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  • 351. Berthelsen, Hanne
    et al.
    Westerlund, Hugo
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Hakanen, Jari J.
    Kristensen, Tage S.
    It is not just about occupation, but also about where you work2017In: Community Dentistry and Oral Epidemiology, ISSN 0301-5661, E-ISSN 1600-0528, Vol. 45, no 4, p. 372-379Article in journal (Refereed)
    Abstract [en]

    Objectives: Dentistry is characterized by a meaningful but also stressful psychosocial working environment. Job satisfaction varies among staff working under different organizational forms. The aim of this study was to identify (i) to what extent crucial psychosocial work environment characteristics differ among occupations in general public dental clinics in Sweden, and (ii) how much of the variation within each occupation is attributable to the organizational level. Methods: All staff (N=1782) employed in four public dental organizations received an email with personal log-in to an electronic questionnaire based on the Copenhagen Psychosocial Questionnaire. After two reminders, a response rate of 75% was obtained. Responses from 880 nonmanagerial dentists, dental hygienists and dental nurses working in general practices were included in our analyses. Results: First, we compared the three dental occupations. We found that job demands, task resources (eg influence, possibilities for development and role clarity), strain symptoms and attitudes to work differed among occupations, dentists having the least favourable situation. Next, we compared the four organizations for each occupational group, separately. For dentists, a significant and relevant amount of variance (P<.05 and ICC >.05) was explained by the organizational level for 15 of 26 subscales, least pronounced for task resources. By contrast, for dental nurses and hygienists, the corresponding number was 2 subscales of 26. The psychosocial working environment of people working at the organization with the highest levels of strain indicators and the least positive work-related attitudes differed systematically from the organization with the most favourable profile, in particular regarding job demands and leadership aspects. Conclusion: In conclusion, the psychosocial working environment depended to a large degree on occupation and, for dentists in particular, also on their organizational affiliation. The findings suggest a potential for designing interventions at organizational level for improvements of the psychosocial working environment for dentists.

  • 352.
    Berthet, Pierre
    et al.
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Royal Institute of Technology, Sweden.
    Hellgren-Kotaleski, Jeanette
    Lansner, Anders
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Royal Institute of Technology, Sweden.
    Action selection performance of a reconfigurable basal ganglia inspired model with Hebbian-Bayesian Go- NoGo connectivity2012In: Frontiers in Behavioral Neuroscience, ISSN 1662-5153, E-ISSN 1662-5153, Vol. 6, article id 65Article in journal (Refereed)
    Abstract [en]

    Several studies have shown a strong involvement of the basal ganglia (BG) in action selection and dopamine dependent learning. The dopaminergic signal to striatum, the input stage of the BG, has been commonly described as coding a reward prediction error (RPE), i.e., the difference between the predicted and actual reward. The RPE has been hypothesized to be critical in the modulation of the synaptic plasticity in cortico-striatal synapses in the direct and indirect pathway. We developed an abstract computational model of the BG, with a dual pathway structure functionally corresponding to the direct and indirect pathways, and compared its behavior to biological data as well as other reinforcement learning models. The computations in our model are inspired by Bayesian inference, and the synaptic plasticity changes depend on a three factor Hebbian-Bayesian learning rule based on co-activation of pre- and post-synaptic units and on the value of the RPE. The model builds on a modified Actor-Critic architecture and implements the direct (Go) and the indirect(NoGo) pathway, as well as the reward prediction (RP) system, acting in a complementary fashion. We investigated the performance of the model system when different configurations of the Go, NoGo, and RP system were utilized, e.g., using only the Go, NoGo, or RP system, or combinations of those. Learning performance was investigated in several types of learning paradigms, such as learning-relearning, successive learning, stochastic learning, reversal learning and a two-choice task. The RPE and the activity of the model during learning were similar to monkey electrophysiological and behavioral data. Our results, however, show that there is not a unique best way to configure this BG model to handle well all the learning paradigms tested. We thus suggest that an agent might dynamically configure its action selection mode, possibly depending on task characteristics and also on how much time is available.

  • 353.
    Berthet, Pierre
    et al.
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Karolinska Institute, Sweden.
    Lindahl, Mikael
    Tully, Philip J.
    Hellgren-Kotaleski, Jeanette
    Lansner, Anders
    Stockholm University, Faculty of Science, Numerical Analysis and Computer Science (NADA). Karolinska Institute, Sweden.
    Functional Relevance of Different Basal Ganglia Pathways Investigated in a Spiking Model with Reward Dependent Plasticity2016In: Frontiers in Neural Circuits, ISSN 1662-5110, E-ISSN 1662-5110, Vol. 10, article id 53Article in journal (Refereed)
    Abstract [en]

    The brain enables animals to behaviorally adapt in order to survive in a complex and dynamic environment, but how reward-oriented behaviors are achieved and computed by its underlying neural circuitry is an open question. To address this concern, we have developed a spiking model of the basal ganglia (BG) that learns to dis-inhibit the action leading to a reward despite ongoing changes in the reward schedule. The architecture of the network features the two pathways commonly described in BG, the direct (denoted D1) and the indirect (denoted D2) pathway, as well as a loop involving striatum and the dopaminergic system. The activity of these dopaminergic neurons conveys the reward prediction error (RPE), which determines the magnitude of synaptic plasticity within the different pathways. All plastic connections implement a versatile four-factor learning rule derived from Bayesian inference that depends upon pre- and post-synaptic activity, receptor type, and dopamine level. Synaptic weight updates occur in the D1 or D2 pathways depending on the sign of the RPE, and an efference copy informs upstream nuclei about the action selected. We demonstrate successful performance of the system in a multiple-choice learning task with a transiently changing reward schedule. We simulate lesioning of the various pathways and show that a condition without the D2 pathway fares worse than one without D1. Additionally, we simulate the degeneration observed in Parkinson's disease (PD) by decreasing the number of dopaminergic neurons during learning. The results suggest that the D1 pathway impairment in PD might have been overlooked. Furthermore, an analysis of the alterations in the synaptic weights shows that using the absolute reward value instead of the RPE leads to a larger change in D1.

  • 354. Besga, A.
    et al.
    Cedazo-Minguez, A.
    Kåreholt, I.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Solomon, A.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Björkhem, I.
    Winblad, B.
    Leoni, V.
    Hooshmand, B.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Spulber, G.
    Gonzalez-Pinto, A.
    Kivipelto, M.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wahlund, L. O.
    Differences in brain cholesterol metabolism and insulin in two subgroups of patients with different CSF biomarkers but similar white matter lesions suggest different pathogenic mechanisms2012In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 510, no 2, p. 121-126Article in journal (Refereed)
    Abstract [en]

    Investigate possible associations of white matter hyperintensities (WMHs) with the metabolism of cholesterol and insulin in two subgroups of patients with memory complaints and different CSF A beta 42 and CSF tau levels. 59 patients from the memory clinic at Karolinska Hospital were included. Degree of WMHs was rated using the ARWMC scale and the following biomarkers were measured in CSF and plasma: insulin, cholesterol, lanosterol, lathosterol, and oxidized cholesterol metabolites. The WMHs in CSF control-like group correlated with increased brain cholesterol synthesis and reduced efflux of oxysterols and insulin in CSF. In the CSF AD-like group, the WMHs correlated with increased peripheral cholesterol metabolism. Despite having similar appearance on FLAIR images, the pathogenic mechanisms of WMHS are likely to be different in the two groups investigated.

  • 355. Beskow, Catharina
    et al.
    Ågren-Cronqvist, Anna-Karin
    Lewensohn, Rolf
    Toma-Dasu, Iuliana
    Stockholm University, Faculty of Science, Department of Physics.
    Biological effective dose evaluation and assessment of rectal and bladder complications for cervical cancer treated with radiotherapy and surgery2012In: Journal of Contemporary Brachytherapy, ISSN 1689-832X, E-ISSN 2081-2841, Vol. 4, no 4, p. 205-212Article in journal (Refereed)
    Abstract [en]

    Purpose: This study aims to retrospectively evaluate dosimetric parameters calculated as biological effective dose in relation to outcome in patients with cervical cancer treated with various treatment approaches including radiotherapy, with and without surgery.

    Methods and Materials: Calculations of biological effective dose (BED) were performed on data from a retrospective analysis of 171 patients with cervical carcinoma stages IB-IIB treated with curative intent between January 1989 and December 1991. 43 patients were treated only with radiotherapy and 128 patients were treated with a combination of radiotherapy and surgery. External beam radiotherapy was delivered with 6-21 MV photons from linear accelerators. Brachytherapy was delivered either with a manual radium technique or with a remote afterloading technique. The treatment outcome was evaluated at 5 years.

    Results: The disease-specific survival rate was 87% for stage IB, 75% for stage IIA and 54% for stage IIB, while the overall survival rates were 84% for stage IB, 68% for stage IIA and 43% for stage IIB. Patients treated only with radiotherapy had a local control rate of 77% which was comparable to that for radiotherapy and surgery patients (78%). Late complications were recorded in 25 patients (15%). Among patients treated with radiotherapy and surgery, differences in radiation dose calculated as BED10 did not seem to influence survival. For patients treated with radiotherapy only, a higher BED10 was correlated to a higher overall survival (p=0.0075). The dose response parameters found based on biological effective dose calculations were D50=85.2 Gy10 and γ=1.62 for survival and D50=61.6 Gy10 and γ=0.92 for local control.

    Conclusions: The outcome correlates with biological effective dose for patients treated with radiation therapy alone, but not for patients treated with radiotherapy and surgery. No correlations were found between BED and late toxicity from bladder and rectum.

