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  • 601. van Hees, Vincent
    et al.
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Wright, A
    Gradmark, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Catt, M
    Chen, K
    Löf, M
    Bluck, L
    Wareham, NJ
    Ekelund, U
    Brage, S
    Franks, Paul W
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Estimation of daily energy expenditure in pregnant and non-pregnant women using a wrist-worn tri-axial accelerometer2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 7, p. e22922-Article in journal (Other academic)
    Abstract [en]

    Background Few studies have compared the validity of objective measures of physical activity energy expenditure (PAEE) in pregnant and non-pregnant women.  PAEE is commonly estimated with accelerometers attached to the hip or waist, but little is known about the validity and participant acceptability of wrist attachment. The objective of the current study was to assess the validity of a simple summary measure derived from a wrist-worn accelerometer (GENEA, Unilever Discover, UK) to estimate PAEE in pregnant and non-pregnant women, and to evaluate participant acceptability.

     

    Methods  Non-pregnant (N=73) and pregnant (N=35) Swedish women (aged 20–35 yrs) wore the accelerometer on their wrist for 10 days during which total energy expenditure (TEE) was assessed using doubly-labelled water. PAEE was calculated as 0.9 x TEE - REE. British participants (N=99; aged 22–65 yrs) wore accelerometers on their non-dominant wrist and hip for seven days and were asked to score the acceptability of monitor placement (scored 1 [least] through 10 [most] acceptable).

     

    Results There was no significant correlation between body weight and PAEE. In non-pregnant women, acceleration explained 24% of the variation in PAEE, which decreased to 17% in leave-one-out cross-validation. In pregnant women, acceleration explained 11% of the variation in PAEE, which was not significant in leave-one-out cross-validation. Median (IQR) acceptability of wrist and hip placement was 9(8-10) and 9(7-10), respectively; a within-individual difference of 0.47 was significant (p<.001).

     

    Conclusions A simple summary measure derived from a wrist-worn tri-axial accelerometer adds significantly to the prediction of energy expenditure in non-pregnant women and is scored acceptable by participants.

  • 602. van Hees, Vincent T.
    et al.
    Gorzelniak, Lukas
    Leon, Emmanuel Carlos Dean
    Eder, Martin
    Pias, Marcelo
    Taherian, Salman
    Ekelund, Ulf
    Renström, Frida
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Horsch, Alexander
    Brage, Soren
    Separating Movement and Gravity Components in an Acceleration Signal and Implications for the Assessment of Human Daily Physical Activity2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 4, p. e61691-Article in journal (Refereed)
    Abstract [en]

    Introduction: Human body acceleration is often used as an indicator of daily physical activity in epidemiological research. Raw acceleration signals contain three basic components: movement, gravity, and noise. Separation of these becomes increasingly difficult during rotational movements. We aimed to evaluate five different methods (metrics) of processing acceleration signals on their ability to remove the gravitational component of acceleration during standardised mechanical movements and the implications for human daily physical activity assessment. Methods: An industrial robot rotated accelerometers in the vertical plane. Radius, frequency, and angular range of motion were systematically varied. Three metrics (Euclidian norm minus one [ENMO], Euclidian norm of the high-pass filtered signals [HFEN], and HFEN plus Euclidean norm of low-pass filtered signals minus 1 g [HFEN+]) were derived for each experimental condition and compared against the reference acceleration (forward kinematics) of the robot arm. We then compared metrics derived from human acceleration signals from the wrist and hip in 97 adults (22-65 yr), and wrist in 63 women (20-35 yr) in whom daily activity-related energy expenditure (PAEE) was available. Results: In the robot experiment, HFEN+ had lowest error during (vertical plane) rotations at an oscillating frequency higher than the filter cut-off frequency while for lower frequencies ENMO performed better. In the human experiments, metrics HFEN and ENMO on hip were most discrepant (within- and between-individual explained variance of 0.90 and 0.46, respectively). ENMO, HFEN and HFEN+ explained 34%, 30% and 36% of the variance in daily PAEE, respectively, compared to 26% for a metric which did not attempt to remove the gravitational component (metric EN). Conclusion: In conclusion, none of the metrics as evaluated systematically outperformed all other metrics across a wide range of standardised kinematic conditions. However, choice of metric explains different degrees of variance in daily human physical activity.

  • 603. Van Hemelrijck, Mieke
    et al.
    Garmo, Hans
    Michaelsson, Karl
    Thorstenson, Andreas
    Akre, Olof
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Holmberg, Lars
    Adolfsson, Jan
    Mortality following Hip Fracture in Men with Prostate Cancer2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e74492-Article in journal (Refereed)
    Abstract [en]

    Background: Hip fractures are associated with increased mortality and are a known adverse effect of androgen deprivation therapy (ADT) for prostate cancer (PCa). It was our aim to evaluate how mortality after hip fracture is modified by PCa and ADT.

    Methods: PCa dataBase Sweden (PCBaSe 2.0) is based on the National PCa Register and also contains age and county-matched PCa-free men. We selected all men (n = 14,205) who had been hospitalized with a hip fracture between 2006 and 2010; 2,300 men had a prior PCa diagnosis of whom 1,518 (66%) were on ADT prior to date of fracture. Risk of death was estimated with cumulative incidence and standardized mortality ratios (SMRs) to make comparisons with the entire PCa population and the general population.

    Results: Cumulative incidences indicated that there was a higher risk of death following a hip fracture for PCa men on ADT than for PCa men not on ADT or PCa-free men, particularly in the first year. The SMRs showed that PCa men on ADT with a hip fracture were 2.44 times more likely to die than the comparison cohort of all PCa men (95% CI: 2.29-2.60). This risk was especially increased during the first month (5.64 (95% CI: 4.16-7.48)). In absolute terms, hip fractures were associated with 20 additional deaths per 1,000 person-years in PCa men not on ADT, but 30 additional deaths per 1,000 person-years for PCa men on ADT, compared to all PCa men.

    Conclusion: Hip fractures are associated with higher all-cause mortality in PCa men on ADT than in PCa men not on ADT or PCa-free men, especially within the first three months.

  • 604. Van Hemelrijck, Mieke
    et al.
    Ulmer, Hanno
    Nagel, Gabriele
    Peter, Raphael Simon
    Fritz, Josef
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Föger, Bernhard
    Concin, Hans
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Uppsala University, Department of Surgical Sciences, Uppsala, Sweden.
    Stattin, Pär
    Uppsala University, Department of Surgical Sciences, Uppsala, Sweden.
    Stocks, Tanja
    Longitudinal study of body mass index, dyslipidemia, hyperglycemia, and hypertension in 60,000 men and women in Sweden and Austria2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 6, article id e0197830Article in journal (Refereed)
    Abstract [en]

    Background: Obesity is suggested to underlie development of other metabolic aberrations, but longitudinal relationships between metabolic factors at various ages has not been studied in detail. Methods: Data from 27,379 men and 32,275 women with in total 122,940 health examinations in the Västerbotten Intervention Project, Sweden and the Vorarlberg Health Monitoring and Prevention Programme, Austria were used to investigate body mass index (BMI), mid-blood pressure, and fasting levels of glucose, triglycerides, and total cholesterol at baseline in relation to 10-year changes of these factors and weight. We included paired examinations performed 10 +/- 2 years apart and used them for longitudinal analysis with linear regression of changes between the ages 30 and 40, 40 and 50, or 50 and 60 years. Results: Higher levels of BMI were associated with increases in glucose and mid-blood pressure as well as triglycerides levels, and, to a lesser extent, decreases in cholesterol levels. For instance, per 5 kg/m(2) higher BMI at age 40, glucose at age 50 increased by 0.24 mmol/l (95%Cl:0.22-0.26) and mid-blood pressure increased by 1.54 mm Hg (95%Cl: 1.35-1.74). The strongest association observed was between BMI at age 30 and mid-blood pressure, which was 2.12 mm Hg (95% CI: 1.79-2.45) increase over ten years per 5 kg/m(2) higher BMI level. This association was observed at an age when blood pressure levels on average remained stable. Other associations than those with BMI at baseline were much weaker. However, triglyceride levels were associated with future glucose changes among individuals with elevated BMI, particularly in the two older age groups. Conclusion: BMI was most indicative of long-term changes in metabolic factors, and the strongest impact was observed for increases in blood pressure between 30 and 40 years of age. Our study supports that lifestyle interventions preventing metabolic aberrations should focus on avoiding weight increases.

  • 605. van Woudenbergh, Geertruida J.
    et al.
    Kuijsten, Anneleen
    Drogan, Dagmar
    van der A, Daphne L.
    Romaguera, Dora
    Ardanaz, Eva
    Amiano, Pilar
    Barricarte, Aurelio
    Beulens, Joline W. J.
    Boeing, Heiner
    Bueno-de-Mesquita, H. Bas
    Dahm, Christina C.
    Chirlaque, M-Doleres
    Clavel, Fran-coise
    Crowe, Francesca L.
    Eomois, Piia-Piret
    Fagher-azzi, Guy
    Franks, Paul W.
    Halkjaer, Jytte
    Khaw, Kay T.
    Masala, Giovanna
    Mattiello, Amalia
    Nilsson, Peter
    Overvad, Kim
    Quiros, J. Ramon
    Rolandsson, Olov
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Romieu, Isabelle
    Sacerdote, Carlotta
    Sanchez, Maria-Jose
    Schulze, Matthias B.
    Slimani, Nadia
    Sluijs, Ivonne
    Spijkerman, Annemieke M. W.
    Tagliabue, Giovanna
    Teucher, Birgit
    Tjonneland, Anne
    Tumino, Rosario
    Forouhi, Nita G.
    Sharp, Stephen
    Langenberg, Claudia
    Feskens, Edith J. M.
    Riboli, Elio
    Wareham, Nicholas J.
    Tea Consumption and Incidence of Type 2 Diabetes in Europe: The EPIC-InterAct Case-Cohort Study2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e36910-Article in journal (Refereed)
    Abstract [en]

    Background: In previous meta-analyses, tea consumption has been associated with lower incidence of type 2 diabetes. It is unclear, however, if tea is associated inversely over the entire range of intake. Therefore, we investigated the association between tea consumption and incidence of type 2 diabetes in a European population. Methodology/Principal Findings: The EPIC-InterAct case-cohort study was conducted in 26 centers in 8 European countries and consists of a total of 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,835 individuals from a total cohort of 340,234 participants with 3.99 million person-years of follow-up. Country-specific Hazard Ratios (HR) for incidence of type 2 diabetes were obtained after adjustment for lifestyle and dietary factors using a Cox regression adapted for a case-cohort design. Subsequently, country-specific HR were combined using a random effects meta-analysis. Tea consumption was studied as categorical variable (0, >0-<1, 1-<4, >= 4 cups/day). The dose-response of the association was further explored by restricted cubic spline regression. Country specific medians of tea consumption ranged from 0 cups/day in Spain to 4 cups/day in United Kingdom. Tea consumption was associated inversely with incidence of type 2 diabetes; the HR was 0.84 [95% CI 0.71, 1.00] when participants who drank >= 4 cups of tea per day were compared with non-drinkers (p(linear) (trend) = 0.04). Incidence of type 2 diabetes already tended to be lower with tea consumption of 1-<4 cups/day (HR = 0.93 [95% CI 0.81, 1.05]). Spline regression did not suggest a non-linear association (p(non-linearity) = 0.20). Conclusions/Significance: A linear inverse association was observed between tea consumption and incidence of type 2 diabetes. People who drink at least 4 cups of tea per day may have a 16% lower risk of developing type 2 diabetes than non-tea drinkers.

