSF Cg levels correlated to sAbetaPP and Abeta peptides in AD, MS, and controls, and to CSF BACE1. Cell medium from BACE1-inhibited cells had decreased CgB levels. These results suggest that a large part of AbetaPP in the human central nervous system is processed in the regulated secretory pathway of neurons.

  • 168.
    Mindemark, Mirja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The Use of Laboratory Analyses in Sweden: Quality and Cost-Effectiveness in Test Utilization2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Laboratory analyses, essential in screening, diagnosis, treatment, and monitoring of disease, are indispensable in health care, but appropriate utilization is intricate. The overall aim of this thesis was to study the use of laboratory tests in Sweden with the objective to evaluate and optimize test utilization.

    Considerable inter-county variations in test utilization in primary health care in Sweden were found; variations likely influenced by local traditions and habits of test ordering leading to over- as well as underutilization. Optimized test utilization was demonstrated to convey improved quality and substantial cost savings.

    It was further established that continuing medical education is a suitable means of optimizing test utilization, and consequently enhancing quality and cost-efficiency, as such education was demonstrated to achieve long-lasting improvements in the test ordering habits of primary health care physicians.

    Laboratory tests are closely associated with other, greater, health care costs, but their indirect effects on other areas of medicine are rarely evaluated or measured in monetary terms. In an illustrative example of the effects that optimal test utilization may have on associated health care costs it was demonstrated that F-calprotectin, a fecal marker of intestinal inflammation, has the potential to substantially reduce the number of invasive investigations necessary in, and the costs associated with, the diagnosis of Inflammatory Bowel Disease.

    Information on trends in test utilization is essential to optimal financial management of laboratories. A longitudinal evaluation revealed that test utilization had increased by 70% in 6 years, and even though the selection of tests more than doubled, a very small number of tests represented a stable, and disproportionally large, share of the total number of tests ordered. The study defines trends and thus has potential predictive values.

    In summary, appropriate utilization of laboratory analyses has both clinical and economical benefits on all levels of health care.

  • 169.
    Mindemark, Mirja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Longitudinal trends in laboratory test utilization at a large tertiary care university hospital in Sweden2011In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 116, no 1, p. 34-38Article in journal (Refereed)
    Abstract [en]

    Background. The aim of the study was to describe and evaluate longitudinal trends in laboratory test utilization over a 7-year period from 2002 to 2008. Method. Retrospective study using test request data from the Clinical Chemistry and Pharmacology Laboratory at Akademiska Sjukhuset, a large tertiary care university hospital in Sweden. Changes in test utilization, charges, and expenditures during the study period were used as main outcome measures. Results. Laboratory test utilization increased by over 70%, with a mean annual increase of 9.3% during the study period. After adjustment for inflation, the laboratory expenditures increased by 20.2% during the study period but represented only approximately 2.0% of the hospital's total expenditure in 2008. The test menu comprised 663 tests in 2008, an increase by 146% from 2002. The mean inflation-adjusted unit price charged per test increased from €34.9 to €37.5 during the study period. The top 10, 20, and 30 tests accounted for, on average, 46.9%, 66.9%, and 75.5% of the total test volume during the study period, and 47.8%, 66.4%, and 75.7% of the total test volume in 2008. In 2008, 10 analyses, i.e. 1.5% of the number of tests on the menu, accounted for almost half the number of generated test results. Conclusions. The total number of generated test results increased by over 70% in less than a decade. Even so, the laboratory's share of the hospital's total expenditure remained low and virtually unchanged. A very small number of tests accounted for a disproportionately large share of the total number of generated test results.

     

  • 170.
    Mindemark, Mirja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Long-term effects of an education programme on the optimal use of clinical chemistry testing in primary health care2009In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 69, no 4, p. 481-486Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to investigate whether continuing education on the optimal use of clinical chemistry testing in primary health care has had any long‐term effects on the test‐ordering behaviour of the participating physicians. Methods: The effects were monitored using 12 laboratory test ratios. Twenty‐three general practitioners at 16 primary health‐care centres in the county of Uppsala, Sweden, participated. A sign test was used to evaluate how individual physicians' test‐ordering patterns have changed during the 8 years since implementation of the educational programme. Maintained or improved ratios were interpreted as a sustained effect on the primary health‐care physician's test‐ordering habits. Results: Eleven out of 12 of the investigated ratios were the same or improved since the time of the short‐term follow‐up 6 months after the education. Conclusion: A short continuation course on optimal use of clinical chemistry assays can achieve permanent changes in the test‐ordering patterns of primary health‐care physicians. These findings highlight education as one possible means towards achieving cost‐efficiency and quality in test‐ordering.

  • 171.
    Mindemark, Mirja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ruling out IBD: Estimation of the possible economic effects of pre-endoscopic screening with F-calprotectin2012In: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 45, no 7-8, p. 552-555Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To estimate the possible economic effects of a sequential testing strategy with F-calprotectin to minimize colonoscopies.

    DESIGN AND METHODS: Retrospective study in a third party payer perspective. The costs were calculated from initial F-calprotectin test results of 3639 patients. Two cut-off levels were used: 50μg/g feces and 100μg/g feces, respectively. The cost-effectiveness of the testing strategy was estimated through the short-term cost avoidance and reduction in demand for colonoscopies.

    RESULTS: The estimated demand for colonoscopies was reduced by 50% with the 50μg/g cut-off and 67% with the 100μg/g cut-off. This corresponded to a cost avoidance of approximately €1.57million and €2.13million, respectively.

    CONCLUSIONS: The use of F-calprotectin as a screening test substantially could reduce the number of invasive measurements necessary in the diagnostic work-up of patients with suspected IBD, as well as the associated costs.

  • 172.
    Mindemark, Mirja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wernroth, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Costly regional variations in primary health care test utilization in Sweden2010In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 70, no 3, p. 164-170Article in journal (Refereed)
    Abstract [en]

    Objective: Laboratory tests are used increasingly in primary health care and they are thus associated with rapidly growing costs. Variations in clinical practice, an important determinant of expenditure for laboratory tests, could further increase the financial burden. The study's threefold objective was to determine the presence and extent of regional variations in test ordering between eight counties in Sweden, to investigate the influence on these variations by factors earlier described in the literature as explanatory, and to calculate the achievable savings that could be realized through optimized test ordering. Design: A retrospective study using test request data. Setting: A total of 223 primary health care centers in eight counties in Sweden. Main outcome measures: Thirteen ratios of commonly used laboratory tests, demographic data and the number of ordered tests per 1000 inhabitants served as the basis of comparison. The total savings per 100,000 inhabitants that could be achieved through optimized test ordering was estimated. Results: Large variations were found between all studied counties for all investigated ratios. However, none of the demographic variables investigated seemed to be able to explain the full extent of the variations. The range of achievable yearly savings per 100,000 inhabitants was euro14,000-euro185,000. Conclusion: The inter-county variations in Sweden are large and the savings associated with optimized test utilization are substantial. The investigated factors previously described as explaining the variations in test ordering only seem to explain a small part of the variation, and the variations are likely influenced by regional habits and traditions.

