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  • 1.
    Allbrand, Marianne
    Örebro University, School of Medical Sciences.
    Gene expression of inflammatory markers and growth factors in placenta in relation to maternal obesity and foetal and postnatal growth2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Maternal obesity is a growing health problem, that contributes to obstetrical complications in pregnancy, as well as neonatal morbidity and mortality. The placenta serves for gas and nutrient exchange between the mother and the foetus, and obesity may influence and modify placental growth and function. The aims of this thesis were to investigate associations between maternal obesity without associated morbidity and gene expression of inflammatory markers and growth factors in the placenta, as well as offspring birth weight and postnatal growth. 

    Study I and III were designed as matched case-control studies including 32 obese women with an early pregnancy body mass index (BMI) ≥ 35.0 kg/m2, study II was an experimental study examining twelve placentas of normal weight women, and study IV was a cohort study including 109 obese women with a BMI ≥ 34.5 kg/m2. In studies I-IV analyses of gene expression were performed and in study III additionally cord blood concentrations were determined. 

    No difference was found in the occurrence of placental gene expression of inflammatory markers or growth factors between obese and normal weight women, nor did the sampling site in placentas of normal weight women influence gene expression of these markers, except for leptin gene (LEP) and insulin receptor gene (INSR) expression. Ghrelin gene (GHRL) and LEP expression, as well as cord blood ghrelin and adiponectin levels, was not altered in maternal obesity, and a negatively U-shaped relationship between LEP expression and infant birth weight (BW) z-scores was observed in the placentas of obese women.

    In conclusion, no statistically significant difference in gene expressions of inflammatory markers and growth factors in the placenta between severely obese and normal weight women was found. These results are in contrast with earlier studies and could be due to the fact that we examined mainly healthy obese women. The correlations we found between gene expression of leptin in the placenta and the birth weight of the infants warrants further studies.

    List of papers
    1. Placental gene expression of inflammatory markers and growth factors: a case control study of obese and normal weight women
    Open this publication in new window or tab >>Placental gene expression of inflammatory markers and growth factors: a case control study of obese and normal weight women
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    2015 (English)In: Journal of Perinatal Medicine, ISSN 0300-5577, E-ISSN 1619-3997, Vol. 43, no 2, p. 159-164Article in journal (Refereed) Published
    Abstract [en]

    Objective: To survey the placental gene expression of inflammatory markers and growth factors in non-smoking obese women with an uncomplicated pregnancy without associated morbidity and delivery at term compared with normal weight women.

    Methods: Placental tissue samples from 32 obese women (body mass index, BMI >= 35.0 kg/m(2)) were compared with samples from 94 normal weight women (BMI 18.5-25.0 kg/m(2)) matched for age (+/- 1 year), gestational age (+/- 3 days), parity and mode of delivery. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to analyse toll receptor-2 and -4, interleukin-6 and -8, tumour necrosis factor-alpha, leptin, adiponectin, insulin-like growth factor-1 and -2, hepatocyte growth factor, hepatocyte growth factor receptor and insulin receptor.

    Results: There was no significant difference in gene expression in placental tissue samples from obese and normal weight women.

    Conclusion: We found no difference in the occurrence of inflammatory marker and growth factor mRNA levels in placental tissue samples from a large group of obese women without associated morbidity and with healthy infants compared to a closely matched control group of healthy normal weight women. Compared with the previous studies, this anomalous finding may be explained by the absence of associated morbidity in the obese women in our study.

    Place, publisher, year, edition, pages
    Walter de Gruyter, 2015
    Keywords
    Obesity, pregnancy
    National Category
    Obstetrics, Gynecology and Reproductive Medicine Pediatrics
    Research subject
    Obstetrics and Gynaecology; Pediatrics
    Identifiers
    urn:nbn:se:oru:diva-44240 (URN)10.1515/jpm-2013-0343 (DOI)000350338000005 ()25014513 (PubMedID)2-s2.0-84945571575 (Scopus ID)
    Note

    Funding Agency:

    Foundation for Medical Research, Orebro University Hospital

    Available from: 2015-04-14 Created: 2015-04-14 Last updated: 2023-12-08Bibliographically approved
    2. Expression of genes involved in inflammation and growth: does sampling site in human full-term placenta matter?
    Open this publication in new window or tab >>Expression of genes involved in inflammation and growth: does sampling site in human full-term placenta matter?
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    2019 (English)In: Journal of Perinatal Medicine, ISSN 0300-5577, E-ISSN 1619-3997, Vol. 47, no 5, p. 539-546Article in journal (Refereed) Published
    Abstract [en]

    Objective: To investigate the placental gene expression of substances in the inflammatory cascade and growth factors at nine different well-defined sampling sites in full-term placentas from 12 normal weight healthy non-smoking women with an uncomplicated singleton pregnancy.

    Methods: All placentas (six girls and six boys) were delivered vaginally. Quantitative real-time polymerase chain reaction was used to analyze toll receptor-2 and -4, interleukin-6 and -8, tumor necrosis factor-α, leptin, ghrelin, insulin-like growth factor-1 and -2, hepatocyte growth factor, hepatocyte growth factor receptor and insulin receptor (IR).

    Results: The leptin gene and the IR gene showed higher expression in lateral regions near the chorionic plate compared to central regions near the basal plate (P = 0.028 and P = 0.041, respectively).

    Conclusion: Our results suggest that the sampling site may influence the gene expression for leptin and IR in placental tissue obtained from full-term normal pregnancies. We speculate that this may be due to differences in placental structure and perfusion and may be important when future studies are designed.

    Place, publisher, year, edition, pages
    Walter de Gruyter, 2019
    Keywords
    Cytokines, gene expression, growth factors, placenta, sampling
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:oru:diva-73427 (URN)10.1515/jpm-2018-0290 (DOI)000473532900008 ()30920955 (PubMedID)2-s2.0-85063721684 (Scopus ID)
    Note

    Funding Agencies:

    Research Committee of Region Örebro County  

    Nyckelfonden, Örebro University Hospital  

    Available from: 2019-04-04 Created: 2019-04-04 Last updated: 2020-12-01Bibliographically approved
    3. Placental ghrelin and leptin expression and cord blood ghrelin, adiponectin, leptin, and C-peptide levels in severe maternal obesity
    Open this publication in new window or tab >>Placental ghrelin and leptin expression and cord blood ghrelin, adiponectin, leptin, and C-peptide levels in severe maternal obesity
    2017 (English)In: The Journal of Maternal-Fetal & Neonatal Medicine, ISSN 1476-7058, E-ISSN 1476-4954, Vol. 31, no 21, p. 2839-2846Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: The purpose of this study is to investigate placental ghrelin and leptin expression as well as cord blood ghrelin and adiponectin levels in maternal obesity and associations between placental ghrelin expression, cord blood ghrelin levels and maternal and infant variables.

    MATERIALS AND METHODS: Placental ghrelin and leptin expression were analyzed by RT-PCR in 32 severely obese and 32 matched normal-weight women. Cord blood ghrelin, adiponectin, leptin, and C-peptide concentrations were analyzed by ELISA.

    RESULTS: Neither ghrelin nor leptin expression and neither cord blood ghrelin nor adiponectin levels differed between the groups. Placental ghrelin expression was associated with BMI at delivery in the obese women (r = 0.424, p = .016) and in the infants born to normal-weight women with their weight z-scores at six (r = -0.642, p = .010), nine (r = -0.441, p = .015), and 12 months of age (r = -0.402, p = .028).

    CONCLUSIONS: Placental ghrelin and leptin expression as well as cord blood ghrelin and adiponectin levels do not seem to be altered in severe maternal obesity. Placenta-derived ghrelin may influence the infants' postnatal weight gain, but possibly only when the mother has normal weight.

    Place, publisher, year, edition, pages
    Taylor & Francis Group, 2017
    Keywords
    Adiponectin, birth weight, ghrelin, leptin, obesity, placenta
    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:oru:diva-61734 (URN)10.1080/14767058.2017.1358262 (DOI)000440610300007 ()28783996 (PubMedID)2-s2.0-85027047254 (Scopus ID)
    Note

    Funding agencies:

    Research Committee of Region Örebro County

    Nyckelfonden, Örebro University Hospital

    Available from: 2017-11-06 Created: 2017-11-06 Last updated: 2020-12-01Bibliographically approved
    4. Gene expression of leptin, leptin receptor isoforms, and inflammatory cytokines in placentas of obese women: associations to birth weight and foetal sex
    Open this publication in new window or tab >>Gene expression of leptin, leptin receptor isoforms, and inflammatory cytokines in placentas of obese women: associations to birth weight and foetal sex
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-85819 (URN)
    Available from: 2020-09-21 Created: 2020-09-21 Last updated: 2020-12-01Bibliographically approved
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  • 2.
    Allbrand, Marianne
    et al.
    Örebro University, School of Medical Sciences.
    Eklund, Daniel
    Örebro University, School of Medical Sciences.
    Cao, Yang
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Åman, Jan
    Örebro universitet, Institutionen för medicinska vetenskaper.
    Nilsson, Kerstin
    Örebro University, School of Medical Sciences.
    Lodefalk, Maria
    Örebro University, School of Medical Sciences. Örebro University Hospital.
    Gene expression of leptin, leptin receptor isoforms, and inflammatory cytokines in placentas of obese women: associations to birth weight and foetal sexManuscript (preprint) (Other academic)
  • 3.
    Asfaw Idosa, Berhane
    Örebro University, School of Medical Sciences.
    Inflammasome polymorphisms and the Inflammatory Response to Bacterial Infections2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    NLRP3 inflammasome; a key component of the innate immune system, can be activated by a number of pathogens and other threats of the body. Activation of the NLRP3 inflammasome triggers caspase-1 mediated maturationof IL-1β and IL-18. Polymorphisms Q705K and C10X are two gene variants of the NLRP3 inflammasome that combined or per se have been associated with higher risk and severity of chronic inflammation and excessive production of IL-1β. Host genetic factors have been found an important determinants of susceptibility of infectious diseases and disease outcome. The aims of this thesis were to investigate the association between polymorphisms Q705K and C10X with bacterial infections and the inflammatory response, moreover to determine the inflammasome activation state in healthy carriers of these polymorphisms. The data of the thesis show higher levels of IL-1β and IL-33 in healthy carriers of combined polymorphisms of Q705K and C10X as compared to non-carrier controls. This may provide individuals with combined polymorphisms a more robust innate immune response against pathogens, but could also lead to the onset of chronic inflammation, and excessive inflammation during acute infection. In addition, individuals with C10X polymorphism per se showed association with the presence of bacteremia as compared withhealthy blood donors. No association was found in severely ill patients with negative blood culture bottle. In addition, the results show that LOS of N. meningitidis is responsible for the priming and activating steps of the inflammasome. The non-LOS components were found to contribute to the priming step. A higher inflammatory response to N. meningitidis was found in individuals who were non-carriers of the polymorphisms than individuals with the Q705K and C10X per se or combined regardless of the strain of bacteria. Taken together, the gene variations of the NLRP3 inflammasome are of importance in explaining inter-individual variation in susceptibility to infectious diseases.

    List of papers
    1. Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome
    Open this publication in new window or tab >>Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the NLRP3 inflammasome
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    2013 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 8, no 10Article in journal (Refereed) Published
    Abstract [en]

    Background: The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1 beta and IL-18. Increased production of IL-1 beta is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene.

    Materials and Methods: Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1 beta, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched non-carrier controls.

    Results & Discussion: The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1 beta and IL-33 were elevated among carriers of combined Q705K+C10X polymorphisms compared to controls, whereas no difference was found for IL-18 and the other cytokines measured. Moreover, carriers of C10X or Q705K per se had similar plasma levels of IL-1 beta as non-carriers. These data suggest that the combined polymorphisms create inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.

    Place, publisher, year, edition, pages
    Public Library of Science (PLoS), 2013
    National Category
    Immunology in the medical area
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-35447 (URN)10.1371/journal.pone.0075457 (DOI)000325483600018 ()24098386 (PubMedID)2-s2.0-84884894455 (Scopus ID)
    Funder
    Swedish Research Council, ES: K2010-57X-21435-01-3
    Note

    Funding Agencies:

    Research committee of the County Council of Örebro

    Nyckelfonden at Örebro University Hospital

    Sund's Foundation for Rheumatic Research

    King Gustaf V Memorial Foundation

    Available from: 2014-06-19 Created: 2014-06-19 Last updated: 2024-01-03Bibliographically approved
    2. C10X polymorphism in the CARD8 gene is associated with bacteraemia
    Open this publication in new window or tab >>C10X polymorphism in the CARD8 gene is associated with bacteraemia
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    2014 (English)In: Immunity, inflammation and disease, E-ISSN 2050-4527, Vol. 2, no 1, p. 13-20Article in journal (Refereed) Published
    Abstract [en]

    The NLRP3 inflammasome is an intracellular multi-protein complex that triggers caspase-1 mediated maturation of interleukin-1β (IL-1β); one of the most potent mediators of inflammation and a major cytokine produced during severe infections, like sepsis. However, the excessive cytokine levels seem to stage for tissue injury and organ failure, and high levels of IL-1β correlates with severity and mortality of sepsis. Instead, recent data suggest caspase-1 to function as a guardian against severe infections. CARD8 has been implied to regulate the synthesis of IL-1β via interaction to caspase-1. In recent years, polymorphism of CARD8 (C10X) per se or in combination with NLRP3 (Q705K) has been implicated with increased risk of inflammation. The aim was to investigate the correlation of these polymorphisms with severe blood stream infection. Human DNA was extracted from blood culture bottles that were found to be positive for microbial growth (i.e. patients with bacteraemia). Polymorphisms Q705K in the NLRP3 gene and C10X in the CARD8 gene were genotyped using TaqMan genotyping assay. The results were compared to healthy controls and to samples from patients with negative cultures. The polymorphism C10X was significantly over-represented among patients with bacteraemia as compared to healthy controls, whereas patients with negative blood culture were not associated with a higher prevalence. No association was observed with polymorphism Q705K of NLRP3 in either group of patients. Patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation.

    Place, publisher, year, edition, pages
    West Sussex, UK: John Wiley & Sons, 2014
    Keywords
    Bacteraemia, blood culture, gene variants, infection, inflammasomes, inflammation, innate immunity, leukocytes, polymorphisims, sepsis
    National Category
    Clinical Laboratory Medicine Microbiology in the medical area Immunology in the medical area
    Identifiers
    urn:nbn:se:oru:diva-42421 (URN)10.1002/iid3.14 (DOI)25400921 (PubMedID)2-s2.0-85031008033 (Scopus ID)
    Available from: 2015-02-05 Created: 2015-02-05 Last updated: 2023-12-08Bibliographically approved
    3. LOS-dependent Neisseria meningitidis-induced caspase-1 activation in human neutrophils
    Open this publication in new window or tab >>LOS-dependent Neisseria meningitidis-induced caspase-1 activation in human neutrophils
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-51769 (URN)
    Available from: 2016-08-24 Created: 2016-08-23 Last updated: 2024-01-03Bibliographically approved
    4. Human gene variants that regulate the NLRP3 activity limit the production of Neisseria meningitidis-induced IL-1β and IL-18
    Open this publication in new window or tab >>Human gene variants that regulate the NLRP3 activity limit the production of Neisseria meningitidis-induced IL-1β and IL-18
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-51776 (URN)
    Available from: 2016-08-24 Created: 2016-08-24 Last updated: 2024-01-03Bibliographically approved
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  • 4.
    Asfaw Idosa, Berhane
    et al.
    Örebro University, School of Medical Sciences.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences.
    Kelly, Anne
    Karolinska University Hospital, Stockholm, Sweden.
    Fredlund, Hans
    Örebro University, School of Medical Sciences.
    Persson, Alexander
    Örebro University, School of Medical Sciences.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Human gene variants that regulate the NLRP3 activity limit the production of Neisseria meningitidis-induced IL-1β and IL-18Manuscript (preprint) (Other academic)
  • 5.
    Asfaw Idosa, Berhane
    et al.
    Örebro University, School of Medical Sciences.
    Persson, Alexander
    Örebro University, School of Medical Sciences.
    Jacobsson, Susanne
    Örebro University, School of Medical Sciences.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Fredlund, Hans
    Örebro University, School of Medical Sciences.
    Särndahl, Eva
    Örebro University, School of Medical Sciences.
    Kelly, Anne
    Karolinska University Hospital, Stockholm, Sweden.
    LOS-dependent Neisseria meningitidis-induced caspase-1 activation in human neutrophilsManuscript (preprint) (Other academic)
  • 6.
    Befekadu, Rahel
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine, Section for Clinical Immunology and Transfusion medicine, Örebro University Hospital, Örebro, Sweden.
    Grenegård, Magnus
    Örebro University, School of Medical Sciences.
    Larsson, Anders
    Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
    Christensen, Kjeld
    Karlstad Central Hospital, Karlstad, Sweden; Department of Cardiology, Örebro University Hospital, Örebro, Sweden.
    Nilsson, Bo
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden.
    Ramström, Sofia
    Örebro University, School of Medical Sciences. Department of Clinical Chemistry, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Activation of the lectin complement pathway during and after ST segment elevation myocardial infarctionManuscript (preprint) (Other academic)
  • 7.
    Befekadu Wodajo, Rahel
    Örebro University, School of Medical Sciences.
    Analysis of new biomarkers and their kinetics in connection with ST-elevation myocardial infarction and percutaneous coronary intervention2022Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis studies different biomarkers in a cohort of patients suffering from ST-elevation myocardial infarction (STEMI) who underwent Percutaneous coronary intervention (PCI) in Örebro in 2011-2012. Blood samples were collected at three time points, at the arrival at the hospital, 1-3 days after PCI and for a smaller group of patients also 3 months after PCI. The study is a sub-study of the TASTE study, so half of the patients were also randomized to thrombus aspiration in conjunction with their PCI. For all patients, it was also recorded whether the culprit coronary vessel was totally occluded or partially patent. In total, there are samples from 165 patients, but not all markers have been measured in all patients, and 3-month samples are only available from those who had their follow-up in Örebro. The plasma levels of the biomarkers have also been measured in plasma from blood donors for comparison. In March 2019, a follow-up was made of the patients' survival, and the time of death was noted in cases where this had occurred.

