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  • 1. Acosta, Stefan
    et al.
    Block, Tomas
    Björnsson, Steinarr
    Resch, Timothy
    Björck, Martin
    Nilsson, Torbjörn K
    Department of Clinical Chemistry, Örebro University Hospital.
    Diagnostic pitfalls at admission in patients with acute superior mesenteric artery occlusion2012In: Journal of Emergency Medicine, ISSN 0736-4679, E-ISSN 1090-1280, Vol. 42, no 6, p. 635-641Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Acute superior mesenteric artery (SMA) occlusion leads to acute intestinal ischemia and is associated with high mortality. Early diagnosis is often missed, and confounding factors leading to diagnostic delays need to be highlighted. OBJECTIVES: To identify potential diagnostic laboratory pitfalls at admission in patients with acute SMA occlusion. METHODS: Fifty-five patients with acute SMA occlusion were identified from the in-hospital register during a 4-year period, 2005-2009. RESULTS: The median age was 76 years; 78% were women. The occlusion was embolic in 53% and thrombotic in 47% of patients. At admission, troponin I was above the clinical decision level (> 0.06 μg/L) for acute ischemic myocardial injury in 9/19 (47%) patients with embolic occlusion. Elevated pancreas amylase and normal plasma lactate were found in 12/45 and 13/27, respectively. A troponin I (TnI) above the clinical decision level was associated with a high frequency of referrals from the general surgeon to a specialist in internal medicine (p = 0.011) or a cardiologist (p = 0.024). The diagnosis was established after computed tomography angiography in 98% of the patients. The overall in-hospital mortality rate was 33%. Attempting intestinal revascularization (n = 43; p < 0.001), with a 95% frequency rate of completion control of the vascular procedure, was associated with a higher survival rate, whereas referral to the cardiologist was associated with a higher mortality rate (p = 0.018). CONCLUSION: Elevated TnI was common in acute SMA occlusion, and referral to the cardiologist was found to be associated with adverse outcome. Elevated pancreas amylase and normal plasma lactate values are also potential pitfalls at admission in patients with acute SMA occlusion.

  • 2. Acosta, Stefan
    et al.
    Nilsson, Torbjörn K
    Department of Clinical Chemistry, Örebro University Hospital.
    Current status on plasma biomarkers for acute mesenteric ischemia2012In: Journal of Thrombosis and Thrombolysis, ISSN 0929-5305, E-ISSN 1573-742X, Vol. 33, no 4, p. 355-361Article in journal (Refereed)
    Abstract [en]

    Clinical diagnosis of acute mesenteric ischemia is difficult. The aim of this review is to provide current status on the search for an accurate plasma biomarker for acute mesenteric ischemia. A search using the medical subject heading terms marker and mesenteric ischemia or intestinal ischemia or superior mesenteric artery occlusion or mesenteric venous thrombosis in the Medline and Embase databases from 1980 to 2011. Studies without a control group or a control group consisted of healthy individuals (human studies), or studies on intestinal reperfusion were excluded. Twenty animal and twelve human studies were identified. In human studies, the studied series of patients had a control group that had a need of laparotomy (n = 2), suspected acute mesenteric ischemia (n = 7), acute abdomen (n = 2) or systemic inflammatory response syndrome (n = 1). D: -dimer has been found to be the most consistent highly sensitive early marker, but specificity was low. The follow-up study on α-glutathione S-transferase yielded inferior sensitivity and accuracy than the preliminary study, clearly questioning the value of this marker. Intestinal fatty acid binding globulin (I-FABP) and D: -lactate are both interesting markers, but the results were conflicting. Different cut-off levels have been used in the studies on I-FABP. The encouraging preliminary result of cobalt-albumin and urinary FABP as an accurate marker needs to be addressed in other study populations. The early clinical and laboratory diagnosis of intestinal ischemia remains a challenge. None of the proposed plasma-derived tests for acute mesenteric ischemia has as yet entered routine clinical practice. The proposed biomarkers need to be evaluated in a prospective clinical research project in patients with acute abdomen.

  • 3. Almon, Ricardo
    et al.
    Alvarez-Leon, Eva E
    Engfeldt, Peter
    Serra-Majem, Lluís
    Magnuson, Anders
    Nilsson, Torbjörn K
    Department of Clinical Chemistry, Örebro University Hospital.
    Associations between lactase persistence and the metabolic syndrome in a cross-sectional study in the Canary Islands2010In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215, Vol. 49, no 3, p. 141-146Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The single nucleotide polymorphism (SNP) LCT -13910 C>T, associated with genetically determined phenotypes of lactase persistence (LP) or non-persistence (LNP), was studied in relation to the metabolic syndrome (MS).

    AIM OF THE STUDY: The aim was to determine if milk intake and MS are associated. We applied Mendelian randomization (MR). The SNP, LCT -13910 C>T, with the genotypes LP (TT/CT) and LNP (CC), was taken as a proxy for milk consumption.

    METHODS: A representative sample of adults belonging to the Canary Islands Nutrition Survey (ENCA) in Spain aged 18-75 years (n = 551) was genotyped for the LCT -13910 C>T polymorphism. We used the International Diabetes Federation (IDF) criteria to define MS.

    RESULTS: 60% of the population was LP and 40% LNP. One hundred seven LP subjects (35.0%) and 53 LNP subjects (25.6%) showed MS (chi (2) = 5.04, p = 0.025). LP subjects showed a significantly higher odds ratio (OR) for MS than LNP subjects computed for the whole population: both the crude OR (1.56; 95% CI 1.06-2.31) and adjusted OR for sex, age, daily energy intake, physical activity and educational level (1.57; 95% CI 1.02-2.43). Adjusted OR for women with LP was 1.93; 95% CI 1.06-3.52.

    CONCLUSIONS: The T allele of the SNP might constitute a nutrigenetic factor increasing the susceptibility of LP subjects, especially women, to develop MS in the Canary Islands.

  • 4. Almon, Ricardo
    et al.
    Nilsson, Torbjörn K
    Department of Laboratory Medicine, Clinical Chemistry, Örebro University Hospital, Örebro, Sweden.
    Sjöström, Michael
    Engfeldt, Peter
    Lactase persistence and milk consumption are associated with body height in Swedish preadolescents and adolescents2011In: Food & Nutrition Research, ISSN 1654-6628, E-ISSN 1654-661X, Vol. 55Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Body height is a classic polygenic trait. About 80%-90% of height is inherited and 10%-20% owed to environmental factors, of which the most important ones are nutrition and diseases in preadolescents and adolescents.

    OBJECTIVE: The aim of this study was to explore potential relations between the LCT (lactase) C>T-13910 polymorphism, milk consumption, and body height in a sample of Swedish preadolescents and adolescents.

    DESIGN: In a cross-sectional study, using a random sample of preadolescents and adolescents (n = 597), dietary intakes were determined. Anthropometric measurements including sexual maturity (Tanner stage) and birth weight were assessed. Parental body height and socio-economic status (SES) were obtained by questionnaires. Genotyping for the LCT C>T-13910 polymorphism that renders individuals lactase persistent (LP) or lactase non-persistent (LNP) was performed by DNA sequencing. Stepwise backward multivariate linear regression was used.

    RESULTS: Milk consumption was significantly and positively associated with body height (β = 0.45; 95% CI: 0.040, 0.87, p = 0.032). Adjustments were performed for sex, parental height, birth weight, body mass index (BMI), SES, and Tanner stage. This model explains 90% of the observed variance of body height (adjusted R(2) = 0.89). The presence of the -13910 T allele was positively associated with body height (β = 2.05; 95% CI: 0.18, 3.92, p = 0.032).

    CONCLUSIONS: Milk consumption is positively associated with body height in preadolescents and adolescents. We show for the first time that a nutrigenetic variant might be able to explain in part phenotypic variation of body height in preadolescents and adolescents. Due to the small sample size further studies are needed.

  • 5. Almon, Ricardo
    et al.
    Patterson, Emma
    Nilsson, Torbjörn K
    Department of Clinical Chemistry, Örebro University Hospital.
    Engfeldt, Peter
    Sjöström, Michael
    Body fat and dairy product intake in lactase persistent and non-persistent children and adolescents2010In: Food & Nutrition Research, ISSN 1654-6628, E-ISSN 1654-661X, Vol. 54, no 5141Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Lactase non-persistent (LNP) individuals may be lactose intolerant and therefore on a more restricted diet concerning milk and milk products compared to lactase persistent (LP) individuals. This may have an impact on body fat mass.

    OBJECTIVE: This study examines if LP and LNP children and adolescents, defined by genotyping for the LCT-13910 C > T polymorphism, differ from each other with regard to milk and milk product intake, and measures of body fat mass.

    DESIGN: Children (n=298, mean age 9.6 years) and adolescents (n=386, mean age 15.6 years), belonging to the Swedish part of the European Youth Heart Study, were genotyped for the LCT-13910 C > T polymorphism. Dietary intakes of reduced and full-fat dairy varieties were determined.

