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  • 251. Forsberg, Simon K. G.
    et al.
    Kierczak, Marcin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ljungvall, Ingrid
    Merveille, Anne-Christine
    Gouni, Vassiliki
    Wiberg, Maria
    Willesen, Jakob Lundgren
    Hanas, Sofia
    Lequarre, Anne-Sophie
    Sorensen, Louise Mejer
    Tiret, Laurent
    McEntee, Kathleen
    Seppala, Eija
    Koch, Jorgen
    Battaille, Geraldine
    Lohi, Hannes
    Fredholm, Merete
    Chetboul, Valerie
    Haggstrom, Jens
    Carlborg, Örjan
    Swedish University of Agricultural Sciences, Uppsala, Sweden.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hoglund, Katja
    The Shepherds' Tale: A Genome-Wide Study across 9 Dog Breeds Implicates Two Loci in the Regulation of Fructosamine Serum Concentration in Belgian Shepherds2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0123173Article in journal (Refereed)
    Abstract [en]

    Diabetes mellitus is a serious health problem in both dogs and humans. Certain dog breeds show high prevalence of the disease, whereas other breeds are at low risk. Fructosamine and glycated haemoglobin (HbA1c) are two major biomarkers of glycaemia, where serum concentrations reflect glucose turnover over the past few weeks to months. In this study, we searched for genetic factors influencing variation in serum fructosamine concentration in healthy dogs using data from nine dog breeds. Considering all breeds together, we did not find any genome-wide significant associations to fructosamine serum concentration. However, by performing breed-specific analyses we revealed an association on chromosome 3 (rho(corrected) approximate to 1:68 x 10(-6)) in Belgian shepherd dogs of the Malinois subtype. The associated region and its close neighbourhood harbours interesting candidate genes such as LETM1 and GAPDH that are important in glucose metabolism and have previously been implicated in the aetiology of diabetes mellitus. To further explore the genetics of this breed specificity, we screened the genome for reduced heterozygosity stretches private to the Belgian shepherd breed. This revealed a region with reduced heterozygosity that shows a statistically significant interaction (rho = 0.025) with the association region on chromosome 3. This region also harbours some interesting candidate genes and regulatory regions but the exact mechanisms underlying the interaction are still unknown. Nevertheless, this finding provides a plausible explanation for breed-specific genetic effects for complex traits in dogs. Shepherd breeds are at low risk of developing diabetes mellitus. The findings in Belgian shepherds could be connected to a protective mechanism against the disease. Further insight into the regulation of glucose metabolism could improve diagnostic and therapeutic methods for diabetes mellitus.

  • 252.
    Forsgren, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Frykstrand, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Grandfield, Kathryn
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Mihranyan, Albert
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    A Template-Free, Ultra-Adsorbing, High Surface Area Carbonate Nanostructure2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e68486-Article in journal (Refereed)
    Abstract [en]

    We report the template-free, low-temperature synthesis of a stable, amorphous, and anhydrous magnesium carbonate nanostructure with pore sizes below 6 nm and a specific surface area of ~ 800 m2 g−1, substantially surpassing the surface area of all previously described alkali earth metal carbonates. The moisture sorption of the novel nanostructure is featured by a unique set of properties including an adsorption capacity ~50% larger than that of the hygroscopic zeolite-Y at low relative humidities and with the ability to retain more than 75% of the adsorbed water when the humidity is decreased from 95% to 5% at room temperature. These properties can be regenerated by heat treatment at temperatures below 100°C.The structure is foreseen to become useful in applications such as humidity control, as industrial adsorbents and filters, in drug delivery and catalysis.

  • 253.
    Forsman, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Physics Didactics.
    Mann, Richard P.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Linder, Cedric
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Physics Didactics.
    Van den Bogaard, Maartje
    Delft University.
    Sandbox University: Estimating Influence of Institutional Action2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e103261-Article in journal (Refereed)
    Abstract [en]

    The approach presented in this article represents a generalizable and adaptable methodology for identifying complexinteractions in educational systems and for investigating how manipulation of these systems may affect educationaloutcomes of interest. Multilayer Minimum Spanning Tree and Monte-Carlo methods are used. A virtual Sandbox Universityis created in order to facilitate effective identification of successful and stable initiatives within higher education, which canaffect students’ credits and student retention – something that has been lacking up until now. The results highlight theimportance of teacher feedback and teacher-student rapport, which is congruent with current educational findings,illustrating the methodology’s potential to provide a new basis for further empirical studies of issues in higher educationfrom a complex systems perspective.

  • 254.
    Fred, Rikard G
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bang-Berthelsen, Claus H
    Mandrup-Poulsen, Thomas
    Grunnet, Lars G
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    High glucose suppresses human islet insulin biosynthesis by inducing miR-133a leading to decreased polypyrimidine tract binding protein-expression2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 5, p. e10843-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Prolonged periods of high glucose exposure results in human islet dysfunction in vitro. The underlying mechanisms behind this effect of high glucose are, however, unknown. The polypyrimidine tract binding protein (PTB) is required for stabilization of insulin mRNA and the PTB mRNA 3'-UTR contains binding sites for the microRNA molecules miR-133a, miR-124a and miR-146. The aim of this study was therefore to investigate whether high glucose increased the levels of these three miRNAs in association with lower PTB levels and lower insulin biosynthesis rates.

    METHODOLOGY/PRINCIPAL FINDINGS:

    Human islets were cultured for 24 hours in the presence of low (5.6 mM) or high glucose (20 mM). Islets were also exposed to sodium palmitate or the proinflammatory cytokines IL-1beta and IFN-gamma, since saturated free fatty acids and cytokines also cause islet dysfunction. RNA was then isolated for real-time RT-PCR analysis of miR-133a, miR-124a, miR-146, insulin mRNA and PTB mRNA contents. Insulin biosynthesis rates were determined by radioactive labeling and immunoprecipitation. Synthetic miR-133a precursor and inhibitor were delivered to dispersed islet cells by lipofection, and PTB was analyzed by immunoblotting following culture at low or high glucose. Culture in high glucose resulted in increased islet contents of miR-133a and reduced contents of miR-146. Cytokines increased the contents of miR-146. The insulin and PTB mRNA contents were unaffected by high glucose. However, both PTB protein levels and insulin biosynthesis rates were decreased in response to high glucose. The miR-133a inhibitor prevented the high glucose-induced decrease in PTB and insulin biosynthesis, and the miR-133a precursor decreased PTB levels and insulin biosynthesis similarly to high glucose.

    CONCLUSION:

    Prolonged high-glucose exposure down-regulates PTB levels and insulin biosynthesis rates in human islets by increasing miR-133a levels. We propose that this mechanism contributes to hyperglycemia-induced beta-cell dysfunction.

  • 255.
    Friberg, Urban
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Miller, Paige M.
    Stewart, Andrew D.
    Rice, William R.
    Mechanisms Promoting the Long-Term Persistence of a Wolbachia Infection in a Laboratory-Adapted Population of Drosophila melanogaster2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 1, p. e16448-Article in journal (Refereed)
    Abstract [en]

    Intracellular bacteria of the genus Wolbachia are widespread endosymbionts across diverse insect taxa. Despite this prevalence, our understanding of how Wolbachia persists within populations is not well understood. Cytoplasmic incompatibility (CI) appears to be an important phenotype maintaining Wolbachia in many insects, but it is believed to be too weak to maintain Wolbachia in Drosophila melanogaster, suggesting that Wolbachia must also have other effects on this species. Here we estimate the net selective effect of Wolbachia on its host in a laboratory-adapted population of D. melanogaster, to determine the mechanisms leading to its persistence in the laboratory environment. We found i) no significant effects of Wolbachia infection on female egg-to-adult survival or adult fitness, ii) no reduced juvenile survival in males, iii) substantial levels of CI, and iv) a vertical transmission rate of Wolbachia higher than 99%. The fitness of cured females was, however, severely reduced (a decline of 37%) due to CI in offspring. Taken together these findings indicate that Wolbachia is maintained in our laboratory environment due to a combination of a nearly perfect transmission rate and substantial CI. Our results show that there would be strong selection against females losing their infection and producing progeny free from Wolbachia.

  • 256.
    Friberg, Urban
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Stewart, Andrew D.
    Rice, William R.
    Empirical Evidence for Son-Killing X Chromosomes and the Operation of SA-Zygotic Drive2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. e23508-Article in journal (Refereed)
    Abstract [en]

    Background: Diploid organisms have two copies of all genes, but only one is carried by each haploid gamete and diploid offspring. This causes a fundamental genetic conflict over transmission rate between alternative alleles. Single genes, or gene clusters, only rarely code for the complex phenotypes needed to give them a transmission advantage (drive phenotype). However, all genes on a male's X and Y chromosomes co-segregate, allowing different sex-linked genes to code for different parts of the drive phenotype. Correspondingly, the well-characterized phenomenon of male gametic drive, occurring during haploid gametogenesis, is especially common on sex chromosomes. The new theory of sexually antagonistic zygotic drive of the sex chromosomes (SA-zygotic drive) extends the logic of gametic drive into the diploid phase of the lifecycle, whenever there is competition among siblings or harmful sib-sib mating. The X and Y are predicted to gain a transmission advantage by harming offspring of the sex that does not carry them. Results: Here we analyzed a mutant X-chromosome in Drosophila simulans that produced an excess of daughters when transmitted from males. We developed a series of tests to differentiate between gametic and SA-zygotic drive, and provide multiple lines of evidence that SA-zygotic drive is responsible for the sex ratio bias. Driving sires produce about 50% more surviving daughters than sons. Conclusion: Sex-ratio distortion due to genetic conflict has evolved via gametic drive and maternally transmitted endosymbionts. Our data indicate that sex chromosomes can also drive by harming the non-carrier sex of offspring.

  • 257.
    Friederich Persson, Malou
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Aslam, Shakil
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Nordquist, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Welch, William J.
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Wilcox, Christopher S.
    Georgetown University Medical Center, Department of Medicine, Division of Nephrology and Hypertension.
    Palm, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Acute knockdown of uncoupling protein-2 increases mitochondria uncoupling via the adenine nucleotide transporter and decreases oxidative stress in diabetic kidneys2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e39635-Article in journal (Refereed)
    Abstract [en]

    Increased O2 metabolism resulting in chronic hypoxia is common in models of endstage renal disease. Mitochondrial uncoupling increases O2 consumption but the ensuing reduction in mitochondrial membrane potential may limit excessive oxidative stress. The present study addressed the hypothesis that mitochondrial uncoupling regulates mitochondria function and oxidative stress in the diabetic kidney. Isolated mitochondria from kidney cortex of control and streptozotocin-induced diabetic rats were studied before and after siRNA knockdown of uncoupling protein-2 (UCP-2). Diabetes resulted in increased UCP-2 protein expression and UCP-2-mediated uncoupling, but normal mitochondria membrane potential. This uncoupling was inhibited by GDP, which also increased the membrane potential. siRNA reduced UCP-2 protein expression in controls and diabetics (−30–50%), but paradoxically further increased uncoupling and markedly reduced the membrane potential. This siRNA mediated uncoupling was unaffected by GDP but was blocked by ADP and carboxyatractylate (CAT). Mitochondria membrane potential after UCP-2 siRNA was unaffected by GDP but increased by CAT. This demonstrated that further increased mitochondria uncoupling after siRNA towards UCP-2 is mediated through the adenine nucleotide transporter (ANT). The increased oxidative stress in the diabetic kidney, manifested as increased thiobarbituric acids, was reduced by knocking down UCP-2 whereas whole-body oxidative stress, manifested as increased circulating malondialdehyde, remained unaffected. All parameters investigated were unaffected by scrambled siRNA. In conclusion, mitochondrial uncoupling via UCP-2 regulates mitochondria membrane potential in diabetes. However, blockade of the diabetes-induced upregulation of UCP- 2 results in excessive uncoupling and reduced oxidative stress in the kidney via activation of ANT.