  • 606. Vanha-Aho, Leena-Maija
    et al.
    Kleino, Anni
    Kaustio, Meri
    Ulvila, Johanna
    Wilke, Bettina
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Valanne, Susanna
    Rämet, Mika
    Functional Characterization of the Infection-Inducible Peptide Edin in Drosophila melanogaster2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e37153-Article in journal (Refereed)
    Abstract [en]

    Drosophila is a well-established model organism for studying innate immunity because of its high resistance against microbial infections and lack of adaptive immunity. In addition, the immune signaling cascades found in Drosophila are evolutionarily conserved. Upon infection, activation of the immune signaling pathways, Toll and Imd, leads to the expression of multiple immune response genes, such as the antimicrobial peptides (AMPs). Previously, we identified an uncharacterized gene edin among the genes, which were strongly induced upon stimulation with Escherichia coli in Drosophila S2 cells. Edin has been associated with resistance against Listeria monocytogenes, but its role in Drosophila immunity remains elusive. In this study, we examined the role of Edin in the immune response of Drosophila both in vitro and in vivo. We report that edin expression is dependent on the Imd-pathway NF-κB transcription factor Relish and that it is expressed upon infection both in vitro and in vivo. Edin encodes a pro-protein, which is further processed in S2 cells. In our experiments, Edin did not bind microbes, nor did it possess antimicrobial activity to tested microbial strains in vitro or in vivo. Furthermore, edin RNAi did not significantly affect the expression of AMPs in vitro or in vivo. However, edin RNAi flies showed modestly impaired resistance to E. faecalis infection. We conclude that Edin has no potent antimicrobial properties but it appears to be important for E. faecalis infection via an uncharacterized mechanism. Further studies are still required to elucidate the exact role of Edin in the Drosophila immune response.

  • 607. Vergnaud, Anne-Claire
    et al.
    Norat, Teresa
    Mouw, Traci
    Romaguera, Dora
    May, Anne M.
    Bueno-de-Mesquita, H. Bas
    van der Daphne, A.
    Agudo, Antonio
    Wareham, Nicholas
    Khaw, Kay-Tee
    Romieu, Isabelle
    Freisling, Heinz
    Slimani, Nadia
    Perquier, Florence
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Palli, Domenico
    Berrino, Franco
    Mattiello, Amalia
    Tumino, Rosario
    Ricceri, Fulvio
    Rodriguez, Laudina
    Molina-Montes, Esther
    Amiano, Pilar
    Barricarte, Aurelio
    Chirlaque, Maria-Dolores
    Crowe, Francesca L.
    Orfanos, Philippos
    Naska, Androniki
    Trichopoulou, Antonia
    Teucher, Birgit
    Kaaks, Rudolf
    Boeing, Heiner
    Buijsse, Brian
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Drake, Isabel
    Sonestedt, Emily
    Jakobsen, Marianne Uhre
    Overvad, Kim
    Tjonneland, Anne
    Halkjaer, Jytte
    Skeie, Guri
    Braaten, Tonje
    Lund, Eiliv
    Riboli, Elio
    Peeters, Petra H. M.
    Macronutrient Composition of the Diet and Prospective Weight Change in Participants of the EPIC-PANACEA Study2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, p. e57300-Article in journal (Refereed)
    Abstract [en]

    Background: The effect of the macronutrient composition of the usual diet on long term weight maintenance remains controversial.

    Methods: 373,803 subjects aged 25-70 years were recruited in 10 European countries (1992-2000) in the PANACEA project of the EPIC cohort. Diet was assessed at baseline using country-specific validated questionnaires and weight and height were measured at baseline and self-reported at follow-up in most centers. The association between weight change after 5 years of follow-up and the iso-energetic replacement of 5% of energy from one macronutrient by 5% of energy from another macronutrient was assessed using multivariate linear mixed-models. The risk of becoming overweight or obese after 5 years was investigated using multivariate Poisson regressions stratified according to initial Body Mass Index.

    Results: A higher proportion of energy from fat at the expense of carbohydrates was not significantly associated with weight change after 5 years. However, a higher proportion of energy from protein at the expense of fat was positively associated with weight gain. A higher proportion of energy from protein at the expense of carbohydrates was also positively associated with weight gain, especially when carbohydrates were rich in fibre. The association between percentage of energy from protein and weight change was slightly stronger in overweight participants, former smokers, participants >= 60 years old, participants underreporting their energy intake and participants with a prudent dietary pattern. Compared to diets with no more than 14% of energy from protein, diets with more than 22% of energy from protein were associated with a 23-24% higher risk of becoming overweight or obese in normal weight and overweight subjects at baseline.

    Conclusion: Our results show that participants consuming an amount of protein above the protein intake recommended by the American Diabetes Association may experience a higher risk of becoming overweight or obese during adult life.

  • 608. Vethanayagam, R. Robert
    et al.
    Almyroudis, Nikolaos G.
    Grimm, Melissa J.
    Lewandowski, David C.
    Pham, Christine T. N.
    Blackwell, Timothy S.
    Petraitiene, Ruta
    Petraitis, Vidmantas
    Walsh, Thomas J.
    Urban, Constantin F.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Segal, Brahm H.
    Role of NADPH Oxidase versus Neutrophil Proteases in Antimicrobial Host Defense2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12, p. e28149-Article in journal (Refereed)
    Abstract [en]

    NADPH oxidase is a crucial enzyme in mediating antimicrobial host defense and in regulating inflammation. Patients with chronic granulomatous disease, an inherited disorder of NADPH oxidase in which phagocytes are defective in generation of reactive oxidant intermediates (ROIs), suffer from life-threatening bacterial and fungal infections. The mechanisms by which NADPH oxidase mediate host defense are unclear. In addition to ROI generation, neutrophil NADPH oxidase activation is linked to the release of sequestered proteases that are posited to be critical effectors of host defense. To definitively determine the contribution of NADPH oxidase versus neutrophil serine proteases, we evaluated susceptibility to fungal and bacterial infection in mice with engineered disruptions of these pathways. NADPH oxidase-deficient mice (p47(phox-/-)) were highly susceptible to pulmonary infection with Aspergillus fumigatus. In contrast, double knockout neutrophil elastase (NE)(-/-) x cathepsin G (CG)(-/-) mice and lysosomal cysteine protease cathepsin C/dipeptidyl peptidase I (DPPI)-deficient mice that are defective in neutrophil serine protease activation demonstrated no impairment in antifungal host defense. In separate studies of systemic Burkholderia cepacia infection, uniform fatality occurred in p47(phox-/-) mice, whereas NE(-/-) x CG(-/-) mice cleared infection. Together, these results show a critical role for NADPH oxidase in antimicrobial host defense against A. fumigatus and B. cepacia, whereas the proteases we evaluated were dispensable. Our results indicate that NADPH oxidase dependent pathways separate from neutrophil serine protease activation are required for host defense against specific pathogens.

  • 609. Vetri, Valeria
    et al.
    Leone, Maurizio
    Morozova-Roche, Ludmilla A.
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Vestergaard, Bente
    Fodera, Vito
    Unlocked Concanavalin A Forms Amyloid-like Fibrils from Coagulation of Long-lived "Crinkled'' Intermediates2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e68912-Article in journal (Refereed)
    Abstract [en]

    Understanding the early events during amyloid aggregation processes is crucial to single out the involved molecular mechanisms and for designing ad hoc strategies to prevent and reverse amyloidogenic disorders. Here, we show that, in conditions in which the protein is positively charged and its conformational flexibility is enhanced, Concanavalin A leads to fibril formation via a non-conventional aggregation pathway. Using a combination of light scattering, circular dichroism, small angle X-ray scattering, intrinsic (Tryptophan) and extrinsic (ANS) fluorescence and confocal and 2-photon fluorescence microscopy we characterize the aggregation process as a function of the temperature. We highlight a multi-step pathway with the formation of an on-pathway long-lived intermediate and a subsequent coagulation of such "crinkled'' precursors into amyloid-like fibrils. The process results in a temperature-dependent aggregation-coagulation pathway, with the late phase of coagulation determined by the interplay between hydrophobic and electrostatic forces. Our data provide evidence for the complex aggregation pathway for a protein with a highly flexible native conformation. We demonstrate the possibility to generate a long-lived intermediate whose proportion and occurrence are easily tunable by experimental parameters (i.e. temperature). As a consequence, in the case of aggregation processes developing through well-defined energy barriers, our results can open the way to new strategies to induce more stable in vitro on-pathway intermediate species through a minute change in the initial conformational flexibility of the protein. This will allow isolating and experimentally studying such transient species, often indicated as relevant in neurodegenerative diseases, both in terms of structural and cytotoxic properties.

  • 610.
    Vicente, André
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Byström, Berit
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Lindström, Mona
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Stenevi, Ulf
    Pedrosa Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB). Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Aniridia-related keratopathy: structural changes in naïve and transplanted corneal buttons2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 6, article id e0198822Article in journal (Refereed)
    Abstract [en]

    Background: To study structural changes in naive and surgically treated corneas of aniridia patients with advanced aniridia-related keratopathy (ARK).

    Methods and findings: Two naive corneal buttons from patients with advanced ARK submitted to penetrating keratoplasty for the first time, one corneal button from an ARK patient that had undergone a keratolimbal allograft (KLAL), two corneal buttons from ARK patients who had previously undergone centered or decentered transplantation and were now retransplanted and two adult healthy donor control corneas were processed for immunohistochemistry. Antibodies against extracellular matrix components in the stroma and in the epithelial basement membrane (collagen I and IV, collagen receptor alpha 11 integrin and laminin alpha 3 chain), markers of fibrosis, wound healing and vascularization (fibronectin, tenascin-C, vimentin, alpha-SMA and caveolin-1), cell division (Ki-67) and macrophages (CD68) were used. Naive ARK, KLAL ARK corneas and transplanted corneal buttons presented similar histopathological changes with irregular epithelium and disruption or absence of epithelial basal membrane. There was a loss of the orderly pattern of collagen lamellae and absence of collagen I in all ARK corneas. Vascularization was revealed by the presence of caveolin-1 and collagen IV in the pannus of all ARK aniridia corneas. The changes observed in decentered and centered transplants were analogous.

    Conclusions: Given the similar pathological features of all cases, conditions inherent to the host seem to play an important role on the pathophysiology of the ARK in the long run.

  • 611.
    Vidman, Linda
    et al.
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Källberg, David
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Cluster analysis on high dimensional RNA-seq data with applications to cancer research: An evaluation study2019In: PLoS ONE, E-ISSN 1932-6203, Vol. 14, no 12, article id e0219102Article in journal (Refereed)
    Abstract [en]

    Background: Clustering of gene expression data is widely used to identify novel subtypes of cancer. Plenty of clustering approaches have been proposed, but there is a lack of knowledge regarding their relative merits and how data characteristics influence the performance. We evaluate how cluster analysis choices affect the performance by studying four publicly available human cancer data sets: breast, brain, kidney and stomach cancer. In particular, we focus on how the sample size, distribution of subtypes and sample heterogeneity affect the performance.

    Results: In general, increasing the sample size had limited effect on the clustering performance, e.g. for the breast cancer data similar performance was obtained for n = 40 as for n = 330. The relative distribution of the subtypes had a noticeable effect on the ability to identify the disease subtypes and data with disproportionate cluster sizes turned out to be difficult to cluster. Both the choice of clustering method and selection method affected the ability to identify the subtypes, but the relative performance varied between data sets, making it difficult to rank the approaches. For some data sets, the performance was substantially higher when the clustering was based on data from only one sex compared to data from a mixed population. This suggests that homogeneous data are easier to cluster than heterogeneous data and that clustering males and females individually may be beneficial and increase the chance to detect novel subtypes. It was also observed that the performance often differed substantially between females and males.

    Conclusions: The number of samples seems to have a limited effect on the performance while the heterogeneity, at least with respect to sex, is important for the performance. Hence, by analyzing the genders separately, the possible loss caused by having fewer samples could be outweighed by the benefit of a more homogeneous data.