    RESULTS: LNP (CC genotype) subjects consumed less milk, soured milk and yoghurt compared to LP (CT/TT genotype) subjects (p<0.001). Subsequent partitioning for age group attenuated this observation (p=0.002 for children and p=0.023 in adolescents). Six subjects were reported by parents to be 'lactose intolerant', none of whom were LNP. LNP children and adolescents consumed significantly less reduced fat milk and milk products than LP children and adolescents (p=0.009 for children and p=0.001 for adolescents).

    CONCLUSIONS: We conclude that LP is linked to an overall higher milk and dairy intake, but is not linked to higher body fat mass in children and adolescents.

  • 6. Almon, Ricardo
    et al.
    Sjöström, Michael
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Department of Laboratory Medicine, Örebro University Hospital and Department of Biomedicine, School of Health and Medical Sciences, Örebro University.
    Lactase non-persistence as a determinant of milk avoidance and calcium intake in children and adolescents2013In: Journal of nutritional science, ISSN 2048-6790, Vol. 2, no e26, p. 1-5Article in journal (Refereed)
    Abstract [en]

    This study examines if lactase non-persistent (LNP) children and adolescents differ from those who are lactase persistent (LP) as regards milk avoidance and Ca intake. We also studied potential differences in anthropometric features related to obesity, and examined if milk avoidance is associated with lactasepersistence status. Additionally, we aimed to determine if heterozygous subjects showed an intermediary phenotype as regards Ca intake. Furthermore, we tested if LP and LNP influence vitamin D intake. The European Youth Heart Study is an ongoing international, multi-centre cohort study primarily designed to address CVD risk factors. Children (n 298, mean age 9·6 years) and adolescents (n 386, mean age 15·6 years) belonging to the Swedish part of the European Youth Heart Study were genotyped for the LCT-13910 C > T polymorphism. Mendelian randomisation was used. Milk avoidance was significantly more common in LNP adolescents (OR 3·2; 95% CI 1·5, 7·3). LP subjects had higher milk consumption (P < 0·001). Accordingly, energy consumption derived from milk and Ca intake was lower in LNP (P < 0·05 and P < 0·001, respectively). Heterozygous subjects did not show an intermediary phenotype concerning milk consumption. LP or LNP status did not affect vitamin D intake or anthropometric variables. LNP in children and adolescents is associated with reduced intake of milk and some milk-product-related nutritional components, in particular Ca. This reduced intake did not affect the studied anthropometric variables, indicators of body fat or estimated vitamin D intake. However, independently of genotype, age and sex, daily vitamin D intake was below the recommended intakes. Milk avoidance among adolescents but not children was associated with LNP.

  • 7. Altmäe, Signe
    et al.
    Stavreus-Evers, Anneli
    Ruiz, Jonatan R
    Laanpere, Margit
    Syvänen, Tiina
    Yngve, Agneta
    Salumets, Andres
    Nilsson, Torbjörn K
    Department of Clinical Chemistry, Örebro University Hospital.
    Variations in folate pathway genes are associated with unexplained female infertility2010In: Fertility and Sterility, ISSN 0015-0282, E-ISSN 1556-5653, Vol. 94, no 1, p. 130-137Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate associations between folate-metabolizing gene variations, folate status, and unexplained female infertility.

    DESIGN: An association study.

    SETTING: Hospital-based IVF unit and university-affiliated reproductive research laboratories.

    PATIENT(S): Seventy-one female patients with unexplained infertility.

    INTERVENTION(S): Blood samples for polymorphism genotyping and homocysteine, vitamin B12, and folate measurements.

    MAIN OUTCOME MEASURE(S): Allele and genotype frequencies of the following polymorphisms: 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C/T, 1298A/C, and 1793G/A, folate receptor 1 (FOLR1) 1314G/A, 1816delC, 1841G/A, and 1928C/T, transcobalamin II (TCN2) 776C/G, cystathionase (CTH) 1208G/T and solute carrier family 19, member 1 (SLC19A1) 80G/A, and concentrations of plasma homocysteine, vitamin B12, and serum folate.

    RESULT(S): MTHFR genotypes 677CT and 1793GA, as well as 1793 allele A were significantly more frequent among controls than in patients. The common MTHFR wild-type haplotype (677, 1298, 1793) CAG was less prevalent, whereas the rare haplotype CCA was more frequent in the general population than among infertility patients. The frequency of SLC19A1 80G/A genotypes differed significantly between controls and patients and the A allele was more common in the general population than in infertile women. Plasma homocysteine concentrations were influenced by CTH 1208G/T polymorphism among infertile women.

    CONCLUSION(S): Polymorphisms in folate pathway genes could be one reason for fertility complications in some women with unexplained infertility.

  • 8.
    Andersson, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hellsten, Gideon
    Nilsson, Torbjörn K
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Boman, Kurt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Effects of heavy endurance physical exercise on inflammatory markers in non-athletes2010In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 209, no 2, p. 601-605Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Physical activity has beneficial effects on cardiovascular disease but the mechanisms are still somewhat unclear. One possible pathway may be through the anti-inflammatory effects attributed to regular physical activity. Our primary aim was to study the effects of endurance physical exercise on C-reactive protein (CRP), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNFalpha) during the acute and recovery phases. Secondarily, we studied the impact of diet on these inflammatory markers.

    METHODS: Twenty men, aged 18-55 years, participated in a 14 days cross-country skiing tour. They traveled 12-30km per day corresponding to about 10h of heavy physical activity. The participants were randomized to a diet with either 30 or 40% of energy derived from fat. Inflammatory variables were analysed at week 0, after 1 and 2 weeks and during the recovery phase at week 6 and 8.

    RESULTS: CRP and TNFalpha increased significantly during the two weeks of exercise (1.4-5.0mg/l, p=0.00 and 6.8-8.4pg/ml, p=0.00). CRP levels were significantly lower during recovery (median 0.7mg/l) compared to baseline (median 1.4mg/l) and did not correlate to metabolic variables. There were no significant changes in IL-6 levels during the study period. For dietary groups significant CRP changes were observed only in the high fat group during recovery.

    CONCLUSIONS: CRP and TNFalpha increased significantly but reacted differently during heavy physical activity while there seemed to be no significant changes in IL-6. No significant differences regarding inflammatory variables were found between the dietary groups.

  • 9. Arfvidsson, Berndt
    et al.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Norgren, Lars
    S100B concentrations increase perioperatively in jugular vein blood despite limited metabolic and inflammatory response to clinically uneventful carotid endarterectomy2015In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 53, no 1, p. 111-117Article in journal (Refereed)
    Abstract [en]

    Background: Our aim was to test the hypothesis that metabolic and inflammatory responses of the brain perioperatively during carotid endarterectomy (CEA) might affect blood brain barrier (BBB) integrity. Methods: Twenty patients with >70% stenosis of internal carotid artery (ICA) were prospectively included. Surgery was performed under general anaesthesia. Blood was sampled from ipsilateral internal jugular vein and radial artery: just before, during, and after ICA clamping S100B protein, glucose, lactate, 20 amino acids, and key cytokines were analysed. Results: Jugular vein S100B increased during clamping and reperfusion, while a marginal systemic increase was recorded, unrelated to stump pressure during clamping. Glucose increased during clamping in jugular vein blood and even more systemically, while jugular lactate values were higher than systemic values initially. Most amino acids did not differ significantly between jugular vein and systemic levels: glutamic acid and aspartic acid decreased during surgery while asparagine increased. Jugular vein interleukin (IL)-6 showed a transient non-significant increase during clamping and decreased systemically. IL-8 and IL-10 increased over time. Conclusions: Rising jugular vein S100B concentrations indicated reduced BBB integrity, and marginal secondary increase of S100B systemically. Limited ischaemic effects on the brain during cross-clamping, unrelated to S100B concentrations, were confirmed by lower brain glucose levels and higher lactate levels than in systemic blood. The lack of increased jugular vein glutamic acid disproves any major ischaemic brain injury following CEA. The inflammatory response was limited, did not differ greatly between jugular and systemic blood, and was unrelated to S100B.

  • 10. Björck, M
    et al.
    Ravn, H
    Nilsson, Torbjörn K
    Department of Clinical Chemistry, Örebro University Hospital.
    Wanhainen, A
    Nilsson, P M
    Blood cell telomere length among patients with an isolated popliteal artery aneurysm and those with multiple aneurysm disease2011In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 219, no 2, p. 946-950Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Short relative telomere length (RTL) is associated with vascular ageing, inflammation and cardiovascular risk factors. Previous studies have reported an association between abdominal aortic aneurysm and short RTL. The presence of atherosclerosis among patients with aneurysm disease may, however, be a confounder. The aim was to explore the associations between short RTL and aneurysm disease, by comparing patients with isolated popliteal artery aneurysms with those having multiple aneurysms.

    DESIGN AND PATIENTS: DNA was retrieved from 183 patients with popliteal artery aneurysm (PAA). They were all examined with ultrasound at the time of blood-sampling, and had a total of 423 aneurysms (range 1-7, mean 2.3/patient).

    METHODS: TL was measured with Real-Time PCR, RTL was calculated by comparing with three reference populations.