  • 258.
    Friman, Tomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafsson, Renata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stuhr, Linda B.
    Chidiac, Jean
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Reed, Rolf K.
    Oldberg, Åke
    Rubin, Kristofer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Increased Fibrosis and Interstitial Fluid Pressure in Two Different Types of Syngeneic Murine Carcinoma Grown in Integrin β3-Subunit Deficient Mice2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. e34082-Article in journal (Refereed)
    Abstract [en]

    Stroma properties affect carcinoma physiology and direct malignant cell development. Here we present data showing that alpha(V)beta(3) expressed by stromal cells is involved in the control of interstitial fluid pressure (IFP), extracellular volume (ECV) and collagen scaffold architecture in experimental murine carcinoma. IFP was elevated and ECV lowered in syngeneic CT26 colon and LM3 mammary carcinomas grown in integrin beta(3)-deficient compared to wild-type BALB/ c mice. Integrin beta(3)-deficiency had no effect on carcinoma growth rate or on vascular morphology and function. Analyses by electron microscopy of carcinomas from integrin beta(3)-deficient mice revealed a coarser and denser collagen network compared to carcinomas in wild-type littermates. Collagen fibers were built from heterogeneous and thicker collagen fibrils in carcinomas from integrin beta(3)-deficient mice. The fibrotic extracellular matrix (ECM) did not correlate with increased macrophage infiltration in integrin beta(3)-deficient mice bearing CT26 tumors, indicating that the fibrotic phenotype was not mediated by increased inflammation. In conclusion, we report that integrin beta(3)-deficiency in tumor stroma led to an elevated IFP and lowered ECV that correlated with a more fibrotic ECM, underlining the role of the collagen network for carcinoma physiology.

  • 259. Frykman, Susanne
    et al.
    Hur, Ji-Yeun
    Frånberg, Jenny
    Aoki, Mikio
    Winblad, Bengt
    Nahalkova, Jarmila
    Department of Neurobiology, Care Sciences and Society (NVS), Karolinska Institutet Dainippon Sumitomo Pharma Alzheimer Center (KASPAC), Novum, Huddinge, Sweden.
    Behbahani, Homira
    Tjernberg, Lars O.
    Synaptic and Endosomal Localization of Active gamma-Secretase in Rat Brain2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 1, p. e8948-Article in journal (Refereed)
    Abstract [en]

    Background

    A key player in the development of Alzheimer's disease (AD) is the gamma-secretase complex consisting of at least four components: presenilin, nicastrin, Aph-1 and Pen-2. gamma-Secretase is crucial for the generation of the neurotoxic amyloid beta-peptide (A beta) but also takes part in the processing of many other substrates. In cell lines, active gamma-secretase has been found to localize primarily to the Golgi apparatus, endosomes and plasma membranes. However, no thorough studies have been performed to show the subcellular localization of the active gamma-secretase in the affected organ of AD, namely the brain.

    Principal Findings

    We show by subcellular fractionation of rat brain that high gamma-secretase activity, as assessed by production of A beta 40, is present in an endosome-and plasma membrane-enriched fraction of an iodixanol gradient. We also prepared crude synaptic vesicles as well as synaptic membranes and both fractions showed high A beta 40 production and contained high amounts of the gamma-secretase components. Further purification of the synaptic vesicles verified the presence of the gamma-secretase components in these compartments. The localization of an active gamma-secretase in synapses and endosomes was confirmed in rat brain sections and neuronal cultures by using a biotinylated gamma-secretase inhibitor together with confocal microscopy.

    Significance

    The information about the subcellular localization of gamma-secretase in brain is important for the understanding of the molecular mechanisms of AD. Furthermore, the identified fractions can be used as sources for highly active gamma-secretase.

  • 260. Fröbert, Ole
    et al.
    Sarno, Giovanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    James, Stefan K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Saleh, Nawsad
    Lagerqvist, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Effect of stent inflation pressure and post-dilatation on the outcome of coronary artery intervention: A report of more than 90 000 stent implantations2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, p. e56348-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Percutaneous coronary intervention (PCI) stent inflation pressure correlates to angiographic lumen improvement and stent expansion but the relation to outcome is not clarified. Using comprehensive registry data our aim was to evaluate how stent inflation pressure influences restenosis, stent thrombosis and death following PCI.

    METHODS:

    We evaluated all consecutive coronary stent implantations in Sweden during 46 months from 2008 using data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). We used logistic regression and Cox proportional hazard modeling to estimate risk of outcomes with different balloon pressures.

    RESULTS:

    In total, 93 697 stents were eligible for analysis and divided into five different pressure interval groups: ≤15 atm, 16-17 atm, 18-19 atm, 20-21 atm and ≥22 atm. The risks of stent thrombosis and restenosis were significantly higher in the ≤15 atm, 18-19 atm and ≥22 atm groups (but not in the 16-17 atm group) compared to the 20-21 atm group. There were no differences in mortality. Post-dilatation was associated with a higher restenosis risk ratio (RR) of 1.22 (95% confidence interval (CI) 1.14-1.32, P<0.001) but stent thrombosis did not differ statistically between procedures with or without post-dilatation. The risk of death was lower following post-dilatation (RR 0.81 (CI 0.71-0.93) P = 0.003) and the difference compared to no post-dilatation was seen immediately after PCI.

    CONCLUSION:

    Our retrospective study of stent inflation pressure identified a possible biological pattern--the risks of stent thrombosis and of restenosis appeared to be higher with low and very high pressures. Post-dilatation might increase restenosis risk.

  • 261.
    Fu, Xi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lindgren, Torsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Wieslander, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Norbäck, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Respiratory Illness and Allergy Related to Work and Home Environment among Commercial Pilots2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164954Article in journal (Refereed)
    Abstract [en]

    The aim was to study associations between work and home environment and prevalence and incidence of respiratory health and a history of atopy in a 3-y cohort of commercial pilots. A questionnaire was mailed in 1997 to all pilots in a Scandinavian airline company (N = 622); 577 (93%) participated. The same questionnaire was sent to the participants 3 years later, 436 participated (76%). There were questions on asthma, respiratory symptoms and infections, allergies, the cabin environment, psychosocial environment and the home environment. Associations were analyzed by multiple logistic regression, calculating odds ratios (OR) with 95% confidence intervals (95% CI). The incidence of doctors' diagnosed asthma and atopy were 2.4 and 16.6 per 1000 person years, respectively. Pilots changing type of flight during follow-up got more airway infections (OR = 11.27; 95% CI 2.39-53.14). Those reporting decreased work control (OR = 1.85; 95% CI 1.03-3.31 for 1 unit change) and those with environmental tobacco smoke (ETS) at home (OR = 3.73; 95% CI 1.09-12.83) had a higher incidence of atopy during follow up. Dampness or mould at home was associated with a higher prevalence of asthma symptoms (OR = 3.55; 95% CI 1.43-8.82) and airway infections (OR = 3.12 95% CI 1.27-7.68). Window pane condensation in winter at home, reported at baseline, was associated with increased incidence of asthma symptoms (OR = 4.14; 95% CI 1.32-12.97) and pilots living in newer buildings at baseline had a higher incidence of airway infections (OR = 5.23; 95% CI 1.43-19.10). In conclusion, lack of work control and ETS at home can be a risk factors for development of allergic symptoms in pilots. Window pane condensation at home can be a risk factor for incidence of asthma symptoms. Dampness and mould at home can be a risk factor for prevalence of asthma symptoms and airway infections and living in newer buildings can be a risk factor for incidence of airway infections.

  • 262.
    Fu, Zhirong
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Thorpe, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Akula, Srinivas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Asp-ase Activity of the Opossum Granzyme B Supports the Role of Granzyme B as Part of Anti-Viral Immunity Already during Early Mammalian Evolution2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, article id e0154886Article in journal (Refereed)
    Abstract [en]

    Granzyme B is one of the key effector molecules in our defense against viruses and intracellular bacteria. This serine protease together with the pore forming protein perforin, induces caspase or Bid-dependent apoptosis in target cells. Here we present the first characterization of a granzyme B homolog, the grathepsodenase, in a non-placental mammal, the American opossum (Monodelphis domestica). The recombinant enzyme was produced in a human cell line and used to study its primary and extended cleavage specificity using a panel of chromogenic substrates and recombinant protein substrates. The opossum granzyme B was found to have a specificity similar to human granzyme B, although slightly less restrictive in its extended specificity. The identification of a granzyme B homolog with asp-ase (cleaving after aspartic acid) specificity in a non-placental mammal provides strong indications that caspase or Bid-dependent apoptosis by a serine protease with a conserved primary specificity has been part of anti-viral immunity since early mammalian evolution. This finding also indicates that an asp-ase together with a chymase were the first two serine protease genes to appear in the mammalian chymase locus.

  • 263.
    Fu, Zhirong
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Thorpe, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    rMCP-2, the Major Rat Mucosal Mast Cell Protease, an Analysis of Its Extended Cleavage Specificity and Its Potential Role in Regulating Intestinal Permeability by the Cleavage of Cell Adhesion and Junction Proteins2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id e0131720Article in journal (Refereed)
    Abstract [en]

    Mast cells of the rat intestinal mucosa express three chymotryptic enzymes named rMCP-2, -3 and 4. rMCP-2, the most abundant of these enzymes, has been shown to increase the permeability of the intestinal epithelium, most likely by cleavage of cell adhesion and junction proteins and thereby play a role in intestinal parasite clearance. However, no target for this effect has yet been identified. To address this question we here present its extended cleavage specificity. Phage display analysis showed that it is a chymase with a specificity similar to the corresponding enzyme in mice, mMCP-1, with a preference for Phe or Tyr in the P1 position, and a general preference for aliphatic amino acids both upstream and downstream of the cleavage site. The consensus sequence obtained from the phage display analysis was used to screen the rat proteome for potential targets. A few of the most interesting candidate substrates were cell adhesion and cell junction molecules. To see if these proteins were also susceptible to cleavage in their native conformation we cleaved 5 different recombinant cell adhesion and cell junction proteins. Three potential targets were identified: the loop 1 of occludin, protocadherin alpha 4 and cadherin 17, which indicated that these proteins were at least partly responsible for the previously observed prominent role of rMCP-2 in mucosal permeability and in parasite clearance.

