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  • 1.
    Ahlström, K.
    et al.
    Anesthesia and Intensive Care Medicine, Sahlgrens University Hospital, Gothenburg, Sweden.
    Biber, B.
    Anesthesia and Intensive Care Medicine, Sahlgrens University Hospital, Gothenburg, Sweden.
    Åberg, A.
    Anesthesia and Intensive Care Medicine, University Hospital of Umeå, Umeå, Sweden.
    Waldenström, A.
    Anesthesia and Intensive Care Medicine, University Hospital of Umeå, Umeå, Sweden.
    Ronquist, G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Abrahamsson, P.
    Anesthesia and Intensive Care Medicine, University Hospital of Umeå, Umeå, Sweden.
    Strandén, P.
    Anesthesia and Intensive Care Medicine, University Hospital of Umeå, Umeå, Sweden.
    Johansson, G.
    Anesthesia and Intensive Care Medicine, University Hospital of Umeå, Umeå, Sweden.
    Haney, Michael F.
    Anesthesia and Intensive Care Medicine, University Hospital of Umeå, Umeå, Sweden.
    Metabolic responses in ischemic myocardium after inhalation of carbon monoxide2009In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 53, no 8, p. 1036-1042Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: To clarify the mechanisms of carbon monoxide (CO) tissue-protective effects, we studied energy metabolism in an animal model of acute coronary occlusion and pre-treatment with CO. METHODS: In anesthetized pigs, a coronary snare and microdialysis probes were placed. CO (carboxyhemoglobin 5%) was inhaled for 200 min in test animals, followed by 40 min of coronary occlusion. Microdialysate was analyzed for lactate and glucose, and myocardial tissue samples were analyzed for adenosine tri-phosphate, adenosine di-phosphate, and adenosine mono-phosphate. RESULTS: Lactate during coronary occlusion was approximately half as high in CO pre-treated animals and glucose levels decreased to a much lesser degree during ischemia. Energy charge was no different between groups. CONCLUSIONS: CO in the low-doses tested in this model results in a more favorable energy metabolic condition in that glycolysis is decreased in spite of maintained energy charge. Further work is warranted to clarify the possible mechanistic role of energy metabolism for CO protection.

  • 2.
    Ahmed, Degmo Said
    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.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Wande, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ryden, Ingvar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Quantitative determination of cerebrospinal fluid bilirubin on a high throughput chemistry analyzer2009In: Clinical laboratory, ISSN 1433-6510, Vol. 55, no 7-8, p. 283-288Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Subarachnoid hemorrhage is a condition with high rates of mortality and morbidity. The diagnosis requires an urgent cerebral computed tomography scan and also a lumbar puncture if the scan fails to demonstrate intracranial blood. In Sweden the cerebrospinal fluid (CSF) is analyzed by spectrophotometric scanning for the presence of hemoglobin and bilirubin. The aim of the study was to develop a quantitative diazo reagent based analysis of cerebrospinal fluid bilirubin as a replacement for spectrophotometric scanning. METHODS: The CSF bilirubin assay on an Architect C8000 chemistry analyzer was compared with spectrophotometry using patient samples. RESULTS: The method correlates with spectrophotometry, has a good linearity and precision. CONCLUSIONS: Quantitative bilirubin measurement offers shorter turnaround times, simplifies the interpretation of the results and reduces work load in comparison with spectrophotometry.

  • 3.
    Akerud, Helena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wiberg-Itzel, Eva
    Dept of Obstetrics and Gynecology, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.
    Lactate distribution in culture medium of human myometrial biopsies incubated under different conditions2009In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 297, no 6, p. E1414-E1419Article in journal (Refereed)
    Abstract [en]

    It is generally believed that a relationship exists between muscle fatigue and intracellular accumulation of lactate. This reasoning is relevant to obstetrical issues. Myocytes in uterus work together during labor, and the contractions need to be strong and synchronized for a child to be delivered. At labor dystocia, the progress of labor becomes slow or arrested after a normal beginning. It has been described that, during labor dystocia, when the force of the contractions is low, the uterus is under hypoxia, and anaerobic conditions with high levels of lactate in amniotic fluid dominate. The purpose of this study was to examine whether myometrial cells are involved in the production of lactate in amniotic fluid and whether there are differences in production and distribution of lactate in cells incubated under aerobic and anaerobic conditions. We also wanted to elucidate the involvement of specific membrane-bound lactate carriers. Women undergoing elective caesarean section were included. Myometrial biopsies from uteri were collected and subjected to either immunohistochemistry to identify lactate carriers or in vitro experiments to analyze production of lactate. The presence of lactate carriers named monocarboxylate transporters 1 and 4 was verified. Myometrial cells produced lactate extracellularly, and the lactate carriers operated differently under anaerobic and aerobic conditions; while being mainly unidirectional under anaerobic conditions, they became bidirectional under aerobic conditions. Human myometrial cells produced and delivered lactate to the extracellular medium under both anaerobic and aerobic conditions. The delivery was mediated by lactate carriers.

  • 4.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Larsson, Marita
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Artery Wall Layer Dimensions during Normal Pregnancy: A longitudinal study using non-invasive high-frequency ultrasound2013In: American Journal of Physiology. Heart and Circulatory Physiology, ISSN 0363-6135, E-ISSN 1522-1539, Vol. 304, no 2, p. H229-H234Article in journal (Refereed)
    Abstract [en]

    The vascular effects of normal pregnancy were investigated by estimating the intima and media thicknesses of the common carotid artery separately using 22MHz ultrasound (Collagenoson, Meudt, Germany) in 57 healthy women with normal pregnancies and pregnancy outcomes, in all three trimesters and at one year postpartum. A thick intima, thin media and high intima/media (I/M) ratio are signs of a less healthy artery wall. The mean artery wall layer dimensions remained fairly constant during pregnancy but the intima thickness and I/M thickness ratio appeared to improve (decrease) postpartum (p<0.001 for both). The cardiovascular risk parameters age, body mass index (BMI), and blood pressure in the first trimester were associated with higher I/M ratios, especially in the second trimester, whereas higher serum estradiol levels were significantly associated with a lower I/M ratio. Changes from the first to second trimesters in I/M ratio, taking into account differential changes in intima and media thickness, were significantly (p<0.05-0.001) associated with all risk parameters tested except age, which was associated with increased intima thickness (p=0.02). Associations with third trimester values and changes from first to third trimesters were similar but less apparent. Thus, fairly constant mean artery wall layer dimensions during pregnancy appeared to improve postpartum. However, higher age, BMI or blood pressure, and lower serum estradiol levels in the first trimester appeared to negatively affect the artery wall, strongly suggesting that pregnancy has negative vascular effects in some women. A less likely explanation involves possible adaptation to physiological changes during and after pregnancy.

  • 5.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Naessen, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Changes in the Artery Wall Layer Dimensions in Women with Preeclampsia: an investigation using non-invasive high frequency ultrasound2012In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 91, no S159, p. 28-28Article in journal (Other academic)
    Abstract [en]

    Background:

    Preeclampsia (PE) is associated with increased risk for cardiovascular disease later in life. Whether, the artery wall layer dimensions differ between PE and normal pregnancy is unclear. The aim of this study was to estimate if women with PE have different common carotid artery wall layer dimensions than women with normal pregnancy, both during pregnancy and about one year postpartum.

    Methods:

    By using high-frequency (22MHz) ultrasound (Collagenoson, Meudt, Germany) separate estimates of the common carotid artery intima and media layers were obtained and the I/M ratio was calculated in women with PE (n=55 during pregnancy and n=48 at postpartum) and with normal pregnancy (n=65 during pregnancy and n=59 at postpartum). Thick intima, thin media and a high intima/media ratio are signs of less healthy artery wall and vice versa.

    Results:

    In women with PE, the intima was thicker (0.18 } 0.03 vs. 0.11 } 0.02; p < .001), the media was thinner (0.47 } 0.12 vs. 0.55 } 0.14; p = .001) and the I/M ratio was higher (0.41 } 0.14 vs. 0.20 } 0.05; p < .001) compared to women with normal pregnancy. Further, for changes from pregnancy to postpartum, both for PE and normal pregnancy, the intima and the I/M ratio had improved but still significantly higher in women with PE than in women with normal pregnancy.

