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  • 201.
    Hammarsten, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Scherdin, Tove Dahl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hagglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersson, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Granfors, Torvald
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High Caveolin-1 Expression in Tumor Stroma Is Associated with a Favourable Outcome in Prostate Cancer Patients Managed by Watchful Waiting2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164016Article in journal (Refereed)
    Abstract [en]

    In the present study we have investigated whether Caveolin-1 expression in non-malignant and malignant prostate tissue is a potential prognostic marker for outcome in prostate cancer patients managed by watchful waiting. Caveolin-1 was measured in prostate tissues obtained through transurethral resection of the prostate from 395 patients diagnosed with prostate cancer. The majority of the patients (n = 298) were followed by watchful waiting after diagnosis. Tissue microarrays constructed from malignant and non-malignant prostate tissue were stained with an antibody against Caveolin-1. The staining pattern was scored and related to clinicopathologic parameters and outcome. Microdissection and qRT-PCR analysis of Cav-1 was done of the prostate stroma from non-malignant tissue and stroma from Gleason 3 and 4 tumors. Cav-1 RNA expression was highest in non-malignant tissue and decreased during cancer progression. High expression of Caveolin-1 in tumor stroma was associated with significantly longer cancer specific survival in prostate cancer patients. This association remained significant when Gleason score and local tumor stage were combined with Caveolin-1 in a Cox regression model. High stromal Caveolin-1 immunoreactivity in prostate tumors is associated with a favourable prognosis in prostate cancer patients managed by watchful waiting. Caveolin-1 could possibly become a useful prognostic marker for prostate cancer patients that are potential candidates for active surveillance.

  • 202.
    Hammarsten, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Winther, Johanna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Rudolfsson, Stina H
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Karalija, Amar
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Egevad, Lars
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm.
    Granfors, Torvald
    Department of Urology, Central Hospital, Västerås, Sweden.
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    ErbB2 Receptor Immunoreactivity in Prostate Cancer: Relationship to the Androgen Receptor, Disease Severity at Diagnosis and Disease Outcome2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, article id e105063Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: ErbB2 is a member of the epidermal growth factor family of tyrosine kinases that is centrally involved in the pathogenesis of prostate cancer and several studies have reported that a high expression of this protein has prognostic value. In the present study, we have investigated whether tumour ErbB2 immunoreactivity (ErbB2-IR) has clinically useful prognostic value, i.e. that it provides additional prognostic information to that provided by routine clinical tests (Gleason score, tumour stage).

    METHODOLOGY/PRINCIPAL FINDINGS: ErbB2-IR was measured in a well-characterised tissue microarray of tumour and non-malignant samples obtained at diagnosis. Additionally, mRNA levels of ErbB2-IR in the prostate were determined in the rat following manipulation of circulating androgen levels. Tumour ErbB2-IR was significantly associated with the downstream signalling molecule phosphorylated-Akt and with the cell proliferation marker Ki-67. The significant association of tumour ErbB2-IR with the Gleason score at diagnosis was lost when controlled for the association of both parameters with Ki-67. In the rat prostate, mRNA for ErbB2 was inversely associated with circulating androgen levels. There was no association between ErbB2-IR and the androgen receptor (AR)-IR in the tumours, but an interaction between the two parameters was seen with respect to their association with the tumour stage. Tumour ErbB2-IR was confirmed to be a prognostic marker for disease-specific survival, but it did not provide significant additive information to the Gleason score or to Ki-67.

    CONCLUSIONS/SIGNIFICANCE: It is concluded that tumour ErbB2-IR is of limited clinical value as a prognostic marker to aid treatment decisions, but could be of pathophysiological importance in prostate cancer.

  • 203.
    Hammarström, Anne
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Annandale, Ellen
    A Conceptual Muddle: An Empirical Analysis of the Use of 'Sex' and 'Gender' in 'Gender-Specific Medicine' Journals2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e34193-Article in journal (Refereed)
    Abstract [en]

    Background: At the same time as there is increasing awareness in medicine of the risks of exaggerating differences between men and women, there is a growing professional movement of 'gender-specific medicine' which is directed towards analysing 'sex' and 'gender' differences. The aim of this article is to empirically explore how the concepts of 'sex' and 'gender' are used in the new field of 'gender-specific medicine', as reflected in two medical journals which are foundational to this relatively new field. Method and Principal Findings: The data consist of all articles from the first issue of each journal in 2004 and an issue published three years later (n = 43). In addition, all editorials over this period were included (n = 61). Quantitative and qualitative content analyses were undertaken by the authors. Less than half of the 104 papers used the concepts of 'sex' and 'gender'. Less than 1 in 10 papers attempted any definition of the concepts. Overall, the given definitions were simple, unspecific and created dualisms between men and women. Almost all papers which used the two concepts did so interchangeably, with any possible interplay between 'sex' and gender' referred to only in six of the papers. Conclusion: The use of the concepts of 'sex' and gender' in 'gender-specific medicine' is conceptually muddled. The simple, dualistic and individualised use of these concepts increases the risk of essentialism and reductivist thinking. It therefore highlights the need to clarify the use of the terms 'sex' and 'gender' in medical research and to develop more effective ways of conceptualising the interplay between 'sex' and 'gender' in relation to different diseases.

  • 204.
    Hammarström, Anne
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Haukenes, Inger
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Fjellman Wiklund, Anncristine
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Lehti, Arja
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Professionell Development.
    Wiklund, Maria
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Evengard, Birgitta
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Stålnacke, Britt-Marie
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine.
    Low-Educated Women with Chronic Pain Were Less Often Selected to Multidisciplinary Rehabilitation Programs2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, article id e97134Article in journal (Refereed)
    Abstract [en]

    Background: There is a lack of research about a potential education-related bias in assessment of patients with chronic pain. The aim of this study was to analyze whether low-educated men and women with chronic pain were less often selected to multidisciplinary rehabilitation than those with high education. Methods: The population consisted of consecutive patients (n = 595 women, 266 men) referred during a three-year period from mainly primary health care centers for a multidisciplinary team assessment at a pain rehabilitation clinic at a university hospital in Northern Sweden. Patient data were collected from the Swedish Quality Registry for Pain Rehabilitation National Pain Register. The outcome variable was being selected by the multidisciplinary team assessment to a multidisciplinary rehabilitation program. The independent variables were: sex, age, born outside Sweden, education, pain severity as well as the hospital, anxiety and depression scale (HADS). Results: Low-educated women were less often selected to multidisciplinary rehabilitation programs than high-educated women (OR 0.55, CI 0.30-0.98), even after control for age, being born outside Sweden, pain intensity and HADS. No significant findings were found when comparing the results between high-and low-educated men. Conclusion: Our findings can be interpreted as possible discrimination against low-educated women with chronic pain in hospital referrals to pain rehabilitation. There is a need for more gender-theoretical research emphasizing the importance of taking several power dimensions into account when analyzing possible bias in health care.

  • 205.
    Hammarström, Anne
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Socialmedicin.
    Lundman, Berit
    Umeå University, Faculty of Medicine, Department of Nursing.
    Ahlgren, Christina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Socialmedicin.
    Wiklund, Maria
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Health and masculinities shaped by agency within structures among young unemployed men in a northern Swedish context2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 5, p. 1-18, article id e0124785Article in journal (Refereed)
    Abstract [en]

    The aim of our paper was to explore expressions of life choices and life chances (aspects of agency within structures) related to power and experiences of health among early unemployed adolescent young men during the transition period to adulthood. These expressions of agency within structure were interpreted in the light of Cockerham’s Health Lifestyles Theory. Furthermore, social constructions of masculinities were addressed in our analysis.

    Repeated interviews with ten young men in a cohort of school leavers were analyzed with qualitative content analysis.

    Cockerham’s model was useful for interpreting our findings and we found disposition to act to be a crucial theoretical tool to capture the will and intentions of participants in relation to health. We developed the model in the following ways: structure and socialization were visualized as surrounding the whole model. Analyses of what enhances or restricts power are important. In addition to practices of health lifestyles, we added experiences of health as outcome as well as emotional aspects in disposition to act. We interpret our findings as constructions of masculinities within certain structures, in relation to choices, habitus and practices.

    Qualitative research could contribute to develop the understanding of the agency within structure relationships. Future studies need to pay attention to experiences of health among young people at the margin of the labor market in various milieus – and to analyze these in relation to gender constructions and within the frame-work of agency within structure.

  • 206.
    Hammarström, Anne
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Social medicine.
    Wiklund, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Social medicine. Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Stålnacke, Britt-Marie
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Rehabilitation Medicine.
    Lehti, Arja
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Professionell Development.
    Haukenes, Inger
    Department of Public Mental Health, Division of Mental Health, Norwegian Institute of Public Health; Research Unit for General Practice, Uni Research Health, Kalfarveien 31, Bergen, Norway.
    Fjellman-Wiklund, Anncristine
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Physiotherapy.
    Developing a Tool for Increasing the Awareness about Gendered and Intersectional Processes in the Clinical Assessment of Patients: A Study of Pain Rehabilitation2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 4, article id e0152735Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: There is a need for tools addressing gender inequality in the everyday clinical work in health care. The aim of our paper was to develop a tool for increasing the awareness of gendered and intersectional processes in clinical assessment of patients, based on a study of pain rehabilitation.

    METHODS: In the overarching project named "Equal care in rehabilitation" we used multiple methods (both quantitative and qualitative) in five sub studies. With a novel approach we used Grounded Theory in order to synthesize the results from our sub studies, in order to develop the gender equality tool. The gender equality tool described and developed in this article is thus based on results from sub studies about the processes of assessment and selection of patients in pain rehabilitation. Inspired by some questions in earlier tools, we posed open ended questions and inductively searched for findings and concepts relating to gendered and social selection processes in pain rehabilitation, in each of our sub studies. Through this process, the actual gender equality tool was developed as 15 questions about the process of assessing and selecting patients to pain rehabilitation. As a more comprehensive way of understanding the tool, we performed a final step of the GT analyses. Here we synthesized the results of the tool into a comprehensive model with two dimensions in relation to several possible discrimination axes.

    RESULTS: The process of assessing and selecting patients was visualized as a funnel, a top down process governed by gendered attitudes, rules and structures. We found that the clinicians judged inner and outer characteristics and status of patients in a gendered and intersectional way in the process of clinical decision-making which thus can be regarded as (potentially) biased with regard to gender, socio-economic status, ethnicity and age.

    IMPLICATIONS: The clinical implications of our tool are that the tool can be included in the systematic routine of clinical assessment of patients for both awareness raising and as a base for avoiding gender bias in clinical decision-making. The tool could also be used in team education for health professionals as an instrument for critical reflection on gender bias.

    CONCLUSIONS: Thus, tools for clinical assessment can be developed from empirical studies in various clinical settings. However, such a micro-level approach must be understood from a broader societal perspective including gender relations on both the macro- and the meso-level.

