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  • Waller, Olle
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Eftersyn vid internprissättning av svårvärderade immateriella tillgångar: Kan OECD:s riktlinjer för internprissättning vara vägledande för korrigeringsregeln?2016Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Thuresson, Tova
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Vd:ns behörighet att lämna anbud i offentliga upphandlingar2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Skoglund, Johanna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Medvetenhet  - var och hur?: Om medvetenhetskravets placering i brottsbegreppet samt dess innebörd för straffrättsligt ansvar2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    I svensk straffrätt utgör medvetenhet ett minimikrav för att dömas till straffrättsligt ansvar. Kravets innebörd regleras inte i lag och har sällan behandlats närmare i vare sig förarbeten eller doktrin. Frågor om medvetenhet ligger nära den straffrättsligt grundläggande konformitetsprincipen, som därmed kan utgöra vägledning för domstolar i oklara fall. I syfte att klargöra kravets närmare innebörd tar detta arbete sikte på hur frågor om medvetenhet behandlats i rättspraxis, hur kravet passar in i brottsbegreppet samt dess vidare förhållande till konformitetsprincipen. Mycket talar för att kravet på medvetenhet har plats i både den subjektiva och objektiva sidan av brottsbegreppet, men rättsfallsgenomgången visar att domstolarna ofta enbart prövar kravet i förhållande till den objektiva sidan. Vidare visar rättsfallsgenomgången att domstolarna ofta utför förhastade och ofullständiga bedömningar av gärningspersonerns medvetandegrad, vilket medför att människor riskerar att dömas till ansvar i strid med konformitetsprincipen. För att undvika en sådan rättstillämpning får det anses önskvärt att domstolarna strävar efter att upprätthålla konformitetsprincipen i sina bedömningar samt att de beaktar medvetenhetskravets tudelade placering i brottsbegreppet.

  • Balsvik, Erika
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Hartman, Daniel
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Business Studies.
    Budgetering på lugnare vatten: En fallstudie om hur uppdragsspecifikation och fasta intäkter påverkar Sveriges Radios budgetprocess2016Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Budgeten har av forskare sagts vara hjärtat av ekonomistyrning. Den traditionella budgeteringen har länge fått kritik för sin stelbenta syn på resurser och organisationer. Det har även förts en debatt gällande hur ekonomistyrning kan ske på bästa sett. Contingencyteorin hävdar att det inte finns ett universellt sätt att styra organisationer, utan att varje organisation måste anpassa sin styrning utifrån sina situationsfaktorer. Syftet med denna studie är att undersöka hur budgetprocessen fungerar inom en organisation med ett specifikt uppdrag och fasta intäkter, samt vilka eventuella nackdelar användning av traditionell årsbudgetering medför. Studien realiseras genom en kvalitativ fallstudie genomförd på Sveriges Radio, vars uppdrag och intäkter beslutas av riksdagen. Undersökningen fokuserar på hur dessa contingencies, omvärldsfaktorer, påverkar budgetprocessen på olika nivåer inom organisationen. Resultaten tyder på att dessa contingencies har en påverkan på budgetprocessen, men inte har samma dysfunktionalitet som tidigare kritik belyser. Slutsatsen av studien är att uppdragsspecifikation och fasta intäkter påverkar budgetprocessen och kan i viss mån bistå med vidare underlag för kritik till budgetprocessen. Studien bidrar till vidare förståelse för budgetprocessen inom organisationer med dessa situationsfaktorer och föreslår vidare forskning på liknande organisationer. 

  • Ramberg, Aili
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Innebörden av svenska konventionsåtaganden: sett utifrån rätten till familjeåterförening för alternativt skyddsbehövande2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Otterheim, Gustaf
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Sambandet mellan redovisning och beskattning utanför det formaliserade sambandet i 14 kap. 2 § IL2016Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Nordlander, Jessie
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Hur ska luckor i lagen hanteras?: En undersökning av metodologin i att lösa mål där lagstiftningstekniken skapar luckor i lagen2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Michelsen Forsgren, Matilda
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Hållbarhetsrapportering: Samspelet mellan frivillighet och lagstiftning samt principen om följ eller förklara2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Public defence: 2017-05-19 13:15 B22, Uppsala
    Kristinsson, Hjalti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Effects of Free Fatty Acids on Insulin and Glucagon Secretion: – with special emphasis on the role of Free fatty acid receptor 12017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Prevalence of type 2 diabetes mellitus (T2DM) is still rising and even so in the juvenile population. Obesity is highly associated with increased risk for developing T2DM. The development has been related to elevated fasting concentrations of the pancreatic islet hormones insulin and glucagon as well as to an increase in plasma lipids that occurs during obesity. Specifically, research has indicated that chronic exposure to high levels of saturated free fatty acids cause dysfunction in islet alpha- and beta-cells. Fatty acids can affect islet cells by various mechanisms one of which is the G-protein coupled receptor FFAR1/GPR40. The role of the receptor in the effects of fatty acids on pancreatic islet-cell function is not clear. The aim of this thesis was to clarify the role of FFAR1 in how fatty acids, and more specifically the long-chain saturated fatty acid palmitate, affect insulin and glucagon secretion.

    In children and adolescents with obesity elevated fasting levels of insulin and glucagon were positively correlated with lipid parameters. Specifically, plasma triglycerides and free fatty acids were positively correlated with insulin and glucagon at fasting as well as with visceral adipose tissue volume. Elevated glucagon levels at fasting were associated with worsening of glucose tolerance in the same population. In in vitro studies of isolated human islets palmitate stimulated basal insulin and glucagon secretion as well as mitochondrial respiration at fasting glucose levels. The effect was mediated by FFAR1 and fatty acid beta-oxidation. At higher glucose concentrations the receptor was involved in the potentiation of insulin secretion from isolated human islets and insulin-secreting MIN6 cells. Furthermore, we found that the effects of palmitate on hormone secretion were associated with enhanced mitochondrial respiration mediated by FFAR1 Gαq signaling and PKC activity as well as increased intracellular metabolism induced by the fatty acid. When islets were exposed to palmitate for long time periods and in the presence of FFAR1 antagonist, normalized insulin and glucagon secretion during culture and insulin response to glucose after culture were observed. In MIN6 cells chronic palmitate treatment increased mitochondrial uncoupling irrespective of FFAR1 involvement. However, FFAR1 antagonism during palmitate exposure resulted in elevated respiration and reduced apoptosis.

    In conclusion, children and adolescents with obesity have elevated fasting concentrations of insulin and glucagon that correlate with free fatty acids and fatty acid sources. High glucagon levels are linked to worsening of glucose tolerance in these subjects. In vitro the combination or synergy of FFAR1 activation and intracellular metabolism caused by palmitate is decisive for both the short-term enhancement effects and the negative chronic effects on insulin and glucagon secretion. 

    List of papers
    1. FFAR1 is involved in both the acute and chronic effects of palmitate on insulin secretion
    Open this publication in new window or tab >>FFAR1 is involved in both the acute and chronic effects of palmitate on insulin secretion
    2013 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, S194-S194 p.Article in journal, Meeting abstract (Other academic) Published
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-218006 (URN)000329196901122 ()
    Conference
    49th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 23-27, 2013, Barcelona, SPAIN
    Available from: 2014-02-07 Created: 2014-02-06 Last updated: 2017-03-23Bibliographically approved
    2. Palmitate stimulates insulin secretion by enhancing mitochondrial respiration via intracellular metabolism and FFAR1 signalling
    Open this publication in new window or tab >>Palmitate stimulates insulin secretion by enhancing mitochondrial respiration via intracellular metabolism and FFAR1 signalling
    2015 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, S214-S214 p.Article in journal, Meeting abstract (Other academic) Published
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-264904 (URN)000359820901120 ()
    Conference
    51st Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 14-18, 2015, Stockholm, SWEDEN
    Note

    Meeting Abstract: 430

    Available from: 2015-11-05 Created: 2015-10-19 Last updated: 2017-03-23Bibliographically approved
    3. Basal hypersecretion of glucagon and insulin from palmitate-exposed human islets depends on FFAR1 but not decreased somatostatin secretion
    Open this publication in new window or tab >>Basal hypersecretion of glucagon and insulin from palmitate-exposed human islets depends on FFAR1 but not decreased somatostatin secretion
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    (English)Article in journal (Refereed) Submitted
    National Category
    Cell and Molecular Biology
    Research subject
    Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-317899 (URN)
    Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2017-03-23
    4. Fatty acids trigger glucagon secretion: a potential link to fasting hyperglucagonemia in children with obesity
    Open this publication in new window or tab >>Fatty acids trigger glucagon secretion: a potential link to fasting hyperglucagonemia in children with obesity
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Endocrinology and Diabetes
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-317898 (URN)
    Available from: 2017-03-21 Created: 2017-03-21 Last updated: 2017-03-23
  • Marrero Ericson, Helena
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Ålder, en dynamisk diskrimineringsgrund: Ett examensarbete om åldersdiskriminering2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Landegren, Märta
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Lagstiftning i allmänhetens intresse och rätten till rättvis och skälig behandling: - ett svenskt perspektiv2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Sverige är idag part i ett flertal bilaterala investeringsskyddsavtal med länder världen över. Dessa avtal skyddar investerare som placerar kapital över landsgränserna. Avtalen ger ett långtgående skydd på så sätt att investerare ges rätt att vid tvist föra värdstaten inför internationell skiljenämnd. I tidigare investeringsrättsliga tvister har värdstaternas lagstiftning i vissa fall ansetts strida mot investerarens rätt till rättvis och skälig behandling. Rätten till rättvis och skälig behandling är en vanligt förekommande skyddsklausul i de bilaterala investeringsskyddsavtalen och uppsatsen avser därför utreda på vilket sätt denna rättighet skulle kunna påverka Sveriges möjlighet att lagstifta i allmänhetens intresse.

     

    Uppsatsen utreder dels innebörden av rättvis och skälig behandling genom att undersöka hur tidigare skiljenämnder har tolkat skyddet, dels hur rätten till rättvis och skälig behandling skulle kunna tolkas i förhållande till tre hypotetiska svenska lagförslag. Utredningen tyder på att rätten till rättvis och skälig behandling ger ett långtgående skydd för utländska investerare. Uppsatsen ger avslutningsvis förslag på hur lagstiftning skulle kunna ske i enlighet med tidigare tolkning och tillämpning av skyddet för rättvis och skälig behandling. 

  • Kindstrand, Ian
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Åtgärdsplan 7 och dess påverkan på svensk rätt2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Karlefors, Elsa
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    En konfliktgenererande lagstiftning på bekostnad av barnets rätt till sin pappa?: En kritisk granskning av gällande rätt och rättstillämpningen i svenska vårdnadstvister2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Isaksson, Fanny
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Bytet av hemvist vid arvsförordningens tillämpning: Särskilt om svenska medborgare som flyttar till Portugal2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Högfeldt Eberdal, Catlin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Moderna tider: Arbetstagares integritetsskydd vid elektronisk övervakning enligt personuppgiftslagen och andra regelverk2016Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Henningsson, Josefin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Ett svenskt perspektiv på det ömsesidiga erkännandet av civilrättsliga skyddsåtgärder inom EU2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Public defence: 2017-05-12 13:15 Gunnesalen, Uppsala
    Johansen, Kine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Towards an evidence-based assessment of early motor performance in the child health services: Psychometric properties and clinical utility of the Structured Observation of Motor Performance in Infants2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The Swedish child health services (CHS) have a unique position in that they reach almost all children 0-6 years of age. The child health nurse has the main responsibility for developmental surveillance. Twelve scheduled visits with the nurse during the child’s first year of life make this an ideal setting to systematically identify infants with motor problems, ranging from asymmetric head positioning that may lead to plagiocephaly to more severe forms such as cerebral palsy (CP). However, the CHS lack evidence-based methods to assess motor development.

    The Structured Observation of Motor Performance in Infants (SOMP-I) assesses motor performance in two domains, i.e. level of motor development and quality of motor performance. SOMP-I is quick, non-invasive, requires minimal handling, and is suitable for a busy clinical setting when applied by physiotherapists. Given the importance of early detection, the increased likelihood of detecting motor problems when using evidence-based assessment methods and the key role of nurses within the CHS, the overall aim of this thesis was investigate the psychometric properties and clinical utility of SOMP-I when used by child health nurses. Furthermore, we aimed to establish the ability of SOMP-I to detect CP.

    Our results show that child health nurses can reliably assess the level of motor development in infants using SOMP-I. More variability was found when they assessed the infants’ quality of motor performance. Although the nurses expressed concern about introducing a more time-consuming assessment in an already tight schedule, they were able to integrate the SOMP-I assessment in routine care. The nurses reported that barriers to using SOMP-I were mostly logistic and practical in nature, and they pointed out the necessity of education and practice in order to become proficient assessors. Using SOMP-I appears to have supported the nurses in the decision-making process regarding motor performance in routine care. SOMP-I detected CP during the first months of life in neonatal intensive care recipients.

    To our knowledge, these studies are the first to evaluate child health nurses’ assessment of early motor performance using an evidence-based assessment method in routine care. The results are promising, but further research is warranted.