    RESULTS: Patients with bilateral PAAs had a mean RTL of 0.985 vs. 1.038 with unilateral PAAs (P = 0.326). Patients with abdominal aortic aneurysm had RTL 1.035, vs. 0.999 without (P = 0.513). No difference was seen with or without femoral or iliac aneurysms. Fifty-six patients with isolated PAA at surgery and at re-examination had RTL 0.974, vs. 1.033 who had >1 aneurysm (P = 0.308). RTL was not associated with the number of aneurysms at re-examination (P = 0.727, one-way ANOVA). There was a trend towards shorter RTL among active smokers (0.93 vs. 1.04, P = 0.066).

    CONCLUSIONS: No association between short RTL and multiple aneurysm disease was found. The previously reported association between AAA and short RTL may be secondary to cardiovascular risk factors, rather than by aneurysm disease.

  • 11. Block, T
    et al.
    Isaksson, H S
    Acosta, S
    Björck, M
    Brodin, D
    Nilsson, Torbjörn K
    Department of Laboratory Medicine, Örebro University Hospital.
    Altered mRNA expression due to acute mesenteric ischaemia in a porcine model2011In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 41, no 2, p. 281-287Article in journal (Refereed)
    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(®) 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.

  • 12.
    Boman, Kurt
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, Torbjörn
    Swedberg, Karl
    Cleland, John G F
    Poole-Wilson, Philip
    Effects of carvedilol or metoprolol on PAI-1, tPA-mass concentration or Von Willebrand factor in chronic heart failure--a COMET substudy.2010In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 125, no 2, p. e46-50Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: In COMET (Carvedilol or Metoprolol European Trial), carvedilol reduced mortality compared with metoprolol in patients with chronic heart failure. We hypothesized that carvedilol might have greater effects on endothelial derived haemostatic factors than metoprolol. We aimed to study the effects of carvedilol or metoprolol on tissue plasminogen activator (tPA), its inhibitor PAI-1 and Von Willebrand factor (VWF) in patients with heart failure. MATERIAL AND METHODS: We recruited 260 patients (134 on carvedilol, 126 on metoprolol), mean age 66 years and 84% of them men. Plasma mass concentrations of tPA and PAI-1and percent of VWF were measured at baseline and after one and two years of treatment. RESULTS: Plasma tPA, PAI-1 and VWF were similar between treatment groups at baseline and no significant differences between groups emerged after one or two years of treatment. In paired analyses in patients assigned to carvedilol, median PAI-1 level decreased from 37.2 to 32.1 microg/l at two years (p=0.034) and of VWF decreased from baseline to one year (240 vs. 218%, p=0.023) in patients assigned to carvedilol but were not reduced at any time in patients assigned to metoprolol. Plasma tPA increased over time in both treatment groups (p=0.013 and 0.027 respectively). CONCLUSION: We found no significant difference in the effects of carvedilol or metoprolol on tPA, PAI-1 and VWF. Comparison over time within treatment groups suggested that PAI-1 and VWF might have declined on carvedilol but not on metoprolol. Our hypothesis is not proved but this may reflect an inadequate sample size rather than lack of an effect.

  • 13. Breimer, Lars H
    et al.
    Eriksson, Clas-Göran
    Nilsson, Torbjörn K
    Klinisk kemi, Laboratoriemedicinska länskliniken, Örebros universitetssjukhus, och Hälsoakademin, Örebro universitet, Örebro, Sverige.
    [Tomorrow's laboratory - already yesterday]2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 37, p. 1624-1624Article in journal (Refereed)
  • 14. Breimer, Lars H
    et al.
    Nilsson, Torbjörn K
    Örebro University Hospital, Örebro, Sweden.
    A longitudinal and cross-sectional study of Swedish biomedical PhD processes 1991-2009 with emphasis on international and gender aspects2010In: Scientometrics, ISSN 0138-9130, E-ISSN 1588-2861, Vol. 85, no 2, p. 401-414Article in journal (Refereed)
    Abstract [en]

    This longitudinal survey of Swedish biomedical PhDs from 1991 to 2009 found a 2.5-fold increase in biomedical PhD graduates, especially women, and mainly non-MDs, while the number of MDs remained fairly constant. The proportion obtaining a biomedical PhD in Sweden in 2006 was two and a half times that in USA compared to population and three and a half times by GDP, but similar to that of the Netherlands. Female non-MD but not female MD candidates were more likely than men to be examined by female examiners. Fewer of the non-MD than MD women continued to publish in English after their PhD. The median number of authors per paper in a thesis had increased by 1 (from 4 to 5) compared with 15–20 years ago. Swedish biomedical research was already well internationalized in 1991, when 38% of the external examiners came from abroad. This rose to 53% in 2003 but in 2009 had returned to 42%. USA and UK were the most common countries but Australia accounted for 2%. When assessed by connection with foreign research teams, Swedish researchers were also internationally well connected. Studies in other countries are needed to assess how generally applicable these findings are. Our findings suggest that the policy and management of Swedish scientific research systems needs revision to harmonize with the national economic capacity.

  • 15. Breimer, Lars H
    et al.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Considerations for appointing an external examiner of a PhD in the biomedical sciences in Sweden: a questionnaire-based survey2014In: Scientometrics, ISSN 0138-9130, E-ISSN 1588-2861, Vol. 98, no 3, p. 2039-2049Article in journal (Refereed)
    Abstract [en]

    A survey of 170 Swedish mentors of PhD-students found that expertise in the research field and avoidance of conflict of interest were big motivators for finding an examiner from abroad for PhD theses. The survey also identified that concern by supervisors for facilitating the career paths of younger scientists in terms of introductions to potential labs for post-doctoral work and obtaining high quality neutral review of one’s research was also important, as was the desire to set up collaborations. An expectation from the management of one’s university of the PR-value of a foreign senior person as examiner also played a part. Although few were willing to admit that PR for one’s own group was a motivating factor. A small fraction of responders expressed concern that, as some of the costs of the PhD-examination were being shifted on to the research groups themselves, this might impact the current situation. Language also played a subordinate role. To get the best out of the visiting examiner, it was important to educate and instruct them in their role in a Swedish PhD-examination protocol. Male supervisors had had more PhD-candidates than female, but they also had used more Sweden-based examiners than their female colleagues. We conclude that using a foreign examiner was motivated by factors that are likely to prevail for the foreseeable future. This Swedish practice may also provide a template for a common standard.

  • 16. Breimer, Lars H
    et al.
    Nilsson, Torbjörn K
    Departments of Laboratory Medicine, Örebro University Hospital; Departments of Clinical Medicine & Biomedicine, School of Health and Medical Sciences, Örebro University.
    Has folate a role in the developing nervous system after birth and not just during embryogenesis and gestation?2012In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 72, no 3, p. 185-191Article in journal (Refereed)
    Abstract [en]

    It is now 30 years since the first publications stating that supplementation with folate could prevent neural tube defects appeared and 20 years since the definitive data, including prevention of other birth defects. Since then epidemiological studies and animal experiments have identified folate as a molecule at the crossroads of neural development. Fortification of food has greatly reduced the incidence of spina bifida. Much interest has focussed on long-term sequelae in children born to mothers severely deprived of folate (and other nutrients) such as during the Dutch Hunger Winter of 1944 and in poor parts of the world. In addition, deficiency in folate and B12 are increasingly discussed as a possible contributing factor in dementia and congenital orofacial and heart malformations. The year 2011 saw the publication of a study that implicated low folate intake in poorer school performance of adolescents as judged by school marks. This has enormous social implications but needs confirmation from other settings. This review assesses the current state of evidence and sets the data in context of whether folate has a role in the development and plasticity of the nervous system even after birth, with particular emphasis on childhood and adolescence.

  • 17. Breimer, Lars H
    et al.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Is ferrotoxicity a new great public health challenge?2015In: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 61, no 4, p. 667-668Article in journal (Refereed)
  • 18. Breimer, Lars H
    et al.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Shedded cell membrane proteins in plasma: pure waste, or informative biomarkers of pathophysiological processes?2015In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 75, no 6, p. 441-443Article in journal (Other academic)
  • 19. Breimer, Lars
    et al.
    Nilsson, Torbjörn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    [Sweden should contemplate article in PNAS].2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 46, p. 2045-Article in journal (Refereed)
  • 20. Dzialanski, Zbigniew
    et al.
    Barany, Michael
    Engfeldt, Peter
    Magnuson, Anders
    Olsson, Lovisa A.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lactase persistence versus lactose intolerance: Is there an intermediate phenotype?2016In: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 49, no 3, p. 248-252Article in journal (Refereed)
    Abstract [en]

    Background: According to the prevailing theory about the genetic background to lactose intolerance, there are three genotypes but only two adult physiological phenotypes: lactase persistence in individuals with the CT and TT genotypes and lactase non-persistence in individuals with the CC genotype. However, analysis of lactase activity from intestinal biopsies has revealed three distinct levels of activity, suggesting that an intermediate physiological phenotype may exist. Aim: To assess possible disparities between different genotypes with regard to biomarkers of lactase activity and physical symptoms during an oral lactose load test. Methods: A retrospective study using an oral lactose load test (n = 487). Concentrations of hydrogen in exhaled air and blood glucose were measured. Afterwards, subjects were asked to provide oral mucosa samples for genotyping and answer a questionnaire (participation rate 56%, n = 274). Results: Mean hydrogen levels in exhaled air at 120 min were significantly higher in the CT genotype than in the TT genotype. There was no significant difference in blood glucose levels between the two groups. Reported symptoms, with the possible exception of abdominal pain, were equally prevalent in both groups. Conclusions: Subjects with the CT and TT genotypes, hitherto classified as lactase-persistent, differ in their physiological response to lactose intake, indicating differences in phenotype which could have clinical significance. 