  • 612. Vigorito, Elena
    et al.
    Kuchenbaecker, Karoline B.
    Beesley, Jonathan
    Adlard, Julian
    Agnarsson, Bjarni A.
    Andrulis, Irene L.
    Arun, Banu K.
    Barjhoux, Laure
    Belotti, Muriel
    Benitez, Javier
    Berger, Andreas
    Bojesen, Anders
    Bonanni, Bernardo
    Brewer, Carole
    Caldes, Trinidad
    Caligo, Maria A.
    Campbell, Ian
    Chan, Salina B.
    Claes, Kathleen B. M.
    Cohn, David E.
    Cook, Jackie
    Daly, Mary B.
    Damiola, Francesca
    Davidson, Rosemarie
    de Pauw, Antoine
    Delnatte, Capucine
    Diez, Orland
    Domchek, Susan M.
    Dumont, Martine
    Durda, Katarzyna
    Dworniczak, Bernd
    Easton, Douglas F.
    Eccles, Diana
    Edwinsdotter Ardnor, Christina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Eeles, Ros
    Ejlertsen, Bent
    Ellis, Steve
    Evans, D. Gareth
    Feliubadalo, Lidia
    Fostira, Florentia
    Foulkes, William D.
    Friedman, Eitan
    Frost, Debra
    Gaddam, Pragna
    Ganz, Patricia A.
    Garber, Judy
    Garcia-Barberan, Vanesa
    Gauthier-Villars, Marion
    Gehrig, Andrea
    Gerdes, Anne-Marie
    Giraud, Sophie
    Godwin, Andrew K.
    Goldgar, David E.
    Hake, Christopher R.
    Hansen, Thomas V. O.
    Healey, Sue
    Hodgson, Shirley
    Hogervorst, Frans B. L.
    Houdayer, Claude
    Hulick, Peter J.
    Imyanitov, Evgeny N.
    Isaacs, Claudine
    Izatt, Louise
    Izquierdo, Angel
    Jacobs, Lauren
    Jakubowska, Anna
    Janavicius, Ramunas
    Jaworska-Bieniek, Katarzyna
    Jensen, Uffe Birk
    John, Esther M.
    Vijai, Joseph
    Karlan, Beth Y.
    Kast, Karin
    Khan, Sofia
    Kwong, Ava
    Laitman, Yael
    Lester, Jenny
    Lesueur, Fabienne
    Liljegren, Annelie
    Lubinski, Jan
    Mai, Phuong L.
    Manoukian, Siranoush
    Mazoyer, Sylvie
    Meindl, Alfons
    Mensenkamp, Arjen R.
    Montagna, Marco
    Nathanson, Katherine L.
    Neuhausen, Susan L.
    Nevanlinna, Heli
    Niederacher, Dieter
    Olah, Edith
    Olopade, Olufunmilayo I.
    Ong, Kai-ren
    Osorio, Ana
    Park, Sue Kyung
    Paulsson-Karlsson, Ylva
    Pedersen, Inge Sokilde
    Peissel, Bernard
    Peterlongo, Paolo
    Pfeiler, Georg
    Phelan, Catherine M.
    Piedmonte, Marion
    Poppe, Bruce
    Angel Pujana, Miquel
    Radice, Paolo
    Rennert, Gad
    Rodriguez, Gustavo C.
    Rookus, Matti A.
    Ross, Eric A.
    Schmutzler, Rita Katharina
    Simard, Jacques
    Singer, Christian F.
    Slavin, Thomas P.
    Soucy, Penny
    Southey, Melissa
    Steinemann, Doris
    Stoppa-Lyonnet, Dominique
    Sukiennicki, Grzegorz
    Sutter, Christian
    Szabo, Csilla I.
    Tea, Muy-Kheng
    Teixeira, Manuel R.
    Teo, Soo-Hwang
    Terry, Mary Beth
    Thomassen, Mads
    Tibiletti, Maria Grazia
    Tihomirova, Laima
    Tognazzo, Silvia
    van Rensburg, Elizabeth J.
    Varesco, Liliana
    Varon-Mateeva, Raymonda
    Vratimos, Athanassios
    Weitzel, Jeffrey N.
    McGuffog, Lesley
    Kirk, Judy
    Toland, Amanda Ewart
    Hamann, Ute
    Lindor, Noralane
    Ramus, Susan J.
    Greene, Mark H.
    Couch, Fergus J.
    Offit, Kenneth
    Pharoah, Paul D. P.
    Chenevix-Trench, Georgia
    Antoniou, Antonis C.
    Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 7, article id e0158801Article in journal (Refereed)
    Abstract [en]

    Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95% CI: 0.68 to 0.79, p-value 2x 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95% CI: 0.59 to 0.80, p-value 1.0 x 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

  • 613. Viluksela, Matti
    et al.
    Heikkinen, Paivi
    van der Ven, Leo T. M.
    Rendel, Filip
    Roos, Robert
    Esteban, Javier
    Korkalainen, Merja
    Lensu, Sanna
    Miettinen, Hanna M.
    Savolainen, Kari
    Sankari, Satu
    Lilienthal, Hellmuth
    Adamsson, Annika
    Toppari, Jorma
    Herlin, Maria
    Finnila, Mikko
    Tuukkanen, Juha
    Leslie, Heather A.
    Hamers, Timo
    Hamscher, Gerd
    Al-Anati, Lauy
    Stenius, Ulla
    Dervola, Kine-Susann
    Bogen, Inger-Lise
    Fonnum, Frode
    Andersson, Patrik L.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Schrenk, Dieter
    Halldin, Krister
    Håkansson, Helen
    Toxicological Profile of Ultrapure 2,2 ',3,4,4 ',5,5 '-Heptachlorbiphenyl (PCB 180) in Adult Rats2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, p. e104639-Article in journal (Refereed)
    Abstract [en]

    PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.

  • 614.
    Vincent, Andrea G.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Department of Forest Ecology and Management, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Sundqvist, Maja K.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Department of Forest Ecology and Management, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Wardle, David A.
    Department of Forest Ecology and Management, Swedish University of Agricultural Sciences, Umeå, Sweden.
    Giesler, Reiner
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Bioavailable Soil Phosphorus Decreases with Increasing Elevation in a Subarctic Tundra Landscape2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 3, p. e92942-Article in journal (Refereed)
    Abstract [en]

    Phosphorus (P) is an important macronutrient in arctic and subarctic tundra and its bioavailability is regulated by the mineralization of organic P. Temperature is likely to be an important control on P bioavailability, although effects may differ across contrasting plant communities with different soil properties. We used an elevational gradient in northern Sweden that included both heath and meadow vegetation types at all elevations to study the effects of temperature, soil P sorption capacity and oxalate-extractable aluminium (Al-ox) and iron (Fe-ox) on the concentration of different soil P fractions. We hypothesized that the concentration of labile P fractions would decrease with increasing elevation (and thus declining temperature), but would be lower in meadow than in heath, given that N to P ratios in meadow foliage are higher. As expected, labile P in the form of Resin-P declined sharply with elevation for both vegetation types. Meadow soils did not have lower concentrations of Resin-P than heath soils, but they did have 2-fold and 1.5-fold higher concentrations of NaOH-extractable organic P and Residual P, respectively. Further, meadow soils had 3-fold higher concentrations of Al-ox + Feox and a 20% higher P sorption index than did heath soils. Additionally, Resin-P expressed as a proportion of total soil P for the meadow was on average half that in the heath. Declining Resin-P concentrations with elevation were best explained by an associated 2.5-3.0 degrees C decline in temperature. In contrast, the lower P availability in meadow relative to heath soils may be associated with impaired organic P mineralization, as indicated by a higher accumulation of organic P and P sorption capacity. Our results indicate that predicted temperature increases in the arctic over the next century may influence P availability and biogeochemistry, with consequences for key ecosystem processes limited by P, such as primary productivity.

  • 615.
    Virel, Ana
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Faergemann, Erik
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Orädd, Greger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Strömberg, Ingrid
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Magnetic Resonance Imaging (MRI) to Study Striatal Iron Accumulation in a Rat Model of Parkinson's Disease2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e112941-Article in journal (Refereed)
    Abstract [en]

    Abnormal accumulation of iron is observed in neurodegenerative disorders. In Parkinson's disease, an excess of iron has been demonstrated in different structures of the basal ganglia and is suggested to be involved in the pathogenesis of the disease. Using the 6-hydroxydopamine (6-OHDA) rat model of Parkinson's disease, the edematous effect of 6-OHDA and its relation with striatal iron accumulation was examined utilizing in vivo magnetic resonance imaging (MRI). The results revealed that in comparison with control animals, injection of 6-OHDA into the rat striatum provoked an edematous process, visible in T2-weighted images that was accompanied by an accumulation of iron clearly detectable in T2*-weighted images. Furthermore, Prussian blue staining to detect iron in sectioned brains confirmed the existence of accumulated iron in the areas of T2* hypointensities. The presence of ED1-positive microglia in the lesioned striatum overlapped with this accumulation of iron, indicating areas of toxicity and loss of dopamine nerve fibers. Correlation analyses demonstrated a direct relation between the hyperintensities caused by the edema and the hypointensities caused by the accumulation of iron.

  • 616. Vishram, Julie K. K.
    et al.
    Borglykke, Anders
    Andreasen, Anne H.
    Jeppesen, Jorgen
    Ibsen, Hans
    Jorgensen, Torben
    Palmieri, Luigi
    Giampaoli, Simona
    Donfrancesco, Chiara
    Kee, Frank
    Mancia, Giuseppe
    Cesana, Giancarlo
    Kuulasmaa, Kari
    Salomaa, Veikko
    Sans, Susana
    Ferrieres, Jean
    Dallongeville, Jean
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Arveiler, Dominique
    Wagner, Aline
    Tunstall-Pedoe, Hugh
    Drygas, Wojciech
    Olsen, Michael H.
    Impact of Age and Gender on the Prevalence and Prognostic Importance of the Metabolic Syndrome and Its Components in Europeans. The MORGAM Prospective Cohort Project2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e107294-Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the influence of age and gender on the prevalence and cardiovascular disease (CVD) risk in Europeans presenting with the Metabolic Syndrome (MetS). Methods: Using 36 cohorts from the MORGAM-Project with baseline between 1982-1997, 69094 men and women aged 19-78 years, without known CVD, were included. During 12.2 years of follow-up, 3.7%/2.1% of men/women died due to CVD. The corresponding percentages for fatal and nonfatal coronary heart disease (CHD) and stroke were 8.3/3.8 and 3.1/2.5. Results: The prevalence of MetS, according to modified definitions of the International Diabetes Federation (IDF) and the revised National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII), increased across age groups for both genders (P<0.0001); with a 5-fold increase in women from ages 19-39 years to 60-78 years (7.4%/7.6% to 35.4%/37.6% for IDF/NCEP-ATPIII) and a 2-fold increase in men (5.3%/10.5% to 11.5%/21.8%). Using multivariate-adjusted Cox regressions, the associations between MetS and all three CVD events were significant (P<0.0001). For IDF/NCEP-ATPIII in men and women, hazard ratio (HR) for CHD was 1.60/1.62 and 1.93/2.03, for CVD mortality 1.73/1.65 and 1.77/2.06, and for stroke 1.51/1.53 and 1.58/1.77. Whereas in men the HRs for CVD events were independent of age (MetS*age, P>0.05), in women the HRs for CHD declined with age (HRs 3.23/3.98 to 1.55/1.56; MetS*age, P = 0.01/P = 0.001 for IDF/NCEP-ATPIII) while the HRs for stroke tended to increase (HRs 1.31/1.25 to 1.55/1.83; MetS*age, P>0.05). Conclusion: In Europeans, both age and gender influenced the prevalence of MetS and its prognostic significance. The present results emphasise the importance of being critical of MetS in its current form as a marker of CVD especially in women, and advocate for a redefinition of MetS taking into account age especially in women.

  • 617. Vives-Cases, Carmen
    et al.
    Goicolea, Isabel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hernandez, Alison
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Sanz-Barbero, Belen
    Gill, Aisha K.
    Baldry, Anna Costanza
    Schroettle, Monika
    Stoeckl, Heidi
    Expert Opinions on Improving Femicide Data Collection across Europe: A Concept Mapping Study2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 2, article id e0148364Article in journal (Refereed)
    Abstract [en]

    Femicide, defined as the killings of females by males because they are females, is becoming recognized worldwide as an important ongoing manifestation of gender inequality. Despite its high prevalence or widespread prevalence, only a few countries have specific registries about this issue. This study aims to assemble expert opinion regarding the strategies which might feasibly be employed to promote, develop and implement an integrated and differentiated femicide data collection system in Europe at both the national and international levels. Concept mapping methodology was followed, involving 28 experts from 16 countries in generating strategies, sorting and rating them with respect to relevance and feasibility. The experts involved were all members of the EU-Cost-Action on femicide, which is a scientific network of experts on femicide and violence against women across Europe. As a result, a conceptual map emerged, consisting of 69 strategies organized in 10 clusters, which fit into two domains: "Political action" and "Technical steps". There was consensus among participants regarding the high relevance of strategies to institutionalize national databases and raise public awareness through different stakeholders, while strategies to promote media involvement were identified as the most feasible. Differences in perceived priorities according to the level of human development index of the experts' countries were also observed.