  • 207. Hanski, Leena
    et al.
    Genina, Natalja
    Uvell, Hanna
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Malinovskaja, Kristina
    Gylfe, Asa
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
    Laaksonen, Timo
    Kolakovic, Ruzica
    Makila, Ermei
    Salonen, Jarno
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hirvonen, Jouni
    Sandler, Niklas
    Vuorela, Pia M.
    Inhibitory Activity of the Isoflavone Biochanin A on Intracellular Bacteria of Genus Chlamydia and Initial Development of a Buccal Formulation2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, article id e115115Article in journal (Refereed)
    Abstract [en]

    Given the established role of Chlamydia spp. as causative agents of both acute and chronic diseases, search for new antimicrobial agents against these intracellular bacteria is required to promote human health. Isoflavones are naturally occurring phytoestrogens, antioxidants and efflux pump inhibitors, but their therapeutic use is limited by poor water-solubility and intense first-pass metabolism. Here, we report on effects of isoflavones against C. pneumoniae and C. trachomatis and describe buccal permeability and initial formulation development for biochanin A. Biochanin A was the most potent Chlamydia growth inhibitor among the studied isoflavones, ;with an IC50=12 mu M on C. pneumoniae inclusion counts and 6.5 mu M on infectious progeny production, both determined by immunofluorescent staining of infected epithelial cell cultures. Encouraged by the permeation of biochanin A across porcine buccal mucosa without detectable metabolism, oromucosal film formulations were designed and prepared by a solvent casting method. The film formulations showed improved dissolution rate of biochanin A compared to powder or a physical mixture, presumably due to the solubilizing effect of hydrophilic additives and presence of biochanin A in amorphous state. In summary, biochanin A is a potent inhibitor of Chlamydia spp., and the in vitro dissolution results support the use of a buccal formulation to potentially improve its bioavailability in antichlamydial or other pharmaceutical applications.

  • 208.
    Hao, Manzhao
    et al.
    Institute of Rehabilitation Engineering, Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
    He, Xin
    Institute of Rehabilitation Engineering, Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
    Xiao, Qin
    Institute of Rehabilitation Engineering, Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
    Alstermark, Bror
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Physiology.
    Lan, Ning
    Institute of Rehabilitation Engineering, Med-X Research Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
    Corticomuscular transmission of tremor signals by propriospinal neurons in Parkinson's disease.2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 11, article id e79829Article in journal (Refereed)
    Abstract [en]

    Cortical oscillatory signals of single and double tremor frequencies act together to cause tremor in the peripheral limbs of patients with Parkinson's disease (PD). But the corticospinal pathway that transmits the tremor signals has not been clarified, and how alternating bursts of antagonistic muscle activations are generated from the cortical oscillatory signals is not well understood. This paper investigates the plausible role of propriospinal neurons (PN) in C3-C4 in transmitting the cortical oscillatory signals to peripheral muscles. Kinematics data and surface electromyogram (EMG) of tremor in forearm were collected from PD patients. A PN network model was constructed based on known neurophysiological connections of PN. The cortical efferent signal of double tremor frequencies were integrated at the PN network, whose outputs drove the muscles of a virtual arm (VA) model to simulate tremor behaviors. The cortical efferent signal of single tremor frequency actuated muscle spindles. By comparing tremor data of PD patients and the results of model simulation, we examined two hypotheses regarding the corticospinal transmission of oscillatory signals in Parkinsonian tremor. Hypothesis I stated that the oscillatory cortical signals were transmitted via the mono-synaptic corticospinal pathways bypassing the PN network. The alternative hypothesis II stated that they were transmitted by way of PN multi-synaptic corticospinal pathway. Simulations indicated that without the PN network, the alternating burst patterns of antagonistic muscle EMGs could not be reliably generated, rejecting the first hypothesis. However, with the PN network, the alternating burst patterns of antagonist EMGs were naturally reproduced under all conditions of cortical oscillations. The results suggest that cortical commands of single and double tremor frequencies are further processed at PN to compute the alternating burst patterns in flexor and extensor muscles, and the neuromuscular dynamics demonstrated a frequency dependent damping on tremor, which may prevent tremor above 8 Hz to occur.

  • 209. Haraldsson, Matilda
    et al.
    Båmstedt, Ulf
    Umeå University, Faculty of Science and Technology, Umeå Marine Sciences Centre (UMF).
    Tiselius, Peter
    Titelman, Josefin
    Aksnes, Dag L.
    Evidence of Diel Vertical Migration in Mnemiopsis leidyi2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 1, p. e86595-Article in journal (Refereed)
    Abstract [en]

    The vertical distribution and migration of plankton organisms may have a large impact on their horizontal dispersal and distribution, and consequently on trophic interactions. In this study we used video-net profiling to describe the fine scale vertical distribution of Mnemiopsis leidyi in the Kattegat and Baltic Proper. Potential diel vertical migration was also investigated by frequent filming during a 24-hour cycle at two contrasting locations with respect to salinity stratification. The video profiles revealed a pronounced diel vertical migration at one of the locations. However, only the small and medium size classes migrated, on average 0.85 m h(-1), corresponding to a total migration distance of 10 m during 12 h. Larger individuals (with well developed lobes, approx. >27 mm) stay on average in the same depth interval at all times. Biophysical data suggest that migrating individuals likely responded to light, and avoided irradiance levels higher than approx. 10 mu mol quanta m(-2) s(-1). We suggest that strong stratification caused by low surface salinity seemed to prohibit vertical migration.

  • 210. Haring, Robin
    et al.
    Rosvall, Martin
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Völker, Uwe
    Völzke, Henry
    Kroemer, Heyo
    Nauck, Matthias
    Wallaschofski, Henri
    A Network-Based Approach to Visualize Prevalence and Progression of Metabolic Syndrome Components2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e39461-Article in journal (Refereed)
    Abstract [en]

    Background: The additional clinical value of clustering cardiovascular risk factors to define the metabolic syndrome (MetS) is still under debate. However, it is unclear which cardiovascular risk factors tend to cluster predominately and how individual risk factor states change over time. Methods & Results: We used data from 3,187 individuals aged 20-79 years from the population-based Study of Health in Pomerania for a network-based approach to visualize clustered MetS risk factor states and their change over a five-year follow-up period. MetS was defined by harmonized Adult Treatment Panel III criteria, and each individual's risk factor burden was classified according to the five MetS components at baseline and follow-up. We used the map generator to depict 32 (2(5)) different states and highlight the most important transitions between the 1,024 (32(2)) possible states in the weighted directed network. At baseline, we found the largest fraction (19.3%) of all individuals free of any MetS risk factors and identified hypertension (15.4%) and central obesity (6.3%), as well as their combination (19.0%), as the most common MetS risk factors. Analyzing risk factor flow over the five-year follow-up, we found that most individuals remained in their risk factor state and that low high-density lipoprotein cholesterol (HDL) (6.3%) was the most prominent additional risk factor beyond hypertension and central obesity. Also among individuals without any MetS risk factor at baseline, low HDL (3.5%), hypertension (2.1%), and central obesity (1.6%) were the first risk factors to manifest during follow-up. Conclusions: We identified hypertension and central obesity as the predominant MetS risk factor cluster and low HDL concentrations as the most prominent new onset risk factor.

  • 211.
    Harlid, Sophia
    et al.
    Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
    Xu, Zongli
    Panduri, Vijayalakshmi
    D'Aloisio, Aimee A
    DeRoo, Lisa A
    Sandler, Dale P
    Taylor, Jack A
    In utero exposure to diethylstilbestrol and blood DNA methylation in women ages 40-59 years from the sister study.2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0118757Article in journal (Refereed)
    Abstract [en]

    In utero exposure to diethylstilbestrol (DES) has been associated with increased risk of adverse health outcomes such as fertility problems and vaginal as well as breast cancer. Animal studies have linked prenatal DES exposure to lasting DNA methylation changes. We investigated genome-wide DNA methylation and in utero DES exposure in a sample of non-Hispanic white women aged 40-59 years from the Sister Study, a large United States cohort study of women with a family history of breast cancer. Using questionnaire information from women and their mothers, we selected 100 women whose mothers reported taking DES while pregnant and 100 control women whose mothers had not taken DES. DNA methylation in blood was measured at 485,577 CpG sites using the Illumina HumanMethylation450 BeadChip. Associations between CpG methylation and DES exposure status were analyzed using robust linear regression with adjustment for blood cell composition and multiple comparisons. Although four CpGs had p<105, after accounting for multiple comparisons using the false discovery rate (FDR), none reached genome-wide significance. In conclusion, adult women exposed to DES in utero had no evidence of large persistent changes in blood DNA methylation.

  • 212.
    Harryson, Lisa
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine. Umeå University, Faculty of Social Sciences, Umeå Centre for Gender Studies (UCGS).
    Strandh, Mattias
    Umeå University, Faculty of Social Sciences, Department of Sociology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Hammarström, Anne
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Domestic work and psychological distress: what is the importance of relative socioeconomic position and gender inequality in the couple relationship?2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e38484-Article in journal (Refereed)
    Abstract [en]

    Aims: The aim of this study was to investigate whether the relation between responsibility for domestic work and psychological distress was influenced by perception of gender inequality in the couple relationship and relative socioeconomic position.

    Methods: In the Northern Swedish Cohort, all pupils who studied in the last year of compulsory school in a northern Swedish town in 1981 have been followed regularly until 2007. In this study, participants living with children were selected (n = 371 women, 352 men). The importance of relative socioeconomic position and perception of gender inequality in the couple relationship in combination with domestic work for psychological distress was examined through logistic regression analysis.

    Results: Two combinations of variables including socioeconomic position ('having less than half of the responsibility for domestic work and partner higher socioeconomic position' and 'having more than half the responsibility for domestic work and equal socioeconomic position') were related to psychological distress. There were also higher ORs for psychological distress for the combinations of having 'less than half of the responsibility for domestic work and gender-unequal couple relationship' and 'more than half the responsibility for domestic work and gender-unequal couple relationship'. Having a lower socioeconomic position than the partner was associated with higher ORs for psychological distress among men.

    Conclusions: This study showed that domestic work is a highly gendered activity as women tend to have a greater and men a smaller responsibility. Both these directions of inequality in domestic work, in combination with experiencing the couple relationship as gender-unequal, were associated with psychological distress There is a need for more research with a relational approach on inequalities in health in order to capture the power relations within couples in various settings.