    Conclusion:

    In women with PE, we found a thicker intima, thinner media and a higher I/M ratio compared to women with normal pregnancy, indicating a more negatively affected artery wall layer dimensions. Persisting negative effects of PE on artery wall at postpartum, despite improvement of artery wall layers compared to values during pregnancy, indicates a permanent damage of the vascular system in this group of women.

  • 6. Allander, Susanne Vilhelmsdotter
    et al.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Marké, Lars-Åke
    Svensson, Maria K
    Björn, Wihlén
    Elinder, Carl-Gustaf
    Kreatinin fortfarande den vanligaste njurfunktionsanalysen: Undersökning av praxis i Sverige2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 19, p. 960-962Article in journal (Refereed)
    Abstract [en]

    Markers of renal function (glomerular filtration rate; GFR) are frequently used. In most cases GFR is estimated based on plasma creatinine, but cystatin C, creatinine clearance (with urine collection), iohexol clearance and 51Cr-EDTA clearance are also used. A questionnaire was sent to representatives for clinical chemistry laboratories in Sweden to collect information regarding the use of these markers during the years 2006 2009. The aim was to compare the use in different parts of Sweden and how it has changed over time. The overall use of markers of renal function, including creatinine, continues to increase on a national level, with the exception for endogenous creatinine clearance and 51Cr-EDTA clearance. Creatinine, the most frequently used marker, continues to grow in numbers. 5,6 million creatinine analyses and about two hundred thousand cystatin C analyses were performed during year 2009. There were considerable variations between counties in the use of the studied markers.

  • 7.
    Alström, Ulrica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Granath, Fredrik
    Oldgren, Jonas
    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.
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Tydén, Hans
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Platelet inhibition assessed with VerifyNow, flow cytometry and PlateletMapping in patients undergoing heart surgery2009In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 124, no 5, p. 572-577Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: A substantial number of patients with coronary artery disease undergo cardiac surgery within five days of discontinuing anti-platelet treatment with aspirin and clopidogrel. The aims of this study were to describe the degree of platelet inhibition in patients with dual anti-platelet treatment scheduled for coronary artery bypass graft (CABG) surgery and to investigate whether the measured platelet inhibition correlated to intra- and postoperative risk for bleeding and transfusion requirements. MATERIAL AND METHODS: Sixty patients were included. Platelet inhibition was analysed with flow cytometry including phosphorylation status of the vasodilator-stimulated phosphoprotein (VASP-assay) and two bed-side analyzers, VerifyNow-System and PlateletMapping, a modified thrombelastograph. All 60 patients were analysed with VerifyNow and PlateletMapping, and 48 were analysed with flow cytometry and VASP-assay. RESULTS: There was a correlation between the ADP-receptor inhibition as measured by VASP-assay and VerifyNowP2Y(12) (r = -0.29, p<0.05), and between VASP-assay and the expression of P-selectin (r = 0.29, p<0.05) as measured by flow cytometry when platelets were stimulated with 5 microM ADP. VerifyNowP2Y(12) was the only measurement of platelet inhibition correlated to total blood loss (Spearman r = 0.29, p=0.03) and red blood cell transfusion (Spearman r = 0.43, p<0.01) requirements, although this might be confounded by aprotinin treatment. CONCLUSION: We found a modest agreement between the methods for preoperative platelet inhibition, though not for PlateletMapping-MA(ADP). There was a correlation between preoperative platelet inhibition measured by VerifyNowP2Y(12) and surgical blood loss or transfusion requirements. However, for the individual patient, preoperative use of VerifyNowP2Y(12) as an instrument to decide bleeding and transfusion risk does not seem helpful.

  • 8.
    Alström, Ulrica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Tydén, Hans
    Oldgren, Jonas
    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.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    The platelet inhibiting effect of a clopidogrel bolus dose in patients on long-term acetylsalicylic acid treatment2007In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 120, no 3, p. 353-359Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Addition of clopidogrel to patients treated with ASA has been shown to decrease the incidence of in-stent thrombosis after percutaneous coronary interventions. However, it has also been reported that up to 30% of patients do not achieve adequate platelet inhibition from standard dosages of ASA and clopidogrel. There is a demand for reliable methods to measure the individual platelet inhibiting effect of this combination therapy. MATERIALS AND METHODS: The primary aim of the present investigation was to compare three methods for evaluation of the platelet inhibiting effect of a clopidogrel bolus dose in patients on long-term acetylsalicylic acid treatment. Thirty patients presenting for coronary angiography/PCI were included. Two patients were excluded due to technical problems. All patients were on 75-100 mg ASA/day for at least 8 days. Blood samples were analysed before and 16 h after a 300 mg clopidogrel bolus dose. The platelet inhibiting effect was measured with (1) Whole blood flow cytometry (17 patients); (2) a bed-side test, Platelet Mapping assay for the thrombelastograph (28 patients); and (3) PFA (Platelet function analyser) -100 (26 patients). RESULTS: With flow cytometry, the percentage of platelets expressing P-selectin (p=0.03) on their surface decreased significantly after the bolus dose of clopidogrel. There was also a reduction of platelets binding fibrinogen when stimulated with ADP. A significantly (p=0.002) increased platelet inhibition could also be demonstrated with Platelet Mapping. PFA-100 could not measure any significant platelet inhibiting effect of clopidogrel. CONCLUSION: A significant platelet inhibition could be demonstrated with flow cytometry and the Platelet Mapping assay, but not with PFA-100. However, levels of response for the individual patient with these three methods were inconsistent. Further studies are needed to evaluate how the results correlate to the clinical risk of thrombosis and bleeding.

  • 9.
    Andersson, Arne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lessons from the recent Journal Citation Report figures2010In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 115, no 3, p. 161-162Article in journal (Refereed)
  • 10.
    Arinell, Karin
    et al.
    Department of Cardiology, Örebro University Hospital, Örebro, Sweden..
    Christensen, Kjeld
    Department of Cardiology, Örebro University Hospital, Örebro, Sweden..
    Blanc, Stephane
    Institut Pluridisciplinaire Hubert Curien–De´partement d’Ecologie, Physiologie,.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Frobert, Ole
    Department of Cardiology, Örebro University Hospital, Örebro, Sweden..
    Effect of prolonged standardized bed rest on cystatin C and other markers of cardiovascular risk2011In: BMC Physiology, ISSN 1472-6793, E-ISSN 1472-6793, Vol. 11, no 1, p. 17-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Sedentary lifestyle is associated with coronary artery disease but even shorter periods of physical inactivity may increase cardiovascular risk. Cystatin C is independently associated with cardiovascular disease and our objective was to investigate the relation between this novel biomarker and standardized bed rest. Research of immobilization physiology in humans is challenging because good biological models are in short supply. From the Women International Space simulation for Exploration study (WISE) we studied markers of atherosclerosis and kidney function, including cystatin C, in a standardized bed rest study on healthy volunteers. Fifteen healthy female volunteers participated in a 20-day ambulatory control period followed by 60 days of bed rest in head-down tilt position (-6degrees) 24 h a day, finalized by 20 days of recovery. The subjects were randomized into two groups during bed rest: a control group (n=8) that remained physically inactive and an exercise group (n=7) that participated in both supine resistance and aerobic exercise training.

    RESULTS:

    Compared to baseline values there was a statistically significant increase in cystatin C in both groups after bed rest (P<0.001). Glomerular filtration rate (GFR), calculated by both cystatin C and Cockcroft-Gault equation, decreased after bed rest while there were no differences in creatinine or creatine kinase levels. CRP did not change during bed rest in the exercise group, but there was an increase of CRP in the control group during recovery compared to both the baseline and the bed rest periods. The apo-B/apo-Ai ratio increased during bed rest and decreased again in the recovery period. Subjects experienced a small but statistically significant reduction in weight during bed rest and compared to baseline weights remained lower at day 8 of recovery.

    CONCLUSION:

    During and following prolonged standardized bed rest the concentrations of several clinically relevant cardiovascular risk markers change.

