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  • 1.
    Abujrais, Sandy
    et al.
    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, Research group (Dept. of women´s and children´s health), Reproductive biology.
    Ahnoff, Martin
    Department of Marine Sciences, University of Gothenburg, Carl Skottbergs gata 22B, SE-41319 Gothenburg, Sweden..
    Rasmusson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Åkerfeldt, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    A sensitive method detecting trace levels of levonorgestrel using LC-HRMS.2019In: Contraception, ISSN 0010-7824, E-ISSN 1879-0518, Vol. 100, no 3, p. 247-249Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To develop a high resolution mass spectrometry (HRMS) method to quantify levonorgestrel (LNG) in serum.

    STUDY DESIGN: Levonorgestrel was extracted using solid phase extraction and measured using liquid chromatography (LC) HRMS.

    RESULTS: Low limit of quantification (LLOQ) was 25pg/mL and low limit of detection (LLOD) was 12.5pg/mL. Precision and accuracy bias were<10%. LNG in serum samples from Mirena® users ranged between 37 to 219pg/mL (n=12). In eight out of 22 patients with suspected intrauterine device (IUD) expulsion LNG was detected (26 to 1272pg/mL).

    CONCLUSION: A sensitive, fast and simple LC-HRMS method was developed to detect trace levels of LNG.

  • 2.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics.
    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.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive biology.
    Sub-clinical atherosclerosis in the common carotid artery in women with/without previous pre-eclampsia: A seven-year follow-up2019In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 290, p. 206-213Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Pre-eclampsia is associated with increased risk of cardiovascular disease and premature death. However, conventional common carotid artery intima-media thickness (CCA-IMT) measurement does not reflect this. In contrast, measurement of the individual CCA intima and media thicknesses clearly indicates increased vascular risk both at diagnosis and about one year after pre-eclampsia. This study examined whether individual CCA wall layers, risk factors for cardiovascular disease, and markers of endothelial dysfunction had normalized or remained unfavorable seven years after pre-eclampsia.

    METHODS: The individual CCA intima and media thicknesses were measured using 22 MHz ultrasound. Conventional cardiovascular risk factors were recorded. A thick intima, thin media and high intima/media thickness ratio (I/M) are signs of sub-clinical atherosclerosis.

    RESULTS: The median age of women with previous pre-eclampsia (cases = 23) or normal pregnancies (controls = 35) was 39/37 years. At follow-up (median about seven years), the intima remained thicker and the I/M was higher in cases than in controls [all p < 0.0001; p < 0.001 after adjustment for time to follow-up, body mass index (BMI), and mean arterial pressure (MAP)], whereas the CCA-IMT was illogically thinner. Further, BMI, MAP, hip circumference, abdominal height, serum endostatin and apolipoprotein B levels were higher in cases (all p < 0.05). Intima and I/M measurements were correlated with age, MAP, endostatin and apolipoprotein B, whereas no logical correlations were found for CCA-IMT.

    CONCLUSIONS: The arteries in cases but not controls were still adversely affected after seven years. Measuring intima thickness and I/M appears preferable to measuring CCA-IMT for demonstrating vascular risk after pre-eclampsia.

  • 3.
    Akhter, Tansim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Gynecological endocrinology.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics. Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Larsson, Marita
    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.
    Wikström, Gerhard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Gynecological endocrinology.
    Serum Pentraxin 3 is associated with signs of arterial alteration in women with preeclampsia.2017In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 241, p. 417-422Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Preeclampsia (PE) in pregnancy is a state of exaggerated inflammation and is associated with an increased risk of cardiovascular disease (CVD) later in life. Levels of pentraxin 3 (PTX3), a novel inflammation marker, are increased during PE and in individuals with CVD. The primary aim of this study was to assess whether serum PTX3 in women with PE is associated with adverse arterial effects; a thicker intima and higher intima/media (I/M) ratio in the common carotid artery (CCA).

    METHODS: Serum PTX3 levels were measured using commercially available enzyme-linked immunosorbent assay kits, and individual CCA intima and media thicknesses were estimated by 22MHz non-invasive ultrasound in 55 women at PE diagnosis and 64 women with normal pregnancies at a similar gestational age, and about one year postpartum. A thick intima, thin media and high I/M ratio indicate a less healthy artery wall.

    RESULTS: During pregnancy serum PTX3 correlated positively with intima thickness and I/M ratio but negatively with media thickness (all p<0.0001), indicating adverse arterial effects. About one year postpartum, PTX3 levels had decreased in both groups and there remained no significant group difference or significant correlation with CCA wall layers.

    CONCLUSIONS: Higher levels of serum PTX3 in women with PE were significantly associated with signs of adverse arterial effects during pregnancy, but not one year postpartum, supporting the rapid dynamics of PTX3.

  • 4. Alehagen, Urban
    et al.
    Aaseth, Jan
    Alexander, Jan
    Svensson, Erland
    Johansson, Peter
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Less fibrosis in elderly subjects supplemented with selenium and coenzyme Q10-A mechanism behind reduced cardiovascular mortality?2018In: Biofactors, ISSN 0951-6433, E-ISSN 1872-8081, Vol. 44, no 2, p. 137-147Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In an intervention study where 221 healthy elderly persons received selenium and coenzyme Q10 as a dietary supplement, and 222 received placebo for 4 years we observed improved cardiac function and reduced cardiovascular mortality. As fibrosis is central in the aging process, we investigated the effect of the intervention on biomarkers of fibrogenic activity in a subanalysis of this intervention study.

    MATERIAL AND METHODS: In the present subanalysis 122 actively treated individuals and 101 controls, the effect of the treatment on eight biomarkers of fibrogenic activity were assessed. These biomarkers were: Cathepsin S, Endostatin, Galectin 3, Growth Differentiation Factor-15 (GDF-15), Matrix Metalloproteinases 1 and 9, Tissue Inhibitor of Metalloproteinases 1 (TIMP 1) and Suppression of Tumorigenicity 2 (ST-2). Blood concentrations of these biomarkers after 6 and 42 months were analyzed by the use of T-tests, repeated measures of variance, and factor analyses.

    RESULTS: Compared with placebo, in those receiving supplementation with selenium and coenzyme Q10, all biomarkers except ST2 showed significant decreased concentrations in blood. The changes in concentrations, that is, effects sizes as given by partial eta2 caused by the intervention were considered small to medium.

    CONCLUSION: The significantly decreased biomarker concentrations in those on active treatment with selenium and coenzyme Q10 compared with those on placebo after 36 months of intervention presumably reflect less fibrogenic activity as a result of the intervention. These observations might indicate that reduced fibrosis precedes the reported improvement in cardiac function, thereby explaining some of the positive clinical effects caused by the intervention. © 2017 BioFactors, 2017.

  • 5.
    Alehagen, Urban
    et al.
    Linkoping Univ, Dept Med & Hlth Sci, Div Cardiovasc Med, SE-58185 Linkoping, Sweden.
    Alexander, Jan
    Norwegian Inst Publ Hlth, N-0403 Oslo, Norway.
    Aaseth, Jan
    Innlandet Hosp Trust, Res Dept, Brumunddal, Norway;Inland Norway Univ Appl Sci, N-2411 Elverum, Norway.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Decrease in inflammatory biomarker concentration by intervention with selenium and coenzyme Q10: a subanalysis of osteopontin, osteoprotergerin, TNFr1, TNFr2 and TWEAK2019In: Journal of Inflammation, ISSN 1476-9255, E-ISSN 1476-9255, Vol. 16, article id 5Article in journal (Refereed)
    Abstract [en]

    Background:

    Inflammation is central to the pathogenesis of many diseases. Supplementation with selenium and coenzyme Q10 has been shown to reduce cardiovascular mortality, and increase cardiac function in elderly persons with a low intake of selenium. There are indications that one of the mechanisms of this positive effect is a decrease in inflammation.

    Methods:

    Osteopontin, osteoprotegerin, sTNF receptor 1, sTNF receptor 2 and the tumor necrosis factor-like weak inducer of apoptosis called TWEAK, were determined in plasma after 6 months and 42months in 219 community-living elderly persons, of whom 119 received supplements of selenium (200g/day) and coenzyme Q10 (200mg/day), and 101 received a placebo. Repeated measures of variance were used to evaluate the levels, and the results were validated through ANCOVA analyses with adjustments for important covariates.

    Results:

    Significantly lower concentrations of four of the five biomarkers for inflammation were observed as a result of the intervention with the supplements. Only TWEAK did not show significant differences.

    Conclusion:

    In this sub-analysis of the intervention with selenium and coenzyme Q10 or placebo in an elderly community-living population, biomarkers for inflammation were evaluated. A significantly lower concentration in four of the five biomarkers tested could be demonstrated as a result of the supplementation, indicating a robust effect on the inflammatory system. The decrease in inflammation could be one of the mechanisms behind the positive clinical results on reduced cardiovascular morbidity and mortality reported earlier as a result of the intervention. The study is small and should be regarded as hypothesis-generating, but nonetheless adds important data about mechanisms presently known to increase the risk of clinical effects such as reduced cardiovascular mortality, increased cardiac function and better health-related quality of life scoring, as previously demonstrated in the active treatment group.

  • 6.
    Alfredsson, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Edén, Desirée
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Christersson, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Åberg, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    miR-223-3p regulates post-transcriptional tissue factor gene expression in human monocytic cellsManuscript (preprint) (Other academic)
  • 7.
    Andersen, Thomas
    et al.
    Stavanger Univ Hosp, Dept Anaesthesiol, Stavanger, Norway.
    Ueland, Thor
    Univ Oslo, Natl Hosp, Res Inst Internal Med, Oslo, Norway;Univ Oslo, KG Jebsen Inflammatory Res Ctr, Oslo, Norway;Univ Oslo, Fac Med, Oslo, Norway;Univ Tromso, Jebsen Thrombosis Res & Expertise Ctr TREC, Tromso, Norway.
    Ghukasyan Lakic, Tatevik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Åkerblom, Axel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Aukrust, Pal
    Univ Oslo, Natl Hosp, Res Inst Internal Med, Oslo, Norway;Univ Oslo, KG Jebsen Inflammatory Res Ctr, Oslo, Norway;Univ Oslo, Fac Med, Oslo, Norway;Univ Tromso, Jebsen Thrombosis Res & Expertise Ctr TREC, Tromso, Norway;Natl Hosp Norway, Oslo Univ Hosp, Sect Clin Immunol & Infect Dis, Oslo, Norway.
    Michelsen, Annika E.
    Univ Oslo, Natl Hosp, Res Inst Internal Med, Oslo, Norway;Univ Oslo, Fac Med, Oslo, Norway.
    James, Stefan K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Becker, Richard C.
    Univ Cincinnati, Coll Med, Heart Lung & Vasc Inst, Div Cardiovasc Hlth & Dis, Cincinnati, OH USA.
    Storey, Robert F.
    Univ Sheffield, Dept Infect Immun & Cardiovasc Dis, Sheffield, S Yorkshire, England.
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Kontny, Frederic
    Stavanger Univ Hosp, Dept Cardiol, Stavanger, Norway;Drammen Heart Ctr, Drammen, Norway.
    C-X-C Ligand 16 Is an Independent Predictor of Cardiovascular Death and Morbidity in Acute Coronary Syndromes2019In: Arteriosclerosis, Thrombosis and Vascular Biology, ISSN 1079-5642, E-ISSN 1524-4636, Vol. 39, no 11, p. 2402-2410Article in journal (Refereed)
    Abstract [en]

    Objective:

    The chemokine CXCL16 (C-X-C motif ligand 16) is a scavenger receptor for OxLDL (oxidized low-density lipoproteins) and involved in inflammation at sites of atherosclerosis. This study aimed to investigate the association of CXCL16 with clinical outcome in patients with acute coronary syndrome.

    Approach and Results:

    Serial measurements of CXCL16 were performed in a subgroup of 5142 patients randomized in the PLATO trial (Platelet Inhibition and Patient Outcome). Associations between CXCL16 and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and the individual components were assessed by multivariable Cox regression analyses. The hazard ratio per 50% increase in admission levels of CXCL16 analyzed as continuous variable was 1.64 (95% CI, 1.44-1.88), P<0.0001. This association remained statistically significant after adjustment for randomized treatment, clinical variables, CRP (C-reactive protein), leukocytes, cystatin C, NT-proBNP (N-terminal pro-brain natriuretic peptide), troponin T, GDF-15 (growth differentiation factor 15), and other biomarkers; hazard ratio 1.23 (1.05-1.45), P=0.0126. The admission level of CXCL16 was independently associated with cardiovascular death (1.50 [1.17-1.92], P=0.0014) but not with ischemic events alone, in fully adjusted analyses. No statistically independent association was found between CXCL16 measured at 1 month, or change in CXCL16 from admission to 1 month, and clinical outcomes.

    Conclusions:

    In patients with acute coronary syndrome, admission level of CXCL16 is independently related to adverse clinical outcomes, mainly driven by an association to cardiovascular death. Thus, CXCL16 measurement may enhance risk stratification in patients with this condition.

  • 8. Barber, RM
    et al.
    Fullman, N
    Sorensen, RJD
    Bollyky, T
    McKee, M
    Nolte, E
    Abajobir, AA
    Abate, KH
    Abbafati, C
    Abbas, KM
    Abd-Allah, F
    Abdulle, AM
    Ärnlöv, Johan
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Younis, MZ
    Yu, C
    Zaidi, Z
    El Sayed Zaki, M
    Zambrana-Torrelio, C
    Zapata, T
    Zenebe, ZM
    Zodpey, S
    Zoeckler, L
    Zuhlke, LJ
    Murray, CJL
    Healthcare Access and Quality Index based on mortality from causes amenable to personal health care in 195 countries and territories, 1990-2015: a novel analysis from the Global Burden of Disease Study 2015.2017In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 390, no 10091, p. 231-266Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: National levels of personal health-care access and quality can be approximated by measuring mortality rates from causes that should not be fatal in the presence of effective medical care (ie, amenable mortality). Previous analyses of mortality amenable to health care only focused on high-income countries and faced several methodological challenges. In the present analysis, we use the highly standardised cause of death and risk factor estimates generated through the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to improve and expand the quantification of personal health-care access and quality for 195 countries and territories from 1990 to 2015.

    METHODS: We mapped the most widely used list of causes amenable to personal health care developed by Nolte and McKee to 32 GBD causes. We accounted for variations in cause of death certification and misclassifications through the extensive data standardisation processes and redistribution algorithms developed for GBD. To isolate the effects of personal health-care access and quality, we risk-standardised cause-specific mortality rates for each geography-year by removing the joint effects of local environmental and behavioural risks, and adding back the global levels of risk exposure as estimated for GBD 2015. We employed principal component analysis to create a single, interpretable summary measure-the Healthcare Quality and Access (HAQ) Index-on a scale of 0 to 100. The HAQ Index showed strong convergence validity as compared with other health-system indicators, including health expenditure per capita (r=0·88), an index of 11 universal health coverage interventions (r=0·83), and human resources for health per 1000 (r=0·77). We used free disposal hull analysis with bootstrapping to produce a frontier based on the relationship between the HAQ Index and the Socio-demographic Index (SDI), a measure of overall development consisting of income per capita, average years of education, and total fertility rates. This frontier allowed us to better quantify the maximum levels of personal health-care access and quality achieved across the development spectrum, and pinpoint geographies where gaps between observed and potential levels have narrowed or widened over time.