    List of papers
    1. Early detection of cerebral palsy in neonatal intensive care recipients achieved using the Structured Observation of Motor Performance in Infants
    Open this publication in new window or tab >>Early detection of cerebral palsy in neonatal intensive care recipients achieved using the Structured Observation of Motor Performance in Infants
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    (English)Article in journal (Refereed) Submitted
    National Category
    Pediatrics
    Identifiers
    urn:nbn:se:uu:diva-316405 (URN)
    Available from: 2017-03-01 Created: 2017-03-01 Last updated: 2017-04-06
    2. Can nurses be key players in assessing early motor development using a structured method in the child health setting?
    Open this publication in new window or tab >>Can nurses be key players in assessing early motor development using a structured method in the child health setting?
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    2015 (English)In: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 21, no 4, 681-687 p.Article in journal (Refereed) Published
    Abstract [en]

    Rational, aims and objectivesIncreasing evidence highlights the importance of early interventions for motor disorders in children. Given the key medical role of the nurse within the Swedish Child Health Service (CHS), we aimed to examine if nurses could apply a structured assessment of early motor development at the child health centre to enable early identification of children at risk. MethodsStructured Observation of Motor Performance in Infants (SOMP-I) assesses infant's level of motor development and quality of motor performance using subscales converted to total scores. The total score for both level and quality can then be plotted within the SOMP-I percentile distribution at the child's age for comparison with a reference population. Fifty-five infants (girls: 30) were assessed according to SOMP-I at three child health centres. Assessments were performed by nurses (n=10) in a clinical setting; one nurse performed the assessment while another nurse and a physiotherapist observed. ResultsAgreement for the assessment of level as a continuous variable was excellent [intraclass correlation coefficient (ICC) 0.97-0.98], but was lower for quality (ICC 0.02-0.46). When the children were categorized according to the percentile range categories, the assessors were in agreement for the majority of the children, with respect to both level (78-82%) and quality (78-87%). ConclusionDespite brief experience with SOMP-I, the agreement was excellent when assessing the level of motor development, but was less satisfactory for the assessment of quality of motor performance. More extensive education and training may be necessary to improve the nurses' ability to assess quality, as this domain was an entirely new concept to the nurses. Further research is warranted to determine the applicability of SOMP-I as a standardized method for nurses to assess motor development within the CHS.

    Keyword
    child public health, development, early assessment, infant, motor performance
    National Category
    Pediatrics
    Identifiers
    urn:nbn:se:uu:diva-260819 (URN)10.1111/jep.12366 (DOI)000358693200019 ()25958886 (PubMedID)
    Available from: 2015-08-28 Created: 2015-08-25 Last updated: 2017-04-06Bibliographically approved
    3. 'Now I use words like asymmetry and unstable': nurses' experiences in using a standardized assessment for motor performance within routine child health care
    Open this publication in new window or tab >>'Now I use words like asymmetry and unstable': nurses' experiences in using a standardized assessment for motor performance within routine child health care
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    2016 (English)In: Journal of Evaluation In Clinical Practice, ISSN 1356-1294, E-ISSN 1365-2753, Vol. 22, no 2, 227-234 p.Article in journal (Refereed) Published
    Abstract [en]

    RATIONALE, AIMS AND OBJECTIVES:

    There is an increasing recognition that early intervention is important for children with motor disorders. The use of standardized assessment methods within the Swedish Child Health Services (CHS) may improve early identification of these children and thereby their development and quality of care. Given the key role of nurses within the CHS, we explored their experiences of using a structured assessment of motor performance (SOMP-I) in a clinical setting, and investigated possible barriers and facilitators for implementation of the method within the CHS.

    METHODS:

    The study was conducted in 2013 in Uppsala County, Sweden. Ten child health nurses participated in two focus group interviews, which were analysed using systematic text condensation.

    RESULTS:

    The analysis yielded three themes: (1) increased knowledge and professional pride - nurses described their desire to provide high-quality care for which SOMP-I was a useful tool; (2) improved parent-provider relationship - nurses felt that using SOMP-I involved both the parents and their infant to a greater extent than routine care; and (3) conditions for further implementation - nurses described that the time and effort needed to master new skills must be considered and practical barriers, such as lack of examination space, resource constraints and difficulties in documenting the assessment must be addressed before implementing the SOMP-I method in routine care.

    CONCLUSION:

    Child health nurses felt that the SOMP-I method fitted well with their professional role and increased the quality of care provided. However, significant barriers to implementing SOMP-I into routine child health care were described.

    National Category
    Pediatrics
    Identifiers
    urn:nbn:se:uu:diva-269209 (URN)10.1111/jep.12459 (DOI)000373135400012 ()26489378 (PubMedID)
    Funder
    Swedish Research Council Formas, 259-2012-68
    Available from: 2015-12-14 Created: 2015-12-14 Last updated: 2017-04-06Bibliographically approved
    4. Testing a standardized method for assessing early motor performance within child health services
    Open this publication in new window or tab >>Testing a standardized method for assessing early motor performance within child health services
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    (English)Article in journal (Refereed) Submitted
    National Category
    Pediatrics
    Identifiers
    urn:nbn:se:uu:diva-316404 (URN)
    Available from: 2017-03-01 Created: 2017-03-01 Last updated: 2017-04-06
  • Hellström, Anna
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Sex, samtycke och oaktsamhet: En rättspolitisk analys av svensk rätts behov av en samtyckesbaserad våldtäktslagstiftning2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Hedbor, Agnes
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    La Procréation Médicalement Assistée: Une comparaison entre la Suède et la France2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    By using the comparative method, the purpose of this thesis is to examine how the

    rules for medically assisted reproduction are designed in France and in Sweden,

    especially concerning the access and recognition of parenthood for both heterosexual

    and homosexual (female) couples. The national regulations are set against

    international commitments made by the countries in order to see whether these are

    respected. Regarding the paternity (even with a sperm donation) the countries have

    similar regulations. When it comes to parenthood in a homosexual couple the ”other”

    mom must always adopt in France, since insemination for homosexuals are not

    allowed. In Sweden the second mother must adopt if the insemination was made

    abroad, but a heterosexual man in a relationship must not – a difference that could be

    seen as discrimination under the ECHR. A significant difference between the two

    countries is also that the donor in Sweden is always known (if the child wants to know

    him) and in France always anonymous. In Sweden this is justified by the principle

    ”the best for the child” a principle that is not as visible and prominent in French law.

  • Public defence: 2017-05-13 09:00 Gunnesalen, Uppsala
    Molnar, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
    Structure and Function of the Retina in Children Born Extremely Preterm and in Children Born At Term2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Optical coherence tomography (OCT), multifocal electroretinography (mfERG) and full-field electroretinography (ffERG) give important information about retinal structure and function.

    Purpose: To collect normative data of macular Cirrus Spectral domain (SD)-OCT assessments and of mfERG measurements of healthy children (papers I and II). To assess the macular thickness with Cirrus SD-OCT and the retinal function with ffERG in 6.5-year-old children born extremely preterm and in children born at term (papers III and IV).

    Methods: Study participants aged 5-15 years and living in Uppsala County were randomly chosen from the Swedish Birth Register (papers I and II). In papers III and IV, the study participants consisted of children born extremely preterm and children born at term – all were aged 6.5 years. In paper III, the children were living in Stockholm and Uppsala health care regions and, in paper IV, in Uppsala health care region only. Macular thickness was assessed with Cirrus SD-OCT and macular function with mfERG, using the Espion Multifocal system and DTL-electrodes. The retinal function was assessed with ffERG and DTL-electrodes, using the Espion Ganzfield system.

    Results: Altogether, 58 children participated in paper I and 49 children in paper II. In paper I, the repeatability and reproducibility of the OCT assessments were good. In paper II, the results of the mfERG measurements were in accordance with retinal cone density and there were no significant differences between the right and left eyes. In paper III, 134 preterm children and 145 children born at term constituted the study population. The central macular thickness was significantly thicker in the preterm group than in the control group. Within the preterm group, gestational age (GA), former retinopathy of prematurity (ROP) and male gender were all important risk factors for an increased macular thickness. In paper IV, 52 preterm children and 45 control children constituted the study population. Significantly lower amplitudes and prolonged implicit times of the combined rod and cone responses, as well as of the isolated cone responses, were found in the preterm group when compared with the control group. In paper IV, there was no association between GA, ROP or male gender and the ffERG assessments.

    Conclusion: Normative data of Cirrus SD-OCT and mfERG assessments were reported. The results of the assessments were reliable. Children aged 6.5 years, born extremely preterm, had a significantly thicker central macula and both rod and cone function were significantly reduced in comparison to children born at term. ROP had an influence on retinal structure but not retinal function in the present cohorts. Our results suggest that retinal development is abnormal in children born extremely preterm. Long-term follow-up studies are necessary in order to evaluate the functional ophthalmological outcome in this vulnerable population of children growing up today.

    List of papers
    1. Macular thickness assessed with spectral domain OCT in a population-based study of children: normative data, repeatability and reproducibility and comparison with time domain OCT
    Open this publication in new window or tab >>Macular thickness assessed with spectral domain OCT in a population-based study of children: normative data, repeatability and reproducibility and comparison with time domain OCT
    2015 (English)In: Acta Ophthalmologica, ISSN 1755-375X, E-ISSN 1755-3768, Vol. 93, no 5, 470-475 p.Article in journal (Refereed) Published
    Abstract [en]

    PurposeTo collect data on macular thickness assessed with Cirrus OCT in healthy children in a population-based study, to examine the repeatability and reproducibility, and to compare the values with Stratus OCT. MethodsFifty-eight 6- to 15-year-old children, born at term, were examined. Best-corrected visual acuity and refraction were assessed. One examiner performed three OCT assessments, and the repeatability was calculated. Thereafter, a second examiner repeated the examinations to calculate the reproducibility. One eye was randomized to be included in the normal material. Finally, the second examiner assessed the macular thickness with the Stratus OCT. ResultsThe mean value (SD) of central macular thickness was 255 +/- 17m, and the total macular volume was 10.3 +/- 0.5mm(3). No correlations were found between macular thickness and age, gender or refraction. The coefficients of variance (CoVs) for both repeatability and reproducibility were <1.21%, and the intraclass correlations (ICCs) were over 0.86. The Cirrus OCT showed a 29% thicker central macular thickness than the Stratus OCT. ConclusionNormal values for macular thickness assessed with Cirrus OCT in healthy full-term children in a population-based study were reported. The assessments showed high repeatability and reproducibility. The values of Cirrus and Stratus OCT differed and the techniques were not interchangeable.

    Keyword
    children, normal values, optical coherence tomography, repeatability, reproducibility
    National Category
    Ophthalmology
    Identifiers
    urn:nbn:se:uu:diva-260806 (URN)10.1111/aos.12695 (DOI)000358440700034 ()25726865 (PubMedID)
    Funder
    Swedish Society of Medicine
    Available from: 2015-08-31 Created: 2015-08-25 Last updated: 2017-03-19Bibliographically approved
    2. Macular function measured by binocular mfERG and compared with macular structure in healthy children
    Open this publication in new window or tab >>Macular function measured by binocular mfERG and compared with macular structure in healthy children
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    2015 (English)In: Documenta Ophthalmologica, ISSN 0012-4486, E-ISSN 1573-2622, Vol. 131, no 3, 169-176 p.Article in journal (Refereed) Published
    Abstract [en]

    To create normative data in children from binocular multifocal ERG (mfERG) recordings and compare results with the macular thickness. Forty-nine 5- to 15-year-old healthy, full-term children were examined with Espion Multifocal System, using DTL electrodes. The stimulus matrix consisted of 37 hexagonal elements. Amplitudes, implicit times and response densities (presented in three rings) of the first-order component P1 were analyzed. Measurements of macular thickness were performed with spectral-domain Cirrus OCT. There were no significant differences between right and left eyes regarding mfERG recordings. Median P1 implicit times of Rings 1-3 of the 46 right eyes were 30.0, 30.0 and 30.8 ms and response densities 20.5, 10.9 and 7.6 nV/deg(2), respectively. Implicit time was longer in boys than in girls (p = 0.009, 0.039, 0.005 in Rings 1-3) and was correlated with age (r (s) = 0.417, 0.316, 0.274 in Rings 1-3). Implicit time in Ring 1 correlated significantly with the inner circle of the OCT measurements (p = 0.014). Binocular mfERG with DTL electrodes is a reliable test of the central macular function in children and correlates with macular structure. As previously not shown, there was a significant difference in implicit time between boys and girls.

    Keyword
    Binocular, Multifocal electroretinogram, DTL electrodes, Healthy children, Optic coherence tomography
    National Category
    Ophthalmology
    Identifiers
    urn:nbn:se:uu:diva-270938 (URN)10.1007/s10633-015-9513-y (DOI)000365757200002 ()
    Available from: 2016-01-05 Created: 2016-01-05 Last updated: 2017-03-19Bibliographically approved
    3. Central macular thickness in 6.5-year-old children born extremely preterm is strongly associated with gestational age even when adjusted for risk factors: Foveal thickness in preterm children
    Open this publication in new window or tab >>Central macular thickness in 6.5-year-old children born extremely preterm is strongly associated with gestational age even when adjusted for risk factors: Foveal thickness in preterm children
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    2017 (English)In: Retina, ISSN 0275-004X, E-ISSN 1539-2864Article in journal (Refereed) Epub ahead of print
    National Category
    Ophthalmology
    Research subject
    Ophtalmology
    Identifiers
    urn:nbn:se:uu:diva-317548 (URN)10.1097/IAE.0000000000001469 (DOI)28098724 (PubMedID)
    Available from: 2017-03-16 Created: 2017-03-16 Last updated: 2017-03-21
    4. Both rod and cone function are reduced in 6.5-year-old children born extremely preterm
    Open this publication in new window or tab >>Both rod and cone function are reduced in 6.5-year-old children born extremely preterm
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Ophthalmology
    Research subject
    Ophtalmology
    Identifiers
    urn:nbn:se:uu:diva-317559 (URN)
    Available from: 2017-03-16 Created: 2017-03-16 Last updated: 2017-03-21
  • Gejrot, Hedda
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Skiljedom i strid med ordre public - ogiltighet eller klander?: En analys av förslag rörande klandertalan som presenterades i SOU 2015:37, Översyn av lagen om skiljeförfarande.2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Galvez Flores, Gabriela
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Kommunalt självstyre, kommunalisering av skolan och friskolereformen - en analys2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Forsberg, Filippa
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Påföljdskonkurrens i iterativa tillämpningssituationer: Syften och principer bakom nya 34 kap. brottsbalken2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Examensarbetet behandlar påföljdskonkurrens i iterativa tillämpningssituationer som regleras i 34 kap. brottsbalken. Syftet är att undersöka om 34 kap. motsvarar vad som åsyftades med den reform som genomfördes år 2016. Därutöver avser jag att undersöka vilka teorier och principer som kommer till uttryck genom de nya reglerna och hur dessa överensstämmer med påföljdssystemet i stort. Den använda metoden är rättsdogmatisk. Arbetets slutsatser är att de nya 34 kap. uppfyller reformens syften avseende konsekvent behandling av återfall och i det att en fällande doms principiella betydelse kommer till uttryck. Reformen innebär delvis en förenkling av reglerna, men kapitlet är fortfarande komplicerat och reformen bidrar också med vissa nya svårigheter. Reformen ger också uttryck för bestraffningens kommunikativa funktion. 34 kap. står bättre i överensstämmelse med påföljdssystemet efter reformen än innan. Den inneboende motsättningen mellan återfallsskärpning och proportionalitet är  emellertid problematisk inom 34 kap. liksom den är inom den centrala påföljdsbestämningen.