  • 264.
    Fält, Elisabet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Sarkadi, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Fabian, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Exploring Nurses', Preschool Teachers' and Parents' Perspectives on Information Sharing Using SDQ in a Swedish Setting - A Qualitative Study Using Grounded Theory2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0168388Article in journal (Refereed)
    Abstract [en]

    Evidence-based methods to identify behavioural problems among children are not regularly used within the Swedish Child healthcare. A new procedure was therefore introduced to assess children through parent- and preschool teacher reports using the Strengths and Difficulties Questionnaire (SDQ). This study aims to explore nurses', preschool teachers' and parents' perspectives of this new information sharing model. Using the grounded theory methodology, semi-structured interviews with nurses (n = 10) at child health clinics, preschool teachers (n = 13) and parents (n = 11) of 3-, 4- and 5-year-old children were collected and analysed between March 2014 and June 2014. The analysis was conducted using constant comparative method. The participants were sampled purposively within a larger trial in Sweden. Results indicate that all stakeholders shared a desire to have a complete picture of the child's health. The perceptions that explain why the stakeholders were in favour of the new procedure-the 'causal conditions' in a grounded theory model included: (1) Nurses thought that visits after 18-months were unsatisfactory, (2) Preschool teachers wanted to identify children with difficulties and (3) Parents viewed preschool teachers as being qualified to assess children. However, all stakeholders had doubts as to whether there was a reliable way to assess children's behaviour. Although nurses found the SDQ to be useful for their clinical evaluation, they noticed that not all parents chose to participate. Both teachers and parents acknowledged benefits of information sharing. However, the former had concerns about parental reactions to their assessments and the latter about how personal information was handled. The theoretical model developed describes that the causal conditions and current context of child healthcare in many respects endorse the introduction of information sharing. However, successful implementation requires considerable work to address barriers: the tension between normative thinking versus helping children with developmental problems for preschool teachers and dealing with privacy issues and inequity in participation for parents.

  • 265.
    Fängström, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    Salari, Raziye
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    Eriksson, Maria
    Ersta Sköndal Bräcke University College.
    Sarkadi, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    The computer-assisted interview In My Shoes can benefit shy preschool children's communication2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 8, article id e0182978Article in journal (Refereed)
    Abstract [en]

    Interviewing children is a cognitively, socially, and emotionally challenging situation, especially for young and shy children. Thus, finding methods that aid rapport and increase these children's communication is important. The present study investigated whether children's verbal and non-verbal communicative behavior developed differently during the rapport phase, depending on whether children were situationally shy or not, and whether the interview was conducted using the computer-assisted interview In My Shoes (IMS) or a Standard verbal interview. The sample consisted of 60 children aged 4 to 5-years-old. The results showed that for the shy children in the IMS group their talkativeness increased and their answer latency decreased including the amount of encouragement the child needed to talk, while no changes were observed for the shy children in the Standard verbal interview group. There were no significant differences in the non-verbal behavior for the shy children regardless of the interview method used. For the non-shy children, overall, the interview method did not affect either the verbal or the non-verbal outcomes. Our findings indicate that IMS can be a useful tool during the rapport-building phase with shy children as it helps these children to improve their verbal communication.

  • 266.
    Galazka, Martyna A
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Roché, Laëtitia
    Nyström, Pär
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Falck-Ytter, Terje
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Human Infants Detect Other People's Interactions Based on Complex Patterns of Kinematic Information.2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e112432-Article in journal (Refereed)
    Abstract [en]

    Do infants perceive other people's interactions by means of a mechanism that integrates biological motion information across the observed individuals? In support of this view, the present study demonstrates that infants (N = 28, Age  = 14 months) discriminate between point light displays representing disrupted and non-disrupted interactions between people, even though the two interaction types are identical at the level of individual point light agents. Moreover, a second experiment (sample 2: N = 28, Age  = 14 months) indicated that visual preference in this context is influenced by an audiovisual integration processes that takes into account the presence of an interaction between people. All these results were found exclusively for upright displays - when stimuli were shown upside-down (disrupting biological motion processing), performance was random. Collectively, these findings point to an important role for biological motion in social perception in human infants.

  • 267.
    Galindo-Romero, Caridad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Murcia, Inst Murciano Invest Biosanitaria, Hosp Virgen de la Arrixaca IMIB Virgen de la Arri, Murcia, Spain;Univ Murcia, Fac Med, Dept Oftalmol, Murcia, Spain.
    Harun-Or-Rashid, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Jiménez-López, Manuel
    Univ Murcia, Inst Murciano Invest Biosanitaria, Hosp Virgen de la Arrixaca IMIB Virgen de la Arri, Murcia, Spain;Univ Murcia, Fac Med, Dept Oftalmol, Murcia, Spain.
    Agudo-Barriuso, Manuel
    Univ Murcia, Inst Murciano Invest Biosanitaria, Hosp Virgen de la Arrixaca IMIB Virgen de la Arri, Murcia, Spain;Univ Murcia, Fac Med, Dept Oftalmol, Murcia, Spain.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Neuroprotection by α2-Adrenergic Receptor Stimulation after Excitotoxic Retinal Injury: A Study of the Total Population of Retinal Ganglion Cells and Their Distribution in the Chicken Retina2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, article id e0161862Article in journal (Refereed)
    Abstract [en]

    We have studied the effect of α2-adrenergic receptor stimulation on the total excitotoxically injured chicken retinal ganglion cell population. N-methyl-D-aspartate (NMDA) was intraocularly injected at embryonic day 18 and Brn3a positive retinal ganglion cells (Brn3a+ RGCs) were counted in flat-mounted retinas using automated routines. The number and distribution of the Brn3a+ RGCs were analyzed in series of normal retinas from embryonic day 8 to post-hatch day 11 retinas and in retinas 7 or 14 days post NMDA lesion. The total number of Brn3a+ RGCs in the post-hatch retina was approximately 1.9x106 with a density of approximately 9.2x103 cells/mm2. The isodensity maps of normal retina showed that the density decreased with age as the retinal size increased. In contrast to previous studies, we did not find any specific region with increased RGC density, rather the Brn3a+ RGCs were homogeneously distributed over the central retina with decreasing density in the periphery and in the region of the pecten oculli. Injection of 5–10 μg NMDA caused 30–50% loss of Brn3a+ cells and the loss was more severe in the dorsal than in the ventral retina. Pretreatment with brimonidine reduced the loss of Brn3a+ cells both 7 and 14 days post lesion and the protective effect was higher in the dorsal than in the ventral retina. We conclude that α2-adrenergic receptor stimulation reduced the impact of the excitotoxic injury in chicken similarly to what has been shown in mammals. Furthermore, the data show that the RGCs are evenly distributed over in the retina, which challenges previous results that indicate the presence of specific high RGC-density regions of the chicken retina.

  • 268.
    Gallini, Radiosa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Huusko, Jenni
    Univ Kuopio, Dept Biotechnol & Mol Med, Al Virtanen Inst Mol Sci, Kuopio, Finland..
    Yla-Herttuala, Seppo
    Univ Kuopio, Dept Biotechnol & Mol Med, Al Virtanen Inst Mol Sci, Kuopio, Finland..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Isoform-Specific Modulation of Inflammation Induced by Adenoviral Mediated Delivery of Platelet-Derived Growth Factors in the Adult Mouse Heart2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0160930Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factors (PDGFs) are key regulators of mesenchymal cells in vertebrate development. To what extent PDGFs also exert beneficial homeostatic or reparative roles in adult organs, as opposed to adverse fibrogenic responses in pathology, are unclear. PDGF signaling plays critical roles during heart development, during which forced overexpression of PDGFs induces detrimental cardiac fibrosis; other studies have implicated PDGF signaling in post-infarct myocardial repair. Different PDGFs may exert different effects mediated through the two PDGF receptors (PDGFR alpha and PDGFR beta) in different cell types. Here, we assessed responses induced by five known PDGF isoforms in the adult mouse heart in the context of adenovirus vector-mediated inflammation. Our results show that different PDGFs have different, in some cases even opposing, effects. Strikingly, whereas the major PDGFRa agonists (PDGF-A and -C) decreased the amount of scar tissue and increased the numbers of PDGFR alpha-positive fibroblasts, PDGFR beta agonists either induced large scars with extensive inflammation (PDGF-B) or dampened the adenovirusinduced inflammation and produced a small and dense scar (PDGF-D). These results provide evidence for PDGF isoform-specific inflammation-modulating functions that may have therapeutic implications. They also illustrate a surprising complexity in the PDGF-mediated pathophysiological responses.

  • 269. Galloway, Aaron W. E.
    et al.
    Brett, Michael T.
    Holtgrieve, Gordon W.
    Ward, Eric J.
    Ballantyne, Ashley P.
    Burns, Carolyn W.
    Kainz, Martin J.
    Mueller-Navarra, Doerthe C.
    Persson, Jonas
    Ravet, Joseph L.
    Strandberg, Ursula
    Taipale, Sami J.
    Alhgren, Gunnel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    A Fatty Acid Based Bayesian Approach for Inferring Diet in Aquatic Consumers2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id e0129723Article in journal (Refereed)
    Abstract [en]

    We modified the stable isotope mixing model MixSIR to infer primary producer contributions to consumer diets based on their fatty acid composition. To parameterize the algorithm, we generated a 'consumer-resource library' of FA signatures of Daphnia fed different algal diets, using 34 feeding trials representing diverse phytoplankton lineages. This library corresponds to the resource or producer file in classic Bayesian mixing models such as MixSIR or SIAR. Because this library is based on the FA profiles of zooplankton consuming known diets, and not the FA profiles of algae directly, trophic modification of consumer lipids is directly accounted for. To test the model, we simulated hypothetical Daphnia comprised of 80% diatoms, 10% green algae, and 10% cryptophytes and compared the FA signatures of these known pseudo-mixtures to outputs generated by the mixing model. The algorithm inferred these simulated consumers were comprised of 82% (63-92%) [median (2.5th to 97.5th percentile credible interval)] diatoms, 11% (4-22%) green algae, and 6% (0-25%) cryptophytes. We used the same model with published phytoplankton stable isotope (SI) data for delta C-13 and delta N-15 to examine how a SI based approach resolved a similar scenario. With SI, the algorithm inferred that the simulated consumer assimilated 52% (4-91%) diatoms, 23% (1-78%) green algae, and 18% (1-73%) cyanobacteria. The accuracy and precision of SI based estimates was extremely sensitive to both resource and consumer uncertainty, as well as the trophic fractionation assumption. These results indicate that when using only two tracers with substantial uncertainty for the putative resources, as is often the case in this class of analyses, the underdetermined constraint in consumer-resource SI analyses may be intractable. The FA based approach alleviated the underdetermined constraint because many more FA biomarkers were utilized (n < 20), different primary producers (e.g., diatoms, green algae, and cryptophytes) have very characteristic FA compositions, and the FA profiles of many aquatic primary consumers are strongly influenced by their diets.

