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  • 201.
    Dvirnas, Albertas
    et al.
    Lund Univ, Dept Astron & Theoret Phys, Lund, Sweden..
    Pichler, Christoffer
    Lund Univ, Dept Astron & Theoret Phys, Lund, Sweden..
    Stewart, Callum L.
    Lund Univ, Dept Astron & Theoret Phys, Lund, Sweden..
    Quaderi, Saair
    Lund Univ, Dept Astron & Theoret Phys, Lund, Sweden.;Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Nyberg, Lena K.
    Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Muller, Vilhelm
    Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Bikkarolla, Santosh Kumar
    Chalmers Univ Technol, Dept Biol & Biol Engn, Gothenburg, Sweden..
    Kristiansson, Erik
    Univ Gothenburg, Chalmers Univ Technol, Dept Math Sci, Gothenburg, Sweden..
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Westerlund, Fredrik
    Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
    Ambjornsson, Tobias
    Lund Univ, Dept Astron & Theoret Phys, Lund, Sweden..
    Facilitated sequence assembly using densely labeled optical DNA barcodes: A combinatorial auction approach2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 3, article id e0193900Article in journal (Refereed)
    Abstract [en]

    The output from whole genome sequencing is a set of contigs, i.e. short non-overlapping DNA sequences (sizes 1-100 kilobasepairs). Piecing the contigs together is an especially difficult task for previously unsequenced DNA, and may not be feasible due to factors such as the lack of sufficient coverage or larger repetitive regions which generate gaps in the final sequence. Here we propose a new method for scaffolding such contigs. The proposed method uses densely labeled optical DNA barcodes from competitive binding experiments as scaffolds. On these scaffolds we position theoretical barcodes which are calculated from the contig sequences. This allows us to construct longer DNA sequences from the contig sequences. This proof-of-principle study extends previous studies which use sparsely labeled DNA barcodes for scaffolding purposes. Our method applies a probabilistic approach that allows us to discard "foreign" contigs from mixed samples with contigs from different types of DNA. We satisfy the contig non-overlap constraint by formulating the contig placement challenge as a combinatorial auction problem. Our exact algorithm for solving this problem reduces computational costs compared to previous methods in the combinatorial auction field. We demonstrate the usefulness of the proposed scaffolding method both for synthetic contigs and for contigs obtained using Illumina sequencing for a mixed sample with plasmid and chromosomal DNA.

  • 202.
    Eaker, Sonja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Wigertz, Annette
    Lambert, Paul C
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Lambe, Mats
    Breast cancer, sickness absence, income and marital status: A study on life situation 1 year prior diagnosis compared to 3 and 5 years after diagnosis2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 3, p. e18040-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Improved cancer survival poses important questions about future life conditions of the survivor. We examined the possible influence of a breast cancer diagnosis on subsequent working and marital status, sickness absence and income.

    MATERIALS:

    We conducted a matched cohort study including 4,761 women 40-59 years of age and registered with primary breast cancer in a Swedish population-based clinical register during 1993-2003, and 2,3805 women without breast cancer. Information on socioeconomic standing was obtained from a social database 1 year prior and 3 and 5 years following the diagnosis. In Conditional Poisson Regression models, risk ratios (RRs) and 95% confidence intervals (CIs) were estimated to assess the impact of a breast cancer diagnosis.

    FINDINGS:

    Three years after diagnosis, women who had had breast cancer more often had received sickness benefits (RR = 1.49, 95% CI 1.40-1.58) or disability pension (RR = 1.47, 95% CI 1.37-1.58) than had women without breast cancer. We found no effect on income (RR = 0.99), welfare payments (RR = 0.98), or marital status (RR = 1.02). A higher use of sickness benefits and disability pension was evident in all stages of the disease, although the difference in use of sickness benefits decreased after 5 years, whereas the difference in disability pension increased. For woman with early stage breast cancer, the sickness absence was higher following diagnosis among those with low education, who had undergone mastectomy, and had received chemo- or hormonal therapy. Neither tumour size nor presence of lymph nodes metastasis was associated with sickness absence after adjustment for treatment.

    INTERPRETATION:

    Even in early stage breast cancer, a diagnosis negatively influences working capacity both 3 and 5 years after diagnosis, and it seems that the type of treatment received had the largest impact. A greater focus needs to be put on rehabilitation of breast cancer patients, work-place adaptations and research on long-term sequelae of treatment.

  • 203.
    Eckerdal, Patricia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Kollia, Natasa
    Department of Biostatistics, Harokopio University, Athens, Greece.
    Löfblad, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Karlsson, Linnea
    Department of Child Psychiatry, Turku University Hospital, Turku, Finland .
    Högberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Delineating the Association between Heavy Postpartum Haemorrhage and Postpartum Depression2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 1, article id e0144274Article in journal (Refereed)
    Abstract [en]

    Objectives

    To explore the association between postpartum haemorrhage (PPH) and postpartum depression (PPD), taking into account the role of postpartum anaemia, delivery experience and psychiatric history.

    Methods

    A nested cohort study (n = 446), based on two population-based cohorts in Uppsala, Sweden. Exposed individuals were defined as having a bleeding of ≥1000ml (n = 196) at delivery, and non-exposed individuals as having bleeding of <650ml (n = 250). Logistic regression models with PPD symptoms (Edinburgh Postnatal Depression scale (EPDS) score ≥ 12) as the outcome variable and PPH, anaemia, experience of delivery, mood during pregnancy and other confounders as exposure variables were undertaken. Path analysis using Structural Equation Modeling was also conducted.

    Results

    There was no association between PPH and PPD symptoms. A positive association was shown between anaemia at discharge from the maternity ward and the development of PPD symptoms, even after controlling for plausible confounders (OR = 2.29, 95%CI = 1.15–4.58). Path analysis revealed significant roles for anaemia at discharge, negative self-reported delivery experience, depressed mood during pregnancy and postpartum stressors in increasing the risk for PPD.

    Conclusion

    This study proposes important roles for postpartum anaemia, negative experience of delivery and mood during pregnancy in explaining the development of depressive symptoms after PPH.

  • 204.
    Edqvist, Per-Henrik D
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Niklasson, Mia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Vidal-Sanz, Manuel
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Platelet-derived growth factor over-expression in retinal progenitors results in abnormal retinal vessel formation2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 8, p. e42488-Article in journal (Refereed)
    Abstract [en]

    Platelet-derived growth factor (PDGF) plays an important role in development of the central nervous system, including the retina. Excessive PDGF signaling is associated with proliferative retinal disorders. We reported previously that transgenic mice in which PDGF-B was over-expressed under control of the nestin enhancer, nes/tk-PdgfB-lacZ, exhibited enhanced apoptosis in the developing corpus striatum. These animals display enlarged lateral ventricles after birth as well as behavioral aberrations as adults. Here, we report that in contrast to the relatively mild central nervous system phenotype, development of the retina is severely disturbed in nes/tk-PdgfB-lacZ mice.

    In transgenic retinas all nuclear layers were disorganized and photoreceptor segments failed to develop properly. Since astrocyte precursor cells did not populate the retina, retinal vascular progenitors could not form a network of vessels. With time, randomly distributed vessels resembling capillaries formed, but there were no large trunk vessels and the intraocular pressure was reduced. In addition, we observed a delayed regression of the hyaloid vasculature. The prolonged presence of this structure may contribute to the other abnormalities observed in the retina, including the defective lamination.

  • 205.
    Edvardsson Rasmussen, Jesper
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Rask-Andersen, Helge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Eriksson, Per Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    The proteome of perilymph in patients with vestibular schwannoma: A possibility to identify biomarkers for tumor associated hearing loss?2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 6, article id e0198442Article in journal (Refereed)
    Abstract [en]

    Background Due to the surrounding bone, the human inner ear is relatively inaccessible and difficult to reach for cellular and molecular analyses. However, these types of investigations are needed to better understand the etiology, pathophysiology and progression of several inner ear disorders. Moreover, the fluid from the inner ear cannot be sampled for micro-chemical analyses from healthy individuals in vivo. Therefore, in the present paper, we studied patients with vestibular schwannoma (VS) undergoing trans-labyrinthine surgery (TLS). Our primary aim was to identify perilymph proteins in patients with VS on an individual level. Our second aim was to investigate the proteins identified at a functional level and our final aim was to search for biological markers for tumor-associated hearing loss and tumor diameter. Methods and findings Sixteen patients underwent TLS for sporadic VS. Perilymph was aspirated through the round window before opening the labyrinth. One sample was contaminated and excluded resulting in 15 usable samples. Perilymph samples were analyzed with an online tandem LTQ-Orbitrap mass spectrometer. Data were analyzed with MaxQuant software to identify the total number of proteins and to quantify proteins in individual samples. Protein function was analyzed using the PANTHER Overrepresentation tool. Associations between perilymph protein content, clinical parameters, tumor-associated hearing loss and tumor diameter were assessed using Random Forest and Boruta. In total, 314 proteins were identified; 60 in all 15 patients and 130 proteins only once in 15 patients. Ninety-one proteins were detected in at least 12 out of 15 patients. Random Forest followed by Boruta analysis confirmed that alpha-2-HS-glycoprotein (P02765) was an independent variable for tumor-associated hearing loss. In addition, functional analysis showed that numerous processes were significantly increased in the perilymph. The top three enriched biological processes were: 1) secondary metabolic processes; 2) complement activation and 3) cell recognition. Conclusions The proteome of perilymph in patients with vestibular schwannoma has an inter-individual stable section. However, even in a cohort with homogenous disease, the variation between individuals represented the majority of the detected proteins. Alpha-2-HS-glycoprotein, P02765, was shown to be an independent variable for tumor-associated hearing loss, a finding that needs to be verified in other studies. In pathway analysis perilymph had highly enriched functions, particularly in terms of increased immune and metabolic processes.

  • 206.
    Eger, Glenda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Papadopoulos, Natalia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    NR4A1 Promotes PDGF-BB-Induced Cell Colony Formation in Soft Agar2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e109047-Article in journal (Refereed)
    Abstract [en]

    The fibroblast mitogen platelet-derived growth factor -BB (PDGF-BB) induces a transient expression of the orphan nuclear receptor NR4A1 (also named Nur77, TR3 or NGFIB). The aim of the present study was to investigate the pathways through which NR4A1 is induced by PDGF-BB and its functional role. We demonstrate that in PDGF-BB stimulated NIH3T3 cells, the MEK1/2 inhibitor CI-1040 strongly represses NR4A1 expression, whereas Erk5 downregulation delays the expression, but does not block it. Moreover, we report that treatment with the NF-κB inhibitor BAY11-7082 suppresses NR4A1 mRNA and protein expression. The majority of NR4A1 in NIH3T3 was found to be localized in the cytoplasm and only a fraction was translocated to the nucleus after continued PDGF-BB treatment. Silencing NR4A1 slightly increased the proliferation rate of NIH3T3 cells; however, it did not affect the chemotactic or survival abilities conferred by PDGF-BB. Moreover, overexpression of NR4A1 promoted anchorage-independent growth of NIH3T3 cells and the glioblastoma cell lines U-105MG and U-251MG. Thus, whereas NR4A1, induced by PDGF-BB, suppresses cell growth on a solid surface, it increases anchorage-independent growth.

  • 207.
    Eiler, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Drakare, S.
    Bertilsson, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Pernthaler, J.
    Peura, S.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Rofner, Carina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Simek, K.
    Yang, Yang
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics.
    Znachor, P.
    Lindström, Eva S.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology.
    Unveiling Distribution Patterns of Freshwater Phytoplankton by a Next Generation Sequencing Based Approach2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e53516-Article in journal (Refereed)
    Abstract [en]

    The recognition and discrimination of phytoplankton species is one of the foundations of freshwater biodiversity research and environmental monitoring. This step is frequently a bottleneck in the analytical chain from sampling to data analysis and subsequent environmental status evaluation. Here we present phytoplankton diversity data from 49 lakes including three seasonal surveys assessed by next generation sequencing (NGS) of 16S ribosomal RNA chloroplast and cyanobacterial gene amplicons and also compare part of these datasets with identification based on morphology. Direct comparison of NGS to microscopic data from three time-series showed that NGS was able to capture the seasonality in phytoplankton succession as observed by microscopy. Still, the PCR-based approach was only semi-quantitative, and detailed NGS and microscopy taxa lists had only low taxonomic correspondence. This is probably due to, both, methodological constraints and current discrepancies in taxonomic frameworks. Discrepancies included Euglenophyta and Heterokonta that were scarce in the NGS but frequently detected by microscopy and Cyanobacteria that were in general more abundant and classified with high resolution by NGS. A deep-branching taxonomically unclassified cluster was frequently detected by NGS but could not be linked to any group identified by microscopy. NGS derived phytoplankton composition differed significantly among lakes with different trophic status, showing that our approach can resolve phytoplankton communities at a level relevant for ecosystem management. The high reproducibility and potential for standardization and parallelization makes our NGS approach an excellent candidate for simultaneous monitoring of prokaryotic and eukaryotic phytoplankton in inland waters.