  • 21. Farkas, Sanja A.
    et al.
    Befekadu, Rahel
    Hahn-Stroemberg, Victoria
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    DNA methylation and expression of the folate transporter genes in colorectal cancer2015In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 36, no 7, p. 5581-5590Article in journal (Refereed)
    Abstract [en]

    Folate has a central role in the cell metabolism. This study aims to explore the DNA methylation pattern of the folate transporter genes FOLR1, PCFT, and RFC1 as well as the corresponding protein expressions in colorectal cancer (CRC) tissue and adjacent non-cancerous mucosa (ANCM). Our results showed statistically significant differences in the DNA-methylated fraction of all three genes at several gene regions; we identified three differentially methylated CpG sites in the FOLR1 gene, five CpG sites in the PCFT gene, and six CpG sites in the RFC1 gene. There was a pronounced expression of the FR alpha and RFC proteins in both the CRC and ANCM tissues, though the expression was attenuated in cancer compared to the paired ANCM tissues. The PCFT protein was undetectable or expressed at a very low level in both tissue types. Higher methylated fractions of the CpG sites 3-5 in the RFC1 gene were associated with a lower protein expression, suggestive of epigenetic regulation by DNA methylation of the RFC1 gene in the colorectal cancer. Our results did not show any association between the RFC and FR alpha protein expression and tumor stage, TNM classification, or tumor location. In conclusion, this is the first study to simultaneously evaluate both DNA methylation and protein expression of all three folate transporter genes, FOLR1, PCFT, and RFC1, in colorectal cancer. The results encourage further investigation into the possible prognostic implications of folate transporter expression and DNA methylation.

  • 22. Farkas, Sanja A
    et al.
    Böttiger, Anna K
    Isaksson, Helena S
    Finnell, Richard H
    Ren, Aiguo
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Örebro Univ Hosp, Dept Lab Med, Örebro, Sweden.
    Epigenetic alterations in folate transport genes in placental tissue from fetuses with neural tube defects and in leukocytes from subjects with hyperhomocysteinemia2013In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 8, no 3, p. 303-316Article in journal (Refereed)
    Abstract [en]

    The objectives of this study were to identify tissue-specific differentially methylated regions (T-DMR's) in the folate transport genes in placental tissue compared with leukocytes, and from placental tissues obtained from normal infants or with neural tube defects (NTDs). Using pyrosequencing, we developed methylation assays for the CpG islands (CGIs) and the CGI shore regions of the folate receptor α (FOLR1), proton-coupled folate transporter (PCFT) and reduced folate carrier 1 (RFC1) genes. The T-DMRs differed in location for each gene and the difference in methylation ranged between 2 and 54%. A higher T-DMR methylated fraction was associated with a lower mRNA level of the FOLR1 and RFC1 genes. Methylation fractions differed according to RFC1 80G > A genotype in the NTD cases and in leukocytes from subjects with high total plasma homocysteine (tHcy). There were no differences in methylated fraction of folate transporter genes between NTD cases and controls. We suggest that T-DMRs participate in the regulation of expression of the FOLR1 and RFC1 genes, that the RFC1 80G > A polymorphism exerts a gene-nutrition interaction on DNA methylation in the RFC1 gene, and that this interaction appears to be most prominent in NTD-affected births and in subjects with high tHcy concentrations.

  • 23.
    Farkas, Sanja A
    et al.
    Department of Laboratory Medicine, Örebro University Hospital, Örebro.
    Milutin-Gašperov, Nina
    Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
    Grce, Magdalena
    Department of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Genome-wide DNA methylation assay reveals novel candidate biomarker genes in cervical cancer2013In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 8, no 11, p. 1213-1225Article in journal (Refereed)
    Abstract [en]

    The oncogenic human papilloma viruses (HPVs) are associated with precancerous cervical lesions and development of cervical cancer. The DNA methylation signatures of the host genome in normal, precancerous and cervical cancer tissue may indicate tissue-specific perturbation in carcinogenesis. The aim of this study was to identify new candidate genes that are differentially methylated in squamous cell carcinoma compared with DNA samples from cervical intraepithelial neoplasia grade 3 (CIN3) and normal cervical scrapes. The Illumina Infinium HumanMethylation450 BeadChip method identifies genome-wide DNA methylation changes in CpG islands, CpG shores and shelves. Our findings showed an extensive differential methylation signature in cervical cancer compared with the CIN3 or normal cervical tissues. The identified candidate biomarker genes for cervical cancer represent several types of mechanisms in the cellular machinery that are epigenetically deregulated by hypermethylation, such as membrane receptors, intracellular signaling and gene transcription. The results also confirm extensive hypomethylation of genes in the immune system in cancer tissues. These insights into the functional role of DNA methylome alterations in cervical cancer could be clinically applicable in diagnostics and prognostics, and may guide the development of new epigenetic therapies.

  • 24. Farkas, Sanja A.
    et al.
    Sorbe, Bengt G.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Epigenetic changes as prognostic predictors in endometrial carcinomas2017In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 12, no 1, p. 19-26Article in journal (Refereed)
    Abstract [en]

    Endometrial carcinoma is one of the most frequent gynecological malignancies of the female. The diagnostic and prognostic markers for the high-risk subgroups with unfavorable prognosis are under intense debate worldwide, and, therefore, the aim of this study was to identify new potential DNA methylation markers for the high-risk groups. We used the Illumina Infinium HumanMethylation450 BeadChip to analyze the DNA methylation pattern and investigated its association with clinicopathological features important for defining the high-risk (FIGO-grade 3) and low-risk (FIGO-grade 1) groups of patients with endometrial cancer (n = 31 and n = 39, respectively). We identified specific DNA methylation signature in high-risk endometrial tumors, and potential molecular biomarker genes (TBX2, CHST11, and NID2) associated with unfavorable clinical predictive and prognostic factors.

  • 25. Farkas, Sanja A.
    et al.
    Vymetalkova, Veronika
    Vodickova, Ludmila
    Vodicka, Pavel
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    DNA methylation changes in genes frequently mutated in sporadic colorectal cancer and in the DNA repair and Wnt/beta-catenin signaling pathway genes2014In: Epigenomics, ISSN 1750-1911, Vol. 6, no 2, p. 179-191Article in journal (Refereed)
    Abstract [en]

    Aim: The onset and progression of colorectal cancer (CRC) involves a cascade of genetic and/or epigenetic events. The aim of the present study was to address the DNA methylation status of genes relevant in colorectal carcinogenesis and its progression, such as genes frequently mutated in CRC, genes involved in the DNA repair and Wnt signaling pathway. Material & methods: We analyzed methylation status in totally 160 genes in 12 paired colorectal tumors and adjacent healthy mucosal tissues using the Illumina Infinium Human Methylation 450 BeadChip. Results: We found significantly aberrant methylation in 23 genes (NEIL1, NEIL3, DCLRE1C, NHEJ1, GTF2H5, CCNH, CTNNB1, DKK2, DKK3, FZD5 LRP5, TLE3, WNT2, WNT3A, WNT6, TCF7L1, CASP8, EDNRB1, GPC6, KIAA1804, MYO1B, SMAD2 and TTN). External validation by mRNA expression showed a good agreement between hypermethylation in cancer and down-regulated mRNA expression of the genes EDNRB1, GPC6 and SMAD2, and between hypomethylation and up-regulated mRNA expression of the CASP8 and DCLRE1C genes. Conclusion: Aberrant methylation of the DCLRE1C and GPC6 genes are presented here for the first time and are therefore of special interest for further validation as novel candidate biomarker genes in CRC, and merit further validation with specific assays.

  • 26. Gasperov, Nina Milutin
    et al.
    Farkas, Sanja A.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Grce, Magdalena
    Epigenetic activation of immune genes in cervical cancer2014In: Immunology Letters, ISSN 0165-2478, E-ISSN 1879-0542, Vol. 162, no 2, p. 256-257Article in journal (Refereed)
    Abstract [en]

    Immune system provides us protection from infectious pathogens and tumors formation during lifetime. Cervical cancer (CC), and its cause, human papillomavirus (HPV) are both challenges for the immune system. We present here evidence of epigenetic activation of immune system genes in CC. Illumina Infinium Human Methylation 450 K BeadChip identified genes, which were all significantly hypomethylated in CC tissue versus normal tissue. The GeneMANIA computer program identified a tight network between those genes. The most strongly correlated genes based on their function are immune effectors' process (AIM2, BST2, BTN3A3, and IL12RB1) and response to virus related genes (AIM2, BST2, and IL12RB1). Thus, activation of those genes through demethylation is probably triggered by HPV oncogenes. In conclusion, the immune system of women who do not develop CC is probably activated earlier through DNA demethylation.