  • 270.
    Gallwitz, Maike
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Enoksson, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Thorpe, Michael
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    The Extended Cleavage Specificity of Human Thrombin2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 2, p. e31756-Article in journal (Refereed)
    Abstract [en]

    Thrombin is one of the most extensively studied of all proteases. Its central role in the coagulation cascade as well as several other areas has been thoroughly documented. Despite this, its consensus cleavage site has never been determined in detail. Here we have determined its extended substrate recognition profile using phage-display technology. The consensus recognition sequence was identified as, P2-Pro, P1-Arg, P1'-Ser/Ala/Gly/Thr, P2'-not acidic and P3'-Arg. Our analysis also identifies an important role for a P3'-arginine in thrombin substrates lacking a P2-proline. In order to study kinetics of this cooperative or additive effect we developed a system for insertion of various pre-selected cleavable sequences in a linker region between two thioredoxin molecules. Using this system we show that mutations of P2-Pro and P3'-Arg lead to an approximate 20-fold and 14-fold reduction, respectively in the rate of cleavage. Mutating both Pro and Arg results in a drop in cleavage of 200-400 times, which highlights the importance of these two positions for maximal substrate cleavage. Interestingly, no natural substrates display the obtained consensus sequence but represent sequences that show only 1-30% of the optimal cleavage rate for thrombin. This clearly indicates that maximal cleavage, excluding the help of exosite interactions, is not always desired, which may instead cause problems with dysregulated coagulation. It is likely exosite cooperativity has a central role in determining the specificity and rate of cleavage of many of these in vivo substrates. Major effects on cleavage efficiency were also observed for residues as far away as 4 amino acids from the cleavage site. Insertion of an aspartic acid in position P4 resulted in a drop in cleavage by a factor of almost 20 times.

  • 271.
    Gandasi, Nikhil R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Vesto, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Helou, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Yin, Peng
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Saras, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Barg, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Survey of Red Fluorescence Proteins as Markers for Secretory Granule Exocytosis2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id e0127801Article in journal (Refereed)
    Abstract [en]

    Fluorescent proteins (FPs) have proven to be valuable tools for high-resolution imaging studies of vesicle transport processes, including exo- and endocytosis. Since the pH of the vesicle lumen changes between acidic and neutral during these events, pH-sensitive FPs with near neutral pKa, such as pHluorin, are particularly useful. FPs with pKa>6 are readily available in the green spectrum, while red-emitting pH-sensitive FPs are rare and often not well characterized as reporters of exo- or endocytosis. Here we tested a panel of ten orange/red and two green FPs in fusions with neuropeptide Y (NPY) for use as secreted vesicle marker and reporter of dense core granule exocytosis and release. We report relative brightness, bleaching rate, targeting accuracy, sensitivity to vesicle pH, and their performance in detecting exocytosis in live cells. Tandem dimer (td)-mOrange2 was identified as well-targeted, bright, slowly bleaching and pH-sensitive FP that performed similar to EGFP. Single exocytosis events were readily observed, which allowed measurements of fusion pore lifetime and the dynamics of the exocytosis protein syntaxin at the release site during membrane fusion and cargo release.

  • 272. Ganna, Andrea
    et al.
    Ortega-Alonso, Alfredo
    Havulinna, Aki
    Salomaa, Veikko
    Kaprio, Jaakko
    Pedersen, Nancy L.
    Sullivan, Patrick F.
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Hultman, Christina M.
    Magnusson, Patrik K. E.
    Utilizing Twins as Controls for Non-Twin Case-Materials in Genome Wide Association Studies2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e83101-Article in journal (Refereed)
    Abstract [en]

    Twin registries around the globe have collected DNA samples from large numbers of monozygotic and dizygotic twins. The twin sample collections are frequently used as controls in disease-specific studies together with non-twins. This approach is unbiased under the hypothesis that twins and singletons are comparable in terms of allele frequencies; i.e. there are no genetic variants associated with being a twin per se. To test this hypothesis we performed a genome-wide association study comparing the allele frequency of 572,352 single nucleotide polymorphisms (SNPs) in 1,413 monozygotic (MZ) and 5,451 dizygotic (DZ) twins with 3,720 healthy singletons. Twins and singletons have been genotyped using the same platform. SNPs showing association with being a twin at P-value < 1 × 10-5 were selected for replication analysis in 1,492 twins (463 MZ and 1,029 DZ) and 1,880 singletons from Finland. No SNPs reached genome-wide significance (P-value < 5 × 10-8) in the main analysis combining MZ and DZ twins. In a secondary analysis including only DZ twins two SNPs (rs2033541 close to ADAMTSL1 and rs4149283 close to ABCA1) were genome-wide significant after meta-analysis with the Finnish population. The estimated proportion of variance on the liability scale explained by all SNPs was 0.08 (P-value=0.003) when MZ and DZ were considered together and smaller for MZ (0.06, P-value=0.10) compared to DZ (0.09, P-value=0.003) when analyzed separately. In conclusion, twins and singletons can be used in genetic studies together with general population samples without introducing large bias. Further research is needed to explore genetic variances associated with DZ twinning.

  • 273.
    Garcia-Faroldi, Gianni
    et al.
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, BMC, Uppsala, Sweden..
    Melo, Fabio R.
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, BMC, Uppsala, Sweden..
    Bruemmer, Dennis
    Univ Kentucky, Coll Med, Saha Cardiovasc Res Ctr, Wethington, KY USA..
    Conneely, Orla M.
    Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA..
    Pejler, Gunnar
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, BMC, Uppsala, Sweden..
    Lundequist, Anders
    Swedish Univ Agr Sci, Dept Anat Physiol & Biochem, BMC, Uppsala, Sweden..
    Nuclear Receptor 4a3 (Nr4a3) Regulates Murine Mast Cell Responses and Granule Content2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, article id e89311Article in journal (Refereed)
    Abstract [en]

    Nuclear receptor 4a3 (Nr4a3) is a transcription factor implicated in various settings such as vascular biology and inflammation. We have recently shown that mast cells dramatically upregulate Nuclear receptor 4a3 upon activation, and here we investigated the functional impact of Nuclear receptor 4a3 on mast cell responses. We show that Nuclear receptor 4a3 is involved in the regulation of cytokine/chemokine secretion in mast cells following activation via the high affinity IgE receptor. Moreover, Nuclear receptor 4a3 negatively affects the transcript and protein levels of mast cell tryptase as well as the mast cell's responsiveness allergen. Together, these findings identify Nuclear receptor 4a3 as a novel regulator of mast cell function.

  • 274. Gardberg, Maria
    et al.
    Kaipio, Katja
    Lehtinen, Laura
    Mikkonen, Piia
    Heuser, Vanina D.
    Talvinen, Kati
    Iljin, Kristiina
    Kampf, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Uhlen, Mathias
    Grenman, Reidar
    Koivisto, Mari
    Carpen, Olli
    FHOD1, a Formin Upregulated in Epithelial-Mesenchymal Transition, Participates in Cancer Cell Migration and Invasion2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e74923-Article in journal (Refereed)
    Abstract [en]

    Cancer cells can obtain their ability to invade and metastasise by undergoing epithelial-to-mesenchymal transition (EMT). Exploiting this mechanism of cellular plasticity, malignant cells can remodel their actin cytoskeleton and down-regulate proteins needed for cell-cell contacts. The mechanisms of cytoskeletal reorganisation resulting in mesenchymal morphology and increased invasive potential are poorly understood. Actin nucleating formins have been implicated as key players in EMT. Here, we analysed which formins are altered in squamous cell carcinoma related EMT. FHOD1, a poorly studied formin, appeared to be markedly upregulated upon EMT. In human tissues FHOD1 was primarily expressed in mesenchymal cells, with little expression in epithelia. However, specimens from oral squamous cell cancers demonstrated consistent FHOD1 upregulation in mesenchymally transformed cells at the invasive edge. This upregulation was confirmed in an oral squamous carcinoma model, where FHOD1 expression was markedly increased upon EMT in a PI3K signalling dependent manner. In the EMT cells FHOD1 contributed to the spindle-shaped morphology and mesenchymal F-actin organization. Furthermore, functional assays demonstrated that FHOD1 contributes to cell migration and invasion. Finally, FHOD1 depletion reduced the ability of EMT cancer cells to form invadopodia and to degrade extracellular matrix. Our results indicate that FHOD1 participates in cytoskeletal changes in EMT. In addition, we show that FHOD1 upregulation occurs during cancer cell EMT in vivo, which indicates that FHOD1 may contribute to tumour progression.

  • 275. Garg, Gaurav
    et al.
    Kumar, Jitender
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    McGuigan, Fiona E.
    Ridderstrale, Martin
    Gerdhem, Paul
    Luthman, Holger
    Akesson, Kristina
    Variation in the MC4R Gene Is Associated with Bone Phenotypes in Elderly Swedish Women2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e88565-Article in journal (Refereed)
    Abstract [en]

    Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs) with body composition, BMD, Ultrasound (QUS), fracture and biomarkers (Homocysteine (Hcy), folate, Vitamin D and Vitamin B12) for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor (MC4R); rs7566605 (insulin induced gene 2 (INSIG2); rs9939609 and rs1121980 (fat mass and obesity associated (FTO) were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n = 1061) and OPRA (age 75, n = 1044). Body mass index (BMI), total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r(2) = 0.2-0.6). MC4R rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to T-allele homozygotes (TT vs. CT vs. CC: BUA: 100 vs. 103 vs. 103; p = 0.002); (SOS: 1521 vs. 1526 vs. 1524; p = 0.008); (Stiffness index: 69 vs. 73 vs. 74; p = 0.0006) after adjustment for confounders. They also had low folate (18 vs. 17 vs. 16; p = 0.03) and vitamin D (93 vs. 91 vs. 90; p = 0.03) and high Hcy levels (13.7 vs 14.4 vs. 14.5; p = 0.06). Fracture incidence was lower among women with the C-allele, (52% vs. 58%; p = 0.067). Variation in MC4R was not associated with BMD or body composition in either OPRA or PEAK-25. SNPs close to FTO and INSIG2 were not associated with any bone phenotypes in either cohort and FTO SNPs were only associated with body composition in PEAK-25 (p <= 0.001). Our results suggest that genetic variation close to MC4R is associated with quantitative ultrasound and risk of fracture.

