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1.
  • Bonagas, Nadilly, et al. (författare)
  • Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
  • 2022
  • Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
  • Tidskriftsartikel (refereegranskat)abstract
    • The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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2.
  • Scheffler, Julia M., et al. (författare)
  • ER alpha Signaling in a Subset of CXCL12-Abundant Reticular Cells Regulates Trabecular Bone in Mice
  • 2022
  • Ingår i: JBMR Plus. - : Wiley. - 2473-4039. ; 6:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen has pronounced effects on the immune system, which also influences bone homeostasis. In recent years, stromal cells in lymphoid organs have gained increasing attention as they not only support the regulation of immune responses but also affect bone remodeling. A conditional knockout mouse model where estrogen receptor alpha (ER alpha) is deleted in CCL19-expressing stromal cells (Ccl19-Cre ER alpha(fl/fl) mice) was generated and bone densitometry was performed to analyze the importance of stromal cell-specific ER alpha signaling on the skeleton. Results showed that female Ccl19-Cre ER alpha(fl/fl) mice display reduced total bone mineral density and detailed X-ray analyses revealed that ER alpha expression in CCL19-expressing stromal cells is important for trabecular but not cortical bone homeostasis. Further analysis showed that the trabecular bone loss is caused by increased osteoclastogenesis. Additionally, the bone formation rate was reduced; however, the expression of osteoprogenitor genes was not altered. Analysis of the bone marrow stromal cell compartment revealed a deletion of ER alpha in a subgroup of CXCL12-abundant reticular (CAR) cells resulting in increased secretion of the pro-osteoclastogenic chemokine CXCL12. In conclusion, this study reveals the importance of ER alpha signaling in CAR cells for bone health. (c) 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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6.
  • Birberg Thornberg, Ulrika, et al. (författare)
  • A Placebo controlled, randomized study of PUFA (Poly Unsaturated Fatty Acids) as treatment for neurodevelopmental problems in 7-year-old children and cognitive performance in relation to an age-matched control group
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • OBJECTIVE: The goal of the present randomized placebo controlled double-blind study was to investigate the potential effect of PUFA supplementation on cognitive and behavioural performance in children with neurodevelopmental problems at 7 years of age (n = 28) and to compare findings with an age matched healthy control group (n = 20). METHODS: Children were screened with parent and teacher rating scales (Conner’s and SNAP-IV), and were included if they showed a range of neurodevelopmental problems that reached ADHD criteria. The group with neurodevelopmental difficulties was randomized to treatment with an EPA rich formula (n = 13) or to placebo (n = 15). Cognitive performance was determined at baseline and after 15 weeks of supplementation with a cognitive test battery including executive function and theory of mind tasks. RESULTS: Children with neurodevelopmental problems differed from the control group regarding working memory, inhibition and language ability, but not on an advanced theory of mind task. Regarding the treatment with EPA supplement there were no significant advantages in the active treatment group compared to placebo in any of the cognitive measures or in parents or teacher rating scales. CONCLUSION: The significant differences in cognitive performance and rating scales between the group with neurodevelopmental problems and the healthy control group at baseline indicate problems at a clinical level and suitability for treatment. However we found no significant effects of PUFA supplementation. The study is small and limited by a number of drop-outs.
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7.
  • Birberg Thornberg, Ulrika, 1971-, et al. (författare)
  • Nutrition and cognitive development
  • 2002
  • Ingår i: Områdesgruppen för utvecklingspsykologi och neuropsykologi,2002.
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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8.
  • Birberg Thornberg, Ulrika, et al. (författare)
  • Nutrition and theory of mind : The role of polyunsaturated fatty acids (PUFA) in the development of theory of mind
  • 2006
  • Ingår i: Prostaglandins, Leukotrienes and Essential Fatty Acids. - : Elsevier BV. - 0952-3278 .- 1532-2823. ; 75:1, s. 33-41
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast-milk provides nutrients required for the development of the brain. n-6 and n-3 long-chain polyunsaturated fatty acids (LCPUFAs) have been suggested to be particularly involved. In this study levels of fatty acids in breast-milk were examined in relation to theory of mind (ToM) (n=13) and WISC-III (n=22) in six-year-old children. ToM tasks comprised four illustrated stories with questions about emotional (sad) events. Single polyunsaturated fatty acids (PUFA) were estimated as well as ratios between different fatty acids in order to describe putative associations between PUFA and psychological measures. Results show correlations between both ToM and WISC-III with single n-6 PUFA and the ratios DHA/AA and DHA/DPA. The correlations remained when socio-demographic factors were statistically controlled for. The positive findings related to the n-6 and n-3 LCPUFAs corroborate previous findings related to child cognitive development. © 2006 Elsevier Ltd. All rights reserved.
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9.
  • Bjursell, Magnus K., et al. (författare)
  • Adenosine Kinase Deficiency Disrupts the Methionine Cycle and Causes Hypermethioninemia, Encephalopathy, and Abnormal Liver Function
  • 2011
  • Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297 .- 1537-6605. ; 89:4, s. 507-515
  • Tidskriftsartikel (refereegranskat)abstract
    • Four inborn errors of metabolism (IEMs) are known to cause hypermethioninemia by directly interfering with the methionine cycle. Hypermethioninemia is occasionally discovered incidentally, but it is often disregarded as an unspecific finding, particularly if liver disease is involved. In many individuals the hypermethioninemia resolves without further deterioration, but it can also represent an early sign of a severe, progressive neurodevelopmental disorder. Further investigation of unclear hypermethioninemia is therefore important. We studied two siblings affected by severe developmental delay and liver dysfunction. Biochemical analysis revealed increased plasma levels of methionine, S-adenosylmethionine (Ado Met), and S-adenosylhomocysteine (AdoHcy) but normal or mildly elevated homocysteine (Hcy) levels, indicating a block in the methionine cycle. We excluded S-adenosylhomocysteine hydrolase (SAHH) deficiency, which causes a similar biochemical phenotype, by using genetic and biochemical techniques and hypothesized that there was a functional block in the SAHH enzyme as a result of a recessive mutation in a different gene. Using exome sequencing, we identified a homozygous c.902C>A (p.Ala301Glu) missense mutation in the adenosine kinase gene (ADK), the function of which fits perfectly with this hypothesis. Increased urinary adenosine excretion confirmed ADK deficiency in the siblings. Four additional individuals from two unrelated families with a similar presentation were identified and shown to have a homozygous c.653A>C (p.Asp218Ala) and c.38G>A (p.Gly13Glu) mutation, respectively, in the same gene. All three missense mutations were deleterious, as shown by activity measurements on recombinant enzymes. ADK deficiency is a previously undescribed, severe IEM shedding light on a functional link between the methionine cycle and adenosine metabolism.
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11.
  • Bosson, Emma, et al. (författare)
  • Influences of shifts in climate, landscape, and permafrost on terrestrial hydrology
  • 2012
  • Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 117
  • Tidskriftsartikel (refereegranskat)abstract
    • This study has simulated the terrestrial hydrology associated with different climate, landscape, and permafrost regime scenarios for the field case example of the relatively well characterized coastal catchment of Forsmark, Sweden. The regime scenarios were selected from long-term simulation results of climate, topographical, shoreline, and associated Quaternary deposit and vegetation development in this catchment with a time perspective of 100,000 years or more and were used as drivers for hydrological simulations with the three-dimensional model MIKE SHE. The hydrological simulations quantify the responses of different water flow and water storage components of terrestrial hydrology to shifts from the present cool temperate climate landscape regime in Forsmark to a possible future Arctic periglacial landscape regime with or without permafrost. The results show complexity and nonlinearity in the runoff responses to precipitation changes due to parallel changes in evapotranspiration, along with changes in surface and subsurface water storage dynamics and flow pathways through the landscape. The results further illuminate different possible perspectives of what constitutes wetter/drier landscape conditions, in contrast to the clearer concept of what constitutes a warmer/colder climate.
