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• 1.
Örebro universitet, Akademin för naturvetenskap och teknik.
5-Aminolevulinic acid and derivatives thereof: properties, lipid permeability and enzymatic reactions2010Doctoral thesis, comprehensive summary (Other academic)

5-aminolevulinic acid (5-ALA) and derivatives thereof are widely usedprodrugs in treatment of pre-malignant skin diseases of the cancer treatmentmethod photodynamic therapy (PDT). The target molecule in 5-ALAPDTis protoporphyrin IX (PpIX), which is synthesized endogenously from5-ALA via the heme pathway in the cell. This thesis is focused on 5-ALA,which is studied in different perspectives and with a variety of computationalmethods. The structural and energetic properties of 5-ALA, itsmethyl-, ethyl- and hexyl esters, four different 5-ALA enols, and hydrated5-ALA have been investigated using Quantum Mechanical (QM) first principlesdensity functional theory (DFT) calculations. 5-ALA is found to bemore stable than its isomers and the hydrolysations of the esters are morespontaneous for longer 5-ALA ester chains than shorter. The keto-enoltautomerization mechanism of 5-ALA has been studied, and a self-catalysismechanism has been proposed to be the most probable. Molecular Dynamics(MD) simulations of a lipid bilayer have been performed to study themembrane permeability of 5-ALA and its esters. The methyl ester of 5-ALAwas found to have the highest permeability constant (PMe-5-ALA = 52.8 cm/s).The mechanism of the two heme pathway enzymes; Porphobilinogen synthase(PBGS) and Uroporphyrinogen III decarboxylase (UROD), have beenstudied by DFT calculations and QM/MM methodology. The rate-limitingstep is found to have a barrier of 19.4 kcal/mol for PBGS and 13.7kcal/mol for the first decarboxylation step in UROD. Generally, the resultsare in good agreement with experimental results available to date.

1. Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives
Open this publication in new window or tab >>Theoretical study of 5-aminolevulinic acid (5ALA) and some pharmaceutically important derivatives
2007 (English)In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 434, no 1-3, p. 101-106Article in journal (Refereed) Published
##### Abstract [en]

5-Aminolevulinic acid (5ALA) is the key synthetic building block in protoporphyrin IX (PpIX), the heme chromophore in mitochondria. The addition of extracorporeal 5ALA and its alkyl ester derivatives are in current clinical use in photodynamical diagnostics and photodynamic therapy of tumors and skin disorders. In the current study density functional theory calculations are performed on 5ALA and its methyl, ethyl, and hexyl esters, in order to explore the basic chemical properties of these species. It is concluded that even in aqueous media the zwitterionic form of 5ALA is less stable than the non-zwitterionic one, that the local environment (lipid vs water) affects the energetics of reaction considerably, and that the hexyl species is most prone to hydrolysis of the three alkyl ester derivatives.

##### Place, publisher, year, edition, pages
Amsterdam: North-Holland Publishing Co, 2007
##### Keywords
5-aminolevulinic acid, 5ALA, B3LYP, DFT, Protonation states, Alkyl esters
##### National Category
Theoretical Chemistry Physical Chemistry
##### Research subject
Biochemistry; Physical Chemistry
##### Identifiers
urn:nbn:se:liu:diva-150073 (URN)10.1016/j.cplett.2006.11.084 (DOI)000243820100020 ()2-s2.0-33846018089 (Scopus ID)
Available from: 2007-06-25 Created: 2018-08-09 Last updated: 2018-08-09
2. Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism
Open this publication in new window or tab >>Theoretical study of 5-aminolevulinic acid tautomerization: a novel self-catalyzed mechanism
2008 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 112, no 18, p. 4367-4374Article in journal (Refereed) Published
##### Abstract [en]

5-Aminolevulinic acid (5ALA) is the key synthetic building block in protoporphyrin IX (PpIX), the heme chromophore in mitochondria. In this study density functional theory calculations were performed on the tautomers of 5ALA and the tautomerization reaction mechanism from its enolic forms (5-amino-4-hydroxypent-3-enoic acid and 5-amino-4-hydroxypent-4-enoic acid) to the more stable 5ALA. The hydrated form 5-amino-4,4-dihydroxypentanoic acid was also studied. The lowest energy pathway of 5ALA tautomerization is by means of autocatalysis, in that an oxygen of the carboxylic group transfers the hydrogen atom as a "crane", with an activation energy of similar to 15 kcal/mol. This should be compared to the barriers of about 35 kcal/mol for water assisted tautomerization, and 60 kcal/mol for direct hydrogen transfer. For hydration of 5ALA, the water catalyzed activation barrier is found to be similar to 35 kcal/mol, approximately 5 kcal/mol lower than direct hydration.

##### Place, publisher, year, edition, pages
Washington DC: American Chemical Society, 2008
##### Keywords
Aminolevulinic Acid/*chemistry, Carboxylic Acids/chemistry, Catalysis, Isomerism, Protons, Quantum Theory, Thermodynamics, Water/chemistry
##### National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Physical Chemistry Theoretical Chemistry
##### Identifiers
urn:nbn:se:liu:diva-150074 (URN)10.1021/jp7118197 (DOI)000255486400026 ()18416542 (PubMedID)2-s2.0-43949116597 (Scopus ID)
Available from: 2008-10-13 Created: 2018-08-09 Last updated: 2018-08-09
3. Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer
Open this publication in new window or tab >>Modelling the behavior of 5-aminolevulinic acid and its alkyl esters in a lipid bilayer
2008 (English)In: Chemical Physics Letters, ISSN 0009-2614, E-ISSN 1873-4448, Vol. 463, no 1-3, p. 178-182Article in journal (Refereed) Published
##### Abstract [en]

5-Aminolevulinic acid (5ALA) and ester derivates thereof are used as prodrugs in photodynamic therapy (PDT). The behavior of 5ALA and three esters of 5ALA in a DPPC lipid bilayer is investigated. In particular, the methyl ester displays a very different free energy profile, where the highest barrier is located in the region with highest lipid density, while the others have their peak in the middle of the membrane, and also displays a considerably lower permeability coefficient than neutral 5ALA and the ethyl ester. The zwitterion of 5ALA has the highest permeability constant, but a significant free energy minimum in the polar head-group region renders an accumulation in this region.