  • 173.
    Mirza, Majd A I
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hansen, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Johansson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Tobias E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Relationship between circulating FGF23 and total body atherosclerosis in the community2009In: Nephrology, Dialysis and Transplantation, ISSN 0931-0509, E-ISSN 1460-2385, Vol. 24, no 10, p. 3125-3131Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Fibroblast growth factor-23 (FGF23) is a regulator of mineral metabolism and has been suggested to play a role in vascular calcification in chronic kidney disease (CKD). Data on the association between FGF23 and atherosclerosis, both in CKD and in the community, is limited. METHODS: The total body atherosclerosis score (AS) was determined by a magnetic resonance imaging-based angiography in 306 elderly men and women, representing a subsample of the community-based PIVUS cohort. Subjects were divided into three categories based on AS: AS = 0, low AS and high AS. Serum FGF23 was measured using a two-site monoclonal antibody ELISA. RESULTS: In continuous and multi-category regression models, higher FGF23 was associated with a significant increase in the odds of having a high AS (OR 1.43, CI 1.06-1.92 to OR 3.01, CI 1.52-5.99). This association was stronger in individuals with eGFR <60 mL/min/1.73 m(2) (n = 27), reaching a nearly 6-fold increase in the odds for a high AS in the upper FGF23 tertile (OR 5.64, CI 2.78-11.5). We found weaker support for a relationship between FGF23 and the presence of atherosclerosis as subjects in the highest FGF23 tertile had an increased risk for an AS > 0 in crude models (OR 1.93, CI 1.05-3.55), but this was not statistically significant in adjusted (OR 1.42, CI 0.74-1.72) models. CONCLUSIONS: We provide novel evidence supporting an association between serum FGF23 and total body atherosclerosis in the community. Additional studies are warranted to determine the prospective relationship between FGF23 and atherosclerosis, and whether FGF23 is a modifiable cardiovascular risk factor.

  • 174.
    Mutschler, Diana K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Gustafsson, Urban
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Larsson, Anders O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Eriksson, Mats B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Ropivacaine may have advantages compared to bupivacaine in porcine endotoxemic shock2006In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 111, no 2, p. 189-199Article in journal (Refereed)
    Abstract [en]

    Patients that undergo major abdominal surgery often receive epidural postoperative analgesia. Septic complications are frequently seen in this cohort. In a porcine model of endotoxemic shock, resembling human gram-negative septic shock, we evaluated the effects of two widely used local anaesthetics, bupivacaine and ropivacaine given intravenously. In the endotoxin-ropivacaine group mixed venous saturation and platelet count were higher as compared to endotoxemic controls. Mean arterial blood pressure and platelet count were higher in ropivacaine-endotoxin pigs than in bupivacaine-endotoxin ones. Bupivacaine augmented endotoxin-mediated decrease in left ventricular stroke work index. Ropivacaine displays pathophysiological advantages compared to bupivacaine in septic shock, which may be explained by improved tissue perfusion by ropivacaine.

  • 175.
    Myrelid, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Frisk, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Annerén, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Normal growth hormone secretion in young adults with Down syndromeManuscript (preprint) (Other academic)
  • 176.
    Mälarstig, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Soluble CD40L levels are regulated by the -3459 A>G polymorphism and predict myocardial infarction and the efficacy of antithrombotic treatment in non-ST elevation acute coronary syndrome2006In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 26, no 7, p. 1667-1673Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES - Current evidence suggests the CD40-CD40L pathway as a key process in the development, progression, and outcome of acute coronary syndrome (ACS). The aim was to investigate the prognostic importance of soluble (s) CD40L levels, single nucleotide polymorphisms (SNP) in the CD40LG gene, and the relation between sCD40L and SNPs in patients with acute coronary syndromes (ACS). METHODS AND RESULTS - Samples were obtained on admission from 2359 patients with non-ST elevation ACS randomized to an early invasive versus a conservative and to placebo controlled long-term dalteparin treatment in the FRISC-II study. The -3459 A>G SNP was identified as a novel regulator of sCD40L levels (P=0.001). In the placebo-treated group, sCD40L levels above median were associated with a 2.5-fold increased risk of myocardial infarction (MI) (P≤0.001) but not with raised mortality. In the dalteparin treated group, sCD40L showed no association with MI (P=0.75). Consequently, dalteparin treatment was effective in reducing the risk of MI only in patients with sCD40L levels above median. A combined assessment of troponin-T and sCD40L complemented the prognostic information on risk of MI. CONCLUSIONS - We identified a SNP in the CD40LG gene as a novel regulator of sCD40L plasma concentrations. Soluble CD40L levels above median reflect a prothrombotic state, which can be managed with the use of intense anti-thrombotic treatments.

  • 177.
    Mälarstig, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The intersubject variability of tissue factor mRNA production in human monocytes: relation with the toll-like receptor 42007In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 120, no 3, p. 407-413Article in journal (Refereed)
    Abstract [en]

    Objective: Tissue factor (TF) is known as the primary initiator of blood coagulation. Previous studies have suggested a considerable variation in the monocytic lipopolysaccharide (LPS) stimulated TF antigen levels and procoagulant activities between different individuals. Our aim with the present study was to investigate the replicability of LPS induced TF mRNA production in a series of standardised experiments with the purpose to identify putative factors influencing the TF high and low response. Results: A constant and reproducible production of LPS induced TF mRNA was identified in five high responders and three low responders (out of 42 individuals) and followed-up in three subsequent experiments performed over 2 years. The LPS induced TF mRNA production correlated with the corresponding expressions of interleukin-8, tumor necrosis factor-alfa and interleukin-1 beta, indicating a common pathway with the TF high and low response. A strong and significant correlation between the LPS induced TF and toll-like receptor 4 mRNA expressions was subsequently identified and replicated. Conclusions: We demonstrated a high and low responder phenomenon of LPS induced TF mRNA in human monocytes. The production of toll-like receptor 4 mRNA was significantly enhanced in TF high responders.