  • 356. Bestas, Burcu
    et al.
    Moreno, Pedro M. D.
    Blomberg, K. Emelie M.
    Mohammad, Dara K.
    Saleh, Amer F.
    Sutlu, Tolga
    Nordin, Joel Z.
    Guterstam, Peter
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Gustafsson, Manuela O.
    Kharazi, Shabnam
    Piatosa, Barbara
    Roberts, Thomas C.
    Behlke, Mark A.
    Wood, Matthew J. A.
    Gait, Michael J.
    Lundin, Karin E.
    EL Andaloussi, Samir
    Mansson, Robert
    Berglof, Anna
    Wengel, Jesper
    Smith, C. I. Edvard
    Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model2014In: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 124, no 9, p. 4067-4081Article in journal (Refereed)
    Abstract [en]

    X-linked agammaglobulinemia (XLA) is an inherited immunodeficiency that results from mutations within the gene encoding Bruton's tyrosine kinase (BTK). Many XLA-associated mutations affect splicing of BTK pre-mRNA and severely impair B cell development. Here, we assessed the potential of antisense, splice-correcting oligonucleotides (SCOs) targeting mutated BTKtranscripts for treating XLA. Both the SCO structural design and chemical properties were optimized using 2'-O-methyl, locked nucleic acid, or phosphorodiamidate morpholino backbones. In order to have access to an animal model of XLA, we engineered a transgenic mouse that harbors a BAC with an authentic, mutated, splice-defective human BTK gene. BTK transgenic mice were bred onto a Btk knockout background to avoid interference of the orthologous mouse protein. Using this model, we determined that BTK-specific SCOs are able to correct aberrantly spliced BTK in B lymphocytes, including pro-B cells. Correction of BTK mRNA restored expression of functional protein, as shown both by enhanced lymphocyte survival and reestablished BTK activation upon B cell receptor stimulation. Furthermore, SCO treatment corrected splicing and restored BTK expression in primary cells from patients with XLA. Together, our data demonstrate that SCOs can restore BTK function and that BTK-targeting SCOs have potential as personalized medicine in patients with XLA.

  • 357. Beziat, Vivien
    et al.
    Liu, Lisa L.
    Malmberg, Jenny-Ann
    Ivarsson, Martin A.
    Sohlberg, Ebba
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Björklund, Andreas T.
    Retiere, Christelle
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Traherne, James
    Ljungman, Per
    Schaffer, Marie
    Price, David A.
    Trowsdale, John
    Michaelsson, Jakob
    Ljunggren, Hans-Gustaf
    Malmberg, Karl-Johan
    NK cell responses to cytomegalovirus infection lead to stable imprints in the human KIR repertoire and involve activating KIRs2013In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 121, no 14, p. 2678-2688Article in journal (Refereed)
    Abstract [en]

    Human natural killer (NK) cells are functionally regulated by killer cell immunoglobulin-like receptors (KIRs) and their interactions with HLA class I molecules. As KIR expression in a given NK cell is genetically hard-wired, we hypothesized that KIR repertoire perturbations reflect expansions of unique NK-cell subsets and may be used to trace adaptation of the NK-cell compartment to virus infections. By determining the human KIR-ome at a single-cell level in more than 200 donors, we were able to analyze the magnitude of NK cell adaptation to virus infections in healthy individuals. Strikingly, infection with human cytomegalovirus (CMV), but not with other common herpesviruses, induced expansion and differentiation of KIR-expressing NK cells, visible as stable imprints in the repertoire. Education by inhibitory KIRs promoted the clonal-like expansion of NK cells, causing a bias for self-specific inhibitory KIRs. Furthermore, our data revealed a unique contribution of activating KIRs (KIR2DS4, KIR2DS2, or KIR3DS1), in addition to NKG2C, in the expansion of human NK cells. These results provide new insight into the diversity of KIR repertoire and its adaptation to virus infection, suggesting a role for both activating and inhibitory KIRs in immunity to CMV infection.

  • 358. Bhandage, A. K.
    et al.
    Hellgren, C.
    Jin, Z.
    Olafsson, Einar B.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sundström-Poromaa, I.
    Birnir, B.
    Expression of GABA receptors subunits in peripheral blood mononuclear cells is gender dependent, altered in pregnancy and modified by mental health2015In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 213, no 3, p. 575-585Article in journal (Refereed)
    Abstract [en]

    AimThe concept of nerve-driven immunity recognizes a link between the nervous and the immune system. -aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain, and receptors activated by GABA can be expressed by immune cells. Here, we examined whether the expression of GABA receptors and chloride transporters in human peripheral blood mononuclear cells (PBMCs) was influenced by gender, pregnancy or mental health. MethodsWe used RT-qPCR to determine the mRNA expression level in PBMCs from men (n=16), non-pregnant women (n=19), healthy pregnant women (n=27) and depressed pregnant women (n=15). ResultsThe 2 subunit had the most prominent expression level of the GABA-A receptor subunits in all samples. The and 2 subunits were up-regulated by pregnancy, whereas the epsilon subunit was more frequently expressed in healthy pregnant women than non-pregnant women who, in turn, commonly expressed the 6 and the 2 subunits. The 1 and epsilon subunits expression was altered by depression in pregnant women. The GABA-B1 receptor was up-regulated by depression in pregnant women, while the transporters NKCC1 and KCC4 were down-regulated by pregnancy. The changes recorded in the mRNA expression levels imply participation of GABA receptors in establishing and maintaining tolerance in pregnancy. Importantly, the correlation of mental health with the expression of specific receptor subunits reveals a connection between the immune cells and the brain. Biomarkers for mental health may be identified in PBMCs. ConclusionThe results demonstrate the impact gender, pregnancy and mental health have on the expression of GABA receptors and chloride transporters expressed in human PBMCs.

  • 359. Bharadwaj, Prashant
    et al.
    Lundborg, Petter
    Rooth, Dan-Olof
    Stockholm University, Faculty of Social Sciences, The Swedish Institute for Social Research (SOFI).
    Birth Weight in the Long Run2018In: The Journal of human resources, ISSN 0022-166X, E-ISSN 1548-8004, Vol. 53, no 1, p. 189-231Article in journal (Refereed)
    Abstract [en]

    We study the effect of birth weight on long-run outcomes using data on Swedish twins born between 1926 and 1958 linked to administrative records spanning entire life-time labor market histories. We find that birth weight positively affects permanent income and income across large parts of the lifecycle. The timing of the birth weight–income relationship is in line with the role of birth weight in determining takeup of sickness benefits and morbidity. The effect of birth weight on labor market outcomes even for cohorts born 30 years apart are similar; for short run health outcomes, birth weight plays a decreasing role over time.

  • 360.
    Bhushan, Shashi
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Kuhn, Claus
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Berglund, Anna-Karin
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Roth, Christian
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    The role of the N-terminal domain of chloroplast targeting peptides in organellar protein import and miss-sorting2006In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 580, no 16, p. 3966-3972Article in journal (Refereed)
    Abstract [en]

    We have analysed 385 mitochondrial and 567 chloroplastic signal sequences of proteins found in the organellar proteomes of Arabidopsis thaliana. Despite overall similarities, the first 16 residues of transit peptides differ remarkably. To test the hypothesis that the N-terminally truncated transit peptides would redirect chloroplastic precursor proteins to mitochondria, we studied import of the N-terminal deletion mutants of ELIP, PetC and Lhcb2.1. The results show that the deletion mutants were neither imported into chloroplasts nor miss-targeted to mitochondria in vitro and in vivo, showing that the entire transit peptide is necessary for correct targeting as well as miss-sorting.

  • 361.
    Bhushan, Shashi
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Pavlov, Pavel F
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Rudhe, Charlotta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Glaser, Elzbieta
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    In vitro and in vivo methods to study protein import into plant mitochondria.2007In: Methods Mol Biol, ISSN 1064-3745, Vol. 390, p. 131-50Article in journal (Refereed)
    Abstract [en]

    Plant mitochondria contain about 1000 proteins, 90-99% of which in different plant species are nuclear encoded, synthesized on cytosolic polyribosomes, and imported into the organelle. Most of the nuclear-encoded proteins are synthesized as precursors containing an N-terminal extension called a presequence or targeting peptide that directs the protein to the mitochondria. Here we describe in vitro and in vivo methods to study mitochondrial protein import in plants. In vitro synthesized precursor proteins can be imported in vitro into isolated mitochondria (single organelle import). However, missorting of chloroplast precursors in vitro into isolated mitochondria has been observed. A novel dual import system for simultaneous import of proteins into isolated mitochondria and chloroplasts followed by reisolation of the organelles is superior over the single import system as it abolishes the mistargeting. Precursor proteins can also be imported into the mitochondria in vivo using an intact cellular system. In vivo approaches include import of transiently expressed fusion constructs containing a presequence or a full-length precursor protein fused to a reporter gene, most commonly the green fluorescence protein (GFP) in protoplasts or in an Agrobacterium-mediated system in intact tobacco leaves.

  • 362.
    Bielawski, Marcin
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Olofsson, Berit
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Efficient one-pot synthesis of bis(4-tert-butylphenyl)iodonium triflate2009In: Organic Syntheses, ISSN 0078-6209, Vol. 86, p. 308-314Article in journal (Refereed)
  • 363. Bijlsma, Maarten J.
    et al.
    Tarkiainen, Lasse
    Myrskylä, Mikko
    Martikainen, Pekka
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS). Max Planck Institute for Demographic Research, Germany: University of Helsinki,, Finland.
    Unemployment and subsequent depression: A mediation analysis using the parametric G-formula2017In: Social Science and Medicine, ISSN 0277-9536, E-ISSN 1873-5347, Vol. 194, p. 142-150Article in journal (Refereed)
    Abstract [en]

    The effects of unemployment on depression are difficult to establish because of confounding and limited understanding of the mechanisms at the population level. In particular, due to longitudinal interdependencies between exposures, mediators and outcomes, intermediate confounding is an obstacle for mediation analyses. Using longitudinal Finnish register data on socio-economic characteristics and medication purchases, we extracted individuals who entered the labor market between ages 16 and 25 in the period 1996 to 2001 and followed them until the year 2007 (n = 42,172). With the parametric G-formula we estimated the population averaged effect on first antidepressant purchase of a simulated intervention which set all unemployed person years to employed. In the data, 74% of person-years were employed and 8% unemployed, the rest belonging to studying or other status. In the intervention scenario, employment rose to 85% and the hazard of first antidepressant purchase decreased by 7.6%. Of this reduction 61% was mediated, operating primarily through changes in income and household status, while mediation through other health conditions was negligible. These effects were negligible for women and particularly prominent among less educated men. By taking complex interdependencies into account in a framework of observed repeated measures data, we found that eradicating unemployment raises income levels, promotes family formation, and thereby reduces antidepressant consumption at the population-level.