##### Place, publisher, year, edition, pages
Amsterdam: North-Holland Publishing Co, 2008
##### Keywords
Molecular-dynamics simulations, photodynamic therapy, adenocarcinoma cells, beta transporters, hydrated DPPC, derivates, permeation, protoporphyrin, transition, membranes
##### National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Medicinal Chemistry Physical Chemistry Theoretical Chemistry
##### Identifiers
urn:nbn:se:liu:diva-150071 (URN)10.1016/j.cplett.2008.08.021 (DOI)000259150400035 ()2-s2.0-51349091343 (Scopus ID)
Available from: 2008-10-13 Created: 2018-08-09 Last updated: 2018-08-09
4. Computational studies on Schiff-base formation: Implications for the catalytic mechanism of porphobilinogen synthase
Open this publication in new window or tab >>Computational studies on Schiff-base formation: Implications for the catalytic mechanism of porphobilinogen synthase
2011 (English)In: Computational and Theoretical Chemistry, ISSN 2210-271X, E-ISSN 2210-2728, Vol. 963, no 2-3, p. 479-489Article in journal (Refereed) Published
##### Abstract [en]

Schiff bases are common and important intermediates in many bioenzymatic systems. The mechanism by which they are formed, however,is dependent on the solvent, pH and other factors. In the present study we have used density functional theory methods in combination with appropriate chemical models to get a better understanding of the inherent chemistry of the formation of two Schiff bases that have been proposed to be involved in the catalytic mechanism of porphobilinogensynthase (PBGS), a key enzyme in the biosynthesis of porphyrins. More specifically, we have investigated the uncatalysed reaction of its substrate 5-aminolevulinic acid (5-ALA) with a lysine residue for theformation of the P-site Schiff base, and as possibly catalysed by the second active site lysine, water or the 5-ALA itself. It is found that cooperatively both the second lysine and the amino group of the initial 5-ALA itself are capable of reducing the rate-limiting energy barrier to14.0 kcal mol-1. We therefore propose these to be likely routes involved in the P-site Schiff-base formation in PBGS.

##### Place, publisher, year, edition, pages
Amsterdam: Elsevier, 2011
##### Keywords
Schiff base, 5-Aminolevulinic acid, Porphobilinogen synthase, Density functional theory, Catalysis
##### National Category
Natural Sciences Physical Chemistry Physical Chemistry Theoretical Chemistry
##### Identifiers
urn:nbn:se:liu:diva-150070 (URN)10.1016/j.comptc.2010.11.015 (DOI)000288834500036 ()2-s2.0-80054879916 (Scopus ID)
Available from: 2011-01-14 Created: 2018-08-09 Last updated: 2018-08-09
5. Computational insights into the mechanism of porphobilinogen synthase
Open this publication in new window or tab >>Computational insights into the mechanism of porphobilinogen synthase
2010 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 114, no 50, p. 16860-16870Article in journal (Refereed) Published
##### Abstract [en]

Porphobilinogen synthase (PBGS) is a key enzyme in heme biosynthesis that catalyzes the formation of porphobilinogen (PBG) from two 5-aminolevulinic acid (5-ALA) molecules via formation of intersubstrateC-N and C-C bonds. The active site consists of several invariant residues, including two lysyl residues (Lys210 and Lys263; yeast numbering) that bind the two substrate moieties as Schiff bases. Based on experimental studies, various reaction mechanisms have been proposed for this enzyme that generally can be classified according to whether the intersubstrate C-C or C-N bond is formed first. However, the detailed catalytic mechanism of PBGS remains unclear. In the present study, we have employed density functional theory methods in combination with chemical models of the two key lysyl residues and two substrate moieties in order to investigate various proposed reaction steps and gain insight into the mechanism of PBGS. Importantly, it is found that mechanisms in which the intersubstrate C-N bond is formed first have a ratelimiting barrier (17.5 kcal/mol) that is lower than those in which the intersubstrate C-C bond is formed first (22.8 kcal/mol).