    FINDINGS: Between 1990 and 2015, nearly all countries and territories saw their HAQ Index values improve; nonetheless, the difference between the highest and lowest observed HAQ Index was larger in 2015 than in 1990, ranging from 28·6 to 94·6. Of 195 geographies, 167 had statistically significant increases in HAQ Index levels since 1990, with South Korea, Turkey, Peru, China, and the Maldives recording among the largest gains by 2015. Performance on the HAQ Index and individual causes showed distinct patterns by region and level of development, yet substantial heterogeneities emerged for several causes, including cancers in highest-SDI countries; chronic kidney disease, diabetes, diarrhoeal diseases, and lower respiratory infections among middle-SDI countries; and measles and tetanus among lowest-SDI countries. While the global HAQ Index average rose from 40·7 (95% uncertainty interval, 39·0-42·8) in 1990 to 53·7 (52·2-55·4) in 2015, far less progress occurred in narrowing the gap between observed HAQ Index values and maximum levels achieved; at the global level, the difference between the observed and frontier HAQ Index only decreased from 21·2 in 1990 to 20·1 in 2015. If every country and territory had achieved the highest observed HAQ Index by their corresponding level of SDI, the global average would have been 73·8 in 2015. Several countries, particularly in eastern and western sub-Saharan Africa, reached HAQ Index values similar to or beyond their development levels, whereas others, namely in southern sub-Saharan Africa, the Middle East, and south Asia, lagged behind what geographies of similar development attained between 1990 and 2015.

    INTERPRETATION: This novel extension of the GBD Study shows the untapped potential for personal health-care access and quality improvement across the development spectrum. Amid substantive advances in personal health care at the national level, heterogeneous patterns for individual causes in given countries or territories suggest that few places have consistently achieved optimal health-care access and quality across health-system functions and therapeutic areas. This is especially evident in middle-SDI countries, many of which have recently undergone or are currently experiencing epidemiological transitions. The HAQ Index, if paired with other measures of health-system characteristics such as intervention coverage, could provide a robust avenue for tracking progress on universal health coverage and identifying local priorities for strengthening personal health-care quality and access throughout the world.

    FUNDING: Bill & Melinda Gates Foundation.

  • 9.
    Barrueta Tenhunen, Annelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Massaro, Fabrizia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Anthea Hosp, GVM Care & Res, Cardiac Anesthesia & Intens Care, Bari, Italy.
    Hansson, Hans Arne
    Univ Gothenburg, Inst Biomed, Gothenburg, Sweden.
    Feinstein, Ricardo
    Natl Vet Inst, Dept Pathol & Wildlife Dis, Uppsala, Sweden.
    Larsson, Anders
    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 Surgical Sciences, Hedenstierna laboratory.
    Perchiazzi, Gaetano
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Does the antisecretory peptide AF-16 reduce lung oedema in experimental ARDS?In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967Article in journal (Refereed)
    Abstract [en]

    Background: Acute respiratory distress syndrome (ARDS) is an acute inflammatory condition with pulmonary capillary leakage and lung oedema formation. There is currently no pharmacologic treatment for the condition. The antisecretory peptide AF-16 reduces oedema in experimental traumatic brain injury. In this study, we tested AF-16 in an experimental porcine model of ARDS.

    Methods: Under surgical anaesthesia 12 piglets were subjected to lung lavage followed by 2 hours of injurious ventilation. Every hour for 4 hours, measurements of extravascular lung water (EVLW), mechanics of the respiratory system, and hemodynamics were obtained.

    Results: There was a statistically significant (p = 0.006, two-way ANOVA) reduction of EVLW in the AF-16 group compared with controls. However, this was not mirrored in any improvement in the wet-to-dry ratio of lung tissue samples, histology, inflammatory markers, lung mechanics, or gas exchange.

    Conclusions: This pilot study suggests that AF-16 might improve oedema resolution as indicated by a reduction in EVLW in experimental ARDS.

  • 10.
    Basu, Samar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Univ Clermont Auvergne, Fac Pharm, Dept Biochem Mol Biol & Nutr, BP 10448, F-63000 Clermont Ferrand, France..
    Kadiiska, Maria B.
    NIEHS, Immun Inflammat & Dis Lab, NIH, Res Triangle Pk, NC 27709 USA..
    Ozone exposure effect on systemic prostaglandin F-2 alpha in rat plasma and urine may not reveal pulmonary damage through inflammation2017In: Prostaglandins, Leukotrienes and Essential Fatty Acids, ISSN 0952-3278, E-ISSN 1532-2823, Vol. 126, p. 79-83Article in journal (Refereed)
    Abstract [en]

    The acute ozone induced lung injury model has been widely used to explore injury and repair processes induced by oxidant overload. The current study evaluated acute ozone exposure effects on prostaglandin F-2 alpha (PGF(2 alpha)) in male Fischer rat plasma and urine with the hypothesis that ozone may induce an inflammatory response in the body that can be measured by the induction of PGF2 alpha. That might then lead to the identification of potential marker for acute lung injury through systemic inflammation. The time and dose-dependent effects of ozone exposure on the plasma and urinary levels of a major PGF(2 alpha) metabolite15-keto-dihydro-PGF(2 alpha) were determined using a radioimmunoassay. No statistically significant differences in the PGF(2 alpha) metabolite were found between the control and the experimental groups at either ozone exposure dose (2 ppm and 5 ppm) or any time point (2 h, 7 h and 16 h) post exposure for plasma and at 7 different post exposure time points (between 2 and 80 h) for urine. It is concluded that acute ozone exposure does not cause changes in plasma and urinary PGF(2 alpha), and therefore their measurement in plasma and urine may not be used to reveal pulmonary inflammation and damage by ozone.

  • 11. Befekadu, Rahel
    et al.
    Christiansen, Kjeld
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Grenegård, Magnus
    Increased plasma cathepsin S and trombospondin-1 in patients with acute ST-segment elevation myocardial infarction2019In: Cardiology journal, ISSN 1897-5593, Vol. 26, no 4, p. 385-393Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The role of cathepsins in the pathological progression of atherosclerotic lesions in ischemic heart disease have been defined in detail more than numerous times. This investigation examined the platelet-specific biomarker trombospondin-1 (TSP-1) and platelet function ex vivo, and compared this with cathepsin S (Cat-S; a biomarker unrelated to platelet activation but also associated this with increased mortality risk) in patients with ST segment elevation myocardial infarction (STEMI).

    METHODS: The STEMI patients were divided into two groups depending on the degree of coronary vessel occlusion: those with closed (n = 90) and open culprit vessel (n = 40). Cat-S and TSP-1 were analyzed before, 1-3 days after and 3 months after percutanous coronary intervention (PCI).

    RESULTS: During acute STEMI, plasma TSP-1 was significantly elevated in patients with closed culprit lesions, but rapidly declined after PCI. In fact, TSP-1 after PCI was significantly lower inpatient samples compared to healthy individuals. In comparison, plasma Cat-S was significantly elevated both before and after PCI. In patients with closed culprit lesions, Cat-S was significantly higher compared to patients with open culprit lesions 3 months after PCI. Although troponin-I were higher (p < 0.01) in patients with closed culprit lesion, there was no correlation with Cat-S and TSP-1.

    CONCLUSIONS: Cat-S but not TSP-1 may be a useful risk biomarker in relation to the severity of STEMI. However, the causality of Cat-S as a predictor for long-term mortality in STEMI remains to be ascertained in future studies.

  • 12.
    Bergman, Daniel
    et al.
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hansson-Hamlin, Helene
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Ström Holst, Bodil
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Investigation of interference from canine anti-mouse antibodies in hormone immunoassays2019In: Veterinary clinical pathology, ISSN 0275-6382, E-ISSN 1939-165X, Vol. 48, no S1, p. 59-69Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Canine anti-mouse antibodies are a potential source of immunoassay interference, but erroneous immunoassay results are not always easily identifiable. Anti-Müllerian hormone (AMH) is a marker for the presence of gonads in dogs, but elevated AMH concentrations in neutered dogs could also be caused by antibody interference. For other assays, a discrepant result obtained after antibody precipitation might indicate antibody interference.

    OBJECTIVES: We aimed to evaluate if canine anti-mouse antibodies are a source of erroneous results in the AMH assay and if antibody precipitation with polyethylene glycol (PEG) is a useful tool for detecting antibody interference in a variety of immunoassays used in the veterinary clinical laboratory.

    METHODS: Twenty-nine positive and 25 negative samples for anti-mouse antibodies were analyzed for AMH, canine total thyroxine (TT4), canine thyroid-stimulating hormone (TSH) and progesterone before and after treatment with PEG. Results that differed by more than four SDs from the intra-assay coefficients of variation were considered discrepant. Elevated AMH concentrations in neutered dogs with anti-mouse antibodies and no visible gonads present were considered evidence of interference.

    RESULTS: Evidence of antibody interference was found in two samples analyzed for AMH. The presence of anti-mouse antibodies did not lead to a higher proportion of discrepant results after PEG treatment for any of the immunoassays. The overall incidence of discrepant results for healthy controls was very high (73%).

    CONCLUSIONS: Canine anti-mouse antibodies are a source of erroneous AMH results. Antibody precipitation with PEG is not a useful tool for detecting interference caused by such antibodies.

  • 13.
    Bergman, Daniel
    et al.
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hansson-Hamlin, Helene
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Svensson, Anna
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Holst, Bodil Ström
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Prevalence of interfering antibodies in dogs and cats evaluated using a species-independent assay.2018In: Veterinary clinical pathology, ISSN 0275-6382, E-ISSN 1939-165X, Vol. 47, no 2, p. 205-212Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Interfering antibodies in human serum and plasma are known to react with mammalian antibodies in immunoassays and cause false-positive test results. Although this phenomenon was recently shown in companion animals, knowledge regarding immunoassay interference in veterinary medicine is very limited.

    OBJECTIVES: The aims of this study were to set up a species-independent immunoassay procedure to detect interference in serum samples, to screen for interference in a cross-section of canine and feline patient samples from an animal hospital, and to determine if the detected interference could be neutralized using an immunoassay based on nonmammalian reagents.

    METHODS: A 2-site sandwich-type interference assay was set up using commercially available mouse reagents. A total of 369 serum samples from 320 dogs and 263 samples from 218 cats were analyzed using the interference assay. Multiple samples were submitted from 36 dogs and 39 cats. Nineteen samples identified as interference-positive were analyzed in an assay using chicken antibodies.

    RESULTS: Interference was detected in samples from 28 dogs (9%) and 10 cats (5%) screened with the interference assay. Except for 1 cat, consistent results were obtained for all 75 dogs and cats that submitted more than 1 sample. The interference was eliminated when analyzed in the chicken-based assay (P < .001).

    CONCLUSIONS: Substances with reactivity toward mouse IgG can be detected in serum samples from dog and cat patients using a 2-site interference assay. The detected substances are most likely interfering antibodies, possibly originating from immunization with other mammalian species.

  • 14.
    Bergman, Daniel
    et al.
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, 750 07, Sweden. .
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hansson-Hamlin, Helene
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, 750 07, Sweden. .
    Åhlén, Emma
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, 750 07, Sweden. .
    Holst, Bodil Ström
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, 750 07, Sweden. .
    Characterization of canine anti-mouse antibodies highlights that multiple strategies are needed to combat immunoassay interference2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, no 1, article id 14521Article in journal (Refereed)
    Abstract [en]

    Immunoassays are widely used for detection and quantification of analytes in biological samples, but are vulnerable to analytical errors caused by interfering sample substances. Of particular interest are endogenous anti-animal antibodies that may bind to the immunoassay antibodies and cause erroneous test results. This phenomenon is a hazard to patient safety in both human and veterinary medicine. Here, we demonstrate that anti-mouse antibodies in dogs bind selectively to different regions of the murine IgG molecule, cross-react with IgG from different species, and consist of all major antibody classes present in canine serum (IgA, IgG and IgM). The antibody characteristics varied among individuals and their prevalence differed between two dog breeds. The selective binding to different IgG regions suggests that the antibodies might not originate from immunization through exposure to mice or other species. These findings show that canine anti-mouse antibodies are highly heterogeneous in nature and therefore require a combination of strategies to be counteracted.

  • 15.
    Bergqvist, Filip
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Ossipova, Elena
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Idborg, Helena
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Raouf, Joan
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Checa, Antonio
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden.
    Englund, Karin
    Stockholm Univ, Dept Analyt Chem, Stockholm, Sweden.
    Englund, Petter
    Stockholm Univ, Dept Analyt Chem, Stockholm, Sweden.
    Emami Khoonsari, Payam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Wheelock, Craig E.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden.
    Larsson, Karin
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Korotkova, Marina
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Jakobsson, Per-Johan
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Rheumatol Unit, SE-17176 Stockholm, Sweden.
    Inhibition of mPGES-1 or COX-2 Results in Different Proteomic and Lipidomic Profiles in A549 Lung Cancer Cells2019In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, article id 636Article in journal (Refereed)
    Abstract [en]

    Pharmacological inhibition of microsomal prostaglandin E synthase (mPGES)-1 for selective reduction in prostaglandin E-2 (PGE(2)) biosynthesis is protective in experimental models of cancer and inflammation. Targeting mPGES-1 is envisioned as a safer alternative to traditional non-steroidal anti-inflammatory drugs (NSAIDs). Herein, we compared the effects of mPGES-1 inhibitor Compound III (CIII) with the cyclooxygenase (COX)-2 inhibitor NS-398 on protein and lipid profiles in interleukin (IL)-1 beta-induced A549 lung cancer cells using mass spectrometry. Inhibition of mPGES-1 decreased PGE(2) production and increased PGF(2 alpha) and thromboxane B-2 (TXB2) formation, while inhibition of COX-2 decreased the production of all three prostanoids. Our proteomics results revealed that CIII downregulated multiple canonical pathways including eIF2, eIF4/P70S6K, and mTOR signaling, compared to NS-398 that activated these pathways. Moreover, pathway analysis predicted that CIII increased cell death of cancer cells (Z = 3.8, p = 5.1E-41) while NS-398 decreased the same function (Z = -5.0, p = 6.5E-35). In our lipidomics analyses, we found alterations in nine phospholipids between the two inhibitors, with a stronger alteration in the lysophospholipid (LPC) profile with NS-398 compared to CIII. Inhibition of mPGES-1 increased the concentration of sphinganine and dihydroceramide (C16:0D hCer), while inhibition of COX-2 caused a general decrease in most ceramides, again suggesting different effects on cell death between the two inhibitors. We showed that CIII decreased proliferation and potentiated the cytotoxic effect of the cytostatic drugs cisplatin, etoposide, and vincristine when investigated in a live cell imaging system. Our results demonstrate differences in protein and lipid profiles after inhibition of mPGES-1 or COX-2 with important implications on the therapeutic potential of mPGES-1 inhibitors as adjuvant treatment in cancer. We encourage further investigations to illuminate the clinical benefit of mPGES-1 inhibitors in cancer.

  • 16. Bikbov, B
    et al.
    Purcell, CA
    Levey, AS
    Smith, M
    Abdoli, A
    Abebe, M
    Adebayo, OM
    Afarideh, M
    Agarwal, SK
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Yamada, T
    Yeshaw, Y
    Yonemoto, N
    Yusefzadeh, H
    Zaidi, Z
    Zaki, L
    Zaman, SB
    Zamora, N
    Zarghi, A
    Zewdie, KA
    Ärnlöv, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Coresh, J
    Perico, N
    Remui, G
    Murray, CJL
    Vos, T
    Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.2020In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, article id S0140-6736(20)30045-3Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout.

    METHODS: The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function.

    FINDINGS: Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, -1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, -1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function.

    INTERPRETATION: Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI.

    FUNDING: Bill & Melinda Gates Foundation.