  • 178. Mälarstig, Anders
    et al.
    Sigurdsson, Snaevar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Eriksson, Per
    Paulsson-Berne, Gabrielle
    Hedin, Ulf
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hamsten, Anders
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Variants of the interferon regulatory factor 5 gene regulate expression of IRF5 mRNA in atherosclerotic tissue but are not associated with myocardial infarction2008In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 28, no 5, p. 975-982Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Signaling events after activation of toll-like receptors (TLRs) are important mechanisms promoting inflammation in the atherosclerotic plaque. INF regulatory factor 5 (IRF5) is one of the mediators of downstream effects of TLRs. Several single nucleotide polymorphisms (SNPs) in the IRF5 gene have been found to be associated with systemic lupus erythematosus.

    METHODS AND RESULTS:

    We examined IRF5 mRNA expression in carotid atherosclerotic tissue (n=99) and the case-control association between SNPs in the IRF5 gene with myocardial infarction (MI) (n=376+387) and unstable coronary artery disease (CAD) (n=3101+445). Among unstable CAD patients, association of IRF5 SNPs with recurrent coronary events (n=401) was also investigated. The IRF5 mRNA expression was increased in atherosclerotic tissue compared with control tissue (P<0.001). Significant associations with IRF5 expression was observed for 6 of 10 SNPs in the study. However, the IRF5 SNPs examined were neither associated with the risk of precocious MI, nor with unstable CAD or risk of recurrent cardiovascular events in unstable CAD patients.

    CONCLUSIONS:

    IRF5 mRNA is expressed in cells in atherosclerotic tissue and its expression is modified by SNPs in the IRF5 gene. Genetic variation at the IRF5 locus was, however, not associated with CAD or related phenotypes.

  • 179.
    Mälarstig, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Tenno, Taavo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Johnston, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Axelsson, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Genetic variations in the tissue factor gene are associated with clinical outcome in acute coronary syndrome and expression levels in human monocytes2005In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 25, no 12, p. 2667-2672Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    Tissue factor (TF) has, among other factors, a prominent role in acute coronary syndrome (ACS). Our goal was to investigate whether single nucleotide polymorphisms (SNP) in the TF gene (F3) are associated with plasma TF, risk, and outcome in patients with ACS. Moreover, we wanted to investigate the impact of associated TF SNPs on mRNA production in human monocytes.

    METHODS AND RESULTS:

    In 725 patients with ACS [Fragmin and Fast Revascularization during Instability in Coronary Artery Disease II (FRISC-II) study] and 376 controls, 13 SNPs were genotyped and plasma TF measured. Thereafter, the 5466 A>G and the -1812 C>T were genotyped among all of the FRISC-II participants (n=3143) and assessed concerning clinical outcome. Associated SNPs were genotyped in 92 healthy blood donors for comparison of TF activity and TF mRNA expression. None of the SNPs were associated with patient/control status. The 5466 A>G SNP was associated with cardiovascular death (odds ratio, 1.8; P=0.025). The CG haplotype by -1812 C>T and 5466 A>G was associated with a 3-fold increased risk of death (P<0.001). TF mRNA and basal TF activity was significantly lower among 5466 AG carriers, whereas the increase in monocyte TF activity on lipopolysaccharide stimulation was significantly stronger (P=0.04).

    CONCLUSIONS:

    The 5466 AG genotype is a novel predictor of cardiovascular death in ACS and may act through a high TF response.

  • 180.
    Mälarstig, Anders
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Genetic variation in the interleukin-6 gene in relation to risk and outcomes in acute coronary syndrome2007In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 119, no 4, p. 467-473Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The concept of inflammation in the acute coronary syndrome (ACS) is today well established. Interleukin-6 (IL-6), a pleiotropic, proinflammatory cytokine, seems to play an important role in the development and progression of ACS. AIM: The aim was to investigate whether IL6 polymorphisms are associated with patient/control status, outcome in patients with ACS and plasma concentrations of IL-6 and C-reactive protein (CRP). METHODS: Samples for citrated plasma and DNA were obtained on admission from 3027 patients with non-ST-elevation ACS in the FRISC-II study. A group of 447 healthy controls of similar age and gender as the patients was also recruited. Eight IL6 polymorphisms were genotyped and plasma concentrations of IL-6 and CRP measured in patients and controls. RESULTS: No associations between patient/control status, clinical outcome, ST-depression, troponin-T elevation or a history of myocardial infarction and IL6 polymorphisms were observed. In the full patient group, there was a trend towards association of the -572 G>C polymorphism with plasma concentrations of IL-6 (p=0.07). This association was statistically significant in patients with available high-sensitivity measurements of IL-6 (p=0.01). The -572 CG genotype was predictive for IL-6 levels above 5 ng/L in patients with a subsequent cardiovascular event, 2.3 (1.1-4.3) (adjusted odds ratio, 95% confidence interval). Comparison with data from HapMap showed that our panel of polymorphisms covered information on approximately 30 other IL6 variants. CONCLUSION: The -572 G>C and other polymorphisms in the study were not associated with outcome in ACS patients. However, the -572 CG genotype may contribute to a more distinct inflammatory response in patients with ACS.

  • 181.
    Ndjole, Annaby Moussa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Bodolea, Constantin
    Nilsen, Tom
    Gentian AS, Moss, Norway.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Flodin, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Determination of cerebrospinal fluid cystatin C on Architect ci82002010In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 360, no 1-2, p. 84-88Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Human cystatin C is a cysteine protease inhibitor produced by all nucleated cells in the body and the protein is present in all body fluids. The concentration in cerebrospinal fluid (CSF) is considerably higher than in plasma. Cystatin C levels seem to influence the development of Alzheimer disease (AD) and low levels in the brain are associated with an increased risk for AD. The aim of this study was to develop a high throughput assay for the quantification of cystatin C in CSF. METHODS: Antigen excess, imprecision, interference, linearity, recovery, sample stability and reference values were evaluated on Architect ci8200 (Abbott Laboratories, Abbott Park, IL, USA). RESULTS: The assay had an antigen-excess limit at 23 mg/L and was linear over the range of 0.84 to 8.33 mg/L. Results > 8.33 mg/L were automatically rerun in a higher dilution. Within-run coefficient of variation (CV) was 1.71, 1.10 and 0.79%, between day CV was 1.71, 0.39 and 1.45%, between-run CV was 0.58, 0.66 and 0.48%, and total CV was 2.49, 1.34 and 1.72% at cystatin C concentrations of 1.39, 3.17 and 6.28 mg/L, respectively. The recovery was 97-102%. No interference at a 7.5% deviation level was observed for 8.5 g/L of hemoglobin or 800 mg/L (1368 micromol/L) of bilirubin. Reference values for cystatin C in cerebrospinal fluid obtained with this method were 2.42-14.33 mg/L.