  • 618. Vogt, Hartmut
    et al.
    Bråbäck, Lennart
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Zetterstrom, Olof
    Zara, Katalin
    Falth-Magnusson, Karin
    Nilsson, Lennart
    Asthma Heredity, Cord Blood IgE and Asthma-Related Symptoms and Medication in Adulthood: A Long-Term Follow-Up in a Swedish Birth Cohort2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e66777-Article in journal (Refereed)
    Abstract [en]

    Cord blood IgE has previously been studied as a possible predictor of asthma and allergic diseases. Results from different studies have been contradictory, and most have focused on high-risk infants and early infancy. Few studies have followed their study population into adulthood. This study assessed whether cord blood IgE levels and a family history of asthma were associated with, and could predict, asthma medication and allergy-related respiratory symptoms in adults. A follow-up was carried out in a Swedish birth cohort comprising 1,701 consecutively born children. In all, 1,661 individuals could be linked to the Swedish Prescribed Drug Register and the Medical Birth Register, and 1,227 responded to a postal questionnaire. Cord blood IgE and family history of asthma were correlated with reported respiratory symptoms and dispensed asthma medication at 32-34 years. Elevated cord blood IgE was associated with a two- to threefold increased risk of pollen-induced respiratory symptoms and dispensed anti-inflammatory asthma medication. Similarly, a family history of asthma was associated with an increased risk of pollen-induced respiratory symptoms and anti-inflammatory medication. However, only 8% of the individuals with elevated cord blood IgE or a family history of asthma in infancy could be linked to current dispensation of anti-inflammatory asthma medication at follow-up. In all, 49 out of 60 individuals with dispensed anti-inflammatory asthma medication at 32-34 years of age had not been reported having asthma at previous check-ups of the cohort during childhood. Among those, only 5% with elevated cord blood IgE and 6% with a family history of asthma in infancy could be linked to current dispensation of anti-inflammatory asthma medication as adults. Elevated cord blood IgE and a positive family history of asthma were associated with reported respiratory symptoms and dispensed asthma medication in adulthood, but their predictive power was poor in this long-time follow-up.

  • 619. Volkmann, Katrin
    et al.
    Pfander, Claudia
    Burstroem, Charlotte
    Ahras, Malika
    Goulding, David
    Rayner, Julian C
    Frischknecht, Friedrich
    Billker, Oliver
    The Wellcome Trust Sanger Institute, Hinxton, United Kingdom.
    Brochet, Mathieu
    The Alveolin IMC1h Is Required for Normal Ookinete and Sporozoite Motility Behaviour and Host Colonisation in Plasmodium berghei2012In: PLoS ONE, E-ISSN 1932-6203, Vol. 7, no 7, article id e41409Article in journal (Refereed)
    Abstract [en]

    Alveolins, or inner membrane complex (IMC) proteins, are components of the subpellicular network that forms a structural part of the pellicle of malaria parasites. In Plasmodium berghei, deletions of three alveolins, IMC1a, b, and h, each resulted in reduced mechanical strength and gliding velocity of ookinetes or sporozoites. Using time lapse imaging, we show here that deletion of IMC1h (PBANKA_143660) also has an impact on the directionality and motility behaviour of both ookinetes and sporozoites. Despite their marked motility defects, sporozoites lacking IMC1h were able to invade mosquito salivary glands, allowing us to investigate the role of IMC1h in colonisation of the mammalian host. We show that IMC1h is essential for sporozoites to progress through the dermis in vivo but does not play a significant role in hepatoma cell transmigration and invasion in vitro. Colocalisation of IMC1h with the residual IMC in liver stages was detected up to 30 hours after infection and parasites lacking IMC1h showed developmental defects in vitro and a delayed onset of blood stage infection in vivo. Together, these results suggest that IMC1h is involved in maintaining the cellular architecture which supports normal motility behaviour, access of the sporozoites to the blood stream, and further colonisation of the mammalian host.

  • 620.
    Vågberg, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Granåsen, Gabriel
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
    Brain parenchymal fraction in healthy adults: a systematic review of the literature2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0170018Article in journal (Refereed)
    Abstract [en]

    Brain atrophy is an important feature of many neurodegenerative disorders. It can be described in terms of change in the brain parenchymal fraction (BPF). In order to interpret the BPF in disease, knowledge on the BPF in healthy individuals is required. The aim of this study was to determine data on the BPF of healthy individuals via a systematic review of the literature. The databases PubMed and Scopus were searched and 95 articles, including a total of 9269 individuals, were identified including the required data. We present values of BPF from healthy individuals stratified by age and post-processing method. The BPF correlated with age and there were significant differences in age-adjusted BPF between methods. This study contributes to increased knowledge on BPF in healthy individuals, which may assist in the interpretation of BPF in the setting of disease. We highlight the differences between post-processing methods and the need for a consensus gold standard. 

  • 621.
    Vågberg, Mattias
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Norgren, Niklas
    UmanDiagnostics AB, Umeå, Sweden.
    Dring, Ann
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lindqvist, Thomas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Birgander, Richard
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Zetterberg, Henrik
    Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL Institute of Neurology, Queen Square, London, United Kingdom.
    Svenningsson, Anders
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Levels and Age Dependency of Neurofilament Light and Glial Fibrillary Acidic Protein in Healthy Individuals and Their Relation to the Brain Parenchymal Fraction2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 8, article id e0135886Article in journal (Refereed)
    Abstract [en]

    Background Neurofilament light (NFL) and Glial Fibrillary Acidic Protein (GFAP) are integral parts of the axonal and astrocytal cytoskeletons respectively and are released into the cerebrospinal fluid (CSF) in cases of cellular damage. In order to interpret the levels of these biomarkers in disease states, knowledge on normal levels in the healthy is required. Another biomarker for neurodegeneration is brain atrophy, commonly measured as brain parenchymal fraction (BPF) using magnetic resonance imaging (MRI). Potential correlations between levels of NFL, GFAP and BPF in healthy individuals have not been investigated. Objectives To present levels of NFL and GFAP in healthy individuals stratified for age, and investigate the correlation between them as well as their correlation with BPF. Methods The CSF was analysed in 53 healthy volunteers aged 21 to 70 (1 sample missing for GFAP analysis) and 48 of the volunteers underwent determination of BPF using MRI. Results Mean (+/- SD) NFL was 355 ng/L (+/- 214), mean GFAP was 421 ng/L (+/- 129) and mean BPF was 0.867 (+/- 0.035). All three biomarkers correlated with age. NFL also correlated with both GFAP and BPF. When controlled for age, only the correlation between NFL and GFAP retained statistical significance. Conclusions This study presents data on age-stratified levels of NFL and GFAP in the CSF of healthy individuals. There is a correlation between levels of NFL and GFAP and both increase with age. A correlation between NFL and BPF was also found, but did not retain statistical significance if controlled for age.

  • 622.
    Wadell, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Jensen, Jens
    Englund, Erling
    Själander, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Triple therapy after PCI - Warfarin treatment quality and bleeding risk2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0209187Article in journal (Refereed)
    Abstract [en]

    Background: A combination of warfarin, aspirin and clopidogrel is indicated after percutaneous coronary intervention (PCI) in some patients, despite the higher risk of bleeding inferred by this triple therapy.

    Objectives: Whether the treatment quality of warfarin measured by iTTR (individual time within therapeutic INR range) is associated with bleeding complications during triple therapy after PCI.

    Methods: A retrospective register study consisting of 601 triple treated PCI patients from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). The cohort was cross-matched with the Swedish Patient Registry for background characteristics and bleeding complications up to 6 months after PCI using ICD10 codes, the Prescribed Drug Registry for ongoing medications, and the national oral anticoagulation registry Auricula for warfarin treatment quality. The patients were grouped into four iTTR groups: <50%, 50–69.9%, 70–84.9% and >85% as well as iTTR above or below 70%.

    Results: Of 601 patients, 39 (6.5%) had a bleeding complication (type 2 according to BARC). Bleeding was more common for iTTR<70% compared to iTTR>70%, 28 (9.3%) vs. 11 (3.7%) (p = 0.005). The bleeding frequency increased gradually from the best group, iTTR>85% with four bleeders (3.3%) up to 17 bleeders (13.3%) in the worst group with iTTR<50% (p = 0.003), with a corresponding bleeding rate per 100 treatment years of 8.0 and 44.9, respectively. In multivariate analysis low BMI, HR 1.11 (95% CI 1.01–1.22), a medical history of anemia HR 3.17 (1.16–8.69) and iTTR < 70% HR 2.86 (1.25–6.53) increased the risk of bleeding.

    Conclusion: Triple therapy after PCI confers a high risk of bleeding events. Warfarin treatment quality measured by iTTR as well as a medical history of anemia are strong independent predictors of bleeding in these patients. Physicians should pay more attention to iTTR after PCI.

  • 623.
    Wagner, Ryan G.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Studies Epidemiol Epilepsy Demog Surveillance Sys, Accra, Ghana; Univ Witwatersrand, Fac Hlth Sci, Sch Publ Hlth, MRC Wits Rural Publ Hlth & Hlth Transit Res Unit, Johannesburg, South Africa.
    Bottomley, Christian
    Ngugi, Anthony K.
    Ibinda, Fredrick
    Gomez-Olive, F. Xavier
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Studies Epidemiol Epilepsy Demog Surveillance Sys, Accra, Ghana; Univ Witwatersrand, Fac Hlth Sci, Sch Publ Hlth, MRC Wits Rural Publ Hlth & Hlth Transit Res Unit, Johannesburg, South Africa; INDEPTH Network, Accra, Ghana.
    Tollman, Stephen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Studies Epidemiol Epilepsy Demog Surveillance Sys, Accra, Ghana; Univ Witwatersrand, Fac Hlth Sci, Sch Publ Hlth, MRC Wits Rural Publ Hlth & Hlth Transit Res Unit, Johannesburg, South Africa; INDEPTH Network, Accra, Ghana.
    Newton, Charles R.
    Incidence, Remission and Mortality of Convulsive Epilepsy in Rural Northeast South Africa2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, article id e0129097Article in journal (Refereed)
    Abstract [en]

    Background Epilepsy is one of the most common neurological conditions globally, estimated to constitute 0.75% of the global burden of disease, with the majority of this burden found in low- and middle- income countries (LMICs). Few studies from LMICs, including much of sub-Saharan Africa, have described the incidence, remission or mortality rates due to epilepsy, which are needed to quantify the burden and inform policy. This study investigates the epidemiological parameters of convulsive epilepsy within a context of high HIV prevalence and an emerging burden of cardiovascular disease. Methods A cross-sectional population survey of 82,818 individuals, in the Agincourt Health and Socio-demographic Surveillance Site (HDSS) in rural northeast South Africa was conducted in 2008, from which 296 people were identified with active convulsive epilepsy. A follow-up survey was conducted in 2012. Incidence and mortality rates were estimated, with duration and remission rates calculated using the DISMOD II software package. Results The crude incidence for convulsive epilepsy was 17.4/100,000 per year (95%CI: 13.1-23.0). Remission was 4.6% and 3.9% per year for males and females, respectively. The standardized mortality ratio was 2.6 (95%CI: 1.7-3.5), with 33.3% of deaths directly related to epilepsy. Mortality was higher in men than women (adjusted rate ratio (aRR) 2.6 (95%CI: 1.2-5.4)), and was significantly associated with older ages (50+ years versus those 0-5 years old (RR 4.8 (95%CI: 0.6-36.4)). Conclusions The crude incidence was lower whilst mortality rates were similar to other African studies; however, this study found higher mortality amongst older males. Efforts aimed at further understanding what causes epilepsy in older people and developing interventions to reduce prolonged seizures are likely to reduce the overall burden of ACE in rural South Africa.

  • 624.
    Wagner, Ryan G.
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Studies of the Epidemiology of Epilepsy in Demographic Surveillance Systems (SEEDS), INDEPTH Network, Accra, Ghana; MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Ibinda, Fredrick
    Tollman, Stephen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Studies of the Epidemiology of Epilepsy in Demographic Surveillance Systems (SEEDS), INDEPTH Network, Accra, Ghana; MRC/Wits Rural Public Health and Health Transitions Research Unit (Agincourt), School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
    Lindholm, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Newton, Charles R.
    Bertram, Melanie Y.
    Differing Methods and Definitions Influence DALY estimates: Using Population-Based Data to Calculate the Burden of Convulsive Epilepsy in Rural South Africa2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, article id e0145300Article in journal (Refereed)
    Abstract [en]

    Background

    The disability adjusted life year (DALY) is a composite measure of disease burden that includes both morbidity and mortality, and is relevant to conditions such as epilepsy that can limit productive functioning. The 2010 Global Burden of Disease (GBD) study introduced a number of new methods and definitions, including a prevalence-based approach and revised disability weights to calculate morbidity and new standard life expectancies to calculate premature mortality. We used these approaches, and local, population-based data, to estimate the burden of convulsive epilepsy in rural South Africa.