  • 17.
    Blom, Kristin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    ElShafie, Amir Ibrahim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Alribat Univ Hosp, Dept Clin Pathol & Microbiol, Khartoum, Sudan.
    Jönsson, Ulla-Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Rönnelid, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Håkansson, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    The genetically determined production of the alarmin eosinophil-derived neurotoxin is reduced in visceral leishmaniasis2018In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, no 1, p. 85-91Article in journal (Refereed)
    Abstract [en]

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

  • 18. Burstein, Roy
    et al.
    Henry, Nathaniel J
    Collison, Michael L
    Marczak, Laurie B
    Sligar, Amber
    Watson, Stefanie
    Marquez, Neal
    Abbasalizad-Farhangi, Mahdieh
    Abbasi, Masoumeh
    Abd-Allah, Foad
    Abdoli, Amir
    Abdollahi, Mohammad
    Abdollahpour, Ibrahim
    Abdulkader, Rizwan Suliankatchi
    Abrigo, Michael R M
    Acharya, Dilaram
    Adebayo, Oladimeji M
    Adekanmbi, Victor
    Adham, Davoud
    Afshari, Mahdi
    Aghaali, Mohammad
    Ahmadi, Keivan
    Ahmadi, Mehdi
    Ahmadpour, Ehsan
    Ahmed, Rushdia
    Akal, Chalachew Genet
    Akinyemi, Joshua O
    Alahdab, Fares
    Alam, Noore
    Alamene, Genet Melak
    Alene, Kefyalew Addis
    Alijanzadeh, Mehran
    Alinia, Cyrus
    Alipour, Vahid
    Aljunid, Syed Mohamed
    Almalki, Mohammed J
    Al-Mekhlafi, Hesham M
    Altirkawi, Khalid
    Alvis-Guzman, Nelson
    Amegah, Adeladza Kofi
    Amini, Saeed
    Amit, Arianna Maever Loreche
    Anbari, Zohreh
    Androudi, Sofia
    Anjomshoa, Mina
    Ansari, Fereshteh
    Antonio, Carl Abelardo T
    Arabloo, Jalal
    Arefi, Zohreh
    Aremu, Olatunde
    Armoon, Bahram
    Arora, Amit
    Artaman, Al
    Asadi, Anvar
    Asadi-Aliabadi, Mehran
    Ashraf-Ganjouei, Amir
    Assadi, Reza
    Ataeinia, Bahar
    Atre, Sachin R
    Quintanilla, Beatriz Paulina Ayala
    Ayanore, Martin Amogre
    Azari, Samad
    Babaee, Ebrahim
    Babazadeh, Arefeh
    Badawi, Alaa
    Bagheri, Soghra
    Bagherzadeh, Mojtaba
    Baheiraei, Nafiseh
    Balouchi, Abbas
    Barac, Aleksandra
    Bassat, Quique
    Baune, Bernhard T
    Bayati, Mohsen
    Bedi, Neeraj
    Beghi, Ettore
    Behzadifar, Masoud
    Behzadifar, Meysam
    Belay, Yared Belete
    Bell, Brent
    Bell, Michelle L
    Berbada, Dessalegn Ajema
    Bernstein, Robert S
    Bhattacharjee, Natalia V
    Bhattarai, Suraj
    Bhutta, Zulfiqar A
    Bijani, Ali
    Bohlouli, Somayeh
    Breitborde, Nicholas J K
    Britton, Gabrielle
    Browne, Annie J
    Nagaraja, Sharath Burugina
    Busse, Reinhard
    Butt, Zahid A
    Car, Josip
    Cárdenas, Rosario
    Castañeda-Orjuela, Carlos A
    Cerin, Ester
    Chanie, Wagaye Fentahun
    Chatterjee, Pranab
    Chu, Dinh-Toi
    Cooper, Cyrus
    Costa, Vera M
    Dalal, Koustuv
    Dandona, Lalit
    Dandona, Rakhi
    Daoud, Farah
    Daryani, Ahmad
    Das Gupta, Rajat
    Davis, Ian
    Davis Weaver, Nicole
    Davitoiu, Dragos Virgil
    De Neve, Jan-Walter
    Demeke, Feleke Mekonnen
    Demoz, Gebre Teklemariam
    Deribe, Kebede
    Desai, Rupak
    Deshpande, Aniruddha
    Desyibelew, Hanna Demelash
    Dey, Sagnik
    Dharmaratne, Samath Dhamminda
    Dhimal, Meghnath
    Diaz, Daniel
    Doshmangir, Leila
    Duraes, Andre R
    Dwyer-Lindgren, Laura
    Earl, Lucas
    Ebrahimi, Roya
    Ebrahimpour, Soheil
    Effiong, Andem
    Eftekhari, Aziz
    Ehsani-Chimeh, Elham
    El Sayed, Iman
    El Sayed Zaki, Maysaa
    El Tantawi, Maha
    El-Khatib, Ziad
    Emamian, Mohammad Hassan
    Enany, Shymaa
    Eskandarieh, Sharareh
    Eyawo, Oghenowede
    Ezalarab, Maha
    Faramarzi, Mahbobeh
    Fareed, Mohammad
    Faridnia, Roghiyeh
    Faro, Andre
    Fazaeli, Ali Akbar
    Fazlzadeh, Mehdi
    Fentahun, Netsanet
    Fereshtehnejad, Seyed-Mohammad
    Fernandes, João C
    Filip, Irina
    Fischer, Florian
    Foigt, Nataliya A
    Foroutan, Masoud
    Francis, Joel Msafiri
    Fukumoto, Takeshi
    Fullman, Nancy
    Gallus, Silvano
    Gebre, Destallem Gebremedhin
    Gebrehiwot, Tsegaye Tewelde
    Gebremeskel, Gebreamlak Gebremedhn
    Gessner, Bradford D
    Geta, Birhanu
    Gething, Peter W
    Ghadimi, Reza
    Ghadiri, Keyghobad
    Ghajarzadeh, Mahsa
    Ghashghaee, Ahmad
    Gill, Paramjit Singh
    Gill, Tiffany K
    Golding, Nick
    Gomes, Nelson G M
    Gona, Philimon N
    Gopalani, Sameer Vali
    Gorini, Giuseppe
    Goulart, Bárbara Niegia Garcia
    Graetz, Nicholas
    Greaves, Felix
    Green, Manfred S
    Guo, Yuming
    Haj-Mirzaian, Arvin
    Haj-Mirzaian, Arya
    Hall, Brian James
    Hamidi, Samer
    Haririan, Hamidreza
    Haro, Josep Maria
    Hasankhani, Milad
    Hasanpoor, Edris
    Hasanzadeh, Amir
    Hassankhani, Hadi
    Hassen, Hamid Yimam
    Hegazy, Mohamed I
    Hendrie, Delia
    Heydarpour, Fatemeh
    Hird, Thomas R
    Hoang, Chi Linh
    Hollerich, Gillian
    Rad, Enayatollah Homaie
    Hoseini-Ghahfarokhi, Mojtaba
    Hossain, Naznin
    Hosseini, Mostafa
    Hosseinzadeh, Mehdi
    Hostiuc, Mihaela
    Hostiuc, Sorin
    Househ, Mowafa
    Hsairi, Mohamed
    Ilesanmi, Olayinka Stephen
    Imani-Nasab, Mohammad Hasan
    Iqbal, Usman
    Irvani, Seyed Sina Naghibi
    Islam, Nazrul
    Islam, Sheikh Mohammed Shariful
    Jürisson, Mikk
    Balalami, Nader Jafari
    Jalali, Amir
    Javidnia, Javad
    Jayatilleke, Achala Upendra
    Jenabi, Ensiyeh
    Ji, John S
    Jobanputra, Yash B
    Johnson, Kimberly
    Jonas, Jost B
    Shushtari, Zahra Jorjoran
    Jozwiak, Jacek Jerzy
    Kabir, Ali
    Kahsay, Amaha
    Kalani, Hamed
    Kalhor, Rohollah
    Karami, Manoochehr
    Karki, Surendra
    Kasaeian, Amir
    Kassebaum, Nicholas J
    Keiyoro, Peter Njenga
    Kemp, Grant Rodgers
    Khabiri, Roghayeh
    Khader, Yousef Saleh
    Khafaie, Morteza Abdullatif
    Khan, Ejaz Ahmad
    Khan, Junaid
    Khan, Muhammad Shahzeb
    Khang, Young-Ho
    Khatab, Khaled
    Khater, Amir
    Khater, Mona M
    Khatony, Alireza
    Khazaei, Mohammad
    Khazaei, Salman
    Khazaei-Pool, Maryam
    Khubchandani, Jagdish
    Kianipour, Neda
    Kim, Yun Jin
    Kimokoti, Ruth W
    Kinyoki, Damaris K
    Kisa, Adnan
    Kisa, Sezer
    Kolola, Tufa
    Kosen, Soewarta
    Koul, Parvaiz A
    Koyanagi, Ai
    Kraemer, Moritz U G
    Krishan, Kewal
    Krohn, Kris J
    Kugbey, Nuworza
    Kumar, G Anil
    Kumar, Manasi
    Kumar, Pushpendra
    Kuupiel, Desmond
    Lacey, Ben
    Lad, Sheetal D
    Lami, Faris Hasan
    Larsson, Anders O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lee, Paul H
    Leili, Mostafa
    Levine, Aubrey J
    Li, Shanshan
    Lim, Lee-Ling
    Listl, Stefan
    Longbottom, Joshua
    Lopez, Jaifred Christian F
    Lorkowski, Stefan
    Magdeldin, Sameh
    Abd El Razek, Hassan Magdy
    Abd El Razek, Muhammed Magdy
    Majeed, Azeem
    Maleki, Afshin
    Malekzadeh, Reza
    Malta, Deborah Carvalho
    Mamun, Abdullah A
    Manafi, Navid
    Manda, Ana-Laura
    Mansourian, Morteza
    Martins-Melo, Francisco Rogerlândio
    Masaka, Anthony
    Massenburg, Benjamin Ballard
    Maulik, Pallab K
    Mayala, Benjamin K
    Mazidi, Mohsen
    McKee, Martin
    Mehrotra, Ravi
    Mehta, Kala M
    Meles, Gebrekiros Gebremichael
    Mendoza, Walter
    Menezes, Ritesh G
    Meretoja, Atte
    Meretoja, Tuomo J
    Mestrovic, Tomislav
    Miller, Ted R
    Miller-Petrie, Molly K
    Mills, Edward J
    Milne, George J
    Mini, G K
    Mir, Seyed Mostafa
    Mirjalali, Hamed
    Mirrakhimov, Erkin M
    Mohamadi, Efat
    Mohammad, Dara K
    Darwesh, Aso Mohammad
    Mezerji, Naser Mohammad Gholi
    Mohammed, Ammas Siraj
    Mohammed, Shafiu
    Mokdad, Ali H
    Molokhia, Mariam
    Monasta, Lorenzo
    Moodley, Yoshan
    Moosazadeh, Mahmood
    Moradi, Ghobad
    Moradi, Masoud
    Moradi, Yousef
    Moradi-Lakeh, Maziar
    Moradinazar, Mehdi
    Moraga, Paula
    Morawska, Lidia
    Mosapour, Abbas
    Mousavi, Seyyed Meysam
    Mueller, Ulrich Otto
    Muluneh, Atalay Goshu
    Mustafa, Ghulam
    Nabavizadeh, Behnam
    Naderi, Mehdi
    Nagarajan, Ahamarshan Jayaraman
    Nahvijou, Azin
    Najafi, Farid
    Nangia, Vinay
    Ndwandwe, Duduzile Edith
    Neamati, Nahid
    Negoi, Ionut
    Negoi, Ruxandra Irina
    Ngunjiri, Josephine W
    Thi Nguyen, Huong Lan
    Nguyen, Long Hoang
    Nguyen, Son Hoang
    Nielsen, Katie R
    Ningrum, Dina Nur Anggraini
    Nirayo, Yirga Legesse
    Nixon, Molly R
    Nnaji, Chukwudi A
    Nojomi, Marzieh
    Noroozi, Mehdi
    Nosratnejad, Shirin
    Noubiap, Jean Jacques
    Motlagh, Soraya Nouraei
    Ofori-Asenso, Richard
    Ogbo, Felix Akpojene
    Oladimeji, Kelechi E
    Olagunju, Andrew T
    Olfatifar, Meysam
    Olum, Solomon
    Olusanya, Bolajoko Olubukunola
    Oluwasanu, Mojisola Morenike
    Onwujekwe, Obinna E
    Oren, Eyal
    Ortega-Altamirano, Doris D V
    Ortiz, Alberto
    Osarenotor, Osayomwanbo
    Osei, Frank B
    Osgood-Zimmerman, Aaron E
    Otstavnov, Stanislav S
    Owolabi, Mayowa Ojo
    P A, Mahesh
    Pagheh, Abdol Sattar
    Pakhale, Smita
    Panda-Jonas, Songhomitra
    Pandey, Animika
    Park, Eun-Kee
    Parsian, Hadi
    Pashaei, Tahereh
    Patel, Sangram Kishor
    Pepito, Veincent Christian Filipino
    Pereira, Alexandre
    Perkins, Samantha
    Pickering, Brandon V
    Pilgrim, Thomas
    Pirestani, Majid
    Piroozi, Bakhtiar
    Pirsaheb, Meghdad
    Plana-Ripoll, Oleguer
    Pourjafar, Hadi
    Puri, Parul
    Qorbani, Mostafa
    Quintana, Hedley
    Rabiee, Mohammad
    Rabiee, Navid
    Radfar, Amir
    Rafiei, Alireza
    Rahim, Fakher
    Rahimi, Zohreh
    Rahimi-Movaghar, Vafa
    Rahimzadeh, Shadi
    Rajati, Fatemeh
    Raju, Sree Bhushan
    Ramezankhani, Azra
    Ranabhat, Chhabi Lal
    Rasella, Davide
    Rashedi, Vahid
    Rawal, Lal
    Reiner, Robert C
    Renzaho, Andre M N
    Rezaei, Satar
    Rezapour, Aziz
    Riahi, Seyed Mohammad
    Ribeiro, Ana Isabel
    Roever, Leonardo
    Roro, Elias Merdassa
    Roser, Max
    Roshandel, Gholamreza
    Roshani, Daem
    Rostami, Ali
    Rubagotti, Enrico
    Rubino, Salvatore
    Sabour, Siamak
    Sadat, Nafis
    Sadeghi, Ehsan
    Saeedi, Reza
    Safari, Yahya
    Safari-Faramani, Roya
    Safdarian, Mahdi
    Sahebkar, Amirhossein
    Salahshoor, Mohammad Reza
    Salam, Nasir
    Salamati, Payman
    Salehi, Farkhonde
    Zahabi, Saleh Salehi
    Salimi, Yahya
    Salimzadeh, Hamideh
    Salomon, Joshua A
    Sambala, Evanson Zondani
    Samy, Abdallah M
    Santric Milicevic, Milena M
    Jose, Bruno Piassi Sao
    Saraswathy, Sivan Yegnanarayana Iyer
    Sarmiento-Suárez, Rodrigo
    Sartorius, Benn
    Sathian, Brijesh
    Saxena, Sonia
    Sbarra, Alyssa N
    Schaeffer, Lauren E
    Schwebel, David C
    Sepanlou, Sadaf G
    Seyedmousavi, Seyedmojtaba
    Shaahmadi, Faramarz
    Shaikh, Masood Ali
    Shams-Beyranvand, Mehran
    Shamshirian, Amir
    Shamsizadeh, Morteza
    Sharafi, Kiomars
    Sharif, Mehdi
    Sharif-Alhoseini, Mahdi
    Sharifi, Hamid
    Sharma, Jayendra
    Sharma, Rajesh
    Sheikh, Aziz
    Shields, Chloe
    Shigematsu, Mika
    Shiri, Rahman
    Shiue, Ivy
    Shuval, Kerem
    Siddiqi, Tariq J
    Silva, João Pedro
    Singh, Jasvinder A
    Sinha, Dhirendra Narain
    Sisay, Malede Mequanent
    Sisay, Solomon
    Sliwa, Karen
    Smith, David L
    Somayaji, Ranjani
    Soofi, Moslem
    Soriano, Joan B
    Sreeramareddy, Chandrashekhar T
    Sudaryanto, Agus
    Sufiyan, Mu'awiyyah Babale
    Sykes, Bryan L
    Sylaja, P N
    Tabarés-Seisdedos, Rafael
    Tabb, Karen M
    Tabuchi, Takahiro
    Taveira, Nuno
    Temsah, Mohamad-Hani
    Terkawi, Abdullah Sulieman
    Tessema, Zemenu Tadesse
    Thankappan, Kavumpurathu Raman
    Thirunavukkarasu, Sathish
    To, Quyen G
    Tovani-Palone, Marcos Roberto
    Tran, Bach Xuan
    Tran, Khanh Bao
    Ullah, Irfan
    Usman, Muhammad Shariq
    Uthman, Olalekan A
    Vahedian-Azimi, Amir
    Valdez, Pascual R
    van Boven, Job F M
    Vasankari, Tommi Juhani
    Vasseghian, Yasser
    Veisani, Yousef
    Venketasubramanian, Narayanaswamy
    Violante, Francesco S
    Vladimirov, Sergey Konstantinovitch
    Vlassov, Vasily
    Vos, Theo
    Vu, Giang Thu
    Vujcic, Isidora S
    Waheed, Yasir
    Wakefield, Jon
    Wang, Haidong
    Wang, Yafeng
    Wang, Yuan-Pang
    Ward, Joseph L
    Weintraub, Robert G
    Weldegwergs, Kidu Gidey
    Weldesamuel, Girmay Teklay
    Westerman, Ronny
    Wiysonge, Charles Shey
    Wondafrash, Dawit Zewdu
    Woyczynski, Lauren
    Wu, Ai-Min
    Xu, Gelin
    Yadegar, Abbas
    Yamada, Tomohide
    Yazdi-Feyzabadi, Vahid
    Yilgwan, Christopher Sabo
    Yip, Paul
    Yonemoto, Naohiro
    Lebni, Javad Yoosefi
    Younis, Mustafa Z
    Yousefifard, Mahmoud
    Yousof, Hebat-Allah Salah A
    Yu, Chuanhua
    Yusefzadeh, Hasan
    Zabeh, Erfan
    Moghadam, Telma Zahirian
    Bin Zaman, Sojib
    Zamani, Mohammad
    Zandian, Hamed
    Zangeneh, Alireza
    Zerfu, Taddese Alemu
    Zhang, Yunquan
    Ziapour, Arash
    Zodpey, Sanjay
    Murray, Christopher J L
    Hay, Simon I
    Mapping 123 million neonatal, infant and child deaths between 2000 and 20172019In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 574, no 7778, p. 353-358Article in journal (Refereed)
    Abstract [en]

    Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2-to end preventable child deaths by 2030-we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000-2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations.