  • 182. Nielsen, Lars Peter
    et al.
    Peterson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Dahl, Ronald
    Serum eosinophil granule proteins predict asthma risk in allergic rhinitis2009In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 64, no 5, p. 733-737Article in journal (Refereed)
    Abstract [en]

    Background: Allergic rhinitis is a common disease, in which some patients will deteriorate or develop asthma. It is important to characterize these patients, thereby offering the possibility for prevention. This study evaluated eosinophil parameters as potential indicators of deteriorating allergic airway disease. Methods: The subjects of the study included all patients who suffered seasonal allergic rhinitis and had participated in a study 6 years earlier, in which blood eosinophils, serum eosinophil cationic protein (ECP) serum eosinophil peroxidase (EPO), nasal lavage ECP and nasal lavage EPO levels were measured. Patients in the present study were interviewed on occurrence of rhinitis symptoms during the last season, rhinitis outside season, asthma-like symptoms and asthma diagnosis, and were skin-prick tested for common aeroallergens. Eosinophil parameters from the study 6 years earlier were then tested for the ability to predict occurrence of new allergies, worsening of rhinitis and occurrence of asthma. Results: Forty-four patients participated in the study. In four patients seasonal rhinitis symptoms had deteriorated, 10 had experienced perennial rhinitis symptoms, 14 reported asthma-like symptoms and seven had been diagnosed with asthma. Thirteen had developed additional sensitization. Patients developing asthma-like symptoms compared with patients with no such symptoms had significantly higher serum ECP (16.7 lg/l vs 8.2 lg/l; P £ 0.01) and serum EPO (17.9 lg/l vs 8.8 lg/l; P £ 0.05). Results were similar, considering patients diagnosed with asthma. Blood eosinophils and nasal lavage parameters were not related to development of asthma and asthma-like symptoms. No eosinophil parameter was related to deterioration of rhinitis or additional sensitization. Conclusion: Serum ECP and EPO in patients with seasonal rhinitis demonstrated a high predictive ability for later development of asthma.

  • 183.
    Nilsson, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Characterization of IgY for Oral Immunotherapy and Prevention of Pseudomonas aeruginosa Infections in Cystic Fibrosis Patients2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Chicken antibodies, commonly referred to as IgY, have several properties that make them suitable for oral treatment of infections and there is essentially no risk for development of resistance. The overall aims of this thesis were to investigate Anti-Pseudomonas IgY as prophylaxis against infections with Pseudomonas aeruginosa for cystic fibrosis (CF) patients and to characterize the antibody treatment.

    We found that Anti-Pseudomonas IgY has affinity for P. aeruginosa flagellin, the major component of the flagellum. This is important since the flagellum is required for host invasion and establishment of infection. Flagellin induces inflammation.

    The main cause of morbidity and mortality among CF patients is chronic colonization of the airways with P. aeruginosa. We have studied prophylactic treatment of 17 Swedish CF patients with Anti-Pseudomonas IgY for up to twelve years. The results were compared with a control group of 23 Danish CF patients. Patients treated with IgY had 2.3 P. aeruginosa positive cultures/100 treatment months vs. 7.0 cultures/100 treatment months in the control group (p=0.028), and the time from inclusion to the first recolonization was significantly longer in the IgY-treated group (p=0.012). Lung function was preserved and patients treated with IgY had good nutritional status at the end of the study. Furthermore, other bacteria have not emerged instead of P. aeruginosa.

    Freeze-drying of IgY and the content of IgY preparations for oral use was investigated. Besides IgY, 26 egg yolk proteins were identified. Some of the proteins are known to have antimicrobial and immunostimulatory effects, and could have a positive additive effect to IgY treatment. Cholesterol levels were low.

    Conclusion: Anti-Pseudomonas IgY is a promising complement in the prevention of Pseudomonas aeruginosa infections in CF patients, partly explained by the fact that IgY binds to flagellin.

  • 184.
    Nilsson, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Amini, Ahmad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Wretlind, Bengt
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Pseudomonas aeruginosa infections are prevented in cystic fibrosis patients by avian antibodies binding Pseudomonas aeruginosa flagellin: Pseudomonas aeruginosa infections are prevented in cystic fibrosis patients by avian antibodies binding Pseudomonas aeruginosa flagellin2007In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 856, no 1-2, p. 75-80Article in journal (Refereed)
    Abstract [en]

    Pseudomonas aeruginosa (PA) is the main cause of morbidity and mortality in cystic fibrosis (CF) patients. CF patients with chronic PA infections have a more rapid deterioration of their lung function and the bacteria become impossible to eradicate from the lungs. Antibiotic resistance among PA strains in CF patients is steadily increasing. Specific chicken (IgY) antibodies against PA have been shown to have potential to prevent PA infections in CF. Anti-Pseudomonas IgY reduces PA adhesion to epithelia, but the mechanism has not been fully elucidated. To gain further insight into the prophylactic effect of these antibodies, the immunoreactivity was investigated by 2D electrophoresis of PA strains, immunoblotting and MALDI-TOF-MS. To confirm the identity of the proteins, the tryptic peptides were analyzed by MALDI-TOF-MS to accurately measure their monoisotopic masses as well as determine their amino acid sequences. In order to facilitate fragmentation of the peptides they were N-terminally or C-terminally labeled. Several strains were investigated and anti-Pseudomonas IgY was immunoreactive against all of these strains, which strengthens its potential as a prophylactic treatment against PA. Flagellin was identified as the major antigen. Flagellin is the main protein of the flagella and is crucial for establishing infections in hosts as well as being involved in PA chemotaxis, motility, adhesion and inflammation. Furthermore, secreted flagellin elicits an inflammatory response. In conclusion, anti-Pseudomonas IgY binds flagellin, which may prevent PA infections in CF patients by hindering host invasion.