    The markers studied are the lysosome protein Cathepsin S (Cat-S), the platelet granule protein thrombospondin 1 (TSP-1), the pentraxins C-reactive protein (CRP) and pentraxin 3 (PTX3), the endopeptidase neprilysin, the soluble forms of TNF-receptor 1 and 2 (sTNFR1 and sTNFR2), markers showing activation of the lectin pathway for complement activation (MASP-1/AT, MASP-1/C1-INH, MASP-2/C1-INH, MASP-2/AT) and common activation markers for complement activation (C3a and sC5b-9).

    In summary, the thesis shows that the plasma levels of all markers, except neprilysin and sC5b-9, are elevated at the time of arrival compared to healthy blood donors. Neprilysin is at the same level, and sC5b-9 is lower compared to blood donors. 1-3 days after PCI, the levels for CRP, sTNFR1 and sC5b-9 have risen strongly (>50%) compared to the levels at arrival. MASP-1/AT and MASP-2/AT have fallen moderately (about 50%), Cat-S and TSP-1 have decreased strongly, while the remaining markers are relatively similar to the levels at arrival (± 25%). The levels for CRP, PTX3, sTNFR1, sTNFR2 and neprilysin decreased even further between 1-3 days and 3 months, sC5b-9 rises slightly while the other markers remain at roughly the same levels. At 3 months, most markers still show higher levels compared to corresponding levels in blood donors, only MASP-2/C1-INH has the same level, while neprilysin is slightly lower and TSP-1 much lower compared to blood donors (the latter presumably an effect of ongoing medication with platelet inhibitors in the patients). No relevant differences were observed between patients with and without thrombus aspiration, and few differences were seen between patients with occluded or partially patent vessels. This may indicate that these factors were of minor importance for the levels of the analyzed markers. In contrast, analysis of survival showed that individuals with plasma levels above the median value for PTX3, sTNFR1 and sTNFR2 at admission and/or at 1-3 days had a significantly increased mortality compared to those with levels below the median value, which indicates that these markers could be interesting for further studies in a material where also analysis of possible interfering factors can be implemented.

    List of papers
    1. Increased plasma cathepsin S and trombospondin-1 in patients with acute ST-segment elevation myocardial infarction
    Open this publication in new window or tab >>Increased plasma cathepsin S and trombospondin-1 in patients with acute ST-segment elevation myocardial infarction
    2019 (English)In: Cardiology Journal, ISSN 1897-5593, Vol. 26, no 4, p. 385-393Article in journal (Refereed) Published
    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.

    Place, publisher, year, edition, pages
    Via Medica, 2019
    Keywords
    ST-segment elevation myocardial infarction, cathepsin S, percutaneous coronary intervention, platelets
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:oru:diva-76449 (URN)10.5603/CJ.a2018.0030 (DOI)000483031700010 ()29611169 (PubMedID)2-s2.0-85071630437 (Scopus ID)
    Note

    Funding Agency:

    Örebro University Hospital Research Foundation AFA Insurance 

    Available from: 2019-09-16 Created: 2019-09-16 Last updated: 2022-11-15Bibliographically approved
    2. Dynamic Changes in Pentraxin-3 and Neprilysin in ST Segment Elevation Myocardial Infarction
    Open this publication in new window or tab >>Dynamic Changes in Pentraxin-3 and Neprilysin in ST Segment Elevation Myocardial Infarction
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    2022 (English)In: Biomedicines, E-ISSN 2227-9059, Vol. 10, no 2, article id 275Article in journal (Refereed) Published
    Abstract [en]

    Pentraxin-3 (PTX3) and neprilysin have been associated with increased morbidity and mortality in chronic inflammatory disease and heart failure, but these biomarkers have been studied less in patients with ST segment elevation myocardial infarction (STEMI). We investigated the dynamic changes in these biomarkers, as well as the well-known C-reactive protein (CRP), in STEMI patients. PTX3, neprilysin and CRP were measured in samples from 165 STEMI patients, collected at the acute stage, 1-3 days after and 3 months after percutaneous coronary intervention (PCI), and from 40 healthy donors. Patient survival was followed for approximately 8 years after the PCI. As compared with samples from healthy donors, plasma levels of CRP and PTX3 were significantly increased in the acute samples and 1-3 days after PCI, but not at 3 months. CRP levels peaked at 1-3 days, while PTX3 was similarly high in both acute and 1-3 days samples. For neprilysin, no significant differences were observed at the group level. We found no significant differences when comparing patients with patent versus occluded culprit vessels or between patients having a thrombus aspiration or not. However, we found a significant reduction in survival for individuals with PTX3 above the median, both for samples collected at the acute stage and 1-3 days after PCI (p = 0.0001 and p = 0.0008, respectively). For CRP, no significant differences were observed using this approach, but patients above the reference range for healthy donors in the acute samples showed significantly lower survival (p = 0.0476). Conclusions: Survival analysis suggests that PTX3 might be a promising marker to predict mortality in this patient population.

    Place, publisher, year, edition, pages
    MDPI, 2022
    Keywords
    C-reactive protein, PTX3 protein, ST elevation myocardial infarction, neprilysin, survival analysis, thrombectomy
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:oru:diva-97695 (URN)10.3390/biomedicines10020275 (DOI)000770833500001 ()35203485 (PubMedID)2-s2.0-85123618888 (Scopus ID)
    Note

    Funding agencies:

    Örebro University Hospital Research Foundation

    AFA Insurance

    Region Örebro County

    Available from: 2022-02-28 Created: 2022-02-28 Last updated: 2022-10-31Bibliographically approved
    3. Levels of soluble tumor necrosis factor receptor 1 and 2 are associated with survival after ST segment elevation myocardial infarction
    Open this publication in new window or tab >>Levels of soluble tumor necrosis factor receptor 1 and 2 are associated with survival after ST segment elevation myocardial infarction
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    2022 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 12, no 1, article id 14762Article in journal (Refereed) Published
    Abstract [en]

    The soluble tumor necrosis factor receptors (sTNFR1 and sTNFR2) are suggested to play dual roles on physiological and pathophysiological actions of TNF-α. The aim of this study was to investigate the dynamic changes of these biomarkers in patients with ST-segment elevation myocardial infarction (STEMI). Blood was collected from 165 STEMI patients at admission, 1-3 days and 3 months after percutaneous coronary intervention (PCI) and from 40 healthy blood donors. sTNFR1 and sTNFR2 were measured with ELISA. The plasma levels of both sTNFR1 and sTNFR2 were significantly higher than in healthy donors at all three time points. We found no significant differences in sTNFR1 or sTNFR2 when comparing patients with patent versus occluded culprit vessels, or between patients having a thrombus aspiration or not. Survival analysis was performed comparing patients with levels of biomarkers above and below the median values at that time point. We found significant differences in survival for sTNFR2 in acute samples (p = 0.0151) and for both sTNFR1 and sTNFR2 in samples 1-3 days after PCI (p = 0.0054 and p = 0.0003, respectively). Survival analyses suggest that sTNFR1 or sTNFR2 could be promising markers to predict mortality in STEMI patients after PCI.

    Place, publisher, year, edition, pages
    Nature Publishing Group, 2022
    National Category
    Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:oru:diva-101044 (URN)10.1038/s41598-022-18972-5 (DOI)000847803100078 ()36042366 (PubMedID)2-s2.0-85136959494 (Scopus ID)
    Funder
    Region Örebro County
    Note

    Funding agencies:

    Örebro University Hospital

    AFA Insurance

    Available from: 2022-09-01 Created: 2022-09-01 Last updated: 2022-10-31Bibliographically approved
    4. Activation of the lectin complement pathway during and after ST segment elevation myocardial infarction
    Open this publication in new window or tab >>Activation of the lectin complement pathway during and after ST segment elevation myocardial infarction
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-101992 (URN)
    Available from: 2022-10-31 Created: 2022-10-31 Last updated: 2022-10-31Bibliographically approved
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  • 8.
    Fagerström, Anna
    Örebro University, School of Medical Sciences.
    Long-term molecular epidemiology of extended-spectrum β-lactamase producing Escherichia coli in a low-endemic setting2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Escherichia coli is a commensal inhabitant in the gastro-intestinal tract of humans and animals but it is also the most common bacterial species causing urinary tract infection, which ranges in severity from distal cystitis to urosepsis and septic shock. During the past decades, the prevalence of antibiotic resistant E. coli has increased worldwide. Extended-spectrum β-lactamases (ESBL) causes resistance to β-lactam antibiotics, the most widely used class of antibiotics. The genes encoding ESBL, bla, are usually carried on conjugative plasmids, which can be transferred between different bacterial lineages and different species. These plasmids frequently also carry resistance genes to additional antibiotic classes, and ESBL-producing E. coli are therefore often multidrug-resistant. The aim of this thesis was to describe the long-term molecular epidemiology of ESBL-producing E. coli in Örebro County during the time when they first started to emerge. In addition, potential transmission to the environment was investigated by performing a comparative analysis on ESBL-producing E. coli isolated from patients and from the aquatic environment in Örebro city. In general, the E. coli population was genetically diverse, but the pandemic lineage ST131, first identified in 2004, appears to have been responsible for the dramatic increase of CTX-M-15-producing E.coli observed during the late 2000s. CTX-M-15 was the most prevalent ESBL-type followed by CTX-M-14 and these genes were mainly found on plasmids belonging to the IncF or IncI1 families. Continuous horizontal transmission of IncI1 ST31 and ST37 plasmids between diverse E. coli lineages have also contributed to the dissemination of blaCTX-M-15 in Örebro County. Extended spectrum β-lactamase-producing E. coli were found to be common in the aquatic environment in Örebro city and E. coli lineages genetically similar to those causing infections in humans were present in environmental waters indicating that transmission of ESBL-producing E. colifrom humans to the aquatic environment likely has occurred.

    List of papers
    1. Molecular and phenotypic characterization of Escherichia coli and Klebsiella pneumoniae producing extended-spectrum β-lactamases with focus on CTX-M in a low-endemic area in Sweden
    Open this publication in new window or tab >>Molecular and phenotypic characterization of Escherichia coli and Klebsiella pneumoniae producing extended-spectrum β-lactamases with focus on CTX-M in a low-endemic area in Sweden
    2011 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 119, no 4-5, p. 287-295Article in journal (Refereed) Published
    Abstract [en]

    During the last decade increasing prevalence of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae has been detected worldwide, mainly due to dissemination of Escherichia coli and Klebsiella pneumoniae producing CTX-M-type ESBLs. CTX-M-15 is the most widespread CTX-M type, and the predominant type in various countries. Dissemination of ESBL-producing organisms is caused not only by horizontal transfer of plasmids, but also by clonal spread of ESBL-producing strains. In this study, the molecular epidemiology of class A ESBL (ESBL(A))-producing E. coli and K. pneumoniae isolated in Örebro County, Sweden, was investigated. Out of 200 ESBL(A) -producing E. coli and K. pneumoniae isolates, collected over a 10-year period, 87% were producing CTX-M, belonging to subgroup CTX-M-1 (64%), CTX-M-9 (34%), or CTX-M-2 (2%). The remaining isolates were producing variants of SHV and TEM. Sequencing of the bla(CTX-M) genes revealed 10 different CTX-M types, with a dominance of CTX-M-15 (E. coli 54%, K. pneumoniae 50%) followed by CTX-M-14 (E. coli 28%, K. pneumoniae 27%). Phenotypic characterization of the CTX-M-producing isolates was performed using the PhenePlate system. Although a few minor clusters of CTX-M-15 and CTX-M-14 producers were identified, the majority of the isolates did not appear to be clonally related.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2011
    Keywords
    Extended-spectrum beta-lactamase; Escherichia coli; Klebsiella pneumoniae; CTX-M; sequencing
    National Category
    Immunology in the medical area Microbiology in the medical area
    Identifiers
    urn:nbn:se:oru:diva-25340 (URN)10.1111/j.1600-0463.2011.02730.x (DOI)000289636600008 ()21492229 (PubMedID)2-s2.0-79954726789 (Scopus ID)
    Note

    Funding Agency:

    Research Committee of Orebro County Council, Sweden 

    Available from: 2012-08-27 Created: 2012-08-27 Last updated: 2020-02-26Bibliographically approved
    2. Characterization of CTX-M-producing Escherichia coli by repetitive sequence-based PCR and real-time PCR-based replicon typing of CTX-M-15 plasmids
    Open this publication in new window or tab >>Characterization of CTX-M-producing Escherichia coli by repetitive sequence-based PCR and real-time PCR-based replicon typing of CTX-M-15 plasmids
    2014 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 122, no 11, p. 1136-1143Article in journal (Refereed) Published
    Abstract [en]

    The emergence of extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae is a major global concern. CTX-M is the dominating ESBL type worldwide, and CTX-M-15 is the most widespread CTX-M type. The dissemination of CTX-M appears to be in part due to global spread of the Escherichia coli clone O25b-ST131. However, the gene-encoding CTX-M is mainly located on mobile genetic elements, such as plasmids, that also promote the horizontal dissemination of the CTX-M genes. In this study, 152 CTX-M-producing E. coli isolated in 1999-2008 in Örebro County, Sweden, were typed using a commercial repetitive sequence-based PCR (the DiversiLab system), and the prevalence of ST131 was investigated by pabB PCR. Real-time PCR-based plasmid replicon typing was performed on 82 CTX-M-15-producing E. coli isolates. In general, the CTX-M-producing E. coli population was genetically diverse; however, ST131 was highly prevalent (27%), and the dominating clone in our area. The blaCTX -M-15 gene was mainly located on IncF plasmids (69%), but a relatively high proportion of IncI1 plasmids (29%) were also detected among E. coli with diverse rep-PCR patterns, indicating that horizontal transmission of IncI1 plasmids carrying blaCTX -M-15 may have occurred between different E. coli strains.