  • 276.
    Gaudio, Santino
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha Jane
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Riva, Giuseppe
    Nonvisual Multisensory Impairment of Body Perception in Anorexia Nervosa: A Systematic Review of Neuropsychological Studies2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e110087-Article in journal (Refereed)
    Abstract [en]

    Background: Body image distortion is a central symptom of Anorexia Nervosa (AN). Even if corporeal awareness is multisensory majority of AN studies mainly investigated visual misperception. We systematically reviewed AN studies that have investigated different nonvisual sensory inputs using an integrative multisensory approach to body perception. We also discussed the findings in the light of AN neuroimaging evidence. Methods: Pub Med and PsycINFO were searched until March, 2014. To be included in the review, studies were mainly required to: investigate a sample of patients with current or past AN and a control group and use tasks that directly elicited one or more nonvisual sensory domains. Results:Thirteen studies were included. They studied a total of 223 people with current or past AN and 273 control subjects. Overall, results show impairment in tactile and proprioceptive domains of body perception in AN patients. lnteroception and multisensory integration have been poorly explored directly in AN patients. A limitation of this review is the relatively small amount of literature available. Conclusions: Our results showed that AN patients had a multisensory impairment of body perception that goes beyond visual misperception and involves tactile and proprioceptive sensory components. Furthermore, impairment of tactile and proprioceptive components may be associated with parietal cortex alterations in AN patients. Interoception and multisensory integration have been weakly explored directly. Further research, using multisensory approaches as well as neuroimaging techniques, is needed to better define the complexity of body image distortion in AN. Key Findings: The review suggests an altered capacity of AN patients in processing and integration of bodily signals: body parts are experienced as dissociated from their holistic and perceptive dimensions. Specifically, it is likely that not only perception but memory, and in particular sensorimotor/proprioceptive memory, probably shapes bodily experience in patients with AN.

  • 277. Gerber, Sophie
    et al.
    Chadoeuf, Joel
    Gugerli, Felix
    Lascoux, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Plant Ecology and Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Buiteveld, Joukje
    Cottrell, Joan
    Dounavi, Aikaterini
    Fineschi, Silvia
    Forrest, Laura L.
    Fogelqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Goicoechea, Pablo G.
    Jensen, Jan Svejgaard
    Salvini, Daniela
    Vendramin, Giovanni G.
    Kremer, Antoine
    High Rates of Gene Flow by Pollen and Seed in Oak Populations across Europe2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 1, p. e85130-Article in journal (Refereed)
    Abstract [en]

    Gene flow is a key factor in the evolution of species, influencing effective population size, hybridisation and local adaptation. We analysed local gene flow in eight stands of white oak (mostly Quercus petraea and Q. robur, but also Q. pubescens and Q. faginea) distributed across Europe. Adult trees within a given area in each stand were exhaustively sampled (range [239, 754], mean 423), mapped, and acorns were collected ([17,147], 51) from several mother trees ([3,47], 23). Seedlings ([65,387], 178) were harvested and geo-referenced in six of the eight stands. Genetic information was obtained from screening distinct molecular markers spread across the genome, genotyping each tree, acorn or seedling. All samples were thus genotyped at 5-8 nuclear microsatellite loci. Fathers/parents were assigned to acorns and seedlings using likelihood methods. Mating success of male and female parents, pollen and seed dispersal curves, and also hybridisation rates were estimated in each stand and compared on a continental scale. On average, the percentage of the wind-borne pollen from outside the stand was 60%, with large variation among stands (21-88%). Mean seed immigration into the stand was 40%, a high value for oaks that are generally considered to have limited seed dispersal. However, this estimate varied greatly among stands (20-66%). Gene flow was mostly intraspecific, with large variation, as some trees and stands showed particularly high rates of hybridisation. Our results show that mating success was unevenly distributed among trees. The high levels of gene flow suggest that geographically remote oak stands are unlikely to be genetically isolated, questioning the static definition of gene reserves and seed stands.

  • 278. Gerlee, Philip
    et al.
    Schmidt, Linnea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Monsefi, Naser
    Kling, Teresia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jornsten, Rebecka
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Searching for Synergies: Matrix Algebraic Approaches for Efficient Pair Screening2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e68598-Article in journal (Refereed)
    Abstract [en]

    Functionally interacting perturbations, such as synergistic drugs pairs or synthetic lethal gene pairs, are of key interest in both pharmacology and functional genomics. However, to find such pairs by traditional screening methods is both time consuming and costly. We present a novel computational-experimental framework for efficient identification of synergistic target pairs, applicable for screening of systems with sizes on the order of current drug, small RNA or SGA (Synthetic Genetic Array) libraries (>1000 targets). This framework exploits the fact that the response of a drug pair in a given system, or a pair of genes' propensity to interact functionally, can be partly predicted by computational means from (i) a small set of experimentally determined target pairs, and (ii) pre-existing data (e.g. gene ontology, PPI) on the similarities between targets. Predictions are obtained by a novel matrix algebraic technique, based on cyclical projections onto convex sets. We demonstrate the efficiency of the proposed method using drug-drug interaction data from seven cancer cell lines and gene-gene interaction data from yeast SGA screens. Our protocol increases the rate of synergism discovery significantly over traditional screening, by up to 7-fold. Our method is easy to implement and could be applied to accelerate pair screening for both animal and microbial systems.

  • 279. Gertow, Karin
    et al.
    Cedervall, Jessica
    Jamil, Seema
    Ali, Rouknuddin
    Imreh, Marta P.
    Gulyas, Miklos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Sandstedt, Bengt
    Hrlund-Richter, Lars A.
    Early Events in Xenograft Development from the Human Embryonic Stem Cell Line HS181-Resemblance with an Initial Multiple Epiblast Formation2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 11, p. e27741-Article in journal (Refereed)
    Abstract [en]

    Xenografting is widely used for assessing in vivo pluripotency of human stem cell populations. Here, we report on early to late events in the development of mature experimental teratoma from a well-characterized human embryonic stem cell (HESC) line, HS181. The results show an embryonic process, increasingly chaotic. Active proliferation of the stem cell derived cellular progeny was detected already at day 5, and characterized by the appearance of multiple sites of engraftment, with structures of single or pseudostratified columnar epithelium surrounding small cavities. The striking histological resemblance to developing embryonic ectoderm, and the formation of epiblast-like structures was supported by the expression of the markers OCT4, NANOG, SSEA-4 and KLF4, but a lack of REX1. The early neural marker NESTIN was uniformly expressed, while markers linked to gastrulation, such as BMP-4, NODAL or BRACHYURY were not detected. Thus, observations on day 5 indicated differentiation comparable to the most early transient cell populations in human post implantation development. Confirming and expanding on previous findings from HS181 xenografts, these early events were followed by an increasingly chaotic development, incorporated in the formation of a benign teratoma with complex embryonic components. In the mature HS181 teratomas not all types of organs/tissues were detected, indicating a restricted differentiation, and a lack of adequate spatial developmental cues during the further teratoma formation. Uniquely, a kinetic alignment of rare complex structures was made to human embryos at diagnosed gestation stages, showing minor kinetic deviations between HS181 teratoma and the human counterpart.

  • 280.
    Ghilotti, Francesca
    et al.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.;Univ Milano Bicocca, Dept Stat & Quantitat Methods, Milan, Italy..
    Pesonen, Ann-Sofie
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Raposo, Sara E.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA USA..
    Winell, Henric
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Nyren, Olof
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Lagerros, Ylva Trolle
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.;Karolinska Univ Hosp Huddinge, Dept Med, Clin Endocrinol Metab & Diabet, Stockholm, Sweden..
    Plymoth, Amelie
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Physical activity, sleep and risk of respiratory infections: A Swedish cohort study2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 1, article id e0190270Article in journal (Refereed)
    Abstract [en]

    Objectives

    Previous studies found higher levels of physical activity to be protective against infections and that short and long sleep negatively affects the immune response. However, these relationships remain debatable. We aimed to investigate if physical activity and sleep habits affect incidence of upper respiratory tract infections (URTI) in a prospective cohort study.

    Methods

    A total of 2,038 adults aged 25-64 years served as a random sample of the gainfully employed population of an industrial town in Sweden. Physical activity and sleep habits were estimated through self-reported questionnaires. Physical activity was expressed as metabolic energy turnover hours per day. Sleep was assessed as number of hours slept per night and its perceived quality. URTI outcome was prospectively self-reported during a 9-month follow-up period. Associations of physical activity and sleep with URTI were estimated using hurdle regression models adjusted for potential confounders.

    Results

    During 1,583 person-years 1,597 URTI occurred, resulting in an incidence of 1.01 infections/person-year (95% CI 0.96-1.06). The fitted regression models did not provide support for an association with physical activity or sleep habits. Factors positively associated with experiencing URTI were having children <= 6 years, female gender, higher education and treatment for allergy, asthma or lung cancer. Having children <= 6 years and female gender were related to a higher number of URTI among those experiencing URTI.

    Conclusions

    We did not find any association between physical activity, sleep duration or sleep quality and the occurrence of upper respiratory tract infections in adult Swedish population.

  • 281.
    Ghith, Nermin
    et al.
    Lund Univ, Fac Med, Unit Social Epidemiol, Malmo, Sweden.;Bispebjerg Hosp, Res Unit Chron Condit, Copenhagen, Denmark..
    Wagner, Philippe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Lund Univ, Fac Med, Unit Social Epidemiol, Malmo, Sweden..
    Frolich, Anne
    Bispebjerg Hosp, Res Unit Chron Condit, Copenhagen, Denmark..
    Merlo, Juan
    Lund Univ, Fac Med, Unit Social Epidemiol, Malmo, Sweden..
    Short Term Survival after Admission for Heart Failure in Sweden: Applying Multilevel Analyses of Discriminatory Accuracy to Evaluate Institutional Performance2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 2, article id e0148187Article in journal (Refereed)
    Abstract [en]

    Background Hospital performance is frequently evaluated by analyzing differences between hospital averages in some quality indicators. The results are often expressed as quality charts of hospital variance (e.g., league tables, funnel plots). However, those analyses seldom consider patients heterogeneity around averages, which is of fundamental relevance for a correct evaluation. Therefore, we apply an innovative methodology based on measures of components of variance and discriminatory accuracy to analyze 30-day mortality after hospital discharge with a diagnosis of Heart Failure (HF) in Sweden. Methods We analyzed 36,943 patients aged 45-80 treated in 565 wards at 71 hospitals during 2007-2009. We applied single and multilevel logistic regression analyses to calculate the odds ratios and the area under the receiver-operating characteristic (AUC). We evaluated general hospital and ward effects by quantifying the intra-class correlation coefficient (ICC) and the increment in the AUC obtained by adding random effects in a multilevel regression analysis (MLRA). Finally, the Odds Ratios (ORs) for specific ward and hospital characteristics were interpreted jointly with the proportional change in variance (PCV) and the proportion of ORs in the opposite direction (POOR). Findings Overall, the average 30-day mortality was 9%. Using only patient information on age and previous hospitalizations for different diseases we obtained an AUC = 0.727. This value was almost unchanged when adding sex, country of birth as well as hospitals and wards levels. Average mortality was higher in small wards and municipal hospitals but the POOR values were 15% and 16% respectively. Conclusions Swedish wards and hospitals in general performed homogeneously well, resulting in a low 30-day mortality rate after HF. In our study, knowledge on a patient's previous hospitalizations was the best predictor of 30-day mortality, and this information did not improve by knowing the sex and country of birth of the patient or where the patient was treated.