  • 185.
    Nilsson, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Kollberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Johannesson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wejåker, Per-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Carlander, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    More than 10 years' continuous oral treatment with specific immunoglobulin Y for the prevention of Pseudomonas aeruginosa infections: a case report2007In: Journal of Medicinal Food, ISSN 1096-620X, E-ISSN 1557-7600, Vol. 10, no 2, p. 375-378Article in journal (Refereed)
    Abstract [en]

    Immunotherapy with specific antibodies is an alternative to antibiotics for the prevention of infections in humans and animals. We have used orally administered immunoglobulin Y (IgY) preparations, purified from eggs of hens immunized with Pseudomonas aeruginosa bacteria, to prevent pulmonary P. aeruginosa infections in a group of patients with cystic fibrosis (CF). Respiratory infections are major problems for CF patients because of the thick mucus in the airways, and chronic P. aeruginosa lung infections occur in virtually all CF patients and cause morbidity and mortality. The IgY-treated group had only 2.5 P. aeruginosa-positive sputum cultures per 100 months, and none of the IgY-treated patients became chronically colonized with P. aeruginosa. In the control group, 13.7 of the cultures per 100 months were positive for P. aeruginosa, and 24% of patients became chronically colonized with P. aeruginosa. The first enrolled patient in this study has now been treated continuously for more than 10 years. During the first 8 years she only had four P. aeruginosa-positive cultures. After 8 years she became chronically infected, but still after 10 years the bacteria have not turned mucoid. No negative side effects of IgY treatment have been noted during these 10 years. To our knowledge this is the longest treatment with specific yolk antibodies for therapeutic purposes.

  • 186.
    Nilsson, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Stability of chicken IgY antibodies freeze-dried in the presence of lactose, sucrose and trehalose2007In: Journal of Poultry Science, ISSN 1349-0486, Vol. 44, no 1, p. 58-62Article in journal (Refereed)
    Abstract [en]

    Freeze-drying is used as a method to stabilize proteins. The process itself may however cause protein unfolding and denaturation, but the risk is reduced if a stabilizing agent is added prior to freeze-drying. Here chicken antibody (IgY) preparations were freeze-dried in the presence or absence of lactose, sucrose and threalose as stabilizing agent at 0.3, 0.06 and 0.012M. The activity of freeze-dried IgY batches in the absence of stabilizing agent was similar before and after freeze-drying, but decreased slowly during eight weeks at 37°C. Addition of disaccharide resulted in a preserved activity after eight weeks in 37°C, compared to samples with no sugar added. The results were similar irrespective of sugar type and concentration (0.012-0.3M). This shows that IgY freeze-dried in the presence of disaccharide is very stable and a method to reduce the cost and simplify transport, storage and use of avian antibodies.

  • 187.
    Nilsson, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Stålberg, Johan
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    IgY stability in eggs stored at room temperature or at +4°C2012In: British Poultry Science, ISSN 0007-1668, E-ISSN 1466-1799, Vol. 53, no 1, p. 42-46Article in journal (Refereed)
    Abstract [en]

    1. The aim of this study was to investigate the stability of immunoglobulin-Y (IgY) in stored eggs from immunised hens.

    2. Eggs from individual hens were randomised and stored for up to one month at room temperature, or for up to 6 months at +4°C. IgY was extracted from the egg yolks and the antibody activities were tested by ELISA.

    3. There was no significant reduction in antibody titres with egg storage under these conditions.

    4. Egg yolks of immunised chickens provide an inexpensive source of large amounts of polyclonal antibodies for use in immunotherapy and immunoassays. By collecting eggs from different immunised hens and pooling their yolks, it should be possible to reduce batch-to-batch variation.

  • 188. Nitsch, Dorothea
    et al.
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Byberg, Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Tuvemo, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Syvänen, Ann-Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
    Koupil, Ilona
    Leon, David A.
    Fetal, Developmental, and Parental Influences on Cystatin C in Childhood: The Uppsala Family Study2011In: American Journal of Kidney Diseases, ISSN 0272-6386, E-ISSN 1523-6838, Vol. 57, no 6, p. 863-872Article in journal (Refereed)
    Abstract [en]

    Background: The aim was to identify determinants (biomedical and social characteristics of children and their parents) of cystatin C levels in healthy children drawn from a population sample. Study Design: Cross-sectional study. Setting & Participants: 425 pairs of consecutive full siblings born 1987-1995 in Uppsala were identified using the Swedish Medical Birth Registry and invited with their parents for examination in 2000-2001. Outcome: Serum cystatin C level was log-transformed and analyzed using random-effects models. Measurements: The examination in parents and children consisted of a nonfasting blood sample, anthropometry, and questionnaires about lifestyle and socioeconomic position. Tanner stage was used for assessment of pubertal status. Results: In age-, height-, and body mass index-adjusted analyses, cystatin C level increased by 2.6% (95% CI, 0.3%-4.8%) higher in Tanner stage 2 vs 1 girls, and 1.6% (95% CI, 0.2%-3.1%) lower in boys than girls. For every 10% increase in maternal cystatin C level, offspring cystatin C level increased by 3.0% (95% CI, 2.2%-3.8%); the equivalent effect for paternal cystatin C level was 2.1% (95% CI, 1.3%-2.9%). Lower maternal education was associated with a 2.4% (95% CI, 0.3%-4.6%) higher cystatin C level in their offspring. Limitations: Cross-sectional study design, missing cystatin C values for subset of parents, lack of urinary measurements, no gold-standard measurement of glomerular filtration rate. Conclusions: There are intergenerational associations of cystatin C level in families in line with previous reports of heritability of kidney disease. Lower maternal education is associated with higher cystatin C levels in their children. Further studies of healthy children are needed to explore the biological mechanisms for these findings. If cystatin C is measured, these studies will need to record pubertal stages.

  • 189. Nordenskjöld, Anna M
    et al.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Eggers, Kai M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Fröbert, Ole
    Jaffe, Allan S
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Short- and Long-term Individual Variation in Cardiac Troponin in Patients with Stable Coronary Artery Disease2013In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 59, no 2, p. 401-409Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    A rise or fall of cardiac troponin is a prerequisite for the diagnosis of acute myocardial infarction. Defining significant changes requires knowledge of both biological and analytical variation. The short-term biological variation of cardiac troponin in healthy individuals is 3%-48%. However, healthy individuals may not be representative for patients in whom cardiac troponin measurement is often of clinical importance. Therefore, we studied the individual variation of cardiac troponin in patients with symptoms of stable coronary artery disease.

    METHODS:

    Twenty-four patients scheduled for elective coronary angiography were included. Blood samples were drawn once at enrollment and serially at six 4-h intervals on the day before coronary angiography. Cardiac troponin was measured with hs-cTn assays from Abbott Laboratories (premarket cTnI assay) and Roche Diagnostics (Elecsys® cTnT assay with two different lots).

