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  • 201.
    Arnberg, Filip K.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Uppsala University, Sweden.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Morey, Jennifer N.
    Segerström, Suzanne C.
    Self-rated health and interleukin-6: Longitudinal relationships in older adults2016In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 54, p. 226-232Article in journal (Refereed)
    Abstract [en]

    Background: Both self-rated health (SRH) and inflammation are implicated in chronic diseases and premature mortality. Better SRH is associated with lower proinflammatory cytokines, but there is little evidence about whether this relationship is more stable or dynamic.

    Objective: To study the between- and within-person associations between SRH and IL-6.

    Methods: Older adults (N=131; Mage=75years) rated their health and provided blood samples for analysis of IL-6 at separate occasions every 6months over a period up to 5years. Age, sex, BMI, neuroticism, and statin use were examined as covariates in multilevel models.

    Results: In bivariate models, better SRH, lower BMI, younger age, and female sex correlated with lower IL-6. In multilevel models, stable SRH (between-person differences; p<.001) but not dynamic SRH (within-person changes; p=.93) correlated with IL-6. The stable relationship persisted with demographic and health covariates in the model.

    Conclusions: Better stable SRH but not dynamic SRH was robustly associated with lower IL-6 among older adults, lending support to previous cross-sectional findings on the relation between inflammatory markers and SRH. The findings suggest that trait-like mechanisms, rather than changes over a time scale of 6-month waves, govern this association. To further investigate the mechanisms behind the SRH-IL-6 association, studies with different measurement frequencies, higher within-person variability, and experimental approaches are warranted.

  • 202.
    Arnberg, Filip K.
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Uppsala University, Sweden.
    Michel, Per-Olof
    Lundin, Tom
    Posttraumatic stress in survivors 1 month to 19 years after an airliner emergency landing2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0119732Article in journal (Refereed)
    Abstract [en]

    Posttraumatic stress (PTS) is common in survivors from life-threatening events. Little is known, however, about the course of PTS after life threat in the absence of collateral stressors (e.g., bereavement, social stigma, property loss) and there is a scarcity of studies about PTS in the long term. This study assessed the short- and long-term course of PTS, and the influence of gender, education and age on the level and course of PTS, in survivors from a non-fatal airliner emergency landing caused by engine failure at an altitude of 1 km. There were 129 persons on board. A survey including the Impact of Event Scale was distributed to 106 subjects after 1 month, 4 months, 14 months, and 25 months, and to 95 subjects after 19 years (response rates 64-83%). There were initially high levels of PTS. The majority of changes in PTS occurred from 1 to 4 months after the event. There were small changes from 4 to 25 months but further decrease in PTS thereafter. Female gender was associated with higher levels of PTS whereas gender was unrelated to the slope of the short- and long-term trajectories. Higher education was related to a quicker recovery although not to initial or long-term PTS. Age was not associated with PTS. The present findings suggest that a life-threatening experience without collateral stressors may produce high levels of acute posttraumatic stress, yet with a benign prognosis. The findings further implicate that gender is unrelated to trajectories of recovery in the context of highly similar exposure and few collateral stressors.

  • 203. Arnetz, Bengt
    et al.
    Frenzel, Lena
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Lisspers, Jan
    The brief fatigue syndrome scale: Validation and utilization in fatigue recovery studies2008In: Fatigue Science for Human Health, Springer , 2008, p. 55-66Chapter in book (Other academic)
  • 204.
    Aronsson, Gunnar
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Astvik, Wanja
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Mälardalen University, Sweden.
    Gustafsson, Klas
    Work conditions, Recovery and Health: A study among workers within Pre-School, Home Care and Social Work2014In: British Journal of Social Work, ISSN 0045-3102, E-ISSN 1468-263X, Vol. 44, no 6, p. 1654-1672Article in journal (Refereed)
    Abstract [en]

    The study investigated the working conditions associated with the accumulation of stress and lack of recovery and how recovery is related to health. The study group was employed in pre-school, home care and social work (n = 193). Recovery was assumed to be an explanatory variable for the relations between work and health. The response rate on a survey was 79 per cent. Cluster analysis identified three groups: the ‘Recovered’ (36 per cent of the total group) and ‘Not Recovered’ (25 per cent) and the ‘In-between’ (39 per cent). The Not Recovered displayed the whole chain of risk factors, involving difficult working conditions to which they responded with increased compensatory strategies. Despite this group having significantly greater reports of ill health, work absenteeism was not greater, which is likely related to their substituting sickness absence with sickness presence. As many as 43 per cent of the social workers were found to belong to the Not Recovered group. Multiple regression analyses controlling for background variables revealed that the Not Recovered group had a significantly higher relative risk for poor self-rated health than those in the Recovered group. Even sharper increases in relative risk existed for the other five symptoms that were analysed. Practical implications and new research questions are discussed.

  • 205.
    Aronsson, Gunnar
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Lundberg, Ulf
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    Interventioner för återgång i arbete vid sjukskrivning: En systematisk kunskapsöversikt av metaanalyser med inriktning på muskuloskeletala och psykiska besvär2015In: Arbete och Hälsa, ISSN 0346-7821, ISSN 0346-7821, Vol. 49, no 2, p. 1-50Article, review/survey (Refereed)
  • 206.
    Aronsson, Gunnar
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Work and organizational psychology.
    Theorell, Töres
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Grape, Tom
    Hammarström, Anne
    Hogstedt, Christer
    Marteinsdottir, Ina
    Skoog, Ingmar
    Träskman-Bendz, Lil
    Hall, Charlotte
    A systematic review including meta-analysis of work environment and burnout symptoms2017In: BMC Public Health, ISSN 1471-2458, E-ISSN 1471-2458, Vol. 17, no 1, article id 264Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Practitioners and decision makers in the medical and insurance systems need knowledge on the relationship between work exposures and burnout. Many burnout studies - original as well as reviews - restricted their analyses to emotional exhaustion or did not report results on cynicism, personal accomplishment or global burnout. To meet this need we carried out this review and meta-analyses with the aim to provide systematically graded evidence for associations between working conditions and near-future development of burnout symptoms.

    METHODS: A wide range of work exposure factors was screened. Inclusion criteria were: 1) Study performed in Europe, North America, Australia and New Zealand 1990-2013. 2) Prospective or comparable case control design. 3) Assessments of exposure (work) and outcome at baseline and at least once again during follow up 1-5 years later. Twenty-five articles met the predefined relevance and quality criteria. The GRADE-system with its 4-grade evidence scale was used.

    RESULTS: Most of the 25 studies focused emotional exhaustion, fewer cynicism and still fewer personal accomplishment. Moderately strong evidence (grade 3) was concluded for the association between job control and reduced emotional exhaustion and between low workplace support and increased emotional exhaustion. Limited evidence (grade 2) was found for the associations between workplace justice, demands, high work load, low reward, low supervisor support, low co-worker support, job insecurity and change in emotional exhaustion. Cynicism was associated with most of these work factors. Reduced personal accomplishment was only associated with low reward. There were few prospective studies with sufficient quality on adverse chemical, biological and physical factors and burnout.

    CONCLUSION: While high levels of job support and workplace justice were protective for emotional exhaustion, high demands, low job control, high work load, low reward and job insecurity increased the risk for developing exhaustion. Our approach with a wide range of work exposure factors analysed in relation to the separate dimensions of burnout expanded the knowledge of associations, evidence as well as research needs. The potential of organizational interventions is illustrated by the findings that burnout symptoms are strongly influenced by structural factors such as job demands, support and the possibility to exert control.

  • 207.
    Aronsson, Vanda
    Stockholm University, Faculty of Social Sciences, Centre for Health Equity Studies (CHESS).
    Health differences between employees in human service professions and other professions: The impact of psychosocial and organizational work environment2016Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    While recent publications indicate that employees in human service professions have higher risk of sickness absence and mental ill-health, little is known about the association with other health outcomes and possible mechanisms behind the differential risk. This study investigates differences in burnout, self-rated health and sickness absence between those in human service professions and other professions and examines whether differences in psychosocial and organizational work environment can explain possible variations. Data were derived from the Swedish Longitudinal Occupational Survey of Health (SLOSH), an approximately representative sample of the Swedish working population (n=4486). Results from binary logistic regressions suggested that those in human service professions had higher odds of burnout and sickness absence those in other professions. Differences in burnout were explained by background variables while differences in sickness absence were explained by psychosocial and organizational work factors. Employees in human service professions had lower odds of suboptimal self-rated health than others in the fully adjusted model. Women were at higher risk of burnout, sickness absence, and all adverse psychosocial and organizational work environment factors except social support. Future studies should investigate the most crucial psychosocial and organizational work factors in human service professions with the objective to improve employee health.  