  • 208. Ek, Anna
    et al.
    Sorjonen, Kimmo
    Eli, Karin
    Lindberg, Louise
    Nyman, Jonna
    Marcus, Claude
    Nowicka, Paulina
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Food, Nutrition and Dietetics. Karolinska Inst, Div Pediat, Dept Clin Sci Intervent & Technol, Stockholm, Sweden.
    Associations between Parental Concerns about Preschoolers' Weight and Eating and Parental Feeding Practices: Results from Analyses of the Child Eating Behavior Questionnaire, the Child Feeding Questionnaire, and the Lifestyle Behavior Checklist2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 1, article id e0147257Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Insight into parents' perceptions of their children's eating behaviors is crucial for the development of successful childhood obesity programs. However, links between children's eating behaviors and parental feeding practices and concerns have yet to be established. This study aims to examine associations between parental perceptions of preschoolers' eating behaviors and parental feeding practices. First, it tests the original 8-factor structure of the Child Eating Behavior Questionnaire (CEBQ). Second, it examines the associations with parental feeding practices, measured with the Child Feeding Questionnaire (CFQ).

    MATERIALS AND METHODS: Questionnaires were sent to parents from 25 schools/preschools in Stockholm, Sweden and to parents starting a childhood obesity intervention. The CEBQ factor structure was tested with confirmatory factor analysis (CFA). Associations between CEBQ subscales Food approach and Food avoidance and CFQ factors Restriction, Pressure to eat and Monitoring were examined with structural equation modelling (SEM), adjusting for child and parental characteristics, and parental confidence, measured with the Lifestyle Behavior Checklist (LBC). CFQ Concern for child weight and Perceived responsibility for child eating were used as mediators.

    RESULTS: 478 parents completed the questionnaires (children: 52% girls, mean age 5.5 years, 20% overweight/obese). A modified 8-factor structure showed an acceptable fit (TLI = 0.91, CFI = 0.92, RMSEA = 0.05 and SRMR = 0.06) after dropping one item and allowing three pairs of error terms to correlate. The SEM model demonstrated that Food approach had a weak direct effect on Restriction, but a moderate (β = 0.30) indirect effect via Concern, resulting in a substantial total effect (β = 0.37). Food avoidance had a strong positive effect on Pressure to eat (β = 0.71).

    DISCUSSION: The CEBQ is a valid instrument for assessing parental perceptions of preschoolers' eating behaviors. Parental pressure to eat was strongly associated with children's food avoidance. Parental restriction, however, was more strongly associated with parents' concerns about their children's weights than with children's food approach. This suggests that childhood obesity interventions should address parents' perceptions of healthy weight alongside perceptions of healthy eating.

  • 209.
    Ekerljung, Lina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    The HER2-binding Affibody Molecule (ZHER2:342)2 Increases Radiosensitivity in SKBR-3 cells2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 11, p. e49579-Article in journal (Refereed)
    Abstract [en]

    We have previously shown that the HER2-specific affibody molecule (ZHER2:342)2 inhibits proliferation of SKBR-3 cells. Here, we continue to investigate its biological effects in vitro by studying receptor dimerization and clonogenic survival following irradiation. We found that (ZHER2:342)2 sensitizes the HER2-overexpressing cell line SKBR-3 to ionizing radiation. The survival after exposure to (ZHER2:342)2 and 8 Gy (S8Gy 0.006) was decreased by a factor of 4 compared to the untreated (S8Gy 0.023). The low HER2-expressing cell line MCF-7 was more radiosensitive than SKBR-3 but did not respond to (ZHER2:342)2. Treatment by (ZHER2:342)2 strongly increased the levels of dimerized and phosphorylated HER2 already after 5 minutes of stimulation. The monomeric ZHER2:342 does not seem to be able to induce receptor phosphorylation and dimerization or sensitize cells to irradiation.

  • 210.
    Ekström, Magnus
    et al.
    Lund Univ, Inst Clin Sci, Dept Resp Med & Allergol, Lund, Sweden..
    Sundh, Josefin
    Orebro Univ, Sch Med Sci, Dept Resp Med, Orebro, Sweden..
    Schiöler, Linus
    Univ Gothenburg, Sahlgrenska Acad, Sect Occupat & Environm Med, Gothenburg, Sweden..
    Lindberg, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Rosengren, Annika
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Med, Wallenberg Lab,Dept Mol & Clin Med, Gothenburg, Sweden..
    Bergström, Göran
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Med, Wallenberg Lab,Dept Mol & Clin Med, Gothenburg, Sweden..
    Angerås, Oskar
    Univ Gothenburg, Sahlgrenska Univ Hosp, Inst Med, Wallenberg Lab,Dept Mol & Clin Med, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Cardiol, Gothenburg, Sweden..
    Hedner, Jan
    Univ Gothenburg, Inst Med, Dept Internal Med, Gothenburg, Sweden..
    Brandberg, John
    Univ Gothenburg, Inst Clin Sci, Dept Radiol, Gothenburg, Sweden..
    Bake, Björn
    Univ Gothenburg, Dept Resp Med & Allergol, Gothenburg, Sweden..
    Toren, Kjell
    Univ Gothenburg, Sahlgrenska Acad, Sect Occupat & Environm Med, Gothenburg, Sweden..
    Absolute lung size and the sex difference in breathlessness in the general population2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 1, article id e0190876Article in journal (Refereed)
    Abstract [en]

    Background: Breathlessness is associated with major adverse health outcomes and is twice as common in women as men in the general population. We evaluated whether this is related to their lower absolute lung volumes.

    Methods: Cross-sectional analysis of the population-based Swedish CardioPulmonarybioImage Study (SCAPIS) Pilot, including static spirometry and diffusing capacity (n = 1,013; 49% women). Breathlessness was measured using the modified Medical Research Council (mMRC) scale and analyzed using ordinal logistic regression adjusting for age, pack-years of smoking, body mass index, chronic airway limitation, asthma, chronic bronchitis, depression and anxiety in all models.

    Results: Breathlessness was twice as common in women as in men; adjusted odds ratio (OR) 2.20 (95% confidence interval, 1.32-3.66). Lower absolute lung volumes were associated with increased breathlessness prevalence in both men and women. The sex difference in breathlessness was unchanged when adjusting for lung function in %predicted, but disappeared when controlling for absolute values of total lung capacity (OR 1.12; 0.59-2.15), inspiratory capacity (OR 1.26; 0.68-2.35), forced vital capacity (OR 0.84; 0.42-1.66), forced expiratory volume in one second (OR 0.70; 0.36-1.35) or lung diffusing capacity (OR 1.07; 0.58-1.97).

    Conclusion: In the general population, the markedly higher prevalence of breathlessness in women is related to their smaller absolute lung volumes.

  • 211.
    El Missiry, Mohamed
    et al.
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway.;Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Canc Res & Mol Med, Trondheim, Norway..
    Richter, Johan
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Stenke, Leif
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Porkka, Kimmo
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Kreutzman, Anna
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Mustjoki, Satu
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, Helsinki, Finland..
    Early BCR-ABL1 Transcript Decline after 1 Month of Tyrosine Kinase Inhibitor Therapy as an Indicator for Treatment Response in Chronic Myeloid Leukemia2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 1, article id e0171041Article in journal (Refereed)
    Abstract [en]

    In chronic myeloid leukemia (CML), early treatment prediction is important to identify patients with inferior overall outcomes. We examined the feasibility of using reductions in BCR-ABL1 transcript levels after 1 month of tyrosine kinase inhibitor (TKI) treatment to predict therapy response. Fifty-two first-line TKI-treated CML patients were included (imatinib n = 26, dasatinib n = 21, nilotinib n = 5), and BCR-ABL1 transcript levels were measured at diagnosis (dg) and 1, 3, 6, 12, 18, 24, and 36 months. The fold change of the BCR-ABL1 transcripts at 1 month compared to initial BCR-ABL1 transcript levels was used to indicate early therapy response. In our cohort, 21% of patients had no decrease in BCR-ABL1 transcript levels after 1 month and were classified as poor responders. Surprisingly, these patients had lower BCR-ABL1 transcript levels at dg compared to responders (31% vs. 48%, p = 0.0083). Poor responders also significantly more often had enlarged spleen (55% vs. 15%; p< 0.01) and a higher percentage of Ph+ CD34+CD38- cells in the bone marrow (91% vs. 75%, p< 0.05). The major molecular response rates were inferior in the poor responders (at 12m 18% vs. 64%, p< 0.01; 18m 27% vs. 75%, p< 0.01; 24m 55% vs. 87%, p< 0.01). In conclusion, early treatment response analysis defines a biologically distinct patient subgroup with inferior long-term outcomes.

  • 212.
    Elfaitouri, Amal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Herrmann, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Bölin-Wiener, Agnes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Wang, Yilin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Gottfries, Carl-Gerhard
    Zachrisson, Olof
    Pipkorn, Ruediger
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Epitopes of Microbial and Human Heat Shock Protein 60 and Their Recognition in Myalgic Encephalomyelitis2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. 55-Article in journal (Refereed)
    Abstract [en]

    Myalgic encephalomyelitis (ME, also called Chronic Fatigue Syndrome), a common disease with chronic fatigability, cognitive dysfunction and myalgia of unknown etiology, often starts with an infection. The chaperonin human heat shock protein 60 (HSP60) occurs in mitochondria and in bacteria, is highly conserved, antigenic and a major autoantigen. The anti-HSP60 humoral (IgG and IgM) immune response was studied in 69 ME patients and 76 blood donors (BD) (the Training set) with recombinant human and E coli HSP60, and 136 30-mer overlapping and targeted peptides from HSP60 of humans, Chlamydia, Mycoplasma and 26 other species in a multiplex suspension array. Peptides from HSP60 helix I had a chaperonin-like activity, but these and other HSP60 peptides also bound IgG and IgM with an ME preference, theoretically indicating a competition between HSP60 function and antibody binding. A HSP60-based panel of 25 antigens was selected. When evaluated with 61 other ME and 399 non-ME samples (331 BD, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients), a peptide from Chlamydia pneumoniae HSP60 detected IgM in 15 of 61 (24%) of ME, and in 1 of 399 non-ME at a high cutoff (p<0.0001). IgM to specific cross-reactive epitopes of human and microbial HSP60 occurs in a subset of ME, compatible with infection-induced autoimmunity.

  • 213.
    Elfaitouri, Amal
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Shao, Xingwu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Ulfstedt, Johan Mattsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Muradrasoli, Shaman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Böhlin Wiener, Agnes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Golbob, Sultan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Öhrmalm, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Matousek, Michael
    Zachrisson, Olof
    Gottfries, Carl-Gerhard
    Blomberg, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Murine Gammaretrovirus Group G3 Was Not Found in Swedish Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 10, article id e24602Article in journal (Refereed)
    Abstract [en]

    Background: The recent report of gammaretroviruses of probable murine origin in humans, called xenotropic murine retrovirus related virus (XMRV) and human murine leukemia virus related virus (HMRV), necessitated a bioinformatic search for this virus in genomes of the mouse and other vertebrates, and by PCR in humans.

    Results: Three major groups of murine endogenous gammaretroviruses were identified. The third group encompassed both exogenous and endogenous Murine Leukemia Viruses (MLVs), and most XMRV/HMRV sequences reported from patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Two sensitive real-time PCRs for this group were developed. The predicted and observed amplification range for these and three published XMRV/HMRV PCRs demonstrated conspicuous differences between some of them, partly explainable by a recombinatorial origin of XMRV. Three reverse transcription real-time PCRs (RTQPCRs), directed against conserved and not overlapping stretches of env, gag and integrase (INT) sequences of XMRV/HMRV were used on human samples. White blood cells from 78 patients suffering from ME/CFS, of which 30 patients also fulfilled the diagnostic criteria for fibromyalgia (ME/CFS/FM) and in 7 patients with fibromyalgia (FM) only, all from the Gothenburg area of Sweden. As controls we analyzed 168 sera from Uppsala blood donors. We controlled for presence and amplifiability of nucleic acid and for mouse DNA contamination. To score as positive, a sample had to react with several of the XMRV/HMRV PCRs. None of the samples gave PCR reactions which fulfilled the positivity criteria.

    Conclusions: XMRV/HMRV like proviruses occur in the third murine gammaretrovirus group, characterized here. PCRs developed by us, and others, approximately cover this group, except for the INT RTQPCR, which is rather strictly XMRV specific. Using such PCRs, XMRV/HMRV could not be detected in PBMC and plasma samples from Swedish patients suffering from ME/CFS/FM, and in sera from Swedish blood donors.