  • 364.
    Bildtgård, Torbjörn
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Social Work.
    Öberg, Peter
    Time as a structuring condition behind new intimate relationships in later life2015In: Ageing & Society, ISSN 0144-686X, E-ISSN 1469-1779, Vol. 35, no 7, p. 1505-1528Article in journal (Refereed)
    Abstract [en]

    Although mobility in and out of intimate relationships has become more common in later life, it has been a neglected issue in social gerontology. In this article, we ask what characterises the formation of new intimate relationships in later life, and whether there are any specific conditions that separate these from relationships in earlier stages of the lifecourse. On the basis of qualitative interviews with 28 persons aged 63-91 who have established a new intimate heterosexual relationship after the age of 60 or who are dating singles, we argue that time constitutes such a central structuring condition. We discuss and theorise two aspects of time - post-(re) productive free time and remaining time - which have an important formative power on new late-in-life relationships. We argue that together these aspects form a central existential structure of ageing in many Western societies - the paradoxical condition of having lots of available free time but little time left in life - which, besides influencing new late-in-life relationships, might also be relevant to other aspects of and choices in later life.

  • 365. Bill-Axelsson, Anna
    et al.
    Holmberg, Lars
    Filen, F
    Ruutu, M
    Garmo, Hans
    Busch, Christer
    Nordling, S
    Hamberg, H
    Häggman, M
    Andersson, S-O
    Bratell, S
    Spångberg, A
    Palmgren, Juni
    Stockholm University, Faculty of Science, Department of Mathematics.
    Adami, Hans-Olov
    Johansson, Jan-Erik
    Radical Prostatectomy versus Wathful Waiting in Localized Prostate Cancer: The Scandinavian Prostate Cancer Group (SPCG-4) Randomized Trial2008In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 100, p. 1144-1154Article in journal (Refereed)
  • 366.
    Birse, Ryan Tyge
    Stockholm University, Faculty of Science, Department of Zoology.
    Tachykinin-related peptide signaling and its role in metabolic stress in Drosophila2006Doctoral thesis, monograph (Other academic)
    Abstract [en]

    Tachykinins (TKs) constitute a highly conserved family of multifunctional neuropeptides that are known to be involved in a multitude of functions in mammals. Peptides that are presumed ancestrally related to tachykinins, so called Tachykinin-related peptides (TKRP) have been identified in invertebrates.

    Little is known about the in vivo actions of TKRPs in invertebrates. Therefore, we decided to study the TKRP signaling in the Drosophila melanogaster. Drosophila has been shown to have a tachykinin system with multiple peptides encoded on a single gene (Tk) and two G-protein coupled receptors (GPCRs), designated DTKR and NKD. The two GPCRs were further characterized in this thesis with native DTKs.

    We raised several antibodies for immunocytochemical detection of DTKR and NKD to investigate the distribution of the two receptors. We found that the two GPCRs are differentially distributed and when combined cover all regions of the DTK distribution.

    To analyze receptor function in vivo we used the GAL4-UAS system to over express DTKR and NKD with different cell specific GAL4 drivers, likely to shed light on metabolic stress responses. We also tested the effect of a DTK RNA interference (Tk-KO) transgene, in, which levels of DTK transcript was decreased by up to 95%. These flies were tested for different parameters like trehalose and lipid levels, longevity, and locomotor activity levels at starvation. We found that the Tk-KO flies displayed a prolonged lifespan and no detectable decrease trehalose. We also showed that over expression of the two GPCRs elicits different responses depending on the cell type they are expressed in. Over expression of NKD in AKH producing cells is likely to cause a release of adipokinetic hormone (AKH) while DTKR appears to have an inhibitory action on release of Drosophila insulin-like peptides (DILPs) when expressed on DILP2 producing cells.

    It has been previously shown in the locust that TKRPs are released into the haemolymph from the midgut upon starvation. We therefore used Gal4s specifically directed to the two different cells types (principal and stellate cells) of the Malpighian tubules to drive DTKR and NKD. Only when expressing the DTKR receptor in the principal cells did we see an altered phenotype during nutritional and desiccative stress. We found that over expression of DTKR produced an abbreviated lifespan. We also tested the Tk-KO flies and found that they exhibited under desiccative stress. Finally, we expressed a DTKR-RNAi construct in the both Malpighian tubules cells type and found that in both cell types the receptor knockdown produced an extended lifespan compared to controls. These data suggests that since only substances in the circulation can activate receptors on the Malpighian tubules DTKs are likely to be released into the circulation upon starvation. In summary our data indicate that DTKs and the two GPCRs are involved in signalling during metabolic stress.

  • 367. Bjaastad, Jon Fauskanger
    et al.
    Haugland, Bente Storm Mowatt
    Fjermestad, Krister W.
    Torsheim, Torbjorn
    Havik, Odd E.
    Heiervang, Einar R.
    Öst, Lars-Goran
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Clinical psychology. Karolinska Institutet, Sweden.
    Competence and Adherence Scale for Cognitive Behavioral Therapy (CAS-CBT) for Anxiety Disorders in Youth: Psychometric Properties2016In: Psychological Assessment, ISSN 1040-3590, E-ISSN 1939-134X, Vol. 28, no 8, p. 908-916Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to evaluate the psychometric properties of the Competence and Adherence Scale for Cognitive Behavioral Therapy (CAS-CBT). The CAS-CBT is an 11-item scale developed to measure adherence and competence in cognitive-behavioral therapy (CBT) for anxiety disorders in youth. A total of 181 videotapes from the treatment sessions in a randomized controlled effectiveness trial (Wergeland et al., 2014) comprising youth (N = 182, M age = 11.5 years, SD = 2.1, range 8-15 years, 53% girls, 90.7% Caucasian) with mixed anxiety disorders were assessed with the CAS-CBT to investigate interitem correlations, internal consistency, and factor structure. Internal consistency was good (Cronbach's alpha = .87). Factor analysis suggested a 2-factor solution with Factor 1 representing CBT structure and session goals (explaining 46.9% of the variance) and Factor 2 representing process and relational skills (explaining 19.7% of the variance). The sum-score for adherence and competence was strongly intercorrelated, r = .79, p < .001. Novice raters (graduate psychology students) obtained satisfactory accuracy (ICC > .40, n = 10 videotapes) and also good to excellent interrater reliability when compared to expert raters (ICC = .83 for adherence and .64 for competence, n = 26 videotapes). High rater stability was also found (n = 15 videotapes). The findings suggest that the CAS-CBT is a reliable measure of adherence and competence in manualized CBT for anxiety disorders in youth. Further research is needed to investigate the validity of the scale and psychometric properties when used with other treatment programs, disorders and treatment formats.

  • 368. Bjerge, Bagga
    et al.
    Houborg, Esben
    Edman, Johan
    Stockholm University, Faculty of Social Sciences, Centre for Social Research on Alcohol and Drugs (SoRAD).
    Perälä, Riikka
    Concepts and policies directed at drug use i Denmark, Finland and Sweden2016In: Concepts of Addictive Behaviours across Time and Place / [ed] Matilda Hellman, Virginia Berridge, Karen Duke, Alex Mold, Oxford: Oxford University Press, 2016Chapter in book (Refereed)
    Abstract [en]

    The Nordic countries are often thought of in terms of social democratic welfare regimes with numerous shared cultural aspects. Based on research from Denmark, Finland, and Sweden, this chapter explores how historical developments, specific ways of constructing policies, and welfare institutions articulate specific conceptions of what drug-related issues are and how they should be managed in three seemingly very similar welfare states. The Nordic welfare states are often described as quite alike and fairly open and inclusive in their approach to welfare policies and concerns, but the chapter demonstrates that similar political systems adopt different policy responses to similar conditions. To explore the similarities and differences, we are inspired by the analytical concepts of policy space and political rationalities; we use this approach to provide an overview of drug policy history in the three countries and present a closer examination of the topics of sanctions against drug users, coercive treatment, and substitution treatment nationally as well as cross-nationally.

  • 369. Björk, Christel
    et al.
    Nenonen, Hannah
    Giwercman, Aleksander
    Bergman, Åke
    Stockholm University, Faculty of Science, Department of Materials and Environmental Chemistry (MMK), Environmental Chemistry.
    Rylander, Lars
    Giwercman, Yvonne Lundberg
    Persistent organic pollutants have dose and CAG repeat length dependent effects on androgen receptor activity in vitro2011In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 32, p. 293-297Article in journal (Refereed)
    Abstract [en]

    Recently, the effect of exposure to persistent organic pollutants (POPS) on sperm concentration was only seen in men with a short androgen receptor (AR) gene CAG repeat. In order to investigate whether these effects could be observed also in vitro, we tested the impact of 2,2’,4,4’,5,5’-hexachlorobiphenyl (CB-153) and 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene (4,4’-DDE) on 5 alpha-dihydrotestosterone activated ARs containing 16,22 and 28 CAG repeats, respectively. Single exposure to 4,4’-DDE had the most pronounced effect on the AR activity containing 16 CAG repeats, whereas 28 CAG was the most sensitive variant when a mixture of the two compounds was added. Thus, our in vitro results have confirmed the in vivo data indicating a CAG repeat length dependent effect of endocrine disrupters on the AR activity.

  • 370. Björk, Tabita
    et al.
    Brus, Ole
    Osika, Walter
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Montgomery, Scott
    Laterality, hand control and scholastic performance: a British birth cohort study2012In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 2, no 2, p. e000314-Article in journal (Refereed)
    Abstract [en]

    Objectives: To use simple measures of laterality and hand control that can identify a greater risk of poorer scholastic ability, potentially signalling suboptimal hemispheric lateralisation.