  • 208.
    Arrighi, Romanico B. G.
    et al.
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Ebikeme, Charles
    Jiang, Yang
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Ranford-Cartwright, Lisa
    Barrett, Michael P.
    Langel, Ülo
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Faye, Ingrid
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Cell-penetrating peptide TP10 shows broad-spectrum activity against both Plasmodium falciparum and Trypanosoma brucei brucei2008In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 52, no 9, p. 3414-3417Article in journal (Refereed)
    Abstract [en]

    Malaria and trypanosomiasis are diseases which afflict millions and for which novel therapies are urgently required. We have tested two well-characterized cell-penetrating peptides (CPPs) for antiparasitic activity. One CPP, designated TP10, has broad-spectrum antiparasitic activity against Plasmodium falciparum, both blood and mosquito stages, and against blood-stage Trypanosoma brucei brucei.

  • 209.
    Arshamian, Artin
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Psychology, Perception and psychophysics. Karolinska Institutet, Sweden; Donders Institute for Brain, Cognition, and Behavior, The Netherlands; Radboud University, The Netherlands.
    Iravani, Behzad
    Majid, Asifa
    Lundström, Johan N.
    Respiration Modulates Olfactory Memory Consolidation in Humans2018In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 38, no 48, p. 10286-10294Article in journal (Refereed)
    Abstract [en]

    In mammals respiratory-locked hippocampal rhythms are implicated in the scaffolding and transfer of information between sensory and memory networks. These oscillations are entrained by nasal respiration and driven by the olfactory bulb. They then travel to the piriform cortex where they propagate further downstream to the hippocampus and modulate neural processes critical for memory formation. In humans, bypassing nasal airflow through mouth-breathing abolishes these rhythms and impacts encoding as well as recognition processes thereby reducing memory performance. It has been hypothesized that similar behavior should be observed for the consolidation process, the stage between encoding and recognition, were memory is reactivated and strengthened. However, direct evidence for such an effect is lacking in human and nonhuman animals. Here we tested this hypothesis by examining the effect of respiration on consolidation of episodic odor memory. In two separate sessions, female and male participants encoded odors followed by a 1 h awake resting consolidation phase where they either breathed solely through their nose or mouth. Immediately after the consolidation phase, memory for odors was tested. Recognition memory significantly increased during nasal respiration compared with mouth respiration during consolidation. These results provide the first evidence that respiration directly impacts consolidation of episodic events, and lends further support to the notion that core cognitive functions are modulated by the respiratory cycle.

  • 210. Asberg, Marie
    et al.
    Nygren, Ake
    Leopardi, Rosario
    Rylander, Gunnar
    Peterson, Ulla
    Wilczek, Lukas
    Källmén, Håkan
    Ekstedt, Mirjam
    Akerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Lekander, Mats
    Ekman, Rolf
    Novel biochemical markers of psychosocial stress in women.2009In: PLoS ONE, ISSN 1932-6203, Vol. 4, no 1, p. e3590-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Prolonged psychosocial stress is a condition assessed through self-reports. Here we aimed to identify biochemical markers for screening and early intervention in women. METHODS: Plasma concentrations of interleukin (IL) 1-alpha, IL1-beta, IL-2, IL-4, IL-6, IL-8, IL-10, interferon-gamma (INF-gamma), tumor necrosis factor-alpha (TNF-alpha), monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), thyroid stimulating hormone (TSH), total tri-iodothyronine (TT3), total thyroxine (TT4), prolactin, and testosterone were measured in: 195 women on long-term sick-leave for a stress-related affective disorder, 45 women at risk for professional burnout, and 84 healthy women. RESULTS: We found significantly increased levels of MCP-1, VEGF and EGF in women exposed to prolonged psychosocial stress. Statistical analysis indicates that they independently associate with a significant risk for being classified as ill. CONCLUSIONS: MCP-1, EGF, and VEGF are potential markers for screening and early intervention in women under prolonged psychosocial stress.

  • 211.
    Asgard, Rikard
    et al.
    Uppsala Univ, Dept Pharmaceut Biosci., Uppsala, Sweden.
    Haghdoost, Siamak
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Golkar, Siv Osterman
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Hellman, Bjorn
    Uppsala Univ, Dept Pharmaceut Biosci., Uppsala, Sweden.
    Czene, Stefan
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Evidence for different mechanisms of action behind the mutagenic effects of 4-NOPD and OPD: the role of DNA damage, oxidative stress and an imbalanced nucleotide pool2013In: Mutagenesis, ISSN 0267-8357, E-ISSN 1464-3804, Vol. 28, no 6, p. 637-644Article in journal (Refereed)
    Abstract [en]

    The mutagenicity of 4-nitro-o-phenylenediamine (4-NOPD) and o-phenylenediamine (OPD) was compared using the Mouse Lymphoma Assay (MLA) with or without metabolic activation (S9). As expected, OPD was found to be a more potent mutagen than 4-NOPD. To evaluate possible mechanisms behind their mutagenic effects, the following end points were also monitored in cells that had been exposed to similar concentrations of the compounds as in the MLA: general DNA damage (using a standard protocol for the Comet assay); oxidative DNA damage (using a modified procedure for the Comet assay in combination with the enzyme hOGG1); reactive oxygen species (ROS; using the CM-H(2)DCFDA assay); and the balance of the nucleotide pool (measured after conversion to the corresponding nucleosides dC, dT, dG and dA using high-performance liquid chromatography). Both compounds increased the level of general DNA damage. Again, OPD was found to be more potent than 4-NOPD (which only increased the level of general DNA damage in the presence of S9). Although less obvious for OPD, both compounds increased the level of oxidative DNA damage. However, an increase in intracellular ROS was only observed in cells exposed to 4-NOPD, both with and without S9 (which in itself induced oxidative stress). Both compounds decreased the concentrations of dA, dT and dC. A striking effect of OPD was the sharp reduction of dA observed already at very low concentration, both with and without S9 (which in itself affected the precursor pool). Taken together, our results indicate that indirect effects on DNA, possibly related to an unbalanced nucleotide pool, mediate the mutagenicity and DNA-damaging effects of 4-NOPD and OPD to a large extent. Although induction of intracellular oxidative stress seems to be a possible mechanism behind the genotoxicity of 4-NOPD, this pathway seems to be of less importance for the more potent mutagen OPD.

  • 212.
    Aslam, Muhammad
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    The fruit fly Drosophila melanogaster GSTE6 and E7; characterization, immobilization and transgenic overexpression2014Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    Glutathione transferases (GSTs) are multifunctional enzymes that are universally distributed in most eukaryotes and prokaryotes. They play a pivotal role in the metabolism and detoxication of numerous endogenous and exogenous electrophiles by conjugating them with ubiquitous tripeptide glutathione. In this study we have immobilized two heterologously expressed and purified Epsilon-class enzymes, GSTE6 and GSTE7, from of Drosophila melanogaster on nanoporous alumina membranes. The membranes were derivatized with 3-aminopropyl-triethoxysilane and the amino groups were activated with carbonyldiimidazole to allow coupling of the enzymes. Kinetic analyses of the immobilized enzymes were carried out in a circulating flow system using CDNB (1-chloro-2,4-dinitrobenzene) as substrate, followed by specificity screening with alternative substrates. A good correlation was observed between the substrate screening data for immobilized enzyme and corresponding data for the enzymes in solution. The stability of the immobilized enzymes was virtually identical to that for the enzymes in solution and no leakage of enzyme from the matrix could be observed.

    Additionally, we have investigated the catalytic activities of GSTE7 with organic isothiocyanates (ITCs). These reactive compounds are strong electrophilic molecules produced in plants by the hydrolysis of glucosinolates and exert toxicity in biological tissues.  Our in vitro studies, showed high catalytic activity of GSTE7 towards ITCs. We have then explored the in vivo effect of phenethyl isothiocyanate (PEITC) and allyl isothiocyanate (AITC) in transgenic fruit flies overexpressing GSTE7. A concentration of 0.25 mM PEITC in standard fly food was shown to be toxic to flies and significantly shortened the lifespan. We noticed that overexpression of GSTE7 could protect females from the initial acute toxic effects, but had no positive effect on long term exposure. The effect on males seems to be the opposite to that of females, where a higher mortality was seen in fly males overexpressing GST E7 after one week of exposure.  On the other hand 1mM concentration of AITC showed no toxic effects, but dramatically reduced the oviposition activity of wild-type flies in comparison to the transgenic flies.