  • 214.
    Elfving, Karin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. Department of Clinical Microbiology, Falu Hospital, Falun, Sweden.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Bergström, Sven
    Department of Molecular Biology, Umeå University.
    Waldenström, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Lundkvist, Åke
    Swedish Institute for Infectious Disease Control, Solna.
    Sjöstedt, Anders
    Clinical Bacteriology, Department of Clinical Mic0robiology, Umeå University Hospital.
    Mejlon, Hans
    Uppsala University, Music and Museums, Museum of Evolution.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Bacteriology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Dissemination of Spotted Fever Rickettsia Agents in Europe by Migrating Birds2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 1, p. e8572-Article in journal (Refereed)
    Abstract [en]

    Migratory birds are known to play a role as long-distance vectors for many microorganisms. To investigate whether this is true of rickettsial agents as well, we characterized tick infestation and gathered ticks from 13,260 migratory passerine birds in Sweden. A total of 1127 Ixodes spp. ticks were removed from these birds and the extracted DNA from 957 of them was available for analyses. The DNA was assayed for detection of Rickettsia spp. using real-time PCR, followed by DNA sequencing for species identification. Rickettsia spp. organisms were detected in 108 (11.3%) of the ticks. Rickettsia helvetica, a spotted fever rickettsia associated with human infections, was predominant among the PCR-positive samples. In 9 (0.8%) of the ticks, the partial sequences of 17kDa and ompB genes showed the greatest similarity to Rickettsia monacensis, an etiologic agent of Mediterranean spotted fever-like illness, previously described in southern Europe as well as to the Rickettsia sp.IrITA3 strain. For 15 (1.4%) of the ticks, the 17kDa, ompB, gltA and ompA genes showed the greatest similarity to Rickettsia sp. strain Davousti, Rickettsia japonica and Rickettsia heilongjiangensis, all closely phylogenetically related, the former previously found in Amblyomma tholloni ticks in Africa and previously not detected in Ixodes spp. ticks. The infestation prevalence of ticks infected with rickettsial organisms was four times higher among ground foraging birds than among other bird species, but the two groups were equally competent in transmitting Rickettsia species. The birds did not seem to serve as reservoir hosts for Rickettsia spp., but in one case it seems likely that the bird was rickettsiemic and that the ticks had acquired the bacteria from the blood of the bird. In conclusion, migratory passerine birds host epidemiologically important vector ticks and Rickettsia species and contribute to the geographic distribution of spotted fever rickettsial agents and their diseases.

  • 215.
    Elfving, Kristina
    et al.
    Department of Infectious Diseases, University of Gothenburg, Sweden.
    Shakely, Deler
    Malaria Research, Department of Microbiology, Tumour and Cell biology, Karolinska Institutet, Stockholm, Sweden.
    Andersson, Maria
    Department of Infectious Diseases, University of Gothenburg, Sweden.
    Baltzell, Kimberly
    Department of Family Health Care Nursing, University of California San Francisco, USA.
    Ali, Abdullah S
    Zanzibar Malaria Elimination Programme, Ministry of Health, Zanzibar, Tanzania.
    Bachelard, Marc
    Department of Paediatrics, University of Gothenburg, Sweden.
    Falk, Kerstin I
    Department of Microbiology, Tumor and Cell biology, Karolinska Institutet, Stockholm, Sweden.
    Ljung, Annika
    Department of Infectious Diseases, University of Gothenburg, Sweden.
    Msellem, Mwinyi I
    Zanzibar Malaria Elimination Programme, Ministry of Health, Zanzibar, Tanzania.
    Omar, Rahila S
    Zanzibar Malaria Elimination Programme, Ministry of Health, Zanzibar, Tanzania.
    Parola, Philippe
    Aix Marseille University, UM63, WHO collaborative centre for rickettsioses and other arthropod borne bacterial diseases, Faculté de Médecine, Marseille, France.
    Xu, Weiping
    Malaria Research, Department of Microbiology, Tumour and Cell biology, Karolinska Institutet, Stockholm, Sweden.
    Petzold, Max
    Akademistatistik, Centre for Applied Biostatistics, Occupational and Environmental Medicine, University of Gothenburg, Sweden.
    Trollfors, Birger
    Department of Paediatrics, University of Gothenburg, Sweden.
    Björkman, Anders
    Malaria Research, Department of Microbiology, Tumour and Cell biology, Karolinska Institutet, Stockholm, Sweden.
    Lindh, Magnus
    Department of Infectious Diseases, University of Gothenburg, Sweden.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
    Acute Uncomplicated Febrile Illness in Children Aged 2-59 months in Zanzibar: Aetiologies, Antibiotic Treatment and Outcome2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 1, article id e0146054Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite the fact that a large proportion of children with fever in Africa present at primary health care facilities, few studies have been designed to specifically study the causes of uncomplicated childhood febrile illness at this level of care, especially in areas like Zanzibar that has recently undergone a dramatic change from high to low malaria transmission.

    METHODS: We prospectively studied the aetiology of febrile illness in 677 children aged 2-59 months with acute uncomplicated fever managed by IMCI (Integrated Management of Childhood Illness) guidelines in Zanzibar, using point-of-care tests, urine culture, blood-PCR, chest X-ray (CXR) of IMCI-pneumonia classified patients, and multiple quantitative (q)PCR investigations of nasopharyngeal (NPH) (all patients) and rectal (GE) swabs (diarrhoea patients). For comparison, we also performed NPH and GE qPCR analyses in 167 healthy community controls. Final fever diagnoses were retrospectively established based on all clinical and laboratory data. Clinical outcome was assessed during a 14-day follow-up. The utility of IMCI for identifying infections presumed to require antibiotics was evaluated.

    FINDINGS: NPH-qPCR and GE-qPCR detected ≥1 pathogen in 657/672 (98%) and 153/164 (93%) of patients and 158/166 (95%) and 144/165 (87%) of controls, respectively. Overall, 57% (387/677) had IMCI-pneumonia, but only 12% (42/342) had CXR-confirmed pneumonia. Two patients were positive for Plasmodium falciparum. Respiratory syncytial virus (24.5%), influenza A/B (22.3%), rhinovirus (10.5%) and group-A streptococci (6.4%), CXR-confirmed pneumonia (6.2%), Shigella (4.3%) were the most common viral and bacterial fever diagnoses, respectively. Blood-PCR conducted in a sub-group of patients (n = 83) without defined fever diagnosis was negative for rickettsiae, chikungunya, dengue, Rift Valley fever and West Nile viruses. Antibiotics were prescribed to 500 (74%) patients, but only 152 (22%) had an infection retrospectively considered to require antibiotics. Clinical outcome was generally good. However, two children died. Only 68 (11%) patients remained febrile on day 3 and three of them had verified fever on day 14. An additional 29 (4.5%) children had fever relapse on day 14. Regression analysis determined C-reactive Protein (CRP) as the only independent variable significantly associated with CXR-confirmed pneumonia.

    CONCLUSIONS: This is the first study on uncomplicated febrile illness in African children that both applied a comprehensive laboratory panel and a healthy control group. A majority of patients had viral respiratory tract infection. Pathogens were frequently detected by qPCR also in asymptomatic children, demonstrating the importance of incorporating controls in fever aetiology studies. The precision of IMCI for identifying infections requiring antibiotics was low.

  • 216. El-Hage, Nazira
    et al.
    Bruce-Keller, Annadora J
    Yakovleva, Tatiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bazov, Igor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Bakalkin, Georgy
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Knapp, Pamela E
    Hauser, Kurt F
    Morphine exacerbates HIV-1 Tat-induced cytokine production in astrocytes through convergent effects on [Ca(2+)](i), NF-kappaB trafficking and transcription2008In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 3, no 12, p. e4093-Article in journal (Refereed)
    Abstract [en]

    Astroglia are key cellular sites where opiate drug signals converge with the proinflammatory effects of HIV-1 Tat signals to exacerbate HIV encephalitis. Despite this understanding, the molecular sites of convergence driving opiate-accelerated neuropathogenesis have not been deciphered. We therefore explored potential points of interaction between the signaling pathways initiated by HIV-1 Tat and opioids in striatal astrocytes. Profiling studies screening 152 transcription factors indicated that the nuclear factor-kappa B (NF-kappaB) subunit, c-Rel, was a likely candidate for Tat or Tat plus opiate-induced increases in cytokine and chemokine production by astrocytes. Pretreatment with the NF-kappaB inhibitor parthenolide provided evidence that Tat+/-morphine-induced release of MCP-1, IL-6 and TNF-alpha by astrocytes is NF-kappaB dependent. The nuclear export inhibitor, leptomycin B, blocked the nucleocytoplasmic shuttling of NF-kappaB; causing p65 (RelA) accumulation in the nucleus, and significantly attenuated cytokine production in Tat+/-morphine exposed astrocytes. Similarly, chelating intracellular calcium ([Ca(2+)](i)) blocked Tat+/-morphine-evoked MCP-1 and IL-6 release, while artificially increasing the concentration of extracellular Ca(2+) reversed this effect. Taken together, these results demonstrate that: 1) exposure to Tat+/-morphine is sufficient to activate NF-kappaB and cytokine production, 2) the release of MCP-1 and IL-6 by Tat+/-morphine are highly Ca(2+)-dependent, while TNF-alpha appears to be less affected by the changes in [Ca(2+)](i), and 3) in the presence of Tat, exposure to opiates augments Tat-induced NF-kappaB activation and cytokine release through a Ca(2+)-dependent pathway.

  • 217. Eli, Karin
    et al.
    Howell, Kyndal
    Fisher, Philip A.
    Nowicka, Paulina
    ‘‘Those Comments Last Forever’’: Parents and Grandparents of Preschoolers Recount How They Became Aware of Their Own Body Weights as Children2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e111974-Article in journal (Refereed)
    Abstract [en]

    Background: Parents’ and grandparents’ willingness to talk about children’s body weights may be influenced by their own childhood experiences of body weight awareness and ‘weight talk’ in the family; however, little is known about how adults describe their recollected weight-related childhood experiences.

    Aims: This paper examines how parents and grandparents of preschoolers describe the emergence of their own body weight awareness in childhood or adolescence. The analysis highlights the sources that participants identify as having instigated their body weight awareness, the feelings and experiences participants associate with the experience of becoming aware of their body weights, and their framings of potential links between childhood experiences and attitudes and practices in adulthood.

    Methods: 49 participants (22 parents, 27 grandparents, 70% women, 60% with overweight/obesity) from sixteen low income families of children aged 3–5 years (50% girls, 56% with overweight/obesity) in the Pacific Northwest were interviewed. The interviews were videotaped, transcribed, and analyzed qualitatively.

    Results: Twenty-five participants (51%) said they became aware of their body weights in childhood or adolescence. Fourteen participants said their body weight awareness emerged through comments made by others, with the majority citing parents or peers. No participant described the emergence of body weight awareness in positive terms. Four participants directly linked their own negative experiences to the decision not to discuss body weight with their  preschoolers. All four cited critical comments from their parents as instigating their own body weight awareness in childhood.

    Conclusions: In most cases, participants associated their emergent awareness of body weight with overtly negative feelings or consequences; some participants said these negative experiences continued to affect them as adults. Since family-based childhood obesity interventions involve open discussion of children’s body sizes, the results suggest that clinicians should reframe the discussion to deconstruct obesity stigma and emphasize inclusive, affirmative, and health-focused messages.

  • 218.
    Ellegaard, Kirsten Maren
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Klasson, Lisa
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Andersson, Siv G. E.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Testing the Reproducibility of Multiple Displacement Amplification on Genomes of Clonal Endosymbiont Populations2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, p. e82319-Article in journal (Refereed)
    Abstract [en]

    The multiple displacement amplification method has revolutionized genomic studies of uncultured bacteria, where the extraction of pure DNA in sufficient quantity for next-generation sequencing is challenging. However, the method is problematic in that it amplifies the target DNA unevenly, induces the formation of chimeric reads and also amplifies contaminating DNA. Here, we have tested the reproducibility of the multiple displacement amplification method using serial dilutions of extracted genomic DNA and intact cells from the cultured endosymbiont Bartonella australis. The amplified DNA was sequenced with the Illumina sequencing technology, and the results were compared to sequence data obtained from unamplified DNA in this study as well as from a previously published genome project. We show that artifacts such as the extent of the amplification bias, the percentage of chimeric reads and the relative fraction of contaminating DNA increase dramatically for the smallest amounts of template DNA. The pattern of read coverage was reproducibly obtained for samples with higher amounts of template DNA, suggesting that the bias is non-random and genome-specific. A re-analysis of previously published sequence data obtained after amplification from clonal endosymbiont populations confirmed these predictions. We conclude that many of the artifacts associated with the use of the multiple displacement amplification method can be alleviated or much reduced by using multiple cells as the template for the amplification. These findings should be particularly useful for researchers studying the genomes of endosymbionts and other uncultured bacteria, for which a small clonal population of cells can be isolated.