    Design: Analysis of material from a birth cohort study.

    Setting: Members of the National Child Development Study, a British birth cohort study following people born in 1958.

    Participants: 10 612 children who undertook tests at age 11 years.

    Primary outcome measures: Teacher-administered tests of non-verbal general ability, verbal general ability, reading comprehension and mathematics. 

    Results Linear regression produced associations (and 95% CIs) with tests of verbal general ability, non-verbal general ability, reading comprehension and mathematics scores for the lowest third (compared with highest) of a left-hand control test involving picking up matches of −1.21 (−1.73 to −0.68; p<0.001), −0.72 (−1.14 to −0.29; p=0.001), −0.70 (−1.06 to −0.35; p<0.001) and −1.32 (−1.90 to −0.73; p<0.001). Among those in the lowest third of the right-hand control test score, mixed-handedness compared with right-handedness was associated with poorer scholastic performance, with regression coefficients (and 95% CIs; p values) of 1.90 (−3.01 to −0.80; p=0.001), −1.25 (−2.15 to −0.35; p=0.007), −1.28 (2.04 to −0.53; p=0.001) and −1.33 (−2.53 to −0.13; p=0.030). The estimates are for a point change in the scholastic test scores, after adjustment for sex, left-hand motor function and social class. Statistically significant associations with mixed-handedness were only observed for the lowest third of right-hand motor function.

    Conclusions Measures involving poorer left-hand motor function may represent useful markers of reduced cognitive function possibly reflecting suboptimal hemispheric lateralisation. Crude measures of laterality such as reported non-right-handedness may be more useful for research when combined with measures of motor function.                        

  • 371.
    Björkander, Sophia
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hell, Lena
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Johansson, Maria A.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mata Forsberg, Manuel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Lasaviciute, Gintare
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Roos, Stefan
    Holmlund, Ulrika
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Sverremark-Ekström, Eva
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Staphylococcus aureus-derived factors induce IL-10, IFN-gamma and IL-17A-expressing FOXP3(+)CD161(+) T-helper cells in a partly monocyte-dependent manner2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 22083Article in journal (Refereed)
    Abstract [en]

    Staphylococcus aureus (S. aureus) is a human pathogen as well as a frequent colonizer of skin and mucosa. This bacterium potently activates conventional T-cells through superantigens and it is suggested to induce T-cell cytokine-production as well as to promote a regulatory phenotype in T-cells in order to avoid clearance. This study aimed to investigate how S. aureus impacts the production of regulatory and pro-inflammatory cytokines and the expression of CD161 and HELIOS by peripheral CD4(+)FOXP3(+) T-cells. Stimulation of PBMC with S. aureus 161:2-cell free supernatant (CFS) induced expression of IL-10, IFN-gamma and IL-17A in FOXP3(+) cells. Further, CD161 and HELIOS separated the FOXP3(+) cells into four distinct populations regarding cytokine-expression. Monocyte-depletion decreased S. aureus 161:2-induced activation of FOXP3(+) cells while pre-stimulation of purified monocytes with S. aureus 161:2-CFS and subsequent co-culture with autologous monocyte-depleted PBMC was sufficient to mediate activation of FOXP3(+) cells. Together, these data show that S. aureus potently induces FOXP3(+) cells and promotes a diverse phenotype with expression of regulatory and pro-inflammatory cytokines connected to increased CD161-expression. This could indicate potent regulation or a contribution of FOXP3(+) cells to inflammation and repression of immune-suppression upon encounter with S. aureus.

  • 372. Björkenstam, C.
    et al.
    Bjorkenstam, E.
    Ljung, R.
    Vinnerljung, Bo
    Stockholm University, Faculty of Social Sciences, Department of Social Work.
    Tuvblad, C.
    Suicidal behavior among delinquent former child welfare clients2013In: European Child and Adolescent Psychiatry, ISSN 1018-8827, E-ISSN 1435-165X, Vol. 22, no 6, p. 349-355Article in journal (Refereed)
    Abstract [en]

    Child welfare clients represent a high-risk group for delinquency and adult criminality, but also for future suicidal behavior. We examine associations between delinquency and suicidal behavior in a national child welfare population. This register-based cohort study is based on data for all Swedish former child welfare clients born between 1972 and 1981 that experienced interventions before their adolescent years. We followed 27,228 individuals from age 20 years until 31 December 2006. Juvenile delinquency was defined as being convicted of at least one crime between age 15 and 19. The risk of suicidal behavior was calculated as incidence rate ratios (IRRs). Fifteen percent of the women and 40 % of the men had at least one conviction between the age 15 and 19. The adjusted risk of suicidal behavior among women with five or more convictions was 3.5 (95 % CI 2.0-6.2); corresponding IRR for men was 3.9 (95 % CI 3.1-4.9). Child welfare experience-specifically of out-of-home care-in combination with delinquency is a potent risk factor for suicidal behavior among young adults. However, we cannot exclude that some of this association is an epiphenomenon of uncontrolled confounders, such as impulsivity or severity of psychiatric disease. Despite this caveat, results should be disseminated to practitioners in the health and correction services.

  • 373. Björkenstam, C.
    et al.
    Björkenstam, E.
    Hjern, Anders
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS). Karolinska Institutet, Sweden.
    Boden, R.
    Reutfors, J.
    Suicide in first episode psychosis: A nationwide cohort study2014In: Schizophrenia Research, ISSN 0920-9964, E-ISSN 1573-2509, Vol. 157, no 1-3, p. 1-7Article in journal (Refereed)
    Abstract [en]

    Background: Relatively little is known about suicide in diagnostic subtypes of first episode psychosis (FEP). Our aim was to assess suicide rates and potential risk factors for suicide in FEP. Methods: This is a national register-based cohort study of patients born in 1973-1978 in Sweden and who were hospitalized with a FEP between ages 15 and 30 years (n = 2819). The patients were followed from date of discharge until death, emigration, or 31st of December 2008. The suicide rates for six diagnostic subtypes of FEP were calculated. Suicide incidence rate ratios (IRRs) were calculated to evaluate the association between suicide and psychiatric, familial, social, and demographic factors. Results: In total 121 patients died by suicide. The overall suicide rate was 4.3 (95% confidence interval [CI] 3.5-5.0) per 1000 person-years. The highest suicide rates were found in depressive disorder with psychotic symptoms and in delusional disorder. In an adjustedmodel, the strongest risk factors for suicide were self-harm (IRR 2.7, CI 1.7-4.4) or a conviction for violent crime (IRR 2.0, CI 1.3-3.2). Also having a first-degree relative with a schizophrenia/bipolar diagnosis (IRR 2.1, CI 1.2-3.6) or substance use disorder (IRR 2.0, CI 1.2-3.2) were significant risk factors for suicide. Conclusions: Impulsive behavior such as self-harm as well as having a family history of severe mental disorder or substance use are important risk factors for suicide in FEP.

  • 374. Björkenstam, C.
    et al.
    Weitoft, G.R.
    Hjern, Anders
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS).
    Nordstrom, P.
    Hallqvist, J.
    Ljung, R.
    School grades, parental education and suicide: a national register-based cohort study2010In: Journal of Epidemiology and Community Health, ISSN 0143-005X, E-ISSN 1470-2738Article in journal (Refereed)
    Abstract [en]

    Background To investigate whether school performance is a risk factor for suicide death later in life and, if so, to what extent this is explained by intergenerational effects of parental education.

    Methods This population-based cohort study comprises national birth cohorts between 1972 and 1981 in Sweden. We followed 898 342 students, graduating between 1988 and 1997 from the 9 years of compulsory school, equivalent to junior high school, until 31 December 2006, generating 11 148 758 person-years and 1490 suicides. Final school grades, in six categories, and risk of suicide were analysed with Poisson regression.

    Results The incidence rate ratio (RR) for suicide death for students with the lowest grades was 4.57 (95% CI 2.82 to 7.40) for men and 2.67 (1.42 to 5.01) for women compared to those with highest grades after adjustment for a number of sociodemographic and parental morbidity variables, such as year of graduation, parental education, lone parenthood, household receiving social welfare or disability pension, place of schooling, adoption, maternal age and parent's mental illness. Students with grades in the middle categories had RRs in between. These relationships were not modified by parental education.

    Conclusions The strong association between low school grades and suicide in youth and young adulthood emphasises the importance of both primary and secondary prevention in schools.

  • 375.
    Björkenstam, Charlotte
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Sociology. University of California, USA; Karolinska Institutet, Sweden .
    Andersson, Gunnar
    Stockholm University, Faculty of Social Sciences, Department of Sociology.
    Dalman, Christina
    Cochran, Susan
    Kosidou, Kyriaki
    Suicide in married couples in Sweden: Is the risk greater in same-sex couples?2016In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 31, no 7, p. 685-690Article in journal (Refereed)
    Abstract [en]

    Minority sexual orientation is a predictor of suicide ideation and attempts, though its association with suicide mortality is less clear. We capitalize on Sweden's extensively linked databases, to investigate whether, among married individuals, same-sex marriage is associated with suicide. Using a population-based register design, we analyzed suicide risk among same-sex married women and men (n = 6456), as compared to different-sex married women and men (n = 1181723) in Sweden. We selected all newly partnered or married individuals in the intervening time between 1/1/1996 and 12/31/2009 and followed them with regard to suicide until 12/31/2011. Multivariate Poisson regression was used to calculate adjusted incidence risk ratios (IRR) with 95 % confidence intervals (CI). The risk of suicide was higher among same-sex married individuals as compared to different-sex married individuals (IRR 2.7, 95 % CI 1.5-4.8), after adjustment for time at risk and socioeconomic confounding. Sex-stratified analyses showed a tentatively elevated risk for same-sex married women (IRR 2.5, 95 % CI 0.8-7.7) as compared to different-sex married women. Among same-sex married men the suicide risk was nearly three-fold greater as compared to different-sex married (IRR 2.895 % CI 1.5-5.5). This holds true also after adjustment for HIV status. Even in a country with a comparatively tolerant climate regarding homosexuality such as Sweden, same-sex married individuals evidence a higher risk for suicide than other married individuals.