    Methods & Findings

    Comprehensive prevalence, incidence and mortality data on convulsive epilepsy were collected within the Agincourt sub-district in rural northeastern South Africa between 2008 and 2012. We estimated DALYs using both prevalence- and incidence-based approaches for calculating years of life lived with disability. Additionally, we explored how changing the disease model by varying the disability weights influenced DALY estimates. Using the prevalence- based approach, convulsive epilepsy in Agincourt resulted in 332 DALYs (95% uncertainty interval (UI): 216-455) and 4.1 DALYs per 1,000 individuals (95% UI: 2.7-5.7) annually. Of this, 26% was due to morbidity while 74% was due to premature mortality. DALYs increased by 10% when using the incidence-based method. Varying the disability weight from 0.072 (treated epilepsy, seizure free) to 0.657 (severe epilepsy) caused years lived with disability to increase from 18 (95%UI: 16-19) to 161 (95%UI: 143-170).

    Conclusions

    DALY estimates are influenced by both the methods applied and population parameters used in the calculation. Irrespective of method, a significant burden of epilepsy is due to premature mortality in rural South Africa, with a lower burden than rural Kenya. Researchers and national policymakers should carefully interrogate the methods and data used to calculate DALYs as this will influence policy priorities and resource allocation.

  • 625.
    Waldenström, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Gennebäck, Nina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Hellman, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Ronquist, Gunnar
    Cardiomyocyte microvesicles contain DNA/RNA and convey biological messages to target cells2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e34653-Article in journal (Refereed)
    Abstract [en]

    Background: Shedding microvesicles are membrane released vesicles derived directly from the plasma membrane. Exosomes are released membrane vesicles of late endosomal origin that share structural and biochemical characteristics with prostasomes. Microvesicles/exosomes can mediate messages between cells and affect various cell-related processes in their target cells. We describe newly detected microvesicles/exosomes from cardiomyocytes and depict some of their biological functions.

    Methodology/Principal Findings: Microvesicles/exosomes from media of cultured cardiomyocytes derived from adult mouse heart were isolated by differential centrifugation including preparative ultracentrifugation and identified by transmission electron microscopy and flow cytometry. They were surrounded by a bilayered membrane and flow cytometry revealed presence of both caveolin-3 and flotillin-1 while clathrin and annexin-2 were not detected. Microvesicle/exosome mRNA was identified and out of 1520 detected mRNA, 423 could be directly connected in a biological network. Furthermore, by a specific technique involving TDT polymerase, 343 different chromosomal DNA sequences were identified in the microvesicles/exosomes. Microvesicle/exosomal DNA transfer was possible into target fibroblasts, where exosomes stained for DNA were seen in the fibroblast cytosol and even in the nuclei. The gene expression was affected in fibroblasts transfected by microvesicles/exosomes and among 333 gene expression changes there were 175 upregulations and 158 downregulations compared with controls.

    Conclusions/Significance: Our study suggests that microvesicles/exosomes released from cardiomyocytes, where we propose that exosomes derived from cardiomyocytes could be denoted "cardiosomes", can be involved in a metabolic course of events in target cells by facilitating an array of metabolism-related processes including gene expression changes.

  • 626. Waller Lidström, Mattias
    et al.
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Lundqvist, Robert
    Forssén, Annika
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Waller, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Time trends of comparative self-rated health in adults aged 25–34 in the Northern Sweden MONICA study, 1990–20142017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, article id e0187896Article in journal (Refereed)
    Abstract [en]

    Self-rated health (SRH) accounts comprehensively for many health domains. The aim of this paper was to investigate time trends and associations between age-comparative self-rated health and some known determinants in a general population aged 24-34 years. Population- based cross-sectional surveys were performed in 1990, 1994, 1999, 2004, 2009 and 2014 in Northern Sweden. Out of 3500 invited persons, 1811 responded. Comparative SRH was measured on a three-grade ordinal scale by the question: "How would you assess your general health condition compared to persons of your own age?" with the alternatives-better/worse/similar". Over the period 1990 to 2014, the percentage of women rating comparative SRH as "worse" increased steadily, from 8.5% in 1990 reaching 20% in 2014 (p for trend 0.007). Among men, this pattern was almost the opposite, with increasing proportions rating "better" (p for trend <0.000). Time trends for physical activity in leisure time; length of education; Body Mass Index; anxiety; depressive emotions and satisfaction with economy showed a similar pattern for men and women. Factors that might contribute to the development of time trends for comparative SRH are discussed.

  • 627.
    Wallgren, Marcus
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lidman, Martin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Pedersen, Anders
    Swedish NMR Centre, University of Gothenburg, Gothenburg, Sweden.
    Brännström, Kristoffer
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Karlsson, B Göran
    Swedish NMR Centre, University of Gothenburg, Gothenburg, Sweden.
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Reconstitution of the anti-apoptotic bcl-2 protein into lipid membranes and biophysical evidence for its detergent-driven association with the pro-apoptotic bax protein2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 4, article id e61452Article in journal (Refereed)
    Abstract [en]

    The anti-apoptotic B-cell CLL/lymphoma-2 (Bcl-2) protein and its counterpart, the pro-apoptotic Bcl-2-associated X protein (Bax), are key players in the regulation of the mitochondrial pathway of apoptosis. However, how they interact at the mitochondrial outer membrane (MOM) and there determine whether the cell will live or be sentenced to death remains unknown. Competing models have been presented that describe how Bcl-2 inhibits the cell-killing activity of Bax, which is common in treatment-resistant tumors where Bcl-2 is overexpressed. Some studies suggest that Bcl-2 binds directly to and sequesters Bax, while others suggest an indirect process whereby Bcl-2 blocks BH3-only proteins and prevents them from activating Bax. Here we present the results of a biophysical study in which we investigated the putative interaction of solubilized full-length human Bcl-2 with Bax and the scope for incorporating the former into a native-like lipid environment. Far-UV circular dichroism (CD) spectroscopy was used to detect direct Bcl-2-Bax-interactions in the presence of polyoxyethylene-(23)-lauryl-ether (Brij-35) detergent at a level below its critical micelle concentration (CMC). Additional surface plasmon resonance (SPR) measurements confirmed this observation and revealed a high affinity between the Bax and Bcl-2 proteins. Upon formation of this protein-protein complex, Bax also prevented the binding of antimycin A2 (a known inhibitory ligand of Bcl-2) to the Bcl-2 protein, as fluorescence spectroscopy experiments showed. In addition, Bcl-2 was able to form mixed micelles with Triton X-100 solubilized neutral phospholipids in the presence of high concentrations of Brij-35 (above its CMC). Following detergent removal, the integral membrane protein was found to have been fully reconstituted into a native-like membrane environment, as confirmed by ultracentrifugation and subsequent SDS-PAGE experiments.

  • 628.
    Wang, Baosheng
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Mao, Jian-Feng
    National Engineering Laboratory for Forest Tree Breeding, Key Laboratory for Genetics and Breeding of Forest Trees and Ornamental Plants of Ministry of Education, Beijing Forestry University, Beijing, People’s Republic of China.
    Zhao, Wei
    State Key Laboratory of Systematic and Evolutionary Botany, Institute of Botany, Chinese Academy of Sciences, Beijing, People’s Republic of China.
    Wang, Xiao-Ru
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Impact of Geography and Climate on the Genetic Differentiation of the Subtropical Pine Pinus yunnanensis2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e67345-Article in journal (Refereed)
    Abstract [en]

    Southwest China is a biodiversity hotspot characterized by complex topography, heterogeneous regional climates and rich flora. The processes and driving factors underlying this hotspot remain to be explicitly tested across taxa to gain a general understanding of the evolution of biodiversity and speciation in the region. In this study, we examined the role played by historically neutral processes, geography and environment in producing the current genetic diversity of the subtropical pine Pinus yunnanensis. We used genetic and ecological methods to investigate the patterns of genetic differentiation and ecological niche divergence across the distribution range of this species. We found both continuous genetic differentiation over the majority of its range, and discrete isolated local clusters. The discrete differentiation between two genetic groups in the west and east peripheries is consistent with niche divergence and geographical isolation of these groups. In the central area of the species' range, population structure was shaped mainly by neutral processes and geography rather than by ecological selection. These results show that geographical and environmental factors together created stronger and more discrete genetic differentiation than isolation by distance alone, and illustrate the importance of ecological factors in forming or maintaining genetic divergence across a complex landscape. Our findings differ from other phylogenetic studies that identified the historical drainage system in the region as the primary factor shaping population structure, and highlight the heterogeneous contributions that geography and environment have made to genetic diversity among taxa in southwest China.

  • 629.
    Wang, Jiehua
    et al.
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC). Tianjin Univ, Coll Agr & Bioengn, Tianjin 300072, Peoples R China.
    Andersson-Gunneras, Sara
    Gaboreanu, Ioana
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Hertzberg, Magnus
    Tucker, Matthew R.
    Zheng, Bo
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Lesniewska, Joanna
    Mellerowicz, Ewa J.
    Laux, Thomas
    Sandberg, Göran
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Jones, Brian
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology. Umeå University, Faculty of Science and Technology, Umeå Plant Science Centre (UPSC).
    Reduced expression of the SHORT-ROOT gene increases the rates of growth and development in hybrid poplar and arabidopsis2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12, article id e28878Article in journal (Refereed)
    Abstract [en]

    SHORT-ROOT (SHR) is a well characterized regulator of cell division and cell fate determination in the Arabidopsis primary root. However, much less is known about the functions of SHR in the aerial parts of the plant. In this work, we cloned SHR gene from Populus trichocarpa (PtSHR1) as an AtSHR ortholog and down-regulated its expression in hybrid poplar (Populus tremula x P. tremuloides Michx-clone T89) in order to determine its physiological functions in shoot development. Sharing a 90% similarity to AtSHR at amino acid level, PtSHR1 was able to complement the Arabidopsis shr mutant. Down regulation of PtSHR1 led to a strong enhancement of primary (height) and secondary (girth) growth rates in the transgenic poplars. A similar approach in Arabidopsis showed a comparable accelerated growth and development phenotype. Our results suggest that the response to SHR could be dose-dependent and that a partial down-regulation of SHR could lead to enhanced meristem activity and a coordinated acceleration of plant growth in woody species. Therefore, SHR functions in plant growth and development as a regulator of cell division and meristem activity not only in the roots but also in the shoots. Reducing SHR expression in transgenic poplar was shown to lead to significant increases in primary and secondary growth rates. Given the current interest in bioenergy crops, SHR has a broader role as a key regulator of whole plant growth and development and SHR suppression has considerable potential for accelerating biomass accumulation in a variety of species.

  • 630. Wang, Ning
    et al.
    Truedsson, Lennart
    Elvin, Kerstin
    Andersson, Bengt A
    Rönnelid, Johan
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindkvist, Annica
    Ludvigsson, Jonas F
    Hammarström, Lennart
    Dahle, Charlotte
    Serological assessment for celiac disease in IgA deficient adults2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e93180-Article in journal (Refereed)
    Abstract [en]

    Purpose: Selective immunoglobulin A deficiency is the most common primary immunodeficiency disorder that is strongly overrepresented among patients with celiac disease (CD). IgG antibodies against tissue transglutaminase (tTG) and deamidated gliadin peptides (DGP) serve as serological markers for CD in IgA deficient individuals, although the diagnostic value remains uncertain. The aim of this study was to investigate the prevalence of these markers in a large cohort of IgA deficient adults with confirmed or suspected CD and relate the findings to gluten free diet.

    Methods: Sera from 488,156 individuals were screened for CD in seven Swedish clinical immunology laboratories between 1998 and 2012. In total, 356 out of 1,414 identified IgA deficient adults agreed to participate in this study and were resampled. Forty-even IgA deficient blood donors served as controls. Analyses of IgG antibodies against tTG and DGP as well as HLA typing were performed and a questionnaire was used to investigate adherence to gluten free diet. Available biopsy results were collected.