    Place, publisher, year, edition, pages
    Malden, USA: John Wiley & Sons, 2014
    Keywords
    Escherichia coli, ESBL, ST131, plasmid
    National Category
    Medical and Health Sciences Microbiology
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-35271 (URN)10.1111/apm.12270 (DOI)000344383200011 ()24735173 (PubMedID)2-s2.0-84922019604 (Scopus ID)
    Note

    Funding Agencies:

    Research Committee of the County Council of Örebro 

    Nyckelfonden at Örebro University Hospital

    Available from: 2014-06-09 Created: 2014-06-09 Last updated: 2024-01-02Bibliographically approved
    3. Comparative analysis of blaCTX-M-15-IncI1 plasmids in clinical Escherichia coli isolated during a 5-year period in a low-endemic setting
    Open this publication in new window or tab >>Comparative analysis of blaCTX-M-15-IncI1 plasmids in clinical Escherichia coli isolated during a 5-year period in a low-endemic setting
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-80208 (URN)
    Available from: 2020-02-26 Created: 2020-02-26 Last updated: 2020-12-01Bibliographically approved
    4. Comparative distribution of extended-spectrum beta-lactamase-producing Escherichia coli from urine infections and environmental waters
    Open this publication in new window or tab >>Comparative distribution of extended-spectrum beta-lactamase-producing Escherichia coli from urine infections and environmental waters
    Show others...
    2019 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 14, no 11, article id e0224861Article in journal (Refereed) Published
    Abstract [en]

    Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli have been reported in natural environments, and may be released through wastewater. In this study, the genetic relationship between ESBL-producing E. coli collected from patient urine samples (n = 45, both hospitalized patients and out-patients) and from environmental water (n = 82, from five locations), during the same time period, was investigated. Three independent water samples were collected from the municipal wastewater treatment plant, both incoming water and treated effluent water; the receiving river and lake; and a bird sanctuary near the lake, on two different occasions. The water was filtered and cultured on selective chromID ESBL agar plates in order to detect and isolate ESBL-producing E. coli. Illumina whole genome sequencing was performed on all bacterial isolates (n = 127). Phylogenetic group B2 was more common among the clinical isolates than the environmental isolates (44.4% vs. 17.1%, p < 0.01) due to a significantly higher prevalence of sequence type (ST) 131 (33.3% vs. 13.4%, p < 0.01). ST131 was, however, one of the most prevalent STs among the environmental isolates. There was no significant difference in diversity between the clinical isolates (DI 0.872 (0.790-0.953)) and the environmental isolates (DI 0.947 (0.920-0.969)). The distribution of ESBL genes was similar: blaCTX-M-15 dominated, followed by blaCTX-M-14 and blaCTX-M-27 in both the clinical (60.0%, 8.9%, and 6.7%) and the environmental isolates (62.2%, 12.2%, and 8.5%). Core genome multi-locus sequence typing showed that five environmental isolates, from incoming wastewater, treated wastewater, Svartån river and Hjälmaren lake, were indistinguishable or closely related (≤10 allele differences) to clinical isolates. Isolates of ST131, serotype O25:H4 and fimtype H30, from the environment were as closely related to the clinical isolates as the isolates from different patients were. This study confirms that ESBL-producing E. coli are common in the aquatic environment even in low-endemic regions and suggests that wastewater discharge is an important route for the release of ESBL-producing E. coli into the aquatic environment.

    Place, publisher, year, edition, pages
    PLOS, 2019
    National Category
    Microbiology
    Identifiers
    urn:nbn:se:oru:diva-77879 (URN)10.1371/journal.pone.0224861 (DOI)000532694400072 ()31697734 (PubMedID)2-s2.0-85074687903 (Scopus ID)
    Funder
    Swedish Research Council Formas, 2192014-837
    Note

    Funding Agency:

    Research committee of Region Örebro County  OLL-406511 OLL-367741 OLL-748091

    Available from: 2019-11-14 Created: 2019-11-14 Last updated: 2021-06-14Bibliographically approved
    Download full text (pdf)
    Long-term molecular epidemiology of extended-spectrum β-lactamase-producing Escherichia coli in a low-endemic setting
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  • 9.
    Fagerström, Anna
    et al.
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Aspelin, Oscar
    1928 Diagnostics, Stena Center 1D, Gothenburg, Sweden.
    Söderquist, Bo
    Örebro University, School of Medical Sciences. Department of Laboratory Medicine.
    Sundqvist, Martin
    Örebro University, School of Medical Sciences. Örebro University Hospital. Department of Laboratory Medicine.
    Mölling, Paula
    Department of Laboratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
    Comparative analysis of blaCTX-M-15-IncI1 plasmids in clinical Escherichia coli isolated during a 5-year period in a low-endemic settingManuscript (preprint) (Other academic)
  • 10.
    Fernberg, Ulrika
    Örebro University, School of Medical Sciences.
    Arterial stiffness and risk factors for cardiovascular disease in young adults2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Atherosclerosis is a complex, chronic vessel wall disease that often leads to severe and acute cardiovascular diseases (CVD), such as myocardial infarction and stroke. CVD are the most common cause of death, both globally and in Sweden. Since most of the risk factors for atherosclerosis are preventable, it is of great importance to highlight the benefits of a healthy lifestyle to young adults who are about to create their own habits.

    A general concern about physical inactivity, low cardiorespiratory fitness (CRF), and high body mass are supported by reports of an increased incidence and prevalence of obesity worldwide. In addition to this, the proportion of Swedish adults with low CRF almost doubled the last 20 years and the decline in CRF is more pronounced in the youngest age group.

    The scientific work presented in this thesis was carried out to investigate the impact of different lifestyle related factors on vascular status, especially arterial stiffness, in young Swedish adults. In total 840 young adults in the age range 18-25 years were recruited to the cross-sectional Lifestyle, Biomarkers, and Atherosclerosis (LBA) study, to examine vascular status, biomarkers, and lifestyle related factors.

    In the LBA study population of young adults in Sweden, 12% were classified as being at risk of future CVD. A high CVD risk was associated with low CRF and less physical activity. In the total study population 24% had unhealthy food habits, and 24% did not spend the recommended 30 minutes per day at moderate or vigorous intensities of physical activity. Low CRF, less physical activity, and overweight and obesity, were associated with stiffer arteries.

    The results raises concerns about future CVD risk and highlights the health enhancing possibilities of high CRF and physical activity on vascular status in young Swedish adults.

    List of papers
    1. Aerobic fitness is associated with low cardiovascular disease risk: the impact of lifestyle on early risk factors for atherosclerosis in young healthy Swedish individuals - the Lifestyle, Biomarker, and Atherosclerosis study
    Open this publication in new window or tab >>Aerobic fitness is associated with low cardiovascular disease risk: the impact of lifestyle on early risk factors for atherosclerosis in young healthy Swedish individuals - the Lifestyle, Biomarker, and Atherosclerosis study
    2017 (English)In: Vascular Health and Risk Management, ISSN 1176-6344, E-ISSN 1178-2048, Vol. 13, p. 91-99Article in journal (Refereed) Published
    Abstract [en]

    Background: The progression of cardiovascular disease (CVD) and atherosclerosis is slow and develops over decades. In the cross-sectional Swedish Lifestyle, Biomarker, and Atherosclerosis study, 834 young, self-reported healthy adults aged 18.0-25.9 years have been studied to identify early risk factors for atherosclerosis.

    Purpose: The aims of this study were to 1) assess selected cardiometabolic biomarkers, carotid intima-media thickness (cIMT) as a marker of subclinical atherosclerosis, and lifestyle-related indicators (food habits, handgrip strength, and oxygen uptake, VO(2)max);2) analyze the associations between cIMT and lifestyle factors; and 3) identify subjects at risk of CVD using a risk score and to compare the characteristics of subjects with and without risk of CVD.

    Method: Blood samples were taken in a fasting state, and food habits were reported through a questionnaire. cIMT was measured by ultrasound, and VO2 max was measured by ergometer bike test. The risk score was calculated according to Wildman.

    Result: cIMT (mean +/- standard deviation) was 0.50 +/- 0.06 mm, and VO2 max values were 37.8 +/- 8.5 and 42.9 +/- 9.9 mL/kg/min, in women and men, respectively. No correlation was found between aerobic fitness expressed as VO2 max (mL/kg/min) and cIMT. Using Wildman's definition, 12% of the subjects were classified as being at risk of CVD, and 15% had homeostasis model assessment of insulin resistance. A total of 35% of women and 25% of men had lower high-density lipoprotein cholesterol than recommended. Food habits did not differ between those at risk and those not at risk. However, aerobic fitness measured as VO2 max (mL/kg/min) differed; 47% of the subjects at risk had low aerobic fitness compared to 23% of the nonrisk subjects (P<0.001).

    Conclusion: High aerobic fitness is associated with low CVD risk in Swedish young adults. The high prevalence of young adults observed with unfavorable levels of high-density lipoprotein cholesterol and homeostasis model assessment of insulin resistance raises concerns about future CVD risk.

    Place, publisher, year, edition, pages
    DOVE Medical Press Ltd., 2017
    Keywords
    cIMT, cholesterol, insulin resistance, body fat, diet, aerobic fitness
    National Category
    Cardiac and Cardiovascular Systems
    Research subject
    Cardiology
    Identifiers
    urn:nbn:se:oru:diva-56877 (URN)10.2147/VHRM.S125966 (DOI)000396188000002 ()28352184 (PubMedID)2-s2.0-85015747630 (Scopus ID)
    Note

    Funding Agency:

    AFA insurance

    Available from: 2017-03-29 Created: 2017-03-29 Last updated: 2024-02-23Bibliographically approved
    2. Arterial stiffness is associated to cardiorespiratory fitness and body mass index in young Swedish adults: The Lifestyle, Biomarkers, and Atherosclerosis study
    Open this publication in new window or tab >>Arterial stiffness is associated to cardiorespiratory fitness and body mass index in young Swedish adults: The Lifestyle, Biomarkers, and Atherosclerosis study
    2017 (English)In: European Journal of Preventive Cardiology, ISSN 2047-4873, E-ISSN 2047-4881, Vol. 24, no 17, p. 1809-1818Article in journal (Refereed) Published
    Abstract [en]

    Background: Early changes in the large muscular arteries are already associated with risk factors as hypertension and obesity in adolescence and young adulthood. The present study examines the association between arterial stiffness measurements, pulse wave velocity and augmentation index and lifestyle-related factors, body composition and cardiorespiratory fitness, in young, healthy, Swedish adults.

    Design: This study used a population-based cross-sectional sample.

    Methods: The 834 participants in the study were self-reported healthy, non-smoking, age 18-25 years. Augmentation index and pulse wave velocity were measured with applanation tonometry. Cardiorespiratory fitness was measured by ergometer bike test to estimate maximal oxygen uptake. Body mass index (kg/m(2)) was calculated and categorised according to classification by the World Health Organisation.

    Results: Young Swedish adults with obesity and low cardiorespiratory fitness have significantly higher pulse wave velocity and augmentation index than non-obese young adults with medium or high cardiorespiratory fitness. The observed U-shaped association between pulse wave velocity and body mass index categories in women indicates that it might be more beneficial to be normal weight than underweight when assessing the arterial stiffness with pulse wave velocity. The highest mean pulse wave velocity was found in overweight/obese individuals with low cardiorespiratory fitness. The lowest mean pulse wave velocity was found in normal weight individuals with high cardiorespiratory fitness. Cardiorespiratory fitness had a stronger effect than body mass index on arterial stiffness in multiple regression analyses.

    Conclusions: The inverse association between cardiorespiratory fitness and arterial stiffness is observed already in young adults. The study result highlights the importance of high cardiorespiratory fitness, but also that underweight individuals may be a possible risk group that needs to be further studied.

    Place, publisher, year, edition, pages
    Sage Publications, 2017
    Keywords
    Arterial stiffness, pulse wave analysis, cardiorespiratory fitness, body mass index, young adult, atherosclerosis
    National Category
    Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
    Identifiers
    urn:nbn:se:oru:diva-62511 (URN)10.1177/2047487317720796 (DOI)000414856300004 ()28696134 (PubMedID)2-s2.0-85033405287 (Scopus ID)
    Funder
    AFA Insurance
    Available from: 2017-11-21 Created: 2017-11-21 Last updated: 2024-02-23Bibliographically approved
    3. Body composition is a strong predictor of local carotid stiffness in Swedish, young adults: the cross sectional Lifestyle, biomarkers, and atherosclerosis study
    Open this publication in new window or tab >>Body composition is a strong predictor of local carotid stiffness in Swedish, young adults: the cross sectional Lifestyle, biomarkers, and atherosclerosis study
    2019 (English)In: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 19, no 1, article id 205Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Obesity has nearly tripled worldwide during the last four decades, especially in young adults, and is of growing concern since it is a risk factor for cardiovascular diseases (CVD). We explored how different body composition measurements are associated with intima media thickness (cIMT) and local stiffness in the common carotid artery, in a subsample of healthy, young women and men, from the Swedish Lifestyle, Biomarkers, and Atherosclerosis (LBA) Study.

    METHODS: From the LBA study, a subsample of 220 randomly selected, self-reported healthy individuals, 18-25 years old, were collected for the automatized local stiffness measurements; arterial distensibility, Young's elastic modulus, and β stiffness index. Blood pressure and mean arterial pressure (MAP) was measured using automatic blood pressure equipment. Body mass index (BMI) was calculated, waist circumference was measured, and percentage of body fat assessed using an impedance body composition analyzer. The carotid artery was scanned by ultrasound and analyzed using B-mode edge wall tracking. cIMT was measured and local stiffness measurements were calculated with carotid blood pressure, measured with applanation tonometry.

    RESULTS: No association was found between cIMT and body composition. Local carotid stiffness was associated with body composition, and women had less stiff arteries than men (p < 0.001). Of the local stiffness measurements, arterial distensibility had the strongest associations with body composition measurements in both women and men (p < 0.05). Multiple regression analyses showed that BMI in women and BMI and percentage of body fat in men had the highest impact on arterial distensibility (p < 0.01 in both women and men).

    CONCLUSIONS: Arterial distensibility was the local stiffness measurement with the strongest associations to different body composition measurements, in both women and men. In this age group, body composition measurements seem to be stronger predictors of common carotid arterial stiffness than MAP, and is a convenient way of detecting young adults who need cardiovascular risk follow-up and lifestyle counseling.

    Place, publisher, year, edition, pages
    BioMed Central, 2019
    Keywords
    Arterial distensibility, Arterial stiffness, Body composition, Carotid artery, Cross-sectional study, Epidemiological, Intima media thickness, Young adults
    National Category
    Nutrition and Dietetics Cardiac and Cardiovascular Systems
    Identifiers
    urn:nbn:se:oru:diva-76105 (URN)10.1186/s12872-019-1180-6 (DOI)000483032600001 ()31455254 (PubMedID)2-s2.0-85071644915 (Scopus ID)
    Note

    Funding Agency:

    Asset Management Arm (AFA)  130275

    Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-11-15Bibliographically approved
    4. Higher total physical activity is associated with lower arterial stiffness in Swedish, young adults: The Lifestyle, Biomarkers, and Atherosclerosis study
    Open this publication in new window or tab >>Higher total physical activity is associated with lower arterial stiffness in Swedish, young adults: The Lifestyle, Biomarkers, and Atherosclerosis study
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-77488 (URN)
    Available from: 2019-10-21 Created: 2019-10-21 Last updated: 2020-03-11Bibliographically approved
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    Arterial stiffness and risk factors for cardiovascular disease in young adults
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  • 11.
    Fernberg, Ulrika
    et al.
    Örebro University, School of Medical Sciences.
    Fernström, Maria
    Åstrand Laboratory of Work Physiology, The Swedish School of Sport and Health Sciences, GIH, Stockholm, Sweden.
    Hurtig-Wennlöf, Anita
    Örebro University, School of Health Sciences.
    Higher total physical activity is associated with lower arterial stiffness in Swedish, young adults: The Lifestyle, Biomarkers, and Atherosclerosis studyManuscript (preprint) (Other academic)
  • 12.
    Ganda Mall, John-Peter
    Örebro University, School of Medical Sciences.
    Non-digestible Polysaccharides and Intestinal Barrier Function: specific focus on its efficacy in elderly and patients with Crohn’s disease2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    A large number of elderly suffer from gastrointestinal (GI) symptoms such as constipation and diarrhoea. The underlying mechanisms of age-acquired GI symptoms are not well studied but are necessary to clarify in order to recommend the right treatment. Non-digestible polysaccharides (NPS) are dietary fibres that could have beneficial effects on the intestinal immune system and barrier function, although their efficacy needs to be evaluated. Paper I showed that elderly with GI symptoms have significantly higher small intestinal permeability than a general elderly population, along with a stronger association to psychological distress. In Paper II we performed a randomised controlled trial with a general population of elderly that consumed either placebo, the NPS’s arabinoxylan or oat β-glucan for a period of 6 weeks. No protective effects were observed related to indomethacin-induced intestinal hyperpermeability, inflammatory markers, or self-reported health if compared to placebo. Paper III showed that stimulation with a yeast-derived β-glucan significantly attenuated Compound (C) 48/80-induced hyperpermeability in colonic biopsies from elderly with GI symptoms mounted in Ussing chambers, but not in young healthy adults. Arabinoxylan attenuated only C48/80-induced transcellular permeability in elderly but both paracellular and transcellular permeability in young healthy adults. Paper IV showed that the same yeast-derived β-glucan from paper III could cross the epithelium of ileal tissues from patients with Crohn’s disease (CD) and non-CD controls, mounted in Ussing chambers, and attenuate C48/80-induced hyperpermeability. In conclusion, we found that elderly with GI symptoms display a deteriorated barrier function and that administration of selective NPS can have beneficial effect on intestinal permeability in selective populations.