  • 376.
    Björkenstam, Charlotte
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Sociology. University of California, USA; Karolinska Institutet, Sweden.
    Björkenstam, Emma
    Andersson, Gunnar
    Stockholm University, Faculty of Social Sciences, Department of Sociology.
    Cochran, Susan
    Kosidou, Kyriaki
    Anxiety and Depression Among Sexual Minority Women and Men in Sweden: Is the Risk Equally Spread Within the Sexual Minority Population?2017In: Journal of Sexual Medicine, ISSN 1743-6095, E-ISSN 1743-6109, Vol. 14, no 3, p. 396-403Article in journal (Refereed)
    Abstract [en]

    Introduction

    Sexual minority individuals have a higher risk of anxiety and depression compared with heterosexuals. However, whether the higher risk is spread equally across the sexual minority population is not clear.

    Aim

    To investigate the association between sexual orientation and self-reported current anxiety and a history of diagnosis of depression, paying particular attention to possible subgroup differences in risks within the sexual minority population, stratified by sex and to examine participants' history of medical care for anxiety disorders and depression.

    Methods

    We conducted a population-based study of 874 lesbians and gays, 841 bisexuals, and 67,980 heterosexuals recruited in 2010 in Stockholm County. Data were obtained from self-administered surveys that were linked to nationwide registers. Main Outcome Measures: By using logistic regression, we compared risks of current anxiety, histories of diagnosed depression, and register-based medical care for anxiety and/or depression in lesbian and gay, bisexual, and heterosexual individuals.

    Results

    Bisexual women and gay men were more likely to report anxiety compared with their heterosexual peers. Bisexual individuals and gay men also were more likely to report a past diagnosis of depression. All sexual minority groups had an increased risk of having used medical care for anxiety and depression compared with heterosexuals, with bisexual women having the highest risk.

    Conclusion

    Bisexual women appear to be a particularly vulnerable sexual minority group. Advocating for nondiscrimination and protections for lesbian, gay, and bisexual people is a logical extension of the effort to lower the prevalence of mental illness.

  • 377.
    Björkenstam, Charlotte
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Sociology. Karolinska Institutet, Sweden; University of California, USA.
    Ekselius, Lisa
    Berlin, Marie
    Stockholm University, Faculty of Social Sciences, Department of Social Work. National Board of Health and Welfare, Sweden.
    Gerdin, Bengt
    Björkenstam, Emma
    Suicide risk and suicide method in patients with personality disorders2016In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 83, p. 29-36Article in journal (Refereed)
    Abstract [en]

    Objective: The influence of psychopathology on suicide method has revealed different distributions among different psychiatric disorders. However, evidence is still scarce. We hypothesized that having a diagnosis of personality disorder (PD) affect the suicide method, and that different PD clusters would influence the suicide method in different ways. In addition, we hypothesized that the presence of psychiatric and somatic co-morbidity also affects the suicide method. Method: We examined 25,217 individuals aged 15-64 who had been hospitalized in Sweden with a main diagnosis of PD the years 1987-2013 (N = 25,217). The patients were followed from the date of first discharge until death or until the end of the follow-up period, i.e. December 31, 2013, for a total of 323,508.8 person-years, with a mean follow up time of 11.7 years. The SMR, i.e. the ratio between the observed number of suicides and the expected number of suicides, was used as a measure of risk. Results: Overall PD, different PD-clusters, and comorbidity influenced the suicide method. Hanging evidenced highest SMR in female PD patients (SMR 34.2 (95% CI: 29.3-39.8)), as compared to non-PD patients and jumping among male PD patients (SMR 24.8 (95% CI: 18.3-33.6)), as compared to non PD-patients. Furthermore, the elevated suicide risk was related to both psychiatric and somatic comorbidity. Conclusion: The increased suicide risk was unevenly distributed with respect to suicide method and type of PD. However, these differences were only moderate and greatly overshadowed by the overall excess suicide risk in having PD. Any attempt from society to decrease the suicide rate in persons with PD must take these characteristics into account.

  • 378.
    Björkenstam, Charlotte
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Sociology. Karolinska Institutet, Sweden; University of California, USA.
    Kosidou, Kyriaki
    Björkenstam, Emma
    Childhood adversity and risk of suicide: cohort study of 548 721 adolescents and young adults in Sweden2017In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 357, article id j1334Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE To examine the relation between childhood adversity, the role of school performance, and childhood psychopathology and the risk of suicide. DESIGN Cohort study of register based indicators of childhood adversity (at ages 0-14) including death in the family (suicide analysed separately), parental substance abuse, parental psychiatric disorder, substantial parental criminality, parental separation/single parent household, receipt of public assistance, and residential instability. SETTING Swedish medical birth register and various Swedish population based registers. PARTICIPANTS 548 721 individuals born 1987-91. MAIN OUTCOME MEASURES Estimates of suicide risk at ages 15-24 calculated as incidence rate ratios adjusted for time at risk and confounders. Results Adjusted incidence rate ratios for the relation between childhood adversity and suicide during adolescence and young adulthood ranged from 1.6 (95% confidence interval 1.1 to 2.4) for residential instability to 2.9 (1.4 to 5.9) for suicide in the family. There was a dose-response relation between accumulating childhood adversity and risk: 1.1 (0.9 to 1.4) for those exposed to one adversity and 1.9 (1.4 to 2.5) and 2.6 (1.9 to 3.4) for those exposed to two and three or more adversities, respectively. The association with increased risk of suicide remained even after adjustment for school performance and childhood psychopathology. CONCLUSION Childhood adversity is a risk factor for suicide in adolescence and young adulthood, particularly accumulated adversity. These results emphasise the importance of understanding the social mechanisms of suicide and the need for effective interventions early in life, aiming to alleviate the risk in disadvantaged children.

  • 379.
    Björkenstam, Charlotte
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Sociology. Karolinska Institutet, Sweden; University of California, USA.
    Kosidou, Kyriaki
    Björkenstam, Emma
    Dalman, Christina
    Andersson, Gunnar
    Stockholm University, Faculty of Social Sciences, Department of Sociology.
    Cochran, Susan
    Self-reported suicide ideation and attempts, and medical care for intentional self-harm in lesbians, gays and bisexuals in Sweden2016In: Journal of Epidemiology and Community Health, ISSN 0143-005X, E-ISSN 1470-2738, Vol. 70, no 9, p. 895-901Article in journal (Refereed)
    Abstract [en]

    Background Minority sexual orientation is a robust risk indicator for self-reported suicidal ideation and attempts. However, little is known about patterns of medical care for intentional self-harm in this vulnerable population. We investigate sexual orientation-related differences in self-reported lifetime suicide symptoms and medical care for intentional self-harm between 1969 and 2010, including age at initial treatment and recurrence. Methods We used data from the Stockholm Public Health Cohort, a population-based sample of 874 lesbians/gays, 841 bisexuals and 67980 heterosexuals, whose self-administered surveys have been linked to nationwide registers. Estimates of risk for medical care were calculated as incidence rate ratios (IRR) with 95% CIs. Results Both suicidal ideation and attempts were more commonly reported by lesbian/gay and bisexual (LGB) individuals. Adjusting for risk-time and confounding, lesbians (IRR 3.8, 95% CI 2.7 to 5.4) and bisexual women (IRR 5.4, 95% CI 4.4 to 6.6) experienced elevated risk for medical care for intentional self-harm, as compared to heterosexual women. Gay men evidenced higher risk (IRR 2.1, 95% CI 1.3 to 3.4) as compared to heterosexual men. Recurrent medical care was more frequent in LGB individuals, especially in bisexual women and gay men. Lesbian and bisexual women were also younger than heterosexual women when they first received medical care for intentional self-harm. Conclusions Positive histories of suicidal ideation, attempts and medical care for intentional self-harm, including higher levels of recurrence, are more prevalent among LGB individuals in contrast to heterosexuals. Lesbian/bisexual women evidence an earlier age of onset of treatment. Tailored prevention efforts are urgently needed.

  • 380. Björkenstam, E.
    et al.
    Björkenstam, C.
    Hjern, Anders
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS).
    Reutfors, J.
    Bodén, R.
    A five year diagnostic follow-up of 1840 patients after a first episode non-schizophrenia and non-affective psychosis2013In: Schizophrenia Research, ISSN 0920-9964, E-ISSN 1573-2509, Vol. 150, no 1, p. 205-210Article in journal (Refereed)
    Abstract [en]

    Objective

    It is not clear which patients with a first psychotic episode will develop schizophrenia. We performed a diagnostic follow-up of patients treated for a first time non-affective, non-schizophrenia psychosis and explored potential predictors of a subsequent schizophrenia or schizoaffective diagnosis.

    Methods

    This register-based cohort study comprises individuals born between 1973 and 1978 in Sweden, with a first hospital-treated psychosis excluding schizophrenia, schizoaffective disorder, bipolar disorder and depressive disorder with psychotic symptoms (n = 1840). The patients were followed for five years regarding subsequent diagnoses. Psychiatric, social, family history of psychiatric illness, premorbid intellectual level, head injuries and obstetrical complications were investigated by logistic regression as predictors of schizophrenia or schizoaffective diagnosis.

    Results

    During the follow-up, 18% were diagnosed with schizophrenia or schizoaffective disorder, 5% were diagnosed with bipolar disorder, whereas 29% were not re-admitted to a psychiatric clinic. Patients with a first-degree relative hospitalized for schizophrenia and/or bipolar disorder had an increased risk of subsequent diagnosis for schizophrenia or schizoaffective disorder (odds ratio 1.9 and 95% confidence interval 1.1 to 3.0)), whereas previous severe criminality was associated with a decreased risk (odds ratio 0.5, 95% confidence interval 0.3–0.8).