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  • Bräutigam, Lars, et al. (författare)
  • Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition
  • 2016
  • Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 76:8, s. 2366-2375
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer cells are commonly in a state of redox imbalance that drives their growth and survival. To compensate for oxidative stress induced by the tumor redox environment, cancer cells upregulate specific nononcogenic addiction enzymes, such as MTH1 (NUDT1), which detoxifies oxidized nucleotides. Here, we show that increasing oxidative stress in nonmalignant cells induced their sensitization to the effects of MTH1 inhibition, whereas decreasing oxidative pressure in cancer cells protected against inhibition. Furthermore, we purified zebrafish MTH1 and solved the crystal structure of MTH1 bound to its inhibitor, highlighting the zebrafish as a relevant tool to study MTH1 biology. Delivery of 8-oxo-dGTP and 2-OH-dATP to zebrafish embryos was highly toxic in the absence of MTH1 activity. Moreover, chemically or genetically mimicking activated hypoxia signaling in zebrafish revealed that pathologic upregulation of the HIF1 alpha response, often observed in cancer and linked to poor prognosis, sensitized embryos to MTH1 inhibition. Using a transgenic zebrafish line, in which the cellular redox status can be monitored in vivo, we detected an increase in oxidative pressure upon activation of hypoxic signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine protected embryos with activated hypoxia signaling against MTH1 inhibition, suggesting that the aberrant redox environment likely causes sensitization. In summary, MTH1 inhibition may offer a general approach to treat cancers characterized by deregulated hypoxia signaling or redox imbalance.
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14.
  • Calmfors, Lars, et al. (författare)
  • Trade in services and in goods with low-wage countries : how do attitudes differ and how are they formed?
  • 2009
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • Frågan om låglönekonkurrens med utstationerad arbetskraft ska tillåtas inom EU eller om denna arbetskraft ska betalas samma löner som i värdlandet har de senaste åren varit flitigt omdebatterad i många EU-länder. I Sverige symboliseras denna debatt av Vaxholmskonflikten. I rapporten Trade in Services and in Goods with Low-Wage Countries - How Do Attitudes Differ and How Are They Formed? analyserar ekonomer och psykologer attityderna till olika typer av låglönekonkurrens. Resultaten bekräftar att attityderna är mer negativa till låglönekonkurrens i tjänstehandel som innefattar utstationerad arbetskraft än till "vanlig" import av varor från låglöneländer. Attitydbildningen verkar ha såväl "rationella" som "irrationella" komponenter. Detta gäller både de som förespråkar fri lönekonkurrens och de som är emot, även om analysen visar att det rationella inslaget tycks vara större för den förra gruppen.
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15.
  • Calmfors, Lars, et al. (författare)
  • Uppfattas tjänstehandel som mindre rättvis än varuhandel? : En studie av attityder till låglönekonkurrens i utrikeshandel
  • 2011
  • Rapport (refereegranskat)abstract
    • Ett antal arbetsmarknadskonflikter relaterade till låglönekonkurrens med utstationerad arbetskraft har blivit livligt uppmärksammade i den offentliga debatten runt om i EU:s medlemsländer. Av debatten att döma tycks de flesta medborgare ha en mer negativ inställning till låglönekonkurrens när det gäller import av tjänster innefattande utstationerad arbetskraft än när det gäller import av varor. Vår rapport studerar hur attityderna till låglönekonkurrens skiljer sig åt mellan olika former av handel genom att kombinera ekonomisk och psykologisk forskning. Resultaten bekräftar att attityderna är mer negativa till låglönekonkurrens i tjänstehandel och till offshoring än till varuimport från låglöneländerna. Demografiska, socioekonomiska och politisk-ideologiska bakgrundsfaktorer påverkar attityderna till handel i linje med resultaten från tidigare studier av handelsattityder. Däremot förefaller bakgrundsvariabler ha liten betydelse för skillnader i attityder mellan olika typer av handel. Vi genomförde även experiment för att klargöra i vilken grad attityden till tjänstehandel bildas utifrån rationella överväganden runt olika aspekter, det vill säga från underliggande attityddimensioner, eller om dessa attityddimensioner på grund av koherenssökande i stället anpassas till den generella attityden. Resultaten ger starkt stöd för att koherenssökande spelar stor roll i attitydbildningen till låglönekonkurrens med utstationerad arbetskraft. Tendensen till koherenssökande tycks vara kraftigare för dem som har en negativ inställning till sådan låglönekonkurrens än för dem som är positiva. Det skulle kunna tolkas som att den negativa gruppen bildar sina attityder på ett mindre rationellt sätt än den positiva gruppen. En alternativ tolkning är att den positiva gruppen ser sig som utmanare av den existerande ordningen, vilket enligt psykologisk forskning kan göra den mindre benägen att nyansera sin inställning.
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16.
  • Calmfors, Lars, et al. (författare)
  • Why Do People Dislike Low-Wage Trade Competition with Posted Workers in the Service Sector?
  • 2012
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • The issue of low-wage competition in services trade involving posted workers is controversial in the EU. Using Swedish survey data, people’s attitudes are found to be more negative to such trade than to goods trade. The differences depend on both a preference for favouring social groups to which individuals belong (here the domestic population) and altruistic justice concerns for foreign workers. In small-group experiments we find a tendency for people to adjust their evaluations of various aspects of trade to their general attitude. This tendency is stronger for those opposed to than those in favour of low-wage trade competition. This may indicate that the former group forms its attitudes in a less rational way than the latter group.
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17.
  • Carter, Megan, et al. (författare)
  • Crystal structure, biochemical and cellular activities demonstrate separate functions of MTH1 and MTH2
  • 2015
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
  • Tidskriftsartikel (refereegranskat)abstract
    • Deregulated redox metabolism in cancer leads to oxidative damage to cellular components including deoxyribonucleoside triphosphates (dNTPs). Targeting dNTP pool sanitizing enzymes, such as MTH1, is a highly promising anticancer strategy. The MTH2 protein, known as NUDT15, is described as the second human homologue of bacterial MutT with 8-oxo-dGTPase activity. We present the first NUDT15 crystal structure and demonstrate that NUDT15 prefers other nucleotide substrates over 8-oxo-dGTP. Key structural features are identified that explain different substrate preferences for NUDT15 and MTH1. We find that depletion of NUDT15 has no effect on incorporation of 8-oxo-dGTP into DNA and does not impact cancer cell survival in cell lines tested. NUDT17 and NUDT18 were also profiled and found to have far less activity than MTH1 against oxidized nucleotides. We show that NUDT15 is not a biologically relevant 8-oxo-dGTPase, and that MTH1 is the most prominent sanitizer of the cellular dNTP pool known to date.
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18.
  • Clemedson, Cecilia, et al. (författare)
  • Development of an in vitro test battery for the estimation of acute human systemic toxicity : An outline of the EDIT project. Evaluation-guided Development of New In Vitro Test Batteries
  • 2002
  • Ingår i: ATLA (Alternatives to Laboratory Animals). - 0261-1929. ; 30:3, s. 313-321
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of the Evaluation-guided Development of new In Vitro Test Batteries (EDIT) multicentre programme is to establish and validate in vitro tests relevant to toxicokinetics and for organ-specific toxicity, to be incorporated into optimal test batteries for the estimation of human acute systemic toxicity. The scientific basis of EDIT is the good prediction of human acute toxicity obtained with three human cell line tests (R(2) = 0.77), in the Multicentre Evaluation of In Vitro Cytotoxicity (MEIC) programme. However, the results from the MEIC study indicated that at least two other types of in vitro test ought to be added to the existing test battery to improve the prediction of human acute systemic toxicity - to determine key kinetic events (such as biotransformation and passage through biological barriers), and to predict crucial organ-specific mechanisms not covered by the tests in the MEIC battery. The EDIT programme will be a case-by-case project, but the establishment and validation of new tests will be carried through by a common, step-wise procedure. The Scientific Committee of the EDIT programme defines the need for a specific set of toxicity or toxicokinetic data. Laboratories are then invited to perform the defined tests in order to provide the "missing" data for the EDIT reference chemicals. The results obtained will be evaluated against the MEMO (the MEIC Monograph programme) database, i.e. against human acute systemic lethal and toxicity data. The aim of the round-table discussions at the 19th Scandinavian Society for Cell Toxicology (SSCT) workshop, held in Ringsted, Denmark on 6-9 September 2001, was to identify which tests are the most important for inclusion in the MEIC battery, i.e. which types of tests the EDIT programme should focus on. It was proposed that it is important to include in vitro methods for various kinetic events, such as biotransformation, absorption in the gut, passage across the blood-brain barrier, distribution volumes, protein binding, and renal clearance/accumulation. Models for target organ toxicity were also discussed. Because several of the outlier chemicals (paracetamol, digoxin, malathion, nicotine, paraquat, atropine and potassium cyanide) in the MEIC in vivo-in vitro evaluation have a neurotoxic potential, it was proposed that the development within the EDIT target organ programme should initially be focused on the nervous system.