    List of papers
    1. Are self-reported gastrointestinal symptoms among older adults associated with increased intestinal permeability and psychological distress?
    Open this publication in new window or tab >>Are self-reported gastrointestinal symptoms among older adults associated with increased intestinal permeability and psychological distress?
    Show others...
    2018 (English)In: BMC Geriatrics, ISSN 1471-2318, E-ISSN 1471-2318, Vol. 18, no 1, article id 75Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Despite the substantial number of older adults suffering from gastrointestinal (GI) symptoms little is known regarding the character of these complaints and whether they are associated with an altered intestinal barrier function and psychological distress. Our aim was to explore the relationship between self-reported gut health, intestinal permeability and psychological distress among older adults.

    METHODS: Three study populations were included: 1) older adults with GI symptoms (n = 24), 2) a group of older adults representing the general elderly population in Sweden (n = 22) and 3) senior orienteering athletes as a potential model of healthy ageing (n = 27). Questionnaire data on gut-health, psychological distress and level of physical activity were collected. Intestinal permeability was measured by quantifying zonulin in plasma. The level of systemic and local inflammation was monitored by measuring C-reactive protein (CRP), hydrogen peroxide in plasma and calprotectin in stool samples. The relationship between biomarkers and questionnaire data in the different study populations was illustrated using a Principal Component Analysis (PCA).

    RESULTS: Older adults with GI symptoms displayed significantly higher levels of both zonulin and psychological distress than both general older adults and senior orienteering athletes. The PCA analysis revealed a separation between senior orienteering athletes and older adults with GI symptoms and showed an association between GI symptoms, psychological distress and zonulin.

    CONCLUSIONS: Older adults with GI symptoms express increased plasma levels of zonulin, which might reflect an augmented intestinal permeability. In addition, this group suffer from higher psychological distress compared to general older adults and senior orienteering athletes. This relationship was further confirmed by a PCA plot, which illustrated an association between GI symptoms, psychological distress and intestinal permeability.

    Place, publisher, year, edition, pages
    BioMed Central, 2018
    Keywords
    Older adults; Gastrointestinal symptoms; Intestinal barrier function; Psychological distress
    National Category
    Geriatrics
    Identifiers
    urn:nbn:se:oru:diva-66053 (URN)10.1186/s12877-018-0767-6 (DOI)000428260300001 ()29554871 (PubMedID)2-s2.0-85044174344 (Scopus ID)
    Funder
    Knowledge Foundation, 20110225
    Note

    Funding Agencies:

    Bo Rydins stiftelse  F0514 

    Faculty of Medicine and Health at Örebro University  

    Diarrheal Disease Research Centre, Linköping University  

    Available from: 2018-03-27 Created: 2018-03-27 Last updated: 2023-12-29Bibliographically approved
    2. Effects of dietary fibres on indomethacin-induced intestinal permeability in elderly: A randomised placebo controlled parallel clinical trial
    Open this publication in new window or tab >>Effects of dietary fibres on indomethacin-induced intestinal permeability in elderly: A randomised placebo controlled parallel clinical trial
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-66863 (URN)
    Available from: 2018-05-04 Created: 2018-05-04 Last updated: 2023-12-29Bibliographically approved
    3. Differential effects of dietary fibres on colonic barrier function in elderly individuals with gastrointestinal symptoms
    Open this publication in new window or tab >>Differential effects of dietary fibres on colonic barrier function in elderly individuals with gastrointestinal symptoms
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-66866 (URN)
    Available from: 2018-05-04 Created: 2018-05-04 Last updated: 2023-12-29Bibliographically approved
    4. A β-Glucan-Based Dietary Fiber Reduces Mast Cell-Induced Hyperpermeability in Ileum From Patients With Crohn's Disease and Control Subjects
    Open this publication in new window or tab >>A β-Glucan-Based Dietary Fiber Reduces Mast Cell-Induced Hyperpermeability in Ileum From Patients With Crohn's Disease and Control Subjects
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    2017 (English)In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 24, no 1, p. 166-178Article in journal (Refereed) Published
    Abstract [en]

    Background: Administration of β-glucan has shown immune-enhancing effects. Our aim was to investigate whether β-glucan could attenuate mast cell (MC)-induced hyperpermeability in follicle-associated epithelium (FAE) and villus epithelium (VE) of patients with Crohn's disease (CD) and in noninflammatory bowel disease (IBD)-controls. Further, we studied mechanisms of β-glucan uptake and effects on MCs in vitro.

    Methods: Segments of FAE and VE from 8 CD patients and 9 controls were mounted in Ussing chambers. Effects of the MC-degranulator compound 48/80 (C48/80) and yeast-derived β-1,3/1,6 glucan on hyperpermeability were investigated. Translocation of β-glucan and colocalization with immune cells were studied by immunofluorescence. Caco-2-cl1- and FAE-cultures were used to investigate β-glucan-uptake using endocytosis inhibitors and HMC-1.1 to study effects on MCs.

    Results: β-glucan significantly attenuated MC-induced paracellular hyperpermeability in CD and controls. Transcellular hyperpermeability was only significantly attenuated in VE. Baseline paracellular permeability was higher in FAE than VE in both groups, P<0.05, and exhibited a more pronounced effect by C48/80 and β-glucan P<0.05. No difference was observed between CD and controls. In vitro studies showed increased passage, P<0.05, of β-glucan through FAE-culture compared to Caco-2-cl1. Passage was mildly attenuated by the inhibitor methyl-β-cyclodextrin. HMC-1.1 experiments showed a trend to decreasing MC-degranulation and levels of TNF-α but not IL-6 by β-glucan. Immunofluorescence revealed more β-glucan-uptake and higher percentage of macrophages and dendritic cells close to β-glucan in VE of CD compared to controls.

    Conclusions: We demonstrated beneficial effects of β-glucan on intestinal barrier function and increased β-glucan-passage through FAE model. Our results provide important and novel knowledge on possible applications of β-glucan in health disorders and diseases characterized by intestinal barrier dysfunction.

    Place, publisher, year, edition, pages
    Lippincott-Raven Publishers, 2017
    Keywords
    Crohn’s disease, intestinal permeability, β-glucan
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:oru:diva-63994 (URN)10.1093/ibd/izx002 (DOI)000427524400018 ()29272475 (PubMedID)2-s2.0-85044196884 (Scopus ID)
    Funder
    Swedish Foundation for Strategic Research , RB13-016Swedish Research Council, 2014-02537
    Note

    Funding Agency:

    LIONS research foundation

    Available from: 2018-01-09 Created: 2018-01-09 Last updated: 2023-12-29Bibliographically approved
    Download full text (pdf)
    Non-digestible Polysaccharides and Intestinal Barrier Function: specific focus on its efficacy in elderly and patients with Crohn’s disease
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  • 13.
    Ganda Mall, John-Peter
    et al.
    Örebro University, School of Medical Sciences.
    Fart, Frida
    Örebro University, School of Medical Sciences.
    Sabet, Julia
    Örebro University, School of Medical Sciences.
    Lindqvist, Carl-Mårten
    Örebro University, School of Medical Sciences.
    Keita, Åsa V.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Brummer, Robert J.
    Örebro University, School of Medical Sciences.
    Schoultz, Ida
    Örebro University, School of Medical Sciences.
    Effects of dietary fibres on indomethacin-induced intestinal permeability in elderly: A randomised placebo controlled parallel clinical trialManuscript (preprint) (Other academic)
  • 14.
    Ganda Mall, John-Peter
    et al.
    Örebro University, School of Medical Sciences.
    Löfvendahl, Lisa
    Örebro University, School of Medical Sciences.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    Keita, Åsa V.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Schoultz, Ida
    Örebro University, School of Medical Sciences.
    Differential effects of dietary fibres on colonic barrier function in elderly individuals with gastrointestinal symptomsManuscript (preprint) (Other academic)
  • 15.
    Greis, Christina
    et al.
    Örebro University, Department of Natural Sciences.
    Karlsson, Stefan
    Örebro University, Department of Natural Sciences.
    Düker, Anders
    Örebro University, Department of Natural Sciences.
    Pettersson, Håkan
    Radiofysikavdelningen, O-centrum US, Universitetssjukhuset, Linköping, Sweden .
    Allard, Bert
    Örebro University, Department of Natural Sciences.
    Determination of plutonium in environmental samples with quadrupole ICP-MS2008In: Journal of Radioanalytical and Nuclear Chemistry, ISSN 0236-5731, E-ISSN 1588-2780, Vol. 275, no 1, p. 55-70Article in journal (Refereed)
    Abstract [en]

    A method for rapid determination of plutonium isotopes in environmental samples with ultrasonic nebulisation and quadrupole ICP-MS detection was established. Techniques for sample dissolution, pre-concentration and chemical separation were evaluated and the optimal scheme outlined. Comparisons with α-spectrometry and high resolution ICP-MS confirmed the suitability of the method when applied to different environmental matrices within the global fallout concentration range in the northern hemisphere as well as more contaminated sites. Operational detection limits were 0.5–1.5 fg/l for fresh waters and 0.03–0.1 ng/kg for lake sediments and saline marsh sediments.

  • 16.
    Günaltay, Sezin
    Örebro University, School of Medical Sciences.
    Dysregulated mucosal immune responses in microscopic colitis patients2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC) is a common cause of chronic watery diarrhea. The diagnosis relies on typical histopathological changes observed upon microscopic examination. The studies in this thesis investigated innate and adaptive immune responses in the colonic mucosa of MC patients, also comparing patients with active disease (CC and LC) and histopathologically in remission (CC/LC-HR). We first analyzed expression of interleukin-1/Toll-like receptor (IL-1/TLR) signaling regulators in MC patients (Paper I). Our results showed enhanced IRAK-M, microRNA-146a, -155 and -21 expressions, whereas IL-37 gene expression was reduced in CC and LC patients as compared to non-inflamed controls. These results suggest different pathophysiological mechanisms in MC patients. The mixed inflammatory cell infiltrations seen in the lamina propria of MC patients might be a result of dysregulated expression of chemotactic mediators. In Paper II, we showed that MC patients display mainly an increased expression of chemokines and chemokine receptors in active disease as compared to noninflamed controls. In Paper III, we examined if the decreased IL-37 expression seen in Paper I could mediate the upregulation of chemokines seen in Paper II. We showed that a relatively small reduction in the ability of epithelial cells to produce IL-37 results in mainly increased chemokine expressions in a pattern similar to the findings in Paper II. In order to understand the nature of infiltrating T cells commonly observed in MC patients, we analyzed the T cell receptor (TCR) β chains in colonic biopsies of MC patients (Paper IV). Our results showed significant differences in TCRβ repertoire, which suggests selectively expanded T cell clones in active MC and histopathologically in remission patients. Altogether, these results i) increase the knowledge of MC pathogenesis by showing changes in TLR signaling regulators, enhanced chemokine and their receptor expressions involved in a mixed immune cell infiltrations and selectively expanded T cell clones in CC and LC patients, as well as in histopathological remission ii) might potentially increase the possibility of more target-specific therapies based on IL-37 induction, chemokines or chemokine receptor inhibitions, or hindering T cell infiltration according to TCR clonality.

    List of papers
    1. Differential expression of interleukin-1/Toll-like receptor signaling regulators in microscopic and ulcerative colitis
    Open this publication in new window or tab >>Differential expression of interleukin-1/Toll-like receptor signaling regulators in microscopic and ulcerative colitis
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    2014 (English)In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 20, no 34, p. 12249-12259Article in journal (Refereed) Published
    Abstract [en]

    AIM: To investigate Toll-like receptor (TLR) signaling regulators in microscopic and ulcerative colitis patients.

    METHODS: Total RNA and microRNA were isolated from fresh frozen colonic biopsies of non-inflamed controls and patients with active or in-remission collagenous colitis (CC), lymphocytic colitis (LC), or ulcerative colitis (UC). We compared expressions of interleukin-1 receptor-associated kinase (IRAK)-2, IRAK-M, interleukin (IL)-37, microRNA (miR)-146a, miR-155, and miR-21 using quantitative real time reverse transcription polymerase chain reaction.

    RESULTS: IRAK-M expression was increased in LC patients with active disease in histopathological remission (LC-HR; P = 0.02) and UC patients (P = 0.01), but no differences in IRAK-2 expression were detected compared to controls. miR-146a, -155 and -21 expressions were increased in LC-HR (P = 0.04, 0.07, and 0.004) and UC (P = 0.02, 0.04 and 0.03) patients. miR-146a and miR-21 expressions were significantly enhanced in UC patients compared to UC remission (UC-R; P = 0.01 and 0.04). Likewise, active CC patients showed significantly increased expression of miR-155 (P = 0.003) and miR-21 (P = 0.006). IL-37 expression was decreased in both CC (P = 0.03) and LC (P = 0.04) patients with a similar trend in UC patients but not statistically significant, whilst it was increased in UC-R patients compared to controls (P = 0.02) and active UC (P = 0.001).

    CONCLUSION: The identification of differentially expressed miRNAs, IL-37, and IRAK-M suggests different pathophysiologic mechanisms in various disease stages in LC, CC, and UC. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

    Place, publisher, year, edition, pages
    WJG Press, 2014
    Keywords
    Interleukin-37, MicroRNA, Lymphocytic colitis, Collagenous colitis, Ulcerative colitis
    National Category
    Gastroenterology and Hepatology
    Identifiers
    urn:nbn:se:oru:diva-37676 (URN)10.3748/wjg.v20.i34.12249 (DOI)000341719100033 ()2-s2.0-84909606787 (Scopus ID)
    Note

    Funding Agencies:

    Research Committee of Örebro County Council

    Örebro University

    Available from: 2014-10-13 Created: 2014-10-13 Last updated: 2020-12-01Bibliographically approved
    2. Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment
    Open this publication in new window or tab >>Enhanced levels of chemokines and their receptors in the colon of microscopic colitis patients indicate mixed immune cell recruitment
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    2015 (English)In: Mediators of Inflammation, ISSN 0962-9351, E-ISSN 1466-1861, article id 132458Article in journal (Refereed) Published
    Abstract [en]

    Microscopic colitis (MC), comprising collagenous colitis (CC) and lymphocytic colitis (LC), is a common cause of chronic diarrhea. Various immune cell infiltrations in the epithelium and lamina propria are seen in MC immunopathology. We compared gene and protein expressions of different immune cell attracting chemokines and their receptors in colon biopsies from MC patients in active disease or histopathological remission (CC/LC-HR) with controls, using qRT-PCR and Luminex, respectively. CC and LC patients with active disease demonstrated a mixed chemokine profile with significantly enhanced gene and/or protein expressions of the chemokines CCL2, CCL3, CCL4, CCL5, CCL7, CCL22, CXCL8, CXCL9, CXCL10, CXCL11, and CX(3)CL1 and the receptors CCR2, CCR3, CCR4, CXCR1, CXCR2, and CX(3)CR1. Enhanced chemokine/chemokine receptor gene and protein levels in LC-HR patients were similar to LC patients, whereas CC-HR patients demonstrated almost normalized levels. These findings expand the current understanding of the involvement of various immune cells in MC immunopathology and endorse chemokines as potential diagnostic markers as well as therapeutic candidates. Moreover, this study further supports the hypothesis that CC and LC are two different entities due to differences in their immunoregulatory responses.