  • Eilertz, Nils
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Lagen om upphandling av koncessioner: En analys av den nya lagen samt koncessioners framtid2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    The act on public procurement of concessions.

    An analysis of the new law and the future of concessions.

  • Carlström Lindeman, Maria
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Hyresgästens ställning vid fastighetsreglering: Särskilt om hyresgästens bundenhet till hyresavtalet2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Berkesten Hägglund, Camilla
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    The Definition of a Permanent Establishment in the BEPS Era: An analysis of the introduction of commissionaire structures in Article 5(5) of the OECD Model Treaty2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Magnusson, Sara
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Nätmobbning via sociala medier i skolan2013Independent thesis Advanced level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    För att besvara mina frågeställningar om och i vilken omfattning kränkning via internet och sociala medier som verktyg förekommer i skolmiljö, gjorde jag en undersökning bland elever i mellan- och högstadiemiljö i form av en enkät. För att utveckla en förståelse för fenomenet har även intervjuer med skolpersonal genomförts. De flesta eleverna och deras lärare var eniga om att mobiltelefoner används som ett redskap vid kränkning, men var osäkra på hur pass utbrett detta är.  Resultaten tyder dock på att många elever blir kränkta i skolan genom internet och sociala medier. I min studie hade 25 % av eleverna upplevt obehag till följd av någon annans användning av mobiltelefonen. Pojkarna i studien kränktes i högre utsträckning än flickorna, vilket är motstridigt med tidigare forskning. Pojkarna uppgav sig även publicera mer på internet och deras föräldrar visste i lägre grad vad de gjorde på internet. Idag är eleverna aldrig fredade från kränkningar och hot, få elever i min undersökning stängde av telefonen ens på natten. Anvarsfrågan är otydlig, ligger den hos hemmet eller skolan? Detta avspeglas i intervjuerna av skolpersonalen som upplever mobiltelefoner som ett problem i skolan och reglerna som luddiga. Dessutom upplever jag att skolpersonalen efterfrågar föräldrarnas ansvar i frågan då de flesta kränkningarna sker utanför skolan. Det finns inga tydliga gränser och det krävs att vuxna hänger med i den tekniska utvecklingen för att förstå och skydda dagens unga. 

  • Sigroth, Maja
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Educational Sciences, Department of Education.
    Förskollärares erfarenheter och syften med att använda sig av barnlitteratur i den dagliga verksamheten2016Independent thesis Advanced level (professional degree), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Syftet med studien är att undersöka på vilket sätt förskollärare förhåller sig till användandet av barnlitteratur i den dagliga verksamheten. Med en specifik undran på vad och hur, samt vilka syften förskollärare har när de använder litteratur. Fem intervjuer har genomförts med olika förskollärare på fyra olika förskolor. Dessa data har sedan sammanställts och analyserats med hjälp av ett sociokulturellt perspektiv på kommunikation (Vygotskij, 1995), samt Lindströms (2008) modell för lärandestrategier. Denna modell innefattar lärande om, i, genom samt med barnlitteraturen, och kunde urskiljas i samtliga intervjupersoners svar. Studiens resultat visade på att lärande med litteraturen var den mest framträdande lärandestrategin, då den innefattade lärarens arbete med att lära barnen vidare kunskaper genom att använda sig av litteraturen som redskap. Lärandet om litteraturen behandlade förskollärarnas kunskaper om barnlitteratur samt vad den kunde ge barngruppen. Lärandet genom barnlitteraturen representerades i undersökningen av vidareutvecklingen som skedde i samband med exempelvis ett temaarbete, då barnen inspirerades av litteraturen att utveckla sitt moraltänk samt sitt lärande om bokstäver. Lärandet i barnlitteraturen blev synligt med hjälp av lärarnas anpassning av miljön på förskolan med syfte att inspirera barnen till läsning.

     

    I studien framkom även att förskollärarna använder sig av barnlitteratur i olika syften vid olika tidpunkter under dagen. De hade alla en mycket positiv inställning till barnlitteratur som inspiration och grund för ett fortsatt lärande, och var medvetna om sin roll som stöttande och medupptäckande under det lärandet som skedde i mötet med litteraturen. Det självklara i att barnen ständigt ska ha tillgång till litteraturen fanns med i samtliga lärares dagliga planering, och samtliga i studien betonade litteraturens del i att skapa inspiration och nyfikenhet hos barnen. Däremot reflekterades det över pedagogernas egen medvetenhet när det kom till att involvera barnlitteraturen i de planerade aktiviteterna. Några fann det enkelt och mer naturligt, medan andra inte var lika medvetna eller endast använde sig av barnlitteratur vid vissa valda tillfällen. Resultatet visade även på vikten av att hitta ”rätt” litteratur för att hålla barnens intresse vid liv, samt att det kan vara väldigt individuellt vad som passar just den barngrupp läraren är ansvarig för – en viktig aspekt för läraren att kunna känna av och arbeta med.

  • Andersson, Erik
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Tillförarprövningen enligt 2 kap. 4 § st. 1 p. 1 JB: Ett spörsmål av och om intresse2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • Arfwidsson, Autilia
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Law, Department of Law.
    Hybridregeln i ATAD: Implementering i svensk rätt2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    I dagens globaliserade samhälle drabbas EU:s medlemsstater av ett betydande inkomstbortfall på grund av vissa globala företags avancerade skatteplanering. En vanligt förekommande metod för att undvika skatt är att utnyttja hybridinstrument. Hybridinstrument är finansiella instrument som innehåller element av såväl skuld som eget kapital. Konsekvensen vid utnyttjande av hybridinstrument vid internationella transaktioner är att hybrida missmatchningar uppstår, dvs. att betalningen medges avdrag i ett land utan att den på motsvarande sätt tas upp till beskattning hos mottagaren. EU-kommissionen har som en motåtgärd tagit fram ett direktiv mot skatteundandraganden. Direktivets artikel 9 tar sikte på hybrida missmatchningar och syftar till att motverka skatteflykt. Sverige har fram till den 31 december 2018 på sig att implementera direktivet.

    Jag har utrett hur en implementering av direktivets artikel 9 kan göras i svensk rätt, så att de nya reglerna är lojala mot dess syfte och förenliga med svenska skatterättsliga principer. För att motverka hybridinstrument är det framförallt hybridregelns p. 2 som är aktuell. Regeln innebär att när en betalning leder till avdrag hos betalaren utan att den på motsvarande sätt beskattas hos mottagaren, ska betalarstaten vägra avdrag för betalningen. Befintliga svenska regler mot hybridinstrument går att finna i inkomstskattelagen, kupongskattelagen och skatteflyktslagen. Jag drar emellertid slutsatsen att nuvarande svenska regler inte ger ett skydd som motsvarar de krav som direktivets artikel 9 uppställer. Reglerna behöver således ändras och/eller kompletteras.

    Mitt förslag är att direktivets artikel 9 implementeras i 24 kap IL i form av en generalklausul. Närståendekravet mellan företagen bör vara samma som direktivets minimikrav, dvs. 25 procent. Rekvisitet ”ränta eller liknande” är en lämplig ordalydelse för de hybridbetalningar som artikel 9 p. 2 avses att tillämpas på.  Vid tillämpandet av regeln bör avdrag vägras till den del den inte beskattas i mottagarstaten.  Den hypotetiska bedömningen som görs enligt mottagarens lagstiftning bör framgå av lag.  Jag har även argumenterat för att ingen omklassificering av instrumentet bör göras, utan att enbart avdrag ska vägras. När en konflikt uppstår mellan 24:19 IL och den implementerade motsvarigheten till hybridregeln i direktivets artikel 9, bör specialregeln i 24:19 IL äga företräde. Slutligen anser jag att den svenska hybridregeln bör vara universellt tillämplig.

  • Sandwall, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Earth Sciences, Department of Earth Sciences.
    Underlagsmodell för prioriterings- och åtgärdsarbete med sjöar och recipienter2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    This thesis constructs a model that is aimed at helping municipalities to a quicker identification of problems with local lakes. It creates a basis of information on pollutant transport, natural and cultural values and ecosystem services that is equal for all lakes, regardless of size or location. To be able to match the needs of a municipality the model was created in accordance with Knivsta kommun. By modelling the catchments for all lakes in Knivsta, subsequent land use within these was mapped and used as input in the StormTac watershed-based model which resulted in pollutant transport. Through further use of data from both county and government sources on both cultural and natural values within these catchments an assessment was made. This assessment looks at not only the natural and cultural values, but also tries to identify objects of value for ecosystem services in the region.

    The results of the model and the resulting basis aims to be the foundation for both policy documents in regards to future water plans and also for action programs for lakes that need measures of restoration. Since the model is only reliant on digital information it is recognized to be a preliminary tool for identifying lakes that are most in need for field studies or sampling. Only after said studies can a more definitive conclusion be drawn. The use of the StormTac-model was found to be a good match for lakes with largely urban land use within its catchments, and less good for forested catchments. In regards to ecosystem services it was concluded that only comparing objects of value was not recommended and further studies, preferably in the field, were needed.

    The lakes that require further studies based on model results in regards to pollutants is Branthammarsjön, in regards to natural values – Valloxen and in regards to cultural values – Valloxen. The study concluded that lake Valloxen should have priority in receiving an action program.

  • Public defence: 2017-05-19 10:00 Geijersalen, Engelska parken, Uppsala
    Callewaert, Teresa
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Theology, Department of Theology.
    Theologies Speak of Justice: A Study of Islamic and Christian Social Ethics2017Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The purpose of this study is to investigate how religious ethics, while retaining its identity, can contribute to political debate and to the understanding of justice. The inquiry addresses these issues by focusing on theological perspectives which challenge the solutions offered to these questions by the liberal paradigm. Three kinds of challenges are studied, each of which is represented by one thinker from the Islamic tradition and one from the Christian tradition, in order to enable a comparative perspective on the contributions of religious traditions. The thinkers studied are: 1) modified liberalism, represented by Abdullahi Ahmed An-Na’im and Duncan B. Forrester; 2) liberationism, represented by Ali Shariati and Gustavo Gutierrez; and 3) radical traditionalism, as developed by Tariq Ramadan and John Milbank.

    The study is organized around three main questions. First, how can innovative interpretations of religious tradition be plausibly justified? Second, what role should religious arguments and reasons play in the political sphere? Third, what can religious ethics and theological thought contribute to the understanding of social justice? The questions are engaged by means of a critical and reconstructive engagement with the six thinkers. The suggested solutions are assessed in terms of the criteria of authenticity, communicability, and potential for transformation. It is argued that a religious ethic can rely on a tradition without accepting conservative understandings of that tradition. Furthermore, it is argued that the coherence of religious ethics can be made available for public discourse but that the hospitability of the public forum to such contributions needs to be realized through a deepened democratic culture and a critique of power structures which condition perceptions of rationality. While religious ethics do not articulate complete alternative understandings of justice, they articulate contributions by relating justice to human sociality and to transcendence. 

  • Aad, G.
    et al.
    Bergeås Kuutmann, Elin
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Brenner, Richard
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ekelöf, Tord
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ellert, Mattias
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Ferrari, Arnaud
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Gardin, P. O. Joakim
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Madsen, Alexander
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Öhman, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Pelikan, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Rangel Smith, Camila
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, High Energy Physics.
    Zwalinski, L.
    Search for lepton-flavour-violating decays of the Higgs and Z bosons with the ATLAS detector2016In: European Physical Journal C, ISSN 1434-6044, E-ISSN 1434-6052, Vol. 77, no 2, 70Article in journal (Refereed)
    Abstract [en]

    Direct searches for lepton flavour violation in decays of the Higgs and Z bosons with the ATLAS detector at the LHC are presented. The following three decays are considered: H -> e tau, H -> mu tau, and Z -> mu tau. The searches are based on the data sample of proton-proton collisions collected by the ATLAS detector corresponding to an integrated luminosity of 20.3 fb(-1) at a centre-of-mass energy of root s = 8 TeV. No significant excess is observed, and upper limits on the lepton-flavour-violating branching ratios are set at the 95% confidence level: Br(H -> e tau) < 1.04%, Br(H -> mu tau) < 1.43%, and Br(Z -> mu tau) < 1.69 x 10(-5).

  • Public defence: 2017-05-12 09:15 B22, Uppsala
    Pazesh, Samaneh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Process-induced disorder of pharmacutical materials: Mechanisms and quantification of disorder2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    One of the most important prerequisites in the drug development is to attain a reproducible and robust product in terms of its nature, and its chemical and physical properties. This can be challenging, since the crystalline form of drugs and excipients can be directly transformed into the amorphous one during normal pharmaceutical processing, referred to as process-induced amorphisation or process-induced disorder. The intention of this thesis was to address the mechanisms causing disorder during powder flow and milling and, in association with this, to evaluate, the ability of Raman spectroscopy and atomic force microscopy (AFM) to quantify and characterize process-induced disorder.

    The amorphisation mechanisms were controlled by stress energy distribution during processing, which in turn was regulated by a series of process parameters. Compression and shearing stress caused by sliding were stress types that acted on the particles during powder flow and ball milling process. However, sliding was the most important inter-particulate contact process giving rise to amorphisation and the transformation was proposed to be caused by vitrification. The plastic stiffness and elastic stiffness of the milling-induced particles were similar to a two-state particle model, however the moisture sorption characteristics of these particles were different. Thus the milled particles could not be described solely by a two-state particle model with amorphous and crystalline domains. 

    Raman spectroscopy proved to be an appropriate and effective technique in the quantification of the apparent amorphous content of milled lactose powder. The disordered content below 1% could be quantified with Raman spectroscopy. AFM was a useful approach to characterize disorder on the particle surfaces.

    In summary, this thesis has provided insight into the mechanisms involved in process-induced amorphisation of pharmaceutical powders and presented new approaches for quantification and characterization of disordered content by Raman spectroscopy and atomic force microscopy.