    Results: Out of the 356 IgA deficient resampled adults, 67 (18.8%) were positive for IgG anti-tTG and 79 (22.2%) for IgG anti-DGP, 54 had biopsy confirmed CD. Among the 47 IgA deficient blood donors, 4 (9%) were positive for IgG anti-tTG and 8 (17%) for anti- DGP. Four were diagnosed with biopsy verified CD, however, 2 of the patients were negative for all markers. Sixty-eight of 69 individuals with positive IgG anti-tTG were HLA-DQ2/DQ8 positive whereas 7 (18.9%) of the 37 individuals positive for IgG anti-DGP alone were not.

    Conclusions: IgG anti- tTG seems to be a more reliable marker for CD in IgA deficient adults whereas the diagnostic specificity of anti-DGP appears to be lower. High levels of IgG antibodies against tTG and DGP were frequently found in IgA deficient adults despite adhering to gluten free diet.

  • 631. Wang, Tao
    et al.
    Moon, Jee-Young
    Wu, Yiqun
    Amos, Christopher I.
    Hung, Rayjean J.
    Tardon, Adonina
    Andrew, Angeline
    Chen, Chu
    Christiani, David C.
    Albanes, Demetrios
    van der Heijdendr, Erik H. F. M.
    Duell, Eric
    Rennert, Gadi
    Goodman, Gary
    Liu, Geoffrey
    Mckay, James D.
    Yuan, Jian-Min
    Field, John K.
    Manjer, Jonas
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Kiemeney, Lambertus A.
    Le Marchand, Loic
    Teare, M. Dawn
    Schabath, Matthew B.
    Johansson, Mattias
    Aldrich, Melinda C.
    Davies, Michael
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tsao, Ming-Sound
    Caporaso, Neil
    Lazarus, Philip
    Lam, Stephen
    Bojesen, Stig E.
    Arnold, Susanne
    Wu, Xifeng
    Zong, Xuchen
    Hong, Yun-Chul
    Ho, Gloria Y. F.
    Pleiotropy of genetic variants on obesity and smoking phenotypes: Results from the Oncoarray Project of The International Lung Cancer Consortium2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0185660Article in journal (Refereed)
    Abstract [en]

    Obesity and cigarette smoking are correlated through complex relationships. Common genetic causes may contribute to these correlations. In this study, we selected 241 loci potentially associated with body mass index (BMI) based on the Genetic Investigation of ANthropometric Traits (GIANT) consortium data and calculated a BMI genetic risk score (BMI-GRS) for 17,037 individuals of European descent from the Oncoarray Project of the International Lung Cancer Consortium (ILCCO). Smokers had a significantly higher BMI-GRS than never-smokers (p = 0.016 and 0.010 before and after adjustment for BMI, respectively). The BMI-GRS was also positively correlated with pack-years of smoking (p<0.001) in smokers. Based on causal network inference analyses, seven and five of 241 SNPs were classified to pleiotropic models for BMI/smoking status and BMI/pack-years, respectively. Among them, three and four SNPs associated with smoking status and pack-years (p<0.05), respectively, were followed up in the ever-smoking data of the Tobacco, Alcohol and Genetics (TAG) consortium. Among these seven candidate SNPs, one SNP (rs11030104, BDNF) achieved statistical significance after Bonferroni correction for multiple testing, and three suggestive SNPs (rs13021737, TMEM18; rs11583200, ELAVL4; and rs6990042, SGCZ) achieved a nominal statistical significance. Our results suggest that there is a common genetic component between BMI and smoking, and pleiotropy analysis can be useful to identify novel genetic loci of complex phenotypes.

  • 632. Wang, Yuhang
    et al.
    Ding, Fangrong
    Wang, Tao
    Liu, Wenjie
    Lindquist, Susanne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Wang, Jianwu
    Li, Jing
    Li, Ling
    Zhao, Yaofeng
    Dai, Yunping
    Li, Ning
    Purification and characterization of recombinant human bile salt-stimulated lipase expressed in milk of transgenic cloned cows2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0176864Article in journal (Refereed)
    Abstract [en]

    Bile salt-stimulated lipase (BSSL) is a lipolytic digestive enzyme with broad substrate specificity secreted from exocrine pancreas into the intestinal lumen in all species and from the lactating mammary gland into the milk of some species, notably humans but not cows. BSSL in breast milk facilitates digestion and absorption of milk fat and promotes growth of small for gestational age preterm infants. Thus, purified recombinant human BSSL (rhBSSL) can be used for treatment of patients with fat malabsorption and expressing rhBSSL in the milk of transgenic cloned cows would therefore be a mean to meet a medical need. In the present study, a vector pBAC-hLF-hBSSL was constructed, which efficiently expressed active rhBSSL in milk of transgenic cloned cows to a concentration of 9.8 mg/ml. The rhBSSL purified from cow milk had the same enzymatic activity, N-terminal amino acid sequence, amino acid composition and isoelectric point and similar physicochemical characteristics as human native BSSL. Our study supports the use of transgenic cattle for the cost-competitive, large-scale production of therapeutic rhBSSL.

  • 633. Wang, Zheng
    et al.
    Iida, Aritoshi
    Miyake, Noriko
    Nishiguchi, Koji M.
    Fujita, Kosuke
    Nakazawa, Toru
    Alswaid, Abdulrahman
    Albalwi, Mohammed A.
    Kim, Ok-Hwa
    Cho, Tae-Joon
    Lim, Gye-Yeon
    Isidor, Bertrand
    David, Albert
    Rustad, Cecilie F.
    Merckoll, Else
    Westvik, Jostein
    Stattin, Eva-Lena
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Grigelioniene, Giedre
    Kou, Ikuyo
    Nakajima, Masahiro
    Ohashi, Hirohumi
    Smithson, Sarah
    Matsumoto, Naomichi
    Nishimura, Gen
    Ikegawa, Shiro
    Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0150555Article in journal (Refereed)
    Abstract [en]

    Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy. We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD. C21orf2 mutations have been recently found to cause isolated retinal degeneration and Jeune syndrome. We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds. The pathogenic effects of the splicing (splice-site and branch-point) mutations were confirmed on RNA level, which showed complex patterns of abnormal splicing. C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora. Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD. Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation. C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function. Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.

  • 634. Watts, Eleanor L.
    et al.
    Appleby, Paul N.
    Albanese, Demetrius
    Black, Amanda
    Chan, June M.
    Chen, Chu
    Cirillo, Piera M.
    Cohn, Barbara A.
    Cook, Michael B.
    Donovan, Jenny L.
    Ferrucci, Luigi
    Garland, Cedric F.
    Giles, Graham G.
    Goodman, Phyllis J.
    Habel, Laurel A.
    Haiman, Christopher A.
    Holly, Jeff M. P.
    Hoover, Robert N.
    Kaaks, Rudolf
    Knekt, Paul
    Kolonel, Laurence N.
    Kubo, Tatsuhiko
    Le Marchand, Loic
    Luostarinen, Tapio
    Maclnnis, Robert J.
    Maenpaa, Hanna O.
    Mannisto, Satu
    Metter, E. Jeffrey
    Milne, Roger L.
    Nomura, Abraham M. Y.
    Oliver, Steven E.
    Parsons, J. Kellogg
    Peeters, Petra H.
    Platz, Elizabeth A.
    Riboli, Elio
    Ricceri, Fulvio
    Rinaldi, Sabina
    Rissanen, Harri
    Sawada, Norie
    Schaefer, Catherine A.
    Schenk, Jeannette M.
    Stanczyk, Frank Z.
    Stampfer, Meir
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Stenman, Ulf-Hakan
    Tjonneland, Anne
    Trichopoulou, Antonia
    Thompson, Ian M.
    Tsugane, Shoichiro
    Vatten, Lars
    Whittemore, Alice S.
    Ziegler, Regina G.
    Allen, Naomi E.
    Key, Timothy J.
    Travis, Ruth C.
    Circulating sex hormones in relation to anthropometric, sociodemographic and behavioural factors in an international dataset of 12,300 men2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0187741Article in journal (Refereed)
    Abstract [en]

    Introduction: Sex hormones have been implicated in the etiology of a number of diseases. To better understand disease etiology and the mechanisms of disease-risk factor associations, this analysis aimed to investigate the associations of anthropometric, sociodemographic and behavioural factors with a range of circulating sex hormones and sex hormone-binding globulin.

    Methods: Statistical analyses of individual participant data from 12,330 male controls aged 25–85 years from 25 studies involved in the Endogenous Hormones Nutritional Biomarkers and Prostate Cancer Collaborative Group. Analysis of variance was used to estimate geometric means adjusted for study and relevant covariates.

    Results: Older age was associated with higher concentrations of sex hormone-binding globulin and dihydrotestosterone and lower concentrations of dehydroepiandrosterone sulfate, free testosterone, androstenedione, androstanediol glucuronide and free estradiol. Higher body mass index was associated with higher concentrations of free estradiol, androstanediol glucuronide, estradiol and estrone and lower concentrations of dihydrotestosterone, testosterone, sex hormone-binding globulin, free testosterone, androstenedione and dehydroepiandrosterone sulfate. Taller height was associated with lower concentrations of androstenedione, testosterone, free testosterone and sex hormone-binding globulin and higher concentrations of androstanediol glucuronide. Current smoking was associated with higher concentrations of androstenedione, sex hormone-binding globulin and testosterone. Alcohol consumption was associated with higher concentrations of dehydroepiandrosterone sulfate, androstenedione and androstanediol glucuronide. East Asians had lower concentrations of androstanediol glucuronide and African Americans had higher concentrations of estrogens. Education and marital status were modestly associated with a small number of hormones.

    Conclusion: Circulating sex hormones in men are strongly associated with age and body mass index, and to a lesser extent with smoking status and alcohol consumption.

  • 635. Welsh, Michelle
    et al.
    Sharpe, Richard M
    Moffat, Lindsey
    Atanassova, Nina
    Saunders, Philippa TK
    Kilter, Sigrid
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Smith, Lee B
    Androgen action via testicular arteriole smooth muscle cells is important for Leydig cell function, vasomotion and testicular fluid dynamics2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 10, p. e13632-Article in journal (Refereed)
    Abstract [en]

    Regulation of blood flow through the testicular microvasculature by vasomotion is thought to be important for normal testis function as it regulates interstitial fluid (IF) dynamics which is an important intra-testicular transport medium. Androgens control vasomotion, but how they exert these effects remains unclear. One possibility is by signalling via androgen receptors (AR) expressed in testicular arteriole smooth muscle cells. To investigate this and determine the overall importance of this mechanism in testis function, we generated a blood vessel smooth muscle cell-specific AR knockout mouse (SMARKO). Gross reproductive development was normal in SMARKO mice but testis weight was reduced in adulthood compared to control littermates; this reduction was not due to any changes in germ cell volume or to deficits in testosterone, LH or FSH concentrations and did not cause infertility. However, seminiferous tubule lumen volume was reduced in adult SMARKO males while interstitial volume was increased, perhaps indicating altered fluid dynamics; this was associated with compensated Leydig cell failure. Vasomotion was impaired in adult SMARKO males, though overall testis blood flow was normal and there was an increase in the overall blood vessel volume per testis in adult SMARKOs. In conclusion, these results indicate that ablating arteriole smooth muscle AR does not grossly alter spermatogenesis or affect male fertility but does subtly impair Leydig cell function and testicular fluid exchange, possibly by locally regulating microvascular blood flow within the testis.

  • 636. Westerlund, Hugo
    et al.
    Gustafsson, Per E.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Theorell, Tores
    Janlert, Urban
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hammarström, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Social Adversity in Adolescence Increases the Physiological Vulnerability to Job Strain in Adulthood: A Prospective Population-Based Study2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e35967-Article in journal (Refereed)
    Abstract [en]

    Background: It has been argued that the association between job strain and health could be confounded by early life exposures, and studies have shown early adversity to increase individual vulnerability to later stress. We therefore investigated if early life exposure to adversity increases the individual's physiological vulnerability job strain in adulthood. Methodology/Principal Findings: In a population-based cohort (343 women and 330 men, 83% of the eligible participants), we examined the association between on the one hand exposure to adversity in adolescence, measured at age 16, and job strain measured at age 43, and on the other hand allostatic load at age 43. Adversity was operationalised as an index comprising residential mobility and crowding, parental loss, parental unemployment, and parental physical and mental illness (including substance abuse). Allostatic load summarised body fat, blood pressure, inflammatory markers, glucose, blood lipids, and cortisol regulation. There was an interaction between adversity in adolescence and job strain (B = 0.09, 95% CI 0.02 to 0.16 after adjustment for socioeconomic status), particularly psychological demands, indicating that job strain was associated with increased allostatic load only among participants with adversity in adolescence. Job strain was associated with lower allostatic load in men (beta = -0.20, 95% CI -0.35 to -0.06). Conclusions/Significance: Exposure to adversity in adolescence was associated with increased levels of biological stress among those reporting job strain in mid-life, indicating increased vulnerability to environmental stressors.