  • 11.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Prothrombotic effects of prostasomes isolated from prostatic cancer cell lines and seminal plasma2007In: Seminars in Thrombosis and Hemostasis, ISSN 0094-6176, E-ISSN 1098-9064, Vol. 33, no 1, p. 80-86Article, review/survey (Refereed)
    Abstract [en]

    Thromboembolism is well recognized as a major complication of cancer. Many tumor cells overexpress tissue factor (TF), which activates blood coagulation in cancer patients. Inflammatory cells expressing TF are also contributors to this activation. In prostate cancer, we believe that prostasomes may also be involved in the initiation of blood coagulation. Prostasomes are submicron secretory granules derived from the prostate gland. They are surrounded by membrane and their extracellular appearance and membrane architecture are complex. Seminal prostasomes are believed to be necessary for successful fertilization and act as protectors of the spermatozoa in the lower and upper female genital tract. Cells from prostate cancer and its metastases are able to produce and export prostasomes to the extracellular environment. These prostasomes may differ quantitatively rather than qualitatively from their normal counterparts with regard to protein composition and function. A majority of human prostate cancers have been found to overexpress TF, and we have demonstrated by various methods that prostasomes derived from prostate cancer cells express considerably higher levels of TF compared with prostasomes of nonmalignant cell origin. The mechanism related to thromboembolic disease generated by prostasomes in prostatic cancer patients may be the early release of prostasomes from prostate cancer cells into the blood circulation, where they will evoke their blood-clotting effects.

  • 12.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hamad, Osama A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Sanchez, Javier
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Prothrombotic effect of prostasomes of metastatic cell and seminal origin2007In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 67, no 4, p. 378-388Article in journal (Refereed)
    Abstract [en]

    BACKGROUND. Prostasomes are secretory granules produced by the glandular epithelial cells of the prostate. Seminal prostasomes contain high amounts of Tissue Factor (TF) but no studies of TF on malignant cell prostasomes have been made. Here we compare the expression, phosphorylation, and function of TF on prostasomes of different origin. METHODS. TF was detected on prostasomes isolated from seminal fluid and human prostate cancer cell lines (PC-3, DU145, and LNCaP) using FACS and enzyme immunoassay (EIA). Incubation of prostasomes with radioactive ATP under conditions favoring protein kinase A activity led to phosphorylation of TF as detected by immunoprecipitation and SDS-PAGE. The prothrombotic effect of prostasomes was investigated in whole blood and recalcified plasma. Blocking experiments were performed using anti-TF antibodies and corn trypsin inhibitor. RESULTS. TF was expressed on all tested prostasome preparations with lowest values found for seminal ones. Prostasomal TF was the main endogenous substrate for prostasomal protein kinase A. All tested prostasome preparations greatly enhanced the rate of clot formation in a dose-dependent fashion, that is, the clotting capability of prostasomes seemed to be related to the extent of their expression of TF. In addition, the density of the clot varied between different prostasome preparations. When incubated in whole blood, prostasomes were found to associate to WBC thereby inducing them to express and release TF. CONCLUSIONS. These data show that TF is overexpressed and also subjected to phosphorylation by malignant cell prostasomes. This suggests major roles for prostasomes in thrombotic events that occur in some advanced cases of prostate cancer.

  • 13.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Magnusson, Peetra U.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ekdahl, Kristina Nilsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Mapping pro- and antiangiogenic factors on the surface of prostasomes of normal and malignant cell origin2010In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 70, no 8, p. 834-847Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Angiogenesis is the formation of new blood vessels by capillary sprouting from pre-existing vessels. Tumor growth is angiogenesis-dependent and the formation of new blood vessels is associated with the increased expression of angiogenic factors. Prostasomes are secretory granules produced, stored and released by the glandular epithelial cells of the prostate. We investigated the expression of selected angiogenic and anti-angiogenic factors on the surface of prostasomes of different origins as well as the direct effect of prostasomes on angiogenesis. METHODS: VEGF, endothelin-1, endostatin, and thrombospondin-1 were determined on prostasomes from seminal fluid and human prostate cancer cell lines (DU145,PC-3,LNCaP) using different immunochemical techniques. Human dermal microvascular endothelial cells were incubated with seminal and DU145 cell-prostasomes and with radioactive thymidine. The effect of prostasomes on angiogenesis was judged by measuring the uptake of labeled thymidine. The presence of any deleterious effects of prostasomes on the endothelial cells was investigated using thymidine assay and confocal laser microscopy. RESULTS: VEGF and endothelin-1 were determined on malignant cell-prostasomes (no difference between cell lines) but not determined on seminal prostasomes. The same applies for the expression of endostatin but with much higher expression on malignant cell-prostasomes with obvious differences between them. Seminal and DU145 cell-prostasomes were found to have anti-angiogenic effect which was more expressed by DU145 cell-prostasomes. No deleterious effect of prostasomes on endothelial function was detected using either thymidine assay or microscopy. CONCLUSIONS: Prostasomes contain pro- and anti-angiogenic factors that function to counteract each other unless the impact from one side exceeds the other to bring about dysequilibrium.

  • 14.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Carlsson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Transfer of functional prostasomal CD59 of metastatic prostatic cancer cell origin protects cells against complement attck2005In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 62, no 2, p. 105-114Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prostasomes are secretory granules produced, stored, and released, by the glandular epithelial cells of the prostate. They express the glycosylphosphatidylinositol (GPI)-anchored complement regulatory protein CD59, which has been shown to be transferred to spermatozoa and erythrocytes.

    METHODS: The CD59 content of prostasomes isolated from seminal fluid and malignant prostate cells (PC-3, DU145, and LNCaP) and the transfer of prostasomal CD59 to rabbit erythrocytes (RE) and to PIPLC-treated and unmanipulated cancer cells were investigated using FACS. All prostasomes were also incubated with RE and tested in a hemolytic assay.

    RESULTS: Prostasomes from cancer cells had higher expression of CD59 than those of normal cells. Prostasomal CD59 of different origin could be transferred to RE, malignant cell lines stripped of CD59 by PIPLC, or unmanipulated LNCaP cells. Malignant cell prostasomes had an increased ability to inhibit complement-mediated lysis compared to those from non-malignant cells.

    CONCLUSIONS: These results point to a novel mechanism by which prostasomes can protect prostatic malignant cells from complement attack.

  • 15.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Overexpression of ecto-protein kinases in prostasomes of metastatic cell origin2006In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 66, no 7, p. 675-686Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Prostasomes are secretory granules produced, stored, and released by the glandular epithelial cells of the prostate. They express numerous enzymes whose physiological roles have so far not been fully evaluated. In this study, we investigated the expression and function of prostasomal protein kinases and ATPase.

    METHODS:

    The protein kinase activities of prostasomes isolated from seminal fluid and malignant prostate cell lines (PC-3, DU145, and LNCaP) were investigated using the model phosphorylation substrates histone and casein, as well as the plasma proteins C3 and fibrinogen, in combination with specific protein kinase inhibitors. The prostasomal ATPase activity was also evaluated. The expression of protein kinases and ATPase on prostasomes was verified by flow cytometry.

    RESULTS:

    Prostasomes (intact or solubilized with octylglucoside or saponin) from prostate cancer cells had higher expression of protein kinases A, C, and casein kinase II compared to prostasomes isolated from seminal plasma, resulting in higher phosphorylation of both exogenous and endogenous substrates. Using intact prostasomes, it was found that prostasomes of metastatic origin had lower ATPase activity, resulting in higher residual ATP available for the phosphorylation reaction. Finally, complement component C3 and fibrinogen (two proteins whose activities are modulated by phosphorylation) were identified as physiologically relevant phosphorylation substrates.

    CONCLUSIONS:

    These results indicate that prostasomes are capable of modifying proteins possibly involved in the innate response by extracellular phosphorylation mediated by ecto-kinases. This is a novel mechanism by which prostatic malignant cells may interact with their environment.

  • 16.
    Babiker, Adil A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nilsson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Nilsson Ekdahl, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Prostasome Involvement in the Development and Growth of Prostate Cancer2010In: The Open Prostate Cancer Journal, ISSN 1876-8229, Vol. 3, p. 1-13Article, review/survey (Refereed)
    Abstract [en]

    Prostasomes are extracellularly occurring submicron, membrane-surrounded organelles produced by the epithelial cells of the prostate and present in semen after secretion. Even dedifferentiated prostate cancer cells have preserved their ability to produce and export prostasomes to the extracellular space. The precise physiological role of prostasomes is not known, although some of their properties assign them to important physiological and patho-physiological functions that could be exploited in prostate cancer growth and development. In this review, some new properties of seminal and malignant cell line (DU145, PC-3 and LNCaP) prostasomes will be discussed.