    List of papers
    1. Mechanism of Amorphisation of Micro-Particles of Griseofulvin During Powder Flow in a Mixer
    Open this publication in new window or tab >>Mechanism of Amorphisation of Micro-Particles of Griseofulvin During Powder Flow in a Mixer
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    2013 (English)In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 102, no 11, 4036-4045 p.Article in journal (Refereed) Published
    Abstract [en]

    The purpose of the research was to investigate the degree of solid-state amorphisation during powder flow and to propose a mechanism for this transformation. Micro-particles of griseofulvin (about 2m in diameter) were mixed in a shear mixer under different conditions to influence the inter-particulate collisions during flow, and the degree of amorphisation was determined by micro-calorimeter. The amorphisation of griseofulvin particles (GPs)during repeated compaction was also determined. The GPs generally became disordered during mixing in a range from about 6% to about 86%. The degree of amorphisation increased with increased mixing time and increased batch size of the mixer, whereas the addition of a lubricant to the blend reduced the degree of amorphisation. Repeated compaction using the press with ejection mode gave limited amorphisation, whereas repeated compaction without an ejection process gave minute amorphisation. It is concluded that during powder flow, the most important inter-particulate contact process that cause the transformation of a crystalline solid into an amorphous state is sliding. On the molecular scale, this amorphisation is proposed to be caused by vitrification, that is the melting of a solid because of the generation of heat during sliding followed by solidification into an amorphous phase.

    Keyword
    powder technology, powder flow, compaction, mixing, amorphisation, mechanical activation, vitrification, crystal defect, friction, sliding
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-210559 (URN)10.1002/jps.23713 (DOI)000325550400019 ()
    Available from: 2013-11-13 Created: 2013-11-11 Last updated: 2017-03-19Bibliographically approved
    2. Comminution-amorphisation relationships during ball milling of lactose at different stress energies
    Open this publication in new window or tab >>Comminution-amorphisation relationships during ball milling of lactose at different stress energies
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The purpose of the study was to investigate the relationship between comminution and amorphisation of α-lactose monohydrate particles during ball milling under different milling conditions, including ball-to-powder mass ratio, milling time and ball diameter.

    The results revealed that at a constant ball filling ratio, ball-to-powder mass ratio of 25:1 resulted in the lowest minimum particle size of ~5 μm and the highest degree of apparent amorphous content of 82%. The rate of comminution was high during early stage of milling whereas the degree of apparent amorphous content increased gradually at a slow rate. An increased ball-to-powder mass ratio during milling increased both the rate of comminution and the rate of amorphisation. Using a given ball-to-powder mass ratio, the ball size affected the degree of apparent amorphous content of the particles while the particle diameter remained unchanged.

    The relationship between comminution and amorphisation could be described as consisting of two regimes, i.e. comminution dominated and amorphisation dominated regime. It was proposed that the rate constant of comminution and amorphisation are controlled by stress energy distribution in the milling jar and the stress energy distribution is regulated by the ball motion pattern that can be affected by the process parameter used.

    Keyword
    Ball milling, process-induced disordering, amorphisation, comminution, comminution rate constant, α-lactose monohydrate, stress energy distribution
    National Category
    Chemical Sciences
    Research subject
    Pharmaceutical Science
    Identifiers
    urn:nbn:se:uu:diva-317797 (URN)
    Available from: 2017-03-19 Created: 2017-03-19 Last updated: 2017-03-19
    3. Influence of degree of disorder on the Heckel yield pressure: a comparison between milled and physical mixtures of lactose
    Open this publication in new window or tab >>Influence of degree of disorder on the Heckel yield pressure: a comparison between milled and physical mixtures of lactose
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    The purpose of this study was to investigate the effect of degree of amorphisation of a series of lactose powders, prepared by milling α-lactose monohydrate powders for different time periods, on the plastic stiffness of the particles. As references, a series of physical mixtures consisting of original crystalline particles and amorphous particles obtained by spray-drying was used. In addition, the effect of powder pre-storage humidity on the mechanical properties was investigated. The particle plastic stiffness was assessed by the Heckel yield pressure derived from the relationship between porosity of the powder column and the applied compression pressure during confined powder compression.

     

    For milled particles of a low degree of disorder, a decreased particle size increased the particle plastic stiffness. For milled particles of constant particle size, the plastic stiffness decreased with an increased degree of disorder while the elastic stiffness seemed independent of the degree of disorder. The presence of moisture caused a recrystallization of milled particles with low degree of disorder which increased their plastic stiffness.

     

    For the physical mixtures of crystalline and amorphous particles, similar relationships between plastic stiffness and amorphous content as for the milled powders were obtained. A reasonable explanation is that the nature of the milled particles is represented by a two-state system with crystalline and amorphous domains.

    Keyword
    Milling-induced disorder, plasticity, elasticity, compression, amorphous lactose, Raman spectroscopy
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-317799 (URN)
    Available from: 2017-03-19 Created: 2017-03-19 Last updated: 2017-03-19
    4. Considerations on the quantitative analysis of apparent amorphicity of milled lactose by Raman spectroscopy
    Open this publication in new window or tab >>Considerations on the quantitative analysis of apparent amorphicity of milled lactose by Raman spectroscopy
    Show others...
    2016 (English)In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 511, no 1, 488-504 p.Article in journal (Refereed) Published
    Abstract [en]

    The main purpose of the study was to evaluate various pre-processing and quantification approaches of Raman spectrum to quantify low level of amorphous content in milled lactose powder. To improve the quantification analysis, several spectral pre-processing methods were used to adjust background effects. The effects of spectral noise on the variation of determined amorphous content were also investigated theoretically by propagation of error analysis and were compared to the experimentally obtained values. Additionally, the applicability of calibration method with crystalline or amorphous domains in the estimation of amorphous content in milled lactose powder was discussed. Two straight baseline pre-processing methods gave the best and almost equal performance. By the succeeding quantification methods, PCA performed best, although the classical least square analysis (CLS) gave comparable results, while peak parameter analysis displayed to be inferior. The standard deviations of experimental determined percentage amorphous content were 0.94% and 0.25% for pure crystalline and pure amorphous samples respectively, which was very close to the standard deviation values from propagated spectral noise. The reasonable conformity between the milled samples spectra and synthesized spectra indicated representativeness of physical mixtures with crystalline or amorphous domains in the estimation of apparent amorphous content in milled lactose.

    Keyword
    Raman spectroscopy, Lactose, Amorphous content, Spectral data analysis, Principal component analysis (PCA), Milling induced disorder
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:uu:diva-304150 (URN)10.1016/j.ijpharm.2016.07.001 (DOI)000382263700051 ()27397869 (PubMedID)
    Available from: 2016-10-03 Created: 2016-10-03 Last updated: 2017-03-19Bibliographically approved
    5. Determination of Interfacial Amorphicity in Functional Powders
    Open this publication in new window or tab >>Determination of Interfacial Amorphicity in Functional Powders
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    2017 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 33, no 4, 920-926 p.Article in journal (Refereed) Published
    Abstract [en]

    The nature of the surfaces of particles of pharmaceutical ingredients, food powders, and polymers is a determining factor for their performance in for example tableting, powder handling, or mixing. Changes on the surface structure of the material will impact the flow properties, dissolution rate, and tabletability of the 2 powder blend. For crystalline materials, surface amorphization is a phenomenon which is known to impact performance. Since it is important to measure and control the level of amorphicity, several characterization techniques are available to determine the bulk amorphous content of a processed material. The possibility of characterizing the degree of amorphicity at the surface, for example by studying the mechanical properties of the particles' surface at the nanoscale, is currently only offered by atomic force microscopy (AFM). The AFM PeakForce QNM technique has been used to measure the variation in energy dissipation (eV) at the surface of the particles which sheds light on the mechanical changes occurring as a result of amorphization or recrystallization events. Two novel approaches for the characterization of amorphicity are presented here. First, since particles are heterogeneous, we present a methodology to present the results of extensive QNM analysis of multiple particles in a coherent and easily interpreted manner, by studying cumulative distributions of dissipation data with respect to a threshold value which can be used to distinguish the crystalline and amorphous states. To exemplify the approach, which is generally applicable to any material, reference materials of purely crystalline alpha-lactose monohydrate and completely amorphous spray dried lactose particles were compared to a partially amorphized alpha-lactose monohydrate sample. Dissipation data are compared to evaluations of the lactose samples with conventional AFM and SEM showing significant topographical differences. Finally, the recrystallization of the surface amorphous regions in response to humidity was followed by studying the dissipation response of a well-defined surface region over time, which confirms both that dissipation measurement is a useful measure of surface amorphicity and that significant recrystallization occurs at the surface in response to humidity.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-317609 (URN)10.1021/acs.langmuir.6b03969 (DOI)000393269700010 ()
    Available from: 2017-03-16 Created: 2017-03-16 Last updated: 2017-03-19Bibliographically approved
  • Burchett, Helen E. D.
    et al.
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Leurent, Baptiste
    London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London, England..
    Baiden, Frank
    Ensign Coll Publ Hlth, Epidemiol Unit, Kpong, Ghana..
    Baltzell, Kimberly
    Univ Calif Berkeley, Dept Family Hlth Care Nursing & Global Hlth Sci, Berkeley, CA 94720 USA..
    Bjorkman, Anders
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden..
    Bruxvoort, Katia
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Clarke, Sian
    London Sch Hyg & Trop Med, Dis Control Dept, London, England..
    DiLiberto, Deborah
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Elfving, Kristina
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Dept Pediat, Gothenburg, Sweden..
    Goodman, Catherine
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Hopkins, Heidi
    London Sch Hyg & Trop Med, Dis Control Dept, London, England..
    Lal, Sham
    London Sch Hyg & Trop Med, Dis Control Dept, London, England..
    Liverani, Marco
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Magnussen, Pascal
    Univ Copenhagen, Fac Hlth & Med Sci, Ctr Med Parasitol, Copenhagen, Denmark..
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Mbacham, Wilfred
    Univ Yaounde, Ctr Biotechnol, Lab Publ Hlth Res Biotechnol, Yaounde, Cameroon..
    Mbonye, Anthony
    Makerere Univ, Sch Publ Hlth, Kampala, Uganda.;Minist Hlth, Commissioner Hlth Serv, Kampala, Uganda..
    Onwujekwe, Obinna
    Univ Nigeria, Dept Therapeut & Pharmacol, Enugu Campus, Enugu, Nigeria..
    Allen, Denise Roth
    Ctr Dis Control & Prevent CDC, Atlanta, GA USA..
    Shakely, Deler
    Karolinska Inst, Dept Microbiol Tumour & Cell Biol, Stockholm, Sweden.;Kungalv Hosp, Dept Med, Kungalv, Sweden..
    Staedke, Sarah
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Vestergaard, Lasse S.
    Univ Copenhagen, Ctr Med Parasitol, DK-1168 Copenhagen, Denmark.;Copenhagen Univ Hosp, Rigshosp, Copenhagen, Denmark.;Statens Serum Inst, Dept Infect Dis Epidemiol, Copenhagen, Denmark..
    Whitty, Christopher J. M.
    London Sch Hyg & Trop Med, Dept Clin Res, London, England..
    Wiseman, Virginia
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England.;Sch Publ Hlth & Community Med, Kensington, NSW, Australia..
    Chandler, Clare I. R.
    London Sch Hyg & Trop Med, Dept Global Hlth & Dev, London, England..
    Improving prescribing practices with rapid diagnostic tests (RDTs): synthesis of 10 studies to explore reasons for variation in malaria RDT uptake and adherence2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, e012973Article in journal (Refereed)
    Abstract [en]

    Objectives: The overuse of antimalarial drugs is widespread. Effective methods to improve prescribing practice remain unclear. We evaluated the impact of 10 interventions that introduced rapid diagnostic tests for malaria (mRDTs) on the use of tests and adherence to results in different contexts. Design: A comparative case study approach, analysing variation in outcomes across different settings. Setting: Studies from the ACT Consortium evaluating mRDTs with a range of supporting interventions in 6 malaria endemic countries. Providers were governmental or non-governmental healthcare workers, private retail sector workers or community volunteers. Each study arm in a distinct setting was considered a case. Participants: 28 cases from 10 studies were included, representing 148 461 patients seeking care for suspected malaria. Interventions: The interventions included different mRDT training packages, supervision, supplies and community sensitisation. Outcome measures: Analysis explored variation in: (1) uptake of mRDTs (% febrile patients tested); (2) provider adherence to positive mRDTs (% Plasmodium falciparum positive prescribed/given Artemisinin Combination Treatment); (3) provider adherence to negative mRDTs (% P. falciparum negative not prescribed/given antimalarial). Results: Outcomes varied widely across cases: 12-100% mRDT uptake; 44-98% adherence to positive mRDTs; 27-100% adherence to negative mRDTs. Providers appeared more motivated to perform well when mRDTs and intervention characteristics fitted with their own priorities. Goodness of fit of mRDTs with existing consultation and diagnostic practices appeared crucial to maximising the impact of mRDTs on care, as did prior familiarity with malaria testing; adequate human resources and supplies; possible alternative treatments for mRDT-negative patients; a more directive intervention approach and local preferences for ACTs. Conclusions: Basic training and resources are essential but insufficient to maximise the potential of mRDTs in many contexts. Programme design should respond to assessments of provider priorities, expectations and capacities. As mRDTs become established, the intensity of supporting interventions required seems likely to reduce.