  • 19. Bäckryd, Emmanuel
    et al.
    Lind, Anne-Li
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Berzelii Technology Center for Neurodiagnostics, Uppsala University, Uppsala, Sweden.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Gerdle, Björn
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala Berzelii Technology Center for Neurodiagnostics, Uppsala University, Uppsala, Sweden.
    High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls2017In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, no 12, p. 2487-2495Article in journal (Refereed)
    Abstract [en]

    Animal models suggest that chemokines are important mediators in the pathophysiology of neuropathic pain. Indeed, these substances have been called "gliotransmitters," a term that illustrates the close interplay between glial cells and neurons in the context of neuroinflammation and pain. However, evidence in humans is scarce. The aim of the study was to determine a comprehensive cerebrospinal fluid (CSF) inflammatory profile of patients with neuropathic pain. Our hypothesis was that we would thereby find indications of a postulated on-going process of central neuroinflammation. Samples of CSF were collected from 2 cohorts of patients with neuropathic pain (n = 11 and n = 16, respectively) and healthy control subjects (n = 11). The samples were analyzed with a multiplex proximity extension assay in which 92 inflammation-related proteins were measured simultaneously (Proseek Multiplex Inflammation I; Olink Bioscience, Uppsala, Sweden). Univariate testing with control of false discovery rate, as well as orthogonal partial least squares discriminant analysis, were used for statistical analyses. Levels of chemokines CXCL6, CXCL10, CCL8, CCL11, CCL23 in CSF, as well as protein LAPTGF-beta-1, were significantly higher in both neuropathic pain cohorts compared with healthy controls, pointing to neuroinflammation in patients. These 6 proteins were also major results in a recent similar study in patients with fibromyalgia. The findings need to be confirmed in larger cohorts, and the question of causality remains to be settled. Because it has been suggested that prevalent comorbidities to chronic pain (eg, depression, anxiety, poor sleep, and tiredness) also are associated with neuroinflammation, it will be important to determine whether neuroinflammation is a common mediator.

  • 20.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology. Centre for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
    Jansson, Jan-Håkan
    Department of Public Health and Clinical Medicine, Research Unit Skellefteå, Umeå University, Umeå, Sweden.
    Söderberg, Stefan
    Department of Public Health and Clinical Medicine, Heart Centre, Umeå University, Umeå, Sweden.
    Ruge, Toralph
    Dept of Medicine Solna, Karolinska Institutet and Function of Emergency Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ärnlöv, Johan
    Centre for Family Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden; School of Health and Social Sciences, Dalarna University, Falun, Sweden.
    Levels of soluble tumor necrosis factor receptor 1 and 2, gender, and risk of myocardial infarction in Northern Sweden2018In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 272, p. 41-46Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS:

    Soluble receptors for tumor necrosis factor alpha (sTNFR1 and sTNFR2) have been associated with cardiovascular diseases, and some evidence points towards a difference in associated risk between men and women. We aimed to study the association between sTNFR1 and sTNFR2 and incident myocardial infarctions (MI) and to explore the influence of established cardiovascular risk factors in men and women.

    METHODS:

    We conducted a nested case control study in three large Swedish cohorts, including 533 myocardial infarction cases, and 1003 age-, sex- and cohort-matched controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated.

    RESULTS:

    An association between circulating sTNFR1 and sTNFR2 and an increased risk for MI was found when comparing cases and controls. The odds ratios were significant after adjustment for established cardiovascular risk factors and C-reactive protein in women (OR 1.44, 95% CI 1.08-1.93 for TNFR1, and 1.61, 95% CI 1.11-2.34 for TNFR2), but was abolished in men. Women with a combination of elevated CRP and values in the upper quartile of TNFR1 or TNFR2 had a 5-fold higher risk of myocardial infarction versus those with normal CRP and values in the lower three quartiles of TNFR1 or TNFR2.

    CONCLUSIONS:

    As the risk estimates for TNFR1 and TNFR2 were higher and remained significant after adjustments for established cardiovascular risk factors in women but not in men, a potential role for TNFR1 and TNFR2 in identifying women with a higher MI risk is possible. The future clinical role of TNFR1 and TNFR2 in combination with CRP to identify high risk patients for coronary heart disease has yet to be determined.

  • 21.
    Carlsson, Axel C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Ruge, Toralph
    Kjøller, Erik
    Hilden, Jørgen
    Kolmos, Hans Jørn
    Sajadieh, Ahmad
    Kastrup, Jens
    Jensen, Gorm Boje
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Nowak, Christoph
    Jakobsen, Janus Christian
    Winkel, Per
    Gluud, Christian
    Ärnlöv, Johan
    10-Year Associations between Tumor Necrosis Factor Receptors 1 and 2 and Cardiovascular Events in Patients with Stable Coronary Heart Disease: A CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) Trial Substudy.2018In: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 7, no 9, article id e008299Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We aimed to assess the associations and predictive powers between the soluble receptors for tumor necrosis factor (TNF)-α (TNFR1 and TNFR2) and cardiovascular outcomes in patients with stable coronary heart disease.

    METHODS AND RESULTS: CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients With Ischemic Heart Disease) is a randomized clinical trial comparing clarithromycin with placebo in patients with stable coronary heart disease. The primary outcome was a composite of nonfatal acute myocardial infarction, unstable angina pectoris, cerebrovascular disease, and all-cause mortality. Patients were followed up for 10 years; discovery sample, those assigned placebo (1204 events in n=1998); and replication sample, those assigned clarithromycin (1220 events in n=1979). We used Cox regression adjusted for C-reactive protein level, established cardiovascular risk factors, kidney function, and cardiovascular drugs. After adjustments, higher serum levels of TNFR1 and TNFR2 were associated with the composite outcome in the discovery sample (hazard ratio per SD increase, 1.13; 95% confidence interval, 1.05-1.22; P=0.001 for TNFR1; hazard ratio, 1.16; 95% confidence interval, 1.08-1.24; P<0.001 for TNFR2). The associations were similar in the replication sample. The associations with the composite outcome were mainly driven by acute myocardial infarction, cardiovascular mortality, and noncardiovascular mortality. The addition of TNFR1 and TNFR2 to established cardiovascular risk factors improved prediction only modestly (<1%).

    CONCLUSIONS: Increased concentrations of circulating TNFR1 and TNFR2 were associated with increased risks of cardiovascular events and mortality in patients with stable coronary heart disease. Yet, the utility of measuring TNFR1 and TNFR2 to improve risk prediction in these patients appears limited.

    CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00121550.

  • 22.
    Carlsson, Axel C
    et al.
    Division of Family Medicine and Primary Care, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Huddinge, Sweden..
    Wessman, T
    Department of Emergency and Internal Medicine, Skånes University Hospital, Malmö, Sweden; Department of Clinical Sciences Malmö, Lund University & Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Leijonberg, G
    Department of Emergency and Internal Medicine, Skånes University Hospital, Malmö, Sweden; Department of Clinical Sciences Malmö, Lund University & Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden..
    Tofik, R
    Department of Emergency and Internal Medicine, Skånes University Hospital, Malmö, Sweden; Department of Clinical Sciences Malmö, Lund University & Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden..
    Ärnlöv, J
    Division of Family Medicine and Primary Care, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Huddinge, Sweden; School of Health and Social Studies, Dalarna University, Falun, Sweden..
    Melander, O
    Department of Emergency and Internal Medicine, Skånes University Hospital, Malmö, Sweden; Department of Clinical Sciences Malmö, Lund University & Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden..
    Ruge, T
    Department of Emergency and Internal Medicine, Skånes University Hospital, Malmö, Sweden; Department of Clinical Sciences Malmö, Lund University & Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden..
    Endostatin predicts mortality in patients with acute dyspnea: A cohort study of patients seeking care in emergency departments2020In: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 75, p. 35-39Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Increased levels of circulating endostatin predicts cardiovascular morbidity and impaired kidney function in the general population. The utility of endostatin as a risk marker for mortality in the emergency department (ED) has not been reported.

    AIM: Our main aim was to study the association between plasma endostatin and 90-day mortality in an unselected cohort of patients admitted to the ED for acute dyspnea.

    Design: Circulating endostatin was analyzed in plasma from 1710 adults and related to 90-day mortality in Cox proportional hazard models adjusted for age, sex, body mass index, oxygen saturation, respiratory rate, body temperature, C-reactive protein, lactate, creatinine and medical priority according to the Medical Emergency Triage and Treatment System-Adult score (METTS-A). The predictive value of endostatin for mortality was evaluated with receiver operating characteristic (ROC) analysis and compared with the clinical triage scoring system and age.

    RESULTS: Each one standard deviation increment of endostatin was associated with a HR of 2.12 (95 % CI 1.31-3.44 p< 0.01) for 90-day mortality after full adjustment. Levels of endostatin were significantly increased in the group of patients with highest METTS-A (p<0.001). When tested for the outcome 90-day mortality, the area under the ROC curve (AUC) was 0.616 for METTS-A, 0.701 for endostatin, 0.708 for METTS -A and age and 0.738 for METTS-A, age and levels of endostatin.

    CONCLUSIONS: In an unselected cohort of patients admitted to the ED with acute dyspnea, endostatin had a string association to 90-day mortality and improved prediction of 90-day mortality in the ED beyond the clinical triage scoring system and age with 3 %.

  • 23.
    Carlsson, Henrik
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Abujrais, Sandy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Herman, Stephanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Emami Khoonsari, Payam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Åkerfeldt, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Svenningsson, Anders
    Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Targeted metabolomics of CSF in healthy individuals and patients with secondary progressive multiple sclerosis using high-resolution mass spectrometry2020In: Metabolomics, ISSN 1573-3882, E-ISSN 1573-3890, Vol. 16, no 2, article id 26Article in journal (Refereed)
    Abstract [en]

    Introduction: Standardized commercial kits enable targeted metabolomics analysis and may thus provide an attractive complement to the more explorative approaches. The kits are typically developed for triple quadrupole mass spectrometers using serum and plasma.

    Objectives: Here we measure the concentrations of preselected metabolites in cerebrospinal fluid (CSF) using a kit developed for high-resolution mass spectrometry (HRMS). Secondarily, the study aimed to investigate metabolite alterations in patients with secondary progressive multiple sclerosis (SPMS) compared to controls.

    Methods: We performed targeted metabolomics in human CSF on twelve SPMS patients and twelve age and sex-matched healthy controls using the Absolute IDQ-p400 kit (Biocrates Life Sciences AG) developed for HRMS. The extracts were analysed using two methods; liquid chromatography-mass spectrometry (LC-HRMS) and flow injection analysis-MS (FIA-HRMS).

    Results: Out of 408 targeted metabolites, 196 (48%) were detected above limit of detection and 35 were absolutely quantified. Metabolites analyzed using LC-HRMS had a median coefficient of variation (CV) of 3% and 2.5% between reinjections the same day and after prolonged storage, respectively. The corresponding results for the FIA-HRMS were a median CV of 27% and 21%, respectively. We found significantly (p < 0.05) elevated levels of glycine, asymmetric dimethylarginine (ADMA), glycerophospholipid PC-O (34:0) and sum of hexoses in SPMS patients compared to controls.

    Conclusion: The Absolute IDQ-p400 kit could successfully be used for quantifying targeted metabolites in the CSF. Metabolites quantified using LC-HRMS showed superior reproducibility compared to FIA-HRMS.

  • 24.
    Cedervall, Jessica
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dragomir, Anca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Saupe, Falk
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Yanyu
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ärnlöv, Johan
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Divis Family Med, Huddinge, Sweden.
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Olsson, Anna-Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.2017In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 8, article id e1320009Article in journal (Refereed)
    Abstract [en]

    Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor-bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer-associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer.

  • 25. Chang, Alex R
    et al.
    Grams, Morgan E
    Ballew, Shoshana H
    Bilo, Henk
    Correa, Adolfo
    Evans, Marie
    Gutierrez, Orlando M
    Hosseinpanah, Farhad
    Iseki, Kunitoshi
    Kenealy, Timothy
    Klein, Barbara
    Kronenberg, Florian
    Lee, Brian J
    Li, Yuanying
    Miura, Katsuyuki
    Navaneethan, Sankar D
    Roderick, Paul J
    Valdivielso, Jose M
    Visseren, Frank L J
    Zhang, Luxia
    Gansevoort, Ron T
    Hallan, Stein I
    Levey, Andrew S
    Matsushita, Kunihiro
    Shalev, Varda
    Woodward, Mark
    Ärnlöv, Johan (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Lannfelt, Lars (Contributor)
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Adiposity and risk of decline in glomerular filtration rate: meta-analysis of individual participant data in a global consortium2019In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 364, article id k5301Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the associations between adiposity measures (body mass index, waist circumference, and waist-to-height ratio) with decline in glomerular filtration rate (GFR) and with all cause mortality.

    DESIGN: Individual participant data meta-analysis.

    SETTING: Cohorts from 40 countries with data collected between 1970 and 2017.

    PARTICIPANTS: Adults in 39 general population cohorts (n=5 459 014), of which 21 (n=594 496) had data on waist circumference; six cohorts with high cardiovascular risk (n=84 417); and 18 cohorts with chronic kidney disease (n=91 607).

    MAIN OUTCOME MEASURES: GFR decline (estimated GFR decline ≥40%, initiation of kidney replacement therapy or estimated GFR <10 mL/min/1.73 m2) and all cause mortality.