    RESULTS:

    The short-term individual variation in cardiac troponin I (cTnI) was 14%, the reference change value (RCV) 49%, and RCV-log-normal (rise/fall) 54%/-35%. The corresponding values for cTnT were 7%, 23%, and 26%/-21%. The long-term variation for cTnI was 24%, RCV 69%, and RCV-log-normal (rise/fall) 97%/-49%. The corresponding values for cTnT were 11%, 32%, and 37%/-27%.

    CONCLUSIONS:

    The short-term individual variation of cardiac troponin in patients with symptoms of stable coronary artery disease is similar to the biological variation previously demonstrated in healthy individuals. Our results suggest that a change in cardiac troponin concentrations of >50% can be used in attempting to diagnose acute myocardial injury. To detect significant long-term changes in cardiac troponin concentrations, larger changes will be required.

  • 190.
    Nordgren, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Rehabilitation Medicine.
    Falck, Björk
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Waldenström, A
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Hemmingson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Postpolio muscular dysfunction: relationships between muscle energy metabolism, subjective symptoms, magnetic resonance imaging, electromyography, and muscle strength1997In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 20, no 11, p. 1341-1351Article in journal (Refereed)
    Abstract [en]

    Eleven patients with previous polio were studied. The concentration of energy-related metabolites and energy charge was measured from the vastus lateralis muscle, as was isometric muscle strength of knee extension. Cross-sectional area of the quadriceps femoris muscle was calculated from magnetic resonance imaging. Reinnervation was studied using macroelectromyography. Muscle weakness, pain, and newly acquired muscle weakness in the legs was estimated by the patients. The findings in the legs in which the patients experienced new loss of muscle function were compared with the stable legs. There were no significant differences between these groups in any of the objectively measured variables. Only hip pain correlated with new loss of muscle function. Creatine phosphate was decreased in 5 patients. The symptoms and subjective muscle strength did not correlate with any of the objective measurements. There were no significant relationships between energy-related metabolites and postpolio symptoms.

  • 191.
    Oldgren, Jonas
    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.
    Budaj, Andrzej
    Granger, Christopher B.
    Khder, Yasser
    Roberts, Juliet
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Tijssen, Jan G. P.
    Van de Werf, Frans
    Wallentin, Lars
    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.
    Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial2011In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 32, no 22, p. 2781-2789Article in journal (Refereed)
    Abstract [en]

    Aim After an acute coronary syndrome, patients remain at risk of recurrent ischaemic events, despite contemporary treatment, including aspirin and clopidogrel. We evaluated the safety and indicators of efficacy of the novel oral direct thrombin inhibitor dabigatran. Methods and results In this double-blind, placebo-controlled, dose-escalation trial, 1861 patients (99.2% on dual antiplatelet treatment) in 161 centres were enrolled at mean 7.5 days (SD 3.8) after an ST-elevation (60%) or non-ST-elevation (40%) myocardial infarction and randomized to twice daily treatment with dabigatran 50 mg (n = 369), 75 mg (n = 368), 110 mg (n = 406), 150 mg (n = 347), or placebo (n = 371). Primary outcome was the composite of major or clinically relevant minor bleeding during the 6-month treatment period. There were 96 primary outcome events and, compared with placebo, a dose-dependent increase with dabigatran, hazard ratio (HR) 1.77 (95% confidence intervals 0.70, 4.50) for 50 mg; HR 2.17 (0.88, 5.31) for 75 mg; HR 3.92 (1.72, 8.95) for 110 mg; and HR 4.27 (1.86, 9.81) for 150 mg. Compared with placebo, D-dimer concentrations were reduced in all dabigatran dose groups by an average of 37 and 45% at weeks 1 and 4, respectively (P < 0.001). Fourteen (3.8%) patients died, had a myocardial infarction or stroke in the placebo group compared with 17 (4.6%) in 50 mg, 18 (4.9%) in 75 mg, 12 (3.0%) in 110 mg, and 12 (3.5%) in the 150 mg dabigatran groups. Conclusions Dabigatran, in addition to dual antiplatelet therapy, was associated with a dose-dependent increase in bleeding events and significantly reduced coagulation activity in patients with a recent myocardial infarction.

  • 192.
    Oldgren, Jonas
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research center.
    Lipoprotein-associated phospholipase A2 does not predict mortality or new ischaemic events in acute coronary syndrome patients2007In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 28, no 6, p. 699-704Article in journal (Refereed)
    Abstract [en]

    AIM: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been suggested as an independent predictor of cardiovascular events in epidemiological studies. We sought to evaluate Lp-PLA(2) as a risk factor for future cardiovascular events in patients with acute coronary syndromes (ACS) and to elucidate the relationship between Lp-PLA(2) and other known risk markers in ACS patients and healthy control subjects. METHODS AND RESULTS: Blood samples were obtained at randomization in a random subset of ACS patients in the FRISC II (n = 1362) and GUSTO IV (n = 904) studies and in 435 apparently healthy controls of similar age and gender. Median Lp-PLA(2) (mass) levels were 305 ng/mL (FRISC II), 373 ng/mL (GUSTO IV), and 254 ng/mL (healthy controls). Time delay from symptom onset did not influence Lp-PLA(2) levels. In the FRISC II patients and healthy controls, Lp-PLA(2) was significantly correlated with cholesterol (r = 0.3), low-density lipoprotein (r = 0.4 and r = 0.3, respectively), and C-reactive protein (r = 0.08 and r = 0.1, respectively), all P < 0.01. Lp-PLA(2) was not correlated with age, interleukin-6, troponin T, or NT-proBNP in any of the three cohorts. There was no difference in the composite of death and myocardial infarction at 30 days (GUSTO IV) or 180 days (FRISC II) in relation to low, middle, and top tertiles of Lp-PLA(2) at randomization. In FRISC II, the 1 year mortality was 4.2, 4.2, and 4.8% in the low, middle, and top Lp-PLA(2) tertiles, respectively, P = 0.8. In GUSTO IV, 1 year mortality was 7.0, 8.3, and 9.6% in the low, middle, and top Lp-PLA(2) tertiles, respectively, P = 0.5. CONCLUSION: ACS patients had higher Lp-PLA(2) levels than healthy controls. Lp-PLA(2) was significantly correlated to lipid levels but only weakly correlated or unrelated to other well-established risk markers in ACS. The risk of future cardiovascular events or mortality was not related to Lp-PLA(2) levels in ACS patients. The biological role of Lp-PLA(2) and its role as a risk marker in ACS patients still remain unclear.