  • 213.
    Aslam, Muhammad
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Dahlberg, Olle
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Mannervik, Bengt
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Mannervik, Mattias
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Transgenic Overexpression of Glutathione Transferase E7 in Drosophila Attenuates Toxicity of Organic Isothiocyanates Affecting Survival and OvipositionManuscript (preprint) (Other academic)
    Abstract [en]

    Organic isothiocyanates (ITCs) are allelochemicals produced by plants in order to combat insects and other herbivores. The compounds are toxic electrophiles that can be inactivated and conjugated with intracellular glutathione in reactions catalyzed by glutathione transferases (GSTs). The Drosophila melanogaster GSTE7 was heterologously expressed in Escherichia coli and purified for functional studies. The enzyme showed high catalytic activity with various isothiocyanates including phenethyl isothiocyanate (PEITC) and allyl isothiocyanate (AITC), which in millimolar dietary concentrations conferred toxicity to adult D. melanogaster leading to death or a shortened life-span of the flies. In situ hybridization revealed a maternal contribution of GSTE7 transcripts to embryos, and strongest zygotic expression in the digestive tract.  Transgenesis involving the GSTE7 gene controlled by an actin promoter produced viable flies expressing the GSTE7 transcript ubiquitously. Transgenic females show a significant extension in life-span when subjected to the same PEITC treatment as the wild-type flies. By contrast, transgenic male flies showed no significant effect in the first few days, and subsequently showed a somewhat lower survival rate. At 1 mM AITC concentration, no toxicity was noted. However, the oviposition activity was dramatically enhanced from a very low level in wild-type flies reared in the presence of 1 mM AITC to values an order of magnitude higher for the transgenic flies. The results demonstrate a clear protective effect of GSTE7 against exposure to ITC allelochemicals which can affect both life-span and fecundity of female flies.

  • 214. Asmat, Tauseef M.
    et al.
    Tenenbaum, Tobias
    Jonsson, Ann-Beth
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Schwerk, Christian
    Schroten, Horst
    Impact of Calcium Signaling during Infection of Neisseria meningitidis to Human Brain Microvascular Endothelial Cells2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, p. e114474-Article in journal (Refereed)
    Abstract [en]

    The pili and outer membrane proteins of Neisseria meningitidis (meningococci) facilitate bacterial adhesion and invasion into host cells. In this context expression of meningococcal PilC1 protein has been reported to play a crucial role. Intracellular calcium mobilization has been implicated as an important signaling event during internalization of several bacterial pathogens. Here we employed time lapse calcium-imaging and demonstrated that PilC1 of meningococci triggered a significant increase in cytoplasmic calcium in human brain microvascular endothelial cells, whereas PilC1-deficient meningococci could not initiate this signaling process. The increase in cytosolic calcium in response to PilC1-expressing meningococci was due to efflux of calcium from host intracellular stores as demonstrated by using 2-APB, which inhibits the release of calcium from the endoplasmic reticulum. Moreover, pre-treatment of host cells with U73122 (phospholipase C inhibitor) abolished the cytosolic calcium increase caused by PilC1-expressing meningococci demonstrating that active phospholipase C (PLC) is required to induce calcium transients in host cells. Furthermore, the role of cytosolic calcium on meningococcal adherence and internalization was documented by gentamicin protection assay and double immunofluorescence (DIF) staining. Results indicated that chelation of intracellular calcium by using BAPTA-AM significantly impaired PilC1-mediated meningococcal adherence to and invasion into host endothelial cells. However, buffering of extracellular calcium by BAPTA or EGTA demonstrated no significant effect on meningococcal adherence to and invasion into host cells. Taken together, these results indicate that meningococci induce calcium release from intracellular stores of host endothelial cells via PilC1 and cytoplasmic calcium concentrations play a critical role during PilC1 mediated meningococcal adherence to and subsequent invasion into host endothelial cells.

  • 215. Assadi, Ghazaleh
    et al.
    Vesterlund, Liselotte
    Bonfiglio, Ferdinando
    Mazzurana, Luca
    Cordeddu, Lina
    Schepis, Danika
    Mjösberg, Jenny
    Ruhrmann, Sabrina
    Fabbri, Alessia
    Vukojevic, Vladana
    Percipalle, Piergiorgio
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. New York University Abu Dhabi, United Arab Emirates.
    Salomons, Florian A.
    Laurencikiene, Jurga
    Törkvist, Leif
    Halfvarson, Jonas
    D'Amato, Mauro
    Functional Analyses of the Crohn's Disease Risk Gene LACC12016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 12, article id e0168276Article in journal (Refereed)
    Abstract [en]

    Background Genetic variation in the Laccase (multicopper oxidoreductase) domain-containing 1 (LACC1) gene has been shown to affect the risk of Crohn's disease, leprosy and, more recently, ulcerative colitis and juvenile idiopathic arthritis. LACC1 function appears to promote fatty-acid oxidation, with concomitant inflammasome activation, reactive oxygen species production, and anti-bacterial responses in macrophages. We sought to contribute to elucidating LACC1 biological function by extensive characterization of its expression in human tissues and cells, and through preliminary analyses of the regulatory mechanisms driving such expression. Methods We implemented Western blot, quantitative real-time PCR, immunofluorescence microscopy, and flow cytometry analyses to investigate fatty acid metabolism-immune nexus (FAMIN; the LACC1 encoded protein) expression in subcellular compartments, cell lines and relevant human tissues. Gene-set enrichment analyses were performed to initially investigate modulatory mechanisms of LACC1 expression. A small-interference RNA knockdown in vitro model system was used to study the effect of FAMIN depletion on peroxisome function. Results FAMIN expression was detected in macrophage-differentiated THP-1 cells and several human tissues, being highest in neutrophils, monocytes/macrophages, myeloid and plasmacytoid dendritic cells among peripheral blood cells. Subcellular co-localization was exclusively confined to peroxisomes, with some additional positivity for organelle endomembrane structures. LACC1 co-expression signatures were enriched for genes involved in peroxisome proliferator-activated receptors (PPAR) signaling pathways, and PPAR ligands downregulated FAMIN expression in in vitro model systems. Conclusion FAMIN is a peroxisome-associated protein with primary role(s) in macrophages and other immune cells, where its metabolic functions may be modulated by PPAR signaling events. However, the precise molecular mechanisms through which FAMIN exerts its biological effects in immune cells remain to be elucidated.

  • 216. Athanasiu, Lavinia
    et al.
    Giddaluru, Sudheer
    Fernandes, Carla
    Christoforou, Andrea
    Reinvang, Ivar
    Lundervold, Astri J.
    Nilsson, Lars-Göran
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Umeå University, Sweden.
    Kauppi, Karolina
    Adolfsson, Rolf
    Eriksson, Elias
    Sundet, Kjetil
    Djurovic, Srdjan
    Espeseth, Thomas
    Nyberg, Lars
    Steen, Vidar M.
    Andreassen, Ole A.
    Le Hellard, Stephanie
    A genetic association study of CSMD1 and CSMD2 with cognitive function2017In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 61, p. 209-216Article in journal (Refereed)
    Abstract [en]

    The complement cascade plays a role in synaptic pruning and synaptic plasticity, which seem to be involved in cognitive functions and psychiatric disorders. Genetic variants in the closely related CSMD1 and CSMD2 genes, which are implicated in complement regulation, are associated with schizophrenia. Since patients with schizophrenia often show cognitive impairments, we tested whether variants in CSMD1 and CSMD2 are also associated with cognitive functions per se. We took a discovery-replication approach, using well-characterized Scandinavian cohorts. A total of 1637 SNPs in CSMD1 and 206 SNPs in CSMD2 were tested for association with cognitive functions in the NCNG sample (Norwegian Cognitive NeuroGenetics; n = 670). Replication testing of SNPs with p-value < 0.001 (7 in CSMD1 and 3 in CSMD2) was carried out in the TOP sample (Thematically Organized Psychosis; n =1025) and the BETULA sample (Betula Longitudinal Study on aging, memory and dementia; n = 1742). Finally, we conducted a meta-analysis of these SNPs using all three samples. The previously identified schizophrenia marker in CSMD1 (SNP rs10503253) was also included. The strongest association was observed between the CSMDI SNP rs2740931 and performance in immediate episodic memory (p-value = 5 Chi 10(-6), minor allele A, MAF 0.48-0.49, negative direction of effect). This association reached the study-wide significance level (p <= 1.2 Chi 10(-5)). SNP rs10503253 was not significantly associated with cognitive functions in our samples. In conclusion, we studied n = 3437 individuals and found evidence that a variant in CSMD1 is associated with cognitive function. Additional studies of larger samples with cognitive phenotypes will be needed to further clarify the role of CSMD1 in cognitive phenotypes in health and disease.