  • 27. Geoghegan, Fintan
    et al.
    Buckland, Robert J.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Rogers, Eric T.
    Khalifa, Karima
    O'Connor, Emma B.
    Rooney, Mary F.
    Behnam-Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Porter, Richard K.
    Bioenergetics of acquired cisplatin resistant H1299 non-small cell lung cancer and P31 mesothelioma cells2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 55, p. 94711-94725Article in journal (Refereed)
    Abstract [en]

    Acquired cisplatin resistance is a common feature of tumours following cancer treatment with cisplatin and also of non-small cell lung cancer (H1299) and mesothelioma (P31) cell lines exposed to cisplatin. To elucidate the cellular basis of acquired cisplatin resistance, a comprehensive bioenergetic analysis was undertaken. We demonstrate that cellular oxygen consumption was significantly decreased in cisplatin resistant cells and that the reduction was primarily due to reduced mitochondrial activity as a result of reduced mitochondrial abundance. The differential mitochondrial abundance was supported by data showing reduced sirtuin 1 (SIRT1), peroxisome-proliferator activator receptor-gamma co-activator 1-alpha (PGC1 alpha), sirtuin 3 (SIRT3) and mitochondrial transcription factor A (TFAM) protein expression in resistant cells. Consistent with these data we observed increased reactive oxygen species (ROS) production and increased hypoxia inducible factor 1-alpha (HIF1 alpha) stabilization in cisplatin resistant cells when compared to cisplatin sensitive controls. We also observed an increase in AMP kinase subunit alpha 2 (AMPK alpha 2) transcripts and protein expression in resistant H1299 cells. mRNA expression was also reduced for cisplatin resistant H1299 cells in these genes, however the pattern was not consistent in resistant P31 cells. There was very little change in DNA methylation of these genes, suggesting that the cells are not stably reprogrammed epigenetically. Taken together, our data demonstrate reduced oxidative metabolism, reduced mitochondrial abundance, potential for increased glycolytic flux and increased ROS production in acquired cisplatin resistant cells. This suggests that the metabolic changes are a result of reduced SIRT3 expression and increased HIF-1 alpha stabilization.

  • 28. Gustafsson, Dan
    et al.
    Breimer, Lars H
    Isaksson, Helena S
    Nilsson, Torbjörn K
    Department of Laboratory Medicine, and Department of Clinical Medicine & Biomedicine, Örebro University, Örebro, Sweden.
    Tissue zinc levels in a child with hypercalprotectinaemia and hyperzincaemia: a case report and a review of the literature2012In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 72, no 1, p. 34-38Article in journal (Refereed)
    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 μmol/L. Zn levels in her hair (102 μg/g), nail (90 μg/g) and urine (3-12 μmol/L; 20-80 μg/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.

  • 29. Hagnelius, Nils-Olof
    et al.
    Boman, Kurt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, Torbjörn K
    Fibrinolysis and von Willebrand factor in Alzheimer's disease and vascular dementia - a case-referent study.2010In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 126, no 1, p. 35-38Article in journal (Refereed)
  • 30. Hagnelius, Nils-Olof
    et al.
    Wahlund, Lars-Olof
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Blood Concentrations of Homocysteine and Methylmalonic Acid among Demented and Non-Demented Swedish Elderly with and without Home Care Services and Vitamin B(12) Prescriptions2012In: Dementia and geriatric cognitive disorders extra, ISSN 1664-5464, Vol. 2, no 1, p. 387-99Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Total plasma homocysteine (tHcy) has been suggested as a risk factor of dementia. Our aim was to investigate potential differences in tHcy status in relation to the prescription of vitamin B(12) and dementia diagnosis. We examined whether vitamin B(12) prescriptions, a family history of dementia, or the need for home care service might be associated with tHcy values. METHODS: A cross-sectional monocenter study comprising 926 consecutive subjects attending our Memory Care Unit was conducted. RESULTS: Demented subjects being prescribed vitamin B(12) had higher serum vitamin B(12) (p = 0.025) but also higher tHcy (p < 0.001) and serum methylmalonate (p = 0.032), and lower serum folate (p < 0.001) than those who did not receive vitamin B(12) prescriptions. tHcy levels were significantly higher in non-demented subjects receiving home care service (p = 0.007). This group also had lower serum albumin (dementia: p < 0.001; non-dementia: p = 0.004). There was no difference in renal function (estimated glomerular filtration rate) in demented or non-demented subjects with or without vitamin B(12) prescriptions (dementia with/without vitamin B(12) prescription: p = 0.561; non-dementia with/without vitamin B(12) prescription: p = 0.710). CONCLUSION: Despite vitamin B(12) prescriptions, demented subjects had higher tHcy and methylmalonate values. The elevated metabolite values could not be explained by differences in renal function. Thus, elderly subjects on vitamin B(12) prescription appear to have unmet nutritional needs.

  • 31. Hahn-Stromberg, Victoria
    et al.
    Askari, Shlear
    Befekadu, Rahel
    Matthiessen, Peter
    Karlsson, Sune
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Polymorphisms in the CLDN1 and CLDN7 genes are related to differentiation and tumor stage in colon carcinoma2014In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 122, no 7, p. 636-642Article in journal (Refereed)
    Abstract [en]

    Tight junction is composed of transmembrane proteins important for maintaining cell polarity and regulating ion flow. Among these proteins are the tissue-specific claudins, proteins that have recently been suggested as tumor markers for several different types of cancer. An altered claudin expression has been observed in colon, prostatic, ovarian, and breast carcinoma. The aim of this study was to analyze the allele frequencies of three common single nucleotide polymorphisms (SNPs) in the genes for claudin 1 and claudin 7 in colon cancer (CC) patients and in a control population of healthy blood donors. Pyrosequencing was used to genotype the CLDN1 SNP rs9869263 (c.369C>T), and the CLDN7 SNPs rs4562 (c.590C>T) and rs374400 (c.606T>G) in DNA from 102 formalin fixed paraffin embedded (FFPE) colon cancer tissue, and 111 blood leukocyte DNA from blood/plasma donors. These results were correlated with clinical parameters such as TNM stage, tumor localization, tumor differentiation, complexity index, sex, and age. We found that there was a significant association between the CLDN1 genotype CC in tumor samples and a higher risk of colon cancer development (OR 3.0, p < 0.001). We also found that the CLDN7 rs4562 (c.590C>T) genotype CT had a higher risk of lymph node involvement (p = 0.031) and a lower degree of tumor differentiation (p = 0.028). In the control population, the allele frequencies were very similar to those in the HapMap cohort for CLDN7. The CLDN1 rs9869263 genotype (c.369C>T) was related to increased risk of colon cancer, and the CLDN7 rs4562 genotype (c.590C>T) was related to tumor differentiation and lymph node involvement in colon carcinoma. Further studies are warranted to ascertain their potential uses as biomarkers predicting tumor development, proliferation, and outcome in this disease.

  • 32. Hahn-Strömberg, Victoria
    et al.
    Askari, Shlear
    Ahmad, Abrar
    Befekadu, Rahel
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Expression of claudin 1, claudin 4, and claudin 7 in colorectal cancer and its relation with CLDN DNA methylation patterns2017In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 39, no 4, article id 697569Article in journal (Refereed)
    Abstract [en]

    Altered claudin expression has been described in colon, prostatic, ovarian, and breast carcinoma. However, the role of epigenetic modifications in these genes and their role in colorectal cancer is unknown. We aimed our study to investigate whether claudin protein expression and methylation of CLDN can influence the tumorigenesis of colorectal cancer. A total of 31 patients diagnosed with colorectal carcinoma was used in this study. Immunohistochemical staining was used to study protein expression in both tumor and the adjacent nonneoplastic mucosa of claudin 1, 4, and 7. To detect the DNA methylation pattern of CLDN1, 4, and 7, genomic DNA was extracted from both the tumor and the adjacent nonneoplastic mucosa. Methylation analysis was carried out using bisulfite pyrosequencing. Cell membrane staining intensity of all claudins was found significantly lower in colorectal cancer tissues when compared to paired normal mucosa (p = 0.001). For claudin 4, the percentage of cells staining positively was also significantly reduced (p = 0.04). In normal mucosa, cytoplasm showed no staining for claudins in any patient, whereas in paired colorectal cancer tissues, significant cytoplasmic staining appeared both for claudin 1 (p = 0.04) and claudin 4 (p = 0.01). Tumor samples were significantly hypomethylated in CLDN1 (p < 0.05). In conclusion, our results show that CLDN1 is significantly hypomethylated in tumor samples and that the membrane staining intensity for claudin 1, 4, and 7 is significantly lower in colorectal cancer tissues than in adjacent nonneoplastic tissue. Colorectal cancer cells showed dystopic cytoplasmic location of claudins.

  • 33.
    Hernestål-Boman, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Individual PAI-1 increase over nine years relates differently in men and women to changes in anthropometric, glycaemic, inflammatory and lipid markers.Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Levels of plasminogen activator inhibitor-1 (PAI-1) is known to correlate to factors related to the metabolic syndrome. We have previously shown that PAI-1 antigen increased by 75% in men and 95% in women over nine years.

    Objective: The aim of this study was to explore relationships between intra-individual changes in PAI-1 and changes in anthropometric measurements, blood pressure, glycaemic, lipid and inflammatory markers, separately for men and women.