    National Category
    Cell and Molecular Biology Immunology in the medical area
    Research subject
    Immunology
    Identifiers
    urn:nbn:se:oru:diva-44605 (URN)10.1155/2015/132458 (DOI)000353128700001 ()2-s2.0-84928473938 (Scopus ID)
    Note

    Funding Agencies:

    Örebro University Hospital Research Foundation (Nyckelfonden)

    Research Committee, Orebro County Council

    Örebro University

    Available from: 2015-05-12 Created: 2015-05-12 Last updated: 2020-12-01Bibliographically approved
    3. Reduced Il-37 production increases the spontaneous chemokine expressions in colon epithelial cells
    Open this publication in new window or tab >>Reduced Il-37 production increases the spontaneous chemokine expressions in colon epithelial cells
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-47897 (URN)
    Available from: 2016-02-02 Created: 2016-02-02 Last updated: 2018-01-10Bibliographically approved
    4. Oligoclonal T cell receptor repertoire in colonic biopsies of microscopic and ulcerative colitis patients
    Open this publication in new window or tab >>Oligoclonal T cell receptor repertoire in colonic biopsies of microscopic and ulcerative colitis patients
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-47898 (URN)
    Available from: 2016-02-02 Created: 2016-02-02 Last updated: 2018-01-10Bibliographically approved
    Download full text (pdf)
    Introductory chapter
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    Omslag
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  • 17.
    Günaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences.
    Ghiboub, Mohammed
    Amsterdam university.
    Hultgren, Olof
    Örebro University, School of Medical Sciences.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Reduced Il-37 production increases the spontaneous chemokine expressions in colon epithelial cellsManuscript (preprint) (Other academic)
  • 18.
    Günaltay, Sezin
    et al.
    Örebro University, School of Medical Sciences.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Helenius, Gisela
    Örebro University, School of Medical Sciences.
    Nyhlin, Nils
    Örebro University, School of Medical Sciences.
    Bohr, Johan
    Örebro University, School of Health Sciences.
    Hultgren-Hörnquist, Elisabeth
    Örebro University, School of Medical Sciences.
    Oligoclonal T cell receptor repertoire in colonic biopsies of microscopic and ulcerative colitis patientsManuscript (preprint) (Other academic)
  • 19.
    Hadad, Ronza
    Örebro University, School of Medical Sciences.
    Implementation of strategies for management and prevention of sexually transmitted infections with focus on Neisseria gonorrhoeae and Chlamydia trachomatis2022Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Sexually transmitted infections (STIs) are a public health issue of great importance worldwide, with effects on fertility and reproduction. Chlamydia trachomatis and Neisseria gonorrhoeae, causative agents of chlamydia and gonorrhoea, respectively, are the most common bacterial STIs with an estimated 127 million new global cases of chlamydia and 87 million new gonorrhoea cases. The continued emergence of antimicrobial resistance (AMR) in N. gonorrhoeae may in the future lead to an untreatable infection. Prevention of these infections and controlling the development of AMR rely on several strategies developed by the World Health Organization (WHO). This thesis aimed to implement several of these strategies, including supporting vaccine development for C. trachomatis and N. gonorrhoeae, evaluating molecular methods for detecting N. gonorrhoeae, predicting AMR and supporting surveillance of the spread and prevalence of AMR in N. gonorrhoeae. The present studies on a C. trachomatis recombinant vaccine antigen and the investigation of similarities of N. gonorrhoeae antigen amino acid sequences to the antigens included in the meningococcal vaccine 4CMenB contributed to the field of vaccine development for STIs. The assay SpeeDx ResistancePlus® GC performed well in detecting N. gonorrhoeae and predicting ciprofloxacin resistance and could be used in AMR surveillance and individualised treatment. In 2016, the first national genomic surveillance of all N. gonorrhoeae isolates in Sweden was performed. This national surveillance study included whole-genome sequencing combined with phenotypic AMR and epidemiological data, which provides valuable information on circulating strains, epidemiology and phylogeny. Greater knowledge of gonorrhoea and gonococcal AMR epidemiology could inform decisions on guidelines and prevention. It is essential to continue to implement WHO strategies at the national and global levels to prevent and control chlamydia and gonorrhoea infections.

    List of papers
    1. Protection against genital tract Chlamydia trachomatis infection following intranasal immunization with a novel recombinant MOMP VS2/4 antigen
    Open this publication in new window or tab >>Protection against genital tract Chlamydia trachomatis infection following intranasal immunization with a novel recombinant MOMP VS2/4 antigen
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    2016 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 124, p. 1078-1086Article in journal (Refereed) Published
    Abstract [en]

    The asymptomatic nature of most Chlamydia trachomatis infections and the lack of appropriate effects by current prevention and management call for vaccine development. We evaluated a recombinant subunit vaccine candidate based on the major outer membrane protein variable segments 2 and 4 (MOMP VS2/4). To achieve maximal immunogenicity and ease of production and purification, MOMP VS2/4 was constructed by using highly immunogenic sequences of MOMP only, thereby minimizing the presence of hydrophobic regions, and spacing the immunogenic epitopes with a flexible amino acid sequence. A purification tag was also added. The MOMP VS2/4 was given intranasally, with or without intravaginal boost, with cholera toxin (CT) adjuvant to C57BL/6 mice, which were screened for immunogenicity and protection against a live challenge infection with C. trachomatis serovar D. Bacterial shedding, cell-mediated responses, and antibody responses were monitored. Immunized mice exhibited significantly less bacterial shedding and were better protected against infertility as compared to unimmunized control mice. Immunizations stimulated both systemic and local specific antibody (IgG1, IgG2c, and IgA) responses, and primed T cells that produced interferon-c and interleukins 13 and 17 upon challenge with recall antigen. Thus, MOMP VS2/4, in combination with CT adjuvant, stimulated Th1, Th2, and Th17 effector cells, and generated protective immunity associated with less pathology. We regard MOMP VS2/4 as a promising candidate for further development into a mucosal chlamydial vaccine.

    Place, publisher, year, edition, pages
    Hoboken, USA: Wiley-Blackwell, 2016
    Keywords
    Chlamydia trachomatis, vaccine, major outer membrane protein, mice, antibody response, T cells
    National Category
    Immunology in the medical area Microbiology in the medical area
    Research subject
    Biochemistry; Immunology; Microbiology; Infectious Diseases
    Identifiers
    urn:nbn:se:oru:diva-53554 (URN)10.1111/apm.12605 (DOI)000388265700008 ()27859689 (PubMedID)2-s2.0-84995753108 (Scopus ID)
    Projects
    Utveckling av vacciner mot sexuellt överförbara sjukdomarMolecular farming
    Funder
    Olle Engkvists stiftelse
    Note

    Funding Agencies:

    Sparbanksstiftelsen Nya

    Örebro University's Faculty for Business, Science, and Technology

    Foundation for Medical Research at Örebro University Hospital

    Available from: 2016-11-18 Created: 2016-11-18 Last updated: 2024-01-16Bibliographically approved
    2. Novel meningococcal 4CMenB vaccine antigens: prevalence and polymorphisms of the encoding genes in Neisseria gonorrhoeae
    Open this publication in new window or tab >>Novel meningococcal 4CMenB vaccine antigens: prevalence and polymorphisms of the encoding genes in Neisseria gonorrhoeae
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    2012 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 120, no 9, p. 750-760Article in journal (Refereed) Published
    Abstract [en]

    The first cross-protective Neisseria meningitidis vaccine (focus on serogroup B), the protein-based 4 component meningococcus serogroup B (4CMenB), includes the New Zealand outer membrane vesicle and three main genome-derived neisserial antigens (GNAs). These GNAs are fHbp (fused to GNA2091), NHBA (fused to GNA1030) and NadA. In this study, the prevalence and polymorphisms of the nucleotide and amino acid sequences of the 4CMenB antigens in a temporally and geographically diverse collection of N. gonorrhoeae isolates (n similar to=similar to 111) were investigated. All the examined GNA genes, except the nadA gene, were present in all gonococcal isolates. However, 25 isolates contained premature stop codons in the fHbp gene and/or the nhba gene, resulting in truncated proteins. Compared with the 4CMenB antigen sequences in reference strain MC58, the gonococcal strains displayed 67.095.4% and 60.994.9% identity in nucleotide sequence and amino acid sequence, respectively, in the equivalent GNA antigens. The absence of NadA, lack of universal expression of fHbp and NHBA and the uncertainty regarding the surface exposure of fHbp as well as the function of NHBA in N. gonorrhoeae will likely limit the use of the identical 4CMenB antigens in a gonococcal vaccine. However, possible cross-immunity of 4CMenB with gonococci and expression and function of the equivalent gonococcal GNAs, as well as of more appropriate GNAs for a gonococcal vaccine, need to be further examined.

    Place, publisher, year, edition, pages
    Wiley-Blackwell, 2012
    Keywords
    Neisseria gonorrhoeae, 4CMenB vaccine, genome-derived neisserial antigen (GNA)
    National Category
    Microbiology in the medical area Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Pharmacology and Toxicology Immunology in the medical area
    Identifiers
    urn:nbn:se:oru:diva-58673 (URN)10.1111/j.1600-0463.2012.02903.x (DOI)000307444600009 ()22882265 (PubMedID)2-s2.0-84865291540 (Scopus ID)
    Note

    Funding Agencies:

    Örebro County Council Research Committee  

    Foundation for Medical Research at Örebro University Hospital, Sweden  

    Novartis VD, Siena, Italy 

    Available from: 2017-07-12 Created: 2017-07-12 Last updated: 2022-06-16Bibliographically approved
    3. Evaluation of the SpeeDx ResistancePlus® GC and SpeeDx GC 23S 2611 (beta) molecular assays for prediction of antimicrobial resistance/susceptibility to ciprofloxacin and azithromycin in Neisseria gonorrhoeae
    Open this publication in new window or tab >>Evaluation of the SpeeDx ResistancePlus® GC and SpeeDx GC 23S 2611 (beta) molecular assays for prediction of antimicrobial resistance/susceptibility to ciprofloxacin and azithromycin in Neisseria gonorrhoeae
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    2021 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 76, no 1, p. 84-90Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Accurate molecular assays for prediction of antimicrobial resistance (AMR)/susceptibility in Neisseria gonorrhoeae (Ng) can offer individualized treatment of gonorrhoea and enhanced AMR surveillance.

    OBJECTIVES: We evaluated the new ResistancePlus® GC assay and the GC 23S 2611 (beta) assay (SpeeDx), for prediction of resistance/susceptibility to ciprofloxacin and azithromycin, respectively.

    METHODS: Nine hundred and sixty-seven whole-genome-sequenced Ng isolates from 20 European countries, 143 Ng-positive (37 with paired Ng isolates) and 167 Ng-negative clinical Aptima Combo 2 (AC2) samples, and 143 non-gonococcal Neisseria isolates and closely related species were examined with both SpeeDx assays.

    RESULTS: The sensitivity and specificity of the ResistancePlus® GC assay to detect Ng in AC2 samples were 98.6% and 100%, respectively. ResistancePlus® GC showed 100% sensitivity and specificity for GyrA S91 WT/S91F detection and 99.8% sensitivity and specificity in predicting phenotypic ciprofloxacin resistance. The sensitivity and specificity of the GC 23S 2611 (beta) assay for Ng detection in AC2 samples were 95.8% and 100%, respectively. GC 23S 2611 (beta) showed 100% sensitivity and 99.9% specificity for 23S rRNA C2611 WT/C2611T detection and 64.3% sensitivity and 99.9% specificity for predicting phenotypic azithromycin resistance. Cross-reactions with non-gonococcal Neisseria species were observed with both assays, but the analysis software solved most cross-reactions.

    CONCLUSIONS: The new SpeeDx ResistancePlus® GC assay performed well in the detection of Ng and AMR determinants, especially in urogenital samples. The GC 23S 2611 (beta) assay performed relatively well, but its sensitivity, especially for predicting phenotypic azithromycin resistance, was suboptimal and further optimizations are required, including detection of additional macrolide resistance determinant(s).

    Place, publisher, year, edition, pages
    Oxford University Press, 2021
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:oru:diva-85867 (URN)10.1093/jac/dkaa381 (DOI)000620811500010 ()32929456 (PubMedID)2-s2.0-85098461440 (Scopus ID)
    Note

    Funding Agencies:

    Örebro County Council Research Committee  

    Foundation for Medical Research at Örebro University Hospital, Örebro, Sweden  

    Available from: 2020-09-23 Created: 2020-09-23 Last updated: 2022-05-23Bibliographically approved
    4. First National Genomic Epidemiological Study of Neisseria gonorrhoeae Strains Spreading Across Sweden in 2016
    Open this publication in new window or tab >>First National Genomic Epidemiological Study of Neisseria gonorrhoeae Strains Spreading Across Sweden in 2016
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    2022 (English)In: Frontiers in Microbiology, E-ISSN 1664-302X, Vol. 12, article id 820998Article in journal (Refereed) Published
    Abstract [en]

    The increasing transmission and antimicrobial resistance (AMR) in Neisseria gonorrhoeae is a global health concern with worrying trends of decreasing susceptibility to also the last-line extended-spectrum cephalosporin (ESC) ceftriaxone. A dramatic increase of reported gonorrhea cases has been observed in Sweden from 2016 and onward. The aim of the present study was to comprehensively investigate the genomic epidemiology of all cultured N. gonorrhoeae isolates in Sweden during 2016, in conjunction with phenotypic AMR and clinical and epidemiological data of patients. In total, 1279 isolates were examined. Etest and whole-genome sequencing (WGS) were performed, and epidemiological data obtained from the Public Health Agency of Sweden. Overall, 51.1%, 1.7%, and 1.3% resistance to ciprofloxacin, cefixime, and azithromycin, respectively, was found. No isolates were resistant to ceftriaxone, however, 9.3% of isolates showed a decreased susceptibility to ceftriaxone and 10.5% to cefixime. In total, 44 penA alleles were found of which six were mosaic (n = 92). Using the typing schemes of MLST, NG-MAST, and NG-STAR; 133, 422, and 280 sequence types, respectively, and 93 NG-STAR clonal complexes were found. The phylogenomic analysis revealed two main lineages (A and B) with lineage A divided into two main sublineages (A1 and A2). Resistance and decreased susceptibility to ESCs and azithromycin and associated AMR determinants, such as mosaic penA and mosaic mtrD, were predominantly found in sublineage A2. Resistance to cefixime and azithromycin was more prevalent among heterosexuals and MSM, respectively, and both were predominantly spread through domestic transmission. Continuous surveillance of the spread and evolution of N. gonorrhoeae, including phenotypic AMR testing and WGS, is essential for enhanced knowledge regarding the dynamic evolution of N. gonorrhoeae and gonorrhea epidemiology.

    Place, publisher, year, edition, pages
    Frontiers Media S.A., 2022
    Keywords
    Neisseria gonorrhoeae, Sweden, antimicrobial resistance, molecular epidemiology, whole-genome sequencing
    National Category
    Infectious Medicine
    Identifiers
    urn:nbn:se:oru:diva-97021 (URN)10.3389/fmicb.2021.820998 (DOI)000748113700001 ()35095823 (PubMedID)2-s2.0-85123806366 (Scopus ID)
    Note

    Funding agencies:

    Örebro County Council Research Committee, Örebro, Sweden

    Foundation for Medical Research at the Örebro University Hospital, Örebro, Sweden

    Available from: 2022-02-01 Created: 2022-02-01 Last updated: 2024-01-17Bibliographically approved
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  • 20.
    Hagberg, Jessika
    Örebro University, School of Science and Technology.
    Analysis of brominated dioxins and furans by high resolution gas chromatography/high resolution mass spectrometry2009In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1216, no 3, p. 376-384Article, review/survey (Refereed)
    Abstract [en]

    This article reviews the available literature on the analysis of brominated dibenzo-p dioxins and furans(PBDD/Fs) by high resolution gas chromatography/high resolution mass spectrometry (HRGC/HRMS).Sample extraction and clean up, injection techniques, chromatographic separation, labelled standardsand QA/QC works are discussed. Furthermore, full separation of PBDD/Fs from polybrominated diphenylethers (PBDEs) during clean up and control of possible chromatographic interference of PBDEs duringinstrumental analysis as well as possible actions to further enhance the quality of published data arediscussed in detail.

  • 21.
    Holster, S.
    et al.
    Faculty of Medicine and Health, School of Medical Sciences, Örebro University, Örebro, Sweden.
    Repsilber, Dirk
    Örebro University, School of Medical Sciences.
    Geng, D.
    Faculty of Business, Science and Engineering, School of Science and Technology, Örebro University, Örebro, Sweden.
    Hyötyläinen, Tuulia
    Örebro University, School of Science and Technology.
    Salonen, A.
    Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
    Lindqvist, Carl Mårten
    Örebro University, School of Medical Sciences.
    Rajan, Sukithar K
    Örebro University, School of Medical Sciences.
    De Vos, W. M.
    Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Laboratory of Microbiology, Wageningen University and Research Centre, Wageningen, The Netherlands.
    Brummer, Robert Jan
    Örebro University, School of Medical Sciences.
    König, Julia
    Örebro University, School of Medical Sciences.
    Correlations between microbiota and metabolites after faecal microbiota transfer in irritable bowel syndromeManuscript (preprint) (Other academic)
  • 22.
    Isaksson, Helena
    Örebro University, School of Medical Sciences.
    Clinical studies of RNA as a prognostic and diagnostic marker for disease2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Technologies for RNA detection are evolving rapidly and gives an op-portunity for discovery of new markers for early detection of complex diseases. Today in clinical work we rely on signs and symptoms in com-bination with the measurement of protein levels for diagnosis. The quick turnaround time of mRNA synthesis may provide an earlier diagnostic signal than protein-based biomarkers assays, in acute dramatic condi-tions such as acute mesenteric ischemia (AMI), for early detection of cancer, as prognostic tool in cancer treatment and as an aid in difficult diagnosis of unknown origin.