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19.
  • Corciulo, Carmen, et al. (författare)
  • Pulsed administration for physiological estrogen replacement in mice
  • 2021
  • Ingår i: F1000Research. - : F1000 Research Ltd. - 2046-1402 .- 1759-796X. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogens are important regulators of body physiology and have major effects on metabolism, bone, the immune- and central nervous systems. The specific mechanisms underlying the effects of estrogens on various cells, tissues and organs are unclear and mouse models constitute a powerful experimental tool to define the physiological and pathological properties of estrogens. Menopause can be mimicked in animal models by surgical removal of the ovaries and replacement therapy with 17β-estradiol in ovariectomized (OVX) mice is a common technique used to determine specific effects of the hormone. However, these studies are complicated by the non-monotonic dose-response of estradiol, when given as therapy. Increased knowledge of how to distribute estradiol in terms of solvent, dose, and administration frequency, is required in order to accurately mimic physiological conditions in studies where estradiol treatment is performed. In this study, mice were OVX and treated with physiological doses of 17β-estradiol-3-benzoate (E2) dissolved in miglyol or PBS. Subcutaneous injections were performed every 4 days to resemble the estrus cycle in mice. Results show that OVX induces an osteoporotic phenotype, fat accumulation and impairment of the locomotor ability, as expected. Pulsed administration of physiological doses of E2 dissolved in miglyol rescues the phenotypes induced by OVX. However, when E2 is dissolved in PBS the effects are less pronounced, possibly due to rapid wash out of the steroid.
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20.
  • Cortés-González, Jeff R, et al. (författare)
  • Early salvage radiation therapy combined with short-term hormonal therapy in recurrent prostate cancer after radical prostatectomy: Single-institution 4-year data on outcome, toxicity, health-related quality of life and co-morbidities from 184 consecutive patients treated with 70 Gy.
  • 2013
  • Ingår i: International journal of oncology. - : Spandidos Publications. - 1791-2423 .- 1019-6439. ; 42:1, s. 109-17
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to investigate the role of 70Gy salvage radiotherapy (SRT) combined with short-term neoadjuvant hormonal therapy (NHT) in the treatment of recurrent disease after radical prostatectomy (RP), and to consider quality of life (QoL), survival outcomes and impact of co-morbidities on treatment-related rectal-genitourinary toxicity. Electronic records of 184 SRT patients treated consecutively between October 2001 and February 2007 were analyzed. Median age was 64 years (median follow-up 48months). NHT was given to 165 patients (median 3 months). Pre-RP and pre-SRT PSA, PSA doubling time, Gleason score (GS), seminal vesicle invasion (SVI) and detectable post-SRT PSA were recorded. Any detectable PSA or PSA >0.1 ng/ml + nadir was considered biochemical failure (BcF). The Charlson co-morbidity index was used to correlate co-morbidities and rectal-genitourinary toxicity. Scores from the health-related QoL EORTC QLQ-C30 and PR-25 questionnaires were also evaluated. In 116 (63%) patients, a long-lasting curative effect was indicated by undetectable PSA levels. In univariate analysis, using BcF as an outcome variable, p<0.001 was found for GS, pre-SRT PSA, SVI and detectable post-SRT PSA. Multivariate analysis showed p=0.01 for SVI, p=0.09 for GS, and detectable post-SRT PSA (p=0.01); with metastases as an outcome variable, only SVI was significant (p=0.007). Cancer-specific and overall survival were 99 and 95%, respectively. Although microscopy showed SVI or GS 8-10 in the prostatectomy specimens 17/40(43%) and 13/29 (45%), respectively, of patients still showed undetectable PSA at long-term follow-up (median 55 months) after SRT. Likewise, 11/31 (36%) patients with pre-SRT PSA >1.0 ng/ml and 80/134 (60%) patients with PSA doubling time (PSADT) <10 still showed undetectable PSA after 50 months. Slightly elevated acute and late rectal-genitourinary grade 3-4 toxicity was observed. No association with co-morbidity/toxicity was found. EORTC QLQ-C30 scores were similar to or slightly better than reference values. SRT with 70 Gy combined with 3-month NHT results in long-term undetectable PSA in >50% of patients with recurrence after RP with acceptable rectal-genitourinary toxicity and without negatively affecting long-term QoL. Non-metastatic patients should not be disqualified from receiving SRT although presenting with poor prognostic factors at surgery.
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21.
  • Dahlgren, Ulrika Skogsberg, et al. (författare)
  • Excellent outcome following emergency deceased donor ABO-incompatible liver transplantation using rituximab and antigen specific immunoadsorption
  • 2022
  • Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 57:1, s. 50-59
  • Tidskriftsartikel (refereegranskat)abstract
    • Background The acceptance of ABO-incompatible (ABOi) liver grafts will expand the donor pool for a patient in urgent need for a liver transplantation (LT). Here we report our results with emergency ABOi DD (deceased donor) LT using rituximab and antigen specific immunoadsorption. Patients and Methods 2009 to 2019 we performed 20 ABOi DD LTs (adults n = 17, children n = 3) for patients in urgent need for a LT. Immunosuppression consisted of rituximab (n = 20) and basiliximab (n = 15) or anti-thymocyte globuline (n = 4), intravenous immunoglobulin (IVIG; n = 6), tacrolimus, prednisolone and mycophenolate mofetil. Fifteen patients were treated with IA (n = 14) or both IA and plasmapheresis (PP; n = 1) pre-transplant and 18 patients were treated with IA (n = 15) or both IA and PP (n = 3) post-transplant. The median pre-transplant MELD- score was 40 (range 18-40). Patient and graft survival and complications were compared to a 1:4 case matched control group of ABO-identical or compatible (ABOid/c) DDLT. Results The 1-, 3- and 5-year patient and graft survival rates were 85, 85 and 78% for the ABOi recipients and not significantly different compared to ABOid/c controls. Only one ABOi patient developed antibody-mediated rejection. Conclusion Patient and graft survival after emergency ABOi DDLT using rituximab and immunoadorption was equal to ABOid/DDLT. ABOi DD LT was a successful approach to expand the donor pool for patients in urgent need for a liver graft.
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22.
  • Englund, Hillevi, et al. (författare)
  • Increase in beta-amyloid levels in cerebrospinal fluid of children with down syndrome
  • 2007
  • Ingår i: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 24:5, s. 369-374
  • Tidskriftsartikel (refereegranskat)abstract
    • <i>Background:</i> Individuals with Down syndrome (DS) invariably develop Alzheimer’s disease (AD) during their life span. It is therefore of importance to study young DS patients when trying to elucidate early events in AD pathogenesis. <i>Aim:</i> To investigate how levels of different amyloid-β (Aβ) peptides, as well as tau and phosphorylated tau, in cerebrospinal fluid (CSF) from children with DS change over time. The first CSF sample was taken at 8 months and the following two samples at 20–40 and 54 months of age. <i>Results:</i> Individual levels of the Aβ peptides, as well as total Aβ levels in CSF increased over time when measured with Western blot. Tau in CSF decreased whereas there was no change in levels of phosphorylated tau over time. <i>Conclusion:</i> The increasing levels of Aβ in CSF during early childhood of DS patients observed in this study are probably due to the trisomy of the Aβ precursor APP, which leads to an overproduction of Aβ. Despite the increased CSF concentrations of Aβ, there were no signs of an AD-indicating tau pattern in CSF, since the levels of total tau decreased and phosphorylated tau remained unchanged. This observation further strengthens the theory of Aβ pathology preceding tau pathology in AD.