    There are typical differences in the expressions and activities of prostasomal CD59, ATPase, protein kinases and tissue factor (TF) as well as in the transfer of prostasomal CD59 to CD59-deficient erythrocytes (rabbit and human PNH erythrocytes). CD59, protein kinases and TF exhibit characteristic patterns of overexpression by malignant cell prostasomes. A high ATPase activity is recognized on seminal prostasomes with minimal activity on malignant cell prostasomes resulting in more residual ATP available for phosphorylation reactions. Several proteins are phosphorylated by prostasomal protein kinases, namely, complement component C3, fibrinogen, vitronectin and E-cadherin. Furthermore, TF is identified as the main endogenous phosphorylation substrate on prostasomes. In addition, prothrombotic effects of prostasomes are demonstrated. DU145 and PC-3 cell-derived prostasomes exert a higher clotting effect on whole blood and plasma compared to LNCaP cell-derived and seminal prostasomes.

    In conclusion, malignant cell prostasomes show an increased ability to interact with the biological system in favor of prostate cancer cell promotion and survival. The roles played by prostasomes in this context may improve the understanding of the mechanisms that help the prostate cancer cells to avoid the complement attack (CD59 transfer and phosphorylation and inactivation of C3), to promote angiogenesis (TF) and to metastasize. It may also provide a better understanding of some of the complications usually seen in some terminal prostate cancer patients like thrombotic events and tendency to develop disseminated intravascular coagulation.

  • 17. Bergenheim, A. Tommy
    et al.
    Roslin, Michael
    Ungerstedt, Urban
    Waldenström, Anders
    Henriksson, Roger
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Metabolic manipulation of glioblastoma in vivo by retrograde microdialysis of L-2, 4 diaminobutyric acid (DAB)2006In: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 80, no 3, p. 285-93Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To study the metabolic effects in vivo of L-2, 4 diaminobutyric acid (DAB) administered by retrograde microdialysis in glioblastoma and to evaluate the feasibility of the technique. METHODS: In 10 patients with glioblastoma, a stereotactic biopsy was performed followed by implantation of microdialysis catheters. One or two catheters were implanted in tumor tissue and two reference catheters were implanted in normal brain tissue and subcutaneous abdominal tissue, respectively. Tumor catheters were perfused with 80 or 120 mmol/l DAB and reference catheters were perfused with a Ringer solution, all with a flow rate of 2.0 microl/min. Treatment was given for at mean 9.1 (5-19) days. RESULTS: The treatment was well tolerated by the patients with the exception of two patients in whom a transient brain edema appeared. No complications related to the technique were encountered. During treatment, an increase in the extracellular amino acids alanine, glycine, glutamate, aspartate, serine, threonine, and taurine was found demonstrating a significant influence on the intracellular pool of free amino acids induced by DAB. No change in glucose metabolism or glycerol was evident. The metabolism in normal brain was unaffected during treatment. CONCLUSIONS: Retrograde microdialysis is a feasible method for intracerebral administration of drugs to tumor tissue in patients with glioblastoma. We found it possible to deliver DAB to glioblastoma tumors in fully mobilized patients and to assess the metabolic effects induced by the treatment. The changes in extracellular amino acids were in concordance to what was expected from in vitro studies. Elevation of glutamate and taurine may be regarded as markers for an induced cellular toxicity while the unchanged level of glycerol may indicate no direct effects on phospholipase activity and membrane phospholipid composition. The effects were restricted to the tumor compartment. Although an improved survival could possibly be suspected no dramatic effect on outcome could be detected. However, the series was small and, most probably, the time for treatment was too short.

  • 18.
    Beshara, Soheir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Physiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Långström, Bengt
    PET Centre, University Hospital, Uppsala, Sweden.
    Antoni, Gunnar
    PET Centre, University Hospital, Uppsala, Sweden.
    Danielsson, Bo G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Pharmacokinetics and red cell utilization of 52Fe/59Fe-labelled iron polymaltose in anaemic patients using positron emission tomography2003In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 120, no 5, p. 853-859Article in journal (Other academic)
    Abstract [en]

    Parenteral iron-polysaccharide complexes are increasingly applied. The pharmacokinetics of iron sucrose have been assessed by our group using positron emission tomography (PET). A single intravenous injection of 100 mg iron as iron (III) hydroxide-polymaltose complex, labelled with a tracer in the form of 52Fe/59Fe, was similarly assessed in six patients using PET for about 8 h. Red cell utilization was followed for 4 weeks. Iron polymaltose was similarly distributed to the liver, spleen and bone marrow. However, a larger proportion of this complex was rapidly distributed to the bone marrow. The shorter equilibration phase for the liver, about 25 min, indicates the minimal role of the liver for direct distribution. Splenic uptake also reflected the reticuloendothelial handling of this complex. Red cell utilization ranged from 61% to 99%. Despite the relatively higher uptake by the bone marrow, there was no saturation of marrow transport systems at this dose level. In conclusion, high red cell utilization of iron polymaltose occurred in anaemic patients. The major portion of the injected dose was rapidly distributed to the bone marrow. In addition, the reticuloendothelial uptake of this complex may reflect the safety of polysaccharide complexes. Non-saturation of transport systems to the bone marrow indicated the presence of a large interstitial transport pool, which might possibly be transferrin.

  • 19.
    Biglarnia, Alireza
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Wadström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Decentralized glomerular filtration rate (GFR) estimates in healthy kidney donors show poor correlation and demonstrate the need for improvement in quality and standardization of GFR measurements in Sweden2007In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 67, no 2, p. 227-235Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Glomerular filtration rate (GFR) is generally accepted as the best overall index of renal function. Thus, all potential live kidney donors are tested to ensure that they have a normal GFR before they are eligible for kidney transplantation. The choice of GFR test is very much dependent on local traditions and may include iohexol, 51Cr-EDTA, inulin, or creatinine clearance based on urine collection, and creatinine clearance calculated from the Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) equation as well as cystatin C. The aim of this study was to compare the results of GFR measurements performed in all actual live kidney donors who have undergone live donor nephrectomy at the University Hospital in Uppsala, Sweden, between the years 2000 and 2004. MATERIAL AND METHODS: The patients were selected from all parts of Sweden and the measurements were performed at their local hospital. RESULTS: We found large discrepancies between repeated iohexol measurements in these presumably healthy individuals. There was also a poor correlation between iohexol clearance and calculated creatinine clearance using the Cockcroft-Gault (R2=0.046) or MDRD formula (R2=0.045). CONCLUSIONS: The study shows that the standardization and quality of GFR measurements in Sweden have to be improved.

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

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

  • 21.
    Blume-Jensen, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Siegbahn, Agneta
    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.
    Zsebo, Krisztina M.
    AMGEN Inc., AMGEN Center, Thousand Oaks, CA 91320, USA.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Activation of the human c-kit product by ligand-induced dimerization mediates circular actin reorganization and chemotaxis1991In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 10, no 13, p. 4121-4128Article in journal (Refereed)
    Abstract [en]

    The proto-oncogene c-kit is allelic with the murine white spotting (W) locus and encodes a transmembrane protein tyrosine kinase that is structurally related to the receptors for platelet-derived growth factor (PDGF) and colony-stimulating factor-1 (CSF-1). Recently the ligand for the c-kit product, stem cell factor (SCF), was identified in both transmembrane and soluble forms. In order to examine the mechanism for receptor activation by SCF and biological properties of the activated c-kit product, we transfected the wild-type human c-kit cDNA into porcine aortic endothelial cells. We found that the receptor was down-regulated and transmitted a mitogenic signal in response to stimulation with soluble SCF. We also demonstrate that SCF induces dimerization of the c-kit product in intact cells, and that dimerization of the receptor is correlated with activation of its kinase. Activation of the c-kit product by SCF was found to induce circular actin reorganization indistinguishable from that mediated by the PDGF beta-receptor in response to PDGF-BB. Furthermore, soluble SCF was a potent chemotactic agent for cells expressing the c-kit product, a property which might be of importance during embryonic development.