  • 637.
    Wiberg, Rebecca
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Jonsson, Samuel
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Novikova, Liudmila N.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Kingham, Paul J
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Investigation of the Expression of Myogenic Transcription Factors, microRNAs and Muscle-Specific E3 Ubiquitin Ligases in the Medial Gastrocnemius and Soleus Muscles following Peripheral Nerve Injury2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 12, article id e0142699Article in journal (Refereed)
    Abstract [en]

    Despite surgical innovation, the sensory and motor outcome after a peripheral nerve injury remains incomplete. One contributing factor to the poor outcome is prolonged denervation of the target organ, leading to apoptosis of both mature myofibres and satellite cells with subsequent replacement of the muscle tissue with fibrotic scar and adipose tissue. In this study, we investigated the expression of myogenic transcription factors, muscle specific microRNAs and muscle-specific E3 ubiquitin ligases at several time points following denervation in two different muscles, the gastrocnemius (containing predominantly fast type fibres) and soleus (slow type) muscles, since these molecules may influence the degree of atrophy following denervation. Both muscles exhibited significant atrophy (compared with the contra-lateral sides) at 7 days following either a nerve transection or crush injury. In the crush model, the soleus muscle showed significantly increased muscle weights at days 14 and 28 which was not the case for the gastrocnemius muscle which continued to atrophy. There was a significantly more pronounced up-regulation of MyoD expression in the denervated soleus muscle compared with the gastrocnemius muscle. Conversely, myogenin was more markedly elevated in the gastrocnemius versus soleus muscles. The muscles also showed significantly contrasting transcriptional regulation of the microRNAs miR-1 and miR-206. MuRF1 and Atrogin-1 showed the highest levels of expression in the denervated gastrocnemius muscle. This study provides further insights regarding the intracellular regulatory molecules that generate and maintain distinct patterns of gene expression in different fibre types following peripheral nerve injury.

  • 638. Wiberg-Itzel, Eva
    et al.
    Pembe, Andrea B.
    Järnbert-Pettersson, Hans
    Norman, Margareta
    Wihlbäck, Anna-Carin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Hoesli, Irene
    Bernasconi, Monya Todesco
    Azria, Elie
    Åkerud, Helena
    Darj, Elisabet
    Lactate in Amniotic Fluid: Predictor of Labor Outcome in Oxytocin-Augmented Primiparas' Deliveries2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0161546Article in journal (Refereed)
    Abstract [en]

    Background: One of the major complications related to delivery is labor dystocia, or an arrested labor progress. Many dystocic deliveries end vaginally after administration of oxytocin, but a large numbers of women with labor dystocia will undergo a long and unsafe parturition. As a result of the exertion required in labor, the uterus produces lactate. The uterine production of lactate is mirrored by the level of lactate in amniotic fluid (AFL). Objectives: To evaluate whether the level of AFL, analysed in a sample of amniotic fluid collected vaginally at arrested labor when oxytocin was needed, could predict labor outcome in nulliparous deliveries. Methods: A prospective multicentre study including 3000 healthy primiparous women all with a singleton pregnancy, gestational age 37 to 42 weeks and no maternal/fetal chronic and/or pregnancy-related conditions. A spontaneous onset of labor, regular contractions and cervical dilation >= 3 cm were required before the women were invited to take part in the study. Results: AFL, analysed within 30 minutes before augmentation, provides information about delivery outcome. Sensitivity for an acute cesarean section according to high (>= 10.1 mmol/l) or low (< 10.1mmol/l) AFL values was 39.0% (95% CI; 27-50), specificity 90.3% (95% CI; 87-93) PPV 37.3% (95% CI; 27-48) and NPV was 91.0% (95% CI; 88-93). The overall percentage of correct predictions of delivery outcome when the AFL level was used was 83.7%. Deliveries with a high AFL-level correlated with delivery time > 12h (p = 0.04), post-partum fever (> 38 degrees C, p = 0.01) and post-partum haemorrhage > 1.5L (p = 0.04). Conclusion: The AFL is a good predictor of delivery outcome in arrested nulliparous deliveries. Low levels of AFL may support the decision to continue a prolonged vaginal labor by augmentation with oxytocin. A high level of AFL correlates with operative interventions and post-partum complications.

  • 639.
    Wibom, Carl
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ghasimi, Soma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Van Loo, Peter
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Trygg, Johan
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lau, Ching
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergenheim, Tommy
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Rydén, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    EGFR gene variants are associated with specific somatic aberrations in glioma2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e47929-Article in journal (Refereed)
    Abstract [en]

    A number of gene variants have been associated with an increased risk of developing glioma. We hypothesized that the reported risk variants may be associated with tumor genomic instability. To explore potential correlations between germline risk variants and somatic genetic events, we analyzed matched tumor and blood samples from 95 glioma patients by means of SNP genotyping. The generated genotype data was used to calculate genome-wide allele-specific copy number profiles of the tumor samples. We compared the copy number profiles across samples and found two EGFR gene variants (rs17172430 and rs11979158) that were associated with homozygous deletion at the CDKN2A/B locus. One of the EGFR variants (rs17172430) was also associated with loss of heterozygosity at the EGFR locus. Our findings were confirmed in a separate dataset consisting of matched blood and tumor samples from 300 glioblastoma patients, compiled from publically available TCGA data. These results imply there is a functional effect of germline EGFR variants on tumor progression.

  • 640.
    Wikgren, Mikael
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Karlsson, Thomas
    Linköping University, Department of Behavioral Sciences and Learning.
    Lind, Johanna
    University of Oslo, Department of Psychology.
    Nilbrink, Therese
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Sleegers, Kristel
    VIB, Department of Molecular Genetics.
    Van Broeckhoven, Christine
    VIB, Department of Molecular Genetics.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nilsson, Lars-Göran
    Stockholm University, Department of Psychology.
    Nyberg, Lars
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology. Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Longer leukocyte telomere length is associated with smaller hippocampal volume among non-demented APOE ε3/ε3 subjects2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e34292-Article in journal (Refereed)
    Abstract [en]

    Telomere length shortens with cellular division, and leukocyte telomere length is used as a marker for systemic telomere length. The hippocampus hosts adult neurogenesis and is an important structure for episodic memory, and carriers of the apolipoprotein E ε4 allele exhibit higher hippocampal atrophy rates and differing telomere dynamics compared with non-carriers. The authors investigated whether leukocyte telomere length was associated with hippocampal volume in 57 cognitively intact subjects (29 ε3/ε3 carriers; 28 ε4 carriers) aged 49-79 yr. Leukocyte telomere length correlated inversely with left (r(s) = -0.465; p = 0.011), right (r(s) = -0.414; p = 0.025), and total hippocampus volume (r(s) = -0.519; p = 0.004) among APOE ε3/ε3 carriers, but not among ε4 carriers. However, the ε4 carriers fit with the general correlation pattern exhibited by the ε3/ε3 carriers, as ε4 carriers on average had longer telomeres and smaller hippocampi compared with ε3/ε3 carriers. The relationship observed can be interpreted as long telomeres representing a history of relatively low cellular proliferation, reflected in smaller hippocampal volumes. The results support the potential of leukocyte telomere length being used as a biomarker for tapping functional and structural processes of the aging brain.

  • 641. Willers, Carl
    et al.
    Iderberg, Hanna
    Axelsen, Mette
    Dahlström, Tobias
    Julin, Bettina
    Leksell, Janeth
    Lindberg, Agneta
    Lindgren, Peter
    Muth, Karin Loostrom
    Svensson, Ann-Marie
    Lilja, Mikael
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sociodemographic determinants and health outcome variation in individuals with type 1 diabetes mellitus: A register-based study2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 6, article id e0199170Article in journal (Refereed)
    Abstract [en]

    Background: Socioeconomic status, origin or demographic attributes shall not determine the quality of healthcare delivery, according to e.g. United Nations and European Union rules. Health equity has been defined as the absence of systematic disparities and unwarranted differences between groups defined by differences in social advantages. A study was performed to investigate whether this was applicable to type 1 diabetes mellitus (T1D) care in a setting with universal, tax-funded healthcare. Methods: This retrospective registry-study was based on patient-level data from individuals diagnosed with T1D during 2010-2011 (n = 16,367) in any of seven Swedish county councils (covering -65% of the Swedish population). Health equity in T1D care was analysed through multivariate regression analyses on absolute HbA1c level at one-year follow-up, one-year change in estimated glomerular filtration rate (eGFR) and one-year change in cardiovascular risk score, using selected sociodemographic dimensions as case-mix factors. Results: Higher educational level was consistently associated with lower levels of HbA1c, and so was being married. Never married was associated with worse eGFR development, and lower educational level was associated with higher cardiovascular risk. Women had higher HbA1c levels than men, and glucose control was significantly worse in patients below the age of 25. Conclusion: Patients' sociodemographic profile was strongly associated with absolute levels of risk factor control in T1 D, but also with an increased annual deterioration in eGFR. Whether these systematic differences stem from patient-related problems or healthcare organisational shortcomings is a matter for further research. The results, though, highlight the need for intensified diabetes management education and secondary prevention directed towards T1D patients, taking sociodemographic characteristics into account.

  • 642.
    Wilms, Torben
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Khan, Gulfaraz
    Coates, Philip J
    Sgaramella, Nicola
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fåhraeus, Robin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Masaryk Mem Canc Inst, RECAMO, Zluty Kopec 7, Brno, Czech Republic; Univ Paris Diderot, INSERM, UMRS1162, 27 Rue Juliette Dodu, Paris, France .
    Hassani, Asma
    Philip, Pretty S
    Norberg Spaak, Lena
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Califano, Luigi
    Colella, Giuseppe
    Olofsson, Katarina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Loizou, Christos
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Franco, Renato
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    No evidence for the presence of Epstein-Barr virus in squamous cell carcinoma of the mobile tongue2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0184201Article in journal (Refereed)
    Abstract [en]

    Squamous cell carcinoma of the head and neck (SCCHN) comprises a large group of cancers in the oral cavity and nasopharyngeal area that typically arise in older males in association with alcohol/tobacco usage. Within the oral cavity, the mobile tongue is the most common site for tumour development. The incidence of tongue squamous cell carcinoma (TSCC) is increasing in younger people, which has been suggested to associate with a viral aetiology. Two common human oncogenic viruses, human papilloma virus (HPV) and Epstein-Barr virus (EBV) are known causes of certain types of SCCHN, namely the oropharynx and nasopharynx, respectively. EBV infects most adults worldwide through oral transmission and establishes a latent infection, with sporadic productive viral replication and release of virus in the oral cavity throughout life. In view of the prevalence of EBV in the oral cavity and recent data indicating that it infects tongue epithelial cells and establishes latency, we examined 98 cases of primary squamous cell carcinoma of the mobile tongue and 15 cases of tonsillar squamous cell carcinoma for the presence of EBV-encoded RNAs (EBERs), EBV DNA and an EBV-encoded protein, EBNA-1. A commercially available in situ hybridisation kit targeting EBER transcripts (EBER-ISH) showed a positive signal in the cytoplasm and/or nuclei of tumour cells in 43% of TSCCs. However, application of control probes and RNase A digestion using in-house developed EBER-ISH showed identical EBER staining patterns, indicating non-specific signals. PCR analysis of the BamH1 W repeat sequences did not identify EBV genomes in tumour samples. Immunohistochemistry for EBNA-1 was also negative. These data exclude EBV as a potential player in TSCC in both old and young patients and highlight the importance of appropriate controls for EBER-ISH in investigating EBV in human diseases.