##### Place, publisher, year, edition, pages
Washington: American Chemical Society (ACS), 2010
##### National Category
Natural Sciences Physical Chemistry Physical Chemistry
##### Identifiers
urn:nbn:se:liu:diva-150069 (URN)10.1021/jp103590d (DOI)000285236700023 ()21090799 (PubMedID)2-s2.0-78650384685 (Scopus ID)
Available from: 2011-01-14 Created: 2018-08-09 Last updated: 2018-08-09
6. The first branching point in porphyrin biosynthesis: a systematic docking, molecular dynamics and quantum mechanical/molecular mechanical study of substrate binding and mechanism of uroporphyrinogen-III decarboxylase
Open this publication in new window or tab >>The first branching point in porphyrin biosynthesis: a systematic docking, molecular dynamics and quantum mechanical/molecular mechanical study of substrate binding and mechanism of uroporphyrinogen-III decarboxylase
2011 (English)In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 32, no 5, p. 822-834Article in journal (Refereed) Published
##### Abstract [en]

In humans, uroporphyrinogen decarboxylase is intimately involved in the synthesis of heme, where the decarboxylation of the uroporphyrinogen-III occurs in a single catalytic site. Several variants of the mechanistic proposal exist; however, the exact mechanism is still debated. Thus, using an ONIOM quantum mechanical/molecular mechanical approach, the mechanism by which uroporphyrinogen decarboxylase decarboxylates ring D of uroporphyrinogen-III has been investigated. From the study performed, it was found that both Arg37 and Arg50 are essential in the decarboxylation of ring D, where experimentally both have been shown to be critical to the catalytic behavior of the enzyme. Overall, the reaction was found to have a barrier of 10.3 kcal mol−1 at 298.15 K. The rate-limiting step was found to be the initial protontransfer from Arg37 to the substrate before the decarboxylation. In addition, it has been found that several key interactions exist between the substrate carboxylate groups and backbone amides of various activesite residues as well as several other functional groups.

##### Place, publisher, year, edition, pages
New York: John Wiley & Sons, 2011
##### Keywords
uroporphyrinogen decarboxylase III, uroporphyrinogen III, porphyrin biosynthesis, quantum mechanics/molecular mechanics and density functional theory
##### National Category
Natural Sciences Physical Chemistry Physical Chemistry Theoretical Chemistry Theoretical Chemistry
##### Identifiers
urn:nbn:se:liu:diva-150066 (URN)10.1002/jcc.21661 (DOI)000288400600007 ()20941734 (PubMedID)2-s2.0-79951968121 (Scopus ID)
Available from: 2011-01-14 Created: 2018-08-09 Last updated: 2018-08-09
• 2.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Västra Götalandsregionen, Södra Älvsborgs Sjukhus, Barn- och ungdomspsykiatriska kliniken.
A Biopsychosocial and Long Term Perspective on Child Behavioral Problems: Impact of Risk and Resilience2016Doctoral thesis, comprehensive summary (Other academic)

Mental health has become a prominent issue in society. Yet, much remains unknown about the etiology of psychiatric disorders. The aim of the present thesis was to investigate the association between biological, psychological and social factors of risk and resilience and behavioral problems in a birth cohort of Swedish children. 1723 mothers and their children were followed from birth to the age of 12 as part of the South East Sweden Birth Cohort Study (the SESBiC study). Information was gathered through register data, standardized questionnaires and DNA samples.

In study I, stability of maternal symptoms of depression and the impact on child behavior at age 12 were investigated. The prevalence of depressive symptoms was found to be 12.0 % postpartum. Symptoms of postpartum depression significantly increased the risk for subsequent depressive symptoms 12 years later in women. Children whose mothers reported concurrent symptoms of depression and anxiety had an increased risk for both internalizing and externalizing problems at age 12, but no long term effect on child behavior was seen for postpartum depressive symptoms. The greatest risk was seen for children whose mothers reported symptoms of depression on both occasions. In study II, the impact of gene-environment interaction of 5-HTTLPR and BDNF Val66Met and experience of life events together with symptoms of maternal depression and anxiety on child behavior at age 12 was studied. A main effect of 5-HTTLPR was noticed, but no geneenvironment effects were shown. Similarly to study I, concurrent symptoms of maternal depression and anxiety were an important predictor of child behavioral problems. A high degree of psychosocial stress around childbirth was found to have long lasting detrimental effects on child behavior, increasing the risk for internalizing problems at age 12. Study III investigated the impact of geneenvironment interactions of 5-HTTLPR and BDNF Val66Met and life events together with symptoms of maternal depression and birth characteristics on behavioral problems at age 3. Symptoms of postpartum depression were found to predict internalizing as well as externalizing problems in children three years later. Child experience of life events was a stable predictor of behavioral problems across the scales similar to sociodemographic factors such as parental immigration status and unemployment. No gene-environment interaction effects of 5-HTTLPR or BDNF Val66Met were shown. Study IV used the risk factors identified in studies I-III to investigate factors of resilience to behavioral problems at age 12. The l/l genotype of 5-HTTLPR was associated with a lower risk for behavioral problems at age 12, especially for children facing low adversity. Good social functioning was found to be a general resource factor, independent of the level of risk, while an easy temperament was associated with resilience for children with a high degree of adversity. However, effect sizes were small.

In summary, the results from the present thesis emphasize the importance of maternal mental health and sociodemographic factors for child mental health at ages 3 and 12, which must be taken into account in clinical settings. Moreover, it adds to the null-findings of the gene-environment effect of 5-HTTLPR and BDNF Val66Met on behavioral problems in children, but indicates a main effect of 5-HTTLPR on internalizing symptoms at age 12.