    RESULTS: Over a mean follow-up of eight years, 246 607 (5.6%) individuals in the general population cohorts had GFR decline (18 118 (0.4%) end stage kidney disease events) and 782 329 (14.7%) died. Adjusting for age, sex, race, and current smoking, the hazard ratios for GFR decline comparing body mass indices 30, 35, and 40 with body mass index 25 were 1.18 (95% confidence interval 1.09 to 1.27), 1.69 (1.51 to 1.89), and 2.02 (1.80 to 2.27), respectively. Results were similar in all subgroups of estimated GFR. Associations weakened after adjustment for additional comorbidities, with respective hazard ratios of 1.03 (0.95 to 1.11), 1.28 (1.14 to 1.44), and 1.46 (1.28 to 1.67). The association between body mass index and death was J shaped, with the lowest risk at body mass index of 25. In the cohorts with high cardiovascular risk and chronic kidney disease (mean follow-up of six and four years, respectively), risk associations between higher body mass index and GFR decline were weaker than in the general population, and the association between body mass index and death was also J shaped, with the lowest risk between body mass index 25 and 30. In all cohort types, associations between higher waist circumference and higher waist-to-height ratio with GFR decline were similar to that of body mass index; however, increased risk of death was not associated with lower waist circumference or waist-to-height ratio, as was seen with body mass index.

    CONCLUSIONS: Elevated body mass index, waist circumference, and waist-to-height ratio are independent risk factors for GFR decline and death in individuals who have normal or reduced levels of estimated GFR.

  • 26.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Berglund, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    The utility of coagulation activity for prediction of risk of mortality and cardiovascular events in guideline-treated myocardial infarction patients2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 4, p. 224-233Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite improved treatment of myocardial infarction (MI), real-world patients still suffer substantial risk for subsequent cardiovascular events. Little is known about coagulation activity shortly after MI and whether coagulation activity markers may identify patients at increased risk despite contemporary treatment.

    OBJECTIVE: To evaluate D-dimer concentration and thrombin generation potential shortly after discharge after MI and evaluate if these markers could predict the risk of future cardiovascular and bleeding events.

    METHODS: Unselected MI patients (n = 421) were included in the observational REBUS study (NCT01102933) and followed for two years. D-dimer concentrations, thrombin peak, and endogenous thrombin potential (ETP) were analyzed at inclusion (3-5 days after MI) and at early follow-up (after 2-3 weeks).

    RESULTS: Seventy-five patients (17.8%) experienced the composite endpoint (all-cause death, MI, congestive heart failure, or all-cause stroke), and 31 patients (7.4%) experienced a clinically relevant bleeding event. D-dimer concentrations at early follow-up were associated with the composite endpoint (HR [per SD increase] 1.51 [95% CI 1.22-1.87]) and with clinically relevant bleeding (HR [per SD increase] 1.80 [95% CI 1.32-2.44]). Thrombin generation potential was not significantly associated with either the composite endpoint or with clinically relevant bleeding. Higher thrombin peak and ETP at early follow-up were both inversely associated with stroke (HR [per SD increase] 0.50 [95% CI 0.30-0.81] and 0.43 [95% CI 0.22-0.83], respectively).

    CONCLUSION: In unselected MI patients treated according to contemporary guidelines, D-dimer measurements may identify patients at increased risk of new cardiovascular and bleeding events. The inverse association of thrombin generation potential and risk of stroke has to be further investigated.

  • 27.
    Christersson, Christina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Thulin, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Microparticles during long-term follow-up after acute myocardial infarction: Association to atherosclerotic burden and risk of cardiovascular events2017In: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 117, no 8, p. 1571-1581Article in journal (Refereed)
    Abstract [en]

    Microparticles (MPs) are formed from platelets (PMPs), endothelial cells (EMPs) and monocytes (MMPs), and in acute myocardial infarction (MI), there is an increase of MPs in the culprit artery. In this study MPs were evaluated in whole blood in 105 patients with MI at five time-points during a two-year follow-up (FU). Patients with non-ST elevated MI had higher concentrations of CD41+MPs compared to ST elevated MI patients (p=0.024). The concentrations of PMPs in whole blood increased during the time period (p<0.001), but no significant change over time was found for EMPs and MMPs. CD62P+MP counts were higher in MI patients with diabetes (p=0.020), and patients with hypertension had increased levels of CD14+MPs (p=0.004). The amount of CD62P+TF+MPs increased significantly during FU (p<0.001). Patients with atherosclerosis in three arterial beds, i.e. coronary, carotid and peripheral arteries, had lower concentrations of CD62P+TF+MPs (p=0.035) and CD144+TF+MPs (p=0.004) compared to patients with atherosclerosis in one or two arterial beds. Higher concentrations of CD62P+MPs early after MI were associated with an increased risk of cardiovascular events during FU, hazard ratio 3.32 (95 %C11.20-9.31). Only small variations in PMP, EMP and MMP concentrations were found during long-term FU after MI and their levels seem to reflect the underlying cardiovascular disease rather than the acute MI. PMPs expressing P-selectin might be a promising biomarker for predicting future cardiovascular events, but further studies are needed to confirm these results.

  • 28.
    Cooper, Lauren B
    et al.
    Department of Medicine, Duke University School of Medicine, Durham, NC, USA..
    Savarese, Gianluigi
    Heart and Vascular Theme, Karolinska University Hospital and Department of Medicine, Unit of Cardiology, Karolinska Institutet, Stockholm, Sweden..
    Carrero, Juan-Jesus
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden..
    Szabo, Barna
    Heart-Lung Physiology Clinic, Örebro University Hospital, Örebro, Sweden..
    Jernberg, Tomas
    Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden..
    Jonsson, Åsa
    Department of Medicine, Division of Cardiology, County Hospital Ryhov, Jönköping, Sweden..
    Dahlbom, Catarina
    Strängnäs Primary Healthcare Center, Strängnäs, Sweden..
    Dahlström, Ulf
    Department of Cardiology and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden..
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lund, Lars H
    Heart and Vascular Theme, Karolinska University Hospital and Department of Medicine, Unit of Cardiology, Karolinska Institutet, Stockholm, Sweden..
    Clinical and research implications of serum versus plasma potassium measurements.2018In: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844Article in journal (Refereed)
  • 29.
    Dubois, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Prostasomes as Diagnostic, Prognostic and Therapeutic Vesicles2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis explores prostasomes and their ability to be used as a new diagnostic tool for prostate cancer. Alongside diagnosis, this thesis also suggests prostasomes as a tool for prognosis and therapeutic treatment in patients with prostate cancer. By further characterizing prostasomes we can identify a biomarker and also a method of visualizing and interpreting the information provided in order to conduct a correct and fast diagnosis for prostate cancer.

    In Paper I, we show that the prostasomal bilayered membrane consists of lipid rafts, clusters that holds cholesterol, sphingolipids and gives receptors a rigid platform upon which to work. We compare the proteomic content of prostasome lipid rafts with the entire prostasome membrane in the search for a specific biomarker. 

    In Paper II, we show that purified lipid rafts from the prostasome membrane can re-vesiculate and create new bioengineered vesicles. These new vesicles can carry different agents inside them and we find that the method is also applicable to blood cells. This suggests a new method for cell-specific delivery of drugs and cancer therapy. 

    In Paper III, we further characterize the prostasome membrane, this time mapping purinergic receptors. This could be used in the development of prostate cancer treatment and to gain better understanding of how prostasomes interact with surrounding cells in their ambient environment.

    In Paper IV, we investigate the difference in thymidine kinase 1 (TK1) enzyme activity between prostasomes and malignant exosomes. TK1 is considered to be a biomarker of cell proliferation and could therefore be used as a biomarker for prostate cancer diagnosis and progression.

    In summary, this thesis contributes to the puzzle of how to better diagnose, prognose and treat prostate cancer. Although it is mainly pre-clinical research it opens up new possibilities for the diagnosis and treatment of prostate cancer.

    List of papers
    1. Proteomic profiling of detergent resistant membranes (lipid rafts) of prostasomes
    Open this publication in new window or tab >>Proteomic profiling of detergent resistant membranes (lipid rafts) of prostasomes
    Show others...
    2015 (English)In: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 14, no 11, p. 3015-3022Article in journal (Refereed) Published
    Abstract [en]

    Prostasomes are exosomes derived from prostate epithelial cells through exocytosis by multivesicular bodies. Prostasomes have a bilayered membrane and readily interact with sperm. The membrane lipid composition is unusual with a high contribution of sphingomyelin at the expense of phosphatidylcholine and saturated and monounsaturated fatty acids are dominant. Lipid rafts are liquid-ordered domains that are more tightly packed than the surrounding non-raft phase of the bilayer. Lipid rafts are proposed to be highly dynamic, submicroscopic assemblies that float freely within the liquid disordered membrane bilayer and some proteins preferentially partition into the ordered raft domains. We asked the question whether lipid rafts do exist in prostasomes and, if so, which proteins might be associated with them. Prostasomes of density range 1.13-1.19g/mL were subjected to density gradient ultracentrifugation in sucrose fabricated by phosphate buffered saline (PBS) containing 1% Triton X-100 with capacity for banding at 1.10g/mL, i.e. the classical density of lipid rafts. Prepared prostasomal lipid rafts (by gradient ultracentrifugation) were analyzed by mass spectrometry and electron microscopy. The clearly visible band on top of 1.10g/mL sucrose in the Triton X-100 containing gradient was subjected to LC-MS/MS and more than 370 lipid raft associated proteins were identified. Several of them were involved in intraluminal vesicle formation, e.g. tetraspanins, ESCRTs and Ras-related proteins. This is the first comprehensive LC-MS/MS profiling of proteins in lipid rafts derived from exosomes. Data are available via ProteomeXchange with identifier PXD002163.

    National Category
    Urology and Nephrology
    Identifiers
    urn:nbn:se:uu:diva-261543 (URN)10.1074/mcp.M114.047530 (DOI)000365636800014 ()26272980 (PubMedID)
    Available from: 2015-09-01 Created: 2015-09-01 Last updated: 2018-12-11Bibliographically approved
    2. Human erythrocyte-derived nanovesicles can readily be loaded with doxorubicin and act as anticancer agents
    Open this publication in new window or tab >>Human erythrocyte-derived nanovesicles can readily be loaded with doxorubicin and act as anticancer agents
    Show others...
    2018 (English)In: Cancer Research Frontiers, ISSN 2328-5249, Vol. 4, no 1, p. 13-26Article in journal (Refereed) Published
    Abstract [en]

    Purpose: In future therapeutics new formulas are needed that assure lower doses, fewer side effects, targeted administration and protection of the drug from degradation. In a first step to fulfil the requirements defined above, we carried out an in vitro study by developing a new procedure to encapsulate drugs using native vesicles first from prostasomes and then from erythrocyte membranes known to be well tolerated. The new method for production of drug delivery vesicles utilized osmotic loading of detergent resistant membranes (DRMs).

    Materials and methods: DRMs of prostasomes and prepared human erythrocyte membranes were extracted and separated in a sucrose gradient at a density of 1.10 g/mL containing 1% Triton X-100. These DRMs were characterized by electron microscopy (transmission and scanning EM) and loaded with low and high molecular compounds. PC3 prostate cancer cells were treated with doxorubicin loaded DRMs in triplicate. DAPI (nuclear fluorescent stain) was included and fluorescence microscopic pictures were taken before the cells were trypsinized and counted after 48h.

    Results: The content of the well separated band was observed ultrastructurally as small spherical, double layered membrane vesicles, (DRM vesicles) which harbored hyperosmolar sucrose of the gradient. Encapsulated hyperosmolar sucrose induced a transient osmotic lysis of the DRM vesicles when suspended in isotonic buffer containing loading molecules allowing vesicular inclusion. After this proof of concept, the method was finally employed for doxorubicin loading of DRM vesicles from human erythrocytes. When incubating such vesicles with PC3 cells a complete arrest of growth was observed in sharp contrast to PC3 cells incubated with plain doxorubicin in similar conditions.

    Conclusion: The present results open up new possibilities for using DRM vesicles as drug delivery vesicles.

    National Category
    Clinical Laboratory Medicine
    Identifiers
    urn:nbn:se:uu:diva-364780 (URN)10.17980/2018.13 (DOI)
    Note

    Louise Dubois and Liza Löf contributed equally to this work.

    Available from: 2018-11-02 Created: 2018-11-02 Last updated: 2019-01-31Bibliographically approved
    3. Occurrence of purinergic receptors in human prostasomes (prostate epithelial cell-derived exosomes)
    Open this publication in new window or tab >>Occurrence of purinergic receptors in human prostasomes (prostate epithelial cell-derived exosomes)
    2018 (English)In: Article in journal (Refereed) Submitted
    National Category
    Clinical Laboratory Medicine
    Identifiers
    urn:nbn:se:uu:diva-369182 (URN)
    Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11
    4. Increased levels of thymidine kinase 1 in malignant cell-derived exosomes
    Open this publication in new window or tab >>Increased levels of thymidine kinase 1 in malignant cell-derived exosomes
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Clinical Laboratory Medicine
    Identifiers
    urn:nbn:se:uu:diva-369188 (URN)
    Available from: 2018-12-11 Created: 2018-12-11 Last updated: 2018-12-11
  • 30.
    Dubois, Louise
    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.
    Occurrence of purinergic receptors in human prostasomes (prostate epithelial cell derived exosomes)Manuscript (preprint) (Other academic)
  • 31.
    Dubois, Louise
    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.
    Occurrence of purinergic receptors in human prostasomes (prostate epithelial cell-derived exosomes)2018In: Article in journal (Refereed)
  • 32.
    Dubois, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Hultenby, Kjell
    Department of Laboratory Medicine, Karolinska Institutet, SE-141 86 Huddinge, Sweden.
    Waldenström, Anders
    Department of Public Health and Clinical Medicine, Umeå University, SE-901 85 Umeå, Sweden.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ronquist, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Ronquist, K. Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Human erythrocyte-derived nanovesicles can readily be loaded with doxorubicin and act as anticancer agents2018In: Cancer Research Frontiers, ISSN 2328-5249, Vol. 4, no 1, p. 13-26Article in journal (Refereed)
    Abstract [en]

    Purpose: In future therapeutics new formulas are needed that assure lower doses, fewer side effects, targeted administration and protection of the drug from degradation. In a first step to fulfil the requirements defined above, we carried out an in vitro study by developing a new procedure to encapsulate drugs using native vesicles first from prostasomes and then from erythrocyte membranes known to be well tolerated. The new method for production of drug delivery vesicles utilized osmotic loading of detergent resistant membranes (DRMs).

    Materials and methods: DRMs of prostasomes and prepared human erythrocyte membranes were extracted and separated in a sucrose gradient at a density of 1.10 g/mL containing 1% Triton X-100. These DRMs were characterized by electron microscopy (transmission and scanning EM) and loaded with low and high molecular compounds. PC3 prostate cancer cells were treated with doxorubicin loaded DRMs in triplicate. DAPI (nuclear fluorescent stain) was included and fluorescence microscopic pictures were taken before the cells were trypsinized and counted after 48h.

    Results: The content of the well separated band was observed ultrastructurally as small spherical, double layered membrane vesicles, (DRM vesicles) which harbored hyperosmolar sucrose of the gradient. Encapsulated hyperosmolar sucrose induced a transient osmotic lysis of the DRM vesicles when suspended in isotonic buffer containing loading molecules allowing vesicular inclusion. After this proof of concept, the method was finally employed for doxorubicin loading of DRM vesicles from human erythrocytes. When incubating such vesicles with PC3 cells a complete arrest of growth was observed in sharp contrast to PC3 cells incubated with plain doxorubicin in similar conditions.

    Conclusion: The present results open up new possibilities for using DRM vesicles as drug delivery vesicles.

  • 33.
    Dubois, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Manouchehri Doulabi, Ehsan
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Löf, Liza
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kamali-Moghaddam, Masood
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Stålhandske, Per
    Biovica International AB.
    Increased Levels of Thymidine Kinase 1 in Malignant Cell-derived ExosomesManuscript (preprint) (Other academic)
  • 34.
    Dubois, Louise
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Manouchehri Doulabi, Ehsan
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Löf, Liza
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kamali-Moghaddam, Masood
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Stålhandske, Per
    Biovica International AB.
    Increased levels of thymidine kinase 1 in malignant cell-derived exosomesManuscript (preprint) (Other academic)
  • 35.
    Edén, Desireé
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Tissue Factor regulation, signaling and functions beyond coagulation with a focus on diabetes2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Tissue factor (TF) is a 47 kDa transmembrane glycoprotein best known for initiating the coagulation cascade upon binding of its ligand FVIIa. Apart from its physiological role in coagulation, TF and TF/FVIIa signaling has proved to be involved in diseases such as diabetes, cancer and cardiovascular diseases. Biological functions coupled to TF/FVIIa signaling include diet-induced obesity, apoptosis, angiogenesis and migration.