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23.
  • Eriksson, Ulf G, et al. (författare)
  • Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran : a population model analysis
  • 2003
  • Ingår i: Clinical Pharmacokinetics. - 0312-5963 .- 1179-1926. ; 42:7, s. 687-701
  • Forskningsöversikt (refereegranskat)abstract
    • OBJECTIVE: Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated creatinine clearance was examined. DESIGN AND METHODS: Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8-11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model. RESULTS: The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT. CONCLUSIONS: The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.
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24.
  • Falkheimer, Jesper, et al. (författare)
  • Greater Copenhagen och mindre Öresund?
  • 2017
  • Ingår i: Slutna rum och öppna landskap. - 9789189673380 ; 69
  • Bokkapitel (refereegranskat)abstract
    • Öresundsregionen har under decennier utvecklats till ett viktigt samarbetsprojektkring arbetsmarknad, bostadsmarknad, näringsliv, konsumtion, turism och kulturlängs den svensk-danska gränsen. Men under senare år har det skett en nedgång ibland annat pendling mellan den danska och den svenska sidan. I detta kapitel kanvi med hjälp av de sydsvenska SOM-undersökningarna visa att skåningarna tycks brysig allt mindre om Öresundsregionen och Danmark. Intresset för nyheter från dendanska sidan minskar, liksom för att arbeta i Danmark eller flytta dit. Språkförståelsengår stadigt nedåt, och det finns vissa indikationer på att stödet för det regionalasamarbetet minskar. Resultaten antyder att om det finns en politisk vilja att utvecklagränsregionen bör åtgärder vidtas för ökad folklig förankring och förståelse.
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25.
  • Fredriksson, Mio, 1976-, et al. (författare)
  • A New Way of Thinking and Talking About Economy : Clinic Managers' Perspectives on the Sustainable Implementation of a Decommissioning Programme in Sweden
  • 2023
  • Ingår i: HEALTH SERVICES INSIGHTS. - : SAGE Publications. - 1178-6329. ; 16
  • Tidskriftsartikel (refereegranskat)abstract
    • Healthcare systems may run into economic problems that may require 'active' decommissioning by policy-makers and managers. The aim of this study was to investigate, from a sustainability perspective, the implementation of an extensive decommissioning programme in one of the Swedish regions. Interviews were performed with 26 clinic managers 3 years after initial implementation. Those were analysed inductively, and then discussed based on a model of potential influences on sustainability. Although the programme was only 'partly sustained', the result point to a sustained attention to the health system's poor economy, visible in a great effort by the clinics to maintain their budgets. The most important influences were intervention fit and modifications made at the clinic level (i. innovation characteristics), clinic and health system leadership (ii. context), champions (iii. capacity) and shared decision-making and relationship building (iv. processes and interactions). When implementing decommissioning, it is particularly important to engage managers responsible for the care of patients and clinic budgets from an early stage and to allow them to design approaches based on the staff's and managers' detailed knowledge of the situation at their clinics and of the disease area, that is, to achieve fit at the clinics. In this way, the decommissioning approaches can more likely get the character of quality improvement efforts, which increases sustainability and may lead to positive quality outcomes. Despite being unpopular, the study suggests that decommissioning can have positive effects as well, such as creating opportunities to make difficult but necessary changes and fostering increased collegial support during the centralisation of services.
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26.
  • Fredriksson, Mio, 1976-, et al. (författare)
  • Cuts without conflict : The use of political strategy in local health system retrenchment in Sweden
  • 2019
  • Ingår i: Social Science and Medicine. - : Elsevier BV. - 0277-9536 .- 1873-5347. ; 237
  • Tidskriftsartikel (refereegranskat)abstract
    • Disinvestment in health services is seen as challenging by decision-makers as the public usually reacts strongly to rationing and retrenchments. Drawing on the literature on welfare state retrenchment - the reduction of public expenditure by cutting costs or spending - this article explores the development and implementation of a comprehensive retrenchment programme in one local health system in Sweden (a so-called region). According to theory, retrenchments are both electorally risky and institutionally difficult. Nonetheless, they take place and in the local health system we investigate, without too extensive public protest and without decision-makers having to resign. The main question in this qualitative study is: why and how was it possible to make such comprehensive retrenchments despite being unpopular and facing many political and institutional barriers? Interviews with 18 local politicians and public servants were carried out between January 18 and April 3, 2017, and analysed from the perspective of political strategy. They showed that the serious budget deficit, and a shared understanding of what the region's problems were, are important explanations for why the retrenchment programme was possible to develop and implement. Based on a thorough internal review of the health system, a crisis discourse developed which partly depoliticized the retrenchment programme. Justification and framing are keys to how it was possible. The retrenchment programme was justified by arguing that current service provision exceeded that in comparable regions, and framed as necessary saving the local health system and enhancing quality. Important strategies were thus to redefine the retrenchments and to blame-share, the latter through politicians and public servants claiming responsibility together after involving the clinic managers. In sum, our study shows that the retrenchment literature and theories on political strategy may be fruitfully applied to the health-care sector as well. By studying the local level, our findings contribute to the retrenchment literature, indicating that political strategy at the local level is more about justification and blame sharing, than blame avoidance.
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27.
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28.
  • Gad, Helge, et al. (författare)
  • MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
  • 2014
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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29.
  • Gupta, Dhanu, et al. (författare)
  • Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles
  • 2021
  • Ingår i: Nature Biomedical Engineering. - Stockholm : Karolinska Institutet, Dept of Laboratory Medicine. - 2157-846X.
  • Tidskriftsartikel (refereegranskat)abstract
    • Extracellular vesicles (EVs) can be functionalized to display specific protein receptors on their surface. However, surface-display technology typically labels only a small fraction of the EV population. Here, we show that the joint display of two different therapeutically relevant protein receptors on EVs can be optimized by systematically screening EV-loading protein moieties. We used cytokine-binding domains derived from tumour necrosis factor receptor 1 (TNFR1) and interleukin-6 signal transducer (IL-6ST), which can act as decoy receptors for the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and IL-6, respectively. We found that the genetic engineering of EV-producing cells to express oligomerized exosomal sorting domains and the N-terminal fragment of syntenin (a cytosolic adaptor of the single transmembrane domain protein syndecan) increased the display efficiency and inhibitory activity of TNFR1 and IL-6ST and facilitated their joint display on EVs. In mouse models of systemic inflammation, neuroinflammation and intestinal inflammation, EVs displaying the cytokine decoys ameliorated the disease phenotypes with higher efficacy as compared with clinically approved biopharmaceutical agents targeting the TNF-α and IL-6 pathways.
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30.