1. Symptoms of Depression Postpartum and 12 years Later-Associations to Child Mental Health at 12 years of Age
Open this publication in new window or tab >>Symptoms of Depression Postpartum and 12 years Later-Associations to Child Mental Health at 12 years of Age
2013 (English)In: Maternal and Child Health Journal, ISSN 1092-7875, E-ISSN 1573-6628, Vol. 17, no 3, p. 405-414Article in journal (Refereed) Published
##### Abstract [en]

Children of depressed mothers have been shown to express behaviour problems to a greater extent than children of non-depressed mothers. The purpose of this study was to examine the persistence of depressive symptoms in mothers and to evaluate the relative importance of symptoms of postpartum depression (PPD) and concurrent maternal symptoms of depression, on child behaviour at age 12. A birth cohort of 1,707 children and their mothers was followed from 3 months after birth to 12 years after birth. Self-reported symptoms of depression in mothers were assessed at baseline and 12-year follow-up where 893 mothers (52.3 %) and their children participated. The mothers reports on the behaviour of their children at age 12 were used. Multivariate analysis was used to assess factors that increased the risk of child behaviour problems. At baseline, 10.4 % scored above the cutoff for symptoms of postpartum depression. At follow up, 18.2 % scored above the cutoff for depressive symptoms. Multivariate analysis showed that ongoing maternal symptoms of depression, as distinct from PPD-symptoms, was the strongest predictor of child behaviour problems at age 12. The gender of the child and socio-demographic factors at baseline were additional factors that affected the risk of behaviour problems in the 12 year old children. Children of mothers who reported symptoms of depression, both postpartum and at follow-up, were at a greater risk of behaviour problems compared to children of women with no depressive symptoms on either occasion. Our findings indicate that recurrent and ongoing maternal depressive symptoms significantly increase the risk of child behaviour problems as reported by mothers, while symptoms of PPD do not seem to result in an increased risk of behaviour problems in 12 year olds. High maternal socio-demographic life stress at childbirth constitutes an important risk factor for later child behaviour problems.

##### Place, publisher, year, edition, pages
Springer Verlag (Germany), 2013
##### Keywords
CBCL, Children, Mental health, Postpartum depression, SESBiC-study
##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-90750 (URN)10.1007/s10995-012-0985-z (DOI)000316021200003 ()
Available from: 2013-04-05 Created: 2013-04-05 Last updated: 2017-12-06
2. Effect of gene, environment and maternal depressive symptoms on pre-adolescence behavior problems - a longitudinal study.
Open this publication in new window or tab >>Effect of gene, environment and maternal depressive symptoms on pre-adolescence behavior problems - a longitudinal study.
2013 (English)In: Child and Adolescent Psychiatry and Mental Health, ISSN 1753-2000, E-ISSN 1753-2000, Vol. 7, no 1, p. 10-Article in journal (Refereed) Published
##### Abstract [en]

BACKGROUND: Depression is a common and disabling condition with a high relapse frequency. Maternal mental health problems and experience of traumatic life events are known to increase the risk of behavior problems in children. Recently, genetic factors, in particular gene-by-environment interaction models, have been implicated to explain depressive etiology. However, results are inconclusive.

METHODS: Study participants were members of the SESBiC-study. A total of 889 mothers and their children were followed during the child's age of 3 months to 12 years. Information on maternal depressive symptoms was gathered postpartum and at a 12 year follow-up. Mothers reported on child behavior and traumatic life events experienced by the child at age 12. Saliva samples were obtained from children for analysis of 5-HTTLPR and BDNF Val66Met polymorphisms.

RESULTS: Multivariate analysis showed a significant association between maternal symptoms of depression and anxiety, and internalizing problems in 12-year-old children (OR 5.72, 95% CI 3.30-9.91). Furthermore, carriers of two short alleles (s/s) of the 5-HTTLPR showed a more than 4-fold increased risk of internalizing problems at age 12 compared to l/l carriers (OR 4.73, 95% CI 2.14-10.48). No gene-by-environment interaction was found and neither depressive symptoms postpartum or traumatic experiences during childhood stayed significant in the final model.

CONCLUSIONS: Concurrent maternal symptoms of depression and anxiety are significant risk factors for behavior problems in children, which need to be taken into account in clinical practice. Furthermore, we found a main effect of 5-HTTLPR on internalizing symptoms in 12-year-old children, a finding that needs to be confirmed in future studies.

##### Place, publisher, year, edition, pages
BioMed Central, 2013
Psychiatry
##### Identifiers
urn:nbn:se:liu:diva-104869 (URN)10.1186/1753-2000-7-10 (DOI)23518193 (PubMedID)
Available from: 2014-02-28 Created: 2014-02-28 Last updated: 2017-12-05Bibliographically approved
3. Early predictors of behavioural problems in pre-schoolers: a longitudinal study of constitutional and environmental main and interaction effects
Open this publication in new window or tab >>Early predictors of behavioural problems in pre-schoolers: a longitudinal study of constitutional and environmental main and interaction effects
2016 (English)In: BMC Pediatrics, ISSN 1471-2431, E-ISSN 1471-2431, Vol. 16Article in journal (Refereed) Published
##### Abstract [en]

Background: The early environment is important for child development and wellbeing. Gene-by-environment studies investigating the impact of the serotonin transporter genelinked polymorphic region (5-HTTLPR) and the Brain Derived Neurotrophic Factor (BDNF) Val66Met polymorphisms by life events on mental health and behaviour problems have been inconclusive. Methodological differences regarding sample sizes, study population, definitions of adversities and measures of mental health problems obstacle their comparability. Furthermore, very few studies included children. The aim of this study was to examine the associations between a broad range of risk factors covering pregnancy and birth, genetic polymorphism, experience of multiple life events and psychosocial environment, and child behaviour at age three, using a comparably large, representative, population-based sample.

Methods: A total of 1,106 children, and their mothers, were followed from pregnancy to age three. Information on pregnancy and birth-related factors was retrieved from the Medical Birth Register. Questionnaires on depressive symptoms, child behaviour and child experiences of life events were filled in by the mothers. Child saliva samples were used for genotyping the 5-HTTLPR and BDNF Val66Met polymorphisms. Multiple logistic regression was used to investigate the association between psychological scales and genetic polymorphisms.