    The main goals of this thesis was to apply a whole genome approach to study different complex diseases to evaluate the applicability of RNA as a diagnostic or prognostic marker for disease, preferably from an easily accessible source such as peripheral blood. This was investigated in an animal model with induced AMI, a cohort of ovarian cancer patients and in a single-patient study of a girl with a severe inflammatory syn-drome.

    Through this thesis we have gained insight into how gene expression is regulated in ischemic intestinal tissue.

    We found that a peripheral blood test can distinguish between ovarian cancer patients with or without residual tumour mass after surgery with the help of expression analysis of six genes. We also found that gene expressions of three genes can predict overall survival in peripheral whole blood from ovarian cancer patients. And that gene expression profiles indeed can significantly distinguish between two groups of high and low risk ovarian cancer. In the single-patient study, we tried but failed to device a successful treatment before it was too late. Neverthe-less, the things we learned and the case studies that were published may serve as a diagnostic tool for clinicians facing similar syndromes.

    List of papers
    1. Altered mRNA Expression due to Acute Mesenteric Ischaemia in a Porcine Model
    Open this publication in new window or tab >>Altered mRNA Expression due to Acute Mesenteric Ischaemia in a Porcine Model
    Show others...
    2011 (English)In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 41, no 2, p. 281-287Article in journal (Refereed) Published
    Abstract [en]

    Introduction: Messenger RNA (mRNA) changes in the small intestine in response to acute mesenteric ischaemia (AMI) could offer novel diagnostic possibilities, but have not been described. The aim was to characterize the mRNA response to experimental AMI. Materials and methods: Twelve pigs underwent catheterisation of the superior mesenteric artery with injection of polivinylalcohol embolisation particles or sodium chloride. Laparotomy and intestinal tissue sampling were performed. Microarray analysis was performed using the GeneChip (R) whole porcine genome array. Results: Seven down-regulated cellular pathways were associated with protein, lipid and carbohydrate metabolism. Seventeen up-regulated pathways were associated with inflammatory and immunological activity, regulation of extracellular matrix and decreased cellular proliferation. Thrombospondin (THS), monocyte chemoattractant protein 1(MCP-1) and gap junction alpha 1(GJA-1) were consistently up-regulated in all embolised pigs. Genes encoding earlier proposed biomarkers for AMI were up-regulated, such as lactate dehydrogenase and creatine kinase, or down-regulated, such as intestinal fatty acid binding protein and glutathione S-transferase. Conclusion: This study describes the intestinal tissue response on a gene expression level to AMI. THS, MCP-1 and GJA-1 were consistently up-regulated by ischaemia, whereas earlier proposed biomarkers for AMI were not. Gene expression may not be directly linked to the use of the corresponding proteins as potential clinical biomarkers. (C) 2010 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

    National Category
    Medical and Health Sciences
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-18783 (URN)10.1016/j.ejvs.2010.09.012 (DOI)000288469000022 ()21095140 (PubMedID)2-s2.0-79651475389 (Scopus ID)
    Available from: 2011-09-29 Created: 2011-09-29 Last updated: 2019-03-29Bibliographically approved
    2. Whole blood RNA expression profiles in ovarian cancer patients with or without residual tumors after primary cytoreductive surgery
    Open this publication in new window or tab >>Whole blood RNA expression profiles in ovarian cancer patients with or without residual tumors after primary cytoreductive surgery
    2012 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 27, no 5, p. 1331-1335Article in journal (Refereed) Published
    Abstract [en]

    Significant improvements in the treatment results of ovarian cancer have been achieved during the last decades, but further improvements require additional methods identifying signs of the disease and its biological behavior, preferably by a simple blood test. We hypothesized that peripheral blood leukocytes may express genes that carry such clinical information. Therefore, we studied the relative gene expressions of 168 cancer- and metastasis-specific genes in blood samples from ovarian cancer patients with different prognoses after primary cytoreductive surgery. Total RNA was extracted from whole blood and the relative gene expression profile of 168 genes were analyzed using real-time qPCR assays. Two groups of patients were analyzed; one group with residual tumor mass after primary surgery, and one group where the tumor was macroscopically radically resected, resulting in no visible tumor mass left behind. The group with the remaining tumor mass after surgery showed significantly different gene expression profiles compared to the group with no remaining tumor mass. Differences were noted for the metastasis associated 1 family, member 2 gene (MTA2), the TNF, alpha-catenin, interleukin 1 beta, the KiSS-1 metastasis suppressor and the matrix metalloproteinase 10 genes. All genes were downregulated with a fold-change between 1.15 to 1.57; there were no upregulated genes. Thus, a signature of genes involved in metastasis, invasion and inflammation was found to be significantly downregulated in native unstimulated blood leukocytes from ovarian cancer patients with a poor prognosis. Preoperatively it may serve as a guide to the biology of the tumor and postoperatively in the optimization of adjuvant treatment of ovarian cancer patients.

    Place, publisher, year, edition, pages
    Athens, Greece: Spandidos Publications Ltd., 2012
    Keywords
    Seropapillary ovarian cancer, residual tumor, leukocyte gene expression, whole blood RNA expression
    National Category
    Medical and Health Sciences Cancer and Oncology
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-23093 (URN)10.3892/or.2012.1680 (DOI)000302202600005 ()22322362 (PubMedID)2-s2.0-84858269622 (Scopus ID)
    Note

    Funding Agencies:

    Lions' Cancer Research Foundation 

    Research Committee of Orebro County Council 

    Available from: 2012-05-31 Created: 2012-05-31 Last updated: 2024-01-03Bibliographically approved
    3. Whole genome expression profiling of blood cells in ovarian cancer patients: prognostic impact of the CYP1B1, MTSS1, NCALD, and NOP14 genes
    Open this publication in new window or tab >>Whole genome expression profiling of blood cells in ovarian cancer patients: prognostic impact of the CYP1B1, MTSS1, NCALD, and NOP14 genes
    2014 (English)In: Oncotarget, E-ISSN 1949-2553, Vol. 5, no 12, p. 4040-4049Article in journal (Refereed) Published
    Abstract [en]

    Ovarian cancer patients with different tumor stages and cell differentiation might be distinguished from each other by gene expression profiles in whole blood cell mRNA by the Affymetrix Human Gene 1.0 ST Array. We also examined if there is any association with other clinical variables, response to therapy, and residual tumor burden after surgery. Patients were divided into two groups, one with poor prognosis, advanced stage and poorly differentiated tumors (n = 22), and one group with good prognosis, early stage and well-to medium differentiated tumors (n = 11). Six genes were found to be differentially expressed: the PDIA3, LYAR, NOP14, NCALD and MTSS1 genes were down-regulated and the CYP1B1 gene expression was up-regulated in the poor prognosis group, all with p value <0.05, adjusted for mass comparison. In survival analyses, CYP1B1, MTSS1, NCALD and NOP14 remained significantly different (p<0.05). Patient groups did not differ in any transcript related to acute phase or immune responses. This minimal gene expression signature of prognostic ovarian cancer-related genes opens up an avenue for more practicable monitoring of ovarian cancer patients by simple peripheral blood tests, which may evolve into a tool to guide selection of curative and postoperative supportive therapies.

    Place, publisher, year, edition, pages
    Impact press, 2014
    Keywords
    ovarian cancer, whole genome profiling, prognosis, mRNA, NCALD, MTSS1, PDA3, CYP1B1, NOP14, LYAR
    National Category
    Cancer and Oncology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:oru:diva-36179 (URN)10.18632/oncotarget.1938 (DOI)000339055200007 ()24961659 (PubMedID)2-s2.0-84905090787 (Scopus ID)
    Note

    Funding Agencies:

    Research Committee of Örebro County Council

    Foundation for Gynecological Oncology, Örebro

    Lions' Cancer Research Foundation, Uppsala-Örebro

    Available from: 2014-09-02 Created: 2014-08-28 Last updated: 2024-01-17Bibliographically approved
    4. Tissue zinc levels in a child with hypercalprotectinaemia and hyperzincaemia: a case report and a review of the literature
    Open this publication in new window or tab >>Tissue zinc levels in a child with hypercalprotectinaemia and hyperzincaemia: a case report and a review of the literature
    2012 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 72, no 1, p. 34-38Article, review/survey (Refereed) Published
    Abstract [en]

    Background: A girl suffering from a rare syndrome of unknown aetiology, termed hypercalprotectinaemia, was evaluated for tissue zinc status, because calprotectin is a protein which chelates Zn at multiple binding-sites, which might have affected the distribution of Zn in her body.

    Methods: Measurement of serum, urine, hair and nail zinc (Zn) concentration, complemented with measurement of total Zn in ultrafiltrates of plasma.

    Results: Her serum Zn concentration was 105-133 mu mol/L. Zn levels in her hair (102 mu g/g), nail (90 mu g/g) and urine (3-12 mu mol/L; 20-80 mu g/dL) were all at the lower end of the reference intervals described in the sparse literature. Zn concentrations in ultrafiltrates of plasma were below the detection limit (<100 nmol/L). Thus, the elevated serum Zn did not translate into a similarly increased level of Zn in any of the tissues tested, nor in free Zn concentrations. Instead it appeared to be a result of Zn being chelated to binder proteins, most probably calprotectin.

    Conclusion: Her grossly elevated serum calprotectin concentration is probably able to raise circulating total Zn concentrations without raising ionized concentrations, but this Zn remains confined to the circulating blood as well as to excreted body fluids, particularly faeces.

    Place, publisher, year, edition, pages
    London, United Kingdom: Informa Healthcare, 2012
    Keywords
    Tissue zinc, zinc excretion, calprotectin, inflammation, growth retardation
    National Category
    Medical Biotechnology Clinical Laboratory Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-21627 (URN)10.3109/00365513.2011.623177 (DOI)000299283700005 ()22017170 (PubMedID)2-s2.0-84856056036 (Scopus ID)
    Available from: 2012-02-14 Created: 2012-02-14 Last updated: 2019-03-29Bibliographically approved
    5. Whole genome microarray expression analysis in blood leucocytes identifies pathways linked to signs and symptoms of a patient with hypercalprotectinaemia and hyperzincaemia
    Open this publication in new window or tab >>Whole genome microarray expression analysis in blood leucocytes identifies pathways linked to signs and symptoms of a patient with hypercalprotectinaemia and hyperzincaemia
    Show others...
    2018 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 191, no 2, p. 240-251Article in journal (Refereed) Published
    Abstract [en]

    A child, 2 years with the "hypercalprotectinemia with hyperzincemia" clinical syndrome presented with atypical symptoms and signs, notably persistent fever of around 38°C, thrombocythaemia of >700 x 10(9) /L, and a predominance of persistent intestinal symptoms. In an effort to find a cure by identifying the dysregulated pathways we analyzed whole-genome mRNA expression by the Affymetrix HG U133 PLUS 2.0 array on three occasions 3 to 5 months apart. Major upregulation was demonstrated for the JAK/STAT pathway including in particular CD177, S100A8, S100A9, and S100A12, accounting for the thrombocytosis; a large number of interleukins, their receptors, and activators, accounting for the febrile apathic state; and the HMBG1 gene, possibly accounting for part of the intestinal symptoms. These results show that gene expression array technology may assist the clinician in the diagnostic workup of individual patients with suspected syndromal states of unknown origin, and the expression data can guide the selection of optimal treatment directed at the identified target pathways.

    Place, publisher, year, edition, pages
    Wiley-Blackwell Publishing Inc., 2018
    Keywords
    expression array, fever, hypercalprotectinaemia, hyperzincaemia, thrombocytaemia
    National Category
    Medical Genetics Immunology in the medical area
    Identifiers
    urn:nbn:se:oru:diva-61444 (URN)10.1111/cei.13064 (DOI)000419624200012 ()28984903 (PubMedID)2-s2.0-85032923253 (Scopus ID)
    Available from: 2017-11-02 Created: 2017-11-02 Last updated: 2023-12-08Bibliographically approved
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  • 23.
    Jayaprakash, Kartheyaene
    Örebro University, School of Medical Sciences.
    Monocyte and Neutrophil Inflammatory Responses to the Periodontopathogen Porphyromonas gingivalis2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Periodontitis is one of the most common adult infections. Duing bacteremia in healthy individuals or patients with chronic periodontitis, a number of oral bacteria such as Porphyromonas gingivalis encounter inflammatory cells in the blood eg. platelets, neutrophils and monocytes. Although several studies have suggested an association between periodontitis and cardiovascular diseases, the infection and inflammatory mechanisms are poorly understood. Hence, the aim of this thesis was to elucidate the mechanisms that are involved in P. gingivalis interaction with blood leukocytes, in order to further understand the molecular pathogenesis that renders periodontitis as a risk factor for several systemic conditions. We have demonstrated that P. gingivalis induces ROS production in neutrophils, THP1 cells and in whole blood, through activation of pattern recognition receptors, such as toll-like receptors, nuclear oligomerizing domains and protease- activated receptors. Besides, we have also shown that monocytes secrete IL-1β and CXCL8 in response to P. gingivalis. Both these cytokines prime neutrophils, endothelial cells and other vascular cells in an autocrine and paracrine manner. P. gingivalis has a plethora of virulence factors of which gingipains are very unique. In addition to activating inflammatory signalling pathways in cells, gingipains also regulate CXCL8 and IL-1β, thereby curtailing the host defence strategies. We demonstrated that oxidized LDL, but not native LDL, induces IL-1β release and CD36 expression on THP1 cells. Furthermore, LDL mildly modifies P. gingivalis-induced inflammatory responses as well as CD36 expression in THP1 cells. We also observed that P. gingivalis is eliminated mainly by phagocytosis in neutrophils. In summary, these studies clarify the mechanisms of interaction between P. gingivalis and leukocytes, which can increase the understanding of the pathogenesis of periodontitis and associated systemic disorders.

    List of papers
    1. Gingipains from Porphyromonas gingivalis play a significant role in induction and regulation of CXCL8 in THP-1 cells
    Open this publication in new window or tab >>Gingipains from Porphyromonas gingivalis play a significant role in induction and regulation of CXCL8 in THP-1 cells
    2014 (English)In: BMC Microbiology, E-ISSN 1471-2180, Vol. 14, article id 193Article in journal (Refereed) Published
    Abstract [en]

    Background: Porphyromonas gingivalis is an important bacterial etiological agent involved in periodontitis. The bacterium expresses two kinds of cysteine proteases called gingipains: arginine gingipains (RgpA/B) and lysine gingipain (Kgp). This study evaluated the interaction between P. gingivalis and THP-1 cells, a widely used monocytic cell line, in vitro with a focus on CXCL8 at the gene and protein levels and its fate thereafter in cell culture supernatants. THP-1 cells were stimulated with viable and heat-killed wild-type strains ATCC 33277 or W50 or viable isogenic gingipain mutants of W50, E8 (Rgp mutant) or K1A (Kgp mutant), for 24 hours.

    Results: ELISA and qPCR results show an elevated CXCL8 expression and secretion in THP-1 cells in response to P. gingivalis, where the heat-killed ATCC33277 and W50 induced higher levels of CXCL8 in comparison to their viable counterparts. Furthermore, the Kgp-deficient mutant K1A caused a higher CXCL8 response compared to the Rgp-deficient E8. Chromogenic quantification of lipopolysaccharide (LPS) in supernatant showed no significant differences between viable and heat killed bacteria except that W50 shed highest levels of LPS. The wild-type strains secreted relatively more Rgp during the co-culture with THP-1 cells. The CXCL8 degradation assay of filter-sterilized supernatant from heat-killed W50 treated cells showed that Rgp was most efficient at CXCL8 hydrolysis. Of all tested P. gingivalis strains, adhesion and internalization in THP-1 cells was least conspicuous by Rgp-deficient P. gingivalis (E8), as demonstrated by confocal imaging.

    Conclusions: W50 and its Kgp mutant K1A exhibit a higher immunogenic and proteolytic function in comparison to the Rgp mutant E8. Since K1A differs from E8 in the expression of Rgp, it is rational to conclude that Rgp contributes to immunomodulation in a more dynamic manner in comparison to Kgp. Also, W50 is a more virulent strain when compared to the laboratory strain ATCC33277.