  • 22.
    Bolander, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Agnarsdóttir, Margrét
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wagenius, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Strömberg, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Pontén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Ekman, Simon
    Brattström, Daniel
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Einarsson, Roland
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hesselius, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Serological and immunohistochemical analysis of S100 and derivatives as markers for prognosis of newly operated malignant melanoma patients2008In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 18, no 6, p. 412-419Article in journal (Refereed)
    Abstract [en]

    The incidence of cutaneous malignant melanoma is rising, and tumour markers are attracting attention as a possible alternative to clinical examination in the follow-up situation. S100 is the preferred marker for malignant melanoma, and correlation between serum S100 and disease relapse and survival has been reported. S100 tests previously used in clinical studies were specified poorly regarding reactivity with S100A1B and S100BB. In this study, a newly designed S100 assay (designed to measure exclusively S100A1B and S100BB) and two newly developed serological assays, S100A1B, and S100BB, were investigated postoperatively in patients undergoing radical surgery for cutaneous malignant melanoma. Additionally, immunohistochemical analysis of S100A4 was performed on the primary malignant melanoma using tissue microarrays. The primary aim of the study was to investigate whether any of these assays, either singly or in combination, can contribute additional information concerning increased risk of relapse and death because of malignant melanoma. In total, 98 patients (54 males, 44 females) with malignant melanoma were included in the study. As a continuous variable, S100BB (P=0.016) was associated statistically with increased risk of relapse; this was not the case for increased values of either S100 (P=0.11) or S100A1B (P=0.92). The Kaplan-Meier overall survival as well as disease specific survival curve for the S100 serum level demonstrated a statistically significant association with better survival if the patient had a S100 level <or=150 ng/l (P<0.001). Survival analyses for S100A1B using a defined cutoff of 50 ng/l showed a statistically significant association concerning overall and disease specific survival (P<0.001). Furthermore, S100BB was associated with overall and disease specific survival using a defined cutoff of 50 ng/l (P<0.001). No statistically significant correlation was found between S100A4 and overall survival (P=0.96) and there was no correlation between elevated levels of S100 and the immunohistochemical staining of S100A4 (P=0.1), nor for serum S100A1B (P=0.1) nor serum S100BB (P=0.17). Circulating S100A1B and S100BB are potential biomarkers in patients with malignant melanoma. S100BB should be considered as the preferred biomarker, showing potential in predicting both relapse and survival, in contrast to both S100 and S100A1B.

  • 23.
    Bolander, Åsa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Wagenius, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Brattström, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ullenhag, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hesselius, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    The Role of Circulating Angiogenic Factors in Patients Operated on for Localized Malignant Melanoma2007In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 27, no 5A, p. 3211-3217Article in journal (Refereed)
    Abstract [en]

    Malignant melanoma is a disease capable of rapid progression and rapidly developing metastases. Angiogenesis is a key event signalling tumour progression and elevated levels of angiogenic markers may indicate metastatic disease. No previously published work has, so far, examined plasma vascular endothelial growth factor (VEGF) and its receptor, VEGFR-1, in melanoma. This study investigated circulating levels of the angiogenic factors, VEGF-A and -D, their receptors 1-3 and hepatocyte growth factor (HGF)/scatter factor, in patients shortly after primary surgery for localized malignant melanoma. Elevated circulating levels of VEGF and its receptors, and of HGF, were found postoperatively, possibly derived from the reactive stroma adjacent to the tumours. Using univariate analysis, a correlation between levels of VEGFR-1 and relapse was found, but a correlation between the investigated angiogenic factors and survival could not be established. The results of the present study indicate that production of these angiogenic factors may be due to sources other than malignant melanoma cells.

  • 24.
    Bolin, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wiberg-Itzel, Eva
    Department of Obstetrics and Gynaecology, Karolinska Institutet, Stockholm, Sweden.
    Wikström, Ann-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Goop, Margareta
    Department of Obstetrics and Gynaecology, Karlstad, Sweden.
    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.
    Akerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Angiopoietin-1/angiopoietin-2 ratio for prediction of preeclampsia2009In: American Journal of Hypertension, ISSN 0895-7061, E-ISSN 1941-7225, Vol. 22, no 8, p. 891-895Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A number of different biophysical and biochemical markers have been proposed as predictors of preeclampsia. Factors involved in the angiogenic balance are suggested as candidate markers. The purpose of this prospective, longitudinal cohort study was to determine whether a ratio between Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) can be used to predict preeclampsia in a low-risk population. METHODS: A cohort of healthy pregnant women (n = 469) were enrolled at gestational weeks 8-12. Plasma samples were collected at gestational weeks 10, 25, 28, 33, and 37. By using commercially available enzyme-linked immunosorbent assay kits Ang-1 and Ang-2 were analyzed. RESULTS: The median Ang-1/Ang-2 ratio increased during pregnancy in all women, but the ratios were significantly lower at gestational weeks 25 and 28 in women who later developed preeclampsia than in normal pregnant women (1.49 compared to 2.19 and 2.12 compared to 3.54, P < 0.05 and P < 0.05). CONCLUSION: Our data indicate that in a low-risk population of women the Ang-1/Ang-2 ratio in plasma constitutes a possible biomarker for prediction of later onset of preeclampsia.

  • 25.
    Bourlev, Vladimir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Ilyasova, Natalia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Adamyan, Leyla
    Research Centre of Obstetrics, Gynecology and Perinatology, Russian Academy of the Medical Sciences, Moscow, Russia.
    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.
    Signs of reduced angiogenic activity after surgical removal of deeply infiltrating endometriosis2010In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 94, no 1, p. 52-57Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study the concentrations of vascular endothelial growth factor A (VEGF-A), soluble vascular endothelial growth factor receptors-1 and -2 (sVEGFR-1 and -2), angiogenin, and angiopoietin-2 (Ang-2) in serum and peritoneal fluid from healthy controls and women with advanced endometriosis. Further, we addressed the question of whether surgical removal of endometriotic lesions was associated with normalization of the serum concentrations of the same markers. DESIGN: Patients with endometriosis before and after surgery were compared with control patients. SETTING: University Hospital. PATIENT(S): Twenty-one healthy controls and 32 women with advanced endometriosis. INTERVENTION(S): In women with endometriosis we performed surgical removal of endometriotic lesions using laparoscopy. MAIN OUTCOME MEASURE(S): Data on serum and peritoneal fluid concentrations of selected markers in healthy controls and women with endometriosis before surgery and in serum 5 to 7 days after surgery. RESULT(S): Women with endometriosis had elevated levels of VEGF-A, sVEGFR-1, and Ang-2 in serum and all studied markers in peritoneal fluid compared with healthy controls. Surgical removal of endometriotic lesions resulted in decreased serum levels of pro-angiogenic VEGF-A and increased levels of sVEGFR-2 that negatively regulates the action of VEGF. CONCLUSION(S): Women with advanced endometriosis have serum and peritoneal fluid concentrations of several factors involved in the regulation of angiogenesis that differ from those in healthy women, and these changes at least partly normalize within a week after surgical removal of the endometriotic lesions.

  • 26.
    Bourlev, Vladimir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Volkov, N.
    Pavlovitch, S.
    Lets, N.
    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.
    The relationship between microvessel density, proliferative activity and expression of vascular endothelial growth factor-A and its receptors in eutopic endometrium and endometriotic lesions2006In: Reproduction, ISSN 1470-1626, E-ISSN 1476-3990, Vol. 132, no 3, p. 501-509Article in journal (Refereed)
    Abstract [en]

    Studies were performed to elucidate the possible relationship between microvessel density, proliferative activity and angiogenesis in eutopic endometrium from women with and without endometriosis and peritoneal endometriotic lesions. The question whether changes in these parameters in endometriotic lesions were reflected by the level of vascular endothelial growth factor-A (VEGF-A) in serum and peritonea fluid was also studied. Biopsy specimens of both eutopic endometrium and peritoneal endometriotic lesions from women with endometriosis (n=25) as well as eutopic endometrium from women without endometriosis (n=14) were analysed immunohistochemically regarding microvessel density, proliferative activity, and expression of VEGF-A and its receptors vascular endothelial growth factor receptors 1 and 2 (VEGFR-1 and VEGFR-2) in stroma, glands and blood vessels. The VEGF-A concentration was measured in peritoneal fluid and serum. Secretory phase eutopic endometrium from women with endometriosis had significantly higher microvessel density, expression of VEGF-A in glandular epithelium and VEGFR-2 in endometrial blood vessels than those from women without endometriosis. Endometriotic lesions with high proliferative activity had a higher microvessel density and showed higher vascular expression of VEGFR-2 as well as being accompanied by higher levels of VEGF-A in peritoneal fluid and serum, compared with lesions with low proliferative activity. In conclusion, there seems to be a dysregulation of angiogenic activity in the eutopic endometrium of women with endometriosis and endometriotic lesions with high proliferative activity were accompanied by higher local angiogenic activity and higher levels of VEGF in serum and peritoneal fluid.