    Conclusion

    Diagnostic outcome was diverse after a first non-schizophrenia and non-affective psychosis. Family history of severe mental illness and no previous conviction for severe criminality were the strongest risk factors for a future schizophrenia or schizoaffective diagnosis.

  • 381. Björkenstam, Emma
    et al.
    Burström, Bo
    Brännström, Lars
    Stockholm University, Faculty of Social Sciences, Department of Social Work.
    Vinnerljung, Bo
    Stockholm University, Faculty of Social Sciences, Department of Social Work.
    Björkenstam, Charlotte
    Pebley, Anne R.
    Cumulative exposure to childhood stressors and subsequent psychological distress. An analysis of US panel data2015In: Social Science and Medicine, ISSN 0277-9536, E-ISSN 1873-5347, Vol. 142, p. 109-117Article in journal (Refereed)
    Abstract [en]

    Research has shown that childhood stress increases the risk of poor mental health later in life. We examined the effect of childhood stressors on psychological distress and self-reported depression in young adulthood. Data were obtained from the Child Development Supplement (CDS) to the national Panel Study of Income Dynamics (PSID), a survey of US families that incorporates data from parents and their children. In 2005 and 2007, the Panel Study of Income Dynamics was supplemented with two waves of Transition into Adulthood (TA) data drawn from a national sample of young adults, 18-23 years old. This study included data from participants in the CDS and the TA (n = 2128), children aged 4-13 at baseline. Data on current psychological distress was used as an outcome variable in logistic regressions, calculated as odds ratios (OR) with 95% confidence intervals (CI). Latent Class Analyses were used to identify clusters based on the different childhood stressors. Associations were observed between cumulative exposure to childhood stressors and both psychological distress and self-reported depression. Individuals being exposed to three or more stressors had the highest risk (crude OR for psychological distress: 2.49 (95% Cl: 1.16-5.33), crude OR for self-reported depression: 2.07 (95% CI: 1.15-3.71). However, a large part was explained by adolescent depressive symptoms. Findings support the long-term negative impact of cumulative exposure to childhood stress on psychological distress. The important role of adolescent depression in this association also needs to be taken into consideration in future studies.

  • 382. Björkenstam, Emma
    et al.
    Burström, Bo
    Vinnerljung, Bo
    Stockholm University, Faculty of Social Sciences, Department of Social Work.
    Kosidou, Kyriaki
    Childhood adversity and psychiatric disorder in young adulthood: An analysis of 107,704 Swedes2016In: Journal of Psychiatric Research, ISSN 0022-3956, E-ISSN 1879-1379, Vol. 77, p. 67-75Article in journal (Refereed)
    Abstract [en]

    Childhood adversity (CA) is associated with increased risks of psychiatric disorder in young adulthood, but details in this association are less known. We aimed to explore the association of a range of CA indicators with psychiatric disorder in young adulthood, and the impact of age at exposure, disorder type and accumulation of indicators. We capitalized on Sweden's extensive and high-quality registers and analyzed a cohort of all Swedes (N = 107,704) born in Stockholm County 1987-1991. Adversities included familial death, parental substance misuse and psychiatric disorder, parental criminality, parental separation, public assistance recipiency and residential instability. Age at exposure was categorized as: 0-6.9 years (infancy and early childhood), 7-11.9 years (middle childhood), and 12-14 years (early adolescence). Psychiatric disorders after age 15 were defined from ICD codes through registers. Risks were calculated as Hazard Ratios (HR) with 95% confidence intervals (CI). Results showed that exposure to at least one CA was associated with an increased risk of psychiatric disorder (HR 1.4, 95% CI: 1.3-1.4). Risks were increased for mood, anxiety, and psychotic disorders and ADHD but not for eating disorders. The risk varied with type of disorder but was similar for all exposure periods. Individuals with multiple (3+) CAs had a two-fold risk of psychiatric disorder (HR 2.0, 95% CI: 1.9-2.1). In conclusion, our findings support the long-term negative impact of CA on mental health, regardless of developmental period of exposure. Given that experience of CA is common, efforts should be put to alleviate the burden of childhood adversities for children, particularly among the most disadvantaged.

  • 383. Björkenstam, Emma
    et al.
    Cheng, Siwei
    Burström, Bo
    Pebley, Anne R.
    Björkenstam, Charlotte
    Stockholm University, Faculty of Social Sciences, Department of Sociology. University of California, USA; Karolinska Institutet, Sweden.
    Kosidou, Kyriaki
    Association between income trajectories in childhood and psychiatric disorder: a Swedish population-based study2017In: Journal of Epidemiology and Community Health, ISSN 0143-005X, E-ISSN 1470-2738, Vol. 71, no 7, p. 648-654Article in journal (Refereed)
    Abstract [en]

    Background Childhood family income variation is an understudied aspect of households' economic context that may have distinct consequences for children. We identified trajectories of childhood family income over a 12-year period, and examined associations between these trajectories and later psychiatric disorders, among individuals born in Sweden between 1987 and 1991 (n=534 294).

    Methods We used annual income data between the ages of 3-14 years and identified 5 trajectories (2 high-income upward, 1 downward and 2 low-income upward trajectories). Psychiatric disorders in the follow-up period after age 15 were defined from International Classification of Disease (ICD)-codes in a nationwide patient register. Multiadjusted risks for all psychiatric disorders, as well as for specific psychiatric diagnoses, were calculated as HRs with 95% CIs.

    Results Of the 5 identified income trajectories, the constant low and the downward trajectories were particularly associated with later psychiatric disorder. Children with these trajectories had increased risks for psychiatric disorder, including mood, anxiety, psychotic disorders and attention deficit/hyperactivity disorder. The association remained, even after adjusting for important variables including parental psychiatric disorder. In contrast, the relationship was reversed for eating disorders, for which children in higher income trajectories had elevated risks.

    Conclusions Findings show that children growing up in a household characterised by low or decreasing family income have an increased risk for psychiatric disorder. Continued work is needed to reduce socioeconomic inequalities in psychiatric disorders. Policies and interventions for psychiatric disorders should consider the socioeconomic background of the family as an important risk or protective factor.

  • 384. Björkenstam, Emma
    et al.
    Dalman, Christina
    Vinnerljung, Bo
    Stockholm University, Faculty of Social Sciences, Department of Social Work.
    Ringbäck Weitoft, Gunilla
    Walder, Deborah J.
    Burström, Bo
    Childhood household dysfunction, school performance and psychiatric care utilisation in young adults: a register study of 96 399 individuals in Stockholm County2016In: Journal of Epidemiology and Community Health, ISSN 0143-005X, E-ISSN 1470-2738, Vol. 70, no 5, p. 473-480Article in journal (Refereed)
    Abstract [en]

    Background Exposure to childhood household dysfunction increases the risk of psychiatric morbidity. Although school performance also has been linked with psychiatric morbidity, limited research has considered school performance as a mediating factor. To address this gap in the literature, the current register study examined whether school performance mediates the association between childhood household dysfunction (experienced between birth and age 14 years) and psychiatric care utilisation in young adulthood.

    Methods We used a Swedish cohort of 96 399 individuals born during 1987–1991. Indicators of childhood household dysfunction were familial death, parental substance abuse and psychiatric morbidity, parental somatic disease, parental criminality, parental separation/single-parent household, public assistance recipiency and residential instability. Final school grades from the 9th year of compulsory school were used to create five categories. Estimates of risk of psychiatric care utilisation (measured as inpatient, outpatient and primary care) after the age of 18 years were calculated as HRs with 95% CIs. Mediation was tested with the bootstrap approach.

    Results Cumulative exposure to childhood household dysfunction was positively associated with psychiatric care utilisation. Specifically, individuals exposed to three or more indicators with incomplete school grades had the highest risk (HR=3.7 (95% CI 3.3 to 4.1) after adjusting for demographics), compared to individuals exposed to no indicators with highest grades. School performance was found to mediate the relationship.

    Conclusions Our findings suggest that future efforts to prevent or mitigate the negative effects of childhood household dysfunction on psychiatric morbidity may benefit from integration of strategies that improve school performance among vulnerable youth.

  • 385. Björkenstam, Emma
    et al.
    Ekselius, Lisa
    Burström, Bo
    Kosidou, Kyriaki
    Björkenstam, Charlotte
    Stockholm University, Faculty of Social Sciences, Department of Sociology. Karolinska Institutet, Sweden; University of California, USA.
    Association between childhood adversity and a diagnosis of personality disorder in young adulthood: a cohort study of 107,287 individuals in Stockholm County2017In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 32, no 8, p. 721-731Article in journal (Refereed)
    Abstract [en]

    Childhood adversity (CA) may increase the risk for later developing of personality disorder (PD). However, less is known about the association between cumulative CA and PD, and the role of childhood psychopathology and school performance. The current study examined the relationship between a range of CAs and a diagnosis of PD in young adulthood, and the roles of childhood psychopathology and school performance in this relationship. All individuals born in Stockholm County 1987-1991 (n = 107,287) constituted our cohort. Seven CAs were measured between birth and age 14: familial death, parental criminality, parental substance abuse and psychiatric morbidity, parental separation and/or single-parent household, household public assistance and residential instability. Individuals were followed from their 18th birthday until they were diagnosed with PD or until end of follow-up (December 31st 2011). Adjusted estimates of risk of PD were calculated as hazard ratios (HR) with 95% confidence intervals (CI). Associations were observed between cumulative CA and PD. During the follow-up 770 individuals (0.7%) were diagnosed with PD. Individuals exposed to 3+ CAs had the highest risks of being diagnosed with PD (HR 3.0, 95% CI 2.4-3.7). Childhood psychopathology and low school grades further increased the risk of PD among individuals exposed to CA. Cumulative CA is strongly associated with a diagnosis of PD in young adulthood. Our findings indicate that special attention should be given in schools and health services to children exposed to adversities to prevent decline in school performance, and to detect vulnerable individuals that may be on negative life-course trajectories.