    Place, publisher, year, edition, pages
    BioMed Central, 2014
    Keywords
    Porphyromonas gingivalis, THP-1 cells, Gingipains, Mutants, CXCL8 degradation
    National Category
    Microbiology
    Research subject
    Microbiology
    Identifiers
    urn:nbn:se:oru:diva-36171 (URN)10.1186/1471-2180-14-193 (DOI)000339837900001 ()2-s2.0-84904275512 (Scopus ID)
    Funder
    Swedish Heart Lung Foundation
    Note

    Funding Agencies:

    Foundation of Olle Engkvist

    Knowledge Foundation

    Available from: 2014-09-03 Created: 2014-08-28 Last updated: 2024-01-17Bibliographically approved
    2. PKC, ERK/p38 MAP kinases and NF-κB targeted signalling plays a crucial role in expression and release of IL-1β and CXCL8 in Porphyromonas gingivalis infected monocytes
    Open this publication in new window or tab >>PKC, ERK/p38 MAP kinases and NF-κB targeted signalling plays a crucial role in expression and release of IL-1β and CXCL8 in Porphyromonas gingivalis infected monocytes
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-49455 (URN)
    Available from: 2016-03-22 Created: 2016-03-22 Last updated: 2024-01-02Bibliographically approved
    3. Porphyromonas gingivalis induced release of reactive oxygen species and interleukin-1 beta and the effects of low density lipoproteins in monocytes and whole blood
    Open this publication in new window or tab >>Porphyromonas gingivalis induced release of reactive oxygen species and interleukin-1 beta and the effects of low density lipoproteins in monocytes and whole blood
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-49456 (URN)
    Available from: 2016-03-22 Created: 2016-03-22 Last updated: 2024-01-02Bibliographically approved
    4. The role of phagocytosis, oxidative burst and neutrophil extracellular traps in the interaction between neutrophils and the periodontal pathogen Porphyromonas gingivalis
    Open this publication in new window or tab >>The role of phagocytosis, oxidative burst and neutrophil extracellular traps in the interaction between neutrophils and the periodontal pathogen Porphyromonas gingivalis
    2015 (English)In: Molecular Oral Microbiology, ISSN 2041-1006, E-ISSN 2041-1014, Vol. 30, no 5, p. 361-375Article in journal (Refereed) Published
    Abstract [en]

    Neutrophils are regarded as the sentinel cells of innate immunity and are found in abundance within the gingival crevice. Discovery of neutrophil extracellular traps (NETs) within the gingival pockets prompted us to probe the nature of the interactions of neutrophils with the prominent periopathogen Porphyromonas gingivalis. Some of the noted virulence factors of this Gram-negative anaerobe are gingipains: arginine gingipains (RgpA/B) and lysine gingipain (Kgp). The aim of this study was to evaluate the role of gingipains in phagocytosis, formation of reactive oxygen species, NETs and CXCL8 modulation by using wild-type strains and isogenic gingipain mutants. Confocal imaging showed that gingipain mutants K1A (Kgp) and E8 (RgpA/B) induced extracellular traps in neutrophils, whereas ATCC33277 and W50 were phagocytosed. The viability of both ATCC33277 and W50 dwindled as the result of phagocytosis and could be salvaged by cytochalasin D, and the bacteria released high levels of lipopolysaccharide in the culture supernatant. Porphyromonas gingivalis induced reactive oxygen species and CXCL8 with the most prominent effect being that of the wild-type strain ATCC33277, whereas the other wild-type strain W50 was less effective. Quantitative real-time polymerase chain reaction revealed a significant CXCL8 expression by E8. All the tested P.gingivalis strains increased cytosolic free calcium. In conclusion, phagocytosis is the primary neutrophil response to P.gingivalis, although NETs could play an accessory role in infection control. Although gingipains do not seem to directly regulate phagocytosis, NETs or oxidative burst in neutrophils, their proteolytic properties could modulate the subsequent outcomes such as nutrition acquisition and survival by the bacteria.

    Keywords
    neutrophils, neutrophil extracellular traps, periodontitis, phagocytosis, reactive oxygen species
    National Category
    Dentistry
    Identifiers
    urn:nbn:se:oru:diva-46034 (URN)10.1111/omi.12099 (DOI)000361007200003 ()25869817 (PubMedID)2-s2.0-84941023684 (Scopus ID)
    Funder
    Swedish Heart Lung FoundationSwedish Research Council
    Note

    Funding Agency:

    Foundation of Olle Engkvist

    Available from: 2015-10-07 Created: 2015-10-07 Last updated: 2024-01-02Bibliographically approved
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  • 24.
    Jayaprakash, Kartheyaene
    et al.
    Örebro University, School of Medical Sciences.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Gunaltay, Sezin
    Örebro University, School of Medical Sciences.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    PKC, ERK/p38 MAP kinases and NF-κB targeted signalling plays a crucial role in expression and release of IL-1β and CXCL8 in Porphyromonas gingivalis infected monocytesManuscript (preprint) (Other academic)
  • 25.
    Jayaprakash, Kartheyaene
    et al.
    Örebro University, School of Medical Sciences.
    Demirel, Isak
    Örebro University, School of Medical Sciences.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    Porphyromonas gingivalis induced release of reactive oxygen species and interleukin-1 beta and the effects of low density lipoproteins in monocytes and whole bloodManuscript (preprint) (Other academic)
  • 26.
    Joukamo, Laura
    et al.
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Lankinen, Maria
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Schwab, Ursula
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Soininen, Pasi
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Kangas, Antti J.
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Kolehmainen, Marjukka
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Paananen, Jussi
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Poutanen, Kaisa
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Mykkänen, Hannu
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Seppänen-Laakso, Tuulikki
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Gylling, Helena
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Oresic, Matej
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Ala-Korpela, Mika
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Uusitupa, Matti
    Itä-Suomen yliopisto, lääketieteen laitos, Teknologian tutkimuskeskus VTT, Kuopio, Finland.
    Rasvainen kala muokkaa HDL-hiukkaskokoa ja lipidipitoisuuksia [Fatty fish modifies HDL particle size and lipid concentrations]2013In: Duodecim, ISSN 0012-7183, E-ISSN 2242-3281, Vol. 129, no 24, p. 2661-2670Article in journal (Refereed)
    Abstract [fi]

    BACKGROUND: We investigated with 1HNMR-spectroscopy the effects of habitual fatty fish intake on serum lipiprotein profiles in persons with features of metabolic syndrome.

    MATERIAL AND METHODS: The participants (n = 105) were randomized into three diet intervention groups. The groups were given different dietary instructions.

    RESULTS: Increased intake of fatty fish had a significant (p < 0.05) increasing effect on the amount of large HDL-lipoprotein subclasses and their lipids.

    CONCLUSIONS: Frequent intake of fatty fish may have beneficial effects on HDL-metabolism beyond that assumed to be related to its serum concentrations.

  • 27.
    Kaliff, Malin
    Örebro University, School of Medical Sciences.
    Human papillomavirus and cellular biomarkers in cervical cancer2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cervical cancer (CC) is caused by a persistent infection of certain types of the human papillomavirus (HPV). Even though great progress has been made in strategies for prevention, and treatment of CC, there is still a need for improved methods in screening and management of women diagnosed with CC. The aim of this thesis was to gain further knowledge of CC by studying HPV-related or cellular biomarkers in precursors and established cancer.

    Mostly molecular methods were used for analysis of both tumour and screening samples. Among the studied biomarkers were HPV genotype, HPV multiplicity, viral load and methylation.

    Initially, HPV was detected in only 86% of the tumours; after careful reinvestigation of the negative samples, the final prevalence was 93%. The results show that analysis of long-term archived samples may require thorough and repeated analysis to obtain accurate results. In the HPV-positive tumour samples, 13% tested positive for multiple genotypes. This finding was associated with poor prognosis for the woman and could be a useful biomarker for prognostic assessment in CC. Viral load was analysed as a potential contributing factor for prognosis differences, however, no such association was detected.

    In the screening cohort, 40% of women with high-grade abnormalities were positive for HPV16 and 18, genotypes included in the vaccine used since 2012 in Sweden, while 88% were positive for the genotypes in the updated vaccine used since 2019. This indicates a large future reduction of high-grade abnormalities in the vaccinated cohorts, and baseline data like these are valuable for surveillance of genotype distribution in the coming decades. A methylation test targeting two human genes, proposed for use in screening, was tested on the screening samples. We detected no association between hypermethylation and HPV, but it was associated with increasing age, something that needs to be considered if using this method in screening.

    List of papers
    1. Findings of multiple HPV genotypes in cervical carcinoma are associated with poor cancer-specific survival in a Swedish cohort of cervical cancer primarily treated with radiotherapy
    Open this publication in new window or tab >>Findings of multiple HPV genotypes in cervical carcinoma are associated with poor cancer-specific survival in a Swedish cohort of cervical cancer primarily treated with radiotherapy
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    2018 (English)In: Oncotarget, E-ISSN 1949-2553, Vol. 9, no 27, p. 18786-18796Article in journal (Refereed) Published
    Abstract [en]

    Cervical cancer (CC) is one of the most common cancers in women and virtually all cases of CC are a result of a persistent infection of human papillomavirus (HPV). For disease detected in early stages there is curing treatment but when diagnosed late with recurring disease and metastasis there are limited possibilities. Here we evaluate HPV impact on treatment resistance and metastatic disease progression. Prevalence and distribution of HPV genotypes and HPV16 variants in a Swedish CC patient cohort (n=209) was evaluated, as well as HPV influence on patient prognosis. Tumor samples suitable for analysis (n=204) were genotyped using two different real-time PCR methods. HPV16 variant analysis was made using pyrosequencing. Results showed that HPV prevalence in the total series was 93%. Of the HPV-positive samples, 13% contained multiple infections, typically with two high-risk HPV together. Primary cure rate for the complete series was 95%. Recurrence rate of the complete series was 28% and distant recurrences were most frequent (20%). Patients with tumors containing multiple HPV-strains and particularly HPV genotypes belonging to the alpha 7 and 9 species together had a significantly higher rate of distant tumor recurrences and worse cancer-specific survival rate.

    Place, publisher, year, edition, pages
    Impact Journals LLC, 2018
    Keywords
    HPV, cervical cancer, recurrences, survival
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:oru:diva-71672 (URN)10.18632/oncotarget.24666 (DOI)29721161 (PubMedID)2-s2.0-85045206587 (Scopus ID)
    Available from: 2019-01-22 Created: 2019-01-22 Last updated: 2024-01-17Bibliographically approved
    2. HPV-negative Tumors in a Swedish Cohort of Cervical Cancer
    Open this publication in new window or tab >>HPV-negative Tumors in a Swedish Cohort of Cervical Cancer
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    2020 (English)In: International Journal of Gynecological Pathology, ISSN 0277-1691, E-ISSN 1538-7151, Vol. 39, no 3, p. 279-288Article in journal (Refereed) Published
    Abstract [en]

    Despite the common perception that the human papilloma virus (HPV) is a requirement for the development of cervical cancer (CC), a considerable number of CCs test HPV negative. Presently, many countries are shifting to HPV primary CC screening, and it is of importance to increase the knowledge about the group of CCs that test HPV negative. The aim of this study was to reinvestigate a proportion of cervical tumors with a primary negative or invalid test result. Reinvestigation with repeated genotyping (targeting L1) was followed by analysis with an alternative target method (targeting E6/E7) on existing or additional tumor material. Consistently negative tumors were histologically evaluated, and cases with low or lacking tumor cell content, consistent invalid test results, or with suspicion of other than cervical origin were excluded. HPV-negative cases were thereafter subjected to immunohistochemistry (Cytokeratin 5, pan cytokeratin, protein 63, P16, and P53). The HPV-negative proportion could after reinvestigation be reduced by one-half (14%-7%). Additional positive samples were often detected in late polymerase chain reaction cycles, with an alternative (E6/E7) or the same (L1) target, or with a method using shorter amplicon lengths. Confirmed HPV negativity was significantly associated with worse prognosis, high patient age, longer storage time, and adenocarcinoma histology. Some of the HPV-negative cases showed strong/diffuse p16 immunoreactivity, indicating some remaining false-negative cases. False HPV negativity in this cohort was mainly linked to methodological limitations in the analysis of stored CC material. The small proportion of presumably true HPV-negative adenocarcinomas is not a reason for hesitation in revision to CC screening with primary HPV testing.

    Place, publisher, year, edition, pages
    Wolters Kluwer, 2020
    Keywords
    Uterine cervical neoplasms, Papillomaviridae, Human papillomavirus DNA tests, Formalin-fixed paraffin-embedded tissues, False-negative reactions
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:oru:diva-79634 (URN)10.1097/PGP.0000000000000612 (DOI)000526400700012 ()31206367 (PubMedID)
    Note

    Supported by Örebro country council research committee in Sweden.

    Available from: 2020-01-31 Created: 2020-01-31 Last updated: 2022-02-11Bibliographically approved
    3. Droplet Digital PCR for type-specific detection and quantification of nine different HPV genotypes in cervical carcinomas
    Open this publication in new window or tab >>Droplet Digital PCR for type-specific detection and quantification of nine different HPV genotypes in cervical carcinomas
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:oru:diva-82327 (URN)
    Available from: 2020-06-03 Created: 2020-06-03 Last updated: 2022-02-11Bibliographically approved
    4. Full genotyping and FAM19A4/miR124-2 methylation analysis in high-risk HPV-positive samples from women over 30 years participating in cervical cancer screening in Örebro, Sweden
    Open this publication in new window or tab >>Full genotyping and FAM19A4/miR124-2 methylation analysis in high-risk HPV-positive samples from women over 30 years participating in cervical cancer screening in Örebro, Sweden
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:oru:diva-82328 (URN)
    Available from: 2020-06-03 Created: 2020-06-03 Last updated: 2022-02-11Bibliographically approved
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  • 28.
    Kardeby, Caroline
    Örebro University, School of Medical Sciences.
    Studies of platelet signalling and endothelial cell responses using unique synthetic drugs2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Haemostasis is a complex and tightly regulated process which protects us from bleeding. Platelets are essential for maintained haemostasis. Under normal conditions platelets are calmed by antithrombotic substances release by the endothelium. During vascular injury, the platelets will activate and form a haemostatic plug to prevent bleeding. Inflammatory processes like atherosclerosis can disturb the haemostatic balance and lead to severe consequences like myocardial infarction and stroke. Inhibition of platelets and coagulation are common treatments to prevent unwanted blood clot formation. There is a great need for increased knowledge on the mechanisms of thrombosis and characterisation of new substances with possible therapeutic potential. This thesis used unique synthetic drugs to study platelet signalling and endothelial responses. Paper I showed that both sulfated polysaccharides from seaweed and synthetic glycopolymers which mimic their chemical properties caused platelet activation.

    Paper II elucidated the molecular mechanism underlying platelet activation by sulfated glycopolymers and polysaccharides. We found that human platelet activation took place via the Platelet endothelial aggregation receptor 1 (PEAR1), while mouse platelet activation was mainly via C-type lectin-like receptor 2. Aggregation was supported by Glycoprotein Ibα in both species.

    Paper III showed the effect of synthetic glycopolymers and natural polysaccharides on cultured human endothelial cells. We found that both the glycopolymers and polysaccharides caused a proinflammatory response after 24h.

    In Paper IV, the effect of a synthetic purine analogue with a nitrate ester motif was studied. We found that the purine analogue reduced platelet functions by inhibiting Rho-associated protein kinase (ROCK).

    This thesis describes unique synthetic drugs that can be used for further studies of the mechanisms underlying the biological processes of thrombosis and inflammation. The synthetic glycopolymers can be used to further elucidate the physiological role of PEAR1, a potential future therapeutic target.

    List of papers
    1. Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets
    Open this publication in new window or tab >>Fucoidan-Mimetic Glycopolymers as Tools for Studying Molecular and Cellular Responses in Human Blood Platelets
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    2017 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 17, no 2, article id UNSP 1600257Article in journal (Refereed) Published
    Abstract [en]

    The marine sulfated polysaccharide fucoidan displays superior ability to induce platelet aggregation compared to other sulfated polysaccharides. As such, it is an attractive tool for studying molecular and cellular responses in activated platelets. The heterogeneous structure, however, poses a problem in such applications. This study describes the synthesis of sulfated α-l-fucoside-pendant poly(methacryl amides) with homogeneous structures. By using both thiol-mediated chain transfer and reversible addition-fragmentation chain transfer polymerization techniques, glycopolymers with different chain lengths are obtained. These glycopolymers show platelet aggregation response and surface changes similar to those of fucoidan, and cause platelet activation through intracellular signaling as shown by extensive protein tyrosine phosphorylation. As the platelet activating properties of the glycopolymers strongly mimic those of fucoidan, this study concludes these fucoidan-mimetic glycopolymers are unique tools for studying molecular and cellular responses in human blood platelets.