  • 217. Athlin, A. Muntlin
    et al.
    Farrokhnia, N.
    von Thiele Schwarz, Ulrica
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Introduction of multi-professional teamwork: a promising approach towards a more patient-centred care in the emergency department2014In: International Emergency Nursing, ISSN 1755-599X, E-ISSN 1878-013X, Vol. 22, no 4, p. 274-275Article in journal (Other academic)
  • 218. Atkinson, Jo-An
    et al.
    Knowles, Dylan
    Wiggers, John
    Livingston, Michael
    Room, Robin
    Stockholm University, Faculty of Social Sciences, Centre for Social Research on Alcohol and Drugs (SoRAD). La Trobe University, Australia.
    Prodan, Ante
    McDonnell, Geoff
    O'Donnell, Eloise
    Jones, Sandra
    Haber, Paul S.
    Muscatello, David
    Ezard, Nadine
    Phung, Nghi
    Freebairn, Louise
    Indig, Devon
    Rychetnik, Lucie
    Ananthapavan, Jaithri
    Wutzke, Sonia
    Harnessing advances in computer simulation to inform policy and planning to reduce alcohol-related harms2018In: International Journal of Public Health, ISSN 1661-8556, E-ISSN 1661-8564, Vol. 63, no 4, p. 537-546Article in journal (Refereed)
    Abstract [en]

    Alcohol misuse is a complex systemic problem. The aim of this study was to explore the feasibility of using a transparent and participatory agent-based modelling approach to develop a robust decision support tool to test alcohol policy scenarios before they are implemented in the real world. A consortium of Australia's leading alcohol experts was engaged to collaboratively develop an agent-based model of alcohol consumption behaviour and related harms. As a case study, four policy scenarios were examined. A 19.5 +/- 2.5% reduction in acute alcohol-related harms was estimated with the implementation of a 3 a.m. licensed venue closing time plus 1 a.m. lockout; and a 9 +/- 2.6% reduction in incidence was estimated with expansion of treatment services to reach 20% of heavy drinkers. Combining the two scenarios produced a 33.3 +/- 2.7% reduction in the incidence of acute alcohol-related harms, suggesting a synergistic effect. This study demonstrates the feasibility of participatory development of a contextually relevant computer simulation model of alcohol-related harms and highlights the value of the approach in identifying potential policy responses that best leverage limited resources.

  • 219. Atkinson, Jo-An
    et al.
    Prodan, Ante
    Livingston, Michael
    Knowles, Dylan
    O'Donnell, Eloise
    Room, Robin
    Indig, Devon
    Page, Andrew
    McDonnell, Geoff
    Wiggers, John
    Impacts of licensed premises trading hour policies on alcohol-related harms2018In: Addiction, ISSN 0965-2140, E-ISSN 1360-0443, Vol. 113, no 7, p. 1244-1251Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIM: Evaluations of alcohol policy changes demonstrate that restriction of trading hours of both 'on'- and 'off'-licence venues can be an effective means of reducing rates of alcohol-related harm. Despite this, the effects of different trading hour policy options over time, accounting for different contexts and demographic characteristics, and the common co-occurrence of other harm reduction strategies in trading hour policy initiatives, are difficult to estimate. The aim of this study was to use dynamic simulation modelling to compare estimated impacts over time of a range of trading hour policy options on various indicators of acute alcohol-related harm.

    METHODS: An agent-based model of alcohol consumption in New South Wales, Australia was developed using existing research evidence, analysis of available data and a structured approach to incorporating expert opinion. Five policy scenarios were simulated, including restrictions to trading hours of on-licence venues and extensions to trading hours of bottle shops. The impact of the scenarios on four measures of alcohol-related harm were considered: total acute harms, alcohol-related violence, emergency department (ED) presentations and hospitalizations.

    RESULTS: Simulation of a 3 a.m. (rather than 5 a.m.) closing time resulted in an estimated 12.3 ± 2.4% reduction in total acute alcohol-related harms, a 7.9 ± 0.8% reduction in violence, an 11.9 ± 2.1% reduction in ED presentations and a 9.5 ± 1.8% reduction in hospitalizations. Further reductions were achieved simulating a 1 a.m. closing time, including a 17.5 ± 1.1% reduction in alcohol-related violence. Simulated extensions to bottle shop trading hours resulted in increases in rates of all four measures of harm, although most of the effects came from increasing operating hours from 10 p.m. to 11 p.m.

    CONCLUSIONS: An agent-based simulation model suggests that restricting trading hours of licensed venues reduces rates of alcohol-related harm and extending trading hours of bottle shops increases rates of alcohol-related harm. The model can estimate the effects of a range of policy options.

  • 220.
    Atti, Anna Rita
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Forlani, Claudia
    de Ronchi, Diana
    Palmer, Katie
    Casadio, Paola
    Dalmonte, Edoardo
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Cognitive Impairment after Age 60: clinical and Social Correlates in the "Faenza Project"2010In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 21, no 4, p. 1325-1334Article in journal (Refereed)
    Abstract [en]

    A total of 7,389 dementia-free elderly (60–102 years old) enrolled in the "Faenza Project" (Northern Italy) were clinically evaluated by nurses and physicians with the aim of detecting the independent and combined association of medical and social factors with cognitive status. Cognitive Impairment No Dementia (CIND) was defined for MMSE scores ⩽ 2 standard deviations than the age- and education-corrected mean score obtained by the non-demented persons of the Faenza cohort. Logistic Regression analysis was used to estimate Odds Ratios and 95% Confidence Intervals (OR, 95%CI) for CIND. The diagnostic procedure identified 402 (5.4%) CIND cases. Diabetes (OR, 95%CI=1.6, 1.2–2.2), stroke (OR, 95%CI=1.9, 1.4–2.6), and depressive symptoms (OR, 95%CI=1.9, 1.4–2.7) emerged as the most relevant medical comorbidities of CIND. Low education (OR, 95%CI=1.8, 1.1–2.9), low Socio Economic Status (SES) (OR, 95%CI=1.5, 1.1–2.1), and unmarried status (OR, 95%CI=1.7, 1.2–2.5) were associated with CIND. Medical and social factors were independently related to CIND occurrence. In comparison to subjects without any of the above mentioned conditions, subjects with one medical and one social factor had an OR, 95%CI for CIND equal to 6.0, 2.9–12.4. The strength of the association increased when more of those conditions occurred in combination, suggesting a synergistic effect. Despite some methodological limitations, data from this cross-sectional population-based Italian study show that low education, low SES, unmarried status together with diabetes, stroke, and depressive symptoms are related to cognitive impairment in the general population. The interaction of medical and social factors further increases the probability of CIND.

  • 221.
    Attoff, Kristina
    Stockholm University, Faculty of Science, Department of Neurochemistry. Stockholm University.
    In vitro developmental neurotoxicity of acrylamide2016Licentiate thesis, comprehensive summary (Other academic)
    Abstract [en]

    The number of children with neurodevelopmental disorders is increasing worldwide which makes it a public concern. Exposure to environmental chemicals has been reported as a source of developmental neurotoxicity. There is also an increase in the number of chemicals reaching the global market each year and currently there are thousands of substances that have not yet been tested for developmental neurotoxicity. The current developmental neurotoxicity testing guidelines are time consuming, expensive, require a lot of animals and have relatively low sensitivity understanding for the mechanisms of toxicology. The field of developmental neurotoxicity testing is in need of a paradigm shift to the use of alternative in vitro methods capable of testing and screening large number of substances. The next generation developmental neurotoxicity testing will consist of both in silico and in vitro testing that has to be used in a combined fashion so that it will generate a more rapid and efficient toxicity testing. The methods need to be standardized between laboratories so that reproducible data can be obtained. Simple endpoints will simply not be enough for in vitro developmental neurotoxicity testing models. Rather, a battery of more refined endpoints that pinpoints the specific toxicity of a compound, discriminate between different neural subpopulations and different stages of neural differentiation is crucial for success. The use of mRNA biomarkers could be a good example of such an endpoint, and have been suggested to be valuable in detecting developmental neurotoxicity. This thesis will give a broad overview of different alternative in vitro models for developmental neurotoxicity. Developmental neurotoxicity of acrylamide was investigated by using selected cell models and endpoints. Acrylamide is a well-known neurotoxic compound and most people get exposed to the compound by food consumption and from environmental pollutants. Since acrylamide crosses the placenta barrier, the fetus is also being exposed and the risk for adverse effects in the developing nervous system is overwhelming. The neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y were used to study proliferation and differentiation as indicators for developmental neurotoxicity. The reduced neurite outgrowth in the SH-SY5Y cell model occurred at up to seven orders of magnitude lower than what have been previously shown for different neural cell systems. Acrylamide also affected the differentiation process in both neurons and glia cells in the C17.2 cell line. We show that acrylamide attenuated neural differentiation at seven orders of magnitude lower concentrations than the estimated plasma concentration of free acrylamide in the fetus. The fact that low concentrations seem to delay the differentiation process in both cell lines, raises cause for an alarm for developmental neurotoxicity induced by acrylamide.  

