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  • 1.
    Abujrais, Sandy
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Olovsson, Matts
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Reproduktionsbiologi.
    Ahnoff, Martin
    Department of Marine Sciences, University of Gothenburg, Carl Skottbergs gata 22B, SE-41319 Gothenburg, Sweden..
    Rasmusson, Annica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakogenomik och osteoporos.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Åkerfeldt, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    A sensitive method detecting trace levels of levonorgestrel using LC-HRMS.2019Inngår i: Contraception, ISSN 0010-7824, E-ISSN 1879-0518, Vol. 100, nr 3, s. 247-249Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Larsson, Marita
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Naessen, Tord
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Sub-clinical atherosclerosis in the common carotid artery in women with/without previous pre-eclampsia: A seven-year follow-up.2019Inngår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, artikkel-id S0021-9150(19)30449-6Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Gynekologisk endokrinologi.
    Wikström, Anna-Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Klinisk obstetrik. Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Larsson, Marita
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Obstetrik & gynekologi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Wikström, Gerhard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Naessén, Tord
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Forskargrupper (Inst. för kvinnor och barns hälsa), Gynekologisk endokrinologi.
    Serum Pentraxin 3 is associated with signs of arterial alteration in women with preeclampsia.2017Inngår i: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 241, s. 417-422Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Less fibrosis in elderly subjects supplemented with selenium and coenzyme Q10-A mechanism behind reduced cardiovascular mortality?2018Inngår i: Biofactors, ISSN 0951-6433, E-ISSN 1872-8081, Vol. 44, nr 2, s. 137-147Artikkel i tidsskrift (Fagfellevurdert)
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Decrease in inflammatory biomarker concentration by intervention with selenium and coenzyme Q10: a subanalysis of osteopontin, osteoprotergerin, TNFr1, TNFr2 and TWEAK2019Inngår i: Journal of Inflammation, ISSN 1476-9255, E-ISSN 1476-9255, Vol. 16, artikkel-id 5Artikkel i tidsskrift (Fagfellevurdert)
    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.
    Alehagen, Urban
    et al.
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, SE-581 85 Linköping, Sweden..
    Alexander, Jan
    Norwegian Institute of Public Health, N-0403 Oslo, Norway..
    Aaseth, Jan
    Inland Norway University of Applied Sciences, N-2411 Elverum, Norway..
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Decrease in inflammatory biomarker concentration by intervention with selenium and coenzyme Q10: a subanalysis of osteopontin, osteoprotergerin, TNFr1, TNFr2 and TWEAK.2019Inngår i: Journal of Inflammation, ISSN 1476-9255, E-ISSN 1476-9255, Vol. 16, artikkel-id 5Artikkel i tidsskrift (Fagfellevurdert)
    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 42 months in 219 community-living elderly persons, of whom 119 received supplements of selenium (200 μg/day) and coenzyme Q10 (200 mg/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 .

    Trial registration: The intervention study was registered at Clinicaltrials.gov, and has the identifier NCT01443780 and registered on 09/30/2011.

  • 7. 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    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 2015.2017Inngår i: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 390, nr 10091, s. 231-266Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 8.
    Basu, Samar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi. 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 inflammation2017Inngår i: Prostaglandins, Leukotrienes and Essential Fatty Acids, ISSN 0952-3278, E-ISSN 1532-2823, Vol. 126, s. 79-83Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 9. Befekadu, Rahel
    et al.
    Christiansen, Kjeld
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Grenegård, Magnus
    Increased plasma cathepsin S and trombospondin-1 in patients with acute ST-segment elevation myocardial infarction2019Inngår i: Cardiology journal, ISSN 1897-5593, Vol. 26, nr 4, s. 385-393Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 10.
    Bergman, Daniel
    et al.
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    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 immunoassays.2019Inngår i: Veterinary clinical pathology, ISSN 0275-6382, E-ISSN 1939-165XArtikkel i tidsskrift (Fagfellevurdert)
    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.

  • 11.
    Bergman, Daniel
    et al.
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden..
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    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.2018Inngår i: Veterinary clinical pathology, ISSN 0275-6382, E-ISSN 1939-165X, Vol. 47, nr 2, s. 205-212Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 12.
    Bergman, Daniel
    et al.
    Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, 750 07, Sweden. .
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    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 interference2019Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, nr 1, artikkel-id 14521Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 13.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Kultima, Kim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    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 Cells2019Inngår i: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 10, artikkel-id 636Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 14.
    Blom, Kristin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    ElShafie, Amir Ibrahim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Alribat Univ Hosp, Dept Clin Pathol & Microbiol, Khartoum, Sudan.
    Jönsson, Ulla-Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Rönnelid, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Håkansson, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Venge, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    The genetically determined production of the alarmin eosinophil-derived neurotoxin is reduced in visceral leishmaniasis2018Inngår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 126, nr 1, s. 85-91Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 15. 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    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 2017.2019Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 574, nr 7778, s. 353-358Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 16. Bäckryd, Emmanuel
    et al.
    Lind, Anne-Li
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. Uppsala Berzelii Technology Center for Neurodiagnostics, Uppsala University, Uppsala, Sweden.
    Thulin, Måns
    Uppsala universitet, Humanistisk-samhällsvetenskapliga vetenskapsområdet, Samhällsvetenskapliga fakulteten, Statistiska institutionen.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Gerdle, Björn
    Gordh, Torsten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Anestesiologi och intensivvård. 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 controls2017Inngår i: Pain, ISSN 0304-3959, E-ISSN 1872-6623, Vol. 158, nr 12, s. 2487-2495Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 17.
    Carlsson, Axel C
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi. 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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    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 Sweden2018Inngår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 272, s. 41-46Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 18.
    Carlsson, Axel C
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiovaskulär epidemiologi.
    Ruge, Toralph
    Kjøller, Erik
    Hilden, Jørgen
    Kolmos, Hans Jørn
    Sajadieh, Ahmad
    Kastrup, Jens
    Jensen, Gorm Boje
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    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.2018Inngår i: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 7, nr 9, artikkel-id e008299Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 19.
    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, A
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    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 departments.2019Inngår i: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, artikkel-id S0009-9120(19)30514-4Artikkel i tidsskrift (Fagfellevurdert)
    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 %.