  • Karjala, Jaana
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Malarsjukhuset Hosp, Dept Paediat, Eskilstuna, Sweden..
    Eriksson, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy. Umea Univ, Dept Community Med & Rehabil, Physiotherapy, Umea, Sweden..
    Inter-rater reliability between nurses for a new paediatric triage system based primarily on vital parameters: the Paediatric Triage Instrument (PETI)2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, e012748Article in journal (Refereed)
    Abstract [en]

    Introduction: The major paediatric triage systems are primarily based on flow charts involving signs and symptoms for orientation and subjective estimates of the patient's condition. In contrast, the 4-level Paediatric Triage Instrument (PETI) is primarily based on vital parameters and was developed exclusively for paediatric triage in patients with medical symptoms. The aim of this study was to assess the inter-rater reliability of this triage system in children when used by nurses. Methods: A design was employed in which triage was performed simultaneously and independently by a research nurse and an emergency department (ED) nurse using the PETI. All patients aged <= 12 years who presented at the ED with a medical symptom were considered eligible for participation. Results: The 89 participants exhibited a median age of 2 years and were triaged by 28 different nurses. The inter-rater reliability between nurses calculated with the quadratic-weighted kappa was 0.78 (95% CI 0.67 to 0.89); the linear-weighted kappa was 0.67 (95% CI 0.56 to 0.80) and the unweighted kappa was 0.59 (95% CI 0.44 to 0.73). For the patients aged <1, 1-3 and >3 years, the quadratic-weighted kappa values were 0.67 (95% CI 0.39 to 0.94), 0.86 (95% CI 0.75 to 0.97) and 0.73 (95% CI 0.49 to 0.97), respectively. The median triage duration was 6 min. Conclusions: The PETI exhibited substantial reliability when used in children aged <= 12 years and almost perfect reliability among children aged 1-3 years. Moreover, rapid application of the PETI was demonstrated. This study has some limitations, including sample size and generalisability, but the PETI exhibited promise regarding reliability, and the next step could be either a larger reliability study or a validation study.

  • Gottvall, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Red Cross Univ Coll, Huddinge, Sweden..
    Stenhammar, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Grandahl, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Parents' views of including young boys in the Swedish national school-based HPV vaccination programme: a qualitative study2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, no 2, e014255Article in journal (Refereed)
    Abstract [en]

    Objective: To explore parents' views of extending the human papillomavirus (HPV) vaccination programme to also include boys. Design: Explorative qualitative design using individual, face-to-face, interviews and inductive thematic analysis. Setting: 11 strategically chosen municipalities in central Sweden. Participants: Parents (n= 42) who were offered HPV vaccination for their 11-12 years old daughter in the national school-based vaccination programme. Results: The key themes were: equality from a public health perspective and perception of risk for disease. Parents expressed low knowledge and awareness about the health benefits of male HPV vaccination, and they perceived low risk for boys to get HPV. Some parents could not see any reason for vaccinating boys. However, many parents preferred gender-neutral vaccination, and some of the parents who had not accepted HPV vaccination for their daughter expressed that they would be willing to accept vaccination for their son, if it was offered. It was evident that there was both trust and distrust in authorities' decision to only vaccinate girls. Parents expressed a preference for increased sexual and reproductive health promotion such as more information about condom use. Some parents shared that it was more important to vaccinate girls than boys since they believed girls face a higher risk of deadly diseases associated with HPV, but some also believed girls might be more vulnerable to side effects of the vaccine. Conclusions: A vaccine offered only to girls may cause parents to be hesitant to vaccinate, while also including boys in the national vaccination programme might improve parents' trust in the vaccine. More information about the health benefits of HPV vaccination for males is necessary to increase HPV vaccination among boys. This may eventually lead to increased HPV vaccine coverage among both girls and boys.

  • Hedman, Åsa K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Solna, Cardiovasc Med Unit, Stockholm, Sweden..
    Mendelson, Michael M.
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Boston, MA 02215 USA.;Boston Childrens Hosp, Dept Cardiol, Boston, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    Marioni, Riccardo E.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Med Genet Sect, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia..
    Gustafsson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Joehanes, Roby
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA.;Harvard Med Sch, Hebrew Senior Life, Boston, MA USA..
    Irvin, Marguerite R.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA..
    Zhi, Degui
    Univ Alabama Birmingham, Dept Biostat, Sect Stat Genet, Birmingham, AL 35294 USA..
    Sandling, Johanna K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Yao, Chen
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    Liu, Chunyu
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Dept Biosci, Boston, MA 02215 USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    Liang, Liming
    Harvard Sch Publ Hlth, Dept Biostat, Boston, MA USA..
    Huan, Tianxiao
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    McRae, Allan F.
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Demissie, Serkalem
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Dept Biosci, Boston, MA 02215 USA..
    Shah, Sonia
    Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia.;Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia..
    Starr, John M.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Alzheimer Scotland Dementia Res Ctr, Edinburgh EH8 9YL, Midlothian, Scotland..
    Cupples, L. Adrienne
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;Boston Univ, Dept Biosci, Boston, MA 02215 USA..
    Deloukas, Panos
    Queen Mary Univ London, Barts & London Sch Med & Dent, William Harvey Res Inst, London, England.;King Abdulaziz Univ, Princess Al Jawhara Al Brahim Ctr Excellence Res, Jeddah, Saudi Arabia..
    Spector, Timothy D.
    Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England..
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Krauss, Ronald M.
    Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA..
    Arnett, Donna K.
    Univ Kentucky, Coll Publ Hlth, Lexington, KY 40506 USA..
    Deary, Ian J.
    Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9YL, Midlothian, Scotland.;Univ Edinburgh, Dept Psychol, Edinburgh EH8 9YL, Midlothian, Scotland..
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiovascular epidemiology.
    Levy, Daniel
    Framingham Heart Dis Epidemiol Study, Framingham, MA USA.;NHLBI, Populat Sci Branch, NIH, Bldg 10, Bethesda, MD 20892 USA..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Stanford Univ, Sch Med, Dept Med, Div Cardiovasc Med, 300 Pasteur Dr,Mail Code 5773, Stanford, CA 94305 USA..
    Epigenetic Patterns in Blood Associated With Lipid Traits Predict Incident Coronary Heart Disease Events and Are Enriched for Results From Genome-Wide Association Studies2017In: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 10, no 1, UNSP e001487Article in journal (Refereed)
    Abstract [en]

    Background- Genome-wide association studies have identified loci influencing circulating lipid concentrations in humans; further information on novel contributing genes, pathways, and biology may be gained through studies of epigenetic modifications. Methods and Results- To identify epigenetic changes associated with lipid concentrations, we assayed genome-wide DNA methylation at cytosine-guanine dinucleotides (CpGs) in whole blood from 2306 individuals from 2 population-based cohorts, with replication of findings in 2025 additional individuals. We identified 193 CpGs associated with lipid levels in the discovery stage (P < 1.08E-07) and replicated 33 (at Bonferroni-corrected P < 0.05), including 25 novel CpGs not previously associated with lipids. Genes at lipid-associated CpGs were enriched in lipid and amino acid metabolism processes. A differentially methylated locus associated with triglyceridesand high-density lipoprotein cholesterol (HDL- C; cg27243685; P= 8.1E-26 and 9.3E-19) was associated with cis-expression of a reverse cholesterol transporter (ABCG1; P= 7.2E-28) and incident cardiovascular disease events (hazard ratio per SD increment, 1.38; 95% confidence interval, 1.15-1.66; P= 0.0007). We found significant cis-methylation quantitative trait loci at 64% of the 193 CpGs with an enrichment of signals from genome-wide association studies of lipid levels (P-TC = 0.004, PHDL-C = 0.008 and P-triglycerides = 0.00003) and coronary heart disease ( P= 0.0007). For example, genome-wide significant variants associated with low-density lipoprotein cholesterol and coronary heart disease at APOB were cis-methylation quantitative trait loci for a low-density lipoprotein cholesterol-related differentially methylated locus. Conclusions-We report novel associations of DNA methylation with lipid levels, describe epigenetic mechanisms related to previous genome-wide association studies discoveries, and provide evidence implicating epigenetic regulation of reverse cholesterol transport in blood in relation to occurrence of cardiovascular disease events.

  • Kaya, Ibrahim
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, S-43180 Molndal, Sweden..
    Brinet, Dimitri
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, S-43180 Molndal, Sweden.;Univ Gothenburg, Dept Chem & Mol Biol, S-41296 Gothenburg, Sweden..
    Michno, Wojciech
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, S-43180 Molndal, Sweden..
    Syvänen, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Sehlin, Dag
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Zetterberg, Henrik
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, S-43180 Molndal, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, S-43180 Molndal, Sweden.;UCL, Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England..
    Blennow, Kaj
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, S-43180 Molndal, Sweden.;Sahlgrens Univ Hosp, Clin Neurochem Lab, S-43180 Molndal, Sweden..
    Hanrieder, Jorg
    Univ Gothenburg, Sahlgrenska Acad, Dept Psychiat & Neurochem, S-43180 Molndal, Sweden.;UCL, Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England.;Chalmers, Dept Chem & Chem Engn, S-41296 Gothenburg, Sweden..
    Delineating Amyloid Plaque Associated Neuronal Sphingolipids in Transgenic Alzheimer's Disease Mice (tgArcSwe) Using MALDI Imaging Mass Spectrometry2017In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 8, no 2, 347-355 p.Article in journal (Refereed)
    Abstract [en]

    The major pathological hallmarks of Alzheimer's disease (AD) are the progressive aggregation and accumulation of beta-amyloid (A beta) and hyperphosphorylated tau protein into neurotoxic deposits. A beta aggregation has been suggested as the critical early inducer, driving the disease progression. However, the factors that promote neurotoxic A beta aggregation remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate the spatial distribution patterns of lipids, peptides, and proteins in biological tissue sections. In the present study, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS)-based imaging was used on transgenic Alzheimer's disease mouse (tgArcSwe) brain tissue to investigate the sphingolipid microenvironment of individual A beta plaques and elucidate plaque-associated sphingolipid alterations. Multivariate data analysis was used to interrogate the IMS data for identifying pathologically relevant, anatomical features based on their lipid chemical profile. This approach revealed sphingolipid species that distinctly located to cortical and hippocampal deposits, whose A beta identity was further verified using fluorescent amyloid staining and immunohistochemistry. Subsequent multivariate statistical analysis of the spectral data revealed significant localization of gangliosides and ceramides species to A beta positive plaques, which was accompanied by distinct local reduction of sulfatides. These plaque-associated changes in sphingolipid levels implicate a functional role of sphingolipid metabolism in A beta plaque pathology and AD pathogenesis. Taken together, the presented data highlight the potential of imaging mass spectrometry as a powerful approach for probing A beta plaque-associated lipid changes underlying AD pathology.

  • Robinson, Anna-Lena
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics. Stockholm Spine Ctr, Stockholm, Sweden..
    Moller, Anders
    Skane Univ Hosp, Dept Orthopaed, Malmo, Sweden..
    Robinson, Yohan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Olerud, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    C2 Fracture Subtypes, Incidence, and Treatment Allocation Change with Age: A Retrospective Cohort Study of 233 Consecutive Cases2017In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, 8321680Article in journal (Refereed)
    Abstract [en]

    The currently available data on the distribution of C2 fracture subtypes is sparse. This study was designed to identify the proportions of the second cervical vertebra (C2) fracture subtypes and to present age and gender specific incidences of subgroups. A dataset of all patients treated between 2002 and 2014 for C2 fractures was extracted from the regional hospital information system. C2 fractures were classified into odontoid fractures types 1, 2, and 3, Hangman's fractures types 1, 2, and 3, and atypical C2 fractures. 233 patients (female 51%, age 72 +/- 19 years) were treated for a C2 fracture. Odontoid fractures were found in 183 patients, of which 2 were type 1, 127 type 2, and 54 type 3, while 26 of C2 fractures were Hangman's fractures and 24 were atypical C2 fractures. In the geriatric subgroup 89% of all C2 fractures were odontoid, of which 71% were type 2 and 29% type 3. There was an increasing incidence of odontoid fractures types 2 and 3 from 2002 to 2014. 40% of C2 fractures were treated surgically. This study presents reliable subset proportions of C2 fractures in a prospectively collected regional cohort. Knowledge of these proportions facilitates future epidemiological studies of C2 fractures.

  • Rodriguez-Wallberg, Kenny A.
    et al.
    Karolinska Univ Hosp, Dept Obstet & Gynecol, Reprod Med, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Tanbo, Tom
    Tinkanen, Helena
    Oslo Univ Hosp, Dept Gynecol, Oslo, Norway.;Tampere Univ Hosp, Tampere, Finland..
    Thurin-Kjellberg, Ann
    Sahlgrens Univ Hosp, Gothenburg, Sweden..
    Nedstrand, Elizabeth
    Linkoping Univ Hosp, Linkoping, Sweden..
    Kitlinski, Margareta Laczna
    Skane Univ Hosp, Malmo, Sweden..
    Macklon, Kirsten T.
    Rigshosp Univ Hosp, Copenhagen, Denmark..
    Ernst, Erik
    Aarhus Univ Hosp, Aarhus, Denmark..
    Fedder, Jens
    Odense Univ Hosp, Odense, Denmark..
    Tiitinen, Aila
    Helsinki Univ Hosp, Helsinki, Finland..
    Morin-Papunen, Laure
    Oulu Univ Hosp, Oulu, Finland.;Univ Oulu, Oulu, Finland..
    Einarsson, Snorri
    ART Medica, Reykjavik, Iceland..
    Jokimaa, Varpu
    Turku Univ Hosp, Turku, Finland..
    Hippelainen, Maritta
    Kuopio Univ Hosp, Kuopio, Finland..
    Lood, Mikael
    Orebro Univ Hosp, Orebro, Sweden..
    Gudmundsson, Johannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Olofsson, Jan I.
    Karolinska Univ Hosp, Dept Obstet & Gynecol, Reprod Med, Stockholm, Sweden.;Karolinska Inst, Div Obstet & Gynecol, Dept Clin Sci Intervent & Technol, Stockholm, Sweden..
    Andersen, Claus Yding
    Rigshosp Univ Hosp, Copenhagen, Denmark.;Univ Copenhagen, Reprod Biol Lab, Copenhagen, Denmark..
    Ovarian tissue cryopreservation and transplantation among alternatives for fertility preservation in the Nordic countries - compilation of 20 years of multicenter experience2016In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 95, no 9, 1015-1026 p.Article in journal (Refereed)
    Abstract [en]

    Introduction. The aim of this study is to report the current status of ovarian tissue cryopreservation among alternatives for fertility preservation in the Nordic countries. Material and methods. A questionnaire was sent to 14 Nordic academic reproductive centers with established fertility preservation programs. It covered fertility preservation cases performed up to December 2014, standard procedures for ovarian tissue cryopreservation and oocyte cryopreservation and reproductive outcomes following ovarian tissue transplantation. Results. Among the Nordic countries, Denmark and Norway practice ovarian tissue cryopreservation as a clinical treatment (822 and 164 cases, respectively) and their programs are centralized. In Sweden (457 cases), ovarian tissue cryopreservation is practiced at five of six centers and in Finland at all five centers (145 cases). Nearly all considered ovarian tissue cryopreservation to be experimental. In Iceland, embryo cryopreservation is the only option for fertility preservation. Most centers use slow-freezing methods for ovarian tissue cryopreservation. Most patients selected for ovarian tissue cryopreservation were newly diagnosed with cancer and the tissue was predominantly retrieved laparoscopically by unilateral oophorectomy. Only minor complications were reported. In total, 46 women have undergone ovarian tissue transplantation aiming at recovering fertility, 17 healthy children have been born and several additional pregnancies are currently ongoing. Whenever patients' clinical condition is permissive, oocyte cryopreservation after hormonal stimulation is preferred for fertility preservation. Between 2012 and 2014, a smaller proportion of females have undergone fertility preservation in the Nordic centers, in comparison to males (1: 3). Conclusions. Overall, ovarian tissue cryopreservation was reported to be safe. Slow freezing methods are still preferred. Promising results of recovery of fertility have been reported in Nordic countries that have initiated ovarian tissue transplantation procedures.