  • 222.
    Attoff, Kristina
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Kertika, Dimitra
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundqvist, Jessica
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Oredsson, S.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry. Stockholm Univ, Dept Neurochem, S-10691 Stockholm, Sweden.
    Acrylamide affects proliferation and differentiation of the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y2016In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 35, p. 100-111Article in journal (Refereed)
    Abstract [en]

    Acrylamide is a well-known neurotoxic compound and people get exposed to the compound by food consumption and environmental pollutants. Since acrylamide crosses the placenta barrier, the fetus is also being exposed resulting in a risk for developmental neurotoxicity. In this study, the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5Y were used to study proliferation and differentiation as alerting indicators for developmental neurotoxicity. For both cell lines, acrylamide reduced the number of viable cells by reducing proliferation and inducing cell death in undifferentiated cells. Acrylamide concentrations starting at 10 fM attenuated the differentiation process in SH-SY5Y cells by sustaining cell proliferation and neurite outgrowth was reduced at concentrations from 10 pM. Acrylamide significantly reduced the number of neurons starting at 1 mu M and altered the ratio between the different phenotypes in differentiating C17.2 cell cultures. Ten micromolar of acrylamide also reduced the expression of the neuronal and astrocyte biomarkers. Although the neurotoxic concentrations in the femtomolar range seem to be specific for the SH-SY5Y cell line, the fact that micromolar concentrations of acrylamide seem to attenuate the differentiation process in both cell lines raises the interest to further investigations on the possible developmental neurotoxicity of acrylamide.

  • 223.
    Attoff, Kristina
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry. Stockholm University.
    Kertika, Dimitra
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Lundqvist, Jessica
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Oredsson, Stina
    Lund University.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Acrylamide affects proliferation and differentiation of the neural progenitor cell line C17.2 and the neuroblastoma cell line SH-SY5YManuscript (preprint) (Other academic)
  • 224. Atzendorf, Josefine
    et al.
    Apfelbacher, Christian
    Gomes de Matos, Elena
    Kraus, Ludwig
    Stockholm University, Faculty of Social Sciences, Department of Public Health Sciences. IFT Institut für Therapieforschung, Germany; Eötvös-Loránd-Universität, Hungary.
    Piontek, Daniela
    Patterns of multiple lifestyle risk factors and their link to mental health in the German adult population: a cross-sectional study2018In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 8, no 12, article id e022184Article in journal (Refereed)
    Abstract [en]

    Objectives Lifestyle risk factors, such as drinking or unhealthy diet, can expotentiate detrimental health effects. Therefore, it is important to investigate multiple lifestyle risk factors instead of single ones. The study aims at: (1) identifying patterns of lifestyle risk factors within the adult general population in Germany and (2) examining associations between the extracted patterns and external factors.

    Design Cross-sectional study.

    Setting General German adult population (aged 18–64 years).

    Participants Participants of the 2015 Epidemiological Survey of Substance Abuse (n=9204).

    Primary outcome measures Lifestyle risk factors (daily smoking, at-risk alcohol consumption, unhealthy diet, low physical activity, weekly use of pharmaceuticals, as well as consumption of cannabis and other illicit drugs).

    Results A latent class analysis was applied to identify patterns of lifestyle risk factors, and a multinomial logistic regression was carried out to examine associations between the extracted classes and external factors. A total of four classes were extracted which can be described as healthy lifestyle (58.5%), drinking lifestyle (24.4%), smoking lifestyle (15.4%) and a cumulate risk factors lifestyle (1.7%). Individuals who were male, at younger age and single as well as individuals with various mental health problems were more likely to show multiple lifestyle risk factors.

    Conclusions Healthcare professionals should be aware of correlations between different lifestyle risk factors as well as between lifestyle risk groups and mental health. Health promotion strategies should further focus especially on younger and single men.

    This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

  • 225. Atzendorf, Josefine
    et al.
    Aschenbrenner, Annika Berit
    de Matos, Elena Gomes
    Kraus, Ludwig
    Stockholm University, Faculty of Social Sciences, Department of Public Health Sciences. FT Institut für Therapieforschung, Germany; Eötvös Loránd University, Hungary.
    Kroeger, Christoph
    Delle, Simone
    Piontek, Daniela
    E-Zigaretten: Einschätzung vonGesundheitsgefahren undNutzung zur Tabakentwöhnung2018In: Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz, ISSN 1436-9990, Vol. 61, no 11, p. 1415-1421Article in journal (Refereed)
    Abstract [de]

    BackgroundThe perception that e-cigarettes are less harmful than traditional tobacco products can influence the consumption of e-cigarettes.ObjectivesThree questions were examined: (1)How do different population groups perceive health risks of e-cigarettes? (2)Do sociodemographic variables explain differences in the risk assessment of e-cigarettes? (3)Does the perception of health risks predict the use of e-cigarettes for smoking cessation?MethodsData came from the 2015 Epidemiological Survey of Substance Abuse (ESA) with asample size of n=9204 participants, aged 18 to 64years (response rate 52.2%). Data were collected by telephone, online, or by written questionnaires. Assessments of risk perception of e-cigarettes and conventional cigarettes (more harmful, just as harmful, less harmful, do not know) were compared. Descriptive statistics and logistic regressions were performed.ResultsIndividuals with lower education rated e-cigarettes as more harmful. Older people and women perceived e-cigarettes as just as harmful. Smokers considered e-cigarettes to be more harmful than or just as harmful as conventional tobacco products. The likelihood of using e-cigarettes for smoking cessation was higher if people thought they were less harmful than conventional cigarettes.ConclusionsOnly one-third of the population knows that e-cigarettes are less harmful to health than conventional cigarettes. The perception of health risks is related to the usage of e-cigarettes for smoking cessation.

  • 226. Atzendorf, Josefine
    et al.
    Gomes de Matos, Elena
    Kröger, Christoph
    Kraus, Ludwig
    Stockholm University, Faculty of Social Sciences, Department of Public Health Sciences. IFT Institut für Therapieforschung, Germany; Eötvös-Loránd-Universität, Hungary.
    Piontek, Daniela
    Die Nutzung von E-Zigaretten in der deutschen Bevölkerung – Ergebnisse des Epidemiologischen Suchtsurvey 20152018In: Das Gesundheitswesen, ISSN 0941-3790, E-ISSN 1439-4421Article in journal (Refereed)
    Abstract [en]

    The use of E-Cigarettes in the German Population: Results of the Epidemiological Survey of Substance Abuse 2015

    Aim Estimates of e-cigarette consumption in Germany vary considerably. The use of e-cigarettes for tobacco cessation is critically discussed. Based on current data, the distribution of the consumption of e-cigarettes and their use in the adult general population of Germany will be presented.

    Methods The 2015 Epidemiological Survey of Substance Abuse, a nationwide survey of 18 to 64 year-old people in Germany (n=9,204, response rate: 52,2%), was used as data basis.

    Results E-cigarettes were known to most of the respondents (85,3%, 43,5 Mio.), whereas only 2,9% (1,5 Mio.) used e-cigarettes in the last 30 days. Higher risk of consuming e-cigarettes was seen in younger people (OR=0,95, 95%-KI=(0,93; 0,97)), men (OR=1,45, 95%-KI=(1,02; 2,07)) and smokers (OR=12,53, 95%-KI=(8,71; 18,03)). About a third of smokers and ex-smokers of conventional cigarettes (36,6%) who consumed e-cigarettes used these for tobacco cessation of which one fifth (21,3%) was able to quit smoking.

    Conclusion E-cigarette users seem to be more likely to be male, younger and smokers of conventional cigarettes. In addition to curiosity, the change in smoking behavior is an important motive for consumption. The results indicate that the use of e-cigarettes can contribute to tobacco cessation, the majority of users, however, continue to consume conventional and/or e-cigarettes.

  • 227. Aufschnaiter, Andreas
    et al.
    Habernig, Lukas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Kohler, Verena
    Diessl, Jutta
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Carmona-Gutierrez, Didac
    Eisenberg, Tobias
    Keller, Walter
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    The Coordinated Action of Calcineurin and Cathepsin D Protects Against alpha-Synuclein Toxicity2017In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 10, article id 207Article in journal (Refereed)
    Abstract [en]

    The degeneration of dopaminergic neurons during Parkinson's disease (PD) is intimately linked to malfunction of alpha-synuclein (alpha Syn), the main component of the proteinaceous intracellular inclusions characteristic for this pathology. The cytotoxicity of alpha Syn has been attributed to disturbances in several biological processes conserved from yeast to humans, including Ca2+ homeostasis, general lysosomal function and autophagy. However, the precise sequence of events that eventually results in cell death remains unclear. Here, we establish a connection between the major lysosomal protease cathepsin D (CatD) and the Ca2+/calmodulin-dependent phosphatase calcineurin. In a yeast model for PD, high levels of human alpha Syn triggered cytosolic acidification and reduced vacuolar hydrolytic capacity, finally leading to cell death. This could be counteracted by overexpression of yeast CatD (Pep4), which re-installed pH homeostasis and vacuolar proteolytic function, decreased alpha Syn oligomers and aggregates, and provided cytoprotection. Interestingly, these beneficial effects of Pep4 were independent of autophagy. Instead, they required functional calcineurin signaling, since deletion of calcineurin strongly reduced both the proteolytic activity of endogenous Pep4 and the cytoprotective capacity of overexpressed Pep4. Calcineurin contributed to proper endosomal targeting of Pep4 to the vacuole and the recycling of the Pep4 sorting receptor Pep1 from prevacuolar compartments back to the trans-Golgi network. Altogether, we demonstrate that stimulation of this novel calcineurin-Pep4 axis reduces alpha Syn cytotoxicity.