  • 219. Elliott, James A.
    et al.
    Abdulhadi, Nadia Noor
    Al-Maniri, Abdullah A.
    Al-Shafaee, Mohammed A.
    Wahlström, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Diabetes Self-Management and Education of People Living with Diabetes: A Survey in Primary Health Care in Muscat Oman2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2, p. e57400-Article in journal (Refereed)
    Abstract [en]

    Background: Although the prevalence of type 2 diabetes in Oman is high and rising, information on how people were self-managing their disease has been lacking. The objective of this study was therefore to assess diabetes self-management and education (DSME) among people living with type 2 diabetes in Oman. Methods: A questionnaire survey was conducted in public primary health care centres in Muscat. Diabetes self-management and education was assessed by asking how patients recognized and responded to hypo- and hyperglycaemia, and if they had developed strategies to maintain stable blood glucose levels. Patients' demographic information, self-treatment behaviours, awareness of potential long-term complications, and attitudes concerning diabetes management were also recorded. Associations between these factors and diabetes self-management and education were analysed. Results: In total, 309 patients were surveyed. A quarter (26%, n = 83) were unaware how to recognize hypoglycaemia or respond to it (26%, n = 81). Around half (49%, n = 151), could not recognize hyperglycaemia and more than half could not respond to it (60%, n = 184). Twelve percent (n = 37) of the patients did not have any strategies to stabilize their blood glucose levels. Patients with formal education generally had more diabetes self-management and education than those without (p<0.001), as had patients with longer durations of diabetes (p<0.01). Self-monitoring of blood glucose was practiced by 38% (n = 117) of the patients, and insulin was used by 22% (n = 67), of which about one third independently adjusted dosages. Patients were most often aware of complications concerning loss of vision, renal failure and cardiac problems. Many patients desired further health education. Conclusions: Many patients displayed dangerous diabetes self-management and education knowledge gaps. The findings suggest a need for improving knowledge transfer to people living with diabetes in the Omani clinical setting.

  • 220. Elmabsout, Ali Ateia
    et al.
    Kumawat, Ashok
    Saenz-Mendez, Patricia
    Krivospitskaya, Olesya
    Sävenstrand, Helena
    Olofsson, Peder S.
    Eriksson, Leif A.
    Strid, Åke
    Valen, Guro
    Törmä, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
    Sirsjö, Allan
    Cloning and Functional Studies of a Splice Variant of CYP26B1 Expressed in Vascular Cells2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 5, p. e36839-Article in journal (Refereed)
    Abstract [en]

    Background: All-trans retinoic acid (atRA) plays an essential role in the regulation of gene expression, cell growth and differentiation and is also important for normal cardiovascular development but may in turn be involved in cardiovascular diseases, i.e. atherosclerosis and restenosis. The cellular atRA levels are under strict control involving several cytochromes P450 isoforms (CYPs). CYP26 may be the most important regulator of atRA catabolism in vascular cells. The present study describes the molecular cloning, characterization and function of atRA-induced expression of a spliced variant of the CYP26B1 gene. Methodology/Principal Findings: The coding region of the spliced CYP26B1 lacking exon 2 was amplified from cDNA synthesized from atRA-treated human aortic smooth muscle cells and sequenced. Both the spliced variant and full length CYP26B1 was found to be expressed in cultured human endothelial and smooth muscle cells, and in normal and atherosclerotic vessel. atRA induced both variants of CYP26B1 in cultured vascular cells. Furthermore, the levels of spliced mRNA transcript were 4.5 times higher in the atherosclerotic lesion compared to normal arteries and the expression in the lesions was increased 20-fold upon atRA treatment. The spliced CYP26B1 still has the capability to degrade atRA, but at an initial rate one-third that of the corresponding full length enzyme. Transfection of COS-1 and THP-1 cells with the CYP26B1 spliced variant indicated either an increase or a decrease in the catabolism of atRA, probably depending on the expression of other atRA catabolizing enzymes in the cells. Conclusions/Significance: Vascular cells express the spliced variant of CYP26B1 lacking exon 2 and it is also increased in atherosclerotic lesions. The spliced variant displays a slower and reduced degradation of atRA as compared to the full-length enzyme. Further studies are needed, however, to clarify the substrate specificity and role of the CYP26B1 splice variant in health and disease.

  • 221. Elshorbagy, Amany K
    et al.
    Jernerén, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Dept. of Pharmacology, University of Oxford.
    Scudamore, Cheryl L
    McMurray, Fiona
    Cater, Heather
    Hough, Tertius
    Cox, Roger
    Refsum, Helga
    Exploring the Lean Phenotype of Glutathione-Depleted Mice: Thiol, Amino Acid and Fatty Acid Profiles.2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0163214Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although reduced glutathione (rGSH) is decreased in obese mice and humans, block of GSH synthesis by buthionine sulfoximine (BSO) results in a lean, insulin-sensitive phenotype. Data is lacking about the effect of BSO on GSH precursors, cysteine and glutamate. Plasma total cysteine (tCys) is positively associated with stearoyl-coenzyme A desaturase (SCD) activity and adiposity in humans and animal models.

    OBJECTIVE: To explore the phenotype, amino acid and fatty acid profiles in BSO-treated mice.

    DESIGN: Male C3H/HeH mice aged 11 weeks were fed a high-fat diet with or without BSO in drinking water (30 mmol/L) for 8 weeks. Amino acid and fatty acid changes were assessed, as well as food consumption, energy expenditure, locomotor activity, body composition and liver vacuolation (steatosis).

    RESULTS: Despite higher food intake, BSO decreased particularly fat mass but also lean mass (both P<0.001), and prevented fatty liver vacuolation. Physical activity increased during the dark phase. BSO decreased plasma free fatty acids and enhanced insulin sensitivity. BSO did not alter liver rGSH, but decreased plasma total GSH (tGSH) and rGSH (by ~70%), and liver tGSH (by 82%). Glutamate accumulated in plasma and liver. Urine excretion of cysteine and its precursors was increased by BSO. tCys, rCys and cystine decreased in plasma (by 23-45%, P<0.001 for all), but were maintained in liver, at the expense of decreased taurine. Free and total plasma concentrations of the SCD products, oleic and palmitoleic acids were decreased (by 27-38%, P <0.001 for all).

    CONCLUSION: Counterintuitively, block of GSH synthesis decreases circulating tCys, raising the question of whether the BSO-induced obesity-resistance is linked to cysteine depletion. Cysteine-supplementation of BSO-treated mice is warranted to dissect the effects of cysteine and GSH depletion on energy metabolism.

  • 222.
    Elwér, Sofia
    et al.
    Umeå universitet, Allmänmedicin.
    Harryson, Lisa
    Umeå universitet, Allmänmedicin.
    Bolin, Malin
    Department of Social Sciences, Mid Sweden University.
    Hammarström, Anne
    Umeå universitet, Allmänmedicin.
    Patterns of gender equality at workplaces and psychological distress2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e53246-Article in journal (Refereed)
    Abstract [en]

    Research in the field of occupational health often uses a risk factor approach which has been criticized by feminist researchers for not considering the combination of many different variables that are at play simultaneously. To overcome this shortcoming this study aims to identify patterns of gender equality at workplaces and to investigate how these patterns are associated with psychological distress. Questionnaire data from the Northern Swedish Cohort (n=715) have been analysed and supplemented with register data about the participants’ workplaces. The register data were used to create gender equality indicators of women/men ratios of number of employees, educational level, salary and parental leave. Cluster analysis was used to identify patterns of gender equality at the workplaces. Differences in psychological distress between the clusters were analysed by chi-square test and logistic regression analyses, adjusting for individual socio-demographics and previous psychological distress. The cluster analysis resulted in six distinctive clusters with different patterns of gender equality at the workplaces that were associated to psychological distress for women but not for men. For women the highest odds of psychological distress was found on traditionally gender unequal workplaces. The lowest overall occurrence of psychological distress as well as same occurrence for women and men was found on the most gender equal workplaces. The results from this study support the convergence hypothesis as gender equality at the workplace does not only relate to better mental health for women, but also more similar occurrence of mental ill-health between women and men. This study highlights the importance of utilizing a multidimensional view of gender equality to understand its association to health outcomes. Health policies need to consider gender equality at the workplace level as a social determinant of health that is of importance for reducing differences in health outcomes for women and men.

  • 223.
    Emami Khoonsari, Payam
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Haggmark, Anna
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, Sci Life Lab, Stockholm, Sweden..
    Lönnberg, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Mikus, Maria
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, Sci Life Lab, Stockholm, Sweden..
    Kilander, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Nilsson, Peter
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, Sci Life Lab, Stockholm, Sweden..
    Kultima, Kim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Shevchenko, Ganna
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Uppsala Univ, Dept Chem BMC, Analyt Chem, Uppsala, Sweden..
    Analysis of the Cerebrospinal Fluid Proteome in Alzheimer's Disease2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0150672Article in journal (Refereed)
    Abstract [en]

    Alzheimer's disease is a neurodegenerative disorder accounting for more than 50% of cases of dementia. Diagnosis of Alzheimer's disease relies on cognitive tests and analysis of amyloid beta, protein tau, and hyperphosphorylated tau in cerebrospinal fluid. Although these markers provide relatively high sensitivity and specificity for early disease detection, they are not suitable for monitor of disease progression. In the present study, we used label-free shotgun mass spectrometry to analyse the cerebrospinal fluid proteome of Alzheimer's disease patients and non-demented controls to identify potential biomarkers for Alzheimer's disease. We processed the data using five programs (DecyderMS, Maxquant, OpenMS, PEAKS, and Sieve) and compared their results by means of reproducibility and peptide identification, including three different normalization methods. After depletion of high abundant proteins we found that Alzheimer's disease patients had lower fraction of low-abundance proteins in cerebrospinal fluid compared to healthy controls (p<0.05). Consequently, global normalization was found to be less accurate compared to using spiked-in chicken ovalbumin for normalization. In addition, we determined that Sieve and OpenMS resulted in the highest reproducibility and PEAKS was the programs with the highest identification performance. Finally, we successfully verified significantly lower levels (p<0.05) of eight proteins (A2GL, APOM, C1QB, C1QC, C1S, FBLN3, PTPRZ, and SEZ6) in Alzheimer's disease compared to controls using an antibody-based detection method. These proteins are involved in different biological roles spanning from cell adhesion and migration, to regulation of the synapse and the immune system.

  • 224.
    Emmert, Kirsten
    et al.
    Univ Geneva, Fac Med, Geneva, Switzerland.;Ecole Polytech Fed Lausanne, Inst Bioengn, Med Image Proc Lab, Geneva, Switzerland..
    Zoller, Daniela
    Ecole Polytech Fed Lausanne, Inst Bioengn, Med Image Proc Lab, Geneva, Switzerland.;Univ Geneva, Dept Psychiat, Off Medicopedag, Geneva, Switzerland..
    Preti, Maria Giulia
    Univ Geneva, Fac Med, Geneva, Switzerland.;Ecole Polytech Fed Lausanne, Inst Bioengn, Med Image Proc Lab, Geneva, Switzerland..
    Van De Ville, Dimitri
    Univ Geneva, Fac Med, Geneva, Switzerland.;Ecole Polytech Fed Lausanne, Inst Bioengn, Med Image Proc Lab, Geneva, Switzerland..
    Giannakopoulos, Panteleimon
    Univ Geneva, Dept Psychiat, Geneva, Switzerland..
    Haller, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Geneva, Fac Med, Geneva, Switzerland.;Affidea Ctr Diagnost Radiol Carouge CDRC, Carouge, Switzerland..
    Influence of Vascular Variant of the Posterior Cerebral Artery (PCA) on Cerebral Blood Flow, Vascular Response to CO2 and Static Functional Connectivity2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 8, article id e0161121Article in journal (Refereed)
    Abstract [en]

    Introduction The fetal origin of the posterior cerebral artery (fPCA) is a frequent vascular variant in 11-29% of the population. For the fPCA, blood flow in the PCA originates from the anterior instead of the posterior circulation. We tested whether this blood supply variant impacts the cerebral blood flow assessed by arterial spin labeling (ASL), cerebrovascular reserve as well as resting-state static functional connectivity (sFC) in the sense of a systematic confound. Methods The study included 385 healthy, elderly subjects (mean age: 74.18 years [range: 68.9-90.4]; 243 female). Participants were classified into normal vascular supply (n = 296, 76.88%), right fetal origin (n = 23, 5.97%), left fetal origin (n = 16, 4.16%), bilateral fetal origin (n = 4, 1.04%), and intermediate (n = 46, 11.95%, excluded from further analysis) groups. ASL-derived relative cerebral blood flow (relCBF) maps and cerebrovascular reserve (CVR) maps derived from a CO2 challenge with blocks of 7% CO2 were compared. Additionally, sFC between 90 regions of interest (ROIs) was compared between the groups. Results CVR was significantly reduced in subjects with ipsilateral fPCA, most prominently in the temporal lobe. ASL yielded a non-significant trend towards reduced relCBF in bilateral posterior watershed areas. In contrast, conventional atlas-based sFC did not differ between groups. Conclusions In conclusion, fPCA presence may bias the assessment of cerebrovascular reserve by reducing the response to CO2. In contrast, its effect on ASL-assessed baseline perfusion was marginal. Moreover, fPCA presence did not systematically impact resting-state sFC. Taken together, this data implies that perfusion variables should take into account the vascularization patterns.