  • Gustafsson, Anki, et al. (författare)
  • Pichia pastoris-produced mucin-type fusion proteins with multivalent O-glycan substitution as targeting molecules for mannose-specific receptors of the immune system
  • 2011
  • Ingår i: Glycobiology. - : Oxford University Press (OUP). - 0959-6658 .- 1460-2423. ; 21:8, s. 1071-1086
  • Tidskriftsartikel (refereegranskat)abstract
    • Mannose-binding proteins like the macrophage mannose receptor (MR), the dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) and mannose-binding lectin (MBL) play crucial roles in both innate and adaptive immune responses. Immunoglobulin fusion proteins of the P-selectin glycoprotein ligand-1 (PSGL-1/mIgG2b) carrying mostly O-glycans and, as a control, the a1-acid glycoprotein (AGP/mIgG2b) carrying mainly N-linked glycans were stably expressed in the yeast Pichia pastoris. P. pastoris-produced PSGL-1/mIgG2b was shown to carry O-glycans that mediated strong binding to mannose-specific lectins in a lectin array and were susceptible to cleavage by a-mannosidases including an a1,2- but not an a1,6-mannosidase. Electrospray ionization - ion trap mass spectrometry (ESI-MS) confirmed the presence of O-glycans containing up to 9 hexoses with the penta- and hexasaccharides being the predominant ones. a1,2- and a1,3-linked, but not a1,6-linked, mannose residues were detected by 1H-nuclear magnetic resonance (1H-NMR) spectroscopy confirming the results of the mannosidase cleavage. The apparent equilibrium dissociation constants for binding of PNGase F-treated mannosylated PSGL-1/mIgG2b to MR, DC-SIGN and MBL were shown by surface plasmon resonance to be 126, 56 and 16 nM, respectively. In conclusion, PSGL-1/mIgG2b expressed in P. pastoris carried O-glycans mainly comprised of a-linked mannoses and with up to nine residues. It bound mannose-specific receptors with high apparent affinity and may become a potent targeting molecule for these receptors in vivo.
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31.
  • Gustafsson, Anneli, 1978- (författare)
  • Riksdagsdebatt iscensatt : Ett feministiskt teatralt perspektiv på subjektskonstruerande makt i det demokratiska samtalet
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • This dissertation studies power and the production of the democratic subject in the context of democratic debate. It is important to understand the role of power in democratic debate. Even more important is to understand how power underpins the construction of the democratic subject in this context. Is it possible for just anybody to be a convincing democratic subject? Or does democratic debate assume a particular kind of body – a democratic “super-body”? This thesis argues that in order to answer such questions it is not sufficient to study the intellectual and verbal aspects of democratic debate. The situation needs to be examined in its material enactment. Since previous research does not offer a coherent way of analysing how power underpins the material construction of the democratic subject, this dissertation develops such an analytical perspective, which it terms a feminist theatrical perspective. The perspective is “theatrical” because it studies democratic debate as intra-active enactment, which assumes stage, costume and stage direction. The perspective is inspired by Foucault and Butler as well as by feminist performance, architectural and design research. The feminist theatrical perspective, and the methodological framework that it offers, constitutes the main contribution of the thesis. The dissertation focuses on democratic debate in the specific form of the parliamentary debate. It identifies three key parliamentary ideals about democratic debate that are materially enacted as ”dramas” during the debate: the idea that democratic debate is built on equality, that it is important as representing the people, and that it is importantly rendered in combative struggle. Empirically, the thesis is based on an ethnographic field-study of the Riksdag, the Swedish parliament, conducted in 2008/2009, and an in-depth study of two debates between party leaders that took place in the Riksdag in 2010. The main finding is that power is necessarily ambivalent in the production of the democratic subject in this context. The thesis identifies frameworks for how the democratic subject should move, behave, sound and look. However, these frameworks are contradictory. No actual physical body could, as a “super-body”, fully correspond to the physical characteristics that are assumed about the democratic subject.
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32.
  • Gustafsson Asting, Annika, et al. (författare)
  • Host knockout of E-prostanoid 2 receptors reduces tumor growth and causes major alterations of gene expression in prostaglandin E2-producing tumors
  • 2017
  • Ingår i: Oncology Letters. - : SPANDIDOS PUBL LTD. - 1792-1074 .- 1792-1082. ; 13:1, s. 476-482
  • Tidskriftsartikel (refereegranskat)abstract
    • Prostaglandin E-2 (PGE(2)) is elevated in a variety of malignant tumors and has been shown to affect several hallmarks of cancer. Accordingly, the PGE, receptor, E-prostanoid 2 (EP2), has been reported to be associated with patient survival and reduced tumor growth in EP2-knockout mice. Thus, the aim of the present study was to screen for major gene expression alterations in tumor tissue growing in EP2-knockout mice. EP2-knockout mice were bred and implanted with EP2 receptor-expressing and PGE(2)-producing epithelial-like tumors. Tumor tissue and plasma were collected and used for analyses with gene expression microarrays and multiplex enzyme-linked immunosorbent assays. Tumor growth, acute phase reactions/systemic inflammation and the expression of interleukin-6 were reduced in EP2-knockout tumor-bearing mice. Several hundreds of genes displayed major changes of expression in the tumor tissue when grown in EP2-knockout mice. Such gene alterations involved several different cellular functions, including sternness, migration and cell signaling. Besides gene expression, several long non-coding RNAs were downregulated in the tumors from the EP2-knockout mice. Overall, PGE(2) signaling via host EP2 receptors affected a large number of different genes involved in tumor progression based on signaling between host stroma and tumor cells, which caused reduced tumor growth.
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33.
  • Gustafsson, Britt, et al. (författare)
  • KI, WU, and Merkel Cell Polyomavirus DNA was not Detected in Guthrie Cards of Children who Later Developed Acute Lymphoblastic Leukemia
  • 2012
  • Ingår i: Journal of pediatric hematology/oncology (Print). - 1077-4114 .- 1536-3678. ; 34:5, s. 364-367
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Neonatal dried blood spots (Guthrie cards) have been used to demonstrate a prenatal origin of clonal leukemia-specific genetic aberrations in several subgroups of childhood acute lymphoblastic leukemia (ALL). One hypothesis suggests that an infectious agent could initiate genetic transformation already in utero. In search for a possible viral agent, Guthrie cards were analyzed for the presence of 3 newly discovered polyomavirus Karolinska Institutet polymavirus (KIPyV), Washington University polyomavirus (WUPyV), and Merkel cell polyomavirus (MCPyV). Methods: Guthrie cards from 50 children who later developed ALL and 100 matched controls were collected and analyzed by standard or real-time polymerase chain reaction for the presence of the VP1 region of KIPyV, WUPyV, and MCPyV, and the LT region for MCPyV. Results and Conclusions: DNA from KIPyV, WUPyV, and MCPyV was not detected in neonatal blood samples from children with ALL or controls. Prenatal infections with these viruses are not likely to be etiological drivers for childhood leukemogenesis.
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34.
  • Gustafsson, Inga-Britt, et al. (författare)
  • Factors that shape the successful implementation of decommissioning programmes : an interview study with clinic managers
  • 2021
  • Ingår i: BMC Health Services Research. - : Springer Science and Business Media LLC. - 1472-6963. ; 21:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: As a response to many years of repetitive budget deficits, Region Dalarna in Sweden started a restructuring process in 2015, and implemented a decommissioning programme to achieve a balanced budget until 2019. Leading politicians and public servants took the overall decisions about the decommissioning programme, but the clinical decision-making and implementation was largely run by the clinic managers and their staff. As the decommissioning programme improved the finances, met relatively little resistance from the clinical departments, and neither patient safety nor quality of care were perceived to be negatively affected, the initial implementation could be considered successful. The aim of this study was to investigate clinic managers' experience of important factors enabling the successful implementation of a decommissioning programme in a local healthcare organization.METHODS: Drawing on a framework of factors and processes that shape successful implementation of decommissioning decisions, this study highlights the most important factors that enabled the clinic managers to successfully implement the decommissioning programme. During 2018, an interview study was conducted with 26 clinic managers, strategically selected to represent psychiatry, primary care, surgery and medicine. A deductive content analysis was used to analyze the interviews. By applying a framework to the data, the most important factors were illuminated.RESULTS: The findings highlighted factors and processes crucial to implementing the decommissioning programme: 1) create a story to get a shared image of the rationale for change, 2) secure an executive leadership team represented by clinical champions, 3) involve clinic managers at an early stage to ensure a fair decision-making process, 4) base the decommissioning decisions on evidence, without compromising quality and patient safety, 5) prepare the organisation to handle a process characterised by tensions and strong emotions, 6) communicate demonstrable benefits, 7) pay attention to the need of cultural and behavioral change and 8) transparently evaluate the outcome of the process.CONCLUSIONS: From these findings, we conclude that in order to successfully implement a decommissioning programme, clinic managers and healthcare professions must be given and take responsibility, for both the process and outcome.