  • 228. Aufschnaiter, Andreas
    et al.
    Kohler, Verena
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    Taking out the garbage: cathepsin D and calcineurin in neurodegeneration2017In: Neural Regeneration Research, ISSN 1673-5374, E-ISSN 1876-7958, Vol. 12, no 11, p. 1776-1779Article, review/survey (Refereed)
    Abstract [en]

    Cellular homeostasis requires a tightly controlled balance between protein synthesis, folding and degradation. Especially long-lived, post-mitotic cells such as neurons depend on an efficient proteostasis system to maintain cellular health over decades. Thus, a functional decline of processes contributing to protein degradation such as autophagy and general lysosomal proteolytic capacity is connected to several age-associated neurodegenerative disorders, including Parkinson's, Alzheimer's and Huntington's diseases. These so called proteinopathies are characterized by the accumulation and misfolding of distinct proteins, subsequently driving cellular demise. We recently linked efficient lysosomal protein breakdown via the protease cathepsin D to the Ca2+/calmodulin-dependent phosphatase calcineurin. In a yeast model for Parkinson's disease, functional calcineurin was required for proper trafficking of cathepsin D to the lysosome and for recycling of its endosomal sorting receptor to allow further rounds of shuttling. Here, we discuss these findings in relation to present knowledge about the involvement of cathepsin D in proteinopathies in general and a possible connection between this protease, calcineurin signalling and endosomal sorting in particular. As dysregulation of Ca2+ homeostasis as well as lysosomal impairment is connected to a plethora of neurodegenerative disorders, this novel interplay might very well impact pathologies beyond Parkinson's disease.

  • 229. Aufschnaiter, Andreas
    et al.
    Kohler, Verena
    Walter, Corvin
    Tosal-Castano, Sergi
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Habernig, Lukas
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Wolinski, Heimo
    Keller, Walter
    Vögtle, F-Nora
    Büttner, Sabrina
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Graz, Austria.
    The Enzymatic Core of the Parkinson's Disease-Associated Protein LRRK2 Impairs Mitochondria Biogenesis in Aging Yeast2018In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 11, article id 205Article in journal (Refereed)
    Abstract [en]

    Mitochondrial dysfunction is a prominent trait of cellular decline during aging and intimately linked to neuronal degeneration during Parkinson's disease (PD). Various proteins associated with PD have been shown to differentially impact mitochondrial dynamics, quality control and function, including the leucine-rich repeat kinase 2 (LRRK2). Here, we demonstrate that high levels of the enzymatic core of human LRRK2, harboring GTPase as well as kinase activity, decreases mitochondrial mass via an impairment of mitochondria! biogenesis in aging yeast. We link mitochondrial depletion to a global downregulation of mitochondria-related gene transcripts and show that this catalytic core of LRRK2 localizes to mitochondria and selectively compromises respiratory chain complex IV formation. With progressing cellular age, this culminates in dissipation of mitochondrial transmembrane potential, decreased respiratory capacity, ATP depletion and generation of reactive oxygen species. Ultimately, the collapse of the mitochondrial network results in cell death. A point mutation in LRRK2 that increases the intrinsic GTPase activity diminishes mitochondrial impairment and consequently provides cytoprotection. In sum, we report that a downregulation of mitochondrial biogenesis rather than excessive degradation of mitochondria underlies the reduction of mitochondrial abundance induced by the enzymatic core of LRRK2 in aging yeast cells. Thus, our data provide a novel perspective for deciphering the causative mechanisms of LRRK2-associated PD pathology.

  • 230. Auguer, Nathalie
    et al.
    Le Serbon, Emelie
    Rostila, Mikael
    Stockholm University, Faculty of Social Sciences, Department of Sociology.
    Leaving Sweden behind: gains in life expectancy in Canada2015In: Scandinavian Journal of Public Health, ISSN 1403-4948, E-ISSN 1651-1905, Vol. 43, no 4, p. 340-347Article in journal (Refereed)
    Abstract [en]

    Aims: Sweden and Canada are known for quality of living and exceedingly high life expectancy, but recent data on how these countries compare are lacking. We measured life expectancy in Canada and Sweden during the past decade, and identified factors responsible for changes over time. Methods: We calculated life expectancy at birth for Canada and Sweden annually from 2000 to 2010, and determined the ages and causes of death responsible for the gap between the two countries using Arriaga's method. We determined how population growth, ageing, and mortality influenced the number of deaths over time. Results: During 2000-2010, life expectancy in Canada caught up with Sweden for men, and surpassed Sweden by 0.4 years for women. Sweden lost ground owing to a slower reduction in circulatory and tumour mortality after age 65 years compared with Canada. Nonetheless, population ageing increased the number of deaths in Canada, especially for mental and nervous system disorders. In Sweden, the number of deaths decreased. Conclusions: In only one decade, life expectancy in Canada caught up and surpassed Sweden due to rapid improvements in circulatory and tumour mortality. Population ageing increased the number of deaths in Canada, potentially stressing the health care system more than in Sweden.

  • 231. Augustsson, Hanna
    et al.
    von Thiele Schwarz, Ulrica
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Stenfors-Hayes, Terese
    Hasson, Henna
    Investigating Variations in Implementation Fidelity of an Organizational-Level Occupational Health Intervention2015In: International Journal of Behavioral Medicine, ISSN 1070-5503, E-ISSN 1532-7558, Vol. 22, no 3, p. 345-355Article in journal (Refereed)
    Abstract [en]

    The workplace has been suggested as an important arena for health promotion, but little is known about how the organizational setting influences the implementation of interventions. The aims of this study are to evaluate implementation fidelity in an organizational-level occupational health intervention and to investigate possible explanations for variations in fidelity between intervention units. The intervention consisted of an integration of health promotion, occupational health and safety, and a system for continuous improvements (Kaizen) and was conducted in a quasi-experimental design at a Swedish hospital. Implementation fidelity was evaluated with the Conceptual Framework for Implementation Fidelity and implementation factors used to investigate variations in fidelity with the Framework for Evaluating Organizational-level Interventions. A multi-method approach including interviews, Kaizen notes, and questionnaires was applied. Implementation fidelity differed between units even though the intervention was introduced and supported in the same way. Important differences in all elements proposed in the model for evaluating organizational-level interventions, i.e., context, intervention, and mental models, were found to explain the differences in fidelity. Implementation strategies may need to be adapted depending on the local context. Implementation fidelity, as well as pre-intervention implementation elements, is likely to affect the implementation success and needs to be assessed in intervention research. The high variation in fidelity across the units indicates the need for adjustments to the type of designs used to assess the effects of interventions. Thus, rather than using designs that aim to control variation, it may be necessary to use those that aim at exploring and explaining variation, such as adapted study designs.

  • 232.
    Aust, Christina
    et al.
    Stockholm University, Faculty of Social Sciences, Specialpedagogiska institutionen.
    Tallkvist, Anna
    Stockholm University, Faculty of Social Sciences, Specialpedagogiska institutionen.
    Idrott för barn och ungdomar med funktionsnedsättning2008Student thesis
  • 233.
    Awah, Nancy
    Stockholm University, Faculty of Science, The Wenner-Gren Institute .
    Studies on Plasmodium falciparum asexual blood stage antigens: RAP-2/RSP-2 and Pf332 in focus2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The life cycle of the malaria parasite is very complex and provides a number of potential targets for vaccination. In this thesis, data on two plasmodial asexual blood stage antigens (RAP-2 and Pf332) are presented.

    A partial aim of the work presented herein was to investigate the mechanisms responsible for the destruction of erythroid cells in anaemia, and more specifically to define the role of the rhoptry associated protein (RAP)-2 and other members of the RAP complex, RAP-1 and -3 in processes resulting in anaemia. Antibodies to the RAP complex were shown to have the potential to mediate the destruction of RAP-2-tagged erythroid cells by phagocytosis or by complement activation and lysis. In addition, antibodies to RAP-1 and RAP-2 could induce the apoptotic death of RAP-2- tagged erythroblasts. The frequency and functionality of naturally occurring RAP-2 antibodies in the sera of anaemic and non-anaemic Cameroonian children were also investigated. All sera tested contained RAP-2-reactive antibodies by both immunofluorescence and flow cytometry. The anaemic group of children had higher levels of IgG than the non-anaemic ones, while the levels of IgM were similar. With respect to IgG subclasses, higher levels of IgG3 were seen in the non-anaemic individuals as compared to anaemic subjects. The non-anaemic individuals recognised a greater proportion of RAP-2-tagged RBCs and activated complement to a greater extent than the anaemic ones.