  • 386. Björkenstam, Emma
    et al.
    Hjern, Anders
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS). Karolinska Institutet, Sweden.
    Björkenstam, Charlotte
    Kosidou, Kyriaki
    Association of Cumulative Childhood Adversity and Adolescent Violent Offending With Suicide in Early Adulthood2018In: JAMA psychiatry, ISSN 2168-6238, E-ISSN 2168-622X, Vol. 75, no 2, p. 185-193Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Childhood adversity (CA) is associated with an increased risk of suicide in young adulthood that might be explained by maladaptive trajectories during adolescence. Although adolescent violent offending is linked with suicide, little is known about its role in the association between CA and suicide. OBJECTIVE To examine whether adolescent violent offending mediates the association between CA and suicide in early adulthood. DESIGN, SETTING, AND PARTICIPANTS This population-based, longitudinal cohort study with a follow-up time spanning 5 to 9 years included 476 103 individuals born in Sweden between 1984 and 1988. The study population was prospectively followed up from 20 years of age until December 31, 2013, with respect to suicide. Data analysis was performed from January 1, 1984, to December 31, 2013. EXPOSURES Register-based CAs included parental death, parental substance abuse and psychiatric disorder, parental criminal offending, parental separation, public assistance recipiency, child welfare intervention, and residential instability. Adolescent violent offending was defined as being convicted of a violent crime between the ages of 15 and 19 years. MAIN OUTCOMES AND MEASURES Estimates of risk of suicide after 20 years of age (from 2004 if born in 1984 and from 2008 if born in 1988) until the end of 2013 were calculated as incidence rate ratios (IRRs) with 95% CIs using Poisson regression analysis. Adjustments were made for demographics and psychiatric disorder. In addition, binary mediation analysis with logistic regression was used. RESULTS A total of 476 103 individuals (231 699 [48.7%] female) were included in the study. Those with a conviction for violent offending had been exposed to all CAs to a greater extent than those with no violent offending. Cumulative CA was associated with risk of suicide in nonconvicted (adjusted IRR, 2.4; 95% CI, 1.5-3.9) and convicted youths, who had a higher risk of suicide (adjusted IRR, 8.5; 95% CI, 4.6-15.7). Adolescent violent offending partly mediated the association between CA and suicide. CONCLUSIONS AND RELEVANCE Individuals with a history of CA who also engage in violent offending in adolescence have a high risk of suicide. Interventions to prevent externalizing behavior during childhood and increased support to youths with delinquent behavior may have the potential to prevent suicide related to CA.

  • 387. Björkenstam, Emma
    et al.
    Hjern, Anders
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS). Karolinska Institutet, Sweden.
    Vinnerljung, Bo
    Stockholm University, Faculty of Social Sciences, Department of Social Work.
    Adverse childhood experiences and disability pension in early midlife: results from a Swedish National Cohort Study2017In: European Journal of Public Health, ISSN 1101-1262, E-ISSN 1464-360X, Vol. 27, no 3, p. 472-477Article in journal (Refereed)
    Abstract [en]

    Background: Few studies have examined the association between adverse childhood experiences (ACEs) and disability pension (DP). The current study aimed to investigate the relationship between different ACEs, cumulative ACEs, and DP, and the mediating role of school performance. Methods: We used a Swedish cohort of 522 880 individuals born between 1973 and 1978. ACEs included parental death, parental substance abuse and psychiatric disorder, substantial parental criminality, household public assistance, parental DP and child welfare intervention. Estimates of risk of DP in 2008 were calculated as odds ratios (OR) with 95% confidence intervals (CIs). Results: A total of 2.3% (3.0% females, 1.7% males) received DP in 2008. All studied ACEs increased the odds for DP, particularly child welfare intervention and household public assistance. Cumulative ACEs increased the odds of DP in a graded manner. Females exposed to 4+ ACEs had a 4-fold odds (OR: 4.0, 95% CI 3.5-4.5) and males a 7-fold odds (OR: 7.1, 95% CI: 6.2-8.1). School performance mediated the ACEs-DP association. Conclusion: This study provides evidence that ACEs is associated with increased odds of DP, particularly when accumulated. The effects of ACEs should be taken into account when considering the determinants of DP, and when identifying high-risk populations.

  • 388. Björkenstam, Emma
    et al.
    Vinnerljung, Bo
    Stockholm University, Faculty of Social Sciences, Department of Social Work. Karolinska Institutet, Sweden.
    Hjern, Anders
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS). Karolinska Institutet, Sweden.
    Impact of childhood adversities on depression in early adulthood: A longitudinal cohort study of 478,141 individuals in Sweden2017In: Journal of Affective Disorders, ISSN 0165-0327, E-ISSN 1573-2517, Vol. 223, p. 95-100Article in journal (Refereed)
    Abstract [en]

    Objective: Although the relationship between childhood adversity (CA) and depression is widely accepted, there is little information on what proportion of depression is attributable to CA. Method: We used a Swedish cohort of 478,141 individuals born in 1984-1988 in Sweden. Register-based CA indicators included parental death, parental substance abuse and psychiatric morbidity, parental criminality, parental separation, public assistance recipiency, child welfare intervention, and residential instability. Estimates of risk of depression, measured as retrieval of prescribed antidepressants and/or psychiatric care with a clinical diagnosis of depression, between 2006 and 2012 were calculated as Hazard Ratios (HR) with 95% confidence intervals (CI), using a Cox regression analysis. Results: All CAs predicted depression in early adulthood. Furthermore, the predictive association between the CA indicators and depression was graded, with highest HRs observed for 4+ CAs (HR: 3.05 (95% CI 2.83-3.29)) for a clinical diagnosis for depression and HR: 1.32 (95% CI 1.25-1.41) for antidepressant medication after adjustments were made for important confounding factors. Of the studied CAs, child welfare intervention entailed highest HR for depression. Conclusion: Regardless of causality issues, children and youth with a history of multiple CA should be regarded as a high-risk group for depression by professionals in social, and health service's that come into contact with this group.

  • 389.
    Björklund, Asa K
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Light, Sara
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Hedin, Linnea
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Quantitative assessment of the structural bias in protein-protein interaction assays.2008In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 8, no 22, p. 4657-46667Article in journal (Refereed)
    Abstract [en]

    With recent publications of several large-scale protein-protein interaction (PPI) studies, the realization of the full yeast interaction network is getting closer. Here, we have analysed several yeast protein interaction datasets to understand their strengths and weaknesses. In particular, we investigate the effect of experimental biases on some of the protein properties suggested to be enriched in highly connected proteins. Finally, we use support vector machines (SVM) to assess the contribution of these properties to protein interactivity. We find that protein abundance is the most important factor for detecting interactions in tandem affinity purifications (TAP), while it is of less importance for Yeast Two Hybrid (Y2H) screens. Consequently, sequence conservation and/or essentiality of hubs may be related to their high abundance. Further, proteins with disordered structure are over-represented in Y2H screens and in one, but not the other, large-scale TAP assay. Hence, disordered regions may be important both in transient interactions and interactions in complexes. Finally, a few domain families seem to be responsible for a large part of all interactions. Most importantly, we show that there are method-specific biases in PPI experiments. Thus, care should be taken before drawing strong conclusions based on a single dataset.

  • 390.
    Björklund, Catarina
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Adolfsson, Hans
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Jansson, Katarina
    Lindberg, Jimmy
    Vrang, Lotta
    Hallberg, Anders
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Discovery of Potent BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Exploration of P1’ Alkoxy Residues and an Aminoethylene (AE) Central Core2010In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 4, p. 1711-1723Article in journal (Refereed)
    Abstract [en]

    In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1’ methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1’ pocket by introducing a set of P1’ alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1’ positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1’ positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed IC50 values in the range of 4-45 nM, where the most potent compounds featured small P1’ groups. The cathepsin D selectivity which was high for the smallest P1’ sustituents (P1’=ethoxy, fold selectively >600) dropped for larger groups (P1’=benzyloxy, fold selectivity of 1.6). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.

  • 391.
    Björklund, Catarina
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Oscarson, Stefan
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Benkestock, Kurt
    Borkakoti, Neera
    Jansson, Katarina
    Lindberg, Jimmy
    Vrang, Lotta
    Hallberg, Anders
    Rosenquist, Åsa
    Samuelsson, Bertil
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Design and synthesis of potent and selective BACE-1 inhibitors2010In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 53, no 4, p. 1458-1464Article in journal (Refereed)
    Abstract [en]

    Several highly potent BACE-1 protease inhibitors have been developed from an inhibitor series containing a novel hydroxyethylene (HE) core structure displaying aryloxymethyl or benzyloxymethyl P1 side chains and a methoxy P1’ side chain. The target molecules were readily synthesized from chiral carbohydrate starting materials, furnishing the inhibitor compounds in good overall yields. The inhibitors show both high BACE-1 potency and good selectivity against cathepsin D, where the most potent inhibitor furnish a BACE-1 IC50 value of 0.32 nM and displays > 3000 fold selectivity over cathepsin D.

  • 392.
    Björklund, Åsa K.
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Ekman, Diana
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Elofsson, Arne
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Expansion of Protein Domain Repeats2006In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 2, no 8, p. 959-970Article in journal (Refereed)
    Abstract [en]

    Many proteins, especially in eukaryotes, contain tandem repeats of several domains from the same family. These repeats have a variety of binding properties and are involved in protein-protein interactions as well as binding to other ligands such as DNA and RNA. The rapid expansion of protein domain repeats is assumed to have evolved through internal tandem duplications. However, the exact mechanisms behind these tandem duplications are not well-understood. Here, we have studied the evolution, function, protein structure, gene structure, and phylogenetic distribution of domain repeats. For this purpose we have assigned Pfam-A domain families to 24 proteomes with more sensitive domain assignments in the repeat regions. These assignments confirmed previous findings that eukaryotes, and in particular vertebrates, contain a much higher fraction of proteins with repeats compared with prokaryotes. The internal sequence similarity in each protein revealed that the domain repeats are often expanded through duplications of several domains at a time, while the duplication of one domain is less common. Many of the repeats appear to have been duplicated in the middle of the repeat region. This is in strong contrast to the evolution of other proteins that mainly works through additions of single domains at either terminus. Further, we found that some domain families show distinct duplication patterns, e. g., nebulin domains have mainly been expanded with a unit of seven domains at a time, while duplications of other domain families involve varying numbers of domains. Finally, no common mechanism for the expansion of all repeats could be detected. We found that the duplication patterns show no dependence on the size of the domains. Further, repeat expansion in some families can possibly be explained by shuffling of exons. However, exon shuffling could not have created all repeats.