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35.
  • Gustafsson, Inga-Britt, et al. (författare)
  • Putting a decommissioning programme into action : an interview study with politicians and public servants in a local healthcare organisation
  • 2024
  • Ingår i: Journal of Health Organization & Management. - : Emerald Group Publishing Limited. - 1477-7266 .- 1758-7247. ; 38:9, s. 258-279
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: A local healthcare organisation providing healthcare to 288,000 residents in Sweden struggled with a longstanding budget deficit. Several attempts to overcome the demanding financial situation have failed. A decommissioning programme was launched, and two years later, an evaluation indicated positive outcomes. The aim of this study was to explore factors politicians and public servants perceived as enablers to the successful implementation of the programme.Design/methodology/approach: A deductive content analysis approach using a framework of factors facilitating successful implementation of decommissioning decisions was applied to analyse interviews with 18 informants.FindingsImportant factors were: (1) a review report contributing to the clarity of evidence, which (2) made the clarity of the rationale for change undeniable and (3) strengthened the political support for change. Additional factors were: (4) the strength of executive leadership, (5) the strength of clinical leadership supported by (6) the quality of project management and (7) a cultural and behavioural change seen as an important outcome for the path forward. A way to maximise the potential for a successful implementation of a large-scale decommissioning programme is to build a shared vision and a collaboration grounded in convincing evidence. Include public servants with a clinical background in the executive leadership team to contribute with legitimacy, competence, and trust in the decommissioning programme's intention.Originality/value: The paper addresses the limited knowledge of best practices in decommissioning processes and contributes empirical knowledge from a successful case.
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36.
  • Gustafsson, Jan-Eric, 1949, et al. (författare)
  • Measuring fluid intelligence at age four
  • 2015
  • Ingår i: Intelligence. - : Elsevier BV. - 0160-2896. ; 50, s. 175-185
  • Tidskriftsartikel (refereegranskat)abstract
    • Individual differences in the broad ability dimension General fluid intelligence (Gf) are typically assessed with visuospatial problem solving tasks, and particularly so among young children. Such tests may, however, contribute construct-irrelevant variance due to the figural content of the tasks. The main aim of the study is, therefore, to investigate if measures of working memory capacity can add to the measurement of Gf. A sample of 364 children aged four were given a test-battery which included 10 tests designed to measure different aspects of Gf: three visuospatial problem solving tests, two visual short-term memory (STM) tests, two verbal STM tests, and three verbal tests of working memory capacity. Confirmatory factor analysis showed that an oblique model with four factors fitted the data well, as did a bifactor model with a general factor, along with verbal and visual modality factors. The bifactor model was the preferred solution, and it was concluded that the general factor in this model represents Gf. It was also observed that the visuospatial problem solving tests were influenced by both Gf and the visual modality factor, the latter contributing construct-irrelevant variance to the intended measurement of Gf.
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37.
  • Gustafsson, Karin L., 1987, et al. (författare)
  • A tissue-specific role of membrane-initiated ERα signaling for the effects of SERMs
  • 2022
  • Ingår i: Journal of Endocrinology. - 0022-0795. ; 253:2, s. 75-84
  • Tidskriftsartikel (refereegranskat)abstract
    • Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ER) agonists or antagonists in a tissue-specific manner. ERs exert effects via nuclear actions but can also utilize membrane-initiated signaling pathways. To dete rmine if membrane-initiated ERα (mERα) signaling affects SERM action in a tissue-specific manner, C451 A mice, lacking mERα signaling due to a mutation at palmitoylation site C451, were treated with Lasofoxifene (Las), Bazedoxifene (Bza), or estradi ol (E2), and various tissues were evaluated. Las and Bza treatment increased uterine weight to a similar extent in C451A and control mice, demonstrating mERα-independent uterine SERM effects, while the E2 effect on the uterus was predominantly mER α-dependent. Las and Bza treatment increased both trabecular and cortical bone mass in controls to a similar degree as E2, while both SERM and E2 treatment effects were abse nt in C451A mice. This demonstrates that SERM effects, similar to E2 effects, in th e skeleton are mERα- dependent. Both Las and E2 treatment decreased thymus weight in controls, while neither treatment affected the thymus in C451A mice, demonstrati ng mERα-dependent SERM and E2 effects in this tissue. Interestingly, both SERM and E2 treatments decreased the total body fat percent in C451A mice, demonstrating the ability of these treatments to affect fat tissue in the absence of functional mER α signaling. In conclusion, mERα signaling can modulate SERM responses in a tissue-specific manne r. This novel knowledge increases the understanding of the mechanisms behind SERM effects and may thereby facilitate the development of new improved SERMs.
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38.
  • Gustafsson, Karin L., 1987, et al. (författare)
  • ER alpha expression in T lymphocytes is dispensable for estrogenic effects in bone
  • 2018
  • Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 238:2, s. 129-136
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen treatment has positive effects on the skeleton, and we have shown that estrogen receptor alpha (ERa) expression in cells of hematopoietic origin contributes to a normal estrogen treatment response in bone tissue. T lymphocytes are implicated in the estrogenic regulation of bone mass, but it is not known whether T lymphocytes are direct estrogen target cells. Therefore, the aim of this study was to determine the importance of ERa expression in T lymphocytes for the estrogenic regulation of the skeleton using female mice lacking ERa expression specifically in T lymphocytes (Lck-ERa-/-) and ERaflox/flox littermate (control) mice. Deletion of ERa expression in T lymphocytes did not affect bone mineral density (BMD) in sham-operated Lck-ERa-/compared to control mice, and ovariectomy (ovx) resulted in a similar decrease in BMD in control and Lck-ERa-/- mice compared to sham-operated mice. Furthermore, estrogen treatment of ovx Lck-ERa-/- led to an increased BMD that was indistinguishable from the increase seen after estrogen treatment of ovx control mice. Detailed analysis of both the appendicular (femur) and axial (vertebrae) skeleton showed that both trabecular and cortical bone parameters responded to a similar extent regardless of the presence of ERa in T lymphocytes. In conclusion, ERa expression in T lymphocytes is dispensable for normal estrogenic regulation of bone mass in female mice.
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39.
  • Gustafsson, Kristin, 1976-, et al. (författare)
  • Written instructions versus physiotherapist-supervised rehabilitation after acute ankle sprain
  • 2017
  • Ingår i: European Journal of Physiotherapy. - : Taylor & Francis Group. - 2167-9169 .- 2167-9177. ; 19:2, s. 76-83
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to compare the effects of written instructions (WIs) versus physiotherapist-supervised rehabilitation on patient-rated ankle function, satisfaction and physical activity ability after an acute ankle sprain. Thirty-nine patients with an acute ankle sprain, recruited from an emergency department, received WIs on functional rehabilitation (WI group). The patients were evaluated six weeks and three months after their injury with the disease-specific Foot and Ankle Outcome Score (FAOS). The patients also rated how satisfied they were with their ankle and physical activity ability using visual analogue scales. The results from the WI group were compared with a group of patients (n ¼ 33) who received physiotherapist-supervised rehabilitation in a previous study (PT group). We found that compared with the PT group, the WI group had significantly worse scores in all of the FAOS subscales six weeks after the injury, and in three of five subscales three months after the injury. They also rated significantly lower satisfaction and significantly lower physical activity ability at both follow-ups. In conclusion, physiotherapist-supervised rehabilitation was more effective than WIs on improving patient-rated ankle function, satisfaction and physical activity ability after an acute ankle sprain.
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40.