  • 213. Hartana, Ciputra Adijaya
    et al.
    Bergman, Emma Ahlén
    Zirakzadeh, A. Ali
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Krantz, David
    Winerdal, Malin E.
    Winerdal, Max
    Johansson, Markus
    Alamdari, Farhood
    Jakubczyk, Tomasz
    Glise, Hans
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Urothelial bladder cancer may suppress perforin expression in CD8+ T cells by an ICAM-1/TGFβ2 mediated pathway2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 7, article id e0200079Article in journal (Refereed)
    Abstract [en]

    The immune system plays a significant role in urothelial bladder cancer (UBC) progression, with CD8+ T cells being capable to directly kill tumor cells using perforin and granzymes. However, tumors avoid immune recognition by escape mechanisms. In this study, we aim to demonstrate tumor immune escape mechanisms that suppress CD8+ T cells cytotoxicity. 42 patients diagnosed with UBC were recruited. CD8+ T cells from peripheral blood (PB), sentinel nodes (SN), and tumor were analyzed in steady state and in vitro-stimulated conditions by flow cytometry, RT-qPCR, and ELISA. Mass spectrometry (MS) was used for identification of proteins from UBC cell line culture supernatants. Perforin was surprisingly found to be low in CD8+ T cells from SN, marked by 1.8-fold decrease of PRF1 expression, with maintained expression of granzyme B. The majority of perforin-deficient CD8+ T cells are effector memory T (TEM) cells with exhausted Tc2 cell phenotype, judged by the presence of PD-1 and GATA-3. Consequently, perforin-deficient CD8+ T cells from SN are low in T-bet expression. Supernatant from muscle invasive UBC induces perforin deficiency, a mechanism identified by MS where ICAM-1 and TGFβ2 signaling were causatively validated to decrease perforin expression in vitro. Thus, we demonstrate a novel tumor escape suppressing perforin expression in CD8+ T cells mediated by ICAM-1 and TGFβ2, which can be targeted in combination for cancer immunotherapy.

  • 214. Hattula, Katarina
    et al.
    Hirschberg, Daniel
    Kalkkinen, Nisse
    Butcher, Sarah J
    Ora, Ari
    Association between the intrinsically disordered protein PEX19 and PEX3.2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7Article in journal (Refereed)
    Abstract [en]

    In peroxisomes, peroxins (PEXs) 3 and 19 are the principal protein components of the machinery required for early peroxisomal biogenesis. For further insight into the interaction of PEX3 and PEX19, we used hydrogen exchange mass spectrometry to monitor conformational changes during complex formation between PEX3 and PEX19 in vitro. Our data showed that PEX19 remained highly flexible during interaction with PEX3. However, we could detect three changes, one each in the N-and C-terminus along with a small stretch in the middle of PEX19 (F64-L74) which became shielded from hydrogen exchange when interacting with PEX3. PEX3 became more protected from hydrogen exchange in the binding groove for PEX19 with only small changes elsewhere. Most likely the N-terminus of PEX19 initiates the binding to PEX3, and then subtle conformational changes in PEX3 affect the surface of the PEX3 molecule. PEX19 in turn, is stabilized by folding of a short helix and its C-terminal folding core permitting PEX19 to bind to PEX3 with higher affinity than just the N-terminal interaction allows. Thus within the cell, PEX3 is stabilized by PEX19 preventing PEX3 aggregation.

  • 215.
    Hedlund, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Nagaeva, Olga
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Kargl, Dominic
    Baranov, Vladimir
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Thermal- and oxidative stress causes enhanced release of NKG2D ligand-bearing immunosuppressive exosomes in leukemia/lymphoma T and B cells2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, p. e16899-Article in journal (Refereed)
    Abstract [en]

    Immune evasion from NK surveillance related to inadequate NK-cell function has been suggested as an explanation of the high incidence of relapse and fatal outcome of many blood malignancies. In this report we have used Jurkat and Raji cell lines as a model for studies of the NKG2D receptor-ligand system in T-and B cell leukemia/lymphoma. Using real-time quantitative RT-PCR and immunoflow cytometry we show that Jurkat and Raji cells constitutively express mRNA and protein for the stress-inducible NKG2D ligands MICA/B and ULBP1 and 2, and up-regulate the expression in a cell-line specific and stress-specific manner. Furthermore, we revealed by electron microscopy, immunoflow cytometry and western blot that these ligands were expressed and secreted on exosomes, nanometer-sized microvesicles of endosomal origin. Acting as a decoy, the NKG2D ligand-bearing exosomes downregulate the in vitro NKG2D receptor-mediated cytotoxicity and thus impair NK-cell function. Interestingly, thermal and oxidative stress enhanced the exosome secretion generating more soluble NKG2D ligands that aggravated the impairment of the cytotoxic response. Taken together, our results might partly explain the clinically observed NK-cell dysfunction in patients suffering from leukemia/lymphoma. The adverse effect of thermal and oxidative stress, enhancing the release of immunosuppressive exosomes, should be considered when cytostatic and hyperthermal anti-cancer therapies are designed.

  • 216. Heikkila, Katriina
    et al.
    Madsen, Ida E. H.
    Nyberg, Solja T.
    Fransson, Eleonor I.
    Ahola, Kirsi
    Alfredsson, Lars
    Bjorner, Jakob B.
    Borritz, Marianne
    Burr, Hermann
    Dragano, Nico
    Ferrie, Jane E.
    Knutsson, Anders
    Koskenvuo, Markku
    Koskinen, Aki
    Nielsen, Martin L.
    Nordin, Maria
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Pejtersen, Jan H.
    Pentti, Jaana
    Rugulies, Reiner
    Oksanen, Tuula
    Shipley, Martin J.
    Suominen, Sakari B.
    Theorell, Tores
    Vaananen, Ari
    Vahtera, Jussi
    Virtanen, Marianna
    Westerlund, Hugo
    Westerholm, Peter J. M.
    Batty, G. David
    Singh-Manoux, Archana
    Kivimaki, Mika
    Job strain and the risk of inflammatory bowel diseases: individual-participant meta-analysis of 95 000 men and women2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e88711-Article in journal (Refereed)
    Abstract [en]

    Background and Aims: Many clinicians, patients and patient advocacy groups believe stress to have a causal role in inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis. However, this is not corroborated by clear epidemiological research evidence. We investigated the association between work-related stress and incident Crohn's disease and ulcerative colitis using individual-level data from 95 000 European adults. Methods: We conducted individual-participant data meta-analyses in a set of pooled data from 11 prospective European studies. All studies are a part of the IPD-Work Consortium. Work-related psychosocial stress was operationalised as job strain (a combination of high demands and low control at work) and was self-reported at baseline. Crohn's disease and ulcerative colitis were ascertained from national hospitalisation and drug reimbursement registers. The associations between job strain and inflammatory bowel disease outcomes were modelled using Cox proportional hazards regression. The study-specific results were combined in random effects meta-analyses. Results: Of the 95 379 participants who were free of inflammatory bowel disease at baseline, 111 men and women developed Crohn's disease and 414 developed ulcerative colitis during follow-up. Job strain at baseline was not associated with incident Crohn's disease (multivariable-adjusted random effects hazard ratio: 0.83, 95% confidence interval: 0.48, 1.43) or ulcerative colitis (hazard ratio: 1.06, 95% CI: 0.76, 1.48). There was negligible heterogeneity among the study-specific associations. Conclusions: Our findings suggest that job strain, an indicator of work-related stress, is not a major risk factor for Crohn's disease or ulcerative colitis.

  • 217. Heikkila, Katriina
    et al.
    Nyberg, Solja T.
    Fransson, Eleonor I.
    Alfredsson, Lars
    De Bacquer, Dirk
    Bjorner, Jakob B.
    Bonenfant, Sebastien
    Borritz, Marianne
    Burr, Hermann
    Clays, Els
    Casini, Annalisa
    Dragano, Nico
    Erbel, Raimund
    Geuskens, Goedele A.
    Goldberg, Marcel
    Hooftman, Wendela E.
    Houtman, Irene L.
    Joensuu, Matti
    Joeckel, Karl-Heinz
    Kittel, France
    Knutsson, Anders
    Koskenvuo, Markku
    Koskinen, Aki
    Kouvonen, Anne
    Leineweber, Constanze
    Lunau, Thorsten
    Madsen, Ida E. H.
    Hanson, Linda L. Magnusson
    Marmot, Michael G.
    Nielsen, Martin L.
    Nordin, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine. Umeå University, Faculty of Social Sciences, Department of Psychology.
    Pentti, Jaana
    Salo, Paula
    Rugulies, Reiner
    Steptoe, Andrew
    Siegrist, Johannes
    Suominen, Sakari
    Vahtera, Jussi
    Virtanen, Marianna
    Vaananen, Ari
    Westerholm, Peter
    Westerlund, Hugo
    Zins, Marie
    Theorell, Tores
    Hamer, Mark
    Ferrie, Jane E.
    Singh-Manoux, Archana
    Batty, G. David
    Kivimaeki, Mika
    Job Strain and Tobacco Smoking: An Individual-Participant Data Meta-Analysis of 166 130 Adults in 15 European Studies2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e35463-Article in journal (Refereed)
    Abstract [en]

    Background: Tobacco smoking is a major contributor to the public health burden and healthcare costs worldwide, but the determinants of smoking behaviours are poorly understood. We conducted a large individual-participant meta-analysis to examine the extent to which work-related stress, operationalised as job strain, is associated with tobacco smoking in working adults. Methodology and Principal Findings: We analysed cross-sectional data from 15 European studies comprising 166 130 participants. Longitudinal data from six studies were used. Job strain and smoking were self-reported. Smoking was harmonised into three categories never, ex- and current. We modelled the cross-sectional associations using logistic regression and the results pooled in random effects meta-analyses. Mixed effects logistic regression was used to examine longitudinal associations. Of the 166 130 participants, 17% reported job strain, 42% were never smokers, 33% ex-smokers and 25% current smokers. In the analyses of the cross-sectional data, current smokers had higher odds of job strain than never-smokers (age, sex and socioeconomic position-adjusted odds ratio: 1.11, 95% confidence interval: 1.03, 1.18). Current smokers with job strain smoked, on average, three cigarettes per week more than current smokers without job strain. In the analyses of longitudinal data (1 to 9 years of follow-up), there was no clear evidence for longitudinal associations between job strain and taking up or quitting smoking. Conclusions: Our findings show that smokers are slightly more likely than non-smokers to report work-related stress. In addition, smokers who reported work stress smoked, on average, slightly more cigarettes than stress-free smokers.