  • 282.
    Ghorbani, Abdolbaset
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology. Shahid Beheshti Univ Med Sci, Tradit Med & Mat Med Res Ctr, Tehran, Iran..
    Saeedi, Yousef
    Shahid Beheshti Univ Med Sci, Tradit Med & Mat Med Res Ctr, Tehran, Iran..
    de Boer, Hugo J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology. Naturalis Biodivers Ctr, Leiden, Netherlands.;Univ Oslo, Nat Hist Museum, Oslo, Norway..
    Unidentifiable by morphology: DNA barcoding of plant material in local markets in Iran2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0175722Article in journal (Refereed)
    Abstract [en]

    Local markets provide a rapid insight into the medicinal plants growing in a region as well as local traditional health concerns. Identification of market plant material can be challenging as plants are often sold in dried or processed forms. In this study, three approaches of DNA barcoding-based molecular identification of market samples are evaluated, two objective sequence matching approaches and an integrative approach that coalesces sequence matching with a priori and a posteriori data from other markers, morphology, ethnoclassification and species distribution. Plant samples from markets and herbal shops were identified using morphology, descriptions of local use, and vernacular names with relevant floras and pharmacopoeias. DNA barcoding was used for identification of samples that could not be identified to species level using morphology. Two methods based on BLAST similaritybased identification, were compared with an integrative identification approach. Integrative identification combining the optimized similarity-based approach with a priori and a posteriori information resulted in a 1.67, 1.95 and 2.00 fold increase for ITS, trnL-F spacer, and both combined, respectively. DNA barcoding of traded plant material requires objective strategies to include data from multiple markers, morphology, and traditional knowledge to optimize species level identification success.

  • 283.
    Gillespie, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Alassaad, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Hammarlund-Udenaes, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Morlin, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Henrohn, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bertilsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Effects of Pharmacists' Interventions on Appropriateness of Prescribing and Evaluation of the Instruments' (MAI, STOPP and STARTs') Ability to Predict Hospitalization-Analyses from a Randomized Controlled Trial2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 5, p. e62401-Article in journal (Refereed)
    Abstract [en]

    Background: Appropriateness of prescribing can be assessed by various measures and screening instruments. The aims of this study were to investigate the effects of pharmacists' interventions on appropriateness of prescribing in elderly patients, and to explore the relationship between these results and hospital care utilization during a 12-month follow-up period. Methods: The study population from a previous randomized controlled study, in which the effects of a comprehensive pharmacist intervention on re-hospitalization was investigated, was used. The criteria from the instruments MAI, STOPP and START were applied retrospectively to the 368 study patients (intervention group (I) n = 182, control group (C) n = 186). The assessments were done on admission and at discharge to detect differences over time and between the groups. Hospital care consumption was recorded and the association between scores for appropriateness, and hospitalization was analysed. Results: The number of Potentially Inappropriate Medicines (PIMs) per patient as identified by STOPP was reduced for I but not for C (1.42 to 0.93 vs. 1.46 to 1.66 respectively, p<0.01). The number of Potential Prescription Omissions (PPOs) per patient as identified by START was reduced for I but not for C (0.36 to 0.09 vs. 0.42 to 0.45 respectively, p<0.001). The summated score for MAI was reduced for I but not for C (8.5 to 5.0 and 8.7 to 10.0 respectively, p<0.001). There was a positive association between scores for MAI and STOPP and drug-related readmissions (RR 8-9% and 30-34% respectively). No association was detected between the scores of the tools and total re-visits to hospital. Conclusion: The interventions significantly improved the appropriateness of prescribing for patients in the intervention group as evaluated by the instruments MAI, STOPP and START. High scores in MAI and STOPP were associated with a higher number of drug-related readmissions.

  • 284.
    Gillman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Muradrasoli, Shaman
    Mårdnäs, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Söderström, Hanna
    Fedorova, Ganna
    Löwenthal, Max
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Wille, Michelle
    Daggfeldt, Annika
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure.2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Wild waterfowl is the natural reservoir of influenza A virus (IAV); hosted viruses are very variable and provide a source for genetic segments which can reassort with poultry or mammalian adapted IAVs to generate novel species crossing viruses. Additionally, wild waterfowl act as a reservoir for highly pathogenic IAVs. Exposure of wild birds to the antiviral drug oseltamivir may occur in the environment as its active metabolite can be released from sewage treatment plants to river water. Resistance to oseltamivir, or to other neuraminidase inhibitors (NAIs), in IAVs of wild waterfowl has not been extensively studied.

    AIM AND METHODS: In a previous in vivo Mallard experiment, an influenza A(H6N2) virus developed oseltamivir resistance by the R292K substitution in the neuraminidase (NA), when the birds were exposed to oseltamivir. In this study we tested if the resistance could be maintained in Mallards without drug exposure. Three variants of resistant H6N2/R292K virus were each propagated during 17 days in five successive pairs of naïve Mallards, while oseltamivir exposure was decreased and removed. Daily fecal samples were analyzed for viral presence, genotype and phenotype.

    RESULTS AND CONCLUSION: Within three days without drug exposure no resistant viruses could be detected by NA sequencing, which was confirmed by functional NAI sensitivity testing. We conclude that this resistant N2 virus could not compete in fitness with wild type subpopulations without oseltamivir drug pressure, and thus has no potential to circulate among wild birds. The results of this study contrast to previous observations of drug induced resistance in an avian H1N1 virus, which was maintained also without drug exposure in Mallards. Experimental observations on persistence of NAI resistance in avian IAVs resemble NAI resistance seen in human IAVs, in which resistant N2 subtypes do not circulate, while N1 subtypes with permissive mutations can circulate without drug pressure. We speculate that the phylogenetic group N1 NAs may easier compensate for NAI resistance than group N2 NAs, though further studies are needed to confirm such conclusions.

  • 285.
    Gillman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Muradrasoli, Shaman
    Söderström, Hanna
    Nordh, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Bröjer, Caroline
    Lindberg, Richard H
    Latorre-Margalef, Neus
    Waldenström, Jonas
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Resistance Mutation R292K Is Induced in Influenza A(H6N2) Virus by Exposure of Infected Mallards to Low Levels of Oseltamivir2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, p. e71230-Article in journal (Refereed)
    Abstract [en]

    Resistance to neuraminidase inhibitors (NAIs) is problematic as these drugs constitute the major treatment option for severe influenza. Extensive use of the NAI oseltamivir (Tamiflu®) results in up to 865 ng/L of its active metabolite oseltamivir carboxylate (OC) in river water. There one of the natural reservoirs of influenza A, dabbling ducks, can be exposed. We previously demonstrated that an influenza A(H1N1) virus in mallards (Anas platyrhynchos) exposed to 1 µg/L of OC developed oseltamivir resistance through the mutation H274Y (N2-numbering). In this study, we assessed the resistance development in an A(H6N2) virus, which belongs to the phylogenetic N2 group of neuraminidases with distinct functional and resistance characteristics. Mallards were infected with A(H6N2) while exposed to 120 ng/L, 1.2 µg/L or 12 µg/L of OC in their sole water source. After 4 days with 12 µg/L of OC exposure, the resistance mutation R292K emerged and then persisted. Drug sensitivity was decreased ≈13,000-fold for OC and ≈7.8-fold for zanamivir. Viral shedding was similar when comparing R292K and wild-type virus indicating sustained replication and transmission. Reduced neuraminidase activity and decrease in recovered virus after propagation in embryonated hen eggs was observed in R292K viruses. The initial, but not the later R292K isolates reverted to wild-type during egg-propagation, suggesting a stabilization of the mutation, possibly through additional mutations in the neuraminidase (D113N or D141N) or hemagglutinin (E216K). Our results indicate a risk for OC resistance development also in a N2 group influenza virus and that exposure to one NAI can result in a decreased sensitivity to other NAIs as well. If established in influenza viruses circulating among wild birds, the resistance could spread to humans via re-assortment or direct transmission. This could potentially cause an oseltamivir-resistant pandemic; a serious health concern as preparedness plans rely heavily on oseltamivir before vaccines can be mass-produced.

  • 286.
    Gingnell, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Bannbers, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Moes, Harmen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Engman, Jonas
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Sylvén, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Kask, Kristiina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wikstrom, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Emotion Reactivity Is Increased 4-6 Weeks Postpartum in Healthy Women: A Longitudinal fMRI Study2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id e0128964Article in journal (Refereed)
    Abstract [en]

    Marked endocrine alterations occur after delivery. Most women cope well with these changes, but the postpartum period is associated with an increased risk of depressive episodes. Previous studies of emotion processing have focused on maternal-infant bonding or postpartum depression (PPD), and longitudinal studies of the neural correlates of emotion processing throughout the postpartum period in healthy women are lacking. In this study, 13 women, without signs of post partum depression, underwent fMRI with an emotional face matching task and completed the MADRS-S, STAI-S, and EPDS within 48 h (early postpartum) and 4-6 weeks after delivery (late postpartum). Also, data from a previous study including 15 naturally cycling controls assessed in the luteal and follicular phase of the menstrual cycle was used. Women had lower reactivity in insula, middle frontal gyrus (MFG), and inferior frontal gyrus (IFG) in the early as compared to the late postpartum assessment. Insular reactivity was positively correlated with anxiety in the early postpartum period and with depressive symptoms late postpartum. Reactivity in insula and IFG were greater in postpartum women than in non-pregnant control subjects. Brain reactivity was not correlated with serum estradiol or progesterone levels. Increased reactivity in the insula, IFG, and MFG may reflect normal postpartum adaptation, but correlation with self-rated symptoms of depression and anxiety in these otherwise healthy postpartum women, may also suggest that these changes place susceptible women at increased risk of PPD. These findings contribute to our understanding of the neurobiological aspects of the postpartum period, which might shed light on the mechanisms underlying affective puerperal disorders, such as PPD.

  • 287.
    Gladh, Hanna
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Folestad, Erika Bergsten
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Muhl, Lars
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Ehnman, Monika
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Tannenberg, Philip
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.;Karolinska Univ Hosp, Div Vasc Surg, Dept Surg Sci, Stockholm, Sweden..
    Lawrence, Anna-Lisa
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden.;Univ Michigan, Sch Med, Dept Internal Med, Div Cardiovasc Med, Ann Arbor, MI USA..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Eriksson, Ulf
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, Stockholm, Sweden..
    Mice Lacking Platelet-Derived Growth Factor D Display a Mild Vascular Phenotype2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0152276Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor D (PDGF-D) is the most recently discovered member of the PDGF family. PDGF-D signals through PDGF receptor beta, but its biological role remains largely unknown. In contrast to other members of the PDGF family of growth factors, which have been extensively investigated using different knockout approaches in mice, PDGF-D has until now not been characterized by gene inactivation in mice. Here, we present the phenotype of a constitutive Pdgfd knockout mouse model (Pdgfd(-/-)), carrying a LacZ reporter used to visualize Pdgfd promoter activity. Inactivation of the Pdgfd gene resulted in a mild phenotype in C57BL/6 mice, and the offspring was viable, fertile and generally in good health. We show that Pdgfd reporter gene activity was consistently localized to vascular structures in both postnatal and adult tissues. The expression was predominantly arterial, often localizing to vascular bifurcations. Endothelial cells appeared to be the dominating source for Pdgfd, but reporter gene activity was occasionally also found in sub-populations of mural cells. Tissue-specific analyses of vascular structures revealed that NG2-expressing pericytes of the cardiac vasculature were disorganized in Pdgfd(-/-) mice. Furthermore, Pdgfd(-/-) mice also had a slightly elevated blood pressure. In summary, the vascular expression pattern together with morphological changes in NG2-expressing cells, and the increase in blood pressure, support a function for PDGF-D in regulating systemic arterial blood pressure, and suggests a role in maintaining vascular homeostasis.