  • Gustafsson, Mats G., et al. (författare)
  • Improving Bayesian credibility intervals for classifier error rates using maximum entropy empirical priors
  • 2010
  • Ingår i: Artificial Intelligence in Medicine. - : Elsevier BV. - 0933-3657 .- 1873-2860. ; 49:2, s. 93-104
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective:Successful use of classifiers that learn to make decisions from a set of patient examples require robust methods for performance estimation. Recently many promising approaches for determination of an upper bound for the error rate of a single classifier have been reported but the Bayesian credibility interval (Cl) obtained from a conventional holdout test still delivers one of the tightest bounds. The conventional Bayesian CI becomes unacceptably large in real world applications where the test set sizes are less than a few hundred. The source of this problem is that fact that the Cl is determined exclusively by the result on the test examples. In other words, there is no information at all provided by the uniform prior density distribution employed which reflects complete lack of prior knowledge about the unknown error rate. Therefore, the aim of the study reported here was to study a maximum entropy (ME) based approach to improved prior knowledge and Bayesian CIs, demonstrating its relevance for biomedical research and clinical practice.Method and material:It is demonstrated how a refined non-uniform prior density distribution can be obtained by means of the ME principle using empirical results from a few designs and tests using non-overlapping sets of examples.Results:Experimental results show that ME based priors improve the CIs when employed to four quite different simulated and two real world data sets.Conclusions:An empirically derived ME prior seems promising for improving the Bayesian Cl for the unknown error rate of a designed classifier.
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41.
  • Gustafsson, Per, 1950-, et al. (författare)
  • Breastfeeding, very long polyunsaturated fatty acids (PUFA) and IQ at 6 1/2 years of age
  • 2004
  • Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 93:10, s. 1280-1287
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: Breastfeeding seems to be favorable for cognitive development. Could levels of polyunsaturated fatty acids (PUFA) explain this? Methods: Pregnant mothers were recruited consecutively at maternity care centres. PUFA were analysed in colostrum and breast milk at 1 and 3 mo. The product-precursor ratios of n-6+n-3 PUFA were examined as measures of activity in respective steps in the fatty acid metabolic chain. Also, the quotient between DHA and AA was analysed. The children were tested with the full WISC-III at 6.5 y. Results: First, the influence of length of breastfeeding was analysed by multiple regression together with relevant cofactors (except for PUFA). In the best models, 46% of the variation in total IQ was explained. Length of breastfeeding contributed significantly to total IQ (beta = 0.228, p = 0.021), verbal IQ (beta = 0.204, p = 0.040) and performance IQ (beta = 0.210, p = 0.056). There were no significant single correlations between PUFA and measures of cognitive development. However, in multiple regression analysis of colostrum, significant beta-coefficients were found for steps 4+5 in the fatty acid metabolic chain (beta = 0.559, p = 0.002). If length of breastfeeding and gestation week were added to steps 4+5, this three-factor model could explain 67% of the variation of total IQ. Introducing length of breastfeeding and gestation week together with the quotient DHA/AA (beta = 0.510, p < 0.001) yielded a three-factor model, which explained 76% of the variation in total IQ. Conclusion: Our findings could be interpreted as supporting the importance of high levels of PUFA for cognitive development. However, the sample is small and the results must be interpreted with caution.
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42.
  • Gustafsson, Per, et al. (författare)
  • EPA supplementation improves teacher-rated behaviour and oppositional symptoms in children with ADHD
  • 2010
  • Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 99:10, s. 1540-1549
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: Measure efficacy of eicosapentaenoic acid (EPA) in children with attention deficit hyperactivity disorder (ADHD). Methods: Randomized controlled trial (RCT) of 0.5 g EPA or placebo (15 weeks) in 92 children (7-12 years) with ADHD. Efficacy measure was Conners' Parent/Teacher Rating Scales (CPRS/CTRS). Fatty acids were analysed in serum phospholipids and red blood cell membranes (RBC) at baseline and endpoint with gas chromatography. Results: EPA improved CTRS inattention/cognitive subscale (p = 0.04), but not Conners' total score. In oppositional children (n = 48), CTRS total score improved >= 25% in 48% of the children receiving EPA vs. 9% for placebo [effect size (ES) 0.63, p = 0.01]. In less hyperactive/impulsive children (n = 44), >= 25% improvement was seen in 36% vs. 18% (ES 0.41, n.s.), and with both these types of symptoms 8/13 with EPA vs. 1/9 for placebo improved >= 25% (p = 0.03). Children responding to treatment had lower EPA concentrations (p = 0.02), higher AA/EPA (p = 0.005) and higher AA/DHA ratios (p = 0.03) in serum at baseline. Similarly, AA/EPA (p = 0.01), AA/DHA (p = 0.038) and total omega-6/omega-3 ratios (p = 0.028) were higher in RBC, probably because of higher AA (p = 0.011). Conclusion: Two ADHD subgroups (oppositional and less hyperactive/impulsive children) improved after 15-week EPA treatment. Increasing EPA and decreasing omega-6 fatty acid concentrations in phospholipids were related to clinical improvement.
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43.
  • Gustafsson, Roberth, et al. (författare)
  • Experiences from implementing ISO 9000 in small enterprises : a study of Swedish organisations
  • 2001
  • Ingår i: TQM Magazine. - : Emerald. - 0954-478X .- 1758-6887. ; 13:4, s. 232-246
  • Tidskriftsartikel (refereegranskat)abstract
    • Describes a project focusing on the experiences of implementing a third-party certified quality system in small (maximum 50 employees) Swedish organisation. The project consisted of a questionnaire to CEOs, and then a more comprehensive case study of selected organisations. Results show that the more the CEO and employees have been involved in the implementation process, the more the system is used, that the CEO is more satisfied with the results; and quality improvements have continued after certification. Furthermore, the higher the level of education within the company, the less help has been required from external consultants, indicates that important factors for a successful implementation are the attitude of the organisation when the implementation starts, that fairly detailed plans for the implementation are performed and that the documentation is adapted to the business and not necessarily to the ISO standard.
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44.
  • Gustafsson, Ulrika, et al. (författare)
  • In service of school digitalisation in Sweden – a study on ICT coordinators' conditions for work in a local municipal context framed by national educational policy
  • 2024
  • Ingår i: Education and Information Technologies. - : Springer Nature. - 1360-2357 .- 1573-7608.
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to explore, analyse, and critically discuss conditions for Swedish ICT coordinators working on school digitalisation in a local municipal school context. More specifcally, the study draws on findings from interviews with 13 Swedish information and communication technology (ICT) coordinators working in eight municipalities that have adopted two contrasting approaches to school digitalisation. One is a general approach with a strong element of individual within-school accountability in the work, and the other a specifc approach in which such work is addressed more as an organisational process with involvement of municipal governing officials. Findings show that the two approaches set different conditions in terms of how and with whom the ICT coordinators work and the foci of their efforts although both are framed by the same national educational policy. A conclusion is that the ICT coordinators' role, function, and responsibility should be considered in parity to the level of support, in-school resources, and mandate given to them, not least when organisational instability and reorganisations hamper the work in progress.
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45.
  • Gustafsson, Ulrika (författare)
  • Local policy work on digitalisation in Swedish municipalities : Different translations in different contexts
  • 2023
  • Konferensbidrag (refereegranskat)abstract
    • When national policies on school digitalisation follow international trends of transferring governing responsibility to local stakeholders, ideas of national policy coherence and school equality are challenged by decentralised school organisations, which is the case in Sweden and the Nordic countries (Moos & Krejsler, 2021). Yet, schools are still expected to uphold a tradition of education equality and digital competence for all.   This paper focuses on Swedish policy work on school digitalisation among local authorities. Conducted as a comparative cross-case study (Simons, 2009) of four contextually different municipalities, the study examines how local contexts influence this type of policy work through interviews with municipality officials (school superintendents), local policy texts on school digitalisation, three years of local education board minutes, and municipality websites. The study seeks to answer the following questions: (1) How do municipalities translate national school digitalisation policy into actions based on local context? (2) What similarities and differences can be found in these translations between different local contexts? (3) Do contextual differences affect the local translations of policy concerning the digitalisation of schools, and if so, in what ways?Each of the four cases is explored in relation to the contextual factors of (a) material contexts, (b) professional cultures, (c) situated context, and (d) external contexts (Ball, Maguire, & Braun, 2012; Braun, Ball, Maguire, & Hoskins, 2011). The findings show that municipalities may approach policy translations of school digitalisation in two ways in which translation power is balanced differently. These approaches are based on contextual factors where size matters. The findings raise questions regarding the importance of local governance and contexts in policy translations of national school digitalisation policy in terms of policy coherence, school equality, and teacher agency.References: Ball, S. J., Maguire, M., & Braun, A. (2012). How schools do policy : policy enactments in secondary schools. Routledge.Braun, A., Ball, S. J., Maguire, M., & Hoskins, K. (2011). Taking context seriously: towards explaining policy enactments in the secondary school. Discourse (Abingdon, England), 32(4), 585-596. doi:10.1080/01596306.2011.601555Moos, L., & Krejsler, J. (2021). What works in nordic school policies? : mapping approaches to evidence, social technologies and transnational influences. Cham, Switzerland: Springer.Simons, H. (2009). Case study research in practice. SAGE.