    Aim: The aim of this thesis was to investigate the role of TF/FVIIa in cells of importance in diabetes, to further investigate the mechanism behind TF/FVIIa anti-apoptotic signaling in cancer cells and lastly to examine the regulation of TF expression in monocytes by micro RNAs (miRNA).

    Results: In paper I we found that TF/FVIIa signaling augments cytokine-induced beta cell death and impairs glucose stimulated insulin secretion from human pancreatic islets. In paper II the relevance of TF/FVIIa in isolated human primary adipocytes was investigated. Adipocytes are a target cell for insulin and diabetics typically have increased lipolysis and impaired glucose uptake. No evidence was found for a role of TF/FVIIa in lipolysis or glucose uptake in adipocytes. However, adipocytes were found to express TF and FVII. The FVII produced was sufficient to initiate coagulation in the adipocytes. In paper III an anti-apoptotic TF/FVIIa induced signaling pathway in prostate and breast cancer cells was investigated in depth. Previous research has shown that TF/FVIIa signaling results in transactivation of insulin-like growth factor 1 receptor (IGF-1R) leading to subsequent protection from apoptosis induced by TNF-related apoptosis inducing ligand (TRAIL). The current results propose a mechanism where IGF-1R transactivation by TF/FVIIa is dependent on integrin β1 (ITGβ1) signaling. TF/FVIIa/ ITGβ1 signaling was found to result in phosphorylation of src and subsequent phosphorylation of caveolin 1 (Cav1). Once phosphorylated, the inhibitory effect of Cav1 on IGF-1R is cancelled, resulting in IGF-1R activation. In paper IV the role of miRNA regulation of TF expression in monocytic cells was investigated. The miRNA miR-223-3p was identified to be differentially expressed in U937 cells undergoing differentiation to a more monocyte-like phenotype and an anti-parallel correlation between TF and miR-223-3p expression in monocytes was proved. Hence, miR-223-3p regulates the inducible expression of TF in monocytes.

    Conclusions: The work in this thesis furthers the knowledge of molecular mechanisms behind TF regulation and TF/FVIIa signaling and some functional consequences as well as their biological relevance in diabetes. 

    List of papers
    1. Tissue factor/factor VIIa signalling promotes cytokine-induced beta cell death and impairs glucose-stimulated insulin secretion from human pancreatic islets
    Open this publication in new window or tab >>Tissue factor/factor VIIa signalling promotes cytokine-induced beta cell death and impairs glucose-stimulated insulin secretion from human pancreatic islets
    2015 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no 11, p. 2563-2572Article in journal (Refereed) Published
    Abstract [en]

    Aims/hypothesis Patients diagnosed with type 1 or type 2 diabetes have elevated levels of coagulation factor VIIa (FVIIa) and its receptor tissue factor (TF) in their bloodstream. This may affect the fate of the beta cells. We aimed to study the effects of TF/FVIIa signalling on cytokine-induced beta cell death and islet function in vitro. Methods Human pancreatic islets and MIN-6 beta cells were used to study TF mRNA and protein expression using real-time PCR, immunoblotting and flow cytometry. The effects of TF/FVIIa on cytokine-induced beta cell death were studied in MIN-6 cells and human pancreatic islets using cell-death ELISA and propidium iodide and cleaved caspase-3 staining. Effects of TF/FVIIa on the phosphorylation of p38, extracellular signal-regulated kinase and c-Jun N-terminal kinase (JNK) were investigated by immunoblotting. Glucose-stimulated insulin secretion (GSIS) from human islets was measured with an insulin ELISA. Results A combination of the cytokines IL-1 beta, TNF-alpha and IFN-gamma induced TF expression in human pancreatic islets and in beta cells. TF/FVIIa did not affect basal beta cell death but, independently of downstream coagulation activity, augmented beta cell death in response to cytokines. The effect of TF/FVIIa on cytokine-induced beta cell death was found to be dependent on the stress kinase JNK, since FVIIa addition potentiated cytokine-induced JNK activation and JNK inhibition abolished the effect of TF/FVIIa on cytokine-induced beta cell death. Moreover, TF/FVIIa signalling resulted in inhibition of GSIS from human pancreatic islets. Conclusions/interpretation These results indicate that TF/FVIIa signalling has a negative effect on beta cell function and promotes beta cell death in response to cytokines.

    Keywords
    Beta cells, Cytokines, Diabetes, FVIIa, Glucose-stimulated insulin secretion, JNK, Pancreatic islets, Tissue factor
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-265663 (URN)10.1007/s00125-015-3729-y (DOI)000361993000013 ()26271343 (PubMedID)
    Funder
    Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyStiftelsen Olle Engkvist ByggmästareMagnus Bergvall FoundationSwedish Society of MedicineSwedish Child Diabetes FoundationSwedish Research Council
    Available from: 2015-11-05 Created: 2015-11-02 Last updated: 2019-12-19Bibliographically approved
    2. Adipocytes express tissue factor and FVII and are procoagulant in a TF/FVIIa-dependent manner
    Open this publication in new window or tab >>Adipocytes express tissue factor and FVII and are procoagulant in a TF/FVIIa-dependent manner
    Show others...
    2019 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 124, no 3, p. 158-167Article in journal (Refereed) Published
    Abstract [en]

    Background: Tissue factor (TF) combined with its ligand FVII initiates blood coagulation and intracellular signaling. Obese and type 2 diabetic subjects have increased TF expression in their adipose tissue and an increased risk for thrombotic complications. Here we address the role of TF/FVII on adipocyte functions.

    Materials and methods: Subcutaneous fat was obtained by means of needle aspiration from healthy volunteers, and adipocytes were isolated after collagenase digestion. 3T3-L1 fibroblasts kept in culture were differentiated into adipocytes by addition of IBMX, dexamethasone, rosiglitazone, and insulin to the media. Proteins and mRNA were analyzed by western blot and RT-PCR. Coagulation activity was determined by a colorimetric FX-assay. Lipolysis was measured as free glycerol using a colorimetric method. Glucose uptake was evaluated by scintillation counting of D-[U-C-14] glucose.

    Results: In isolated human primary adipocytes we found expression of TF and FVII. TF expression was confirmed in 3T3-L1 adipocytes, and both cell types were found to be procoagulant in a TF/FVIIa-dependent manner. FXa was generated without FVIIa added to the coagulation assay, and active site-inhibited FVIIa blocked FXa formation, supporting our finding of FVII production by human primary adipocytes. There was no evidence for a role of TF in either lipolysis or glucose uptake in our experimental settings.

    Conclusion: Human primary adipocytes express active TF and FVII, and the TF/FVIIa complex formed on the adipocyte surface can activate substrate FX. Whether the TF/FVIIa complex conveys signaling pathways leading to biological functions and has any biological activity in adipocytes beyond coagulation remains to be elucidated.

    Place, publisher, year, edition, pages
    TAYLOR & FRANCIS LTD, 2019
    Keywords
    Adipocytes, coagulation, FVII, lipolysis, tissue factor
    National Category
    Cardiac and Cardiovascular Systems Medicinal Chemistry
    Identifiers
    urn:nbn:se:uu:diva-396115 (URN)10.1080/03009734.2019.1645248 (DOI)000481057900001 ()31407948 (PubMedID)
    Funder
    Swedish Research CouncilSwedish Heart Lung FoundationErik, Karin och Gösta Selanders Foundation
    Available from: 2019-10-31 Created: 2019-10-31 Last updated: 2019-12-19Bibliographically approved
    3. Activation of β1 integrins and caveolin-1 by TF/FVIIa promotes IGF-1R signaling and cell survival
    Open this publication in new window or tab >>Activation of β1 integrins and caveolin-1 by TF/FVIIa promotes IGF-1R signaling and cell survival
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-399437 (URN)
    Available from: 2019-12-18 Created: 2019-12-18 Last updated: 2019-12-19
    4. miR-223-3p regulates post-transcriptional tissue factor gene expression in human monocytic cells
    Open this publication in new window or tab >>miR-223-3p regulates post-transcriptional tissue factor gene expression in human monocytic cells
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-399598 (URN)
    Available from: 2019-12-18 Created: 2019-12-18 Last updated: 2019-12-19
  • 36.
    Edén, Desireé
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Panagiotou, Grigorios
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Mokhtari, Dariush
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Åberg, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Adipocytes express tissue factor and FVII and are procoagulant in a TF/FVIIa-dependent manner2019In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 124, no 3, p. 158-167Article in journal (Refereed)
    Abstract [en]

    Background: Tissue factor (TF) combined with its ligand FVII initiates blood coagulation and intracellular signaling. Obese and type 2 diabetic subjects have increased TF expression in their adipose tissue and an increased risk for thrombotic complications. Here we address the role of TF/FVII on adipocyte functions.

    Materials and methods: Subcutaneous fat was obtained by means of needle aspiration from healthy volunteers, and adipocytes were isolated after collagenase digestion. 3T3-L1 fibroblasts kept in culture were differentiated into adipocytes by addition of IBMX, dexamethasone, rosiglitazone, and insulin to the media. Proteins and mRNA were analyzed by western blot and RT-PCR. Coagulation activity was determined by a colorimetric FX-assay. Lipolysis was measured as free glycerol using a colorimetric method. Glucose uptake was evaluated by scintillation counting of D-[U-C-14] glucose.

    Results: In isolated human primary adipocytes we found expression of TF and FVII. TF expression was confirmed in 3T3-L1 adipocytes, and both cell types were found to be procoagulant in a TF/FVIIa-dependent manner. FXa was generated without FVIIa added to the coagulation assay, and active site-inhibited FVIIa blocked FXa formation, supporting our finding of FVII production by human primary adipocytes. There was no evidence for a role of TF in either lipolysis or glucose uptake in our experimental settings.

    Conclusion: Human primary adipocytes express active TF and FVII, and the TF/FVIIa complex formed on the adipocyte surface can activate substrate FX. Whether the TF/FVIIa complex conveys signaling pathways leading to biological functions and has any biological activity in adipocytes beyond coagulation remains to be elucidated.

  • 37.
    Eggers, Kai M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lindahl, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Predictors of 10-year changes in levels of N-terminal pro B-type natriuretic peptide and cardiac troponin I in the elderly2018In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 257, p. 300-305Article in journal (Refereed)
    Abstract [en]

    Background: Measurement of N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) might be useful for monitoring of cardiovascular disease in the elderly. However, it is not clear whether changes in these biomarkers are associated with changes in the cardiovascular risk profile and if this pattern could be modified by changes in lifestyle habits or medications.

    Methods: We measured levels of NT-proBNP and cTnI in community-dwelling subjects (PIVUS study) upon visits scheduled at age 70 (n = 1007), 75 (n = 825) and 80 (n = 602). The associations of these biomarkers with repeated measurements of clinical variables (risk factors, lifestyle habits, echocardiographic data and medications) were investigated using sex-adjusted linear mixed random effect models.

    Results: NT-proBNP and cTnI were positively associated with increasing age. NT-proBNP, but not cTnI, was affected by changes of renal function and the degree of obesity. NT-proBNP was more closely related than cTnI to changes in echocardiographic estimates of cardiac geometry and function. Biomarker levels and/or their changes were inversely associated with a physically more active lifestyle (both NT-proBNP and cTnI) and statin treatment at age 70 (only cTnI). Changes in smoking status or antihypertensive treatment had no effect on biomarker levels.

    Conclusions: Changes in NT-proBNP and cTnI levels are associated with different patterns of cardiovascular disease burden when using a longitudinal approach. However, levels of both biomarkers and their changes also reflect changes in the cardiovascular risk profile that might be modifiable. This is an important aspect for the use of any cardiovascular biomarker in an elderly population.

  • 38.
    Emami Khoonsari, Payam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Proteomics Studies of Subjects with Alzheimer’s Disease and Chronic Pain2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Alzheimer’s disease (AD) is a neurodegenerative disease and the major cause of dementia, affecting more than 50 million people worldwide. Chronic pain is long-lasting, persistent pain that affects more than 1.5 billion of the world population. Overlapping and heterogenous symptoms of AD and chronic pain conditions complicate their diagnosis, emphasizing the need for more specific biomarkers to improve the diagnosis and understand the disease mechanisms.

    To characterize disease pathology of AD, we measured the protein changes in the temporal neocortex region of the brain of AD subjects using mass spectrometry (MS). We found proteins involved in exo-endocytic and extracellular vesicle functions displaying altered levels in the AD brain, potentially resulting in neuronal dysfunction and cell death in AD.

    To detect novel biomarkers for AD, we used MS to analyze cerebrospinal fluid (CSF) of AD patients and found decreased levels of eight proteins compared to controls, potentially indicating abnormal activity of complement system in AD.

    By integrating new proteomics markers with absolute levels of Aβ42, total tau (t-tau) and p-tau in CSF, we improved the prediction accuracy from 83% to 92% of early diagnosis of AD. We found increased levels of chitinase-3-like protein 1 (CH3L1) and decreased levels of neurosecretory protein VGF (VGF) in AD compared to controls.

    By exploring the CSF proteome of neuropathic pain patients before and after successful spinal cord stimulation (SCS) treatment, we found altered levels of twelve proteins, involved in neuroprotection, synaptic plasticity, nociceptive signaling and immune regulation.

    To detect biomarkers for diagnosing a chronic pain state known as fibromyalgia (FM), we analyzed the CSF of FM patients using MS. We found altered levels of four proteins, representing novel biomarkers for diagnosing FM. These proteins are involved in inflammatory mechanisms, energy metabolism and neuropeptide signaling.

    Finally, to facilitate fast and robust large-scale omics data handling, we developed an e-infrastructure. We demonstrated that the e-infrastructure provides high scalability, flexibility and it can be applied in virtually any fields including proteomics. This thesis demonstrates that proteomics is a promising approach for gaining deeper insight into mechanisms of nervous system disorders and find biomarkers for diagnosis of such diseases.

    List of papers
    1. Increased levels of extracellular microvesicle markers and decreased levels of endocytic/exocytic proteins in the Alzheimer’s disease brain
    Open this publication in new window or tab >>Increased levels of extracellular microvesicle markers and decreased levels of endocytic/exocytic proteins in the Alzheimer’s disease brain
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    2016 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 54, no 4, p. 71p. 1671-1686Article in journal (Refereed) Published
    Abstract [en]

    Background: Alzheimer's disease (AD) is a chronic neurodegenerative disorder accounting for more than 50% of all dementia cases. AD neuropathology is characterized by the formation of extracellular plaques and intracellular neurofibrillary tangles consisting of aggregated amyloid-beta and tau, respectively. The disease mechanism has only been partially elucidated and is believed to also involve many other proteins.

    Objective: This study intended to perform a proteomic profiling of post mortem AD brains and compare it with control brains as well as brains from other neurological diseases to gain insight into the disease pathology.

    Methods: Here we used label-free shotgun mass spectrometry to analyze temporal neocortex samples from AD, other neurological disorders, and non-demented controls, in order to identify additional proteins that are altered in AD. The mass spectrometry results were verified by antibody suspension bead arrays.

    Results: We found 50 proteins with altered levels between AD and control brains. The majority of these proteins were found at lower levels in AD. Pathway analyses revealed that several of the decreased proteins play a role in exocytic and endocytic pathways, whereas several of the increased proteins are related to extracellular vesicles. Using antibody-based analysis, we verified the mass spectrometry results for five representative proteins from this group of proteins (CD9, HSP72, PI42A, TALDO, and VAMP2) and GFAP, a marker for neuroinflammation.

    Conclusions: Several proteins involved in exo-endocytic pathways and extracellular vesicle functions display altered levels in the AD brain. We hypothesize that such changes may result in disturbed cellular clearance and a perturbed cell-to-cell communication that may contribute to neuronal dysfunction and cell death in AD.