    Earlier studies observed that humans continuously exposed to malaria, recognised Pf332 extensively. Further studies revealed that Pf332 antibodies were able to inhibit parasite growth and cytoadherence in vitro. Making use of Pf332-C231, a sub-fragment of Pf332, we studied the effects/mode of action of C231-specific antibodies on P. falciparum parasite growth and development in vitro. The antibodies appeared to act mainly on late stage parasites by two main mechanisms: 1) through the induction of abnormal/pyknotic parasites, and, 2) RBC lysis (disintegration of RBCs), thus limiting parasite growth and development. The antibody isotype in this context was IgG. Following the removal of immune pressure, parasites resumed growth, albeit at a much slower rate. The results suggest that during natural infections, antibodies to C231 could play a role in parasite control.

    In summary, these data suggest that antibodies to both antigens could be instrumental in immune responses leading to disease control, but could also mediate pathology.

  • 234.
    Awah, Nancy
    et al.
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Balogun, Halima
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Achidi, E.
    Mariuba, L. A.
    Nogueira, P. A.
    Orlandi, P.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Gysin, J.
    Berzins, Klavs
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Immunology.
    Antibodies to the Plasmodium falciparum rhoptry protein RAP-2/RSP-2 in relation to anaemia in Cameroonian children2011In: Parasite immunology (Print), ISSN 0141-9838, E-ISSN 1365-3024, Vol. 33, no 2, p. 104-115Article in journal (Refereed)
    Abstract [en]

    Previous studies have implicated reactive antibodies to the low molecular weight rhoptry-associated proteins (RAP-1, RAP-2/RSP-2 and RAP-3) in erythroid cell destruction during Plasmodium falciparum infection. In this pilot study, the frequency, specificity and functional capacity of naturally acquired anti-RAP-2/RSP-2 antibodies were investigated in the sera of anaemic and nonanaemic malaria-infected Cameroonian children. All sera recognized RAP-2/RSP-2 by FACS, irrespective of the clinical status of the subjects. However, the anaemic children showed higher levels of IgG antibodies than the nonanaemic group, while both groups showed similar levels of IgM antibodies. Only few individuals had detectable levels of RAP-2/RSP-2-specific IgG1 and IgG3 subclass antibodies, while no IgG2 and IgG4 subclass antibodies were detected in these subjects. By ELISA, the anaemic group tended to show higher levels of antibodies to RAP-2/RSP-2 regarding all antibody classes tested, except for IgG4 and IgE. Unexpectedly, sera from the nonanaemic group activated complement to a greater extent than those from the anaemic group. These results need to be confirmed in extended studies but indicate that the effector functions of the RAP-2/RSP-2-reactive antibodies may be more important than their amounts. Such antibodies could play a role in both immunity and pathogenesis during P. falciparum infection.

  • 235. Axelsson, J
    et al.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Gustavsson, P
    Rudman, A
    Selection into shift and night work2013Conference paper (Refereed)
  • 236.
    Axelsson, John
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Sleep, appearance and social interactions2014Conference paper (Other academic)
  • 237.
    Axelsson, John
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Sömn och fysisk aktivitet2016In: FYSS 2017: fysisk aktivitet i sjukdomsprevention och sjukdomsbehandling, Stockholm: Läkartidningen förlag AB , 2016, 3, p. 171-183Chapter in book (Other academic)
  • 238. Axelsson, John
    et al.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Akerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Donofrio, Paolo
    Lekander, Mats
    Ingre, Michael
    Sleepiness and performance in response to repeated sleep restriction and subsequent recovery during semi-laboratory conditions.2008In: Chronobiol Int, ISSN 1525-6073, Vol. 25, no 2, p. 297-308Article in journal (Refereed)
    Abstract [en]

    Sleepiness and performance in response to repeated sleep restriction and subsequent recovery during semi-laboratory conditions.

    Axelsson J, Kecklund G, Akerstedt T, Donofrio P, Lekander M, Ingre M.

    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. john.axelsson@ki.se

    There is an ongoing debate of how best to measure the effects of sleep loss in a reliable and feasible way, partly because well controlled laboratory studies and field studies have come to different conclusions. The aims of the present study were to investigate both sleepiness and performance in response to long-term sleep restriction and recovery in a semi-laboratory environment, investigate order effects (i.e., whether levels return to baseline) in a study with seven days of recovery, and characterize individual differences in tolerance to restricted sleep. Nine healthy men (age 23-28 yrs) participated in the protocol, which included one habituation day (sleep 23:00-07:00 h), two baseline days (23:00-07:00 h), five days with restricted sleep (03:00-07:00 h), and seven recovery days (23:00-07:00 h). Participants went outdoors at least twice each day. Reaction-time tests were performed at 08:00, 14:00, and 20:00 h each day in the laboratory. Sleepiness was self-rated by the Karolinska Sleepiness Scale (KSS)after each test. The mixed-effect regression models showed that each day of restricted sleep resulted in an increase of sleepiness by 0.64+/- .05 KSS units (a nine-step scale, p < .001), increase of median reaction times of 6.6+/- 1.6 ms ( p = .003), and increase of lapses/test of 0.69 +/- .16 ms ( p < .001). Seven days of recovery allowed participants to return to the baseline for sleepiness and median reaction time, but not for lapses.The individual differences were larger for performance measures than for sleepiness; the between-subject standard deviation for the random intercept was in the magnitude of the effects of 1.1 days of restricted sleep for sleepiness, 6.6 days of restricted sleep for median reaction time, and 3.2 days for lapses. In conclusion, the present study shows that sleepiness is closely related to sleep pressure, while performance measures, to a larger extent, appear determined by specific individual traits. Moreover, it is suggested to measure sleepiness in a standardized situation so as to minimize the influences of contextual factors.

  • 239.
    Axelsson, John
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Kecklund, Göran
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Tigerström, L
    Does rapid eye movement (REM) sleep prepare the brain for wakening?2014In: Journal of sleep research, Special issue: 22nd Congress of the European Sleep Research Society, 16-20 September, 2014, Tallinn, Estonia, 2014Conference paper (Other academic)
  • 240.
    Axelsson, John
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Man flu is related to health communication rather than symptoms and suffering2018In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 360, article id k450Article in journal (Other academic)
  • 241.
    Axelsson, John
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Karshikoff, B.
    Hedman, E.
    Is health anxiety related to disease avoidance?2015In: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 49, article id e47Article in journal (Refereed)
  • 242.
    Axelsson, John
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Rehman, Javaid-ur
    Åkerstedt, Torbjörn
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Ekman, Rolf
    Miller, Gregory E.
    Höglund, Caroline Olgart
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska institutet, Sweden.
    Effects of Sustained Sleep Restriction on Mitogen-Stimulated Cytokines, Chemokines and T Helper 1/ T Helper 2 Balance in Humans2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, article id e82291Article in journal (Refereed)
    Abstract [en]

    Background: Recent studies suggest that acute sleep deprivation disrupts cellular immune responses by shifting T helper (Th) cell activity towards a Th2 cytokine profile. Since little is known about more long-term effects, we investigated how five days of sleep restriction would affect pro-inflammatory, chemotactic, Th1- and Th2 cytokine secretion. Methods: Nine healthy males participated in an experimental sleep protocol with two baseline sleep-wake cycles (sleep 23.00 - 07.00 h) followed by 5 days with restricted sleep (03.00 - 07.00 h). On the second baseline day and on the fifth day with restricted sleep, samples were drawn every third hour for determination of cytokines/chemokines (tumor necrosis factor alpha (TNF-alpha), interleukin (IL) -1 beta, IL-2, IL-4 and monocyte chemoattractant protein-1 (MCP-1)) after in vitro stimulation of whole blood samples with the mitogen phytohemagglutinin (PHA). Also leukocyte numbers, mononuclear cells and cortisol were analysed. Results: 5-days of sleep restriction affected PHA-induced immune responses in several ways. There was a general decrease of IL-2 production (p<.05). A shift in Th1/Th2 cytokine balance was also evident, as determined by a decrease in IL2/IL4 ratio. No other main effects of restricted sleep were shown. Two significant interactions showed that restricted sleep resulted in increased TNF-alpha and MCP-1 in the late evening and early night hours (p's<.05). In addition, all variables varied across the 24 h day. Conclusions: 5-days of sleep restriction is characterized by a shift towards Th2 activity (i.e. lower 1L-2/IL-4 ratio) which is similar to the effects of acute sleep deprivation and psychological stress. This may have implications for people suffering from conditions characterized by excessive Th2 activity like in allergic disease, such as asthma, for whom restricted sleep could have negative consequences.