  • 393.
    Björling, Thomas
    Stockholm University, Faculty of Science, Department of Physical, Inorganic and Structural Chemistry.
    Synthesis and characterisation of Zintl hydrides2008Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The synthesis, structural characterisation and the properties of the Zintl hydrides AeE2H2 and AeAlSiH (Ae = Ba, Ca, Sr; E = Al, Ga, In, Si, Zn) are reported. The first hydride in this class of compounds is SrAl2H2 which was discovered under an experiment by Gingl, who hydrogenated SrAl2 at various temperatures. (Gingl et al, Journal of Alloys and Compounds 306 (2000) 127-132). The intention was to form alanates, e.g. AlH4-, by terminating the three dimensional four connected aluminium network in SrAl2. The new hydride, SrAl2H2, has a partially conserved aluminium network. The three dimensional anionic network in SrAl2 is reduced to two dimensions in the hydride, with aluminium bonded to both aluminium and hydrogen. This type of bonding configuration has not been observed before.

    The hydrogenation of SrAl2 is straight forward, 190 oC and 50 bar, compared to the difficult synthesis of alanates and alane, AlH3. The latter synthesises uses aluminium in its zero oxidation state in contrast to the synthesis of SrAl2H2 from SrAl2. (In the SrAl2-precursor aluminium is reduced by the electropositive metal to -I.) Thus, the discovery shows a different route to alanates by using precursors with aluminium in a reduced state. If SrAl2H2 is further hydrogenated at 250 oC the two dimensional network breaks and Sr2AlH7 forms.

    We wanted to investigate if SrAl2H2 was a singularity or if other similar compounds exist. We wanted to study how hydrogenation of precursors similar to the aluminide result in 1) new routes to compounds with high hydrogen content, as alanates, 2) to investigate how the E-H bond is affected as function of the network composition among different ternary hydrides, in particular BaAlxSi2-xHx, and choice of active metal.

    BaGa2H2 and SrGa2H2, two hydrides isostructural with SrAl2H2, were synthesized from its precursors BaGa2 and SrGa2. In addition three ternary hydrides BaAlSiH, CaAlSiH and SrAlSiH were manufactured from their related AeAlSi precursors.

    All powders were characterized by neutron and x-ray diffraction methods.

    An increased stability towards water/moisture compared to ordinary saline hydrides was noticed, especially for the ternary hydrides. Heat stability was measured with DSC (differential scanning calorimetry). The hydrides BaGa2H2 and SrGa2H2 decompose around 300 oC at 1 atm. This is similar to isostructural SrAl2H2. The ternary hydrides BaAlSiH and SrAlSiH decompose at 600 oC, at 1 atm, which is the highest noticed temperature for compounds with Al-H bonds. Inelastic neutron scattering experiments showed that these hydrides Al-H and Sr-H bonds are really weak, even weaker then the Al-H interactions in alanates and alanes. These hydrides are probably stabilized be their lattices. The electric properties among the ternary hydrides were measured with IR-spectroscopy (diffuse reflectance). The ternary hydrides, AeAlSiH, are indirect semi conductors. BaGa2H2 and SrGa2H2 are conductors. The ternary hydrides, AeAlxSi2-xHx, may have adjustable band gaps, which we were not able to determine.

    This work is leading into a new research area within the field of metal hydrides.

  • 394. Blair, Mitch
    et al.
    Stewart-Brown, Sarah
    Hjern, Anders
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS).
    Bremberg, Sven
    Barnhälsovetenskap2013 (ed. 1.)Book (Other academic)
  • 395. Blom, Victoria
    et al.
    Richter, Anne
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden; Stockholm County Council, Sweden.
    Hallsten, Lennart
    Svedberg, Pia
    The associations between job insecurity, depressive symptoms and burnout: The role of performance-based self-esteem2018In: Economic and Industrial Democracy, ISSN 0143-831X, E-ISSN 1461-7099, Vol. 39, no 1, p. 48-63Article in journal (Refereed)
    Abstract [en]

    Despite agreement on the negative effects of job insecurity, more knowledge needs to be generated on the health effects in terms of burnout and depressive symptoms and for whom job insecurity has these negative effects. The present study aims to investigate the associations between job insecurity and burnout and depressive symptoms respectively, by studying the moderation influences of performance-based self-esteem (PBSE), a form of contingent self-esteem. A population-based sample with 4145 twins was used. The results showed that job insecurity was significantly associated with both burnout and depressive symptoms, and that PBSE acted as a moderator, so that the associations were stronger for individuals with high PBSE than for individuals with low PBSE. The study contributes by including a personality characteristic to gain more knowledge about the mechanisms of job insecurity on mental ill-health, and by illustrating that job insecurity has an impact on severe health outcomes in terms of burnout and depressive symptoms.

  • 396. Blom, Victoria
    et al.
    Sverke, Magnus
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Bodin, Lennart
    Bergström, Gunnar
    Lindfors, Petra
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Svedberg, Pia
    Work-Home Interference and Burnout A Study Based on Swedish Twins2014In: Journal of Occupational and Environmental Medicine, ISSN 1076-2752, E-ISSN 1536-5948, Vol. 56, no 4, p. 361-366Article in journal (Refereed)
    Abstract [en]

    Objective: This study sets out to investigate the impact of work-home interference on burnout in women and men, while taking genetic and family environmental factors into account. Methods: A total of 4446 Swedish twins were included in the study. The effects of work-home conflict (WHC) and home-work conflict (HWC) on burnout between and within pairs were analyzed with co-twin control analyses. Results: Both WHC and HWC were significantly associated with burnout. Genetic factors may be involved in the association between HWC and burnout in women. Familial factors were not involved for WHC and burnout, neither for women nor for men. Conclusions: This study shows the importance to encounter WHC per se to prevent burnout. Because of genetic confounding in HWC and burnout in women, preventive efforts may also take into account individual characteristics.

  • 397.
    Blomqvist, Helen
    Stockholm University, Faculty of Science, Department of Physical, Inorganic and Structural Chemistry.
    Magnesium ions stabilizing solid-state transition metal hydrides2003Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is focused on hydrides containing first-row transition metal–hydrido complexes counterbalanced by magnesium. In particular, fundamental properties of the promising hydrogen storage material Mg2NiH4 have been studied. Results presented in the thesis provide detailed knowledge of the electronic structure and bonding mechanisms and are of significance for improving the hydrogen desorption process of complex transition metal hydrides in general.Two competing stabilization mechanisms in Mg2NiH4 have been identified; presence of microtwinning in the structure and the extra Mg added to the melt-cast Mg2Ni starting alloys, which acts as stabilizing dopant in the Mg2NiH4 system. When eliminating both stabilization mechanisms, the hydrogen release pressure was doubled at 453 K. Mg2NiH4 behaves like a heavily doped semiconductor at lower temperatures, but the conductivity is counteracted by the introduction of microtwinning in the structure at elevated temperatures, which makes the hydride non-conducting at » 400 K. The conductivity can be regained by reducing the amount of microtwinning with an applied mechanical pressure. Size, coordination and type of cation framework have decisive roles in determining the structure type of complex metal hydrides, as shown by ab initio total-energy calculations. Compared to the rich variety of Pd-based complex hydrides, the few Ni hydrido complexes hitherto found only contain Mg2+, solely or in combination with Ca2+, Sr2+, Yb2+, Eu2+ or La3+. Apparently the rather weak Ni–H bond needs a small and polarizing cation, e.g. Mg2+, to be stabilized in the solid state. The rather strong Mg–H interaction makes Mg2NiH4 a hybrid of ionic and complex transition metal hydride. This stabilization mechanism where electron density is redistributed by the polarizable hydrido ligand explains why Mg2NiH4 is very sensitive to disturbances of the crystal ordering, e.g. doping and ball milling, which profoundly affect stability, conductivity, color, structure and phasetransition conditions. Mg2+ also has the ability to stabilize Mn hydrido complexes, as observed in the novel Mg3MnH~6 compound, synthesized at GPa pressure in the solid state.

  • 398.
    Blomqvist, Jan
    Stockholm University, Faculty of Social Sciences, Centre for Social Research on Alcohol and Drugs (SoRAD).
    Av egen kraft - med andras stöd2013In: Hjälpande möten i vård och omvärld: brukare, praktiker och forskare reflekterar / [ed] Ingemar Ljungqvist, Håkan Jenner, Stockholm: Liber, 2013, p. 182-210Chapter in book (Other academic)
  • 399.
    Blomqvist, Jan
    Stockholm University, Faculty of Social Sciences, Centre for Social Research on Alcohol and Drugs (SoRAD).
    Dogmer som dödar: Vägval för svensk narkotikapolitik2017In: Dogmer som dödar: Vägval för svensk narkotikapolitik / [ed] Niklas Eklund, Mikaela Hildebrand, Stockholm: Verbal , 2017, p. 291-311Chapter in book (Other academic)
  • 400. Blomqvist, Jan
    et al.
    Raitasalo, Kirsimarja
    Koski-Jännes, Anja
    Klingemann, Justyna
    Melberg, Hans Olov
    Schreckenberg, Dirk
    Peschel, Christine
    Popular Images of Adiction in five European Countries2014Report (Other academic)
567891011 351 - 400 of 3867
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