  • 288. Glaeser, Stefanie P.
    et al.
    Berghoff, Bork A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Stratmann, Verena
    Grossart, Hans-Peter
    Glaeser, Jens
    Contrasting Effects of Singlet Oxygen and Hydrogen Peroxide on Bacterial Community Composition in a Humic Lake2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 3, p. e92518-Article in journal (Refereed)
    Abstract [en]

    Light excitation of humic matter generates reactive oxygen species (ROS) in surface waters of aquatic ecosystems. Abundant ROS generated in humic matter rich lakes include singlet oxygen (O-1(2)) and hydrogen peroxide (H2O2). Because these ROS differ in half-life time and toxicity, we compared their effects on microbial activity (C-14-Leucine incorporation) and bacterial community composition (BCC) in surface waters of humic Lake Grosse Fuchskuhle (North-eastern Germany). For this purpose, experiments with water samples collected from the lake were conducted in July 2006, September 2008 and August 2009. Artificially increased O-1(2) and H2O2 concentrations inhibited microbial activity in water samples to a similar extent, but the effect of the respective ROS on BCC varied strongly. BCC analysis by 16S rRNA gene clone libraries and RT-PCR DGGE revealed ROS specific changes in relative abundance and activity of major bacterial groups and composition of dominating phylotypes. These changes were consistent in the three experiments performed in different years. The relative abundance of Polynucleobacter necessarius, Limnohabitans-related phylotypes (Betaproteobacteria), and Novosphingobium acidiphilum (Alphaproteobacteria) increased or was not affected by photo-sensitized O-1(2) exposure, but decreased after H2O2 exposure. The opposite pattern was found for Actinobacteria of the freshwater AcI-B cluster which were highly sensitive to O-1(2) but not to H2O2 exposure. Furthermore, group-specific RT-PCR DGGE analysis revealed that particle-attached P. necessarius and Limnohabitans-related phylotypes exhibit higher resistance to O-1(2) exposure compared to free-living populations. These results imply that O-1(2) acts as a factor in niche separation of closely affiliated Polynucleobacter and Limnohabitans-related phylotypes. Consequently, oxidative stress caused by photochemical ROS generation should be regarded as an environmental variable determining abundance, activity, and phylotype composition of environmentally relevant bacterial groups, in particular in illuminated and humic matter rich waters.

  • 289.
    Goropashnaya, Anna V.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
    Fedorov, Vadim B.
    Seifert, Bernhard
    Pamilo, Pekka
    Phylogenetic relationships of Palaearctic Formica species (Hymenoptera, Formicidae) based on mitochondrial cytochrome b sequences2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e41697-Article in journal (Refereed)
    Abstract [en]

    Ants of genus Formica demonstrate variation in social organization and represent model species for ecological, behavioral, evolutionary studies and testing theoretical implications of the kin selection theory. Subgeneric division of the Formica ants based on morphology has been questioned and remained unclear after an allozyme study on genetic differentiation between 13 species representing all subgenera was conducted. In the present study, the phylogenetic relationships within the genus were examined using mitochondrial DNA sequences of the cytochrome b and a part of the NADH dehydrogenase subunit 6. All 23 Formica species sampled in the Palaearctic clustered according to the subgeneric affiliation except F. uralensis that formed a separate phylogenetic group. Unlike Coptoformica and Formica s. str., the subgenus Serviformica did not form a tight cluster but more likely consisted of a few small clades. The genetic distances between the subgenera were around 10%, implying approximate divergence time of 5 Myr if we used the conventional insect divergence rate of 2% per Myr. Within-subgenus divergence estimates were 6.69% in Serviformica, 3.61% in Coptoformica, 1.18% in Formica s. str., which supported our previous results on relatively rapid speciation in the latter subgenus. The phylogeny inferred from DNA sequences provides a necessary framework against which the evolution of social traits can be compared. We discuss implications of inferred phylogeny for the evolution of social traits.

  • 290.
    Grandahl, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Larsson, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Dalianis, Tina
    Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
    Stenhammar, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Tydén, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Westerling, Ragnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social Medicine.
    Nevéus, Tryggve
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Paediatric Inflammation Research.
    Catch-up HPV vaccination status of adolescents in relation to socioeconomic factors, individual beliefs and sexual behaviour2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, article id e0187193Article in journal (Refereed)
    Abstract [en]

    In 2012, human papillomavirus (HPV) vaccination was introduced free of charge in the Swedish national school-based vaccination programme for 10-12-year-old girls, and as catch-up vaccination for young women. In Sweden, there is an ongoing discussion about including boys in the national vaccination programme. Few studies are undertaken about adolescents' knowledge, beliefs and HPV vaccination status in relation to socioeconomic status and sexual experience. Thus, the aim was to examine HPV catch-up vaccination status in adolescents in relation to 1) socioeconomic factors, 2) beliefs and knowledge about HPV prevention, and 3) sexual behaviour. The Health Belief Model was used as a theoretical framework. Upper secondary school students (n = 832) aged 16, randomly chosen from a larger sample, were invited to participate in conjunction with the general health interview with the school nurse. A total of 751/832 (90.3%), girls (n = 391, 52%) and boys (n = 360, 48%) completed the questionnaire. HPV vaccination was associated with ethnicity and the mothers' education level; i.e. girls with a non-European background and girls with a less educated mother were less likely to have received the vaccine (p<0.01 and p = 0.04 respectively). Vaccinated girls perceived HPV infection as more severe (p = 0.01), had more insight into women's susceptibility to the infection (p = 0.02), perceived more benefits of the vaccine as protection against cervical cancer (p<0.01) and had a higher intention to engage in HPV-preventive behaviour (p = 0.01). Furthermore, boys and girls were almost equally sexually experienced, although fewer girls had used condom during first intercourse with their latest partner (p = 0.03). Finally, HPV vaccinated girls were less likely to have unprotected sex (p<0.01). In summary, catch-up HPV vaccination among young girls was associated with a European background and high maternal education level, as well as more favourable beliefs towards HPV prevention and less sexual risk-taking. Further preventive measures should therefore be directed at the migrant population.

  • 291.
    Grandahl, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Larsson, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Tydén, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stenhammar, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    School nurses' attitudes towards and experiences of the Swedish school-based HPV vaccination programme - A repeated cross sectional study2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0175883Article in journal (Refereed)
    Abstract [en]

    The aim was to investigate school nurses' attitudes towards, and experiences of vaccination against human papillomavirus (HPV), and compare the results with a similar study three years earlier. School nurses (n = 736) from all counties in Sweden completed a questionnaire in spring 2016, four years after the implementation of the national HPV vaccination programme, and three years after the previous survey. Overall, the school nurses had more favourable attitudes towards the HPV vaccination programme compared to the study in 2013 (p = 0.015). More than half of the nurses (n = 415, 56%) strongly agreed that boys should also be offered the vaccine (p<0.001). There were no differences in school nurses' perceived knowledge about HPV in order to inform and to answer questions about the vaccine from the girls or from the parents. More than half of the nurses (n = 409, 56%) reported that they needed more education about HPV. Almost all nurses (n = 659, 90%) had been contacted by parents with questions about the vaccine, and most questions were related to vaccine safety. School nurses have a more favourable attitude towards the vaccination programme against HPV compared to three years earlier, although almost all nurses had been contacted by parents with diverse questions and concerns. The nurses believed that they needed more education about HPV. Thus, it is essential to provide ongoing education and training for school nurses who are key healthcare professionals for providing information about HPV and HPV vaccination to parents and to pupils.

  • 292.
    Grandahl, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research. Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden..
    Paek, Seung Chun
    Mahidol Univ, Dept Soc & Hlth, Salaya Campus, Bangkok, Thailand..
    Grisurapong, Siriwan
    Mahidol Univ, Dept Soc & Hlth, Salaya Campus, Bangkok, Thailand..
    Sherer, Penchan
    Mahidol Univ, Dept Soc & Hlth, Salaya Campus, Bangkok, Thailand..
    Tydén, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research. Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden..
    Lundberg, Pranee
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Parents' knowledge, beliefs, and acceptance of the HPV vaccination in relation to their socio-demographics and religious beliefs: A cross-sectional study in Thailand2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 2, article id e0193054Article in journal (Refereed)
    Abstract [en]

    Thailand has one of the world's highest prevalence of cervical cancer, mainly caused by the human papillomavirus (HPV). HPV infections can successfully be prevented by vaccination, which is available at a cost but not yet implemented in the national vaccination program. Parents play a critical role in deciding whether to vaccinate their child against HPV. Thus, the aim was to examine the association between parents' knowledge, beliefs, and acceptance of the HPV vaccination for their daughters, considering their socio-demographics and religious beliefs. A cross-sectional design was used among three schools in Thailand: Nakorn Phatom province (suburban) and Bangkok (urban). Parents of 9-12-year-old daughters completed the questionnaires, guided by the Health Belief Model. In total, 359 parents completed the questionnaires; of those, 301 were included in the final analyses. The ordinary least squares (OLS) regression analysis showed that background knowledge of HPV and the HPV vaccine was positively related to knowledge of HPV and cervical cancer. For beliefs, knowledge was positively associated with susceptibility (i.e., parents' perceived risk of an HPV infection/related disease), severity, and benefit. However, knowledge was not significantly related to barriers. For acceptance, higher susceptibility and benefit were related to higher acceptance, and greater knowledge was associated with higher acceptance. Thus, we found associations between parents' knowledge, beliefs, and acceptance of the HPV vaccination for their daughters, considering their socio-demographics and religious beliefs. Parents, who reported religion as important, as opposed to those who did not, were more favorable toward the HPV vaccination. Four out of ten mothers had never undergone a cervical cancer screening, but most had accepted previous childhood vaccinations for their daughters. The overall acceptance of the vaccine was high, and we believe our results are promising for future implementation of the HPV vaccination in the national childhood vaccination program in Thailand.