  • 218. Heikkila, Katriina
    et al.
    Nyberg, Solja T.
    Fransson, Eleonor I.
    Alfredsson, Lars
    De Bacquer, Dirk
    Bjorner, Jakob B.
    Bonenfant, Sebastien
    Borritz, Marianne
    Burr, Hermann
    Clays, Els
    Casini, Annalisa
    Dragano, Nico
    Erbel, Raimund
    Geuskens, Goedele A.
    Goldberg, Marcel
    Hooftman, Wendela E.
    Houtman, Irene L.
    Joensuu, Matti
    Joeckel, Karl-Heinz
    Kittel, France
    Knutsson, Anders
    Koskenvuo, Markku
    Koskinen, Aki
    Kouvonen, Anne
    Leineweber, Constanze
    Lunau, Thorsten
    Madsen, Ida E. H.
    Hanson, Linda L. Magnusson
    Marmot, Michael G.
    Nielsen, Martin L.
    Nordin, Maria
    Umeå University, Faculty of Social Sciences, Department of Psychology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Pentti, Jaana
    Salo, Paula
    Rugulies, Reiner
    Steptoe, Andrew
    Siegrist, Johannes
    Suominen, Sakari
    Vahtera, Jussi
    Virtanen, Marianna
    Vaananen, Ari
    Westerholm, Peter
    Westerlund, Hugo
    Zins, Marie
    Theorell, Tores
    Hamer, Mark
    Ferrie, Jane E.
    Singh-Manoux, Archana
    Batty, G. David
    Kivimaki, Mika
    Job Strain and Alcohol Intake: A Collaborative Meta-Analysis of Individual-Participant Data from 140 000 Men and Women2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e40101-Article in journal (Refereed)
    Abstract [en]

    Background: The relationship between work-related stress and alcohol intake is uncertain. In order to add to the thus far inconsistent evidence from relatively small studies, we conducted individual-participant meta-analyses of the association between work-related stress (operationalised as self-reported job strain) and alcohol intake. Methodology and Principal Findings: We analysed cross-sectional data from 12 European studies (n = 142 140) and longitudinal data from four studies (n = 48 646). Job strain and alcohol intake were self-reported. Job strain was analysed as a binary variable (strain vs. no strain). Alcohol intake was harmonised into the following categories: none, moderate (women: 1-14, men: 1-21 drinks/week), intermediate (women: 15-20, men: 22-27 drinks/week) and heavy (women: > 20, men: > 27 drinks/week). Cross-sectional associations were modelled using logistic regression and the results pooled in random effects meta-analyses. Longitudinal associations were examined using mixed effects logistic and modified Poisson regression. Compared to moderate drinkers, non-drinkers and (random effects odds ratio (OR): 1.10, 95% CI: 1.05, 1.14) and heavy drinkers (OR: 1.12, 95% CI: 1.00, 1.26) had higher odds of job strain. Intermediate drinkers, on the other hand, had lower odds of job strain (OR: 0.92, 95% CI: 0.86, 0.99). We found no clear evidence for longitudinal associations between job strain and alcohol intake. Conclusions: Our findings suggest that compared to moderate drinkers, non-drinkers and heavy drinkers are more likely and intermediate drinkers less likely to report work-related stress.

  • 219.
    Hellman, Urban
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Malm, Linus
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Ma, Li-Ping
    Larsson, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Mörner, Stellan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Fu, Michael
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Waldenström, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Growth factor PDGF-BB stimulates cultured cardiomyocytes to synthesize the extracellular matrix component hyaluronan2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 12, p. e14393-Article in journal (Refereed)
    Abstract [en]

    Co-cultivation of cardiomyocytes and fibroblasts (80%/20%) increased HA concentration far more that can be explained by HA synthesis by the two cell types separately, revealing a crosstalk between cardiomyocytes and fibroblasts that induces HA synthesis. We conclude that dynamic changes of the myocardium, such as in cardiac hypertrophy, do not depend on the cardiomyocyte alone, but are achieved when both cardiomyocytes and fibroblasts are present.

  • 220.
    Hendrikx, Tijn
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sundqvist, Martin
    Sandström, Herbert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Sahlin, Carin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Rohani, Morteza
    Al-Khalili, Faris
    Hörnsten, Rolf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Clinical Physiology.
    Blomberg, Anders
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
    Wester, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rosenqvist, Mårten
    Franklin, Karl A
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Atrial fibrillation among patients under investigation for suspected obstructive sleep apnea2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0171575Article in journal (Refereed)
    Abstract [en]

    STUDY OBJECTIVES: Obstructive sleep apnea is common among patients with atrial fibrillation, but the prevalence and risk factors for atrial fibrillation among patients who are being investigated on suspicion of sleep apnea are not well known. The aim of the study was to estimate the prevalence of atrial fibrillation among patients investigated for suspected obstructive sleep apnea and to identify risk factors for atrial fibrillation among them.

    METHODS: The prevalence of atrial fibrillation was investigated among 201 patients referred for suspected obstructive sleep apnea. Patients without known atrial fibrillation were investigated with a standard 12-lead ECG at hospital and short intermittent handheld ECG recordings at home, during 14 days.

    RESULTS: Atrial fibrillation occurred in 13 of 201 subjects (6.5%), and in 12 of 61 men aged 60 years and older (20%). The prevalence of atrial fibrillation increased with sleep apnea severity (p = 0.038). All patients with atrial fibrillation were men and all had sleep apnea. Age 60 or older, the occurrence of central sleep apnea and diabetes mellitus were independent risk factors for atrial fibrillation after adjustments for body mass index, gender, sleep apnea and cardiovascular disease.

    CONCLUSIONS: Atrial fibrillation is common among subjects referred for sleep apnea investigation and the prevalence of atrial fibrillation increases with sleep apnea severity. Independent risk factors for atrial fibrillation among patients investigated for suspected obstructive sleep apnea include the occurrence of coexisting central sleep apnea, age 60 years or older and diabetes mellitus.

  • 221.
    Henriksson, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Björklund, Fredrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Mooe, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    The introduction of ticagrelor is associated with lower rates of recurrent ischemic stroke after myocardial infarction2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 5, article id e0216404Article in journal (Refereed)
    Abstract [en]

    Background: Previous ischemic stroke is a predictor of recurrent ischemic stroke after an acute myocardial infarction (AMI). Dual antiplatelet therapy, including a P2Y12-inhibitor, is important in secondary prevention after AMI. Ticagrelor, a P2Y12-inhibitor, is more potent than the commonly used clopidogrel. Here, we evaluated the impact of ticagrelor on the risk of ischemic stroke following AMI in patients with previous ischemic stroke.

    Methods: Data for patients with AMI that had a previous ischemic stroke were obtained from the Swedish Registry of Information and Knowledge about Swedish Heart Intensive Care Admissions. Patients were assigned to early and late cohorts, each covering a two-year time period before and after, respectively, the introduction of ticagrelor prescriptions (20 Dec 2011). Patients in the early cohort (n = 1633) were treated with clopidogrel (100%); those in the late cohort (n = 1642) were treated with either clopidogrel (66.3%) or ticagrelor (33.7%). We assessed the risk of ischemic stroke and intracranial bleeding over time with Kaplan-Meier analyses. We identified predictors of ischemic stroke with multivariable Cox regression analyses.

    Results: Of 3275 patients, 311 experienced ischemic stroke after AMI. Cumulative Kaplan-Meier incidence estimates of ischemic stroke within one year after AMI were 12.1% versus 8.6% for the early and late cohorts, respectively (p<0.01). Intracranial bleeding incidences (1.2% versus 1.5%) were similar between the two cohorts.

    Conclusions: Ticagrelor introduction was associated with a lower rate of ischemic stroke, with no increase in intracranial bleeding, in an AMI population with a history of ischemic stroke.

  • 222. Henrion, Marc Y R
    et al.
    Purdue, Mark P
    Scelo, Ghislaine
    Broderick, Peter
    Frampton, Matthew
    Ritchie, Alastair
    Meade, Angela
    Li, Peng
    McKay, James
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France .
    Lathrop, Mark
    Larkin, James
    Rothman, Nathaniel
    Wang, Zhaoming
    Chow, Wong-Ho
    Stevens, Victoria L
    Diver, W Ryan
    Albanes, Demetrius
    Virtamo, Jarmo
    Brennan, Paul
    Eisen, Timothy
    Chanock, Stephen
    Houlston, Richard S
    Common variation at 1q24.1 (ALDH9A1) is a potential risk factor for renal cancer2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0122589Article in journal (Refereed)
    Abstract [en]

    So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (Pcombined =2.30x10-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; Pcombined =2.73x10-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation.

  • 223. Hernandez, Jorge
    et al.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Stedt, Johan
    Bengtsson, Stina
    Porczak, Aleksandra
    Granholm, Susanne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Gonzalez-Acuna, Daniel
    Olsen, Björn
    Bonnedahl, Jonas
    Drobni, Mirva
    Characterization and Comparison of Extended-Spectrum beta-Lactamase (ESBL) Resistance Genotypes and Population Structure of Escherichia coli Isolated from Franklin's Gulls (Leucophaeus pipixcan) and Humans in Chile2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e76150-Article in journal (Refereed)
    Abstract [en]

    We investigated the general level of antibiotic resistance with further analysis of extended-spectrum beta-lactamase (ESBL) prevalence, as well as the population structure of E. coli in fecal flora of humans and Franklin's gulls (Leucophaeus pipixcan) in central parts of Chile. We found a surprisingly high carriage rate of ESBL-producing E. coli among the gulls 112/372 (30.1%) as compared to the human population 6/49 (12.2%.) Several of the E. coli sequence types (STs) identified in birds have previously been reported as Multi Drug Resistant (MDR) human pathogens including the ability to produce ESBLs. This means that not only commensal flora is shared between birds and humans but also STs with pathogenic potential. Given the migratory behavior of Franklin's gulls, they and other migratory species, may be a part of ESBL dissemination in the environment and over great geographic distances. Apart from keeping the antibiotic use low, breaking the transmission chains between the environment and humans must be a priority to hinder the dissemination of resistance.

  • 224.
    Hii, Yien Ling
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Ng, Nawi
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Short term effects of weather on hand, foot and mouth disease2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, p. e16796-Article in journal (Refereed)
    Abstract [en]

    Background: Hand, foot, and mouth disease (HFMD) outbreaks leading to clinical and fatal complications have increased since late 1990s; especially in the Asia Pacific Region. Outbreaks of HFMD peaks in the warmer season of the year, but the underlying factors for this annual pattern and the reasons to the recent upsurge trend have not yet been established. This study analyzed the effect of short-term changes in weather on the incidence of HFMD in Singapore.

    Methods: The relative risks between weekly HFMD cases and temperature and rainfall were estimated for the period 20012008 using time series Poisson regression models allowing for over-dispersion. Smoothing was used to allow non-linear relationship between weather and weekly HFMD cases, and to adjust for seasonality and long-term time trend. Additionally, autocorrelation was controlled and weather was allowed to have a lagged effect on HFMD incidence up to 2 weeks.

    Results: Weekly temperature and rainfall showed statistically significant association with HFMD incidence at time lag of 1-2 weeks. Every 1 degrees C increases in maximum temperature above 32 degrees C elevated the risk of HFMD incidence by 36% (95% CI = 1.341-1.389). Simultaneously, one mm increase of weekly cumulative rainfall below 75 mm increased the risk of HFMD by 0.3% (CI = 1.002-1.003). While above 75 mm the effect was opposite and each mm increases of rainfall decreased the incidence by 0.5% (CI = 0.995-0.996). We also found that a difference between minimum and maximum temperature greater than 7 degrees C elevated the risk of HFMD by 41% (CI = 1.388-1.439).