  • 193.
    Oldgren, Jonas
    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.
    Johnston, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Xa inhibition and coagulation activity: the influence of prolonged dalteparin treatment and gender in patients with acute coronary syndrome and healthy individuals2008In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 155, no 3, p. 493.e1-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We evaluated coagulation activity in relation to gender in patients with acute coronary syndromes and in healthy individuals of similar age, and related coagulation activity to levels of Xa inhibition during dalteparin treatment. METHODS: Serial blood samples were obtained from 555 (172 women) of 2267 patients in the Scandinavian FRISC II study, and a single sample in 457 (151 women) apparently healthy age- and sex-matched individuals. After randomization, all patients received dalteparin 120 IU/kg s.c. (maximum 10,000 IU) twice daily for 5 to 7 days inhospital and thereafter placebo (n = 285) or sex- and weight-adjusted doses of dalteparin (5000 or 7500 IU) twice daily (n = 270) for 3 months. RESULTS: Before randomization, 96% of the patients had open-label anticoagulation with unfractionated heparin or dalteparin. Therapeutic anti-Xa levels (> 0.5 IU/mL) were found in 74%, 55%, 58%, and 33% of the dalteparin-treated patients at randomization, 2 days, 4 to 7 weeks, and 3 months, respectively, and were significantly related to lower levels of coagulation activity, ie, factor VIIa, prothrombin fragment 1+2, and D-dimer, during prolonged treatment. Female patients had higher anti-Xa levels than men at randomization (median 0.69 vs 0.60 IU/mL, P = .01) and at 2 days (0.65 vs 0.59 IU/mL, P < .001). Female patients had also significantly higher levels of all 3 coagulation markers at randomization, 2 days, 4 to 7 weeks, and 3 and 6 months. Similarly, healthy women had higher prothrombin fragment 1+2 levels (median 1.19 vs 0.94 nmol/L) and D-dimer levels than men (26 vs 21 microg/L) (both P < .001). CONCLUSIONS: Despite weight-adjusted dosing, female patients reached higher anti-Xa levels, suggesting increased sensitivity to dalteparin treatment. Healthy women and female patients also had higher coagulation activity, which might increase the risk of thrombus formation. The large proportion of patients with subtherapeutic anti-Xa during prolonged dalteparin treatment may reflect poor compliance and could thus contribute to the gradual loss of clinical efficacy.

  • 194.
    Oldgren, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Grip, L
    Linder, R
    Nørgaard, B
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Myocardial Damage, Inflammation and Thrombin Inhibition in Unstable Coronary Artery Disease2003In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 24, no 1, p. 86-93Article in journal (Refereed)
    Abstract [en]

    AIM:

    Unstable coronary artery disease (CAD) is a multifactorial disease involving both thrombotic and inflammatory processes. We have assessed the time-course and the influence of thrombin inhibitors on changes in fibrinogen and C-reactive protein levels, and their relation to myocardial ischaemia in unstable CAD.

    METHODS AND RESULTS:

    Three hundred and twenty patients were randomized to 72 h infusion with three different doses of inogatran, a direct thrombin inhibitor, or unfractionated heparin. There were no significant differences between the treatment groups in fibrinogen or C-reactive protein levels. Overall, the fibrinogen levels were significantly increased in the first 24-96 h and still elevated at 30 days. The C-reactive protein levels showed a more pronounced increase during the first 24-96 h, but then markedly decreased over 30 days. Troponin-positive compared to troponin-negative patients had higher fibrinogen and C-reactive protein levels up to 96 h, although there was an increase compared to pre-treatment levels in both groups. A high fibrinogen level (pre-treatment top tertile) was associated with an increased rate of death or myocardial (re-)infarction at 30 days, 13% vs 5.6%, P=0.03, and increased long-term mortality. A high C-reactive protein level was related to increased 30-day mortality, 4% vs 0%, P=0.01.

    CONCLUSION:

    Myocardial cell injury was related to a high degree of inflammation, only some of which is an acutephase response due to tissue damage. The rise in fibrinogen was sustained, which might reflect low grade inflammation with long-term risk of thrombosis. The transient elevation of C-reactive protein levels might indicate a propensity to a pronounced inflammatory response and is associated with increased mortality.

  • 195.
    Olovsson, Matts
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Human Anatomy.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Biotin labelling of chicken antibodies and their subsequent use in ELISA and immunohistochemistry1993In: Comparative Immunology, Microbiology & Infectious Diseases, ISSN 0147-9571, E-ISSN 1878-1667, Vol. 16, no 2, p. 145-152Article in journal (Refereed)
    Abstract [en]

    Avian antibodies have many advantages to mammalian antibodies due to the phylogenetic differences between birds and mammals, resulting in an increased sensitivity and a decreased background in many immunological assays. Since the avidin-biotin system is an efficient detection system for antibodies with a high sensitivity, we wanted to investigate the activity and unspecific binding of optimally biotin labelled chicken antibodies in ELISA and immunohistochemistry. We report on the conditions for biotinylation of chicken antibodies and that optimally biotinylated antibodies show a high activity and a low background in both ELISA and immunohistochemistry.

  • 196.
    Olovsson, Matts
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Nordling, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Ulmsten, U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Lindblom, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Waldenström, A
    Ronquist, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Human uterine myocytes retain their energy charge with No gross alterations in morphology for at least 8 days when cultured under anaerobic conditions2000In: Gynecologic and Obstetric Investigation, ISSN 0378-7346, E-ISSN 1423-002X, Vol. 49, no 3, p. 165-169Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:

    To investigate the ability of human uterine myocytes to grow under anaerobic conditions for a prolonged time period.

    METHODS:

    Cells were isolated from fundal myometrium and cultured until subconfluency. The cell type was confirmed by immunostaining for the smooth muscle cell-specific cytoskeletal proteins alpha-actin and desmin. Some cells were further cultured under aerobic conditions and others under anaerobic conditions. Cells were harvested after 0, 4 and 8 days in culture and analyzed for their content of adenylates.

    RESULTS:

    Immunostaining revealed that all three preparations contained almost only smooth muscle cells. Energy charge of the myocytes was 0.88 on average at the beginning of the culture experiment. A moderate decrease was noted on day 4 for myocytes grown under both aerobic and anaerobic conditions and no further decrease was noted between days 4 and 8. Morphologically the cells retained their normal appearance and they seemed healthy for at least 8 days in culture under both aerobic and anaerobic conditions.