  • Public defence: 2017-05-12 13:00 Gunnar Johansson salen, Uppsala
    Björkstrand, Johannes
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    The Amygdala, Fear and Reconsolidation: Neural and Behavioral Effects of Retrieval-Extinction in Fear Conditioning and Spider Phobia2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The amygdala is crucially involved in the acquisition and retention of fear memories. Experimental research on fear conditioning has shown that memory retrieval shortly followed by pharmacological manipulations or extinction, thereby interfering with memory reconsolidation, decreases later fear expression. Fear memory reconsolidation depends on synaptic plasticity in the amygdala, which has been demonstrated in rodents using both pharmacological manipulations and retrieval-extinction procedures. The retrieval-extinction procedure decreases fear expression also in humans, but the underlying neural mechanism have not been studied. Interfering with reconsolidation is held to alter the original fear memory representation, resulting in long-term reductions in fear responses, and might therefore be used in the treatment of anxiety disorders, but few studies have directly investigated this question.

    The aim of this thesis was to examine the effects of the retrieval-extinction procedure on amygdala activity and behavioral fear expression in humans. The work presented here also investigated whether findings from studies on recent fear memories, established through fear conditioning, extends to naturally occurring long-term phobic fears.

    Study I, combining fear conditioning and a retrieval-extinction procedure with functional magnetic resonance imaging (fMRI), demonstrated that memory retrieval shortly followed by extinction reduces later amygdala activity and fear expression in healthy subjects. In Study II, these subjects were re-tested 18 months later. The results showed that the effects on fear expression were still present and that initial amygdala activity predicted long-term fear expression. Using an adapted version of the retrieval-extinction procedure, Study III showed that memory retrieval shortly followed by exposure to spider pictures, attenuates subsequent amygdala activity and increases approach behavior in subjects with life-long fear of spiders. In Study IV, these subjects were re-tested 6 months later, and the results showed that effects on amygdala activity as well as approach behavior were maintained.

    In summation, retrieval-extinction leads to long-lasting reductions in amygdala activity and fear expression. These findings are consistent with the hypothesis that retrieval-extinction alters an amygdala dependent fear memory. Retrieval-extinction can also attenuate long-term phobic fears, indicating that this manipulation could be used to enhance exposure-based treatments for anxiety disorders. 

    List of papers
    1. Disruption of reconsolidation erases a fear memory trace in the human amygdala
    Open this publication in new window or tab >>Disruption of reconsolidation erases a fear memory trace in the human amygdala
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    2012 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 337, no 6101, 1550-1552 p.Article in journal (Refereed) Published
    Abstract [en]

    Memories become labile when recalled. In humans and rodents alike, reactivated fear memories can be attenuated by disrupting reconsolidation with extinction training. Using functional brain imaging, we found that, after a conditioned fear memory was formed, reactivation and reconsolidation left a memory trace in the basolateral amygdala that predicted subsequent fear expression and was tightly coupled to activity in the fear circuit of the brain. In contrast, reactivation followed by disrupted reconsolidation suppressed fear, abolished the memory trace, and attenuated fear-circuit connectivity. Thus, as previously demonstrated in rodents, fear memory suppression resulting from behavioral disruption of reconsolidation is amygdala-dependent also in humans, which supports an evolutionarily conserved memory-update mechanism.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-181451 (URN)10.1126/science.1223006 (DOI)000308912900054 ()22997340 (PubMedID)
    Available from: 2012-09-24 Created: 2012-09-24 Last updated: 2017-03-20Bibliographically approved
    2. Disruption of Memory Reconsolidation Erases a Fear Memory Trace in the Human Amygdala: An 18-Month Follow-Up.
    Open this publication in new window or tab >>Disruption of Memory Reconsolidation Erases a Fear Memory Trace in the Human Amygdala: An 18-Month Follow-Up.
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    2015 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 10, no 7, e0129393- p.Article in journal (Refereed) Published
    Abstract [en]

    Fear memories can be attenuated by reactivation followed by disrupted reconsolidation. Using functional magnetic resonance imaging we recently showed that reactivation and reconsolidation of a conditioned fear memory trace in the basolateral amygdala predicts subsequent fear expression over two days, while reactivation followed by disrupted reconsolidation abolishes the memory trace and suppresses fear. In this follow-up study we demonstrate that the behavioral effect persists over 18 months reflected in superior reacquisition after undisrupted, as compared to disrupted reconsolidation, and that neural activity in the basolateral amygdala representing the initial fear memory predicts return of fear. We conclude that disrupting reconsolidation have long lasting behavioral effects and may permanently erase the fear component of an amygdala-dependent memory.

    National Category
    Psychology
    Identifiers
    urn:nbn:se:uu:diva-259785 (URN)10.1371/journal.pone.0129393 (DOI)000358153000028 ()26132145 (PubMedID)
    Funder
    Swedish Research Council, 521-2010-3284, 421-2009-2343The Swedish Brain Foundation, FO2014-0151
    Note

    Boethius stiftelse  PSYK2010/143, Swedish Council for Working Life and Social Research, Heumanska stiftelsen

    Available from: 2015-08-11 Created: 2015-08-11 Last updated: 2017-03-20Bibliographically approved
    3. Disrupting Reconsolidation Attenuates Long-Term Fear Memory in the Human Amygdala and Facilitates Approach Behavior
    Open this publication in new window or tab >>Disrupting Reconsolidation Attenuates Long-Term Fear Memory in the Human Amygdala and Facilitates Approach Behavior
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    2016 (English)In: Current Biology, ISSN 0960-9822, E-ISSN 1879-0445, Vol. 26, no 19, 2690-95 p.Article in journal (Refereed) Published
    Abstract [en]

    Memories become labile and malleable to modification when recalled [1]. Fear-conditioning experiments in both rodents and humans indicate that amygdala-localized short-term fear memories can be attenuated by disruption of their reconsolidation with extinction training soon after memory activation [2-7]. However, this may not be true for natural long-term fears. Studies in rodents indicate that although it is possible to disrupt the reconsolidation of older memories [8-11], they appear to be more resistant [1, 3, 9, 12, 13]. In humans, 1-week-old conditioned fear memories have been attenuated by behaviorally induced disruption of reconsolidation [14], but it remains to be seen whether this is possible for naturally occurring long-term fears and whether the underlying neural mechanisms are similar to those found in experimental fear-conditioning paradigms. Using functional brain imaging in individuals with a lifelong fear of spiders, we show that fear memory activation followed by repeated exposure to feared cues after 10 min, which disrupts reconsolidation, attenuates activity in the basolateral amygdala at re-exposure 24 hr later. In contrast, repeated exposure 6 hr after fear memory activation, which allows for reconsolidation, did not attenuate amygdala activity. Disrupted, but not undisrupted, reconsolidation facilitated approach behavior to feared cues, and approach behavior was inversely related to amygdala activity during re-exposure. We conclude that memory activation immediately preceding exposure attenuates the neural and behavioral expression of decades-old fear memories and that, similar to experimentally induced fear memories, the basolateral amygdala is crucially involved in this process.

    National Category
    Psychology Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-302737 (URN)10.1016/j.cub.2016.08.022 (DOI)000385690800032 ()27568591 (PubMedID)
    Funder
    Swedish Research CouncilThe Swedish Brain Foundation
    Available from: 2016-09-08 Created: 2016-09-08 Last updated: 2017-03-20Bibliographically approved
    4. Think twice, it́s all right: Long lasting effects of disrupted reconsolidation on brain and behavior in human long-term fear
    Open this publication in new window or tab >>Think twice, it́s all right: Long lasting effects of disrupted reconsolidation on brain and behavior in human long-term fear
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    2017 (English)In: Behavioural Brain Research, ISSN 0166-4328, E-ISSN 1872-7549, Vol. 324, 125-129 p.Article in journal (Refereed) Published
    Abstract [en]

    Memories can be modified when recalled. Experimental fear conditioning studies support that amygdala-localized fear memories are attenuated when reconsolidation is disrupted through extinction training immediately following memory activation. Recently, using functional brain imaging in individuals with lifelong spider fears, we demonstrated that fear memory activation followed by repeated exposure to feared cues after 10minutes, thereby disrupting reconsolidation, attenuated activity in the amygdala during later re-exposure, and also facilitated approach behavior to feared cues. In contrast, repeated exposure 6hours after fear memory activation, allowing for reconsolidation, did not attenuate amygdala activity and resulted in less approach behavior as compared to the group that received disrupted reconsolidation. We here evaluated if these effects are stable after 6 months and found that amygdala activity was further reduced in both groups, with a tendency towards greater reductions in the 10min than the 6h group. Hence, disrupted reconsolidation results in long lasting attenuation of amygdala activity. The behavioral effect, with more approach towards previously feared cues, in the 10min than the 6h group also persisted. Thus, the brain effect of disrupted reconsolidation is stable over 6 months and the behavioral effect also remained. We therefore conclude that disrupted reconsolidation result in a long-lasting diminished fear memory representation in the amygdala which may have clinical importance.

    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-315854 (URN)10.1016/j.bbr.2017.02.016 (DOI)28214541 (PubMedID)
    Available from: 2017-02-21 Created: 2017-02-21 Last updated: 2017-03-20Bibliographically approved
  • David, Samer
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics.
    Testtäckningsstruktur för fälttestning av SDP3: Skapande och visualisering av testtäckningsstruktur för SDP3 med hjälp av användardata2017Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    A big part of software development is testing and quality assurance. At the department of service market, Scania R&D, the software Scania Diagnose and Programmer 3 (SDP3) is developed and tested. The quality assurance is conducted by internal and external testing. However, the external testing of SDP3 lacks guidelines for measuring the quality of a field test. The purpose of this project was to create and implement a framework for the field test process of SDP3. This framework is later used to determine the quality of a field test. To create the framework, literature study, interviews and workshops were conducted. The workshops laid the foundation of the framework, and the interviews were used to specify the parameters in the framework. For the implementation of the framework studies were done to analyse the available data, later the framework was implemented into the data base management system Splunk as a real time Dashboard. The results of this study describes a framework that can be used to determine the quality of a field test. Unfortunately the whole framework could not be implemented into Splunk since all data needed could not be accessed through Splunk, instead, recommendations were made. 

  • Public defence: 2017-05-12 09:00 Skoogsalen, Uppsala
    Haylock, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Targeting molecules for diagnostics of Head and Neck squamous cell carcinoma2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    To personalize treatment for cancer, correct staging of the primary tumor, nodal disease and metastatic disease is of essence. By targeting tumor specific receptors with radiolabeled antibodies, specificity and accuracy of imaging may be improved. Radio-immunodiagnostics can potentially detect small volume disease, occult metastasis and recurrent cancer in treated tissue. This thesis focuses on evaluation of radio-immunoconjugates directed towards CD44v6, which is a surface receptor overexpressed in many head and neck squamous cell carcinomas. At the outset, the monoclonal chimeric antibody cMab U36 and its cleavage products Fab’ and F(ab’)2 were labeled with 125I and assessed in vitro and in vivo (paper I). The best distribution pattern and tumor to organ ratio was achieved with F(ab’)2. Due to the immunological responses humans can develop towards chimeric antibodies, they are not optimal for clinical use, and subsequently fully human antibody fragments were developed. AbD15179, which is a monovalent fragment, was labeled with 111In and 125I and evaluated in vitro and in mice bearing CD44v6-expressing tumors. Tumor to organ ratios were improved compared to cMab U36 derived fragments, and 111In-AbD15179 displayed a more favorable distribution compared to 125I-AbD15179 (Paper II). A bivalent Fab-dHXL, AbD19384 derived from AbD15179, was then constructed and labeled with 125I and evaluated in cell- and biodistribution studies. Furthermore, an imaging study in a small animal PET was performed with 124I-AbD19384 (Paper III). Uptake in kidneys was reduced and liver uptake increased compared to AbD15179 reflecting the larger molecule. The high CD44v6 expressing tumor was clearly visualized with maximum uptake at 48 hours post injection.In paper IV human single chain fragments towards CD44v6v were selected, and the top candidates A11 and H12 were further evaluated in vitro and in vivo. Single chain fragments are small molecules exhibiting fast clearance and high affinity to the target. The study proved this by demonstrating superior tumor to blood ratios of radiolabeled A11 and H12 compared to previously studied molecules. 