    Conclusion: Our findings suggest a strong association between HFMD and weather. However, the exact reason for the association is yet to be studied. Information on maximum temperature above 32 degrees C and moderate rainfall precede HFMD incidence could help to control and curb the up-surging trend of HFMD.

  • 225. Hjalten, Joakim
    et al.
    Axelsson, E. Petter
    Julkunen-Tiitto, Riitta
    Wennström, Anders
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Pilate, Gilles
    Innate and Introduced Resistance Traits in Genetically Modified Aspen Trees and Their Effect on Leaf Beetle Feeding2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e73819-Article in journal (Refereed)
    Abstract [en]

    Genetic modifications of trees may provide many benefits, e. g. increase production, and mitigate climate change and herbivore impacts on forests. However, genetic modifications sometimes result in unintended effects on innate traits involved in plant-herbivore interactions. The importance of intentional changes in plant defence relative to unintentional changes and the natural variation among clones used in forestry has not been evaluated. By a combination of biochemical measurements and bioassays we investigated if insect feeding on GM aspens is more affected by intentional (induction Bt toxins) than of unintentional, non-target changes or clonal differences in innate plant defence. We used two hybrid wildtype clones (Populus tremula x P. tremuloides and Populus tremula x P. alba) of aspen that have been genetically modified for 1) insect resistance (two Bt lines) or 2) reduced lignin properties (two lines COMT and CAD), respectively. Our measurements of biochemical properties suggest that unintended changes by GM modifications (occurring due to events in the transformation process) in innate plant defence (phenolic compounds) were generally smaller but fundamentally different than differences seen among different wildtype clones (e. g. quantitative and qualitative, respectively). However, neither clonal differences between the two wildtype clones nor unintended changes in phytochemistry influenced consumption by the leaf beetle (Phratora vitellinae). By contrast, Bt induction had a strong direct intended effect as well as a post experiment effect on leaf beetle consumption. The latter suggested lasting reduction of beetle fitness following Bt exposure that is likely due to intestinal damage suffered by the initial Bt exposure. We conclude that Bt induction clearly have intended effects on a target species. Furthermore, the effect of unintended changes in innate plant defence traits, when they occur, are context dependent and have in comparison to Bt induction probably less pronounced effect on targeted herbivores.

  • 226.
    Hjältén, Joakim
    et al.
    SLU, Umeå.
    Axelsson, E Petter
    SLU, Umeå.
    Whitham, Thomas G
    Arizona, United States of America.
    LeRoy, Carri J
    Washington, United States of America.
    Julkunen-Tiitto, Riitta
    Joensuu, Finland.
    Wennström, Anders
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Pilate, Gilles
    Orle´ans, France.
    Increased Resistance of Bt Aspens to Phratora vitellinae (Coleoptera) Leads to Increased Plant Growth under Experimental Conditions2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 1, article id e30640Article in journal (Refereed)
    Abstract [en]

    One main aim with genetic modification (GM) of trees is to produce plants that are resistant to various types of pests. The effectiveness of GM-introduced toxins against specific pest species on trees has been shown in the laboratory. However, few attempts have been made to determine if the production of these toxins and reduced herbivory will translate into increased tree productivity. We established an experiment with two lines of potted aspens (Populus tremulaxPopulus tremuloides) which express Bt (Bacillus thuringiensis) toxins and the isogenic wildtype (Wt) in the lab. The goal was to explore how experimentally controlled levels of a targeted leaf beetle Phratora vitellinae (Coleoptera; Chrysomelidae) influenced leaf damage severity, leaf beetle performance and the growth of aspen. Four patterns emerged. Firstly, we found clear evidence that Bt toxins reduce leaf damage. The damage on the Bt lines was significantly lower than for the Wt line in high and low herbivory treatment, respectively. Secondly, Bt toxins had a significant negative effect on leaf beetle survival. Thirdly, the significant decrease in height of the Wt line with increasing herbivory and the relative increase in height of one of the Bt lines compared with the Wt line in the presence of herbivores suggest that this also might translate into increased biomass production of Bt trees. This realized benefit was context-dependent and is likely to be manifested only if herbivore pressure is sufficiently high. However, these herbivore induced patterns did not translate into significant affect on biomass, instead one Bt line overall produced less biomass than the Wt. Fourthly, compiled results suggest that the growth reduction in one Bt line as indicated here is likely due to events in the transformation process and that a hypothesized cost of producing Bt toxins is of subordinate significance.

  • 227. Hobson, Keith A.
    et al.
    Van Wilgenburg, Steven L.
    Wassenaar, Leonard I.
    Larson, Keith W.
    Department of Zoology, Lund University, Lund, Scania, Sweden.
    Linking Hydrogen (δ2H) Isotopes in Feathers and Precipitation: sources of Variance and Consequences for Assignment to Isoscapes2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, article id e35137Article in journal (Refereed)
    Abstract [en]

    Tracking small migrant organisms worldwide has been hampered by technological and recovery limitations and sampling bias inherent in exogenous markers. Naturally occurring stable isotopes of H (δ2H) in feathers provide an alternative intrinsic marker of animal origin due to the predictable spatial linkage to underlying hydrologically driven flow of H isotopes into foodwebs. This approach can assess the likelihood that a migrant animal originated from a given location(s) within a continent but requires a robust algorithm linking H isotopes in tissues of interest to an appropriate hydrological isotopic spatio-temporal pattern, such as weighted-annual rainfall. However, a number of factors contribute to or alter expected isotopic patterns in animals. We present results of an extensive investigation into taxonomic and environmental factors influencing feather δ2H patterns across North America. Stable isotope data were measured from 544 feathers from 40 species and 140 known locations. For δ2H, the most parsimonious model explaining 83% of the isotopic variance was found with amount-weighted growing-season precipitation δ2H, foraging substrate and migratory strategy. This extensive H isotopic analysis of known-origin feathers of songbirds in North America and elsewhere reconfirmed the strong coupling between tissue δ2H and global hydrologic δ2H patterns, and accounting for variance associated with foraging substrate and migratory strategy, can be used in conservation and research for the purpose of assigning birds and other species to their approximate origin.

  • 228.
    Hof, Anouschka R.
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Jansson, Roland
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Nilsson, Christer
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Future Climate Change Will Favour Non-Specialist Mammals in the (Sub)Arctics2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e52574-Article in journal (Refereed)
    Abstract [en]

    Arctic and subarctic (i.e., [sub] arctic) ecosystems are predicted to be particularly susceptible to climate change. The area of tundra is expected to decrease and temperate climates will extend further north, affecting species inhabiting northern environments. Consequently, species at high latitudes should be especially susceptible to climate change, likely experiencing significant range contractions. Contrary to these expectations, our modelling of species distributions suggests that predicted climate change up to 2080 will favour most mammals presently inhabiting (sub) arctic Europe. Assuming full dispersal ability, most species will benefit from climate change, except for a few cold-climate specialists. However, most resident species will contract their ranges if they are not able to track their climatic niches, but no species is predicted to go extinct. If climate would change far beyond current predictions, however, species might disappear. The reason for the relative stability of mammalian presence might be that arctic regions have experienced large climatic shifts in the past, filtering out sensitive and range-restricted taxa. We also provide evidence that for most (sub) arctic mammals it is not climate change per se that will threaten them, but possible constraints on their dispersal ability and changes in community composition. Such impacts of future changes in species communities should receive more attention in literature.

  • 229.
    Holm, Linus
    et al.
    Umeå University, Faculty of Social Sciences, Department of Psychology.
    Engel, Stephen
    Department of Psychology, University of Minnesota, Minneapolis, Minnesota, USA.
    Schrater, Paul
    Department of Computer Science, University of Minnesota, Minneapolis, Minnesota, USA.
    Object learning improves feature extraction but does not improve feature selection2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e51325-Article in journal (Refereed)
    Abstract [en]

    A single glance at your crowded desk is enough to locate your favorite cup. But finding an unfamiliar object requires more effort. This superiority in recognition performance for learned objects has at least two possible sources. For familiar objects observers might: 1) select more informative image locations upon which to fixate their eyes, or 2) extract more information from a given eye fixation. To test these possibilities, we had observers localize fragmented objects embedded in dense displays of random contour fragments. Eight participants searched for objects in 600 images while their eye movements were recorded in three daily sessions. Performance improved as subjects trained with the objects: The number of fixations required to find an object decreased by 64% across the 3 sessions. An ideal observer model that included measures of fragment confusability was used to calculate the information available from a single fixation. Comparing human performance to the model suggested that across sessions information extraction at each eye fixation increased markedly, by an amount roughly equal to the extra information that would be extracted following a 100% increase in functional field of view. Selection of fixation locations, on the other hand, did not improve with practice.

  • 230.
    Holme, Petter
    Umeå University, Faculty of Science and Technology, Department of Physics. Sungkyunkwan University, Suwon, Korea and tockholm University, Stockholm, Sweden.
    Extinction Times of Epidemic Outbreaks in Networks2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, article id e84429Article in journal (Refereed)
    Abstract [en]

    In the Susceptible–Infectious–Recovered (SIR) model of disease spreading, the time to extinction of the epidemics happens at an intermediate value of the per-contact transmission probability. Too contagious infections burn out fast in the population. Infections that are not contagious enough die out before they spread to a large fraction of people. We characterize how the maximal extinction time in SIR simulations on networks depend on the network structure. For example we find that the average distances in isolated components, weighted by the component size, is a good predictor of the maximal time to extinction. Furthermore, the transmission probability giving the longest outbreaks is larger than, but otherwise seemingly independent of, the epidemic threshold.

  • 231.
    Holme, Petter
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Metabolic robustness and network modularity: a model study2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 2, p. e16605-Article in journal (Refereed)
    Abstract [en]

    Background Several studies have mentioned network modularity—that a network can easily be decomposed into subgraphs that are densely connected within and weakly connected between each other—as a factor affecting metabolic robustness. In this paper we measure the relation between network modularity and several aspects of robustness directly in a model system of metabolism.

    Methodology/Principal Findings By using a model for generating chemical reaction systems where one can tune the network modularity, we find that robustness increases with modularity for changes in the concentrations of metabolites, whereas it decreases with changes in the expression of enzymes. The same modularity scaling is true for the speed of relaxation after the perturbations.

    Conclusions/Significance Modularity is not a general principle for making metabolism either more or less robust; this question needs to be addressed specifically for different types of perturbations of the system.