    Place, publisher, year, edition, pages
    Weinheim, Germany: Wiley-VCH Verlagsgesellschaft, 2017
    Keywords
    biological applications of polymers; biomimetic; radical polymerization; reversible addition fragmentation chain transfer; structure-property relations
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:oru:diva-52179 (URN)10.1002/mabi.201600257 (DOI)000394592600012 ()27616165 (PubMedID)2-s2.0-84987653303 (Scopus ID)
    Note

    Funding Agency:

    AFA Insurance, VR Treatments of the Future grant

    Available from: 2016-09-21 Created: 2016-09-14 Last updated: 2019-05-06Bibliographically approved
    2. Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα
    Open this publication in new window or tab >>Synthetic glycopolymers and natural fucoidans cause human platelet aggregation via PEAR1 and GPIbα
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    2019 (English)In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 3, no 3, p. 275-287Article in journal (Refereed) Published
    Abstract [en]

    Fucoidans are sulfated fucose-based polysaccharides that activate platelets and have pro- and anticoagulant effects; thus, they may have therapeutic value. In the present study, we show that 2 synthetic sulfated α-l-fucoside-pendant glycopolymers (with average monomeric units of 13 and 329) and natural fucoidans activate human platelets through a Src- and phosphatidylinositol 3-kinase (PI3K)-dependent and Syk-independent signaling cascade downstream of the platelet endothelial aggregation receptor 1 (PEAR1). Synthetic glycopolymers and natural fucoidan stimulate marked phosphorylation of PEAR1 and Akt, but not Syk. Platelet aggregation and Akt phosphorylation induced by natural fucoidan and synthetic glycopolymers are blocked by a monoclonal antibody to PEAR1. Direct binding of sulfated glycopolymers to epidermal like growth factor (EGF)-like repeat 13 of PEAR1 was shown by avidity-based extracellular protein interaction screen technology. In contrast, synthetic glycopolymers and natural fucoidans activate mouse platelets through a Src- and Syk-dependent pathway regulated by C-type lectin-like receptor 2 (CLEC-2) with only a minor role for PEAR1. Mouse platelets lacking the extracellular domain of GPIbα and human platelets treated with GPIbα-blocking antibodies display a reduced aggregation response to synthetic glycopolymers. We found that synthetic sulfated glycopolymers bind directly to GPIbα, substantiating that GPIbα facilitates the interaction of synthetic glycopolymers with CLEC-2 or PEAR1. Our results establish PEAR1 as the major signaling receptor for natural fucose-based polysaccharides and synthetic glycopolymers in human, but not in mouse, platelets. Sulfated α-l-fucoside-pendant glycopolymers are unique tools for further investigation of the physiological role of PEAR1 in platelets and beyond.

    Place, publisher, year, edition, pages
    American Society of Hematology, 2019
    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Hematology
    Identifiers
    urn:nbn:se:oru:diva-72478 (URN)10.1182/bloodadvances.2018024950 (DOI)000458442500007 ()30700416 (PubMedID)2-s2.0-85060943358 (Scopus ID)
    Funder
    Knowledge Foundation
    Note

    Funding Agencies:

    BHF  PG/16/53/32242  RG/13/18/30563 

    Deutsche Forschungsgemeinschaft  DFG: Eb 177/14-1 

    Fonds voor Wetenschappelijk Onderzoek Vlaanderen grant  G0A6514N 

    Available from: 2019-02-14 Created: 2019-02-14 Last updated: 2022-12-19Bibliographically approved
    3. Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cells
    Open this publication in new window or tab >>Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cells
    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-74033 (URN)
    Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-05-06Bibliographically approved
    4. A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
    Open this publication in new window or tab >>A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibition
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-74034 (URN)
    Available from: 2019-05-06 Created: 2019-05-06 Last updated: 2019-05-06Bibliographically approved
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    Studies of platelet signalling and endothelial cell responses using unique synthetic drugs
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  • 29.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Paramel Varghese, Geena
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Pournara, Dimitra
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fotopoulou, Theano
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Koufaki, Maria
    National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Athens, Greece.
    Fransén, Karin
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    A novel purine analogue bearing nitrate ester prevents platelet activation by ROCK activity inhibitionManuscript (preprint) (Other academic)
  • 30.
    Kardeby, Caroline
    et al.
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sirsjö, Allan
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Ljungberg, Liza
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Grenegård, Magnus
    Örebro University, School of Medical Sciences. Cardiovascular Research Centre (CVRC).
    Sulfated glycopolymers and polysaccharides regulate inflammation-related proteins in human vascular endothelial cellsManuscript (preprint) (Other academic)
  • 31.
    Karpanen, Terhi
    et al.
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; .
    Bry, Maija
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Ollila, Hanna M.
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Seppänen-Laakso, Tuulikki
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Liimatta, Erkki
    Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland.
    Leskinen, Hanna
    Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
    Kivelä, Riikka
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Helkamaa, Teemu
    Institute of Biomedicine, Department of Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Merentie, Mari
    A.I. Virtanen Institute, Department of Biotechnology and Molecular Medicine, University of Kuopio, Kuopio, Finland.
    Jeltsch, Michael
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Paavonen, Karri
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Andersson, Leif C.
    Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland.
    Mervaala, Eero
    Institute of Biomedicine, Department of Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Hassinen, Ilmo E.
    Department of Medical Biochemistry and Molecular Biology, University of Oulu, Oulu, Finland.
    Ylä-Herttuala, Seppo
    A.I. Virtanen Institute, Department of Biotechnology and Molecular Medicine, University of Kuopio, Kuopio, Finland.
    Oresic, Matej
    VTT Technical Research Centre of Finland, Espoo, Finland.
    Alitalo, Kari
    Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy2008In: Circulation Research, ISSN 0009-7330, E-ISSN 1524-4571, Vol. 103, no 9, p. 1018-1026Article in journal (Refereed)
    Abstract [en]

    Vascular endothelial growth factor (VEGF)-B is poorly angiogenic but prominently expressed in metabolically highly active tissues, including the heart. We produced mice expressing a cardiac-specific VEGF-B transgene via the alpha-myosin heavy chain promoter. Surprisingly, the hearts of the VEGF-B transgenic mice showed concentric cardiac hypertrophy without significant changes in heart function. The cardiac hypertrophy was attributable to an increased size of the cardiomyocytes. Blood capillary size was increased, whereas the number of blood vessels per cell nucleus remained unchanged. Despite the cardiac hypertrophy, the transgenic mice had lower heart rate and blood pressure than their littermates, and they responded similarly to angiotensin II-induced hypertension, confirming that the hypertrophy does not compromise heart function. Interestingly, the isolated transgenic hearts had less cardiomyocyte damage after ischemia. Significantly increased ceramide and decreased triglyceride levels were found in the transgenic hearts. This was associated with structural changes and eventual lysis of mitochondria, resulting in accumulation of intracellular vacuoles in cardiomyocytes and increased death of the transgenic mice, apparently because of mitochondrial lipotoxicity in the heart. These results suggest that VEGF-B regulates lipid metabolism, an unexpected function for an angiogenic growth factor.

  • 32.
    Klasson, Maria
    Örebro University, School of Medical Sciences.
    Cobalt in the hard metal production industry: exposure via inhalation and skin and the inflammatory response in human keratinocytes2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Cobalt is a strong sensitizer and can cause contact allergy upon both direct contact or from airborne exposure on the skin. In the skin, keratinocytes are the first cells to come in contact with the metal and will react and respond to the danger by triggering an alarm system resulting in an inflammatory response in the skin. Keratinocytes have been shown to produce IL-1β, which is one of the most potent  inflammatory agents in our body and is associated with a variety of diseases.

    The aims of this thesis was to investigate cobalt air concentrations for different particle fractions for possible use as proxies for other article measures and to examine if cobalt skin and inhalable air exposure contributes to uptake. Also, to investigate the effect of cobalt on cultured human keratinocyte cell viability, pro-inflammatory cytokine/chemokine release and NLRP3 inflammasome activation using cells cultured at low or high calcium (the latter yielding a more differentiated cell type).

    Air exposure to cobalt was found in all departments and for all work tasks in the hard metal production facility and exposures were in general below the Swedish OEL for inhalable cobalt. The highest exposure levels were found in the powder production department and for laboratory and furnace work. Good correlations for the mass based measures enable us to use the findings for future references. When personal inhalable air levels of cobalt, cobalt skin levels skin and biological monitoring of cobalt in blood were analysed, the skin exposure was determined to be import as a route of uptake. Skin exposure to cobalt in the hard metal industry, could further affect the total uptake in the same order of magnitude as air exposure. In vitro investigations of cobalt using the human keratinocyte cell line HaCaT, showed that CoCl2 triggered an alarm system in cells where the proinflammatory cytokines/chemokines IL-6, CXCL8 and CCL2, known to be involved in skin inflammation, were secreted in a time- and dosedependent manner. Comparing HaCaT cells of high- and low differentiation stages indicated that the effect of cobalt chloride on cell toxicity occurs throughout the living epidermis. CoCl2 exposure also resulted in secretion of the proinflammatory cytokines IL-1β and IL-18, and caspase-1, which indicates activation of the NLRP3 inflammasome in the cells. CoCl2 regulates the inflammasome both as primer and as an activator. Our mRNA results indicates a negative feedback mechanism in the inflamamsome due to the exposure. The inflammatory response in general is more dose than time dependent, which be important for understanding the mechanisms of allergic sensitization.

    List of papers
    1. Occupational Exposure to Cobalt and Tungsten in the Swedish Hard Metal Industry: Air Concentrations of Particle Mass, Number, and Surface Area
    Open this publication in new window or tab >>Occupational Exposure to Cobalt and Tungsten in the Swedish Hard Metal Industry: Air Concentrations of Particle Mass, Number, and Surface Area
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    2016 (English)In: Annals of Occupational Hygiene, ISSN 0003-4878, E-ISSN 1475-3162, Vol. 60, no 6, p. 684-699Article in journal (Refereed) Published
    Abstract [en]

    Exposure to cobalt in the hard metal industry entails severe adverse health effects, including lung cancer and hard metal fibrosis. The main aim of this study was to determine exposure air concentration levels of cobalt and tungsten for risk assessment and dose-response analysis in our medical investigations in a Swedish hard metal plant. We also present mass-based, particle surface area, and particle number air concentrations from stationary sampling and investigate the possibility of using these data as proxies for exposure measures in our study. Personal exposure full-shift measurements were performed for inhalable and total dust, cobalt, and tungsten, including personal real-time continuous monitoring of dust. Stationary measurements of inhalable and total dust, PM2.5, and PM10 was also performed and cobalt and tungsten levels were determined, as were air concentration of particle number and particle surface area of fine particles. The personal exposure levels of inhalable dust were consistently low (AM 0.15mg m(-3), range <0.023-3.0mg m(-3)) and below the present Swedish occupational exposure limit (OEL) of 10mg m(-3) The cobalt levels were low as well (AM 0.0030mg m(-3), range 0.000028-0.056mg m(-3)) and only 6% of the samples exceeded the Swedish OEL of 0.02mg m(-3) For continuous personal monitoring of dust exposure, the peaks ranged from 0.001 to 83mg m(-3) by work task. Stationary measurements showed lower average levels both for inhalable and total dust and cobalt. The particle number concentration of fine particles (AM 3000 p·cm(-3)) showed the highest levels at the departments of powder production, pressing and storage, and for the particle surface area concentrations (AM 7.6 µm(2)·cm(-3)) similar results were found. Correlating cobalt mass-based exposure measurements to cobalt stationary mass-based, particle area, and particle number concentrations by rank and department showed significant correlations for all measures except for particle number. Linear regression analysis of the same data showed statistically significant regression coefficients only for the mass-based aerosol measures. Similar results were seen for rank correlation in the stationary rig, and linear regression analysis implied significant correlation for mass-based and particle surface area measures. The mass-based air concentration levels of cobalt and tungsten in the hard metal plant in our study were low compared to Swedish OELs. Particle number and particle surface area concentrations were in the same order of magnitude as for other industrial settings. Regression analysis implied the use of stationary determined mass-based and particle surface area aerosol concentration as proxies for various exposure measures in our study.

    Place, publisher, year, edition, pages
    Oxford, United Kingdom: Oxford University Press, 2016
    Keywords
    Cobalt exposure in the hard metal industry, occupational exposure, particle mass, particle number, particle surface area, personal exposure measurements, stationary measurements
    National Category
    Occupational Health and Environmental Health
    Identifiers
    urn:nbn:se:oru:diva-50312 (URN)10.1093/annhyg/mew023 (DOI)000381195200003 ()27143598 (PubMedID)2-s2.0-84978734681 (Scopus ID)
    Note

    Funding Agency:

    Swedish hard metal company

    Available from: 2016-05-27 Created: 2016-05-16 Last updated: 2020-09-11Bibliographically approved
    2. Biological monitoring of dermal and air exposure to cobalt at a Swedish hard metal production plant: does dermal exposure contribute to uptake?
    Open this publication in new window or tab >>Biological monitoring of dermal and air exposure to cobalt at a Swedish hard metal production plant: does dermal exposure contribute to uptake?
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    2017 (English)In: Contact Dermatitis, ISSN 0105-1873, E-ISSN 1600-0536, Vol. 77, no 4, p. 201-207Article in journal (Refereed) Published
    Abstract [en]

    Background: Occupational exposure to cobalt is well established in hard metal manufacture. Cobalt is known to cause contact allergy, asthma, hard metal lung disease, and lung cancer. The relationship between skin exposure and uptake determined in blood has not been extensively investigated.

    Objective: To examine whether skin and inhalable air exposure to cobalt contributes to uptake, determined as cobalt in blood, in a hard metal manufacturing factory.

    Methods: The amount of cobalt on the skin found with an acid wash technique, the air concentrations of inhalable cobalt and cobalt blood concentrations were determined and correlated in exposed workers.

    Results: We found a significant rank correlation for cobalt concentrations on the skin, in inhalable air, and in blood (0.376-0.498). Multiple linear regression showed significant regression coefficients for cobalt skin exposure and blood (B = 0.01, p < 0.05) and for inhalable cobalt in air and blood (B = 49.1, p < 0.001). According to our model based on data from the regression analyses, a twofold increase in skin exposure levels at different air concentrations caused a 3 - 14% increase in blood levels.

    Conclusions: Our data suggest that skin exposure to cobalt in the hard metal industry could affect the total uptake at the same order of magnitude as air exposure.

    Place, publisher, year, edition, pages
    John Wiley & Sons, 2017
    Keywords
    Acid wash technique, blood concentration, cobalt, hard metal, skin absorption, skin exposure
    National Category
    Dermatology and Venereal Diseases Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:oru:diva-61031 (URN)10.1111/cod.12790 (DOI)000409110100002 ()28675438 (PubMedID)2-s2.0-85021784690 (Scopus ID)
    Note

    Funding Agency:

    Swedish hard metal company

    Available from: 2017-09-19 Created: 2017-09-19 Last updated: 2020-09-11Bibliographically approved
    3. Dose- and time-dependent changes in viability and IL-6, CXCL8 and CCL2 production by HaCaT-cells exposed to cobalt: Effects of high and low calcium growth conditions
    Open this publication in new window or tab >>Dose- and time-dependent changes in viability and IL-6, CXCL8 and CCL2 production by HaCaT-cells exposed to cobalt: Effects of high and low calcium growth conditions
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    (English)Manuscript (preprint) (Other academic)
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    Other Basic Medicine
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    urn:nbn:se:oru:diva-85681 (URN)
    Available from: 2020-09-11 Created: 2020-09-11 Last updated: 2020-09-11Bibliographically approved
    4. Dermal exposure to cobalt: possible effects of cobalt exposure on inflammasome, cytokine and mRNA response studied in vitro in keratinocytes
    Open this publication in new window or tab >>Dermal exposure to cobalt: possible effects of cobalt exposure on inflammasome, cytokine and mRNA response studied in vitro in keratinocytes
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:oru:diva-85683 (URN)
    Available from: 2020-09-11 Created: 2020-09-11 Last updated: 2020-09-11Bibliographically approved
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    Cobalt in the hard metal production industry: exposure via inhalation and skin and the inflammatory response in human keratinocytes
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    Klasson, Maria