  • 225. Engström, Anna
    et al.
    Zardán Gómez de la Torre, Teresa
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Strømme, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Nilsson, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Herthnek, David
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Detection of Rifampicin Resistance in Mycobacterium tuberculosis by Padlock Probes and Magnetic Nanobead- Based Readout2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 4, p. e62015-Article in journal (Refereed)
    Abstract [en]

    Control of the global epidemic tuberculosis is severely hampered by the emergence of drug-resistant Mycobacterium tuberculosis strains. Molecular methods offer a more rapid means of characterizing resistant strains than phenotypic drug susceptibility testing. We have developed a molecular method for detection of rifampicin-resistant M. tuberculosis based on padlock probes and magnetic nanobeads. Padlockprobes were designed to target the most common mutations associated with rifampicinresistance in M. tuberculosis, i.e. at codons 516, 526 and 531 in the gene rpoB. Fordetection of the wild type sequence at all three codons simultaneously, a padlock probe and two gap-fill oligonucleotides were used in a novel assay configuration, requiring three ligation events for circularization. The assay also includes a probe for identificationof the M. tuberculosis complex. Circularized probes were amplified by rolling circle amplification. Amplification products were coupled to oligonucleotide-conjugatedmagnetic nanobeads and detected by measuring the frequency-dependent magneticresponse of the beads using a portable AC susceptometer.

  • 226. Engström, Maria
    et al.
    Warntjes, Jan B M
    Tisell, Anders
    Landtblom, Anne-Marie
    Division of Radiation Physics, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Lundberg, Peter
    Multi-parametric representation of voxel-based quantitative magnetic resonance imaging2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, article id e111688Article in journal (Refereed)
    Abstract [en]

    The aim of the study was to explore the possibilities of multi-parametric representations of voxel-wise quantitative MRI data to objectively discriminate pathological cerebral tissue in patients with brain disorders. For this purpose, we recruited 19 patients with Multiple Sclerosis (MS) as benchmark samples and 19 age and gender matched healthy subjects as a reference group. The subjects were examined using quantitative Magnetic Resonance Imaging (MRI) measuring the tissue structure parameters: relaxation rates, R[Formula: see text] and R[Formula: see text], and proton density. The resulting parameter images were normalized to a standard template. Tissue structure in MS patients was assessed by voxel-wise comparisons with the reference group and with correlation to a clinical measure, the Expanded Disability Status Scale (EDSS). The results were visualized by conventional geometric representations and also by multi-parametric representations. Data showed that MS patients had lower R[Formula: see text] and R[Formula: see text], and higher proton density in periventricular white matter and in wide-spread areas encompassing central and sub-cortical white matter structures. MS-related tissue abnormality was highlighted in posterior white matter whereas EDSS correlation appeared especially in the frontal cortex. The multi-parameter representation highlighted disease-specific features. In conclusion, the proposed method has the potential to visualize both high-probability focal anomalies and diffuse tissue changes. Results from voxel-based statistical analysis, as exemplified in the present work, may guide radiologists where in the image to inspect for signs of disease. Future clinical studies must validate the usability of the method in clinical practice.

  • 227.
    Engvall, Gunn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Psychosocial oncology and supportive care.
    Cernvall, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Psychosocial oncology and supportive care.
    Larsson, Gunnel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Psychosocial oncology and supportive care.
    von Essen, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Psychosocial oncology and supportive care.
    Mattsson, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Psychosocial oncology and supportive care.
    Cancer during adolescence: negative and positive consequences reported three and four years after diagnosis2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12, p. e29001-Article in journal (Refereed)
    Abstract [en]

    Persons diagnosed with cancer during adolescence have reported negative and positive cancer-related consequences two years after diagnosis. The overall aim was to longitudinally describe negative and positive cancer-related consequences reported by the same persons three and four years after diagnosis. A secondary aim was to explore whether reports of using vs. not using certain coping strategies shortly after diagnosis are related to reporting or not reporting certain consequences four years after diagnosis. Thirty-two participants answered questions about coping strategies shortly after diagnosis and negative and positive consequences three and four years after diagnosis. Answers about consequences were analysed with content analysis, potential relations between coping strategies and consequences were analysed by Fisher's exact test. The great majority reported negative and positive consequences three and four years after diagnosis and the findings indicate stability over time with regard to perceived consequences during the extended phase of survival. Findings reveal a potential relation between seeking information shortly after diagnosis and reporting a more positive view of life four years after diagnosis and not using fighting spirit shortly after diagnosis and not reporting good self-esteem and good relations four years after diagnosis. It is concluded that concomitant negative and positive cancer-related consequences appear stable over time in the extended phase of survival and that dialectical forces of negative and positive as well as distress and growth often go hand-in-hand after a trauma such as cancer during adolescence.

  • 228.
    Engvall, Gunn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Ångstrom-Brännstrom, Charlotte
    Umea Univ, Dept Nursing, Umea, Sweden..
    Mullaney, Tara
    Umea Univ, Umea Inst Design, Umea, Sweden..
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wickart-Johansson, Gun
    Karolinska Univ Hosp, Radiumhemmet, Dept Oncol, Stockholm, Sweden..
    Svärd, Anna-Maja
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Nyholm, Tufve
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Lindh, Jack
    Umea Univ, Dept Radiat Sci, Umea, Sweden..
    Lindh, Viveca
    Umea Univ, Dept Nursing, Umea, Sweden..
    It Is Tough and Tiring but It Works - Children's Experiences of Undergoing Radiotherapy2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0153029Article in journal (Refereed)
    Abstract [en]

    Approximately 300 children ages 0 to 18 are diagnosed with cancer in Sweden every year, and 80 to 90 of them undergo radiotherapy treatment. The aim was to describe children's experiences of preparing for and undergoing radiotherapy, and furthermore to describe children's suggestions for improvement. Thirteen children between the ages of 5 and 15 with various cancer diagnoses were interviewed. Data was analyzed using qualitative content analysis. The findings revealed five categories: positive and negative experiences with hospital stays and practical arrangements; age-appropriate information, communication, and guidance to various degrees; struggle with emotions; use of distraction and other suitable coping strategies; and children's suggestions for improvement during radiotherapy. An overarching theme emerged: "It is tough and tiring but it works". Some key areas were: explanatory visits, the need for information and communication, being afraid, discomfort and suffering, the need for media distraction, dealing with emotions, and the need for support. A systematic, family-centered preparation program could possible help families prepare and individualized distraction during radiotherapy could contribute to reducing distress. Further studies with interventions could clarify successful programs.

  • 229.
    Enroth, Stefan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bornelöv, Susanne
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Combinations of histone modifications mark exon inclusion levels2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 1, article id e29911Article in journal (Refereed)
    Abstract [en]

    Splicing is a complex process regulated by sequence at the classical splice sites and other motifs in exons and introns with an enhancing or silencing effect. In addition, specific histone modifications on nucleosomes positioned over the exons have been shown to correlate both positively and negatively with exon expression. Here, we trained a model of "IF … THEN …" rules to predict exon inclusion levels in a transcript from histone modification patterns. Furthermore, we showed that combinations of histone modifications, in particular those residing on nucleosomes preceding or succeeding the exon, are better predictors of exon inclusion levels than single modifications. The resulting model was evaluated with cross validation and had an average accuracy of 72% for 27% of the exons, which demonstrates that epigenetic signals substantially mark alternative splicing.

  • 230. Erezyilmaz, Deniz F.
    et al.
    Hayward, Alexander
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Huang, Yan
    Paps, Jordi
    Acs, Zoltan
    Delgado, Juan A.
    Collantes, Francisco
    Kathirithamby, Jeyaraney
    Expression of the Pupal Determinant broad during Metamorphic and Neotenic Development of the Strepsipteran Xenos vesparum Rossi2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e93614-Article in journal (Refereed)
    Abstract [en]

    Derived members of the endoparasitic order Strepsiptera have acquired an extreme form of sexual dimorphism whereby males undergo metamorphosis and exist as free-living adults while females remain larviform, reaching sexual maturity within their hosts. Expression of the transcription factor, broad (br) has been shown to be required for pupal development in insects in which both sexes progress through metamorphosis. A surge of br expression appears in the last larval instar, as the epidermis begins pupal development. Here we ask if br is also up-regulated in the last larval instar of male Xenos vesparum Rossi (Stylopidae), and whether such expression is lost in neotenic larviform females. We clone three isoforms of br from X. vesparum (Xv'br), and show that they share greatest similarity to the Z1, Z3 and Z4 isoforms of other insect species. By monitoring Xv'br expression throughout development, we detect elevated levels of total br expression and the Xv'Z1, Xv'Z3, and Xv'Z4 isoforms in the last larval instar of males, but not females. By focusing on Xv'br expression in individual samples, we show that the levels of Xv'BTB and Xv'Z3 in the last larval instar of males are bimodal, with some males expressing 3X greater levels of Xv'br than fourth instar femlaes. Taken together, these data suggest that neoteny (and endoparasitism) in females of Strepsiptera Stylopidia could be linked to the suppression of pupal determination. Our work identifies a difference in metamorphic gene expression that is associated with neoteny, and thus provides insights into the relationship between metamorphic and neotenic development.

  • 231.
    Eriksson Crommert, Martin
    et al.
    Univ Orebro, Fac Med & Hlth, SE-70182 Orebro, Sweden.;Swedish Sch Sport & Hlth Sci GIH, Stockholm, Sweden..
    Halvorsen, Kjartan
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Systems and Control. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Automatic control. KTH Royal Inst Technol, Sch Technol & Hlth, Stockholm, Sweden..
    Ekblom, Maria M.
    Swedish Sch Sport & Hlth Sci GIH, Stockholm, Sweden.;Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Trunk Muscle Activation at the Initiation and Braking of Bilateral Shoulder Flexion Movements of Different Amplitudes2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, article id e0141777Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate if trunk muscle activation patterns during rapid bilateral shoulder flexions are affected by movement amplitude. Eleven healthy males performed shoulder flexion movements starting from a position with arms along sides (0 degrees) to either 45 degrees, 90 degrees or 180 degrees. EMG was measured bilaterally from transversus abdominis (TrA), obliquus internus (OI) with intra-muscular electrodes, and from rectus abdominis (RA), erector spinae (ES) and deltoideus with surface electrodes. 3D kinematics was recorded and inverse dynamics was used to calculate the reactive linear forces and torque about the shoulders and the linear and angular impulses. The sequencing of trunk muscle onsets at the initiation of arm movements was the same across movement amplitudes with ES as the first muscle activated, followed by TrA, RA and OI. All arm movements induced a flexion angular impulse about the shoulders during acceleration that was reversed during deceleration. Increased movement amplitude led to shortened onset latencies of the abdominal muscles and increased level of activation in TrA and ES. The activation magnitude of TrA was similar in acceleration and deceleration where the other muscles were specific to acceleration or deceleration. The findings show that arm movements need to be standardized when used as a method to evaluate trunk muscle activation patterns and that inclusion of the deceleration of the arms in the analysis allow the study of the relationship between trunk muscle activation and direction of perturbing torque during one and the same arm movement.

  • 232.
    Eriksson, Leif
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Bergström, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). Institute for Global Health, London, United Kingdom.
    Hoa, Dinh Thi Phuong
    Hanoi School of Public Health, Hanoi, Vietnam.
    Nga, Nguyen Thu
    Research Institute for Child Health, Hanoi, Vietnam.
    Eldh, Ann Catrine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research. Högskolan Dalarna.
    Sustainability of knowledge implementation in a low- and middle- income context: Experiences from a facilitation project in Vietnam targeting maternal and neonatal health2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 8, article id e0182626Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In a previous trial in Vietnam, a facilitation strategy to secure evidence-based practice in primary care resulted in reduced neonatal mortality over a period of three years. While little is known as to what ensures sustainability in the implementation of community-based strategies, the aim of this study was to investigate factors promoting or hindering implementation, and sustainability of knowledge implementation strategies, by means of the former Neonatal Knowledge Into Practice (NeoKIP) trial.