  • 232.
    Holme, Petter
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Masuda, Naoki
    Umeå University, Faculty of Science and Technology, Department of Physics.
    The Basic Reproduction Number as a Predictor for Epidemic Outbreaks in Temporal Networks2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0120567Article in journal (Refereed)
    Abstract [en]

    The basic reproduction number R-0-the number of individuals directly infected by an infectious person in an otherwise susceptible population-is arguably the most widely used estimator of how severe an epidemic outbreak can be. This severity can be more directly measured as the fraction of people infected once the outbreak is over, Omega. In traditional mathematical epidemiology and common formulations of static network epidemiology, there is a deterministic relationship between R-0 and Omega. However, if one considers disease spreading on a temporal contact network-where one knows when contacts happen, not only between whom-then larger R-0 does not necessarily imply larger Omega. In this paper, we numerically investigate the relationship between R-0 and Omega for a set of empirical temporal networks of human contacts. Among 31 explanatory descriptors of temporal network structure, we identify those that make R-0 an imperfect predictor of Omega. We find that descriptors related to both temporal and topological aspects affect the relationship between R-0 and Omega, but in different ways.

  • 233.
    Holmlund, Sophia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Ntaganira, Joseph
    Edvardsson, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Judith Lumley Centre, School of Nursing and Midwifery, La Trobe University, Melbourne, Australia.
    Lan, Pham Thi
    Semasaka Sengoma, Jean Paul
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. School of Public Health, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda.
    Kidanto, Hussein Lesio
    Ngarina, Matilda
    Small, Rhonda
    Mogren, Ingrid
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Judith Lumley Centre, School of Nursing and Midwifery, La Trobe University, Melbourne, Australia.
    Health professionals' experiences and views on obstetric ultrasound in Rwanda: A cross-sectional study2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0208387Article in journal (Refereed)
    Abstract [en]

    Objectives: Implementation of ultrasound in antenatal care (ANC) in low-income countries has been shown to increase pregnant women’s compliance with ANC visits, and facilitate detection of high-risk pregnancies. In Rwanda, as in other low-income countries, access to ultrasound has increased significantly, but lack of training is often a barrier to its use. The aim of this study was to investigate Rwandan health professionals’ experiences and views of obstetric ultrasound in relation to clinical management, resources and skills.

    Methods: A cross-sectional questionnaire study was undertaken between November 2016 and March 2017, as part of the CROss Country UltraSound Study (CROCUS). Data were collected at 108 health facilities located in both rural and urban areas of Rwanda, including provincial, referral, district and private hospitals as well as health centres. Participants were obstetricians (n = 29), other physicians (n = 222), midwives (n = 269) and nurses (n = 387).

    Results: Obstetricians/gynecologists/other physicians commonly performed ultrasound examinations but their self-rated skill levels implied insufficient training. Access to ultrasound when needed was reported as common in hospitals, but available to a very limited extent in health centres. The vast majority of participants, independent of health profession, agreed that maternity care would improve if midwives learned to perform basic ultrasound examinations.

    Conclusions: Barriers to provision of high quality ultrasound services include variable access to ultrasound depending on health facility level and insufficient skills of ultrasound operators. Physicians in general need more training to perform ultrasound examinations. Implementation of a general dating ultrasound examination seems to be a relevant goal as most health professionals agree that pregnant woman would benefit from this service. To further improve maternity care services, the possibility of educating midwives to perform ultrasound examinations should be further explored.

  • 234.
    Holmner, Åsa
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Ebi, Kristie L
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. ClimAdapt, LLC, Seattle, Washington, United States of America.
    Lazuardi, Lutfan
    Department of Public Health, Faculty of Medicine, Gadjah Mada University, Yogyakarta, Indonesia.
    Nilsson, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Carbon footprint of telemedicine solutions - unexplored opportunity for reducing carbon emissions in the health sector2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, article id e105040Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The healthcare sector is a significant contributor to global carbon emissions, in part due to extensive travelling by patients and health workers.

    OBJECTIVES: To evaluate the potential of telemedicine services based on videoconferencing technology to reduce travelling and thus carbon emissions in the healthcare sector.

    METHODS: A life cycle inventory was performed to evaluate the carbon reduction potential of telemedicine activities beyond a reduction in travel related emissions. The study included two rehabilitation units at Umeå University Hospital in Sweden. Carbon emissions generated during telemedicine appointments were compared with care-as-usual scenarios. Upper and lower bound emissions scenarios were created based on different teleconferencing solutions and thresholds for when telemedicine becomes favorable were estimated. Sensitivity analyses were performed to pinpoint the most important contributors to emissions for different set-ups and use cases.

    RESULTS: Replacing physical visits with telemedicine appointments resulted in a significant 40-70 times decrease in carbon emissions. Factors such as meeting duration, bandwidth and use rates influence emissions to various extents. According to the lower bound scenario, telemedicine becomes a greener choice at a distance of a few kilometers when the alternative is transport by car.

    CONCLUSIONS: Telemedicine is a potent carbon reduction strategy in the health sector. But to contribute significantly to climate change mitigation, a paradigm shift might be required where telemedicine is regarded as an essential component of ordinary health care activities and not only considered to be a service to the few who lack access to care due to geography, isolation or other constraints.

  • 235.
    Horstkotte, Tim
    et al.
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Moen, Jon
    Lämås, Tomas
    Helle, Timo
    The legacy of logging-estimating arboreal lichen occurrence in a boreal multiple-use landscape on a two century scale2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12, p. e28779-Article in journal (Refereed)
    Abstract [en]

    In northern Sweden, the availability of arboreal lichens (Bryoria fuscescens, Alectoria sarmentosa) as winter grazing resources is an important element in reindeer husbandry. With the industrialization of forestry, forests rich in arboreal lichens have diminished considerably. Here, we analyze how forestry has impacted lichen availability from the 1920's to the present day and model its future development assuming different forest management scenarios. We recorded the current occurrence of B. fuscescens in 144 sampling plots, stratified by forest age class and dominant tree species in a 26,600 ha boreal forest landscape that is used for both reindeer herding and forestry. Lichen abundance was visually estimated in four classes: none, sparse, moderate and abundant. A binary logistic model using forest age as the independent variable was developed to predict the probability of lichens being present. Using this model, we found that lichens were present in stands that are at least 63 years old. Because of the relative paucity of stands rich in arboreal lichens, it was not possible to reliably determine how age affects the variation in abundance of older forest stands. The historical development of forests where arboreal lichens could potentially occur was studied using historic forestry records dating back 80 years. Between 1926 and the present day, forestry has reduced the cover of forests older than 60 years from 84% to 34%. The likely future spatial coverage of these stands over the next 120 years was estimated for two different management scenarios and an unmanaged reference scenario, using the Heureka strategic planning program. Under both the "business as usual'' scenario and that involving more intensive forestry, continued decreases in lichen availability are projected. Our results emphasize the importance of alternative forestry practices, such as prolonged rotation periods, to increase the availability of arboreal lichens as a grazing resource for reindeer.

  • 236. Hosseinpoor, Ahmad Reza
    et al.
    Stewart Williams, Jennifer
    Research Centre for Gender Health and Ageing, Faculty of Health, University of Newcastle, Newcastle, New South Wales, Australia.
    Amin, Avni
    Araujo de Carvalho, Islene
    Beard, John
    Boerma, Ties
    Kowal, Paul
    Naidoo, Nirmala
    Chatterji, Somnath
    Social determinants of self-reported health in women and men: understanding the role of gender in population health2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e34799-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Women and men share similar health challenges yet women report poorer health. The study investigates the social determinants of self-reported health in women and men, and male-female differences in health.

    METHODS: Data on 103154 men and 125728 women were analysed from 57 countries in the World Health Survey 2002-2004. Item Response Theory was used to construct a composite measure of health. Associations between health and determinants were assessed using multivariate linear regression. Blinder-Oaxaca decomposition partitioned the inequality in health between women and men into an "explained" component that arises because men and women differ in social and economic characteristics, and an "unexplained" component due to the differential effects of these characteristics. Decomposition was repeated for 18 countries in the World Health Organization (WHO) African region and 19 countries in the WHO European region.

    RESULTS: Women's health was significantly lower than men's. Health was associated with education, household economic status, employment, and marital status after controlling for age. In the pooled analysis decomposition showed that 30% of the inequality was "explained", of which almost 75% came from employment, education, marital status. The differential effects of being in paid employment increased the inequality. When countries in Africa and Europe were compared, the "explained" component (31% and 39% respectively) was largely attributed to the social determinants in the African countries and to women's longevity in the European countries. Being in paid employment had a greater positive effect on the health of males in both regions.

    CONCLUSIONS: Ways in which age and the social determinants contribute to the poorer health status of women compared with men varies between groups of countries. This study highlights the need for action to address social structures, institutional discrimination and harmful gender norms and roles that differently influence health with ageing.

  • 237.
    Hosseinzadeh, Ava
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Urban, Constantin F.
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Novel Insight into Neutrophil Immune Responses by Dry Mass Determination of Candida albicans Morphotypes2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, article id e77993Article in journal (Refereed)
    Abstract [en]

    The common fungal pathogen Candida albicans has the ability to grow as a yeast or as a hypha and can alternate between these morphotypes. The overall biomass of both morphotypes increases with growth. However, only yeasts, but not hyphae, exist as discrete cellular entities. Multiplicity of infection (MOI) is a useful parameter to determine the initial inoculum of yeasts for in vitro infection assays. Since the amount of hyphae is difficult to quantify, comparable starting conditions in such assays cannot be determined accurately for yeasts and hyphae using MOI. To circumvent this problem, we have established a set of correlation coefficients to convert fungal metabolic activity and optical density to dry mass. Using these correlations, we were able to accurately compare ROS production and IL-8 release by polymorphonuclear neutrophils upon infection with equal dry mass amounts of yeast and hyphal morphotypes. Neutrophil responses depended on the initial form of infection, irrespective of C. albicans wild-type yeasts transforming to hyphal growth during the assay. Infection with a high mass of live C. albicans yeasts resulted in lower neutrophil ROS and this decrease stems from efficient ROS detoxification by C. albicans without directly affecting the phagocyte ROS machinery. Moreover, we show that dead C. albicans induces significantly less ROS and IL-8 release than live fungi, but thimerosal-killed C. albicans were still able to detoxify neutrophil ROS. Thus, the dry mass approach presented in this study reveals neutrophil responses to different amounts and morphotypes of C. albicans and serves as a template for studies that aim to identify morphotype-specific responses in a variety of immune cells.