  • 27.
    Branth, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hambraeus, Leif
    Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
    Piehl-Aulin, Karin
    Department of Caring Science, Division for Biomedicine, University of Örebro, Örebro, Sweden.
    Essén-Gustavsson, Birgitta
    Department of Clinical Sciences, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Åkerfeldt, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Olsson, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Metabolic stress-like condition can be induced by prolonged strenuous exercise in athletes2009In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 114, no 1, p. 12-25Article in journal (Refereed)
    Abstract [en]

    Few studies have examined energy metabolism during prolonged, strenuous exercise. We wanted therefore to investigate energy metabolic consequences of a prolonged period of continuous strenuous work with very high energy expenditure. Twelve endurance-trained athletes (6 males and 6 females) were recruited. They performed a 7-h bike race on high work-load intensity. Physiological, biochemical, endocrinological, and anthropometric muscular compartment variables were monitored before, during, and after the race. The energy expenditure was high, being 5557 kcal. Work-load intensity (% of VO2 peak) was higher in females (77.7%) than in men (69.9%). Muscular glycogen utilization was pronounced, especially in type I fibres (>90%). Additionally, muscular triglyceride lipolysis was considerably accelerated. Plasma glucose levels were increased concomitantly with an unchanged serum insulin concentration which might reflect an insulin resistance state in addition to proteolytic glyconeogenesis. Increased reactive oxygen species (malondialdehyde (MDA)) were additional signs of metabolic stress. MDA levels correlated with glycogen utilization rate. A relative deficiency of energy substrate on a cellular level was indicated by increased intracellular water of the leg muscle concomitantly with increased extracellular levels of the osmoregulatory amino acid taurine. A kindred nature of a presumed insulin-resistant state with less intracellular availability of glucose for erythrocytes was also indicated by the findings of decreased MCV together with increased MCHC (haemoconcentration) after the race. This strenuous energy-demanding work created a metabolic stress-like condition including signs of insulin resistance and deteriorated intracellular glucose availability leading to compromised fuelling of ion pumps, culminating in a disturbed cellular osmoregulation indicated by taurine efflux and cellular swelling.

  • 28.
    Branth, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hambraeus, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindgren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Olsson, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Carlander, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Arnetz, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    Development of abdominal fat and incipient metabolic syndrome in young healthy men exposed to long-term stress2007In: NMCD. Nutrition Metabolism and Cardiovascular Diseases, ISSN 0939-4753, E-ISSN 1590-3729, Vol. 17, no 6, p. 427-435Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIM: The sympathetic nervous system may be involved in the pathophysiology of insulin resistance and metabolic cardiovascular syndrome in young men. The aim was to study the effects of long-term stress on different features of the metabolic syndrome (MES) in formerly non-obese healthy young males during 5 months of defined conditions. METHODS AND RESULTS: Sixteen healthy male sailors (mean age 36.5 (SD)+/-7 years) participating in a sailing race around the world were recruited for the study. Investigations were done before the start and at stop overs after finishing laps 1, 2 and 4 (1, 2(1/2) and 5 months, respectively). Anthropometric and blood pressure data as well as biochemical data associated with MES were substantiated. Food intake and exercise were chartered and largely controlled. A mean weight loss of 4.5+/-2 kg (P<0.005), comprising both fat and lean body mass, was recorded during the first lap. Subsequently after 5 months, a weight gain, mainly consisting of 1.2+/-1.1 kg body fat (P<0.05), took place, concomitantly with a protein mass drop of 0.6+/-1.1 kg (P<0.05). The body fat gain accumulated on the abdominal region. Elevated blood levels of HbA1c, insulin and the triglycerides/high-density lipoprotein ratio were also observed during the race. Likewise heart rate and systolic blood pressure increased slightly but to a statistically significant extent. CONCLUSIONS: Non-obese healthy young men exposed to long-term stress developed abdominal obesity and signs of a metabolic syndrome in embryo, also emphasized by biochemical and blood pressure alterations. It is suggested that long-term and sustained stress activation might be an additional risk factor for the development of MES, even after control of dietary and exercise habits.

  • 29.
    Brattström, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Hesselius, Patrik
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wagenius, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Brodin, Ola
    Serum VEGF and bFGF adds prognostic information in patients with normal platelet counts when sampled before, during and after treatment for locally advanced non-small cell lung cancer2003In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 43, no 1, p. 55-62Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) have both been implicated to have roles in tumour angiogenesis. In the present retrospective study, serum VEGF and bFGF from patients with locally advanced non-small cell lung cancer (NSCLC) were analysed before, during and after treatment. Seventy-three patients and a total of 460 serum samples were analysed for VEGF and 443 serum samples were analysed for bFGF. Pre-treatment bFGF levels in patients with normal platelet counts, were correlated to poorer survival, P-value = 0.047. During chemotherapy, each rise of one unit bFGF corresponded to a hazard ratio of 4.06 (P=0.022). In patients with normal platelet counts, VEGF levels after radiotherapy significantly correlated to good prognosis (P=0.023), during radiotherapy VEGF levels indicated the same correlation (P=0.085). We conclude that serum VEGF and especially bFGF are of clinical interest as prognostic factors, especially in patients presenting with normal platelet counts.

  • 30. Byström, Per
    et al.
    Björkegren, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Johansson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Berglund, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Serum vitamin B12 and folate status among patients with chemotherapy treatment for advanced colorectal cancer2009In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 114, no 3, p. 160-164Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: There are conflicting results on the role of cobalamin and folate for epidemiology and carcinogenesis in colorectal cancer patients and the need of supplementation for prevention of chemotherapy toxicity. PATIENTS AND METHODS: Serum cobalamin, folate, and homocysteine were analysed before and during the treatment of 93 patients with advanced colorectal cancer (ACRC) with first-line chemotherapy treatment. This cohort was compared with a healthy control group of 224 individuals. RESULTS: Patients with ACRC had similar cobalamin, folate, and homocysteine values as the healthy control group. There were no correlations between serum cobalamin, folate, and homocysteine values and objective response. There were no correlations to anaemia or other severe toxicity for cobalamin and homocysteine. A total of 12 patients had folate deficiency, and 10 of those suffered from severe toxicity (grade 3 or more). All patients had markedly increased folate values after 2 months of treatment. Folate and homocysteine did not predict patient outcome; however, patients with subclinically low cobalamin values (<300 pmol/L) had significant better overall survival and time to progression than patients with normal or high cobalamin values. CONCLUSION: Patients with ACRC seem to have fairly adequate cobalamin and folate status before and during chemotherapy treatment. This study indicates that ACRC patients receiving chemotherapy do not need supplementation with vitamin B12 and folate. A minor portion of the patients had folate deficiency, and most of those patients had severe toxicity. Patients with subclinically low cobalamin values had surprisingly better survival.

  • 31.
    Cai, Linjun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Borowiec, Jan
    Xu, Shengyuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Han, Wenyu
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Assays of urine levels of HNL/NGAL in patients undergoing cardiac surgery and the impact of antibody configuration on their clinical performances2009In: Clinica Chimica Acta, ISSN 0009-8981, E-ISSN 1873-3492, Vol. 403, no 1-2, p. 121-125Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Acute kidney injury (AKI) is one of the most serious postoperative complications of cardiac surgery. The lack of early and powerful markers for AKI makes the morbidity and mortality still very high. HNL (Human neutrophil lipocalin)/NGAL (Neutrophil gelatinase-associated lipocalin) was recently shown as a novel biomarker for AKI after cardiac surgery. METHODS: Serial urine samples from 59 patients undergoing cardiac surgery were analyzed by polyclonal antibody based radioimmunoassay (RIA), monoclonal-polyclonal antibody based enzyme-linked immunosorbent assay (ELISA). RESULTS: We found 10 to 100-fold increases in urine HNL/NGAL levels in about half of the patients 2 h after termination of the operation and elevated levels in all patients 72 h post operation. The urine levels of HNL/NGAL showed a weak, but significant relation with kidney function as measured by plasma levels of cystatin C or creatinine. The 2 h-HNL/NGAL levels were positively correlated to extracorporeal circulation time (p<0001). The assays were well correlated, but had different clinical performances. CONCLUSIONS: We confirmed that urine HNL/NGAL may be a useful early biomarker of postoperative kidney injury. The results indicate that the antibody configuration of the assay has an impact on the clinical performance of the assay.