    List of papers
    1. A novel CD44v6 targeting antibody fragment with improved tumor-to-blood ratio
    Open this publication in new window or tab >>A novel CD44v6 targeting antibody fragment with improved tumor-to-blood ratio
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    2012 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 40, no 5, 1525-1532 p.Article in journal (Refereed) Published
    Abstract [en]

    The chimeric monoclonal antibody U36 (cMAb U36) recognizes the CD44v6 antigen. Its potential as a radioimmunotargeting agent, as well as its safety, has been shown in previous studies in head and neck cancer patients. However, intact MAbs have long circulation time in the blood and tumor targeting may also be hampered due to the slow and incomplete diffusion into solid tumors. In comparison, smaller monovalent Fab' and divalent F(ab')2 fragments are expected to exhibit shorter circulating half-lives, better tumor penetration and are thus more likely to yield better imaging results. In this study, novel F(ab')2 and Fab' fragments from cMAb U36 were radiolabeled with 125I and the characteristics of the conjugates in vitro were examined. The biodistribution of the conjugates were then evaluated in nude mice bearing CD44v6-expressing xenograft tumors. Furthermore, the penetration depth and distribution in tumor tissue was assessed by autoradiography in selected tumor samples. The in vitro experiments showed that the conjugates were stable and had intact affinity to CD44v6. The biodistribution study demonstrated superior tumor-to-blood ratio for the novel cMAb U36 fragment 125I-F(ab')2 compared with both the intact MAb and the monovalent fragment form. Autoradiography also revealed better tumor penetration for 125I-F(ab')2. This study demonstrates that the use of antibody fragments may improve radioimmunotargeting and possibly improve the management of head and neck malignancies.

    National Category
    Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Otorhinolaryngology
    Research subject
    Oto-Rhino-Laryngology
    Identifiers
    urn:nbn:se:uu:diva-170945 (URN)10.3892/ijo.2012.1352 (DOI)000302273400023 ()22307465 (PubMedID)
    Available from: 2012-03-14 Created: 2012-03-14 Last updated: 2017-03-20Bibliographically approved
    2. In vivo characterization of the novel CD44v6-targeting Fab fragment AbD15179 for molecular imaging of squamous cell carcinoma: a dual-isotope study
    Open this publication in new window or tab >>In vivo characterization of the novel CD44v6-targeting Fab fragment AbD15179 for molecular imaging of squamous cell carcinoma: a dual-isotope study
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    2014 (English)In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 4, 11Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Patients with squamous cell carcinoma in the head and neck region (HNSCC) offer a diagnostic challenge due to difficulties to detect small tumours and metastases. Imaging methods available are not sufficient, and radio-immunodiagnostics could increase specificity and sensitivity of diagnostics. The objective of this study was to evaluate, for the first time, the in vivo properties of the radiolabelled CD44v6-targeting fragment AbD15179 and to assess its utility as a targeting agent for radio-immunodiagnostics of CD44v6-expressing tumours.

    METHODS: The fully human CD44v6-targeting Fab fragment AbD15179 was labelled with 111In or 125I, as models for radionuclides suitable for imaging with SPECT or PET. Species specificity, antigen specificity and internalization properties were first assessed in vitro. In vivo specificity and biodistribution were then evaluated in tumour-bearing mice using a dual-tumour and dual-isotope setup.

    RESULTS: Both species-specific and antigen-specific binding of the conjugates were demonstrated in vitro, with no detectable internalization. The in vivo studies demonstrated specific tumour binding and favourable tumour targeting properties for both conjugates, albeit with higher tumour uptake, slower tumour dissociation, higher tumour-to-blood ratio and higher CD44v6 sensitivity for the 111In-labelled fragment. In contrast, the 125I-Fab demonstrated more favourable tumour-to-organ ratios for liver, spleen and kidneys.

    CONCLUSIONS: We conclude that AbD15179 efficiently targets CD44v6-expressing squamous cell carcinoma xenografts, and particularly, the 111In-Fab displayed high and specific tumour uptake. CD44v6 emerges as a suitable target for radio-immunodiagnostics, and a fully human antibody fragment such as AbD15179 can enable further clinical imaging studies.

    Keyword
    Radio-immunodiagnostics, Antibody fragment, CD44v6, Molecular imaging, Fab, I-125, In-111
    National Category
    Radiology, Nuclear Medicine and Medical Imaging
    Identifiers
    urn:nbn:se:uu:diva-221094 (URN)10.1186/2191-219X-4-11 (DOI)000357859200001 ()24598405 (PubMedID)
    Available from: 2014-03-25 Created: 2014-03-25 Last updated: 2017-03-20Bibliographically approved
    3. Evaluation of a novel type of imaging probe based on a recombinant bivalent mini-antibody construct for detection of CD44v6-expressing squamous cell carcinoma
    Open this publication in new window or tab >>Evaluation of a novel type of imaging probe based on a recombinant bivalent mini-antibody construct for detection of CD44v6-expressing squamous cell carcinoma
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    2015 (English)In: International journal of oncology, ISSN 1791-2423, Vol. 48, no 2, 461-470 p.Article in journal (Refereed) Published
    Abstract [en]

    We have developed the CD44v6-targeting human bivalent antibody fragment AbD19384, an engineered recombinant human bivalent Fab antibody formed via dimerization of dHLX (synthetic double helix loop helix motif) domains, for potential use in antibody-based molecular imaging of squamous cell carcinoma in the head and neck region. This is a unique construct that has, to the best of our knowledge, never been assessed for molecular imaging in vivo before. The objective of the present study was to evaluate for the first time the in vitro and in vivo binding properties of radio-iodinated AbD19384, and to assess its utility as a targeting agent for molecular imaging of CD44v6-expressing tumors. Antigen specificity and binding properties were assessed in vitro. In vivo specificity and biodistribution of 125I-AbD19384 were next evaluated in tumor-bearing mice using a dual-tumor setup. Finally, AbD19384 was labeled with 124I, and its imaging properties were assessed by small animal PET/CT in tumor bearing mice, and compared with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG). In vitro studies demonstrated CD44v6-specific binding with slow off-rate for AbD19384. A favorable biodistribution profile was seen in vivo, with tumor-specific uptake. Small animal PET/CT images of 124I-AbD19384 supported the results through clearly visible high CD44v6-expressing tumors and faintly visible low expressing tumors, with superior imaging properties compared to 18F-FDG. Tumor-to-blood ratios increased with time for the conjugate (assessed up to 72 h p.i.), although 48 h p.i. proved best for imaging. Biodistribution and small-animal PET studies demonstrated that the recombinant Fab-dHLX construct AbD19384 is a promising tracer for imaging of CD44v6 antigen expression in vivo, with the future aim to be used for individualized diagnosis and early detection of squamous cell carcinomas in the head and neck region. Furthermore, this proof-of-concept research established the feasibility of using recombinant Fab-dHLX constructs for in vivo imaging of tumor biomarkers.

    Keyword
    molecular imaging; CD44v6; Fab-dHLX; F(ab')(2); recombinant antibodies; immuno-PET; head and neck squamous cell carcinoma
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-270259 (URN)10.3892/ijo.2015.3290 (DOI)000366897500003 ()26676731 (PubMedID)
    Available from: 2015-12-22 Created: 2015-12-22 Last updated: 2017-03-20Bibliographically approved
    4. Generation and evaluation of antibody agents for molecular imaging of CD44v6 expressing cancers
    Open this publication in new window or tab >>Generation and evaluation of antibody agents for molecular imaging of CD44v6 expressing cancers
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    (English)Manuscript (preprint) (Other academic)
    Keyword
    scFv, recombinant antibody formats, CD44v6, squamous cell carcinoma, molecular imaging
    National Category
    Other Basic Medicine
    Identifiers
    urn:nbn:se:uu:diva-316722 (URN)
    Available from: 2017-03-14 Created: 2017-03-14 Last updated: 2017-03-20
  • Gouveia, Leonor
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, Integrated Cardio Metab Ctr, Huddinge, Sweden..
    Andrae, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Expression analysis of platelet-derived growth factor receptor alpha and its ligands in the developing mouse lung2017In: Physiological Reports, E-ISSN 2051-817X, Vol. 5, no 6, e13092Article in journal (Refereed)
    Abstract [en]

    Activation of the platelet-derived growth factor receptor-a (PDGFRa) signaling pathway is critically important during lung alveogenesis, the process in lung development during which alveoli are formed from the terminal alveolar sacs. Several studies have aimed to characterize the expression patterns of PDGFRa and its two ligands (PDGF-A and -C) in the lung, but published analyses have been limited to embryonic and/or perinatal time points, and no attempts have been made to characterize both receptor and ligand expression simultaneously. In this study, we present a detailed map of the expression patterns of PDGFRa, PDGF-A and PDGF-C during the entire period of lung development, that is, from early embryogenesis until adulthood. Three different reporter mice were analyzed (Pdgfa ex4-COIN-INV-lacZ, Pdgfc tm1Nagy, and Pdgfra tm11(EGFP) Sor), in which either lacZ or H2B-GFP were expressed under the respective promoter in gene-targeted alleles. A spatiotemporal dynamic expression was identified for both ligands and receptor. PDGF-A and PDGF-C were located to distinct populations of epithelial and smooth muscle cells, whereas PDGFRa expression was located to different mesenchymal cell populations. The detailed characterization of gene expression provides a comprehensive map of PDGFRa signaling in lung cells, opening up for a better understanding of the role of PDGF signaling during lung development.

  • Addo, Rebecka N.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Stockholm Univ, Dept Psychol, Gosta Ekman Lab, Frescati Hagvag 9A, S-10691 Stockholm, Sweden..
    Wiens, Stefan
    Stockholm Univ, Dept Psychol, Gosta Ekman Lab, Frescati Hagvag 9A, S-10691 Stockholm, Sweden..
    Nord, Marie
    Stockholm Univ, Dept Psychol, Gosta Ekman Lab, Frescati Hagvag 9A, S-10691 Stockholm, Sweden..
    Larsson, Maria
    Stockholm Univ, Dept Psychol, Gosta Ekman Lab, Frescati Hagvag 9A, S-10691 Stockholm, Sweden..
    Olfactory Functions in Adults With Autism Spectrum Disorders2017In: Perception, ISSN 0301-0066, E-ISSN 1468-4233, Vol. 46, no 3-4, 530-537 p.Article in journal (Refereed)
    Abstract [en]

    Autism spectrum disorders (ASD) are often characterized by atypical sensory behavior (hyperor hyporeactivity) although evidence is scarce regarding olfactory abilities in ASD; 16 adults with high-functioning ASD (mean age: 38.2, SD: 9.7) and 14 healthy control subjects (mean age: 42.0 years, SD: 12.5) were assessed in odor threshold, free and cued odor identification, and perceived pleasantness, intensity, and edibility of everyday odors. Although results showed no differences between groups, the Bayes Factors (close to 1) suggested that the evidence for no group differences on the threshold and identification tests was inconclusive. In contrast, there was some evidence for no group differences on perceived edibility (BF01 = 2.69) and perceived intensity (BF01 = 2.80). These results do not provide conclusive evidence for or against differences between ASD and healthy controls on olfactory abilities. However, they suggest that there are no apparent group differences in subjective ratings of odors.

  • Janson, Svante
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Mathematics, Analysis and Probability Theory.
    Luczak, Malwina
    Queen Mary Univ London, Sch Math Sci, Mile End Rd, London E1 4NS, England..
    Windridge, Peter
    Queen Mary Univ London, Sch Math Sci, Mile End Rd, London E1 4NS, England..
    House, Thomas
    Univ Manchester, Sch Math, Manchester M13 9PL, Lancs, England..
    Near-critical SIR epidemic on a random graph with given degrees2017In: Journal of Mathematical Biology, ISSN 0303-6812, E-ISSN 1432-1416, Vol. 74, no 4, 843-886 p.Article in journal (Refereed)
    Abstract [en]

    Emergence of new diseases and elimination of existing diseases is a key public health issue. In mathematical models of epidemics, such phenomena involve the process of infections and recoveries passing through a critical threshold where the basic reproductive ratio is 1. In this paper, we study near-critical behaviour in the context of a susceptible-infective-recovered epidemic on a random (multi)graph on n vertices with a given degree sequence. We concentrate on the regime just above the threshold for the emergence of a large epidemic, where the basic reproductive ratio is , with tending to infinity slowly as the population size, n, tends to infinity. We determine the probability that a large epidemic occurs, and the size of a large epidemic. Our results require basic regularity conditions on the degree sequences, and the assumption that the third moment of the degree of a random susceptible vertex stays uniformly bounded as . As a corollary, we determine the probability and size of a large near-critical epidemic on a standard binomial random graph in the 'sparse' regime, where the average degree is constant. As a further consequence of our method, we obtain an improved result on the size of the giant component in a random graph with given degrees just above the critical window, proving a conjecture by Janson and Luczak.

  • Zhao, Yani
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Holmgren, Benjamin T.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Hinas, Andrea
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    The conserved SNARE SEC-22 localizes to late endosomes and negatively regulates RNA interference in Caenorhabditis elegans2017In: RNA: A publication of the RNA Society, ISSN 1355-8382, E-ISSN 1469-9001, Vol. 23, no 3, 297-307 p.Article in journal (Refereed)
    Abstract [en]

    Small RNA pathways, including RNA interference (RNAi), play crucial roles in regulation of gene expression. Initially considered to be cytoplasmic, these processes have later been demonstrated to associate with membranes. For example, maturation of late endosomes/multivesicular bodies (MVBs) is required for efficient RNAi, whereas fusion of MVBs to lysosomes appears to reduce silencing efficiency. SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) mediate membrane fusion and are thus at the core of membrane trafficking. In spite of this, no SNARE has previously been reported to affect RNAi. Here, we demonstrate that in Caenorhabditis elegans, loss of the conserved SNARE SEC-22 results in enhanced RNAi upon ingestion of double-stranded RNA. Furthermore, SEC-22 overexpression inhibits RNAi in wild-type animals. We find that overexpression of SEC-22 in the target tissue (body wall muscle) strongly suppresses the sec-22(-) enhanced RNAi phenotype, supporting a primary role for SEC-22 in import of RNAi silencing signals or cell autonomous RNAi. A functional mCherry:: SEC-22 protein localizes primarily to late endosomes/MVBs and these compartments are enlarged in animals lacking sec-22. SEC-22 interacts with late endosome-associated RNA transport protein SID-5 in a yeast two-hybrid assay and functions in a sid-5-dependent manner. Taken together, our data indicate that SEC-22 reduces RNAi efficiency by affecting late endosome/MVB function, for example, by promoting fusion between late endosomes/MVBs and lysosomes. To our knowledge, this is the first report of a SNARE with a function in small RNA-mediated gene silencing.