Results: Symptoms of postpartum depression increased the risk of both internalizing and externalizing problems. Experience of multiple life events was also a predictor of behavioural problems across the scales. No gene-by-environment or gene-bygene-by-environment interactions were found. Children of immigrants had an increased risk of internalizing problems and parental unemployment was significantly associated with both internalizing and externalizing type of problems.

Conclusion: This study shows the importance of the psychosocial environment for psychosocial health in preschool children, and adds to  the literature of null-findings of gene-by-environment effects of 5-HTTLPR and BDNF in children

Psychiatry
##### Identifiers
urn:nbn:se:liu:diva-124207 (URN)10.1186/s12887-016-0614-x (DOI)000377535800002 ()
##### Note

Funding agencies:Funding was obtained from the Swedish Council for Working Life and Social Research (FAS), the Swedish Research Council (VR), the Clas Groschinsky Memorial Foundation, Stockholm, Samariten Foundation, Stockholm, the Hallsten Research Foundation and ALF, County Council of Ostergotland.

Vid tiden för publicering förelåg publikationen endast som manuskript

Available from: 2016-01-22 Created: 2016-01-22 Last updated: 2017-11-30Bibliographically approved
4. A biopsychosocial approach to risk and resilience on behavior in children followed from birth to age twelve
Open this publication in new window or tab >>A biopsychosocial approach to risk and resilience on behavior in children followed from birth to age twelve
##### Abstract [en]

An increasing prevalence of mental health problems calls for more knowledge into factors associated with resilience in the context of child behavior. Biological factors are seldom considered in psychosocial models of resilience. The present study used multiple statistical methodologies to examine a biopsychosocial model of risk and resilience on behavior at preadolescence. Data from 889 children and their mothers were used. A cumulative adversity score was created by combining maternal symptoms of depression, psychosocial risk and children’s experiences of life events. The proposed resilience factors investigated were candidate genetic polymorphisms, child temperament and social functioning, and maternal sense of coherence. Results show that the l/l genotype of the serotonin transporter linked polymorphic region (5-HTTLPR) was associated with lower internalizing scores, especially for children exposed to low adversity. An easy temperament was associated with resilient outcomes for children exposed to high adversity. Child social functioning was found to be more of a general resource variable buffering risk in both high and low adversity groups. The results support a multiple level model of resilience indicating effects, though small, of both biological and psychosocial factors. The present findings call for both preventive actions and further studies on biopsychosocial models in resilience research.

##### Keywords
Child, genotype, longitudinal, mental health, resilience
Psychiatry
##### Identifiers
urn:nbn:se:liu:diva-124208 (URN)
Available from: 2016-01-22 Created: 2016-01-22 Last updated: 2016-01-22Bibliographically approved
• 3.
Linköping University, The Tema Institute, Department of Water and Environmental Studies. Linköping University, Faculty of Arts and Sciences.
A Changing Arctic Climate: Science and Policy in the Arctic Climate Impact Assessment2007Doctoral thesis, monograph (Other academic)

Climate change has often been framed as a global issue but slow progress in the global climate negotiations and an increasing need to plan for local adaptation have made it increasingly salient to also discuss the potential of other arenas for climate policy and knowledge production. This dissertation analyzes the interplay between science and policy at the international regional level based on a study of an assessment of the impacts of climate change in the Arctic. In this case, the regional arena brought new actors into climate knowledge production and policy with an increased emphasis on the complexity of social and cultural impacts of climate change among indigenous peoples. The dissertation also shows how the structure of regional political cooperation played a role in highlighting the Arctic as a bellwether for global change. Meanwhile, the political negations that were linked to the regional climate impact assessment were ruled by the same political dynamics and policy positions as the global climate negotiations. The process illustrates how the structure of international cooperation can influence knowledge production about climate change. The dissertation emphasizes the role of vertical interplay among political regimes and how new arenas can make an assessment salient, credible, and legitimate to different actors. It also highlights the political dimensions of focusing on particular spatial scales and governance levels in climate knowledge production and policy.

• 4.
Linköping University, Department of Mathematics, Mathematical Statistics . Linköping University, Faculty of Science & Engineering.
A class of infinite dimensional stochastic processes with unbounded diffusion and its associated Dirichlet forms2015Doctoral thesis, comprehensive summary (Other academic)

This thesis consists of two papers which focuses on a particular diffusion type Dirichlet form

$\varepsilon(F,G) = \int \langle ADF,DG \rangle \mathbb_{H} d \nu,$

where $A = \small\sum\nolimits_{i=1}^\infty \ \lambda_i \langle S_i, \cdot \rangle \mathbb{H} S_i.$ Here $\small {S_i}, \ i \ \varepsilon \ \mathbb{N},$ is the basis in the Cameron-Martin space, H, consisting of the Schauder functions, and ν denotes the Wiener measure.

In Paper I, we let $\small\lambda_i \, i \, \varepsilon \, \mathbb{N}$ vary over the space of wiener trajectories in a way that the diffusion operator A is almost everywhere an unbounded operator on the Cameron–Martin space. In addition we put a weight function $\small\varphi$ on theWiener measure $\small\nu$ and show that under these changes of the reference measure, the Malliavin derivative and divergence are closable operators with certain closable inverses. It is then shown that under certain conditions on $\small\lambda_i \ i \ \varepsilon \ N$, and these changes of reference measure, the Dirichlet form is quasi-regular. This is done first in the classical Wiener space and then the results are transferred to the Wiener space over a Riemannian manifold.