    CONCLUSIONS:

    The results of this study suggest that human myometrial cells can survive for an extended period of time under in vitro conditions regardless of oxygen availability for energy metabolism. This means that anaerobic energy metabolism is enough to sustain vital processes during that period of time.

  • 197.
    Palm, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wernroth, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Involvement of inflammation in normal pregnancy2013In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 92, no 5, p. 601-605Article in journal (Refereed)
    Abstract [en]

    Objective.

    To study the role of inflammatory biomarkers of cytokine and cyclooxygenase origin throughout normal pregnancy and postpartum.

    Design.

    Longitudinal prospective study.

    Setting.

    One outpatient antenatal clinic in Uppsala, Sweden.

    Population.

    Thirty-seven healthy women with normal pregnancies and normal neonatal outcome were included. 

    Methods.

    Blood and urine samples were collected from each woman at least 6 times during pregnancy and postpartum. Plasma levels of IL-6 and TNF-α were measured by using ELISA kits and urine levels of PGF2α metabolite were measured by using RIA.

    Main outcome measures.

    Median plasma and urine levels, the 25:th to the 75:th percentile and the average change per gestational week of IL-6, TNF-α and PGF2α metabolite .

    Results.

    IL-6 levels increased significantly throughout pregnancy and postpartum levels remained high. No change in TNF-α could be seen with advancing gestational age or postpartum period. The PGF2α metabolite levels increased significantly throughout pregnancy and decreased in postpartum period.

    Conclusion.

    These results suggest that mild but significant inflammatory activity is involved in development of normal pregnancy and might have important physiological effects.

  • 198.
    Palm, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Basu, Samar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Oxidative Stress and Inflammation.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wernroth, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , UCR-Uppsala Clinical Research Center.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    A longitudinal study of plasma levels of soluble fms-like tyrosine kinase 1 (sFlt1), placental growth factor (PlGF), sFlt1: PlGF ratio and vascular endothelial growth factor (VEGF-A) in normal pregnancy2011In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 90, no 11, p. 1244-1251Article in journal (Refereed)
    Abstract [en]

    Objective: To describe plasma levels of angiogenic (PlGF, VEGF-A) and anti-angiogenic (sFlt1) factors as well as the sFlt1:PlGF ratio throughout normal pregnancy and postpartum.

    Design: Longitudinal prospective study.

    Setting: One outpatient antenatal clinic in Uppsala, Sweden.

    Population: Thirty-seven healthy women with normal pregnancies and normal neonatal outcome were included.

    Methods: Blood samples were collected from each woman at least six times. Plasma levels of sFlt1, PlGF and VEGF-A were measured using commercially available ELISA kits. Main outcome measures. Median plasma levels, the 25th to the 75th percentile and the average change per gestational week of sFlt1, PlGF and the sFlt1:PlGF ratio.

    Results: sFlt1 levels were relatively constant until weeks 29-30, when they increased, reaching a peak at week 40. An increase of 643pg/ml per week was observed from weeks 30 to 40. Postpartum levels were low. PlGF increased by 16pg/ml per week from early pregnancy until weeks 29-30 and thereafter decreased by 14pg/ml per week until week 40. The sFlt1:PlGF ratio decreased from weeks 9-12, was constantly low from weeks 19-20 to 37-38 and then increased to weeks 39-40. VEGF-A was detectable in only 8% of the samples during pregnancy and in 64% postpartum.

    Conclusion: This longitudinal study demonstrates how sFlt1, PlGF and the sFlt1:PlGF ratio fluctuate throughout normal pregnancy and postpartum and may serve as a reference against which these factors can be studied in complicated pregnancies. VEGF-A levels were more often detectable postpartum.

  • 199. Patrono, Carlo
    et al.
    Andreotti, Felicita
    Arnesen, Harald
    Badimon, Lina
    Baigent, Colin
    Collet, Jean-Philippe
    De Caterina, Raffaele
    Gulba, Dietrich
    Huber, Kurt
    Husted, Steen
    Kristensen, Steen Dalby
    Morais, João
    Neumann, Franz-Josef
    Rasmussen, Lars Hvilsted
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Steg, Philippe-Gabriel
    Storey, Robert F
    Van de Werf, Frans
    Verheugt, Freek
    Antiplatelet agents for the treatment and prevention of atherothrombosis2011In: European Heart Journal, ISSN 0195-668X, E-ISSN 1522-9645, Vol. 32, no 23, p. 2922-32Article, review/survey (Refereed)
    Abstract [en]

    The clinical pharmacology of antiplatelet drugs has been reviewed previously by the European Society of Cardiology (ESC) Task force and by the 8th American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines. Moreover, information on the efficacy and safety of antiplatelet drugs in the treatment and prevention of atherothrombosis is provided by collaborative meta-analyses of 287 secondary prevention trials and 6 primary prevention trials. The present document intends to provide practicing physicians with an updated instrument to guide their choice of the most suitable antiplatelet strategy for the individual patient at risk, or with different clinical manifestations, of atherothrombosis.

  • 200.
    Pauksens, Karlis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Fjaertoft, Gustav
    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.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Neutrophil and monocyte receptor expression in uncomplicated and complicated influenza A infection with pneumonia2008In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 40, no 4, p. 326-37Article in journal (Refereed)
    Abstract [en]

    Following influenza, the elderly and those with chronic heart/lung diseases are often affected by bacterial complications such as pneumonia. Whether neutrophil and monocyte functions are affected differently in patients with or without complications is less well known. Therefore, blood neutrophil and monocyte surface receptor expressions were measured in patients with influenza A, with or without complications, by means of flow cytometry. Neutrophil expressions of the adhesion molecules CD11b and CD66b were increased in influenza A, with the highest expression of CD11b in uncomplicated influenza. Monocyte expressions of CD11b and CD18 were also higher in influenza compared with bacterial infection and healthy controls. Neutrophil expressions of the phagocyte receptors CD64 and CD32 and the complement receptor CD35 were impaired in influenza with and without pneumonia compared with bacterial infection, whereas the expressions in monocytes were increased in all infected groups. The expression of the phagocyte receptor CD16 on neutrophils was impaired in all infected groups. Our results suggest increased recruitment of neutrophils and monocytes to infected areas by up-regulation of adhesion molecules in influenza that may be involved in the inflammatory response during infection. In contrast, depression of phagocyte receptor expression on neutrophils in patients with influenza pneumonia may contribute to increased susceptibility to bacterial infections and impaired clearance of encapsulated bacteria such as pneumococci.

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