    Method: In northern Sweden, 125 men and 116 women were examined first in 1990 and re-examined in 1999 during the morning hours. Changes over time (Δ) were calculated as the value at 1999 minus the value at 1990.

    Results: In men, ΔPAI-1 was significantly correlated to ΔBMI (r =0.33), ΔCRP (r =0.25), Δtriglycerides (r =0.39), Δfasting plasma glucose (r =0.41) and Δ2-hour plasma glucose (r =0.29). In women, ΔPAI-1 was significantly correlated to ΔBMI (r =0.36), Δwaist circumference (r =0.38), Δhip circumference (r =0.27), ΔCRP (r =0.27) and Δtotal cholesterol (r =0.19). The multivariate linear regression analysis showed that ΔPAI-1 was significantly related to Δfasting plasma glucose and ΔCRP in men (R2 for the complete model was 0.31). In women, ΔPAI-1 was significantly related to Δwaist circumference (R2 for the complete model was 0.17).

    Conclusion: We expected that changes in anthropometric, glycaemic, inflammatory and lipid markers would explain a large part of the observed PAI-1 increase. However, the multivariate analysis explained only 20% of the variation in ΔPAI-1 in women and 30% in men. Interestingly, the patterns of components correlating with the changes in PAI-1 differed between sexes.

  • 34.
    Hernestål-Boman, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, Torbjörn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Individual changes in fibrinolytic factors, von Willebrand factor, and C-reactive protein over a nine-year period.Manuscript (preprint) (Other academic)
    Abstract [en]

    Background: Intra-individual changes in haemostatic factor concentrations over time are unknown, in the general population.

    Objective: To describe intra-individual longitudinal changes in tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), tPA/PAI-1 complex, von Willebrand factor (VWF), and C-reactive protein (CRP) over nine years, in different age groups, stratified for sex.

    Methods: The MONICA survey in 1990 examined randomly selected men and women in four age groups (25–64 years) who were re-examined in 1999. A total of 309 individuals donated venous blood samples in Stabilyte tubes for both surveys during the morning hours, after an overnight fast. We analysed tPA activity and antigens of tPA, PAI-1, tPA/PAI-1 complex, VWF, and CRP.

    Results: Over nine years, in both men and women, we found significant intra-individual increases in the antigen levels of tPA, PAI-1, tPA/PAI-1 complex, VWF, and CRP (P < 0.001). PAI-1 antigen levels increased by 75% for men and 95% for women. Compared to men, women had a significantly higher CRP increase (0.92 vs. 0.22 mg/L; P = 0.044). The P for trend for mean Δ1999–1990 across age groups showed a significant linear trend for VWF (P = 0.001 for men; P < 0.001 for women), but not for the other studied variables.

    Conclusions: There were intra-individual longitudinal increases in the antigen levels of tPA, PAI-1, tPA/PAI-1 complex, VWF, and CRP over nine years in both men and women, with PAI-1 showing the highest relative increase. VWF increased significantly across age groups; however, fibrinolytic variables did not.

  • 35.
    Hernestål-Boman, Jenny
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Long-term stability of fibrinolytic factors stored at -80 degrees C.2010In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 125, no 5, p. 451-456Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Blood samples in epidemiological studies are often stored for several years and analysed at different occasions. The reagent kits are continually modified for better precision and accuracy. Our hypothesis was that epidemiological studies are affected by long-term storage and/or modifications of reagent kits.

    MATERIALS AND METHODS: Plasma samples stored at -80( degrees )C from two populations were used: A case-referent study with samples collected from 1985 to 2000 and analysed 2005 (n=1598) were used to study influence of long-term storage. A cross-sectional study analysed 1990 (n=1558) and re-analysed 2001 (n=78) and 2005 (n=828) was used to study influence of reagent kit modifications. Fibrinolytic analyses included immunoassays of tPA, PAI-1 and tPA-PAI-1 complex and chromogenic substrate assays of the activities of tPA and PAI-1.

    RESULTS: Long-term storage for a median time of 11.6years (range 5 to 20) showed an effect of time on tPA antigen R(2)=0.01, PAI-1 antigen R(2)=0.01 and tPA-PAI-1 complex R(2) = 0.02. Modifications in reagent kits affected the levels of fibrinolytic factors; for tPA antigen the slope coefficients were between 0.72 and 0.95 (R(2) 0.47 - 0.75), whereas tPA activity showed an agreement with slope coefficients 1.06 to 1.09 (R(2) 0.67 - 0.93).

    CONCLUSIONS: This study showed that long-term storage affects fibrinolytic variables to a negligible extent, but modifications in reagent kits introduced an element of bias. We conclude that analysis of samples on a single occasion is preferable to multiple occasions, as storage has negligible effect.

  • 36.
    Hultdin, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Winkvist, Anna
    Department of Clinical Nutrition, Göteborg University, Gothenburg, Sweden.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, Torbjörn K.
    Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Prospective study of first stroke in relation to plasma homocysteine and MTHFR 677C > T and 1298A > C genotypes and haplotypes: evidence for an association with hemorrhagic stroke2011In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 49, no 9, p. 1555-1562Article in journal (Refereed)
    Abstract [en]

    Background: Abnormalities in homocysteine metabolism have been suggested as risk factors for stroke. The aim of this prospective study was to examine whether total plasma homocysteine concentration (tHcy) and its main genetic determinant, methylene tetrahydrofolate reductase (MTHFR) polymorphisms, were associated with first ischemic or hemorrhagic stroke.

    Methods: This was a nested case-referent study of 321 ischemic and 60 hemorrhagic stroke cases, defined by WHO MONICA criteria and each matched with two event-free referents for sex, age, cohort, recruitment date and geographical area. All subjects were from the population-based Northern Sweden Health and Disease Study cohorts. Odds ratios were determined by conditional logistic regression.

    Results: The mean follow-up time was 4.2 years. Both tHcy and MTHFR were independent predictors of hemorrhagic stroke in multivariate models including body mass index, hypertension and, for MTHFR, tHcy [OR for the highest vs. lowest tHcy quartile 8.13 (95% CI 1.83-36.1), p(trend)=0.002; OR for MTHFR 677TT vs. 677CC genotype 3.62 (95% CI 0.77-17.0), p(trend)=0.040]. Haplotype analyses confirmed that the MTHFR 677T-1298A haplotype was positively associated with hemorrhagic stroke [OR 1.81 (95% CI 1.09-3.00), p=0.022], whereas the MTHFR 677C-1298C haplotype was not significantly related to either hemorrhagic or ischemic stroke. Neither tHcy nor the MTHFR polymorphisms were significant predictors of ischemic stroke.

    Conclusion: Both elevated plasma homocysteine levels and the MTHFR 677T allele are indicators of increased risk of hemorrhagic stroke in the northern Swedish population.

  • 37. Isaksson, H. S.
    et al.
    Farkas, S. A.
    Mueller, P.
    Gustafsson, D.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Whole genome microarray expression analysis in blood identifies pathways linked to signs and symptoms of a patient with hypercalprotectinaemia and hyperzincaemia2018In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 191, no 2, p. 240-251Article in journal (Refereed)
    Abstract [en]

    A child, 2 years with the hypercalprotectinaemia with hyperzincaemia' clinical syndrome, presented with atypical symptoms and signs, notably persistent fever of approximately 38 degrees C, thrombocythaemia of >700x10(9)/l and a predominance of persistent intestinal symptoms. In an effort to find a cure by identifying the dysregulated pathways we analysed whole-genome mRNA expression by the Affymetrix HG U133 Plus 20 array in blood on three occasions 3-5 months apart. Major up-regulation was demonstrated for the Janus kinase/signal transducer and activators of transcription (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 high mobility group box 1 (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 work-up 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.

  • 38. Isaksson, Helena S
    et al.
    Sorbe, Bengt
    Nilsson, Torbjörn K
    Department of Clinical Chemistry, Örebro University Hospital.
    Whole blood RNA expression profiles in ovarian cancer patients with or without residual tumors after primary cytoreductive surgery2012In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 27, no 5, p. 1331-1335Article in journal (Refereed)
    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, α-catenin, interleukin 1β, the KiSS-1 metastasis suppressor and the matrix metallo-proteinase 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.

  • 39. Isaksson, Helena S.
    et al.
    Sorbe, Bengt
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Whole genome expression profiling of blood cells in ovarian cancer patients: prognostic impact of the CYP1B1, MTSS1, NCALD, and NOP14 genes2014In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 12, p. 4040-4049Article in journal (Refereed)
    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.

  • 40.
    Johansson, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Bylesjö, Ingemar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Lind, Marcus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Factor XII as a Risk Marker for Hemorrhagic Stroke: A Prospective Cohort Study2017In: Cerebrovascular diseases extra, ISSN 1664-5456, Vol. 7, no 1, p. 84-94Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Coagulation factor XII (FXII) is involved in pathological thrombus formation and is a suggested target of anticoagulants. It is unclear whether FXII levels are correlated with cardiovascular risk factors and whether they are associated with myocardial infarction or ischemic or hemorrhagic stroke. The aim of this study was to investigate the correlation between FXII and cardiovascular risk factors in the general population. We also aimed to study the associations between FXII levels and future myocardial infarction and ischemic and hemorrhagic stroke.