  • 243. Axelsson, John
    et al.
    Sundelin, Tina
    Karolinska Institutet, Sweden.
    Ingre, Michael
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Van Someren, Eus J. W.
    Olsson, Andreas
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Beauty sleep: experimental study on the perceived health and attractiveness of sleep deprived people2010In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 341, article id c6614Article in journal (Refereed)
    Abstract [en]

    Our findings show that sleep deprived people appear less healthy, less attractive, and more tired compared with when they are well rested. This suggests that humans are sensitive to sleep related facial cues, with potential implications for social and clinical judgments and behaviour. Studies are warranted for understanding how these effects may affect clinical decision making and can add knowledge with direct implications in a medical context.

  • 244.
    Axelsson, John
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Sundelin, Tina
    Olsson, Mats J.
    Sorjonen, Kimmo
    Axelsson, Charlotte
    Lasselin, Julie
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; Universitätsklinikum Essen, Germany.
    Lekander, Mats
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden.
    Identification of acutely sick people and facial cues of sickness2018In: Proceedings of the Royal Society of London. Biological Sciences, ISSN 0962-8452, E-ISSN 1471-2954, Vol. 285, no 1870, article id 20172430Article in journal (Refereed)
    Abstract [en]

    Detection and avoidance of sick individuals have been proposed as essential components in a behavioural defence against disease, limiting the risk of contamination. However, almost no knowledge exists on whether humans can detect sick individuals, and if so by what cues. Here, we demonstrate that untrained people can identify sick individuals above chance level by looking at facial photos taken 2 h after injection with a bacterial stimulus inducing an immune response (2.0 ng kg-1 lipopolysaccharide) or placebo, the global sensitivity index being d' = 0.405. Signal detection analysis (receiver operating characteristic curve area) showed an area of 0.62 (95% confidence intervals 0.60-0.63). Acutely sick people were rated by naive observers as having paler lips and skin, a more swollen face, droopier corners of the mouth, more hanging eyelids, redder eyes, and less glossy and patchy skin, as well as appearing more tired. Our findings suggest that facial cues associated with the skin, mouth and eyes can aid in the detection of acutely sick and potentially contagious people.

  • 245.
    Axelsson, John
    et al.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institute, Sweden.
    Vyazovskiy, Vladyslav V.
    Banking Sleep and Biological Sleep Need2015In: Sleep, ISSN 0161-8105, E-ISSN 1550-9109, Vol. 38, no 12, p. 1843-1845Article in journal (Refereed)
  • 246.
    Axelsson, Martin
    Stockholm University, Faculty of Social Sciences, Department of Psychology.
    HR-medarbetares upplevelser kring spelprevention och policyimplementering på arbetsplatsen2017Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    The complex concept regarding harmful use of different nature, could be related to the use of alcohol, drugs or gambling. Such activities could affect the efficiency and productivity of an employee in a workplace environment in a negative way. At the request of the Public Health Agency of Sweden, a group of scientist was given the task to evaluate a project regarding education concerning problematic gambling. The purpose of the current study is to evaluate a project regarding education concerning gambling and gambling prevention, and was carried out by the organization Alna. Thematic analysis was used and collection of data was done with semi structured interviews, with ten HR-employees whose five organisations was included in the project Gambling and gambling preventive efforts directed towards the labour market. The results show that the methods and tools used by Alna is perceived as efficient and valuable by the participants. Some obstacles which works against efficient implementation of updated policies and guidelines were identified and these could consist of time constraints, under staffing or subordinated priority of the gambling issue per se. Furthermore it seems that the education project regarding gambling prevention performed by Alna has contributed to the development of policies and guidelines regarding harmful use of different kinds with focus on the gambling issue.  

  • 247.
    Axelsson, Sara
    et al.
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    Eriksson, Kåre
    Department of Occupational and Environmental Medicine, University Hospital of Northern Sweden, Umeå, Sweden.
    Hagström, Katja
    Department of Environmental Science, Örebro University, Örebro.
    Bryngelsson, Ing-Liss
    Nilsson, Ulrika
    Stockholm University, Faculty of Science, Department of Analytical Chemistry.
    HPLC/neg-ESI-MS determination of resin acids in urine from Swedish wood pellets production plants workers and correlation with air concentrations2012In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650Article in journal (Refereed)
  • 248.
    Axelsson, Viktoria
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Evaluation of neurotoxic properties of gliotoxin2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The occurrence of mould in food and animal feed is a severe problem due to the secondary metabolites, called mycotoxins, which can possess toxic activity. Aspergillus fumigatus is a common fungus found in improperly stored animal feed and the abundance of spores of the fungus is frequently spread into the air. Gliotoxin has been identified as one of the most toxic second metabolites produced by A. fumigatus. Although A. fumigatus is known to produce mycotoxins that induce neurological syndromes, the neurotoxic properties of gliotoxin have not previously been studied. In this thesis a neurotoxic activity of gliotoxin was demonstrated by using differentiated human neuroblastoma SH-SY5Y cells as a surrogate for the nervous system. The major findings were as follows:

    i. Gliotoxin is highly toxic to SH-SY5Y cells and there is a correlation between the toxicity and the cellular redox status.

    ii. Gliotoxin reduces the number of neurites, but does not affect the cell bodies morphologically, at non-cytotoxic concentrations. This indicates that the toxin may induce peripheral axonopathy in vivo.

    iii. The intracellular free Ca2+ concentration is increased after exposure to gliotoxin, an effect that is the most ubiquitous feature of neuronal cell death. Simultaneously, calpains and caspases, proteases known to be involved in neuronal death and axonal degeneration, are activated.

    iv. The observed irreversible neurite degenerative effects of gliotoxin are mainly dependent on caspase activation, whereas calpains are involved in the gliotoxin-induced cytotoxicity.

    v. Gliotoxin induces a decreased rate of protein synthesis at non-cytotoxic concentration, which may contribute to the degeneration of neurites.

    vi. We did also succeed in developing an in vitro method for determination of toxic activity in animal feed. This study was done in collaboration with National Veterinary Institute (SVA) in Uppsala, and the method is today established and in use at Department of Animal Feed, SVA.

  • 249.
    Axelsson, Viktoria
    et al.
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Holback, Sofia
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Sjögren, Maria
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Gustafsson, Helena
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Forsby, Anna
    Stockholm University, Faculty of Science, Department of Neurochemistry.
    Gliotoxin induces caspase-dependent neurite degeneration and calpain-mediated general cytotoxicity in differentiated human neuroblastoma SH-SY5Y cells.2006In: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 345, no 3, p. 1068-74Article in journal (Refereed)
    Abstract [en]

    In this study, a significant increase by 50% in intracellular free calcium concentration ([Ca(2+)](i)) was observed in differentiated human neuroblastoma (SH-SY5Y) cells after exposure to 0.25microM of the fungal metabolite gliotoxin for 72h. Further, the involvement of caspases and calpains was demonstrated to underlie the gliotoxin-induced cytotoxic and neurite degenerative effects. The caspase inhibitor Z-VAD-fmk almost completely reduced the neurite degeneration from 40% degeneration of neurites to 5% as compared to control. Inhibition of calpains with calpeptin significantly attenuated gliotoxin-induced cytotoxicity, determined as reduction in total cellular protein content, from 43% to 14% as compared to control cells. Western blot analyses of alphaII-spectrin breakdown fragments confirmed activity of the proteases, and that alphaII-spectrin was cleaved by caspases in gliotoxin-exposed cells. These results show that calpains and caspases have a role in the toxicity of gliotoxin in differentiated SH-SY5Y cells and that the process may be Ca(2+)-mediated.

  • 250.
    Aydin, Juhanes
    et al.
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Senthil, Kumar K
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Sayah, Mahmoud J
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Wallner, Olov A
    Stockholm University, Faculty of Science, Department of Organic Chemistry.
    Szabó, Kálmán J
    Synthesis and catalytic application of chiral 1,1'-Bi-2-naphthol- and biphenanthrol-based pincer complexes: selective allylation of sulfonimines with allyl stannane and allyl trifluoroborate.2007In: Journal of Organic Chemistry, Vol. 72, no 13, p. 4689-4697Article in journal (Refereed)
    Abstract [en]

    New easily accessible 1,1'-bi-2-naphthol- (BINOL-) and biphenanthrol-based chiral pincer complex catalysts were prepared for selective (up to 85% enantiomeric excess) allylation of sulfonimines. The chiral pincer complexes were prepared by a flexible modular approach allowing an efficient tuning of the selectivity of the catalysts. By employment of the different enantiomeric forms of the catalysts, both enantiomers of the homoallylic amines could be selectively obtained. Both allyl stannanes and allyl trifluoroborates can be employed as allyl sources in the reactions. The biphenanthrol-based complexes gave higher selectivity than the substituted BINOL-based analogues, probably because of the well-shaped chiral pocket generated by employment of the biphenanthrol complexes. The enantioselective allylation of sulfonimines presented in this study has important implications for the mechanism given for the pincer complex-catalyzed allylation reactions, confirming that this process takes place without involvement of palladium(0) species.

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