    METHODS: In 2014 we targeted all levels in the Vietnamese healthcare system: six individual interviews with representatives at national, provincial and district levels, and six focus group discussions with representatives at the commune level. The interviews were transcribed verbatim, translated to English, and analysed using inductive and deductive thematic analysis.

    RESULTS: To achieve successful implementation and sustained effect of community-based knowledge implementation strategies, engagement of leaders and key stakeholders at all levels of the healthcare system is vital-prior to, during and after a project. Implementation and sustainability require thorough needs assessment, tailoring of the intervention, and consideration of how to attain and manage funds. The NeoKIP trial was characterised by a high degree of engagement at the primary healthcare system level. Further, three years post trial, maternal and neonatal care was still high on the agenda for healthcare workers and leaders, even though primary aspects such as stakeholder engagement at all levels, and funding had been incomplete or lacking.

    CONCLUSIONS: The current study illustrates factors to support successful implementation and sustain effects of community-based strategies in projects in low- and middle-income settings; some but not all factors were represented during the post-NeoKIP era. Most importantly, trials in this and similar contexts require deliberate management throughout and beyond the project lifetime, and engagement of key stakeholders, in order to promote and sustain knowledge implementation.

  • 233.
    Eriksson, Olle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Olsson, Ulf
    Swedish Univ Agr Sci, Unit Appl Stat & Math, Uppsala, Sweden..
    Marteinsdottir, Ina
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Holstad, Maria
    Univ Uppsala Hosp, Dept Neurosci, Psychiat Unit, Uppsala, Sweden..
    Ågren, Hans
    Univ Gothenburg, Inst Neurosci & Physiol, Gothenburg, Sweden..
    Hartvig, Per
    Univ Copenhagen, Dept Drug Design & Pharmacol, Copenhagen, Denmark..
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Naessén, Tord
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Women with Premenstrual Dysphoria Lack the Seemingly Normal Premenstrual Right-Sided Relative Dominance of 5-HTP-Derived Serotonergic Activity in the Dorsolateral Prefrontal Cortices - A Possible Cause of Disabling Mood Symptoms2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, article id e0159538Article in journal (Refereed)
    Abstract [en]

    Study Objective To investigate potential quantitative and qualitative differences in brain serotonergic activity between women with Premenstrual Dysphoria (PMD) and asymptomatic controls. Background Serotonin-augmenting drugs alleviate premenstrual mood symptoms in the majority of women with PMD while serotonin-depleting diets worsen PMD symptoms, both indicating intrinsic differences in brain serotonergic activity in women with PMD compared to asymptomatic women. Methods Positron-emission tomography with the immediate precursor of serotonin, 5-hydroxytryptophan (5-HTP), radiolabelled by 11C in the beta-3 position, was performed in the follicular and luteal phases for 12 women with PMD and 8 control women. Brain radioactivity-a proxy for serotonin precursor uptake and synthesis-was measured in 9 regions of interest (ROIs): the right and left sides of the medial prefrontal cortex, dorsolateral prefrontal cortex, putamen and caudate nucleus, and the single "whole brain". Results There were no significant quantitative differences in brain 5-HTP-derived activity between the groups in either of the menstrual phases for any of the 9 ROIs. However, multivariate analysis revealed a significant quantitative and qualitative difference between the groups. Asymptomatic control women showed a premenstrual right sided relative increase in dorsolateral prefrontal cortex 5-HTP derived activity, whereas PMD women displayed the opposite (p = 0.0001). Menstrual phase changes in this asymmetry (premenstrual-follicular) correlated with changes in self ratings of 'irritability' for the entire group (rs = -0.595, p = 0.006). The PMD group showed a strong inverse correlation between phase changes (pre-menstrual-follicular) in plasma levels of estradiol and phase changes in the laterality (dx/sin) of radiotracer activity in the dorsolateral prefrontal ROI (r(s) = -0.635; 0.027). The control group showed no such correlation. Conclusion Absence of increased premenstrual right-sided relative 5-HTP-derived activity of the dorsolateral prefrontal cortices was found to strongly correlate to premenstrual irritability. A causal relationship here seems plausible, and the findings give further support to an underlying frontal brain disturbance in hormonally influenced serotonergic activity in women with PMD. Because of the small number of subjects in the study, these results should be considered preliminary, requiring verification in larger studies.

  • 234.
    Ersdal, Hege L.
    et al.
    Stavanger Univ Hosp, Dept Anaesthesiol & Intens Care, Stavanger, Norway..
    Singhal, Nalini
    Univ Calgary, Div Neonatol, Calgary, AB, Canada..
    Msemo, Georgina
    Minist Hlth & Social Serv, Reprod & Child Hlth Serv, Dar Es Salaam, Tanzania..
    KC, Ashish
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH). UNICEF, Hlth Sect, Kathmandu, Nepal..
    Data, Santorino
    Mbarara Univ Sci & Technol, Pediat & Child Hlth, Mbarara, Uganda..
    Moyo, Nester T.
    Int Confederat Midwives, Harare, Zimbabwe..
    Evans, Cherrie L.
    Johns Hopkins Univ, Jhpiego, Baltimore, MD USA..
    Smith, Jeffrey
    Johns Hopkins Univ, Jhpiego, Baltimore, MD USA..
    Perlman, Jeffrey M.
    Weill Cornell Med Coll, Div Newborn Med, New York, NY USA..
    Niermeyer, Susan
    Univ Colorado, Sch Med, Sect Neonatol, Aurora, CO USA..
    Successful implementation of Helping Babies Survive and Helping Mothers Survive programs-An Utstein formula for newborn and maternal survival2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0178073Article in journal (Refereed)
    Abstract [en]

    Globally, the burden of deaths and illness is still unacceptably high at the day of birth. Annually, approximately 300.000 women die related to childbirth, 2.7 million babies die within their first month of life, and 2.6 million babies are stillborn. Many of these fatalities could be avoided by basic, but prompt care, if birth attendants around the world had the necessary skills and competencies to manage life-threatening complications around the time of birth. Thus, the innovative Helping Babies Survive (HBS) and Helping Mothers Survive (HMS) programs emerged to meet the need for more practical, low-cost, and low-tech simulation-based training. This paper provides users of HBS and HMS programs a 10-point list of key implementation steps to create sustained impact, leading to increased survival of mothers and babies. The list evolved through an Utstein consensus process, involving a broad spectrum of international experts within the field, and can be used as a means to guide processes in low-resourced countries. Successful implementation of HBS and HMS training programs require country-led commitment, readiness, and follow-up to create local accountability and ownership. Each country has to identify its own gaps and define realistic service delivery standards and patient outcome goals depending on available financial resources for dissemination and sustainment.

  • 235. Escott-Price, Valentina
    et al.
    Bellenguez, Celine
    Wang, Li-San
    Choi, Seung-Hoan
    Harold, Denise
    Jones, Lesley
    Holmans, Peter
    Gerrish, Amy
    Vedernikov, Alexey
    Richards, Alexander
    DeStefano, Anita L.
    Lambert, Jean-Charles
    Ibrahim-Verbaas, Carla A.
    Naj, Adam C.
    Sims, Rebecca
    Jun, Gyungah
    Bis, Joshua C.
    Beecham, Gary W.
    Grenier-Boley, Benjamin
    Russo, Giancarlo
    Thornton-Wells, Tricia A.
    Denning, Nicola
    Smith, Albert V.
    Chouraki, Vincent
    Thomas, Charlene
    Ikram, M. Arfan
    Zelenika, Diana
    Vardarajan, Badri N.
    Kamatani, Yoichiro
    Lin, Chiao-Feng
    Schmidt, Helena
    Kunkle, Brian
    Dunstan, Melanie L.
    Vronskaya, Maria
    Johnson, Andrew D.
    Ruiz, Agustin
    Bihoreau, Marie-Therese
    Reitz, Christiane
    Pasquier, Florence
    Hollingworth, Paul
    Hanon, Olivier
    Fitzpatrick, Annette L.
    Buxbaum, Joseph D.
    Campion, Dominique
    Crane, Paul K.
    Baldwin, Clinton
    Becker, Tim
    Gudnason, Vilmundur
    Cruchaga, Carlos
    Craig, David
    Amin, Najaf
    Berr, Claudine
    Lopez, Oscar L.
    De Jager, Philip L.
    Deramecourt, Vincent
    Johnston, Janet A.
    Evans, Denis
    Lovestone, Simon
    Letenneur, Luc
    Hernandez, Isabel
    Rubinsztein, David C.
    Eiriksdottir, Gudny
    Sleegers, Kristel
    Goate, Alison M.
    Fievet, Nathalie
    Huentelman, Matthew J.
    Gill, Michael
    Brown, Kristelle
    Kamboh, M. Ilyas
    Keller, Lina
    Barberger-Gateau, Pascale
    McGuinness, Bernadette
    Larson, Eric B.
    Myers, Amanda J.
    Dufouil, Carole
    Todd, Stephen
    Wallon, David
    Love, Seth
    Rogaeva, Ekaterina
    Gallacher, John
    St George-Hyslop, Peter
    Clarimon, Jordi
    Lleo, Alberto
    Bayer, Anthony
    Tsuang, Debby W.
    Yu, Lei
    Tsolaki, Magda
    Bossu, Paola
    Spalletta, Gianfranco
    Proitsi, Petra
    Collinge, John
    Sorbi, Sandro
    Garcia, Florentino Sanchez
    Fox, Nick C.
    Hardy, John
    Deniz Naranjo, Maria Candida
    Bosco, Paolo
    Clarke, Robert
    Brayne, Carol
    Galimberti, Daniela
    Scarpini, Elio
    Bonuccelli, Ubaldo
    Mancuso, Michelangelo
    Siciliano, Gabriele
    Moebus, Susanne
    Mecocci, Patrizia
    Del Zompo, Maria
    Maier, Wolfgang
    Hampel, Harald
    Pilotto, Alberto
    Frank-Garcia, Ana
    Panza, Francesco
    Solfrizzi, Vincenzo
    Caffarra, Paolo
    Nacmias, Benedetta
    Perry, William
    Mayhaus, Manuel
    Lannfelt, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Hakonarson, Hakon
    Pichler, Sabrina
    Carrasquillo, Minerva M.
    Ingelsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Beekly, Duane
    Alvarez, Victoria
    Zou, Fanggeng
    Valladares, Otto
    Younkin, Steven G.
    Coto, Eliecer
    Hamilton-Nelson, Kara L.
    Gu, Wei
    Razquin, Cristina
    Pastor, Pau
    Mateo, Ignacio
    Owen, Michael J.
    Faber, Kelley M.
    Jonsson, Palmi V.
    Combarros, Onofre
    O'Donovan, Michael C.
    Cantwell, Laura B.
    Soininen, Hilkka
    Blacker, Deborah
    Mead, Simon
    Mosley, Thomas H., Jr.
    Bennett, David A.
    Harris, Tamara B.
    Fratiglioni, Laura
    Holmes, Clive
    de Bruijn, Renee F. A. G.
    Passmore, Peter
    Montine, Thomas J.
    Bettens, Karolien
    Rotter, Jerome I.
    Brice, Alexis
    Morgan, Kevin
    Foroud, Tatiana M.
    Kukull, Walter A.
    Hannequin, Didier
    Powell, John F.
    Nalls, Michael A.
    Ritchie, Karen
    Lunetta, Kathryn L.
    Kauwe, John S. K.
    Boerwinkle, Eric
    Riemenschneider, Matthias
    Boada, Merce
    Hiltunen, Mikko
    Martin, Eden R.
    Schmidt, Reinhold
    Rujescu, Dan
    Dartigues, Jean-Francois
    Mayeux, Richard
    Tzourio, Christophe
    Hofman, Albert
    Noethen, Markus M.
    Graff, Caroline
    Psaty, Bruce M.
    Haines, Jonathan L.
    Lathrop, Mark
    Pericak-Vance, Margaret A.
    Launer, Lenore J.
    Van Broeckhoven, Christine
    Farrer, Lindsay A.
    van Duijn, Cornelia M.
    Ramirez, Alfredo
    Seshadri, Sudha
    Schellenberg, Gerard D.
    Amouyel, Philippe
    Williams, Julie
    Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, p. e94661-Article in journal (Refereed)
    Abstract [en]

    Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

  • 236. Escudero, Marcial
    et al.
    Martin-Bravo, Santiago
    Mayrose, Itay
    Fernandez-Mazuecos, Mario
    Fiz-Palacios, Omar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Hipp, Andrew L.
    Pimentel, Manuel
    Jimenez-Mejias, Pedro
    Valcarcel, Virginia
    Vargas, Pablo
    Luceno, Modesto
    Karyotypic Changes through Dysploidy Persist Longer over Evolutionary Time than Polyploid Changes2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 1, p. e85266-Article in journal (Refereed)
    Abstract [en]

    Chromosome evolution has been demonstrated to have profound effects on diversification rates and speciation in angiosperms. While polyploidy has predated some major radiations in plants, it has also been related to decreased diversification rates. There has been comparatively little attention to the evolutionary role of gains and losses of single chromosomes, which may or not entail changes in the DNA content (then called aneuploidy or dysploidy, respectively). In this study we investigate the role of chromosome number transitions and of possible associated genome size changes in angiosperm evolution. We model the tempo and mode of chromosome number evolution and its possible correlation with patterns of cladogenesis in 15 angiosperm clades. Inferred polyploid transitions are distributed more frequently towards recent times than single chromosome gains and losses. This is likely because the latter events do not entail changes in DNA content and are probably due to fission or fusion events (dysploidy), as revealed by an analysis of the relationship between genome size and chromosome number. Our results support the general pattern that recently originated polyploids fail to persist, and suggest that dysploidy may have comparatively longer-term persistence than polyploidy. Changes in chromosome number associated with dysploidy were typically observed across the phylogenies based on a chi-square analysis, consistent with these changes being neutral with respect to diversification.