    METHODS: This prospective cohort study measured FXII levels in 1,852 randomly selected participants in a health survey performed in northern Sweden in 1994. Participants were followed until myocardial infarction, stroke, death, or until December 31, 2011.

    RESULTS: During the median follow-up of 17.9 years, 165 individuals were diagnosed with myocardial infarction, 108 with ischemic stroke, and 30 with hemorrhagic stroke. There were weak correlations between FXII and body mass index, cholesterol, and hypertension. There was no association between FXII and myocardial infarction or ischemic stroke, neither in univariable Cox regression analysis nor after adjustment for age, sex, smoking, body mass index, cholesterol, hypertension, and diabetes. In univariable Cox regression analysis, the hazard ratio for the association between FXII levels and hemorrhagic stroke was 1.42 per SD (95% confidence interval: 0.99-2.05). In the multivariable model, higher levels of FXII were associated with increased risk of hemorrhagic stroke (hazard ratio 1.51 per SD; 95% confidence interval: 1.03-2.21).

    CONCLUSION: We found an independent association between FXII levels and the risk of hemorrhagic stroke, but not between FXII levels and ischemic stroke or myocardial infarction.

  • 41.
    Johansson, Kristina
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lind, Marcus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    D-Dimer is associated with first-ever intracerebral hemorrhage: a nested case-control study2018In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 49, no 9, p. 2034-2039Article in journal (Refereed)
    Abstract [en]

    Background and Purpose - Hypertension is the most important risk factor for intracerebral hemorrhage (ICH), but further characterization is needed for groups at high risk of ICH. One way to predict the risk of developing a disease is with plasma biomarkers. This study aimed to investigate the association between the biomarker, D-dimer, and ICH risk.

    Methods - This population-based, nested case-control study was conducted using data from 2 population-based surveys; the Vasterbotten Intervention Programme and MONICA Northern Sweden (Monitoring Trends and Determinants in Cardiovascular Disease). All participants underwent a health examination and blood sampling at baseline before the event. Cases (n=141) were diagnosed with a first-ever ICH between 1985 and March 2007. One or 2 controls (n=255) were matched to each case.

    Results - The median age was 60 years; 39% of participants were women; and the median time from blood sampling to ICH was 5.2 years. When D-dimer was evaluated as a continuous variable, it was significantly associated with ICH. After multivariable adjustment (for hypertension, body mass index, cholesterol levels, diabetes mellitus, and smoking), the odds ratio was 1.36 per SD of D-dimcr (95% CI, 1.05-1.77). When participants were stratified in 3 groups according to time from blood sampling at health examination to ICH, we found that the association between D-dimer levels and ICH was most pronounced in individuals with the shortest time from blood sampling to ICH event (<3.5 years; odds ratio, 1.78; 95% CI, 1.05-3.05).

    Conclusions - High plasma concentrations of D-dimer were associated with increased risk of a future ICH, after adjusting for cardiovascular risk factors. This association was predominantly driven by the cases with the shortest time from blood sampling to ICH event.

  • 42. Jonsson, T. B.
    et al.
    Nilsson, Torbjörn K
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Breimer, L. H.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Arfvidsson, B.
    Norgren, L.
    Cloxacillin concentrations in serum, subcutaneous fat, and muscle in patients with chronic critical limb ischemia2014In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 70, no 8, p. 957-963Article in journal (Refereed)
    Abstract [en]

    Patients suffering from critical limb ischemia (CLI) have poor wound healing in the ankle and foot areas. Secondary wound infections are frequent and often treated with prolonged courses of antibiotics. This study set out to investigate to what extent the unbound fraction of 4 g of cloxacillin i.v. reaches its target organ in poorly vascularized tissues, i.e., the calf and foot of patients suffering from CLI. Cloxacillin concentrations were measured by HPLC in serum and in microdialysis samples from skin and muscle of the lower part of the calf and as reference subcutaneously at the pectoral level in eight patients suffering from CLI (four males, four females, mean age 78 years, range 66-85 years) and in three healthy controls (two females, one male, mean age 67, range 66-68 years). In patients suffering from CLI, the tissue penetration of cloxacillin after a single 4 g dose was comparable to that of healthy controls, despite impaired blood circulation. The reduced blood flow in the peripheral vessels of the CLI patients presented here apparently is not the rate-limiting factor for delivery or tissue penetration of cloxacillin.

  • 43.
    Keskin, Isil
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Berdynski, Mariusz
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Polish Academy of Sciences, Warsaw, Poland.
    Hjertkvist, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Glass, Jonathan D.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Comprehensive analysis to explain reduced or increased SOD1 enzymatic activity in ALS patients and their relatives2017In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, no 5-6, p. 457-463Article in journal (Refereed)
    Abstract [en]

    Objective: To characterise stabilities in erythrocytes of mutant SOD1 proteins, compare SOD1 enzymatic activities between patients with different genetic causes of ALS and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations.Methods: Blood samples from 4072 individuals, ALS patients with or without a SOD1 mutation, family members and controls were studied. Erythrocyte SOD1 enzymatic activities normalised to haemoglobin content were determined, and effects of haemoglobin disorders on dismutation assessed. Coding SOD1 sequences were analysed by Sanger sequencing, exon copy number variations by fragment length analysis and by TaqMan Assay.Results: Of the 44 SOD1 mutations found, 75% caused severe destabilisation of the mutant protein but in 25% it was physically stable. Mutations producing structural changes caused halved erythrocyte SOD1 activities. There were no differences in SOD1 activities between patients without a SOD1 mutation and control individuals or carriers of TBK1 mutations and C9orf72(HRE). In the low and high SOD1 activity groups no deviations were found in exon copy numbers and intron gross structures. Thalassemias and iron deficiency were associated with increased SOD1 activity/haemoglobin ratios.Conclusion: Adjunct erythrocyte SOD1 activity analysis reliably signals destabilising SOD1 mutations including intronic mutations that are missed by exon sequencing.

  • 44.
    Keskin, Isil
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Berdynski, Mariusz
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hjertkvist, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Rofougaran, Reza
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Glass, Jonathan D.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Comprehensive analysis to explain reduced or increased SOD1 enzymatic activity in erythrocytes in ALS patients and their relativesManuscript (preprint) (Other academic)
    Abstract [en]

    Our objective was to in blood samples from 3723 individuals including ALS patients without a coding SOD1 mutation and 372 control individuals characterize stabilities of mutant SOD1s, compare SOD1 enzymatic activities between patients with different genetic causes of ALS, and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations. Erythrocyte SOD1 enzymatic activities normalized to hemoglobin content were determined. Coding SOD1 sequences were analyzed by Sanger sequencing, copy number variations by fragment length analysis and by TaqMan Assay. Hemoglobin disorders were searched for. Of the 46 SOD1 mutations found, ¾ caused severe destabilization of the mutant protein but in ¼ SOD1 was essentially physically stable. Mutations producing structural changes all caused halved SOD activities. There were no differences in SOD1 activities between controls and patients without any detected SOD1 mutations or patients with C9ORF72HRE or TBK1 mutations. In the low and high SOD1 activity groups no deviations were found in exon copy numbers and intron gross structures. Also, no uncommon variants in exon-flanking sequences were detected. Thalassemias and iron deficiency anemia were associated with increased SOD1 activity/hemoglobin ratios. In conclusion, adjunct erythrocyte SOD activity analysis is of value to signal the presence of exon and splice-site-intron mutations that influence the SOD1 structure.

  • 45. Kim, Jimi
    et al.
    Lei, Yunping
    Guo, Jin
    Kim, Sung-Eun
    Wlodarczyk, Bogdan J.
    Cabrera, Robert M.
    Lin, Ying Linda
    Nilsson, Torbjörn K.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Zhang, Ting
    Ren, Aiguo
    Wang, Linlin
    Yuan, Zhengwei
    Zheng, Yu-Fang
    Wang, Hong-Yan
    Finnell, Richard H.
    Formate rescues neural tube defects caused by mutations in Slc25a322018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 18, p. 4690-4695Article in journal (Refereed)
    Abstract [en]

    Periconceptional folic acid (FA) supplementation significantly reduces the prevalence of neural tube defects (NTDs). Unfortunately, some NTDs are FA resistant, and as such, NTDs remain a global public health concern. Previous studies have identified SLC25A32 as a mitochondrial folate transporter (MFT), which is capable of transferring tetrahydrofolate (THF) from cellular cytoplasm to the mitochondria in vitro. Herein, we show that gene trap inactivation of Slc25a32 (Mft) in mice induces NTDs that are folate (5-methyltetrahydrofolate, 5-mTHF) resistant yet are preventable by formate supplementation. Slc25a32gt/gt embryos die in utero with 100% penetrant cranial NTDs. 5-mTHF supplementation failed to promote normal neural tube closure (NTC) in mutant embryos, while formate supplementation enabled the majority (78%) of knockout embryos to complete NTC. A parallel genetic study in human subjects with NTDs identified biallelic loss of function SLC25A32 variants in a cranial NTD case. These data demonstrate that the loss of functional Slc25a32 results in cranial NTDs in mice and has also been observed in a human NTD patient.