  • 643. Wilson, Lauren E
    et al.
    Kim, Sangmi
    Xu, Zongli
    Harlid, Sophia
    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
    Sandler, Dale P
    Taylor, Jack A
    Non-Steroidal Anti-Inflammatory Drug Use and Genomic DNA Methylation in Blood.2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0138920Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Non-steroidal anti-inflammatory drug (NSAID) use is associated with decreased risk of some cancers. NSAID use modulates the epigenetic profile of normal colonic epithelium and may reduce risk of colon cancer through this pathway; however, the effect of NSAID use on the DNA methylation profile of other tissues including whole blood has not yet been examined.

    FINDINGS: Using the Sister Study cohort, we examined the association between NSAID usage and whole genome methylation patterns in blood DNA. Blood DNA methylation status across 27,589 CpG sites was evaluated for 871 women using the Illumina Infinium HumanMethylation27 Beadchip, and in a non-overlapping replication sample of 187 women at 485,512 CpG sites using the Infinium HumanMethylation450 Beadchip. We identified a number of CpG sites that were differentially methylated in regular, long-term users of NSAIDs in the discovery group, but none of these sites were statistically significant in our replication group.

    CONCLUSIONS: We found no replicable methylation differences in blood related to NSAID usage. If NSAID use does effect blood DNA methylation patterns, differences are likely small.

  • 644.
    Winberg, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    West, Christina E.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Strinnholm, Åsa
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Nordström, Lisbet
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hedman, Linnea
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Rönmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Assessment of Allergy to Milk, Egg, Cod, and Wheat in Swedish Schoolchildren: A Population Based Cohort Study2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0131804Article in journal (Refereed)
    Abstract [en]

    Objectives Knowledge about the prevalence of allergies to foods in childhood and adolescence is incomplete. The purpose of this study was to investigate the prevalence of allergies to milk, egg, cod, and wheat using reported data, clinical examinations, and double-blind placebo-controlled food challenges, and to describe the phenotypes of reported food hypersensitivity in a cohort of Swedish schoolchildren. Methods In a population-based cohort of 12-year-old children, the parents of 2612 (96% of invited) completed a questionnaire. Specific IgE antibodies to foods were analyzed in a random sample (n=695). Children reporting complete avoidance of milk, egg, cod, or wheat due to perceived hypersensitivity and without physician-diagnosed celiac disease were invited to undergo clinical examination that included specific IgE testing, a celiac screening test, and categorization into phenotypes of food hypersensitivity according to preset criteria. Children with possible food allergy were further evaluated with double-blind challenges. Results In this cohort, the prevalence of reported food allergy to milk, egg, cod, or wheat was 4.8%. Food allergy was diagnosed in 1.4% of the children after clinical evaluation and in 0.6% following double-blind placebo-controlled food challenge. After clinical examination, children who completely avoided one or more essential foods due to perceived food hypersensitivity were categorized with the following phenotypes: allergy (29%), outgrown allergy (19%), lactose intolerance (40%), and unclear (12%). Conclusions There was a high discrepancy in the prevalence of allergy to milk, egg, cod and wheat as assessed by reported data, clinical evaluation, and double-blind food challenges. Food hypersensitivity phenotyping according to preset criteria was helpful for identifying children with food allergy.

  • 645.
    Wiren, Sara
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Drevin, Linda
    Regional Cancer Centre, Uppsala University Hospital, Uppsala, Sweden.
    Akre, Olof
    Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
    Robinson, David
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Fathering of dizygotic twins and risk of prostate cancer: nationwide, population-based case-control study2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e110506-Article in journal (Refereed)
    Abstract [en]

    Background: An association between male fertility and risk of prostate cancer has been suggested, possibly through lower androgen levels in subfertile men. We evaluated male fertility in relation to risk of prostate cancer by assessing the frequency of fathering of dizygotic twins, a marker of high fertility, among cases of prostate cancer and controls. Methods: We performed a case-control study in Prostate Cancer data Base Sweden (PCBaSe), a nationwide, population-based cohort. PCBaSe was linked to the Swedish twin register for information on zygosity for same-sex twins and to other nationwide health care registers and demographic databases for information on socioeconomic factors, comorbidity, and tumor characteristics for 96 301 prostate cancer cases and 378 583 matched controls. To account for the influence of in vitro fertilization on dizygotic twinning, analyses were restricted to men who had fathered children before 1991, when in vitro fertilization was still uncommon in Sweden. Results: 1 112 cases and 4 538 controls had fathered dizygotic twins. Men with dizygotic twins had no increased risk of prostate cancer compared to fathers of singletons; neither for total prostate cancer odds ratio (OR) 0.95(95% CI 0.89-1.02), nor for any risk category, OR 0.97 (95% CI 0.84-1.12) for low-risk disease, and OR 1.04 (95% CI 0.90-1.22) for metastatic disease. Conclusion: The lack of association between fathering of dizygotic twins and prostate cancer risk give no support for an association between male fertility and prostate cancer risk.

  • 646.
    Witek, Barbara
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    El Wakil, Abeer
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Vernersson-Lindahl, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Helland, Aslaug
    Alexeyev, Oleg A.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallberg, Bengt
    Palmer, Ruth H.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg.
    Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, article id e0123542Article in journal (Refereed)
    Abstract [en]

    Mice lacking ALK activity have previously been reported to exhibit subtle behavioral phenotypes. In this study of ALK of loss of function mice we present data supporting a role for ALK in hypogonadotropic hypogonadism in male mice. We observed lower level of serum testosterone at P40 in ALK knock-out males, accompanied by mild disorganization of seminiferous tubules exhibiting decreased numbers of GATA4 expressing cells. These observations highlight a role for ALK in testis function and are further supported by experiments in which chemical inhibition of ALK activity with the ALK TKI crizotinib was employed. Oral administration of crizotinib resulted in a decrease of serum testosterone levels in adult wild type male mice, which reverted to normal levels after cessation of treatment. Analysis of GnRH expression in neurons of the hypothalamus revealed a significant decrease in the number of GnRH positive neurons in ALK knock-out mice at P40 when compared with control littermates. Thus, ALK appears to be involved in hypogonadotropic hypogonadism by regulating the timing of pubertal onset and testis function at the upper levels of the hypothalamic-pituitary gonadal axis.

  • 647. Woltmann, Andrea
    et al.
    Chen, Bowang
    Lascorz, Jesus
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Eyfjord, Jorunn E.
    Hamann, Ute
    Manjer, Jonas
    Enquist-Olsson, Kerstin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Herms, Stefan
    Hoffmann, Per
    Hemminki, Kari
    Lenner, Per
    Forsti, Asta
    Systematic Pathway Enrichment Analysis of a Genome-Wide Association Study on Breast Cancer Survival Reveals an Influence of Genes Involved in Cell Adhesion and Calcium Signaling on the Patients' Clinical Outcome2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, p. e98229-Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWASs) may help to understand the effects of genetic polymorphisms on breast cancer (BC) progression and survival. However, they give only a focused view, which cannot capture the tremendous complexity of this disease. Therefore, we investigated data from a previously conducted GWAS on BC survival for enriched pathways by different enrichment analysis tools using the two main annotation databases Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The goal was to identify the functional categories (GO terms and KEGG pathways) that are consistently overrepresented in a statistically significant way in the list of genes generated from the single nucleotide polymorphism (SNP) data. The SNPs with allelic p-value cut-offs 0.005 and 0.01 were annotated to the genes by excluding or including a 20 kb up-and down-stream sequence of the genes and analyzed by six different tools. We identified eleven consistently enriched categories, the most significant ones relating to cell adhesion and calcium ion binding. Moreover, we investigated the similarity between our GWAS and the enrichment analyses of twelve published gene expression signatures for breast cancer prognosis. Five of them were commonly used and commercially available, five were based on different aspects of metastasis formation and two were developed from meta-analyses of published prognostic signatures. This comparison revealed similarities between our GWAS data and the general and the specific brain metastasis gene signatures as well as the Oncotype DX signature. As metastasis formation is a strong indicator of a patient's prognosis, this result reflects the survival aspect of the conducted GWAS and supports cell adhesion and calcium signaling as important pathways in cancer progression.

  • 648.
    Wuolikainen, Anna
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Acimovic, Jure
    Loevgren-Sandblom, Anita
    Parini, Paolo
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bjoerkhem, Ingemar
    Cholesterol, Oxysterol, Triglyceride, and Coenzyme Q Homeostasis in ALS. Evidence against the Hypothesis That Elevated 27-Hydroxycholesterol Is a Pathogenic Factor2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e113619-Article in journal (Refereed)
    Abstract [en]

    High plasma levels of cholesterol have been suggested to be neuroprotective for the degenerative disease amyotrophic lateral sclerosis (ALS) and to be associated with increased survival time. The gene encoding cholesterol 27-hydroxylase, CYP27A1, was recently identified as a susceptibility gene for sporadic ALS. A product of this enzyme is 27-hydroxycholesterol. We investigated plasma samples from 52 ALS patients and 40 control subjects (spouses) regarding cholesterol homeostasis, lipid profiles, and coenzyme Q. Eleven of the patients carried mutations in C9orf72 and seven in SOD1. Plasma levels of 27-hydroxycholesterol were significantly lower in male patients with ALS than in controls. It was not possible to link the reduced levels to any specific mutation, and there was no significant correlation between 27-hydroxycholesterol and survival. With normalization for diet using the spouses, a correlation was found between survival and total cholesterol, very low density lipoprotein cholesterol, low density lipoprotein cholesterol, and coenzyme Q. We conclude that cholesterol, 24S-hydroxycholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol and lipid profiles in plasma are of limited prognostic value in individual ALS patients.

  • 649. Xu, Caihua
    et al.
    Wu, Chen
    Xia, Yang
    Zhong, Zhaopeng
    Liu, Xiang
    Xu, Jing
    Cui, Fei
    Chen, Bin
    Røe, Oluf Dimitri
    Li, Aihong
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Chen, Yijiang
    WT1 promotes cell proliferation in non-small cell lung cancer cell lines through up-regulating cyclin D1 and p-pRb in vitro and in vivo2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, article id e68837Article in journal (Refereed)
    Abstract [en]

    The Wilms' tumor suppressor gene (WT1) has been identified as an oncogene in many malignant diseases such as leukaemia, breast cancer, mesothelioma and lung cancer. However, the role of WT1 in non-small-cell lung cancer (NSCLC) carcinogenesis remains unclear. In this study, we compared WT1 mRNA levels in NSCLC tissues with paired corresponding adjacent tissues and identified significantly higher expression in NSCLC specimens. Cell proliferation of three NSCLC cell lines positively correlated with WT1 expression; moreover, these associations were identified in both cell lines and a xenograft mouse model. Furthermore, we demonstrated that up-regulation of Cyclin D1 and the phosphorylated retinoblastoma protein (p-pRb) was mechanistically related to WT1 accelerating cells to S-phase. In conclusion, our findings demonstrated that WT1 is an oncogene and promotes NSCLC cell proliferation by up-regulating Cyclin D1 and p-pRb expression.

  • 650. Xu, Weixin
    et al.
    Zhang, Ce
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Derreumaux, Philippe
    Graslund, Astrid
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mu, Yuguang
    Intrinsic determinants of A beta(12-24) pH-dependent self-assembly revealed by combined computational and experimental studies2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, p. e24329-Article in journal (Refereed)
    Abstract [en]

    The propensity of amyloid-beta (A beta) peptide to self-assemble into highly ordered amyloid structures lies at the core of their accumulation in the brain during Alzheimer's disease. By using all-atom explicit solvent replica exchange molecular dynamics simulations, we elucidated at the atomic level the intrinsic determinants of the pH-dependent dimerization of the central hydrophobic segment A beta(12-24) and related these with the propensity to form amyloid fibrils measured by experimental tools such as atomic force microscopy and fluorescence. The process of A beta(12-24) dimerization was evaluated in terms of free energy landscape, side-chain two-dimensional contact probability maps, beta-sheet registries, potential mean force as a function of inter-chain distances, secondary structure development and radial solvation distributions. We showed that dimerization is a key event in A beta(12-24) amyloid formation; it is highly prompted in the order of pH 5.0 > 2.9 > > 8.4 and determines further amyloid growth. The dimerization is governed by a dynamic interplay of hydrophobic, electrostatic and solvation interactions permitting some variability of beta-sheets at each pH. These results provide atomistic insight into the complex process of molecular recognition detrimental for amyloid growth and pave the way for better understanding of the molecular basis of amyloid diseases.

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