  • 293.
    Gravningen, Kirsten
    et al.
    Department of Microbiology and Infection Control, University Hospital of North Norway, N - 9038 Tromsø, Norway and Faculty of Health Sciences, University of Tromsø, N – 9037 Tromsø, Norway.
    Christerson, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Furberg, Anne-Sofie
    Department of Microbiology and Infection Control, University Hospital of North Norway, N - 9038 Tromsø, Norway and Faculty of Health Sciences, University of Tromsø, N – 9037 Tromsø, Norway.
    Simonsen, Gunnar Skov
    Department of Microbiology and Infection Control, University Hospital of North Norway, N - 9038 Tromsø, Norway.
    Ödman, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Ståhlsten, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Herrmann, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology.
    Multilocus Sequence Typing of Genital Chlamydia trachomatis in Norway Reveals Multiple New Sequence Types and a Large Genetic Diversity2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. e34452-Article in journal (Refereed)
    Abstract [en]

    Background: The Chlamydia trachomatis incidence rate in Finnmark, the most northern and sparsely populated county in Norway, has been twice the national average. This population based cross-sectional study among Finnmark high school students had the following aims: i) to examine distribution of multilocus sequence types (STs) of C. trachomatis in a previously unmapped area, ii) to compare chlamydia genetic diversity in Finnmark with that of two urban regions, and iii) to compare discriminatory capacity of multilocus sequence typing (MLST) with conventional ompA sequencing in a large number of chlamydia specimens.

    Methodology: ompA sequencing and a high-resolution MLST system based on PCR amplification and DNA sequencing of five highly variable genetic regions were used. Eighty chlamydia specimens from adolescents aged 15-20 years in Finnmark were collected in five high schools (n = 60) and from routine clinical samples in the laboratory (n = 20). These were compared to routine clinical samples from adolescents in Tromso (n = 80) and Trondheim (n = 88), capitals of North and Central Norway, respectively.

    Principal Findings: ompA sequencing detected 11 genotypes in 248 specimens from all three areas. MLST displayed 50 STs providing a five-fold higher resolution. Two-thirds of all STs were novel. The common ompA E/Bour genotype comprised 46% and resolved into 24 different STs. MLST identified the Swedish new variant of C. trachomatis not discriminated by ompA sequencing. Simpson's discriminatory index (D) was 0.93 for MLST, while a corrected D-c was 0.97. There were no statistically significant differences in ST genetic diversity between geographic areas. Finnmark had an atypical genovar distribution with G being predominant. This was mainly due to expansion of specific STs of which the novel ST161 was unique for Finnmark.

    Conclusions/Significance: MLST revealed multiple new STs and a larger genetic diversity in comparison to ompA sequencing and proved to be a useful tool in molecular epidemiology of chlamydia infections.

  • 294.
    Gredebäck, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Melinder, Annika
    Teleological Reasoning in 4-Month-Old Infants: Pupil Dilations and Contextual Constraints2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 10, p. e26487-Article in journal (Refereed)
    Abstract [en]

    Four-month-old infants were presented with feeding actions performed in a rational or irrational manner. Infants reacted to the irrational feeding actions by dilating their pupils, but only in the presence of rich contextual constraints. The study demonstrates that teleological processes are online at 4 months of age and illustrates the usefulness of pupil dilations as a measure of social cognitive processes early in infancy.

  • 295.
    Griesser, Michael
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Population and Conservation Biology.
    Ma, Qi
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Analysis and Applied Mathematics.
    Webber, Simone
    Bowgen, Katharine
    Sumpter, David J. T.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Analysis and Applied Mathematics.
    Understanding Animal Group-Size Distributions2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. e23438-Article in journal (Refereed)
    Abstract [en]

    One of the most striking aspects of animal groups is their remarkable variation in size, both within and between species. While a number of mechanistic models have been proposed to explain this variation, there are few comprehensive datasets against which these models have been tested. In particular, we only vaguely understand how environmental factors and behavioral activities affect group-size distributions. Here we use observations of House sparrows (Passer domesticus) to investigate the factors determining group-size distribution. Over a wide range of conditions, we observed that animal group sizes followed a single parameter distribution known as the logarithmic distribution. This single parameter is the mean group size experienced by a randomly chosen individual (including the individual itself). For sparrows, the experienced mean group size, and hence the distribution, was affected by four factors: morning temperature, place, behavior and the degree of food spillage. Our results further indicate that the sparrows regulate the mean group size they experience, either by groups splitting more or merging less when local densities are high. We suggest that the mean experienced group size provides a simple but general tool for assessing the ecology and evolution of grouping.

  • 296.
    Grundström, Jeanette
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Reimer, Jenny M.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Magnusson, Sofia E.
    Nilsson, Gunnar
    Wernersson, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Hellman, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Human Cord Blood Derived Immature Basophils Show Dual Characteristics, Expressing Both Basophil and Eosinophil Associated Proteins2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e48308-Article in journal (Refereed)
    Abstract [en]

    Basophils are blood cells of low abundance associated with allergy, inflammation and parasite infections. To study the transcriptome of mature circulating basophils cells were purified from buffy coats by density gradient centrifugations and two-step magnetic cell sorting. However, after extensive analysis the cells were found to be transcriptionally inactive and almost completely lack functional mRNA. In order to obtain transcriptionally active immature basophils for analysis of their transcriptome, umbilical cord blood cells were therefore cultured in the presence of interleukin (IL)-3 for 9 days and basophils were enriched by removing non-basophils using magnetic cell sorting. The majority of purified cells demonstrated typical metachromatic staining with Alcian blue dye (95%) and expression of surface markers FcεRI and CD203c, indicating a pure population of cells with basophil-like phenotype. mRNA was extracted from these cells and used to construct a cDNA library with approximately 600 000 independent clones. This library served as tool to determine the mRNA frequencies for a number of hematopoietic marker proteins. It was shown that these cells express basophil/mast cell-specific transcripts, i.e. β-tryptase, serglycin and FcεRI α-chain, to a relatively low degree. In contrast, the library contained a high number of several eosinophil-associated transcripts such as: major basic protein (MBP), charcot leyden crystal (CLC), eosinophil cationic protein (ECP), eosinophil derived neurotoxin (EDN) and eosinophil peroxidase (EPO). Out of these transcripts, MBP and EPO were the most frequently observed, representing 8% and 3.2% of the total mRNA pool, respectively. Moreover, in a proteome analysis of cultured basophils we identified MBP and EPO as the two most prominent protein bands, suggesting a good correlation between protein and mRNA analyses of these cells. The mixed phenotype observed for these cells strengthens the conclusion that eosinophils and basophils are closely linked during human hematopoietic development. The dual phenotype also indicates that other cytokines than IL-3 or cell surface interactions are needed to obtain the full basophil specific phenotype in vivo.

  • 297.
    Grönberg, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Ahlin, Cecilia
    Orebro Univ, Fac Med & Hlth, Dept Oncol, Orebro, Sweden..
    Naeser, Ylva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Kings Coll London, Fac Life Sci & Med, London, England..
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Ghrelin is a prognostic marker and a potential therapeutic target in breast cancer2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0176059Article in journal (Refereed)
    Abstract [en]

    Ghrelin and obestatin are gastrointestinal peptides, encoded by the same preproghrelin gene. Both are expressed in breast cancer tissue and ghrelin has been implicated in breast cancer tumorigenesis. Despite recent advances in breast cancer management the need for new prognostic markers and potential therapeutic targets in breast cancer remains high. We studied the prognostic impact of ghrelin and obestatin in women with node negative breast cancer. Within a cohort of women with breast cancer with tumor size <= 50 mm, no lymph node metastases and no initiation of adjuvant chemotherapy, 190 women were identified who died from breast cancer and randomly selected 190 women alive at the corresponding time as controls. Tumor tissues were immunostained with antibodies versus the peptides. Ghrelin expression was associated with better breast cancer specific survival in univariate analyses (OR 0.55, 95% CI 0.36-0.84) and in multivariate models, adjusted for endocrine treatment and age (OR 0.57, 95% CI 0.36-0.89). Obestatin expression was non-informative (OR 1.2, 95% CI 0.60-2.46). Ghrelin expression is independent prognostic factor for breast cancer death in node negative patients-halving the risk for dying of breast cancer. Our data implies that ghrelin could be a potential therapeutic target in breast cancer treatment.

  • 298.
    Grönlund, Andreas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Analysis and Applied Mathematics.
    Yi, Il Gu
    Kim, Beom Jun
    Fractal Profit Landscape of the Stock Market2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e33960-Article in journal (Refereed)
    Abstract [en]

    We investigate the structure of the profit landscape obtained from the most basic, fluctuation based, trading strategy applied for the daily stock price data. The strategy is parameterized by only two variables, p and q Stocks are sold and bought if the log return is bigger than p and less than -q, respectively. Repetition of this simple strategy for a long time gives the profit defined in the underlying two-dimensional parameter space of p and q. It is revealed that the local maxima in the profit landscape are spread in the form of a fractal structure. The fractal structure implies that successful strategies are not localized to any region of the profit landscape and are neither spaced evenly throughout the profit landscape, which makes the optimization notoriously hard and hypersensitive for partial or limited information. The concrete implication of this property is demonstrated by showing that optimization of one stock for future values or other stocks renders worse profit than a strategy that ignores fluctuations, i.e., a long-term buy-and-hold strategy.

  • 299.
    Gunnarsdottir, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Cnattingius, Sven
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska University Hospital, and Institutet.
    Maria, Lundgren
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Katarina, Selling
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Högberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Department of Clinical Sciences, Danderyds sjukhus, Karolinska Institutet.
    Prenatal exposure to preeclampsia is associated with accelerated height gain in early childhoodIn: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203Article in journal (Refereed)
  • 300. Gunnarsson, Gunnar
    et al.
    Latorre-Margalef, Neus
    Hobson, Keith A.
    Van Wilgenburg, Steven L.
    Elmberg, Johan
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Fouchier, Ron A. M.
    Waldenstrom, Jonas
    Disease Dynamics and Bird Migration: Linking Mallards Anas platyrhynchos and Subtype Diversity of the Influenza A Virus in Time and Space2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e35679-Article in journal (Refereed)
    Abstract [en]

    The mallard Anas platyrhynchos is a reservoir species for influenza A virus in the northern hemisphere, with particularly high prevalence rates prior to as well as during its prolonged autumn migration. It has been proposed that the virus is brought from the breeding grounds and transmitted to conspecifics during subsequent staging during migration, and so a better understanding of the natal origin of staging ducks is vital to deciphering the dynamics of viral movement pathways. Ottenby is an important stopover site in southeast Sweden almost halfway downstream in the major Northwest European flyway, and is used by millions of waterfowl each year. Here, mallards were captured and sampled for influenza A virus infection, and positive samples were subtyped in order to study possible links to the natal area, which were determined by a novel approach combining banding recovery data and isotopic measurements (delta H-2) of feathers grown on breeding grounds. Geographic assignments showed that the core natal areas of studied mallards were in Estonia, southern and central Finland, and northwestern Russia. This study demonstrates a clear temporal succession of latitudes of natal origin during the course of autumn migration. We also demonstrate a corresponding and concomitant shift in virus subtypes. Acknowledging that these two different patterns were based in part upon different data, a likely interpretation worth further testing is that the early arriving birds with more proximate origins have different influenza A subtypes than the more distantly originating late autumn birds. If true, this knowledge would allow novel insight into the origins and transmission of the influenza A virus among migratory hosts previously unavailable through conventional approaches.

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