  • 46. Laanpere, M
    et al.
    Altmäe, S
    Kaart, T
    Stavreus-Evers, A
    Nilsson, Torbjörn K
    Department of Clinical Chemistry, Örebro University Hospital.
    Salumets, A
    Folate-metabolizing gene variants and pregnancy outcome of IVF2011In: Reproductive Biomedicine Online, ISSN 1472-6483, E-ISSN 1472-6491, Vol. 22, no 6, p. 603-614Article in journal (Refereed)
    Abstract [en]

    There is growing evidence that folate status and variation in folate-metabolizing genes are involved in female reproductive functions. This study evaluated the influence of maternal blood folate, vitamin B(12), homocysteine and 10 folate pathway gene variants on IVF outcome. Also, the prevalence of these polymorphisms was compared in 439 female IVF patients and 225 fertile controls. MTHFR 677 CT heterozygotes had a higher proportion of good-quality embryos and an increased chance of pregnancy. MTHFR 1793 GA heterozygosity was associated with a lower percentage of previously failed IVF treatments. Heterozygosity for FOLR1 1816 C/delC and 1841 G/A was associated with a raised risk of pregnancy loss. The CTH 1208 GT genotype was associated with an increased chance of pregnancy and a smaller number of previously failed IVF cycles and the genotype frequency was lower in IVF patients with three or more previously failed IVF treatments compared with fertile controls. SLC19A1 80 GA heterozygotes had a decreased number of previously failed IVF treatments and were more prevalent among fertile controls. In conclusion, polymorphisms in folate-metabolizing genes may affect ovarian stimulation and pregnancy outcome of IVF, and heterozygous individuals, rather than the wild-type homozygotes, appeared to have more favourable outcomes.

  • 47. Laanpere, Margit
    et al.
    Altmäe, Signe
    Stavreus-Evers, Anneli
    Nilsson, Torbjörn K
    Department of Clinical Chemistry, Örebro University Hospital.
    Yngve, Agneta
    Salumets, Andres
    Folate-mediated one-carbon metabolism and its effect on female fertility and pregnancy viability2010In: Nutrition reviews, ISSN 0029-6643, E-ISSN 1753-4887, Vol. 68, no 2, p. 99-113Article in journal (Refereed)
    Abstract [en]

    This review summarizes current knowledge of the effect of folate-mediated one-carbon metabolism and related genetic variants on female fertility and pregnancy viability. Insufficient folate status disrupts DNA methylation and integrity and increases blood homocysteine levels. Elevated levels of follicular fluid homocysteine correlate with oocyte immaturity and poor early embryo quality, while methylenetetrahydrofolate reductase (MTHFR) gene variants are associated with lower ovarian reserves, diminished response to follicular stimulation, and reduced chance of live birth after in vitro fertilization. Embryos carrying multiple MTHFR variants appear to have a selective disadvantage; however, the heterozygous MTHFR 677CT genotype in the mother and fetus provides the greatest chance for a viable pregnancy and live birth, possibly due to a favorable balance in folate cofactor distribution between methyl donor and nucleotide synthesis. The results of previous studies clearly emphasize that imbalances in folate metabolism and related gene variants may impair female fecundity as well as compromise implantation and the chance of a live birth.

  • 48. Labayen, Idoia
    et al.
    Olsson, Lovisa A
    Ortega, Francisco B
    Nilsson, Torbjörn K
    Department of Clinical Chemistry, Örebro University Hospital.
    Sjöström, Michael
    Lucia, Alejandro
    Ruiz, Jonatan R
    Cardiorespiratory fitness modifies the association between the UCP3-55C>T (rs1800849) polymorphism and plasma homocysteine in Swedish youth2010In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 210, no 1, p. 183-187Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Whether the polymorphisms in the UCP3 gene have an influence on plasma homocysteine levels during youth is not known, and to elucidate the putative modifying role of fitness is also of clinical interest. We analysed the association between polymorphisms in the UCP3 gene and plasma homocysteine in youth and to examine whether fitness modifies this association.

    METHODS: The study population comprised 267 Swedish children (8-10 years) and 305 adolescents (14-16 years). Fasting total plasma homocysteine was the outcome variable. We genotyped five UCP3 polymorphisms (rs1800849, rs1800006, rs2075577, rs647126, and rs591758) and one MTHFR 677C>T (rs1801133) polymorphism. Cardiorespiratory fitness was measured with a maximal ergometer bike test.

    RESULTS: Youth homozygous or heterozygous for the T allele of the rs1800849 polymorphism had significantly higher levels of homocysteine than those carrying the CC genotype (8.56+/-4.72 micromol/L vs. 7.72+/-2.73 micromol/L, respectively, P=0.011) after adjusting for gender, age, pubertal status, folate and vitamin B(12) intake and MTHFR 677C>T polymorphism, whereas no association was observed for the other analysed polymorphisms. There was a significant interaction effect of fitnessxrs1800849 polymorphism (P=0.042). The effect of the rs1800849 polymorphism on homocysteine levels persisted in youth with low fitness, whereas it was abolished in those with moderate or high cardiorespiratory fitness (P>0.1).

    CONCLUSIONS: Cardiorespiratory fitness modifies the association between the rs1800849 polymorphism and homocysteine so that the negative effect of the T allele does not persist in youth with moderate to high levels of fitness.

  • 49.
    Lind, Marcus
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Boman, Kurt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, Torbjörn K
    Slunga-Järvholm, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Von Willebrand factor predicts major bleeding and mortality during oral anticoagulant treatment2012In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 271, no 3, p. 239-246Article in journal (Refereed)
    Abstract [en]

    Aims.  Oral anticoagulation (OAC), predominantly with warfarin, is an effective treatment to prevent thromboembolic events. Serious bleeding is a frequent and feared treatment complication. In this longitudinal cohort study of OAC-treated patients, we aimed to evaluate the relationship between von Willebrand factor (VWF) levels and risk of bleeding complications, cardiovascular mortality and all-cause mortality.

    Methods and results.  A total of 719 patients receiving warfarin treatment were observed for a mean duration of 4.2 years. All bleeding complications causing hospitalization were registered and classified into clinically relevant bleeding (CRB) and major bleeding. Ischaemic stroke, peripheral arterial embolism, myocardial infarction, and death were also recorded. We identified 113 cases of CRB and 73 of major bleeding. In total, 161 deaths occurred during follow-up with cardiovascular disease identified as the cause of death in 110 patients. Patients in the highest tertile of VWF had a significantly increased risk of bleeding complications: hazard ratio (HR) 2.53 (95% CI 1.41-4.56) for major bleeding and HR 2.19 (95% CI 1.38-3.48) for CRB. VWF, expressed either in tertiles or as a continuous variable, showed a significant association with cardiovascular mortality (HR 1.68, 95% CI 1.40-2.01) and all-cause mortality (HR 1.77, 95% CI 1.52-2.05). In multivariate Cox regression analysis, the findings remained significant after adjusting for age, high-sensitivity C-reactive protein and creatinine.

    Conclusions.  Patients with high levels of VWF had an increased risk of bleeding complications, cardiovascular mortality and all-cause mortality during OAC treatment. Our findings imply that the use of VWF as a risk marker for thromboembolic events is complicated by the association of VWF with bleeding complications.

  • 50.
    Lind, Marcus
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Boman, Kurt
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Johansson, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nilsson, Torbjörn
    Slunga-Järvholm, Lisbeth
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    D-dimer predicts major bleeding, cardiovascular events and all-cause mortality during warfarin treatment2014In: Clinical Biochemistry, ISSN 0009-9120, E-ISSN 1873-2933, Vol. 47, no 7-8, p. 570-573Article in journal (Refereed)
    Abstract [en]

    Objectives: Previous studies have shown that biomarkers in blood plasma can predict bleeding complications during anticoagulant treatment as well as thromboembolic events and may improve existing risk stratification schemes in patients on or considered for oral anticoagulant treatment. The aim of this study was to investigate if levels of D-dimer, tissue plasminogen activator (tPA) and its complex with plasminogen inhibitor type 1 (tPA/PAI-1 complex) can predict major bleedings, cardiovascular events and all-cause mortality in patients with warfarin treatment.

    Design and methods: In a longitudinal cohort study, 719 patients on oral anticoagulant treatment were followed for a total of 3001 treatment years. Major bleeding, stroke, arterial emboli, myocardial infarction and death were recorded and classified. Blood samples collected at baseline were analyzed for D-dimer, tPA, and tPA/PAI-1 complex.

    Results: In multivariate Cox regression analysis, high levels of D-dimer were associated with major bleeding (HR 1.27 per SD; 95% CI: 1.01-1.60), cardiovascular events (HR 1.23 per SD; 95% CI: 1.05-1.45) and all-cause mortality (HR 1.25 per SD; 95% CI: 1.06-1.47). Neither tPA nor the tPA/PAI-1 complex was associated with major bleeding, cardiovascular events or all-cause mortality.

    Conclusion: We conclude that high levels of D-dimer predict major bleeding, cardiovascular events and all-cause mortality during warfarin treatment. (C) 2014 The Canadian Society of Clinical Chemists. 

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