  • 20.
    Cedervall, Jessica
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Dragomir, Anca
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Saupe, Falk
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Zhang, Yanyu
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Ärnlöv, Johan
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Divis Family Med, Huddinge, Sweden.
    Larsson, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Olsson, Anna-Karin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.2017Inngår i: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, nr 8, artikkel-id e1320009Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 21. 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 ()
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Lannfelt, Lars ()
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Adiposity and risk of decline in glomerular filtration rate: meta-analysis of individual participant data in a global consortium2019Inngår i: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 364, artikkel-id k5301Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 22.
    Christersson, Christina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Lindahl, Bertil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Berglund, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Oldgren, Jonas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    The utility of coagulation activity for prediction of risk of mortality and cardiovascular events in guideline-treated myocardial infarction patients2017Inngår i: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, nr 4, s. 224-233Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 23.
    Christersson, Christina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Thulin, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Microparticles during long-term follow-up after acute myocardial infarction: Association to atherosclerotic burden and risk of cardiovascular events2017Inngår i: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 117, nr 8, s. 1571-1581Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 24.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    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.2018Inngår i: European Journal of Heart Failure, ISSN 1388-9842, E-ISSN 1879-0844Artikkel i tidsskrift (Fagfellevurdert)
  • 25.
    Dubois, Louise
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Prostasomes as Diagnostic, Prognostic and Therapeutic Vesicles2019Doktoravhandling, med artikler (Annet vitenskapelig)
    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.

    Delarbeid
    1. Proteomic profiling of detergent resistant membranes (lipid rafts) of prostasomes
    Åpne denne publikasjonen i ny fane eller vindu >>Proteomic profiling of detergent resistant membranes (lipid rafts) of prostasomes
    Vise andre…
    2015 (engelsk)Inngår i: Molecular & Cellular Proteomics, ISSN 1535-9476, E-ISSN 1535-9484, Vol. 14, nr 11, s. 3015-3022Artikkel i tidsskrift (Fagfellevurdert) 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.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-261543 (URN)10.1074/mcp.M114.047530 (DOI)000365636800014 ()26272980 (PubMedID)
    Tilgjengelig fra: 2015-09-01 Laget: 2015-09-01 Sist oppdatert: 2018-12-11bibliografisk kontrollert
    2. Human erythrocyte-derived nanovesicles can readily be loaded with doxorubicin and act as anticancer agents
    Åpne denne publikasjonen i ny fane eller vindu >>Human erythrocyte-derived nanovesicles can readily be loaded with doxorubicin and act as anticancer agents
    Vise andre…
    2018 (engelsk)Inngår i: Cancer Research Frontiers, ISSN 2328-5249, Vol. 4, nr 1, s. 13-26Artikkel i tidsskrift (Fagfellevurdert) 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.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-364780 (URN)10.17980/2018.13 (DOI)
    Merknad

    Louise Dubois and Liza Löf contributed equally to this work.

    Tilgjengelig fra: 2018-11-02 Laget: 2018-11-02 Sist oppdatert: 2019-01-31bibliografisk kontrollert
    3. Occurrence of purinergic receptors in human prostasomes (prostate epithelial cell-derived exosomes)
    Åpne denne publikasjonen i ny fane eller vindu >>Occurrence of purinergic receptors in human prostasomes (prostate epithelial cell-derived exosomes)
    2018 (engelsk)Inngår i: Artikkel i tidsskrift (Fagfellevurdert) Submitted
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-369182 (URN)
    Tilgjengelig fra: 2018-12-11 Laget: 2018-12-11 Sist oppdatert: 2018-12-11
    4. Increased levels of thymidine kinase 1 in malignant cell-derived exosomes
    Åpne denne publikasjonen i ny fane eller vindu >>Increased levels of thymidine kinase 1 in malignant cell-derived exosomes
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-369188 (URN)
    Tilgjengelig fra: 2018-12-11 Laget: 2018-12-11 Sist oppdatert: 2018-12-11
  • 26.
    Dubois, Louise
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Occurrence of purinergic receptors in human prostasomes (prostate epithelial cell derived exosomes)Manuskript (preprint) (Annet vitenskapelig)
  • 27.
    Dubois, Louise
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Occurrence of purinergic receptors in human prostasomes (prostate epithelial cell-derived exosomes)2018Inngår i: Artikkel i tidsskrift (Fagfellevurdert)
  • 28.
    Dubois, Louise
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Löf, Liza
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Larsson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    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 universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ronquist, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.
    Ronquist, K. Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk kemi.