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46.
  • Gustafsson, Ulrika, et al. (författare)
  • Local translation work on national school digitalisation policy in Sweden – a challenging endeavour with signs of strong rural resilience
  • 2023
  • Ingår i: NERA Conference 2023. - Umeå.
  • Konferensbidrag (refereegranskat)abstract
    • Research topic/aim: This abstract explores rural municipality contexts in Sweden and signs of rural resilience in local translation work on national policy on school digitalisation. The goal with this abstract is to contribute with knowledge about rural municipalities and their contextual capacity of responding and adapting to national school policy and change in a digital age. In the abstract, two research questions are addressed: (1) How do rural municipalities work with translating national school digitalisation policies into local and contextual actions? and (2) How can this work be understood from a rural resilience perspective?Theoretical framework: The abstract uses a combined theoretical framework to explore signs of rural resilience building in the municipalities. This framework builds on (a) Selwyn’s (2018) areas of policy activity of digital technology in school policy - (1) technology resources, (2) use of digital tools in the schools, (3) curriculum concerns, and, (4) issues of organisation and governance as well as 8b) Roberts’ et al. (2017a; 2017b) central forms in resilience thinking – (1) multi-scalar resilience, (2) normative resilience and (3) integrated policy conceptions of resilience.Methodology/research design: During August until December in 2021, data were in two steps collected from 36 out of 40 Swedish municipalities categorized by the Swedish Association of Local Authorities and Regions as C8 (rural, not large on tourism). First, short phone interviews with municipality key persons asking them to describe their work with three recent Swedish national school policies on digitalisation and digital competence. Second, via the key persons collecting any additional written local policy in terms of strategic and/or action-oriented plans for the work with school digitalisation and/or digital competence.Expected results/findings: The findings in the proposed abstract makes it possible to argue in favour of the adaptability in Swedish rural municipalities in terms of resilience building. That rural municipality contexts need recognition in their national school digitalisation policy work, and that increased national clarity of both the intended meaning and desirable outcome of local policy translations could provide a more solid support for the rural municipalities - including further development of a strong rural resilience.Relevance to Nordic educational research: This abstract is relevant due to the rural perspectives have been lacking in Nordic educational research concerned with aspects of local translation work on national school digitalisation policy. Moreover, and in opposite to the abstract proposed here, such research seldom highlights the contextual complexity of this policy work when addressing the various levels of policy, challenges of local mobilisation, and individual approaches to policy.References:Roberts, E., Anderson, B.A., Skerratt, S., & Farrington, J. (2017). A review of the rural-digital policy agenda from a community resilience perspective. Journal of Rural Studies, 54, 372-385.Roberts, E., Beel, D., Philip, L., & Townsend, L. (2017). Rural resilience in a digital society: Editorial. Journal of Rural Studies, 54, 355-359.Selwyn, N. (2018). Technology as a focus of education policy. In R. Papa and S. W. Armfield (Eds.), The Wiley Handbook of Educational Policy (pp. 457-477). Hoboken, NJ: John Wiley & Sons, Inc.
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47.
  • Gustafsson, Ulrika (författare)
  • Size matters : contextual factors in local policy translations of National School Digitalisation Policy
  • 2022
  • Ingår i: Education and Information Technologies. - : Springer-Verlag New York. - 1360-2357 .- 1573-7608. ; 27, s. 11741-11758
  • Tidskriftsartikel (refereegranskat)abstract
    • National policies on school digitalisation take shape in their local contexts. Consequently, to understand the outcome of national policy, the local translations must be set within a contextual perspective. This article explores how four contextually different municipalities in Sweden translate national school digitalisation policy. It draws on a comparative cross-case study with data gathered from interviews, and over 150 local documents dating from 2018 to 2020. The results show how contextual aspects affects responses to national policy, and that municipalities approach school digitalisation in two distinct ways. The first, general approach, emphasises competitiveness and the creation of an enabling environment for the teachers. This is manifested in the development of special support organisations, and generous access to digital technology. The second, specific approach, emphasises local consensus in policy translations along with unity in policy adherence. Here, critique of national policy is explicit. The two approaches exemplify how translational power may be distributed differently, the former prioritising individual translational precedency for teachers over a unifying policy translation controlled through local governance. The paper suggests that contextual factors matters in the choice of approaches, one in which size matters. The paper concludes that policy makers need to acknowledge contextual dimensions within governance by weighing translational power in relation to translational coherence.
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48.
  • Gustafsson, Ulrika (författare)
  • Taking a step back for a leap forward : policy formation for the digitalisation of schools from the views of Swedish national policymakers
  • 2021
  • Ingår i: Education Inquiry. - : Taylor & Francis Group. - 2000-4508. ; 12:4, s. 329-346
  • Tidskriftsartikel (refereegranskat)abstract
    • The modest impact of national policy efforts on school digitalisation relates to a gap between views among policy-makers and practitioners, giving rise to complexity in translating policy into action. Acknowledging changes in governing through alternative policy formation-processes, and Ward and Parr’s (2011) arguing for the importance of strategic- and operational policy coherence, the focus of this paper is the forming of a national plan of action for the digitalisation of schools in Sweden (#skolDigiplan). Within this interview study, the views on policy work and challenges of digitalisation of schools are explored among an exclusive management group of non-traditional Swedish policy-makers appointed to produce the #skolDigiplan. Based on the findings, I conclude that national policy making regarding the digitalisation of schools may be conducted through a collective process, with several educational stakeholders contributing. Furthermore, I suggest that non-traditional national policy-makers, arguing a lack of digital competence knowledge concerning schools at the governing or authority level, may consider taking a step back in the policy-formation process as a supportive action. Teacher training programmes, despite being portrayed as important for the policy outcome, were declared distant in this policy process.
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49.
  • Gustafsson, Ulrika, et al. (författare)
  • 'This Is How We Do It!' : rural resilience in local translation work on national school digitalization policy
  • 2024. - 1
  • Ingår i: Digitalization and digital competence in educational contexts. - London : Routledge. - 9781032409863 - 9781032409870 - 9781003355694 ; , s. 28-38
  • Bokkapitel (refereegranskat)abstract
    • This chapter explores the building of rural resilience with the influence of national school digitalization policy visible in local policy translations. Focusing on 36 Swedish rural municipalities, the chapter reflects on the ability of rural municipalities to respond and adapt to national school policy and change in a digital age. The findings show that local work on translating national school digitalization policy is a rather challenging endeavor for rural municipalities. The findings in four areas of policy activity of digital technology in school policy – (a) technology resources, (b) use of digital tools in the schools, (c) curriculum concerns, and (d) issues of organization and governance – make it possible to argue in favor of adaptability in rural municipalities in terms of resilience building. We conclude that rural municipal contexts need recognition for their national school digitalization policy work. Moreover, increased national clarity of the intended meaning and desirable outcome of local policy translations could better support the rural municipalities, including further development of strong rural resilience.
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50.
  • Gustafsson, Åsa, et al. (författare)
  • Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles
  • 2015
  • Ingår i: Toxicology and Applied Pharmacology. - : Elsevier BV. - 0041-008X .- 1096-0333. ; 288:1, s. 1-11
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 and 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials.
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