  • 32.
    Cai, Linjun
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Rubin, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Han, Wenyu
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Xu, Shengyuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The Origin of Multiple Molecular Forms in Urine of HNL/NGAL2010In: Clinical Journal of the American Society of Nephrology, ISSN 1555-9041, Vol. 5, no 12, p. 2229-2235Article in journal (Refereed)
    Abstract [en]

    Background and objectives: Several molecular forms of human neutrophil lipocalin/neutrophil gelatinase-associated lipocalin (HNL/NGAL), a novel biomarker for acute kidney injury (AKI), have been found in urine. The origin of these different forms and the effect of antibody configuration on assay performances were investigated in this report. Design, setting, participants, & measurements: The molecular forms of HNL/NGAL from human neutrophils and present in urine obtained from cardiac surgery patients and patients with urinary tract infection (UTI), as well as secreted from HK-2 cells, were studied by Western blotting. The levels of HNL/NGAL in urine were measured by ELISAs. Kidney injury was simulated by incubation of HK-2 cells under stressful conditions. Results: The major molecular form of HNL/NGAL secreted by neutrophils is dimeric, whereas the major form secreted by HK-2 cells is monomeric. This was reflected by a predominance of the monomeric form in urine from patients with AKI and the dimeric form in patients with UTIs. The epitope specificities of the antibody used in the ELISAs had a profound effect on assay performance and paralleled differences of the antibodies to identify the different forms of urine HNL/NGAL. Conclusions: The monomeric form is the predominant form secreted by tubular epithelial cells, and the dimeric form is the predominant form secreted by neutrophils. The development of molecular form-specific assays for HNL/NGAL may be a means to identify the origin of HNL/NGAL in urine and construct more specific tools for the diagnosis of AKI.

  • 33.
    Carlander, David
    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.
    Avian Antibodies Can Eliminate Interference Due To Complement Activation In ELISA2002In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 106, no 3, p. 189-195Article in journal (Refereed)
    Abstract [en]

    Antibodies derived from egg yolk offer many advantages over mammalian antibodies in several aspects. Chicken antibodies do not activate the human complement system and are sometimes a more suitable choice in designing solid-phase immunometric assays than mammalian antibodies. The material often recommended for immunological assays is serum. A freshly drawn serum sample contains an active complement system, which is inactivated during storage. Mammalian antibodies used in most immunological assays may activate the human complement system. Activated complement components will bind to the antibodies thereby partly block the antibody binding epitopes. We show that an active complement system in undiluted samples reduce the absorbance values by approximately 50 % when using goat antibodies but not when using chicken antibodies. This difference will cause erroneous test results that will vary depending on the handling of the samples. Chicken antibodies can be used to eliminate this interference problem.

  • 34. Carlson, Marie
    et al.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lampinen, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    C3b-induced eosinophil degranulation involves PI3-kinases and is inhibited by protein kinase C activity2011In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 119, no 2, p. 119-126Article in journal (Refereed)
    Abstract [en]

    Selective release of individual eosinophil granule proteins has been demonstrated in eosinophilic conditions and in vitro using different stimuli. The aim of this study was to investigate if selective release of eosinophil cationic protein (ECP), eosinophil protein X/eosinophil derived-neurotoxin (EPX/EDN) and eosinophil peroxidase (EPO) could be due to the involvement of different signal transduction pathways. Peripheral blood granulocytes from healthy donors were incubated with Wortmannin, LY294002, Genistein, Staurosporine, GÖ6976 or PD98059 prior to the induction of degranulation by C3b. The released amounts of ECP, EPO and EPX/EDN were determined by immunoassays, and related to the total cell content of respective protein. Wortmannin caused a significant, dose-dependent inhibition of all three granule proteins. LY294002 (10(-6)  M) also inhibited the release of all proteins. Genistein (10(-6)  M) inhibited the release of ECP, whereas the release of EPO was increased. However, there was a tendency towards similar concentration-dependent patterns of release of all three proteins. Staurosporine (10(-7)  M), GÖ6976 (10(-6)  M) and PD98059 (10(-5)  M) caused an increased release of the three proteins. PI3-kinases play an important role in the C3b-induced release of ECP, EPO and EPX/EDN, whereas protein kinase C seems to have inhibitory effects on C3b-induced degranulation.

  • 35.
    Carlsson, Lena
    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.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Elevated levels of thymidine kinase 1 peptide in serum from patients with breast cancer2009In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 114, no 2, p. 116-120Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Thymidine kinase (TK) has an important role in DNA synthesis and is thus related to cell proliferation and turn-over. Traditionally, TK has been measured by enzymatic activity or radioimmunoassays. These assays are difficult to adapt to random access instruments. The aim of this study was to evaluate a new immunological sandwich assay for detection of TK peptides in serum from breast cancer patients. MATERIAL AND METHODS: Serum samples were collected from patients with breast cancer and stored frozen at -70 degrees C. The samples were collected after surgery, after metastatic tumor recurrence and after chemotherapy due to tumour recurrence. Patients' serum samples were analysed by the TK enzyme-linked immunosorbent assay (ELISA). RESULTS: In receiver operating characteristics (ROC) analyses of TK1 for diagnosis of breast cancer, the area under the curve (AUC) collected four weeks after surgery was 0.56 (95% CI 0.47-0.65), for samples collected postsurgically after tumour recurrence 0.73 (95% CI 0.65-0.80), and after chemotherapy 0.64 (95% CI 0.56-0.72). CONCLUSIONS: This study indicates that the tumour proliferation marker TK has a potential as a serum marker in breast cancer. Further studies are warranted to verify this observation.

  • 36.
    Carlsson, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lennartsson, Lena
    Ronquist, Gunnar
    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.
    Nilsson, Sten
    Nilsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mode of growth determines differential expression of prostasomes in cultures of prostate cancer cell lines and opens for studies of prostasome gene expression2006In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 111, no 3, p. 293-301Article in journal (Refereed)
    Abstract [en]

    The exocrine secretion of the acinar gland cells in the human prostate consists of, among other components, a serous secretion and prostasomes. The prostasomes are functionally associated with both reproduction and prostate cancer development and are capable to raise autoantibodies at various pathologies. Therefore, we are trying to characterize prostasome antigens by analysing prostasome- producing cell lines of prostate cancers with the cDNA microarray technique. To obtain one state with synthesis of prostasomes and another state without synthesis, we checked whether the prostasome differentiation was influenced by the mode of growing the cells, that is, whether the cells had been growing on a solid support or on a flexible one.

    We studied the expression of prostasomes in the cell lines PC3, DU145 and LNCaP. We grew the cells with the following methods: Monocellular layers on microbeads, multicellular spheroids, single cells in suspension cultures, and xenotransplants in nude rats. The presence of prostasomes was examined by ELISA, immunocytochemistry or electron microscopy.

    The results showed that growing the cells on microbeads (solid support) produced a differentiation of prostasomes, while growing the cells in multicellular spheroids (flexible support) did not. Thus it should be possible to apply cDNA microarray analyses for characterizing the genes which are active at the cellular expression of prostasomes and then deduce the prostasome antigens.

  • 37.
    Carlsson, Lena
    et al.
    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, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Reference Values for 27 Clinical Chemistry Tests in 70-Year-Old Males and Females2010In: Gerontology, ISSN 0304-324X, E-ISSN 1423-0003, Vol. 56, no 3, p. 259-265Article in journal (Refereed)
    Abstract [en]

    Background: Reference values are usually defined based on blood samples from healthy men or nonpregnant women in the age range of 20-50 years. These values are not optimal for elderly patients, as many biological markers change over time and adequate reference values are important for correct clinical decisions. Objective: To validate NORIP (Nordic Reference Interval Project) reference values in a 70-year-old population. Methods: We studied 27 frequently used laboratory tests. The 2.5th and 97.5th percentiles for these markers were calculated according to the recommendations of the International Federation of Clinical Chemistry on the statistical treatment of reference values. Results: Reference values are reported for plasma alanine aminotransferase, albumin, alkaline phosphatase, pancreas amylase, apolipoprotein A1, apolipoprotein B, aspartate aminotransferase, bilirubin, calcium, chloride, cholesterol, creatinine, creatine kinase, C-reactive protein, glucose, gamma-glutamyltransferase, HDL-cholesterol, iron, lactate dehydrogenase, LDL-cholesterol, magnesium, phosphate, potassium, sodium, transferrin, triglycerides, urate and urea. Conclusion: Reference values calculated from the whole population and a subpopulation without cardiovascular disease showed strong concordance. Several of the reference interval limits were outside the 90% CI of a Scandinavian population (NORIP).