Paper II focuses on the case when $\small\lambda_i \ i \ \varepsilon \ \mathbb{N}$ is a sequence of non-decreasing real numbers. The process X associated to $\small(\varepsilon, \ D(\varepsilon))$ is then an infinite dimensional Ornstein-Uhlenbeck process. In this case we show that the distributions of a sequence of certain finite dimensional Ornstein-Uhlenbeck processes converge weakly to the distribution of the infinite dimensional Ornstein-Uhlenbeck process. We also investigate the quadratic variation for this process, both in the classical sense and in the recent framework of stochastic calculus via regularization. Since the process is Banach space valued, the tensor quadratic variation is an appropriate tool to establish the Itô formula for the infinite dimensional Ornstein-Uhlenbeck process X. Sufficient conditions are presented for the scalar as well as the tensor quadratic variation to exist.

1. A class of infinite dimensional stochastic processes with unbounded diffusion
Open this publication in new window or tab >>A class of infinite dimensional stochastic processes with unbounded diffusion
2015 (English)In: Stochastics: An International Journal of Probablitiy and Stochastic Processes, ISSN 1744-2508, E-ISSN 1744-2516, Vol. 87, no 3, p. 424-457Article in journal (Refereed) Published
##### Abstract [en]

The paper studies Dirichlet forms on the classical Wiener space and the Wiener space over non-compact complete Riemannian manifolds. The diffusion operator is almost everywhere an unbounded operator on the Cameron-Martin space. In particular, it is shown that under a class of changes of the reference measure, quasi-regularity of the form is preserved. We also show that under these changes of the reference measure, derivative and divergence are closable with certain closable inverses. We first treat the case of the classical Wiener space and then we transfer the results to the Wiener space over a Riemannian manifold.

##### Place, publisher, year, edition, pages
Taylor and Francis: STM, Behavioural Science and Public Health Titles, 2015
##### Keywords
Dirichlet form on Wiener space; Dirichlet form on Wiener space over non-compact manifold; closability; weighted Wiener measure; quasi-regularity
Mathematics
##### Identifiers
urn:nbn:se:liu:diva-118070 (URN)10.1080/17442508.2014.959952 (DOI)000353580300004 ()
Available from: 2015-05-20 Created: 2015-05-20 Last updated: 2017-12-04
2. Infinite dimensional Ornstein-Uhlenbeck processes with unbounded diffusion: Approximation, quadratic variation, and Itô formula
Open this publication in new window or tab >>Infinite dimensional Ornstein-Uhlenbeck processes with unbounded diffusion: Approximation, quadratic variation, and Itô formula
2016 (English)In: Mathematische Nachrichten, ISSN 0025-584X, E-ISSN 1522-2616, Vol. 289, no 17-18, p. 2192-2222Article in journal (Refereed) Published
##### Abstract [en]

The paper studies a class of Ornstein-Uhlenbeck processes on the classical Wiener space. These processes are associated with a diffusion type Dirichlet form whose corresponding diffusion operator is unbounded in the Cameron- Martin space. It is shown that the distributions of certain finite dimensional Ornstein-Uhlenbeck processes converge weakly to the distribution of such an infinite dimensional Ornstein-Uhlenbeck process. For the infinite dimensional processes, the ordinary scalar quadratic variation is calculated. Moreover, relative to the stochastic calculus via regularization, the scalar as well as the tensor quadratic variation are derived. A related Itô formula is presented.

##### Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2016
##### Keywords
Infinite dimensional Ornstein-Uhlenbeck process, quadratic variation, Itô formula, weak approximation
Mathematics
##### Identifiers
urn:nbn:se:liu:diva-122181 (URN)10.1002/mana.201500146 (DOI)000389128100008 ()
##### Note

At the time for thesis presentation publication was in status: Manuscript.

Available from: 2015-10-23 Created: 2015-10-23 Last updated: 2017-12-01Bibliographically approved
• 5.
Linköping University, Department of Science and Technology, Communications and Transport Systems. Linköping University, Faculty of Science & Engineering.
A Comprehensive Analysis of Optimal Link Scheduling for Emptying a Wireless Network2016Doctoral thesis, comprehensive summary (Other academic)

Wireless communications have become an important part of modern life. The ubiquitous wireless networks and connectivities generate exponentially increasing data traffic. In view of this, wireless network optimization, which aims at utilizing the limited resource, especially spectrum and energy, as efficiently as possible from a network perspective, is essential for performance improvement and sustainable development of wireless communications.

In the dissertation, we focus on a fundamental problem of wireless network optimization, link scheduling, as well as its subproblem, link activation. The problem type arises because of the nature of wireless media and hence it is of relevance to a wide range of networks with multiple access. We freshen these classic problems up by novel extensions incorporating new technologies of interference management or with new performance metrics. We also revisit the problems in their classic setup to gain new theoretical results and insights for problem-solving. Throughout the study, we consider the problems with a general setup, such that the insights presented in this dissertation are not constrained to a specific technology or network type. Since link activation and scheduling are key elements of access coordination in wireless communications, the study opens up new approaches that significantly improve network performance, and eventually benefit practical applications.

The dissertation consists of five research papers. The first paper addresses maximum link activation with cooperative transmission and interference cancellation. Papers II and III investigate the minimum-time link scheduling problem in general and a particular class of networks, respectively. In Paper IV, we consider the scheduling problem of emptying a network in its broad form and provide a general optimality condition. In Paper V, we study the scheduling problem with respect to age of information.