    Publisher
    p. 71
    Keywords
    Brain, Proteomics, Mass spectrometry, Alzheimer's disease
    National Category
    Analytical Chemistry Geriatrics Neurosciences
    Research subject
    Chemistry with specialization in Analytical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-277617 (URN)10.3233/JAD-160271 (DOI)000386749900034 ()27636840 (PubMedID)
    Funder
    VINNOVALars Hierta Memorial FoundationSwedish Research Council, P29797-1; 621-2011-4423Knut and Alice Wallenberg FoundationStiftelsen Gamla Tjänarinnor
    Available from: 2016-02-22 Created: 2016-02-22 Last updated: 2019-04-29Bibliographically approved
    2. Analysis of the Cerebrospinal Fluid Proteome in Alzheimer's Disease
    Open this publication in new window or tab >>Analysis of the Cerebrospinal Fluid Proteome in Alzheimer's Disease
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    2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0150672Article in journal (Refereed) Published
    Abstract [en]

    Alzheimer's disease is a neurodegenerative disorder accounting for more than 50% of cases of dementia. Diagnosis of Alzheimer's disease relies on cognitive tests and analysis of amyloid beta, protein tau, and hyperphosphorylated tau in cerebrospinal fluid. Although these markers provide relatively high sensitivity and specificity for early disease detection, they are not suitable for monitor of disease progression. In the present study, we used label-free shotgun mass spectrometry to analyse the cerebrospinal fluid proteome of Alzheimer's disease patients and non-demented controls to identify potential biomarkers for Alzheimer's disease. We processed the data using five programs (DecyderMS, Maxquant, OpenMS, PEAKS, and Sieve) and compared their results by means of reproducibility and peptide identification, including three different normalization methods. After depletion of high abundant proteins we found that Alzheimer's disease patients had lower fraction of low-abundance proteins in cerebrospinal fluid compared to healthy controls (p<0.05). Consequently, global normalization was found to be less accurate compared to using spiked-in chicken ovalbumin for normalization. In addition, we determined that Sieve and OpenMS resulted in the highest reproducibility and PEAKS was the programs with the highest identification performance. Finally, we successfully verified significantly lower levels (p<0.05) of eight proteins (A2GL, APOM, C1QB, C1QC, C1S, FBLN3, PTPRZ, and SEZ6) in Alzheimer's disease compared to controls using an antibody-based detection method. These proteins are involved in different biological roles spanning from cell adhesion and migration, to regulation of the synapse and the immune system.

    National Category
    Neurology Geriatrics
    Identifiers
    urn:nbn:se:uu:diva-283774 (URN)10.1371/journal.pone.0150672 (DOI)000371990100049 ()26950848 (PubMedID)
    Funder
    Knut and Alice Wallenberg FoundationMarianne and Marcus Wallenberg FoundationThe Swedish Brain FoundationSwedish Research Council FormasSwedish Research Council, P29797-1Swedish Research Council, 621-2011-4423
    Available from: 2016-04-14 Created: 2016-04-14 Last updated: 2019-04-29Bibliographically approved
    3. Chitinase-3-like protein 1 (CH3L1) and Neurosecretory protein VGF (VGF) as two novel CSF biomarker candidates for improved diagnostics in Alzheimer’s disease
    Open this publication in new window or tab >>Chitinase-3-like protein 1 (CH3L1) and Neurosecretory protein VGF (VGF) as two novel CSF biomarker candidates for improved diagnostics in Alzheimer’s disease
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    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by amyloid-β (Aβ) plaque deposition and accumulation of intracellular neurofibrillary tangles. This pathology is mirrored in the cerebrospinal fluid (CSF), where decreased Aβ42 together with increased total (t-tau) and phospho-tau (p-tau) today is used as a diagnostic marker. Although these biomarkers have a fairly good sensitivity and specificity, additional biomarkers are needed to further improve the accuracy for early disease detection and to monitor disease development. In this study, we used mass spectrometry-based shotgun proteomics to investigate the CSF proteome of patients with AD and mild cognitive impairment (MCI) as well as of non-demented controls. By combining the diagnostic markers (Aβ42, total t-tau, and p-tau) with a selection of proteomics biomarkers, the accuracy of predicting MCI to AD conversion increased from 83% to 92% with a specificity of 1.0 and sensitivity of 0.86. Among these markers, the levels of protein chitinase-3-like protein 1 (CH3L1) were significantly higher in AD and MCI converters compared to controls. In addition to Aβ42, t-tau, and p-tau the protein CH3L1 contributed mostly to the prediction accuracy. We also found statistically significant lower CSF levels of the neurosecretory protein VGF (VGF) in AD compared to controls. Taken together, our findings suggest that incorporating new CSF biomarkers can further enhance early diagnosis of AD.

    Keywords
    Alzheimer's disease, cerebrospinal fluid, biomarker, diagnostics, neurodegenerative disorder, dementia
    National Category
    Geriatrics Neurosciences
    Research subject
    Geriatrics; Medical Science; Neurology
    Identifiers
    urn:nbn:se:uu:diva-331711 (URN)
    Available from: 2017-10-17 Created: 2017-10-17 Last updated: 2018-01-13
    4. Spinal Cord Stimulation Alters Protein Levels in the Cerebrospinal Fluid of Neuropathic Pain Patients: A Proteomic Mass Spectrometric Analysis
    Open this publication in new window or tab >>Spinal Cord Stimulation Alters Protein Levels in the Cerebrospinal Fluid of Neuropathic Pain Patients: A Proteomic Mass Spectrometric Analysis
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    2016 (English)In: Neuromodulation (Malden, Mass.), ISSN 1094-7159, E-ISSN 1525-1403, Vol. 19, no 6, p. 549-562Article in journal (Refereed) Published
    Abstract [en]

    ObjectivesElectrical neuromodulation by spinal cord stimulation (SCS) is a well-established method for treatment of neuropathic pain. However, the mechanism behind the pain relieving effect in patients remains largely unknown. In this study, we target the human cerebrospinal fluid (CSF) proteome, a little investigated aspect of SCS mechanism of action. MethodsTwo different proteomic mass spectrometry protocols were used to analyze the CSF of 14 SCS responsive neuropathic pain patients. Each patient acted as his or her own control and protein content was compared when the stimulator was turned off for 48 hours, and after the stimulator had been used as normal for three weeks. ResultsEighty-six proteins were statistically significantly altered in the CSF of neuropathic pain patients using SCS, when comparing the stimulator off condition to the stimulator on condition. The top 12 of the altered proteins are involved in neuroprotection (clusterin, gelsolin, mimecan, angiotensinogen, secretogranin-1, amyloid beta A4 protein), synaptic plasticity/learning/memory (gelsolin, apolipoprotein C1, apolipoprotein E, contactin-1, neural cell adhesion molecule L1-like protein), nociceptive signaling (neurosecretory protein VGF), and immune regulation (dickkopf-related protein 3). ConclusionPreviously unknown effects of SCS on levels of proteins involved in neuroprotection, nociceptive signaling, immune regulation, and synaptic plasticity are demonstrated. These findings, in the CSF of neuropathic pain patients, expand the picture of SCS effects on the neurochemical environment of the human spinal cord. An improved understanding of SCS mechanism may lead to new tracks of investigation and improved treatment strategies for neuropathic pain.

    Keywords
    Cerebrospinal fluid, mechanism of action, neuropathic pain, spinal cord stimulation
    National Category
    Neurology Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-304434 (URN)10.1111/ner.12473 (DOI)000382755300001 ()27513633 (PubMedID)
    Funder
    VINNOVASwedish Research Council
    Available from: 2016-10-05 Created: 2016-10-05 Last updated: 2019-04-29Bibliographically approved
    5. Systematic Analysis of the Cerebrospinal Fluid Proteome of Fibromyalgia patients
    Open this publication in new window or tab >>Systematic Analysis of the Cerebrospinal Fluid Proteome of Fibromyalgia patients
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    2019 (English)In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, p. 35-43Article in journal (Refereed) Published
    Abstract [en]

    Fibromyalgia (FM) is a syndrome characterized by widespread muscular pain, fatigue and functional symptoms, which is known to be difficult to diagnose as the various symptoms overlap with many other conditions. Currently, there are no biomarkers for FM, and the diagnosis is made subjectively by the clinicians. We have performed shotgun proteomics on cerebrospinal fluid (CSF) from FM patients and non-pain controls to find potential biomarker candidates for this syndrome. Based on our multivariate and univariate analyses, we found that the relative differences in the CSF proteome between FM patients and controls were moderate. Four proteins, important to discriminate FM patients from non-pain controls, were found: Apolipoprotein C-III, Galectin-3-binding protein, Malate dehydrogenase cytoplasmic and the neuropeptide precursor protein ProSAAS. These proteins are involved in lipoprotein lipase (LPL) activity, inflammatory signaling, energy metabolism and neuropeptide signaling.

    Keywords
    cerebrospinal fluid, biomarker, chronic pain, fibromyalgia, inflammation, neuroinflammation, mass spectrometry
    National Category
    Neurosciences Clinical Laboratory Medicine Biomedical Laboratory Science/Technology
    Research subject
    Bioinformatics; Biology with specialization in Molecular Biology; Chemistry with specialization in Analytical Chemistry; Medical Science; Clinical Chemistry
    Identifiers
    urn:nbn:se:uu:diva-331615 (URN)10.1016/j.jprot.2018.04.014 (DOI)000450381500006 ()29656018 (PubMedID)
    Funder
    Magnus Bergvall FoundationLars Hierta Memorial FoundationÅke Wiberg FoundationThe Karolinska Institutet's Research Foundation
    Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2019-04-29Bibliographically approved
    6. Interoperable and scalable data analysis with microservices: Applications in metabolomics
    Open this publication in new window or tab >>Interoperable and scalable data analysis with microservices: Applications in metabolomics
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    2019 (English)In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 35, no 19, p. 3752-3760Article in journal (Refereed) Published
    Abstract [en]

    Motivation

    Developing a robust and performant data analysis workflow that integrates all necessary components whilst still being able to scale over multiple compute nodes is a challenging task. We introduce a generic method based on the microservice architecture, where software tools are encapsulated as Docker containers that can be connected into scientific workflows and executed using the Kubernetes container orchestrator.

    Results

    We developed a Virtual Research Environment (VRE) which facilitates rapid integration of new tools and developing scalable and interoperable workflows for performing metabolomics data analysis. The environment can be launched on-demand on cloud resources and desktop computers. IT-expertise requirements on the user side are kept to a minimum, and workflows can be re-used effortlessly by any novice user. We validate our method in the field of metabolomics on two mass spectrometry, one nuclear magnetic resonance spectroscopy and one fluxomics study. We showed that the method scales dynamically with increasing availability of computational resources. We demonstrated that the method facilitates interoperability using integration of the major software suites resulting in a turn-key workflow encompassing all steps for mass-spectrometry-based metabolomics including preprocessing, statistics and identification. Microservices is a generic methodology that can serve any scientific discipline and opens up for new types of large-scale integrative science.

    Keywords
    Bioinformatics, e-infrastructure, microservices, metabolomics, kubernetes, Docker, container
    National Category
    Bioinformatics (Computational Biology)
    Identifiers
    urn:nbn:se:uu:diva-390670 (URN)10.1093/bioinformatics/btz160 (DOI)000499322300026 ()30851093 (PubMedID)
    Funder
    EU, Horizon 2020, 654241Swedish Research Council FormasÅke Wiberg FoundationSwedish National Infrastructure for Computing (SNIC)
    Note

    Title in thesis list of papers: Interoperable and scalable metabolomics data analysis with microservices

    Available from: 2019-03-09 Created: 2019-08-13 Last updated: 2020-01-07Bibliographically approved
  • 39.
    Emami Khoonsari, Payam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Moreno, Pablo
    Bergmann, Sven
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Capuccini, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Carone, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cascante, Marta
    de Atauri, Pedro
    Foguet, Carles
    Gonzalez-Beltran, Alejandra N.
    Hankemeier, Thomas
    Haug, Kenneth
    He, Sijin
    Herman, Stephanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Johnson, David
    Kale, Namrata
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Neumann, Steffen
    Peters, Kristian
    Pireddu, Luca
    Rocca-Serra, Philippe
    Roger, Pierrick
    Rueedi, Rico
    Ruttkies, Christoph
    Sadawi, Noureddin
    Salek, Reza M.
    Sansone, Susanna-Assunta
    Schober, Daniel
    Selivanov, Vitaly
    Thévenot, Etienne A.
    van Vliet, Michael
    Zanetti, Gianluigi
    Steinbeck, Christoph
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Spjuth, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Interoperable and scalable data analysis with microservices: Applications in metabolomics2019In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 35, no 19, p. 3752-3760Article in journal (Refereed)
    Abstract [en]

    Motivation

    Developing a robust and performant data analysis workflow that integrates all necessary components whilst still being able to scale over multiple compute nodes is a challenging task. We introduce a generic method based on the microservice architecture, where software tools are encapsulated as Docker containers that can be connected into scientific workflows and executed using the Kubernetes container orchestrator.

    Results

    We developed a Virtual Research Environment (VRE) which facilitates rapid integration of new tools and developing scalable and interoperable workflows for performing metabolomics data analysis. The environment can be launched on-demand on cloud resources and desktop computers. IT-expertise requirements on the user side are kept to a minimum, and workflows can be re-used effortlessly by any novice user. We validate our method in the field of metabolomics on two mass spectrometry, one nuclear magnetic resonance spectroscopy and one fluxomics study. We showed that the method scales dynamically with increasing availability of computational resources. We demonstrated that the method facilitates interoperability using integration of the major software suites resulting in a turn-key workflow encompassing all steps for mass-spectrometry-based metabolomics including preprocessing, statistics and identification. Microservices is a generic methodology that can serve any scientific discipline and opens up for new types of large-scale integrative science.

  • 40.
    Emami Khoonsari, Payam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Musunri, Sravani
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Herman, Stephanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Svensson, Camilla I
    Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden..
    Tanum, Lars
    Department of R&D in Mental Health, Akershus University Hospital, Lørenskog, Norway..
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Systematic Analysis of the Cerebrospinal Fluid Proteome of Fibromyalgia patients2019In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, p. 35-43Article in journal (Refereed)
    Abstract [en]

    Fibromyalgia (FM) is a syndrome characterized by widespread muscular pain, fatigue and functional symptoms, which is known to be difficult to diagnose as the various symptoms overlap with many other conditions. Currently, there are no biomarkers for FM, and the diagnosis is made subjectively by the clinicians. We have performed shotgun proteomics on cerebrospinal fluid (CSF) from FM patients and non-pain controls to find potential biomarker candidates for this syndrome. Based on our multivariate and univariate analyses, we found that the relative differences in the CSF proteome between FM patients and controls were moderate. Four proteins, important to discriminate FM patients from non-pain controls, were found: Apolipoprotein C-III, Galectin-3-binding protein, Malate dehydrogenase cytoplasmic and the neuropeptide precursor protein ProSAAS. These proteins are involved in lipoprotein lipase (LPL) activity, inflammatory signaling, energy metabolism and neuropeptide signaling.