  • 238. Hou, Miao
    et al.
    Liu, Yanhua
    Zhu, Lijun
    Sun, Bin
    Guo, Mei
    Burén, Jonas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Li, Xiaonan
    Neonatal overfeeding induced by small litter rearing causes altered glucocorticoid metabolism in rats2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 11, p. e25726-Article in journal (Refereed)
    Abstract [en]

    Elevated glucocorticoid (GC) activity may be involved in the development of the metabolic syndrome. Tissue GC exposure is determined by the tissue-specific GC-activating enzyme 11 beta-hydroxysteriod dehydrogenase type 1 (11 beta-HSD1) and the GC-inactivating enzyme 5 alpha-reductase type 1 (5 alpha R1), as well as 5 beta-reductase (5 beta R). Our aim was to study the effects of neonatal overfeeding induced by small litter rearing on the expression of GC-regulating enzymes in adipose tissue and/or liver and on obesity-related metabolic disturbances during development. Male Sprague-Dawley rat pup litters were adjusted to litter sizes of three (small litters, SL) or ten (normal litters, NL) on postnatal day 3 and then given standard chow from postnatal week 3 onward (W3). Small litter rearing induced obesity, hyperinsulinemia, and higher circulating corticosterone in adults. 11 beta-HSD1 expression and enzyme activity in retroperitoneal, but not in epididymal, adipose tissue increased with postnatal time and peaked at W5/W6 in both groups before declining. From W8, 11 beta-HSD1 expression and enzyme activity levels in retroperitoneal fat persisted at significantly higher levels in SL compared to NL rats. Hepatic 11 beta-HSD1 enzyme activity in SL rats was elevated from W3 to W16 compared to NL rats. Hepatic 5 alpha R1 and 5 beta R expression was higher in SL compared to NL rats after weaning until W6, whereupon expression decreased in the SL rats and remained similar to that in NL rats. In conclusion, small litter rearing in rats induced peripheral tissue-specific alterations in 11 beta-HSD1 expression and activity and 5 alpha R1 and 5 beta R expression during puberty, which could contribute to elevated tissue-specific GC exposure and aggravate the development of metabolic dysregulation in adults.

  • 239. Houle, Brian
    et al.
    Clark, Samuel J
    Gomez-Olive, F Xavier
    Kahn, Kathleen
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Tollman, Stephen M
    The unfolding counter-transition in rural South Africa: mortality and cause of death, 1994-20092014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 6, p. e100420-Article in journal (Refereed)
    Abstract [en]

    The HIV pandemic has led to dramatic increases and inequalities in adult mortality, and the diffusion of antiretroviral treatment, together with demographic and socioeconomic shifts in sub-Saharan Africa, has further changed mortality patterns. We describe all-cause and cause-specific mortality patterns in rural South Africa, analyzing data from the Agincourt health and socio-demographic surveillance system from 1994 to 2009 for those aged 5 years and older. Mortality increased during that period, particularly after 2002 for ages 30-69. HIV/AIDS and TB deaths increased and recently plateaued at high levels in people under age 60. Noncommunicable disease deaths increased among those under 60, and recently also increased among those over 60. There was an inverse gradient between mortality and household SES, particularly for deaths due to HIV/AIDS and TB and noncommunicable diseases. A smaller and less consistent gradient emerged for deaths due to other communicable diseases. Deaths due to injuries remained an important mortality risk for males but did not vary by SES. Rural South Africa continues to have a high burden of HIV/AIDS and TB mortality while deaths from noncommunicable diseases have increased, and both of these cause-categories show social inequalities in mortality.

  • 240. Howard, Bethany J.
    et al.
    Hurtig-Wennlof, Anita
    Olsson, Lovisa A.
    Nilsson, Torbjorn K.
    Dunstan, David W.
    Wennberg, Patrik
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Family Medicine.
    Self-Reported Sitting Time, Physical Activity and Fibrinolytic and Other Novel Cardio-Metabolic Biomarkers in Active Swedish Seniors2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 9, article id e0163409Article in journal (Refereed)
    Abstract [en]

    Background: Too much sitting is linked with an increased risk of cardiovascular disease and mortality. The mediating mechanisms for these associations are largely unknown, however dysregulated fibrinolysis have emerged as a possible contributor.

    Objective: We examined the associations of self-reported overall sitting time and physical activity with fibrinolytic and other novel cardio-metabolic biomarkers in older adults.

    Materials and Methods: Data was analysed for 364 participants (74±7 yrs) of the Active Seniors group (retired, living independently in their own homes). Linear regression analyses examined associations of categories of categories of sitting time (≤3, 3–6, >6 hrs/day) and overall physical activity (Low, Moderate and High) with biomarkers in serum or plasma, adjusting for age, gender and smoking (with further adjustment for either overall physical activity or sitting time and BMI in secondary analyses).

    Results: Compared to sitting ≤ 3 hrs/day, sitting >6 hrs/day was associated with higher tissue plasminogen activator (tPA) and tissue plasminogen activator/plasminogen activator inhibitor-1 complex (tPA-PAI-1 complex). These associations were not independent of overall physical activity or BMI. Compared to those in the high physical activity, low physical activity was associated with a higher BMI, high-sensitivity C-reactive protein (hs-CRP) and tPA-PAI-1 complex levels. Only the associations of BMI and hs-CRP were independent of sitting time.

    Conclusions: These findings provide preliminary cross-sectional evidence for the relationships of sitting time with fibrinolytic markers in older adults. They also reinforce the importance of regular physical activity for cardio-metabolic health.

  • 241. Howe, Christoph
    et al.
    Moparthi, Vamsi K.
    Ho, Felix M.
    Persson, Karina
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Stensjo, Karin
    The Dps4 from Nostoc punctiforme ATCC 29133 is a member of His-type FOC containing Dps protein class that can be broadly found among cyanobacteria2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 8, article id e0218300Article in journal (Refereed)
    Abstract [en]

    Dps proteins (DNA-binding proteins from starved cells) have been found to detoxify H2O2. At their catalytic centers, the ferroxidase center (FOC), Dps proteins utilize Fe2+ to reduce H2O2 and therefore play an essential role in the protection against oxidative stress and maintaining iron homeostasis. Whereas most bacteria accommodate one or two Dps, there are five different Dps proteins in Nostoc punctiforme, a phototrophic and filamentous cyanobacterium. This uncommonly high number of Dps proteins implies a sophisticated machinery for maintaining complex iron homeostasis and for protection against oxidative stress. Functional analyses and structural information on cyanobacterial Dps proteins are rare, but essential for understanding the function of each of the NpDps proteins. In this study, we present the crystal structure of NpDps4 in its metal-free, iron-and zinc-bound forms. The FOC coordinates either two iron atoms or one zinc atom. Spectroscopic analyses revealed that NpDps4 could oxidize Fe2+ utilizing O-2, but no evidence for its use of the oxidant H2O2 could be found. We identified Zn2+ to be an effective inhibitor of the O-2-mediated Fe2+ oxidation in NpDps4. NpDps4 exhibits a FOC that is very different from canonical Dps, but structurally similar to the atypical one from DpsA of Thermosynechococcus elongatus. Sequence comparisons among Dps protein homologs to NpDps4 within the cyanobacterial phylum led us to classify a novel FOC class: the His-type FOC. The features of this special FOC have not been identified in Dps proteins from other bacterial phyla and it might be unique to cyanobacterial Dps proteins.

  • 242. Hu, Xian-Ge
    et al.
    Jin, Yuqing
    Wang, Xiao-Ru
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Mao, Jian-Feng
    Li, Yue
    Predicting Impacts of Future Climate Change on the Distribution of the Widespread Conifer Platycladus orientalis2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0132326Article in journal (Refereed)
    Abstract [en]

    Chinese thuja (Platycladus orientalis) has a wide but fragmented distribution in China. It is an important conifer tree in reforestation and plays important roles in ecological restoration in the arid mountains of northern China. Based on high-resolution environmental data for current and future scenarios, we modeled the present and future suitable habitat for P. orientalis, evaluated the importance of environmental factors in shaping the species' distribution, and identified regions of high risk under climate change scenarios. The niche models showed that P. orientalis has suitable habitat of ca. 4.2x10(6) km(2) across most of eastern China and identified annual temperature, monthly minimum and maximum ultraviolet-B radiation and wet-day frequency as the critical factors shaping habitat availability for P. orientalis. Under the low concentration greenhouse gas emissions scenario, the range of the species may increase as global warming intensifies; however, under the higher concentrations of emissions scenario, we predicted a slight expansion followed by contraction in distribution. Overall, the range shift to higher latitudes and elevations would become gradually more significant. The information gained from this study should be an useful reference for implementing long-term conservation and management strategies for the species.

  • 243. Hu, Xian-Ge
    et al.
    Liu, Hui
    Jin, YuQing
    Sun, Yan-Qiang
    Li, Yue
    Zhao, Wei
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Beijing Forestry Univ, Natl Engn Lab Tree Breeding, Key Lab Genet & Breeding Forest Trees & Ornamenta, Beijing, China.
    El-Kassaby, Yousry A.
    Wang, Xiao-Ru
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences. Beijing Forestry Univ, Natl Engn Lab Tree Breeding, Key Lab Genet & Breeding Forest Trees & Ornamenta, Beijing, China.
    Mao, Jian-Feng
    De Novo Transcriptome Assembly and Characterization for the Widespread and Stress-Tolerant Conifer Platycladus orientalis2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 2, article id e0148985Article in journal (Refereed)
    Abstract [en]

    Platycladus orientalis, of the family Cupressaceae, is a widespread conifer throughout China and is extensively used for ecological reforestation, horticulture, and in medicine. Transcriptome assemblies are required for this ecologically important conifer for understanding genes underpinning adaptation and complex traits for breeding programs. To enrich the species' genomic resources, a de novo transcriptome sequencing was performed using Illumina paired-end sequencing. In total, 104,073,506 high quality sequence reads (approximately 10.3 Gbp) were obtained, which were assembled into 228,948 transcripts and 148,867 unigenes that were longer than 200 nt. Quality assessment using CEGMA showed that the transcriptomes obtained were mostly complete for highly conserved core eukaryotic genes. Based on similarity searches with known proteins, 62,938 (42.28% of all unigenes), 42,158 (28.32%), and 23,179 (15.57%) had homologs in the Nr, GO, and KOG databases, 25,625 (17.21%) unigenes were mapped to 322 pathways by BLASTX comparison against the KEGG database and 1,941 unigenes involved in environmental signaling and stress response were identified. We also identified 43 putative terpene synthase (TPS) functional genes loci and compared them with TPSs from other species. Additionally, 5,296 simple sequence repeats (SSRs) were identified in 4,715 unigenes, which were assigned to 142 motif types. This is the first report of a complete transcriptome analysis of P. orientalis. These resources provide a foundation for further studies of adaptation mechanisms and molecular-based breeding programs.