1. Maximum Link Activation with Cooperative Transmission and Interference Cancellation in Wireless Networks
Open this publication in new window or tab >>Maximum Link Activation with Cooperative Transmission and Interference Cancellation in Wireless Networks
2017 (English)In: IEEE Transactions on Mobile Computing, ISSN 1536-1233, E-ISSN 1558-0660, Vol. 16, no 2, p. 408-421Article in journal (Refereed) Published
##### Abstract [en]

We address the maximum link activation problem in wireless networks with new features, namely when the transmitters can perform cooperative transmission, and the receivers are able to perform successive interference cancellation. In this new problem setting, which transmitters should transmit and to whom, as well as the optimal cancellation patterns at the receivers, are strongly intertwined. We present contributions along three lines. First, we provide a thorough tractability analysis, proving the NP-hardness as well as identifying tractable cases. Second, for benchmarking purposes, we deploy integer linear programming for achieving global optimum using off-theshelf optimization methods. Third, to overcome the scalability issue of integer programming, we design a sub-optimal but efficient optimization algorithm for the problem in its general form, by embedding maximum-weighted bipartite matching into local search. Numerical results are presented for performance evaluation, to validate the benefit of cooperative transmission and interference cancellation for maximum link activation and to demonstrate the effectiveness of the proposed algorithm.

IEEE, 2017
##### National Category
Communication Systems Telecommunications
##### Identifiers
urn:nbn:se:liu:diva-112447 (URN)10.1109/TMC.2016.2546906 (DOI)000393808500009 ()
##### Conference
2014 IEEE 25th Annual International Symposium on Personal, Indoor, and Mobile Radio Communications (PIMRC), September 2-5, Washington DC, DC, USA
##### Note

Funding agencies: Swedish Research Council; EU FP7 Marie Curie [324515, 329313]; National Science Foundation [CCF-0728966, CCF-1420651]; ONR [N000141410107]

Available from: 2014-11-27 Created: 2014-11-27 Last updated: 2018-08-14Bibliographically approved
2. Minimum-Time Link Scheduling for Emptying Wireless Systems: Solution Characterization and Algorithmic Framework
Open this publication in new window or tab >>Minimum-Time Link Scheduling for Emptying Wireless Systems: Solution Characterization and Algorithmic Framework
2014 (English)In: IEEE Transactions on Information Theory, ISSN 0018-9448, E-ISSN 1557-9654, Vol. 60, no 2, p. 1083-1100Article in journal (Refereed) Published
##### Abstract [en]

We consider a set of transmitter-receiver pairs, or links, that share a wireless medium and address the problem of emptying backlogged queues with given initial size at the transmitters in minimum time. The problem amounts to determining activation subsets of links, and their time durations, to form a minimum-time schedule. Scheduling in wireless networks has been studied under various formulations before. In this paper, we present fundamental insights and solution characterizations that include: 1) showing that the complexity of the problem remains high for any continuous and increasing rate function; 2) formulating and proving sufficient and necessary optimality conditions of two baseline scheduling strategies that correspond to emptying the queues using one-at-a-time or all-at-once strategies; and 3) presenting and proving the tractability of the special case in which the transmission rates are functions only of the cardinality of the link activation sets. These results are independent of physical-layer system specifications and are valid for any form of rate function. We then develop an algorithmic framework for the solution to this problem. The framework encompasses exact as well as sub-optimal, but fast, scheduling algorithms, all under a unified principle design. Through computational experiments, we finally investigate the performance of several specific algorithms from this framework.

##### Place, publisher, year, edition, pages
Institute of Electrical and Electronics Engineers (IEEE), 2014
##### Keywords
Algorithm; optimality; scheduling; wireless networks
##### National Category
Engineering and Technology
##### Identifiers
urn:nbn:se:liu:diva-104836 (URN)10.1109/TIT.2013.2292065 (DOI)000330286100022 ()
Available from: 2014-02-28 Created: 2014-02-28 Last updated: 2018-08-14
3. Polynomial Complexity Minimum-Time Scheduling in a Class of Wireless Networks
Open this publication in new window or tab >>Polynomial Complexity Minimum-Time Scheduling in a Class of Wireless Networks
2015 (English)In: IEEE Transactions on Control of Network Systems, ISSN 2325-5870, Vol. 3, no 3, p. 322-331Article in journal (Other academic) Published
##### Abstract [en]

We consider a wireless network with a set of transmitter-receiver pairs, or links, that share a common channel, and address the problem of emptying finite traffic volume from the transmitters in minimum time. This, so called, minimum-time scheduling problem has been proved to be NP-hard in general. In this paper, we study a class of minimum-time scheduling problems in which the link rates have a particular structure. We show that global optimality can be reached in polynomial time and derive optimality conditions. Then we consider a more general case in which we apply the same approach and obtain an approximation as well as lower and upper bounds to the optimal solution. Simulation results confirm and validate our approach.