  • 41.
    Emami Khoonsari, Payam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Ossipova, Elena
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Clin, Unit Rheumatol,Dept Med, Stockholm, Sweden.
    Lengqvist, Johan
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Clin, Unit Rheumatol,Dept Med, Stockholm, Sweden.
    Svensson, Camilla, I
    Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
    Kosek, Eva
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Kadetoff, Diana
    Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden.
    Jakobsson, Per-Johan
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Clin, Unit Rheumatol,Dept Med, Stockholm, Sweden.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lampa, Jon
    Karolinska Univ Hosp, Karolinska Inst, Rheumatol Clin, Unit Rheumatol,Dept Med, Stockholm, Sweden.
    The human CSF pain proteome2019In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 190, p. 67-76Article in journal (Refereed)
    Abstract [en]

    Chronic pain represents one of the major medical challenges in the 21st century, affecting > 1.5 billion of the world population. Overlapping and heterogenous symptoms of various chronic pain conditions complicate their diagnosis, emphasizing the need for more specific biomarkers to improve the diagnosis and understand the disease mechanisms. We have here investigated proteins found in human CSF with respect to known "pain" genes and in a cohort of patients with dysfunctional pain (fibromyalgia, FM), inflammatory pain (rheumatoid arthritis patients, RA) and non-pain controls utilized semi-quantitative proteomics using mass spectrometry (MS) to explore quantitative differences between these cohorts of patients. We found that "pain proteins" detected in CSF using MS are typically related to synaptic transmission, inflammatory responses, neuropeptide signaling- and hormonal activity. In addition, we found ten proteins potentially associated with chronic pain in FM and RA: neural cell adhesion molecule L1, complement C4-A, lysozyme C, receptor-type tyrosine-protein phosphatase zeta, apolipoprotein D, alpha-1-antichymotrypsin, granulins, calcium/calmodulin-dependent protein kinase type II subunit alpha, mast/stem cell growth factor receptor Kit, prolow-density lipoprotein receptor-related protein 1. These proteins might be of importance for understanding the mechanisms of dysfunctional/inflammatory chronic pain and also for use as potential biomarkers. Significance: Chronic pain is a common disease and it poses a large burden on worldwide health. Fibromyalgia (FM) is a heterogeneous disease of unknown etiology characterized by chronic widespread pain (CWP). The diagnosis and treatment of FM is based on the analysis of clinical assessments and no measurable biomarkers are available. Cerebrospinal fluid (CSF) has been historically considered as a rich source of biomarkers for diseases of nervous system including chronic pain. Here, we explore CSF proteome of FM patients utilizing mass spectrometry based quantitative proteomics method combined with multivariate data analysis in order to monitor the dynamics of the CSF proteome. Our findings in this exploratory study support notable presence of pain related proteins in CSF yet with specific domains including inflammatory responses, neuropeptide signaling- and hormonal activity. We have investigated molecular functions of significantly altered proteins and demonstrate presence of 176 known pain related proteins in CSF. In addition, we found ten proteins potentially associated with pain in FM and RA: neural cell adhesion molecule L1, complement C4-A, lysozyme C, receptor-type tyrosine-protein phosphatase zeta, apolipoprotein D, alpha-1-antichymotrypsin, granulins, calcium/calmodulindependent protein kinase type II subunit alpha, mast/stem cell growth factor receptor Kit, prolow-density lipoprotein receptor-related protein 1. These proteins are novel in the context of FM but are known to be involved in pain mechanisms including inflammatory response and signal transduction. These results should be of clear significance and interest for researchers and clinicians working in the field of pain utilizing human CSF and MS based proteomics.

  • 42.
    Emami Khoonsari, Payam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Herman, Stephanie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Remnestal, Julia
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, SciLifeLab, Stockholm, Sweden.
    Giedraitis, Vilmantas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Brundin, RoseMarie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Degerman Gunnarsson, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Zetterberge, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Psychiat & Neurochem, Mölndal, Sweden; Sahlgrens Univ Hosp, Clin Neurochem Lab, Molndal, Sweden; UK Dementia Res Inst UCL, London, England; UCL Inst Neurol, Dept Mol Neurosci, Queen Sq, London, England.
    Nilsson, Peter
    KTH Royal Inst Technol, Dept Prot Sci, Div Affin Prote, SciLifeLab, Stockholm, Sweden.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Improved Differential Diagnosis of Alzheimer's Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers2019In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 67, no 2, p. 639-651Article in journal (Refereed)
    Abstract [en]

    Background: Alzheimer’s disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD.

    Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects.

    Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n = 206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4–9 years and 21 of these converted to AD, whereas 53 remained stable.

    Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively.

    Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

  • 43.
    Ericson, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Abu Hamdeh, Sami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Stiger, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Backryd, Emmanuel
    Linkoping Univ, Dept Med Hlth Sci, Pain & Rehabil Ctr, Linkoping, Sweden.
    Svenningsson, Anders
    Karolinska Inst, Dept Clin Sci, Danderyd Hosp, Stockholm, Sweden.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Anti-inflammatory drugs with more penetration into the central nervous system may contribute to the treatment of trigeminal neuralgia Reply2019In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 160, no 12, p. 2898-2899Article in journal (Other academic)
  • 44.
    Ericson, Hans
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Abu Hamdeh, Sami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Enblad: Neurosurgery.
    Freyhult, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Stiger, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Bäckryd, Emmanuel
    Svenningsson, Anders
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Cerebrospinal fluid biomarkers of inflammation in trigeminal neuralgia patients operated with microvascular decompression2019In: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 160, no 11, p. 2603-2611Article in journal (Refereed)
    Abstract [en]

    Compression of the trigeminal root entry zone by a blood vessel can cause trigeminal neuralgia (TN). However, a neurovascular conflict does not explain all cases of TN, and TN can exist without a neurovascular contact. A common observation during microvascular decompression surgery to treat TN is arachnoiditis in the region of the trigeminal nerve. Thus, aberrant inflammatory mechanisms may be involved in the pathophysiology of TN but information about the role of inflammation in TN is scarce. We used Proximity Extension Assay technology to analyse the levels of 92 protein biomarkers related to inflammation in lumbar cerebrospinal fluid from patients with TN (n = 27) before and after microvascular decompression compared to individuals without TN. We aimed to analyse the pattern of inflammation-related proteins in order to improve our understanding of the pathophysiology of TN. The main finding was that immunological protein levels in the cerebrospinal fluid from patients with TN decreased after surgery towards levels observed in healthy controls. Two proteins seemed to be of specific interest for TN: TRAIL and TNF-beta. Thus, inflammatory activity might be one important mechanism in TN.

  • 45.
    Eriksson, Mats B
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Strandberg, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    The effect of hemorrhagic shock and intraosseous adrenaline injection on the delivery of a subsequently administered drug - an experimental study2019In: Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine, ISSN 1757-7241, E-ISSN 1757-7241, Vol. 27, article id 29Article in journal (Refereed)
    Abstract [en]

    Background: Intraosseous (IO) access is a recommended method when venous access cannot be rapidly established in an emergency. Experimental data suggest that major hemorrhage and catecholamine administration both reduce bone marrow blood flow. We studied the uptake of gentamicin as a tracer substance administered IO following adrenaline administration in hemorrhagic shock and in cardiac arrest.

    Methods: Twenty anesthetized pigs underwent hemorrhage corresponding to 50% of the blood volume. They then received injections of either; adrenaline IO (n=5), saline IO n=5), adrenaline IO during cardiac arrest and cardiopulmonary resuscitation (CPR, n=5), or intravenous adrenaline. The injections were followed by an injection of gentamicin by the same route. Doses and volumes were equivalent among the groups. In all animals, mixed venous antibiotic concentrations were analyzed at 5, 15 and 30min after administration.

    Results: Mean (SD) plasma gentamicin concentrations (mg x L-1) at 5min were 26.4 (2.3) in the group with previous IO adrenaline administration, 26.6 (4.5) in the IO saline group, 31. 2 (12) in the IO adrenaline + CPR group and 23 (4.5) in the IV group. Concentrations in the CPR group were significantly higher than the others.

    Conclusions: No impairment of drug uptake with IO administration after recent IO adrenaline exposure was demonstrable in this shock model.

  • 46.
    Fall, Tove
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedman, Anna
    Karolinska Institutet.
    Pershagen, Göran
    Karolinska Institutet.
    Andolf, Ellika
    Karolinska Institutet.
    Almqvist, Catarina
    Karolinska Institutet.
    Helmersson-Karlqvist, Johanna
    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.
    Reference Intervals for Fecal Calprotectin in Pregnant Women Using a Particle Enhanced Turbidimetric Assay2019In: Clinical Laboratory, ISSN 1433-6510, Vol. 65, no 7, p. 1293-1297Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Fecal calprotectin is widely used as a marker for inflammatory bowel diseases (IBD). IBD often affects women during their reproductive years, but there are no established reference intervals during pregnancy. The aim of the present study was to define reference values during pregnancy and in the postpartum period to allow comparisons between patient results and reference values.

    METHODS: Fecal samples were collected from 84 healthy females during pregnancy week 26 to 28 and a second sample was collected six months after delivery. The samples were weighed, extracted, and centrifugated to remove debris. The extracted samples were then analyzed on a chemistry analyzer using a particle enhanced turbidimetric immunoassay reagent.

    RESULTS: The calculated reference interval during pregnancy was < 127 μg/g (90% confidence interval, 90 - 164 μg/g) and the corresponding reference interval during the postpartum period was < 143 μg/g (60 - 226 μg/g). There were no significant statistical differences between F-calprotectin values analyzed at the two sampling times.

    CONCLUSIONS: The reference values are slightly higher than the cutoff values of 50 - 100 μg/g often used as General cutoff for fecal calprotectin.

  • 47. Feigin, VL
    et al.
    Abate, KH
    Abd-Allah, F
    Abdulle, AM
    Abera, SF
    Abyu, GY
    Ahmed, MB
    Aichour, AN
    Aichour, I
    Aichour, MTE
    Akinyemi, RO
    Alabed, S
    Al-Raddadi, R
    Alvis-Guzman, N
    Amare, AT
    Ärnlöv, Johan
    Karolinska institute; Dalarna university.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Yimam, HH, ,
    Yonemoto, N,
    Yu, C,
    Zaidi, Z
    El Sayed Zaki, M
    Zunt, JR
    Murray, CJL
    Vos, T
    Global, regional, and national burden of neurological disorders during 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015.2017In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 16, no 11, p. 877-897Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level.

    METHODS: We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development.

    FINDINGS: Neurological disorders ranked as the leading cause group of DALYs in 2015 (250·7 [95% uncertainty interval (UI) 229·1 to 274·7] million, comprising 10·2% of global DALYs) and the second-leading cause group of deaths (9·4 [9·1 to 9·7] million], comprising 16·8% of global deaths). The most prevalent neurological disorders were tension-type headache (1505·9 [UI 1337·3 to 1681·6 million cases]), migraine (958·8 [872·1 to 1055·6] million), medication overuse headache (58·5 [50·8 to 67·4 million]), and Alzheimer's disease and other dementias (46·0 [40·2 to 52·7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36·7%, and the number of DALYs by 7·4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26·1% and 29·7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs.

    INTERPRETATION: Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services.

    FUNDING: Bill & Melinda Gates Foundation.

  • 48.
    Fellström, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Helmersson-Karlqvist, Johanna
    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, Clinical Epidemiology.
    Soveri, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Wu, Ping-Hsun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Thulin, Måns
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Ärnlöv, Johan
    Dalarna Univ, Dept Sch Hlth & Social Studies, Falun, Sweden;Karolinska Inst, Div Family Med, Dept Neurobiol Care Sci & Soc, Huddinge, Sweden.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Associations Between Apolipoprotein A1, High-Density Lipoprotein Cholesterol, and Urinary Cytokine Levels in Elderly Males and Females2020In: Journal of Interferon and Cytokine Research, ISSN 1079-9907, E-ISSN 1557-7465, Vol. 40, no 2, p. 71-74Article in journal (Refereed)
    Abstract [en]

    There exists a close relationship between cardiovascular diseases and chronic kidney disease. Apolipoprotein A1 and high-density lipoprotein (HDL) cholesterol are widely used as cardiovascular risk markers but they also have anti-inflammatory properties. The aim of this study was to investigate any associations between HDL levels and cytokine levels in urine. We randomly selected 90 urine samples from the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females). The samples were analyzed with 2 multiplex assays, Multiplex Inflammation I and Cardiovascular II kits (Olink Bioscience, Uppsala, Sweden). We analyzed the correlations between 158 cytokines in urine with apolipoprotein A1, HDL cholesterol, apolipoprotein B, and low-density lipoprotein cholesterol. There were strong correlations for apolipoprotein A1 and HDL cholesterol with individual cytokines. After adjustment for multiplicity testing, there were 33 significant correlations between apolipoprotein A1 and cytokine levels and 14 of these were also significantly correlated with HDL cholesterol. The strongest associations were observed for IL-1 alpha, SPON2, RAGE, PAR-1, TRAIL-R2, IL-4RA, TNFRSF11A, and SCF. A total of 28 out of 33 correlations were negative, indicating a negative relationship between apolipoprotein A1 and urinary cytokines. The study shows a negative correlation between apolipoprotein A1 and HDL cholesterol and urinary cytokine levels. The finding is in agreement with the anti-inflammatory properties of HDL.

  • 49.
    Feresiadou, Amalia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Landtblom: Neurology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Press, Rayomand
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden..
    Kmezic, Ivan
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden..
    Nygren, Ingela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Svenningsson, Anders
    Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden..
    Niemelä, Valter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Gordh, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Kultima, Kim
    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.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Measurement of sCD27 in the cerebrospinal fluid identifies patients with neuroinflammatory disease2019In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 332, p. 31-36Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Laboratory tests to assist in the diagnosis and monitoring of neuroinflammatory diseases are scarce. The soluble form of the CD27 molecule (sCD27) is shed in high concentrations by activated T cells and can be detected in the cerebrospinal fluid. The aim of this study was to investigate whether CSF quantitation of sCD27 could discriminate between inflammatory and non-inflammatory neurological diseases.

    METHODS: The concentration of sCD27 was measured using a commercially available ELISA in 803 well-defined subjects from a study cohort comprised of 338 patients with neuroinflammatory disease, 338 with non-inflammatory neurological disease and 127 controls without neurological disease.

    RESULTS: The median value of cerebrospinal fluid sCD27 was 64 pg/mL (IQR 0-200) in controls, 58 pg/mL (IQR 0-130) in patients with non-inflammatory disease and 740 pg/mL (IQR 230-1800) in patients with inflammatory disease. The likelihood ratio of having an inflammatory disease was 10 (sensitivity 74% and specificity 93%) if the sCD27 concentration was >250 pg/mL. In patients with a known inflammatory condition, the likelihood ratio of having an infection was 10 (sensitivity 40% and specificity 96%) if the sCD27 concentration was >2500 pg/mL.

    CONCLUSIONS: The likelihood of having an inflammatory neurological condition is increased with elevated concentrations of sCD27 in cerebrospinal fluid. Rapid tests of sCD27 should be developed to assist clinicians in diagnosis of neuroinflammatory disease.

  • 50.
    Frithiof, Robert
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Bandert, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Larsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry.
    Lipcsey, Miklós
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory.
    Smekal, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Central Venous Line and Dialysis Catheter Position Affects Drug Clearance during Continuous Renal Replacement Therapy in an Animal Model.2019In: ASAIO journal (1992), ISSN 1058-2916, E-ISSN 1538-943X, Vol. 65, no 4, p. 408-413Article in journal (Refereed)
    Abstract [en]

    In intensive care, drugs are commonly administered through central venous catheters (CVC). These catheters and central venous dialysis catheters (CVDC) are often placed in the same vessel for practical reasons. The aim of this experimental study was to investigate if the position of CVC and CVDC influences the elimination of infused drugs, during continuous renal replacement therapy (CRRT). In a randomized, cross-over model, anesthetized piglets received both a CVC and a CVDC in a jugular vein. Another CVDC was placed in a femoral vein for comparison. After baseline measurements, CRRT was performed in either of the CVDC, each CRRT-period separated by another baseline period. Hypotension was induced by peripherally given sodium nitroprusside. In the CVC, both gentamicin and noradrenaline were administered. Noradrenaline was titrated to reach a target blood pressure. When CRRT was performed using the CVDC in the same vessel as the drugs were infused, the plasma concentration of gentamicin was reduced compared with when the infusion and CVDC were in different vessels (5.66 [standard deviation (SD) ± 1.23] vs. 7.76 [SD ± 2.30] mg/L [p = 0.02]). The noradrenaline infusion rate needed to reach the target blood pressure was more than doubled (0.32 [SD ± 0.16] vs. 0.15 [SD ± 0.08] µg/kg/min [p = 0.006]). This experimental study indicates that the removal of drugs is increased if infusion is in close vicinity of the CVDC, during CRRT.

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