  • 38.
    Carlsson, Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Eliasson, R
    The Andrology Laboratory at Queen Sophia Hospital, Stockholm, Sweden.
    Egberg, N
    The Andrology Laboratory at Queen Sophia Hospital, Stockholm, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Association of cystatin C with prostasomes in human seminal plasma2011In: International Journal of Andrology, ISSN 0105-6263, E-ISSN 1365-2605, Vol. 33, no 4, p. 363-368Article in journal (Refereed)
    Abstract [en]

    It was recently elucidated that cystatin C, a protein targeted to the classical secretory pathway by its signal peptide sequence, can also be secreted in association with exosomes. Accordingly, we wanted to investigate whether there is a secretory link between cystatin C and prostasomes in human seminal plasma. Cystatin C concentrations in seminal plasma from 50 men including 6 vasectomized men were measured by turbidimetry on an Architect Ci8200. Some of the seminal plasma samples were also analysed utilizing an Epics Profile XL-MCL cytometer. We found high concentrations of cystatin C in seminal plasma. The 2.5-97.5 percentiles, performed by bootstrap estimation, were 25.8 [95% confidence interval (CI): 22.3-29.4] to 77.0 mg/L (95% CI: 71.9-82.1). Cystatin C is present in approximately 50 times higher concentration in seminal plasma compared with blood plasma. There was no clear difference as regards seminal plasma content of cystatin C between vasectomized men and the rest of the group. Immunoblot analysis with chicken anti-cystatin C antibody revealed a firm association of cystatin C with prostasomes. Flow cytometric analysis demonstrated that cystatin C was linked to prostasomes also meaning an at least partial prostasomal membrane surface localization.

  • 39.
    Carlsson, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lipcsey, Miklós
    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.
    Tano, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Rubertsson, Sten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Eriksson, Mats
    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, Infectious Diseases.
    Inflammatory and circulatory effects of the reduction of endotoxin concentration in established porcine endotoxemic shock: a model of endotoxin elimination2009In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 37, no 3, p. 1031-e4Article in journal (Refereed)
    Abstract [en]

    Objective:

    To study whether a reduction of the endotoxin load, once a generalized inflammatory state has been established, reduces the inflammatory response and endotoxin-induced effects on circulation, hypoperfusion, and organ dysfunction.

    Design:

    Prospective parallel-grouped placebo-controlled randomized interventional experimental study.

    Setting:

    University research unit.

    Subjects:

    Healthy pigs.

    Interventions:

    The animals were subjected to a continuous endotoxin infusion rate of either 4.0 or 0.063 µg endotoxin × kg-1 × h-1 for 1, 2, or 6 hours. The 1- and 2-hour infusion groups represented the applied therapy by a reduction of the endotoxin load of 5/6 and 2/3, respectively.

    Measurements and Main Results:

    During a 6-hour experiment, laboratory and physiologic parameters were recorded hourly in 26 anesthetized and mechanically ventilated pigs. Primary end point was to detect differences in tumor necrosis factor-[alpha] (TNF-[alpha]) concentration during the last 3 hours of the experiment. Despite the early reduction of the endotoxin load, no effect on TNF-[alpha] concentration was observed. Similarly, in circulatory parameters, such as mean arterial pressure and oxygen delivery, and in platelet count and renal function, no effects were noted. However, there was some improvement in pulmonary compliance and function as determined by Pao2, Paco2, and pH. These changes were associated with slight improvements in leukocyte response and capillary leakage.

    Conclusions:

    Termination of the endotoxin infusion represents an incontestable model of endotoxin concentration reduction. Endotoxin elimination strategies applied at the TNF-[alpha] peak or later will have very little or no effect on TNF-[alpha]–mediated toxicity. Nevertheless, there was an effect on the leukocyte response that was associated with an improvement in respiratory function and microcirculation, making it impossible to rule out fully the beneficial effect of this strategy. However, the effects were limited in relation to the magnitude of the endotoxin concentration reduction and the very early application of the antiendotoxin measure.

  • 40.
    Castegren, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i D län (CKFD).
    Skorup, Paul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lipcsey, Miklós
    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.
    Sjölin, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Endotoxin tolerance variation over 24 h during porcine endotoxemia: association to changes in circulation and organ dysfunction2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e53221-Article in journal (Refereed)
    Abstract [en]

    Endotoxin tolerance (ET), defined as reduced inflammatory responsiveness to endotoxin challenge following a first encounter with endotoxin, is an extensively studied phenomenon. Although reduced mortality and morbidity in the presence of ET has been demonstrated in animal studies, little is known about the temporal development of ET. Further, in acute respiratory distress syndrome ET correlates to the severity of the disease, suggesting a complicated relation between ET and organ dysfunction. Eighteen pigs were subjected to intensive care and a continuous endotoxin infusion for 24 h with the aim to study the time course of early ET and to relate ET to outcome in organ dysfunction. Three animals served as non-endotoxemic controls. Blood samples for cytokine analyses were taken and physiological variables registered every third hour. Production of TNF-α, IL-6, and IL-10 before and after endotoxin stimulation ex vivo was measured. The difference between cytokine values after and before ex vivo LPS stimulation (Δ-values) was calculated for all time points. ΔTNF-α was employed as the principal marker of ET and lower ΔTNF-α values were interpreted as higher levels of ET. During endotoxin infusion, there was suppression of ex vivo productions of TNF-α and IL-6 but not of IL-10 in comparison with that at 0 h. The ex vivo TNF-α values followed another time concentration curve than those in vivo. ΔTNF-α was at the lowest already at 6 h, followed by an increase during the ensuing hours. ΔTNF-α at 6 h correlated positively to blood pressure and systemic vascular resistance and negatively to cardiac index at 24 h. In this study a temporal variation of ET was demonstrated that did not follow changes in plasma TNF-α concentrations. Maximal ET occurred early in the course and the higher the ET, the more hyperdynamic the circulation 18 h later.

  • 41. Chen, Yuqing
    et al.
    Mahata, Manjula
    Rao, Fangwen
    Khandrika, Srikrishna
    Courel, Maite
    Fung, Maple M
    Zhang, Kuixing
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ziegler, Michael G
    Hamilton, Bruce A
    Lipkowitz, Michael S
    Taupenot, Laurent
    Nievergelt, Caroline
    Mahata, Sushil K
    O'Connor, Daniel T
    Chromogranin A regulates renal function by triggering Weibel-Palade body exocytosis2009In: Journal of the American Society of Nephrology, ISSN 1046-6673, E-ISSN 1533-3450, Vol. 20, no 7, p. 1623-1632Article in journal (Refereed)
    Abstract [en]

    Chromogranin A (CHGA), a protein released from secretory granules of chromaffin cells and sympathetic nerves, triggers endothelin-1 release from endothelial cells. CHGA polymorphisms associate with an increased risk for ESRD, but whether altered CHGA-endothelium interactions may explain this association is unknown. Here, CHGA led to the release of endothelin-1 and Weibel-Palade body exocytosis in cultured human umbilical vein endothelial cells. In addition, CHGA triggered secretion of endothelin-1 from glomerular endothelial cells and TGF-beta1 from mesangial cells cocultured with glomerular endothelial cells. In humans, plasma CHGA correlated positively with endothelin-1 and negatively with GFR. GFR was highly heritable in twin pairs, and common promoter haplotypes of CHGA predicted GFR. In patients with progressive hypertensive renal disease, a CHGA haplotype predicted rate of GFR decline. In conclusion, these data suggest that CHGA acts through the glomerular endothelium to regulate renal function.

  • 42. Chorell, Ellin
    et al.
    Moritz, Thomas
    Branth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Antti, Henrik
    Svensson, Michael B.
    Predictive Metabolomics Evaluation of Nutrition-Modulated Metabolic Stress Responses in Human Blood Serum During the Early Recovery Phase of Strenuous Phys