  • 237. Falahati-Anbaran, Mohsen
    et al.
    Lundemo, Sverre
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics.
    Ansell, Stephen W.
    Stenoien, Hans K.
    Contrasting Patterns of Genetic Structuring in Natural Populations of Arabidopsis lyrata Subsp petraea across Different Regions in Northern Europe2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e107479-Article in journal (Refereed)
    Abstract [en]

    Level and partitioning of genetic diversity is expected to vary between contrasting habitats, reflecting differences in strength of ecological and evolutionary processes. Therefore, it is necessary to consider processes acting on different time scales when trying to explain diversity patterns in different parts of species' distributions. To explore how historical and contemporary factors jointly may influence patterns of genetic diversity and population differentiation, we compared genetic composition in the perennial herb Arabidopsis lyrata ssp. petraea from the northernmost parts of its distribution range on Iceland to that previously documented in Scandinavia. Leaf tissue and soil were sampled from ten Icelandic populations of A. lyrata. Seedlings were grown from soil samples, and tissue from above-ground and seed bank individuals were genotyped with 21 microsatellite markers. Seed bank density in Icelandic populations was low but not significantly different from that observed in Norwegian populations. While within-population genetic diversity was relatively high on Iceland (H-E = 0.35), among-population differentiation was low (F-ST = 0.10) compared to Norwegian and Swedish populations. Population differentiation was positively associated with geographical distance in both Iceland and Scandinavia, but the strength of this relationship varied between regions. Although topography and a larger distribution range may explain the higher differentiation between mountainous Norwegian relative to lowland populations in Sweden, these factors cannot explain the lower differentiation in Icelandic compared to Swedish populations. We propose that low genetic differentiation among Icelandic populations is not caused by differences in connectivity, but is rather due to large historical effective population sizes. Thus, rather than contemporary processes, historical factors such as survival of Icelandic lineages in northern refugia during the last glacial period may have contributed to the observed pattern.

  • 238.
    Falck-Ytter, Terje
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    The relation between reading skills and eye movement patterns in typically developing German-speaking (Austrian) adolescents: evidence from word reading, text reading and pseudoword readingIn: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203Article in journal (Refereed)
  • 239.
    Falck-Ytter, Terje
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Rehnberg, Erik
    Bolte, Sven
    Lack of Visual Orienting to Biological Motion and Audiovisual Synchrony in 3-Year-Olds with Autism2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 7, p. e68816-Article in journal (Refereed)
    Abstract [en]

    It has been suggested that children with autism orient towards audiovisual synchrony (AVS) rather than biological motion and that the opposite pattern is to be expected in typical development. Here, we challenge this notion by showing that 3-year-old neurotypical children orient to AVS and to biological motion in point-light displays but that 3-year-old children with autism orient to neither of these types of information. Thus, our data suggest that two fundamental mechanisms are disrupted in young children with autism: one that supports orienting towards others' movements and one that supports orienting towards multimodally specified events. These impairments may have consequences for socio-cognitive development and brain organization.

  • 240.
    Fard, Shahrzad Shirazi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Jarrin, Miguel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Boije, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Fillon, Valerie
    All-Eriksson, Charlotta
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Heterogenic Final Cell Cycle by Chicken Retinal Lim1 Horizontal Progenitor Cells Leads to Heteroploid Cells with a Remaining Replicated Genome2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 3, p. e59133-Article in journal (Refereed)
    Abstract [en]

    Retinal progenitor cells undergo apical mitoses during the process of interkinetic nuclear migration and newly generated post-mitotic neurons migrate to their prospective retinal layer. Whereas this is valid for most types of retinal neurons, chicken horizontal cells are generated by delayed non-apical mitoses from dedicated progenitors. The regulation of such final cell cycle is not well understood and we have studied how Lim1 expressing horizontal progenitor cells (HPCs) exit the cell cycle. We have used markers for S-and G2/M-phase in combination with markers for cell cycle regulators Rb1, cyclin B1, cdc25C and p27Kip1 to characterise the final cell cycle of HPCs. The results show that Lim1+ HPCs are heterogenic with regards to when and during what phase they leave the final cell cycle. Not all horizontal cells were generated by a non-apical (basal) mitosis; instead, the HPCs exhibited three different behaviours during the final cell cycle. Thirty-five percent of the Lim1+ horizontal cells was estimated to be generated by non-apical mitoses. The other horizontal cells were either generated by an interkinetic nuclear migration with an apical mitosis or by a cell cycle with an S-phase that was not followed by any mitosis. Such cells remain with replicated DNA and may be regarded as somatic heteroploids. The observed heterogeneity of the final cell cycle was also seen in the expression of Rb1, cyclin B1, cdc25C and p27Kip1. Phosphorylated Rb1-Ser608 was restricted to the Lim1+ cells that entered S-phase while cyclin B1 and cdc25C were exclusively expressed in HPCs having a basal mitosis. Only HPCs that leave the cell cycle after an apical mitosis expressed p27Kip1. We speculate that the cell cycle heterogeneity with formation of heteroploid cells may present a cellular context that contributes to the suggested propensity of these cells to generate cancer when the retinoblastoma gene is mutated.

  • 241.
    Farooqi, A.
    et al.
    Umea Univ, Inst Clin Sci, Pediat, Umea, Sweden..
    Adamsson, M.
    Umea Univ, Inst Clin Sci, Pediat, Umea, Sweden..
    Serenius, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hägglöf, B.
    Umea Univ, Inst Clin Sci Child & Adolescent Psychiat, Umea, Sweden..
    Executive Functioning and Learning Skills of Adolescent Children Born at Fewer than 26 Weeks of Gestation2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0151819Article in journal (Refereed)
    Abstract [en]

    Aims To assess the cognitive and behavioral aspects of executive functioning (EF) and learning skills in extremely preterm (EPT) children compared with term control children aged 10 to 15 years. Methods A total of 132 of 134 (98% of all eligible survivors) EPT children born at the 2 Swedish regional tertiary care centers from 1992 to 1998 (mean age = 12 years, mean birth weight = 718 g, and mean gestational age = 24.4 weeks) and 103 matched term controls were assessed. General intelligence was assessed using the Wechsler Intelligence Scale for Children (WISC-III-R), and cognitive aspects of EF were analyzed using EF-sensitive sub-scales of the WISC-III-R and Tower test of the Delis-Kaplan Executive Function Scale (D-KEFS). Behaviors related to EF and learning skills were assessed using the Five to Fifteen questionnaire, which is a validated parent and teacher instrument. Academic performance in school was assessed by teachers' responses on Achenbach's Teachers Report Form. Analyses performed included multivariate analyses of covariance (ANCOVA and MANCOVA) and logistic regression analyses. Results The EPT children displayed significant deficits in cognitive aspects of EF compared with the controls, exhibiting decreases on the order of 0.9 SD to 1.2 SD for tasks of verbal conceptual reasoning, verbal and non-verbal working memory, processing speed and planning ability (P < 0.001 for all). After excluding the children with major neurosensory impairment (NSI) or a Full Scale intelligence quotient (FSIQ) of < 70, significant differences were observed on all tests. Compared with controls, parents and teachers of EPT children reported significantly more EF-related behavioral problems. MANCOVA of teacher-reported learning skills in children with FSIQ > 70 and without major NSI revealed no interactions, but significant main effects were observed for the behavioral composite executive function score, group status (EPT vs control) and FSIQ, for which all effect sizes were medium to large. The corresponding findings of MANCOVA of the parent-reported learning skills were very similar. According to the teachers' ratings, the EPT children were less well adjusted to the school environment. Conclusion EPT children born in the 1990s who received active perinatal care are at an increased risk of executive dysfunction, even after excluding children with significant neurodevelopmental disabilities. Even mild to moderate executive dysfunctions has a significant impact on learning skills. These findings suggest the need for timely interventions that address specific cognitive vulnerabilities and executive dysfunctions.

  • 242. Farshbaf, Mozhgan
    et al.
    Lindberg, Mikael J
    Truong, Anh
    Bevens, Zachery
    Chambers, Elaina
    Pournara, Angeliki
    Wallberg, Annika E
    White, J Brandon
    Mastermind-Like 1 Is Ubiquitinated: Functional Consequences for Notch Signaling.2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7Article in journal (Refereed)
    Abstract [en]

    Early studies demonstrated the involvement of ubiquitination of the Notch intracellular domain for rapid turnover of the transcriptional complex at Notch target genes. It was shown that this ubiquitination was promoted by the co-activator Mastermind like 1 (MAML1). MAML1 also contains numerous lysine residues that may also be ubiquitinated and necessary for protein regulation. In this study, we show that over-expressed MAML1 is ubiquitinated and identify eight conserved lysine residues which are required for ubiquitination. We also show that p300 stimulates ubiquitination and that Notch inhibits ubiquitination. Furthermore, we show that a mutant MAML1 that has decreased ubiquitination shows increased output from a HES1 reporter gene assay. Therefore, we speculate that ubiquitination of MAML1 might be a mechanism to maintain low levels of the protein until needed for transcriptional activation. In summary, this study identifies that MAML1 is ubiquitinated in the absence of Notch signaling to maintain low levels of MAML1 in the cell. Our data supports the notion that a precise and tight regulation of the Notch pathway is required for this signaling pathway.

  • 243.
    Faulks, Leanne
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Univ Tsukuba, Sugadaira Montane Res Ctr, Sugadaira Kogen 1278-294, Ueda, Nagano 3862204, Japan..
    Östman, Örjan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology. Inst Coastal Res, Dept Aquat Resources, Skolvagen 6, S-74242 Oregrund, Sweden..
    Genetic Diversity and Hybridisation between Native and Introduced Salmonidae Fishes in a Swedish Alpine Lake2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0152732Article in journal (Refereed)
    Abstract [en]

    Understanding the processes underlying diversification can aid in formulating appropriate conservation management plans that help maintain the evolutionary potential of taxa, particularly under human-induced activities and climate change. Here we assessed the microsatellite genetic diversity and structure of three salmonid species, two native (Arctic charr, Salvelinus alpinus and brown trout, Salmo trutta) and one introduced (brook charr, Salvelinus fontinalis), from an alpine lake in sub-arctic Sweden, Lake Ann. The genetic diversity of the three species was similar and sufficiently high from a conservation genetics perspective: corrected total heterozygosity, H'(T) = 0.54, 0.66, 0.60 and allelic richness, A(R) = 4.93, 5.53 and 5.26 for Arctic charr, brown trout and brook charr, respectively. There were indications of elevated inbreeding coefficients in brown trout (G(IS) = 0.144) and brook charr (G(IS) = 0.129) although sibling relationships were likely a confounding factor, as a high proportion of siblings were observed in all species within and among sampling locations. Overall genetic structure differed between species, Fst = 0.01, 0.02 and 0.04 in Arctic charr, brown trout and brook charr respectively, and there was differentiation at only a few specific locations. There was clear evidence of hybridisation between the native Arctic charr and the introduced brook charr, with 6% of individuals being hybrids, all of which were sampled in tributary streams. The ecological and evolutionary consequences of the observed hybridisation are priorities for further research and the conservation of the evolutionary potential of native salmonid species.

  • 244. Fayad, Walid
    et al.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Brnjic, Slavica
    Olofsson, Maria Hägg
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Linder, Stig
    Identification of a novel topoisomerase inhibitor effective in cells overexpressing drug efflux transporters2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 10, p. e7238-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Natural product structures have high chemical diversity and are attractive as lead structures for discovery of new drugs. One of the disease areas where natural products are most frequently used as therapeutics is oncology.