  • 244. Huang, Qin
    et al.
    Sun, Dan
    Hussain, Muhammad Zubair
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Department of Zoology, Government Emerson College, Multan, Pakistan.
    Liu, Yonggang
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. Laboratory of Stem Cell and Tissue Engineering, Chongqing Medical University, Chongqing, China.
    Morozova-Roche, Ludmilla
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Zhang, Ce
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. State Key Laboratory of Cultivation Base for Photoelectric Technology and Functional Materials, Institute of Photonics and Photon-Technology, Northwest University, Xi’an, China.
    HEWL interacts with dissipated oleic acid micelles, and decreases oleic acid cytotoxicity2019In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, no 2, article id e0212648Article in journal (Refereed)
    Abstract [en]

    Senile plaques are well-known hallmarks of Alzheimer's Diseases (AD). However, drugs targeting tangles of the protein tau and plaques of beta-amyloid have no significant effect on disease progression, and the studies on the underlying mechanism of AD remain in high demand. Growing evidence supports the protective role of senile plaques in local inflammation driven by S100A9. We herein demonstrate that oleic acid (OA) micelles interact with hen egg white lysozyme (HEWL) and promote its amyloid formation. Consequently, SH-SY5Y cell line and mouse neural stem cells are rescued from OA toxicity by co-aggregation of OA and HEWL. Using atomic force microscopy in combination with fluorescence microscopy, we revealed that HEWL forms round-shaped aggregates in the presence of OA micelles instead of protofibrils of HEWL alone. These HEWL amyloids act as a sink for toxic OA micelles and their co-aggregate form large clumps, suggesting a protective function in amyloid and OA cytotoxicity.

  • 245.
    Huang, Shenghua
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Hainzl, Tobias
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Grundström, Christin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Forsman, Cecilia
    Orphan Biovitrum AB, Umeå, Sweden.
    Samuelsson, Göran
    Umeå University, Faculty of Science and Technology, Department of Plant Physiology.
    Sauer-Eriksson, A Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Structural studies of β-Carbonic Anhydrase from the Green Alga Coccomyxa: Inhibitor complexes with Anions and Acetazolamide2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12, p. e28458-Article in journal (Refereed)
    Abstract [en]

    The β-class carbonic anhydrases (β-CAs) are widely distributed among lower eukaryotes, prokaryotes, archaea, and plants. Like all CAs, the β-enzymes catalyze an important physiological reaction, namely the interconversion between carbon dioxide and bicarbonate. In plants the enzyme plays an important role in carbon fixation and metabolism. To further explore the structure-function relationship of β-CA, we have determined the crystal structures of the photoautotroph unicellular green alga Coccomyxa β-CA in complex with five different inhibitors: acetazolamide, thiocyanate, azide, iodide, and phosphate ions. The tetrameric Coccomyxa β-CA structure is similar to other β-CAs but it has a 15 amino acid extension in the C-terminal end, which stabilizes the tetramer by strengthening the interface. Four of the five inhibitors bind in a manner similar to what is found in complexes with α-type CAs. Iodide ions, however, make contact to the zinc ion via a zinc-bound water molecule or hydroxide ion - a type of binding mode not previously observed in any CA. Binding of inhibitors to Coccomyxa β-CA is mediated by side-chain movements of the conserved residue Tyr-88, extending the width of the active site cavity with 1.5-1.8 Å. Structural analysis and comparisons with other α- and β-class members suggest a catalytic mechanism in which the movements of Tyr-88 are important for the CO(2)-HCO(3) (-) interconversion, whereas a structurally conserved water molecule that bridges residues Tyr-88 and Gln-38, seems important for proton transfer, linking water molecules from the zinc-bound water to His-92 and buffer molecules.

  • 246.
    Huber, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Henriksson, Robin
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jakobsson, Stina
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Mooe, Thomas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Nurse-led telephone-based follow-up of secondary prevention after acute coronary syndrome: One-year results from the randomized controlled NAILED-ACS trial2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 9, article id e0183963Article in journal (Refereed)
    Abstract [en]

    Background. Secondary prevention after acute coronary syndrome (ACS) could reduce morbidity and mortality, but guideline targets are seldom reached. We hypothesized that nurse-led telephone- based intervention would increase adherence.

    Methods. The NAILED ACS trial is a prospective, controlled, randomized trial. Patients admitted for ACS at Ostersund hospital, Sweden, were randomized to usual follow-up by a general practitioner or a nurse-led intervention. The intervention comprised telephone follow-up after 1 month and then yearly with lifestyle counselling and titration of medications until reaching target values for LDL-C (< 2.5 mmol/L) and blood pressure (BP; < 140/90 mmHg) or set targets were deemed unachievable. This is a 12-month exploratory analysis of the intervention.

    Results. A total of 768 patients (396 intervention, 372 control) completed the 12-month follow-up. After titration at the 1-month follow-up, mean LDL-C was 0.38 mmol/L (95% CI 0.28 to 0.48, p< 0.05), mean systolic BP 7 mmHg (95% CI 4.5 to 9.2, p< 0.05), and mean diastolic BP 4 mmHg (95% CI 2.4 to 4.1, p< 0.05) lower in the intervention group. Target values for LDL-C and systolic BP were met by 94.1% and 91.9% of intervention patients and 68.4% and 65.6% of controls (p< 0.05). At 12 months, mean LDL was 0.3 mmol/L (95% CI 0.1 to 0.4, p < 0.05), systolic BP 1.5 mmHg (95% CI -1.0 to 4.1, p = 0.24), and mean diastolic BP 2.1 mmHg (95% CI 0.6 to 3.6, p < 0.05) lower in the intervention group. Target values for LDL-C and systolic BP were met in 77.7% and 68.9% of intervention patients and 63.2% and 63.7% of controls (p< 0.05 and p = 0.125).

    Conclusion. Nurse-led telephone-based secondary prevention was significantly more efficient at improving LDL-C and diastolic BP levels than usual care. The effect of the intervention declined between 1 and 12 months. Further evaluation of the persistence to the intervention is needed.

  • 247. Huesgen, Pitter F.
    et al.
    Alami, Meriem
    Lange, Philipp F.
    Foster, Leonard J.
    Schröder, Wolfgang P.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Overall, Christopher M.
    Green, Beverley R.
    Proteomic Amino-Termini Profiling Reveals Targeting Information for Protein Import into Complex Plastids2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e74483-Article in journal (Refereed)
    Abstract [en]

    In organisms with complex plastids acquired by secondary endosymbiosis from a photosynthetic eukaryote, the majority of plastid proteins are nuclear-encoded, translated on cytoplasmic ribosomes, and guided across four membranes by a bipartite targeting sequence. In-depth understanding of this vital import process has been impeded by a lack of information about the transit peptide part of this sequence, which mediates transport across the inner three membranes. We determined the mature N-termini of hundreds of proteins from the model diatom Thalassiosira pseudonana, revealing extensive N-terminal modification by acetylation and proteolytic processing in both cytosol and plastid. We identified 63 mature N-termini of nucleus-encoded plastid proteins, deduced their complete transit peptide sequences, determined a consensus motif for their cleavage by the stromal processing peptidase, and found evidence for subsequent processing by a plastid methionine aminopeptidase. The cleavage motif differs from that of higher plants, but is shared with other eukaryotes with complex plastids.

  • 248. Hughes, Maria F.
    et al.
    Saarela, Olli
    Stritzke, Jan
    Kee, Frank
    Silander, Kaisa
    Klopp, Norman
    Kontto, Jukka
    Karvanen, Juha
    Willenborg, Christina
    Salomaa, Veikko
    Virtamo, Jarmo
    Amouyel, Phillippe
    Arveiler, Dominique
    Ferrieres, Jean
    Wiklund, Per-Gunnar
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Baumert, Jens
    Thorand, Barbara
    Diemert, Patrick
    Tregouet, David-Alexandre
    Hengstenberg, Christian
    Peters, Annette
    Evans, Alun
    Koenig, Wolfgang
    Erdmann, Jeanette
    Samani, Nilesh J.
    Kuulasmaa, Kari
    Schunkert, Heribert
    Genetic Markers Enhance Coronary Risk Prediction in Men: The MORGAM Prospective Cohorts2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e40922-Article in journal (Refereed)
    Abstract [en]

    Background: More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design. Methods: Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5-18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived. Results: Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50-59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events. Conclusions: Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men.

  • 249.
    Hugosson, Fredrik
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Sjögren, Camilla
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hedlund, Ludmilla
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Eriksson, Therese
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Palmer, Ruth H.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    The Drosophila Midkine/Pleiotrophin Homologues Miple1 and Miple2 Affect Adult Lifespan but Are Dispensable for Alk Signaling during Embryonic Gut Formation2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 11, p. e112250-Article in journal (Refereed)
    Abstract [en]

    Midkine (MDK) and Pleiotrophin (PTN) are small heparin-binding cytokines with closely related structures. The Drosophila genome harbours two genes encoding members of the MDK/PTN family of proteins, known as miple1 and miple2. We have investigated the role of Miple proteins in vivo, in particular with regard to their proposed role as ligands for the Alk receptor tyrosine kinase (RTK). Here we show that Miple proteins are neither required to drive Alk signaling during Drosophila embryogenesis, nor are they essential for development in the fruit fly. Additionally we show that neither MDK nor PTN can activate hALK in vivo when ectopically co-expressed in the fly. In conclusion, our data suggest that Alk is not activated by MDK/PTN related growth factors Miple1 and Miple 2 in vivo.

  • 250. Hussain-Alkhateeb, Laith
    et al.
    Kroeger, Axel
    Olliaro, Piero
    Rocklöv, Joacim
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health. Institute of Public Health, Heidelberg University, Heidelberg, Germany.
    Sewe, Maquins Odhiambo
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Tejeda, Gustavo
    Benitez, David
    Gill, Balvinder
    Hakim, S. Lokman
    Carvalho, Roberta Gomes
    Bowman, Leigh
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Petzold, Max
    Early warning and response system (EWARS) for dengue outbreaks: recent advancements towards widespread applications in critical settings2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 5, article id e0196811Article in journal (Refereed)
    Abstract [en]

    Background: Dengue outbreaks are increasing in frequency over space and time, affecting people's health and burdening resource-constrained health systems. The ability to detect early emerging outbreaks is key to mounting an effective response. The early warning and response system (EWARS) is a toolkit that provides countries with early-warning systems for efficient and cost-effective local responses. EWARS uses outbreak and alarm indicators to derive prediction models that can be used prospectively to predict a forthcoming dengue outbreak at district level.

    Methods: We report on the development of the EWARS tool, based on users' recommendations into a convenient, user-friendly and reliable software aided by a user's workbook and its field testing in 30 health districts in Brazil, Malaysia and Mexico.

    Findings: 34 Health officers from the 30 study districts who had used the original EWARS for 7 to 10 months responded to a questionnaire with mainly open-ended questions. Qualitative content analysis showed that participants were generally satisfied with the tool but preferred open-access vs. commercial software. EWARS users also stated that the geographical unit should be the district, while access to meteorological information should be improved. These recommendations were incorporated into the second-generation EWARS-R, using the free R software, combined with recent surveillance data and resulted in higher sensitivities and positive predictive values of alarm signals compared to the first-generation EWARS. Currently the use of satellite data for meteorological information is being tested and a dashboard is being developed to increase user-friendliness of the tool. The inclusion of other Aedes borne viral diseases is under discussion.

    Conclusion: EWARS is a pragmatic and useful tool for detecting imminent dengue outbreaks to trigger early response activities.

2345678 201 - 250 of 662
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