  • Tuorda, Tor L.
    Sámi Land Free University.
    Uppsala universitet och ärkebiskopens rikedomar: Laxfisket vid Luossamuorkke, Edeforsen2017In: Uppsala mitt i Sápmi – Sábme – Saepmie: En supradisciplinär antologi härrörande från vårsymposium organiserat av Uppsam –Föreningen for samiskrelaterad forskning i Uppsala, Uppsala universitet, 28–29 april 2014 / [ed] May-Britt Öhman, Cecilia Hedlund, Gunilla Larsson, Vulkanmedia , 2017, 120-130 p.Chapter in book (Other academic)
    Abstract [en]

    The article is combining historical facts with fiction to tell the history of salmon fishing and natural resources in the land of the Indigenous Sámi, Sábme. Sábme was and still is the core territory for the natural resource extractions providing the wealth of the colonial Swedish state since the establishment of the state in the 16th century. The silver, iron ore, the forest, hydropower, taken from here has made the state and its elites rich and wealthy. It is a colonial process, as much as any colonial project elsewhere in the world, yet the word “colonisation” has until recently seldom been used for analysing the relationships between the Swedish state and the Sámi territories.  Salmon fishing was an important source of livelihood for the Sámi in the area. The fishing rights was as early as in the 14th century transferred to colonialist from the south and came to play a major importance in the creation of the wealth of Swedish noblemen, as well as of Uppsala University and the Church of Sweden. In 1960 the salmon fishing ended with the hydropower exploitations. Today there are no more any salmon here, they are stopped at the first hydropower station at Boden, close to the coast.   

    Photo archival research work has been made by May-Britt Öhman. Work with the article has been supported by the research project Rivers, Resistance, Resilience: Sustainable Futures in Sápmi and in Other Indigenous Peoples’ Territories, led by Dr. May-Britt Öhman and financed by Formas, 2012-2015.

  • Public defence: 2017-05-12 09:15 Häggsalen, Ångströmlaboratoriet, Uppsala
    Ajaxon, Ingrid
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Can Bone Void Fillers Carry Load?: Behaviour of Calcium Phosphate Cements Under Different Loading Scenarios2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Calcium phosphate cements (CPCs) are used as bone void fillers and as complements to hardware in fracture fixation. The aim of this thesis was to investigate the possibilities and limitations of the CPCs’ mechanical properties, and find out if these ceramic bone cements can carry application-specific loads, alone or as part of a construct. Recently developed experimental brushite and apatite cements were found to have a significantly higher strength in compression, tension and flexion compared to the commercially available CPCs chronOS™ Inject and Norian® SRS®. By using a high-resolution measurement technique the elastic moduli of the CPCs were determined and found to be at least twice as high compared to earlier measurements, and closer to cortical bone than trabecular bone. Using the same method, Poisson's ratio for pure CPCs was determined for the first time. A non-destructive porosity measurement method for wet brushite cements was developed, and subsequently used to study the porosity increase during in vitro degradation. The compressive strength of the experimental brushite cement was still higher than that of trabecular bone after 25 weeks of degradation, showing that the cement can carry high loads over a time span sufficiently long for a fracture to heal. This thesis also presents the first ever fatigue results for acidic CPCs, and confirms the importance of testing the materials under cyclic loading as the cements may fail at stress levels much lower than the material’s quasi-static compressive strength. A decrease in fatigue life was found for brushite cements containing higher amounts of monetite. Increasing porosity and testing in a physiological buffer solution (PBS), rather than air, also decreased the fatigue life. However, the experimental brushite cement had a high probability of surviving loads found in the spine when tested in PBS, which has previously never been accomplished for acidic CPCs. In conclusion, available brushite cements may be able to carry the load alone in scenarios where the cortical shell is intact, the loading is mainly compressive, and the expected maximum stress is below 10 MPa. Under such circumstances this CPC may be the preferred choice over less biocompatible and non-degradable materials.

    List of papers
    1. Mechanical Properties of Brushite Calcium Phosphate Cements
    Open this publication in new window or tab >>Mechanical Properties of Brushite Calcium Phosphate Cements
    2017 (English)In: The World Scientific Encyclopedia of Nanomedicine and Bioengineering II: Bioimplants, Regenerative Medicine, and Nano-Cancer Diagnosis and Phototherapy: Volume 3: Design of Bioactive Materials for Bone Repair and Regeneration / [ed] Shi, D., Singapore: World Scientific Pte Ltd. , 2017Chapter in book (Refereed)
    Place, publisher, year, edition, pages
    Singapore: World Scientific Pte Ltd., 2017
    National Category
    Biomaterials Science Ceramics Medical Materials
    Identifiers
    urn:nbn:se:uu:diva-316712 (URN)978-981-4667-58-6 (ISBN)
    Funder
    Swedish Research Council, GA 621-2011-6258
    Available from: 2017-03-22 Created: 2017-03-22 Last updated: 2017-03-22
    2. Compressive, diametral tensile and biaxial flexural strength of cutting-edge calcium phosphate cements
    Open this publication in new window or tab >>Compressive, diametral tensile and biaxial flexural strength of cutting-edge calcium phosphate cements
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    2016 (English)In: Journal of The Mechanical Behavior of Biomedical Materials, ISSN 1751-6161, E-ISSN 1878-0180, Vol. 60, 617-627 p.Article in journal (Refereed) Published
    Abstract [en]

    Calcium phosphate cements (CPCs) are widely used in bone repair. Currently there are two main types of CPCs, brushite and apatite. The aim of this project was to evaluate the mechanical properties of particularly promising experimental brushite and apatite formulations in comparison to commercially available brushite- and apatite-based cements (chronOS Inject and Norian® SRS®, respectively), and in particular evaluate the diametral tensile strength and biaxial flexural strength of these cements in both wet and dry conditions for the first time. The cements׳ porosity and their compressive, diametral tensile and biaxial flexural strength were tested in wet (or moist) and dry conditions. The surface morphology was characterized by scanning electron microscopy. Phase composition was assessed with X-ray diffraction. It was found that the novel experimental cements showed better mechanical properties than the commercially available cements, in all loading scenarios. The highest compressive strength (57.2±6.5 MPa before drying and 69.5±6.0 MPa after drying) was found for the experimental brushite cement. This cement also showed the highest wet diametral tensile strength (10.0±0.8 MPa) and wet biaxial flexural strength (30.7±1.8 MPa). It was also the cement that presented the lowest porosity (approx. 12%). The influence of water content was found to depend on cement type, with some cements showing higher mechanical properties after drying and some no difference after drying.

    Keyword
    Calcium phosphate cement; Brushite; Apatite; Compressive strength; Tensile strength; Flexural strength
    National Category
    Ceramics
    Identifiers
    urn:nbn:se:uu:diva-284218 (URN)10.1016/j.jmbbm.2016.03.028 (DOI)000378969100055 ()27082025 (PubMedID)
    Funder
    The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IG2011-2047Swedish Research Council, 621-2011-6258
    Available from: 2016-04-15 Created: 2016-04-15 Last updated: 2017-03-22Bibliographically approved
    3. Elastic properties and strain-to-crack-initation of calcium phosphate bone cements: revelations of a high-resolution measurement technique
    Open this publication in new window or tab >>Elastic properties and strain-to-crack-initation of calcium phosphate bone cements: revelations of a high-resolution measurement technique
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    (English)Manuscript (preprint) (Other academic)
    National Category
    Ceramics Medical Materials Biomaterials Science
    Identifiers
    urn:nbn:se:uu:diva-316718 (URN)
    Funder
    The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IG2011-2047Swedish Research Council, 621-2011-6258
    Available from: 2017-03-22 Created: 2017-03-22 Last updated: 2017-03-22
    4. Evaluation of a porosity measurement method for wet calcium phosphate cements
    Open this publication in new window or tab >>Evaluation of a porosity measurement method for wet calcium phosphate cements
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    2015 (English)In: Journal of biomaterials applications, ISSN 0885-3282, E-ISSN 1530-8022, Vol. 30, no 5, 526-536 p.Article in journal (Refereed) Published
    Abstract [en]

    The porosity of a calcium phosphate cement is a key parameter as it affects several important properties of the cement. However, a successful, non-destructive porosity measurement method that does not include drying has not yet been reported for calcium phosphate cements. The aim of this study was to evaluate isopropanol solvent exchange as such a method. Two different types of calcium phosphate cements were used, one basic (hydroxyapatite) and one acidic (brushite). The cements were allowed to set in an aqueous environment and then immersed in isopropanol and stored under three different conditions: at room temperature, at room temperature under vacuum (300 mbar) or at 37􏰀C. The specimen mass was monitored regularly. Solvent exchange took much longer time to reach steady state in hydroxyapatite cements compared to brushite cements, 350 and 18 h, respectively. Furthermore, the immersion affected the quasi-static compressive strength of the hydroxyapatite cements. However, the strength and phase composition of the brushite cements were not affected by isopropanol immersion, suggesting that isopropanol solvent exchange can be used for brushite calcium phosphate cements. The main advantages with this method are that it is non-destructive, fast, easy and the porosity can be evaluated while the cements remain wet, allowing for further analysis on the same specimen. 

    Place, publisher, year, edition, pages
    Sage Publications, 2015
    Keyword
    Calcium phosphate, bone cement, porosity, solvent exchange, brushite, hydroxyapatite
    National Category
    Ceramics Biomaterials Science Medical Materials
    Research subject
    Engineering Science with specialization in Materials Science
    Identifiers
    urn:nbn:se:uu:diva-258636 (URN)10.1177/0885328215594293 (DOI)000367743900003 ()26163278 (PubMedID)
    Funder
    The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IG2011-2047Swedish Research Council, 621-2011-6258
    Available from: 2015-07-17 Created: 2015-07-17 Last updated: 2017-03-22Bibliographically approved
    5. Long-term in vitro degradation of a high-strength brushite cement in water, PBS, and serum solution
    Open this publication in new window or tab >>Long-term in vitro degradation of a high-strength brushite cement in water, PBS, and serum solution
    2015 (English)In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, 575079Article in journal (Refereed) Published
    Abstract [en]

    Bone loss and fractures may call for the use of bone substituting materials, such as calcium phosphate cements (CPCs). CPCs can be degradable, and, to determine their limitations in terms of applications, their mechanical as well as chemical properties need to be evaluated over longer periods of time, under physiological conditions. However, there is lack of data on how the in vitro degradation affects high-strength brushite CPCs over longer periods of time, that is, longer than it takes for a bone fracture to heal. This study aimed at evaluating the long-term in vitro degradation properties of a high-strength brushite CPC in three different solutions: water, phosphate buffered saline, and a serum solution. Microcomputed tomography was used to evaluate the degradation nondestructively, complemented with gravimetric analysis. The compressive strength, chemical composition, and microstructure were also evaluated. Major changes from 10 weeks onwards were seen, in terms of formation of a porous outer layer of octacalcium phosphate on the specimens with a concomitant change in phase composition, increased porosity, decrease in object volume, and mechanical properties. This study illustrates the importance of long-term evaluation of similar cement compositions to be able to predict the material’s physical changes over a relevant time frame. 

    Place, publisher, year, edition, pages
    Hindawi Publishing Corporation, 2015
    Keyword
    Calcium phosphate, brushite, bone cement, degradation, in vitro, solvent exchange, compressive strength, micro-CT, porosity
    National Category
    Ceramics Bio Materials Biomaterials Science Medical Materials
    Research subject
    Engineering Science with specialization in Materials Science
    Identifiers
    urn:nbn:se:uu:diva-265319 (URN)10.1155/2015/575079 (DOI)000364660000001 ()
    Funder
    The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IG2011-207Swedish Research Council, 621-2011-6258
    Available from: 2015-10-27 Created: 2015-10-27 Last updated: 2017-03-22Bibliographically approved
    6. Compressive fatigue properties of an acidic calcium phosphate cement—effect of phase composition
    Open this publication in new window or tab >>Compressive fatigue properties of an acidic calcium phosphate cement—effect of phase composition
    2017 (English)In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 28, no 3, 41Article in journal (Refereed) Published
    Abstract [en]

    Calcium phosphate cements (CPCs) are synthetic bone grafting materials that can be used in fracture stabilization and to fill bone voids after, e.g., bone tumour excision. Currently there are several calcium phosphate-based formulations available, but their use is partly limited by a lack of knowledge of their mechanical properties, in particular their resistance to mechanical loading over longer periods of time. Furthermore, depending on, e.g., setting conditions, the end product of acidic CPCs may be mainly brushite or monetite, which have been found to behave differently under quasi-static loading. The objectives of this study were to evaluate the compressive fatigue properties of acidic CPCs, as well as the effect of phase composition on these properties. Hence, brushite cements stored for different lengths of time and with different amounts of monetite were investigated under quasi-static and dynamic compression. Both storage and brushite-to-monetite phase transformation was found to have a pronounced effect both on quasi-static compressive strength and fatigue performance of the cements, whereby a substantial phase transformation gave rise to a lower mechanical resistance. The brushite cements investigated in this study had the potential to survive 5 million cycles at a maximum compressive stress of 13 MPa. Given the limited amount of published data on fatigue properties of CPCs, this study provides an important insight into the compressive fatigue behaviour of such materials. 

    Keyword
    Bone cement, brushite, monetite, fatigue, mechanical properties
    National Category
    Ceramics Medical Materials Biomaterials Science
    Research subject
    Engineering Science with specialization in Materials Science
    Identifiers
    urn:nbn:se:uu:diva-314237 (URN)10.1007/s10856-017-5851-5 (DOI)000394242700006 ()28144853 (PubMedID)
    Funder
    Swedish Research Council, 621-2011-6258
    Available from: 2017-02-03 Created: 2017-01-31 Last updated: 2017-04-03Bibliographically approved
    7. Compressive fatigue properties of a high-strength, degradable calcium phosphate bone cement – influence of porosity and environment
    Open this publication in new window or tab >>Compressive fatigue properties of a high-strength, degradable calcium phosphate bone cement – influence of porosity and environment
    (English)Manuscript (preprint) (Other academic)
    National Category
    Ceramics Medical Materials Biomaterials Science
    Identifiers
    urn:nbn:se:uu:diva-316717 (URN)
    Funder
    Swedish Research Council, 621-2011-6258
    Available from: 2017-03-22 Created: 2017-03-22 Last updated: 2017-03-22