    METHOD AND FINDINGS:

    A library of natural products (NCI Natural Product set) was screened for compounds that induce apoptosis of HCT116 colon carcinoma cells using an assay that measures an endogenous caspase-cleavage product. One of the apoptosis-inducing compounds identified in the screen was thaspine (taspine), an alkaloid from the South American tree Croton lechleri. The cortex of this tree is used for medicinal purposes by tribes in the Amazonas basin. Thaspine was found to induce conformational activation of the pro-apoptotic proteins Bak and Bax, mitochondrial cytochrome c release and mitochondrial membrane permeabilization in HCT116 cells. Analysis of the gene expression signature of thaspine-treated cells suggested that thaspine is a topoisomerase inhibitor. Inhibition of both topoisomerase I and II was observed using in vitro assays, and thaspine was found to have a reduced cytotoxic effect on a cell line with a mutated topoisomerase II enzyme. Interestingly, in contrast to the topoisomerase II inhibitors doxorubicin, etoposide and mitoxantrone, thaspine was cytotoxic to cell lines overexpressing the PgP or MRP drug efflux transporters. We finally show that thaspine induces wide-spread apoptosis in colon carcinoma multicellular spheroids and that apoptosis is induced in two xenograft mouse models in vivo.

    CONCLUSIONS:

    The alkaloid thaspine from the cortex of Croton lechleri is a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids.

  • 245.
    Fegraeus, Kim Jäderkvist
    et al.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Lawrence, Chameli
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Petäjistö, Katrine
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Johansson, Maria K.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Wiklund, Maja
    Swedish Univ Agr Sci, Dept Clin Sci, Uppsala, Sweden..
    Olsson, Christina
    Swedish Trotting Assoc, Bromma, Sweden..
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA..
    Andersson, Lisa S.
    Capilet Genet AB, Vasteras, Sweden..
    Roed, Knut H.
    Norwegian Univ Life Sci, Dept Basic Sci & Aquat Med, Fac Vet Med, Oslo, Norway..
    Ihler, Carl-Fredrik
    Norwegian Univ Life Sci, Dept Compan Anim Clin Sci, Fac Vet Med, Oslo, Norway..
    Strand, Eric
    Norwegian Univ Life Sci, Dept Compan Anim Clin Sci, Fac Vet Med, Oslo, Norway..
    Lindgren, Gabriella
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Velie, Brandon D.
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Lack of significant associations with early career performance suggest no link between the DMRT3 "Gait Keeper" mutation and precocity in Coldblooded trotters2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0177351Article in journal (Refereed)
    Abstract [en]

    The Swedish-Norwegian Coldblooded trotter (CBT) is a local breed in Sweden and Norway mainly used for harness racing. Previous studies have shown that a mutation from cytosine (C) to adenine (A) in the doublesex and mab-3 related transcription factor 3 (DMRT3) gene has a major impact on harness racing performance of different breeds. An association of the DMRT3 mutation with early career performance has also been suggested. The aim of the current study was to investigate this proposed association in a randomly selected group of CBTs. 769 CBTs (485 raced, 284 unraced) were genotyped for the DMRT3 mutation. The association with racing performance was investigated for 13 performance traits and three different age intervals: 3 years, 3 to 6 years, and 7 to 10 years of age, using the statistical software R. Each performance trait was analyzed for association with DMRT3 using linear models. The results suggest no association of the DMRT3 mutation with precocity (i.e. performance at 3 years of age). Only two traits (race time and number of disqualifications) were significantly different between the genotypes, with AA horses having the fastest times and CC horses having the highest number of disqualifications at 3 years of age. The frequency of the AA genotype was significantly lower in the raced CBT sample compared with the unraced sample and less than 50% of the AA horses participated in a race. For the age intervals 3 to 6 and 7 to 10 years the AA horses also failed to demonstrate significantly better performance than the other genotypes. Although suggested as the most favorable genotype for racing performance in Standardbreds and Finnhorses across all ages, the AA genotype does not appear to be associated with superior performance, early or late, in the racing career of CBTs.

  • 246.
    Fehling, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Systematic Biology.
    Davidson, Keith
    Bolch, Christopher J. S.
    Brand, Tim D.
    Narayanaswamy, Bhavani E.
    The Relationship between Phytoplankton Distribution and Water Column Characteristics in North West European Shelf Sea Waters2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 3, p. e34098-Article in journal (Refereed)
    Abstract [en]

    Phytoplankton underpin the marine food web in shelf seas, with some species having properties that are harmful to human health and coastal aquaculture. Pressures such as climate change and anthropogenic nutrient input are hypothesized to influence phytoplankton community composition and distribution. Yet the primary environmental drivers in shelf seas are poorly understood. To begin to address this in North Western European waters, the phytoplankton community composition was assessed in light of measured physical and chemical drivers during the "Ellett Line" cruise of autumn 2001 across the Scottish Continental shelf and into adjacent open Atlantic waters. Spatial variability existed in both phytoplankton and environmental conditions, with clear differences not only between on and off shelf stations but also between different on shelf locations. Temperature/salinity plots demonstrated different water masses existed in the region. In turn, principal component analysis (PCA), of the measured environmental conditions (temperature, salinity, water density and inorganic nutrient concentrations) clearly discriminated between shelf and oceanic stations on the basis of DIN:DSi ratio that was correlated with both salinity and temperature. Discrimination between shelf stations was also related to this ratio, but also the concentration of DIN and DSi. The phytoplankton community was diatom dominated, with multidimensional scaling (MDS) demonstrating spatial variability in its composition. Redundancy analysis (RDA) was used to investigate the link between environment and the phytoplankton community. This demonstrated a significant relationship between community composition and water mass as indexed by salinity (whole community), and both salinity and DIN: DSi (diatoms alone). Diatoms of the Pseudo-nitzschia seriata group occurred at densities potentially harmful to shellfish aquaculture, with the potential for toxicity being elevated by the likelihood of DSi limitation of growth at most stations and depths.

  • 247. Feitosa, Eloi
    et al.
    Adati, Renata D.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Thermal and Structural Behavior of Dioctadecyldimethylammonium Bromide Dispersions Studied by Differential Scanning Calorimetry and X-Ray Scattering2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 9, p. e44702-Article in journal (Refereed)
    Abstract [en]

    Dioctadecyldimethylammonium bromide (DODAB) is a double chain cationic lipid, which assembles as bilayer structures in aqueous solution. The precise structures formed depend on, e.g., lipid concentration and temperature. We here combine differential scanning calorimetry (DSC) and X-ray scattering (SAXS and WAXS) to investigate the thermal and structural behavior of up to 120 mM DODAB in water within the temperature range 1-70 degrees C. Below 1 mM, this system is dominated by unilamellar vesicles (ULVs). Between 1 and 65 mM, ULVs and multilamellar structures (MLSs) co-exist, while above 65 mM, the MLSs are the preferred structure. Depending on temperature, DSC and X-ray data show that the vesicles can be either in the subgel (SG), gel, or liquid crystalline (LC) state, while the MLSs (with lattice distance d = 36.7 angstrom) consist of interdigitated lamellae in the SG state, and ULVs in the LC state (no Bragg peak). Critical temperatures related to the thermal transitions of these bilayer structures obtained in the heating and cooling modes are reported, together with the corresponding transition enthalpies.

  • 248. Fernandez, Vincent
    et al.
    Buffetaut, Eric
    Suteethorn, Varavudh
    Rage, Jean-Claude
    Tafforeau, Paul
    Kundrat, Martin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Evidence of Egg Diversity in Squamate Evolution from Cretaceous Anguimorph Embryos2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0128610Article in journal (Refereed)
    Abstract [en]

    Lizards are remarkable amongst amniotes, for they display a unique mosaic of reproduction modes ranging from egg-laying to live-bearing. Within this patchwork, geckoes are believed to represent the only group to ever have produced fully calcified rigid-shelled eggs, contrasting with the ubiquitous parchment shelled-eggs observed in other lineages. However, this hypothesis relies only on observations of modern taxa and fossilised gecko-like eggshells which have never been found in association with any embryonic or parental remains. We report here the first attested fossil eggs of lizards from the Early Cretaceous of Thailand, combining hard eggshells with exquisitely preserved embryos of anguimoph (e.g. Komodo dragons, mosasaurs). These fossils shed light on an apparently rare reproduction strategy of squamates, demonstrate that the evolution of rigid-shelled eggs are not an exclusive specialization of geckoes, and suggest a high plasticity in the reproductive organs mineralizing eggshells.

  • 249.
    Ferrando, Carlos
    et al.
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Suarez-Sipmann, Fernando
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Hedenstierna laboratory. Inst Salud Carlos III, GIBER Enfermedades Resp, Madrid, Spain.
    Tusman, Gerardo
    Hosp Privado Comunidad Mar Del Plata, Dept Anesthesiol, Mar Del Plata, Buenos Aires, Argentina..
    Leon, Irene
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Romero, Esther
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Gracia, Estefania
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Mugarra, Ana
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Arocas, Blanca
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Pozo, Natividad
    Hosp Clin Univ, INCLIVA Clin Res Inst, Valencia, Spain..
    Soro, Marina
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Belda, Francisco J.
    Hosp Clin Univ, Dept Anesthesiol & Crit Care, Valencia, Spain..
    Open lung approach versus standard protective strategies: Effects on driving pressure and ventilatory efficiency during anesthesia - A pilot, randomized controlled trial2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 5, article id e0177399Article in journal (Refereed)
    Abstract [en]

    Background: Low tidal volume (VT) during anesthesia minimizes lung injury but may be associated to a decrease in functional lung volume impairing lung mechanics and efficiency. Lung recruitment (RM) can restore lung volume but this may critically depend on the post-RM selected PEEP. This study was a randomized, two parallel arm, open study whose primary outcome was to compare the effects on driving pressure of adding a RM to low-VT ventilation, with or without an individualized post-RM PEEP in patients without known previous lung disease during anesthesia.

    Methods: Consecutive patients scheduled for major abdominal surgery were submitted to low-VT ventilation (6 ml.kg(-1)) and standard PEEP of 5 cmH(2)O (pre-RM, n = 36). After 30 min estabilization all patients received a RM and were randomly allocated to either continue with the same PEEP (RM-5 group, n = 18) or to an individualized open-lung PEEP (OL-PEEP) (Open Lung Approach, OLA group, n = 18) defined as the level resulting in maximal Cdyn during a decremental PEEP trial. We compared the effects on driving pressure and lung efficiency measured by volumetric capnography.

    Results: OL-PEEP was found at 8 +/- 2 cmH(2)O. 36 patients were included in the final analysis. When compared with pre-RM, OLA resulted in a 22% increase in compliance and a 28% decrease in driving pressure when compared to pre-RM. These parameters did not improve in the RM-5. The trend of the DP was significantly different between the OLA and RM-5 groups (p = 0.002). VDalv/VTalv was significantly lower in the OLA group after the RM (p = 0.035).

    Conclusions: Lung recruitment applied during low-VT ventilation improves driving pressure and lung efficiency only when applied as an open-lung strategy with an individualized PEEP in patients without lung diseases undergoing major abdominal surgery.

  • 250. Figueiredo, Joana
    et al.
    Simoes-Correia, Joana
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Suriano, Gianpaolo
    Seruca, Raquel
    ADP-Ribosylation Factor 6 Mediates E-Cadherin Recovery by Chemical Chaperones2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. e23188-Article in journal (Refereed)
    Abstract [en]

    E-cadherin plays a powerful tumor suppressor role. Germline E-cadherin mutations justify 30% of Hereditary Diffuse Gastric Cancer (HDGC) and missense mutations are found in 30% of these families. We found possible to restore in vitro mutant E-cadherin associated to HDGC syndrome by using Chemical Chaperones (CCs). Herein, our aim was to disclose the molecular mechanisms underlying the CCs effects in E-cadherin regulation. Using cells stably expressing WT E-cadherin or two HDGC-associated missense mutations, we show that upon DMSO treatment, not only mutant E-cadherin is restored and stabilized at the plasma membrane (PM), but also Arf6 and PIPKI gamma expressions are altered. We show that modulation of Arf6 expression partially mimics the effect of CCs, suggesting that the cellular effects observed upon CCs treatment are mediated by Arf6. Further, we show that E-cadherin expression recovery is specifically linked to Arf6 due to its role on endocytosis and recycling pathways. Finally, we demonstrated that, as DMSO, several others CCs are able to modulate the trafficking machinery through an Arf6 dependent mechanism. Interestingly, the more effective compounds in E-cadherin recovery to PM are those that simultaneously inhibit Arf6 and stimulate PIPKI gamma expression and binding to E-cadherin. Here, we present the first evidence of a direct influence of CCs in cellular trafficking machinery and we show that this effect is of crucial importance in the context of juxtamembrane E-cadherin missense mutations associated to HDGC. We propose that this influence should be taken into account when exploring the therapeutic potential of this type of chemicals in genetic diseases associated to protein-misfolding.

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