##### Place, publisher, year, edition, pages
Institute of Electrical and Electronics Engineers (IEEE), 2015
##### Keywords
algorithm, interference, optimality, scheduling, wireless networks
##### National Category
Communication Systems Telecommunications
##### Identifiers
urn:nbn:se:liu:diva-112446 (URN)10.1109/TCNS.2015.2512678 (DOI)
##### Note

At the time for thesis presentation publication was in status: Manuscript

Available from: 2014-11-27 Created: 2014-11-27 Last updated: 2018-08-14Bibliographically approved
4. A general optimality condition of link scheduling for emptying a wireless network
Open this publication in new window or tab >>A general optimality condition of link scheduling for emptying a wireless network
2016 (English)In: 2016 IEEE INTERNATIONAL SYMPOSIUM ON INFORMATION THEORY, IEEE , 2016, p. 1446-1450Conference paper, Published paper (Refereed)
##### Abstract [en]

We consider link scheduling in wireless networks for emptying the queues of the source nodes, and provide a unified mathematical formulation that accommodates all meaningful settings of link transmission rates and network configurations. We prove that, any scheduling problem is equivalent to solving a convex problem defined over the convex hull of the rate region. Based on the fundamental insight, a general optimality condition is derived, that yields a unified treatment of optimal scheduling. Furthermore, we demonstrate the implications and usefulness of the result. Specifically, by applying the theoretical insight to optimality characterization and complexity analysis of scheduling problems, we can both unify and extend previously obtained results.

IEEE, 2016
##### Series
IEEE International Symposium on Information Theory. Proceedings, ISSN 2157-8095, E-ISSN 2157-8117
##### National Category
Computer Engineering Information Systems Software Engineering
##### Identifiers
urn:nbn:se:liu:diva-131357 (URN)10.1109/ISIT.2016.7541538 (DOI)000390098701102 ()
##### Conference
IEEE International Symposium on Information Theory (ISIT), 2016, Universitat Pompeu Fabra, Barcelona, Spain, July l0-l5, 2016
Available from: 2016-09-15 Created: 2016-09-15 Last updated: 2018-08-14Bibliographically approved
• 6.
Linköping University, Department of Medical and Health Sciences, Nursing Science. Linköping University, Faculty of Health Sciences.
A comprehensive picture of ethical values in caring encounters, based on experiences of those involved: Analysis of concepts developed from empirical studies2011Doctoral thesis, comprehensive summary (Other academic)

Older people should have a life with a sense of value and should feel confident. These ethical values, which are expressed in normative ethics, are expected to prevail in empirical ethics. Central components of nursing are the ethical issues of autonomy, beneficence, non-maleficence and the principles of justice. The general aim of this thesis is to identify and describe the ethical values that are apparent in the caring encounter and their influence on the people involved. This is done from the perspective of the older person in study (I), next of kin in study (II) and nurses in study (III). In study (IV) the aim was to synthesize the concepts from empirical studies (I- III) and analyze, compare and interrelate them with normative ethics. Studies (I, III) were empirical observational studies including follow-up interviews. Twenty-two older people participated voluntarily in study (I), and in study (III) 20 nurses participated voluntarily. In study (II) fourteen next of kin were interviewed. In studies (I- III) constant comparative analysis, the core foundation of grounded theory, was used. Five concepts were used in the analysis in study (IV); three from the grounded theory studies (I- III) and two from the theoretical framework on normative ethics i.e. the ICN code and SFS law. Five categories; being addressed, receiving respect, desiring to participate, increasing self-determination and gaining self-confidence formed the basis for the core category ‚Approaching‛ in study (I). ‘Approaching’ indicates the ethical values that guide nurses in their caring encounters with older people. These ethical values are noted by the older people and are greatly appreciated by them, and also lead to improved quality of care. Four categories were identified in study (II): Receiving, showing respect, facilitating participation and showing professionalism. These categories formed the basis of the core category ‚Being amenable‛, a concept identified in the next of kin’s description of the ethical values that they and the older patients perceive in the caring encounter. In study (III), three categories were identified: showing consideration, connecting, and caring for. These categories formed the basis of the core category ‚Corroborating‛. Corroborating deals with support and interaction. Empirical ethics and normative ethics are intertwined, according to the findings of this study (IV). Normative ethics influence the nurse’s practical performance and could have a greater influence in supporting nurses as professionals. Criteria of good ethical care according to this thesis are: showing respect, invitation to participation, allowing self-determination, and providing safe and secure care. These criteria are elements of the concept of being professional. Professionalism of nurses is shown by: the approach nurses adapt to the performance of their duties, and their competence and knowledge, but also how they apply laws and professional codes

1. The importance of ‘approaching’ older people: a grounded theory
Open this publication in new window or tab >>The importance of ‘approaching’ older people: a grounded theory
2012 (English)In: International Journal of Older People Nursing, ISSN 1748-3735, E-ISSN 1748-3743, Vol. 7, no 1, p. 29-36Article in journal (Refereed) Published
##### Abstract [en]

Aims and objectives. The aim of this study was to identify and describe the ethical values in caring encounters as experienced by older patients in their daily interaction with nurses in wards for older people.

Background. Ethical values and morals are important aspects that influence the quality of care.

Methods. Empirical observational study including follow-up interviews. Twenty-two older patients participated voluntarily in this study. Constant comparative analysis, the core foundation of grounded theory was used.

Results. Five categories: being addressed, receiving respect, desiring to participate, increasing self-determination and gaining self-confidence formed the bases for the core category.

Approaching. Approaching concerns how people become closer to each other in a physical space. It also includes how people become closer to each other in a dialogue, involving verbal or bodily communication.

Conclusions and relevance to clinical practice. Approaching indicates the ethical values that guide nurses in their caring encounters with older patients. These values are noted by the patient and have an individual value as well as leading to improved quality of their care. The older patient will be confident and satisfied with the caring encounter if the desired components in the nurse's approaching are exhibited.

Wiley, 2012
##### Keywords
Ethics, nursing care, older people, qualitative methods
##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-67874 (URN)10.1111/j.1748-3743.2010.00248.x (DOI)
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2017-12-11Bibliographically approved
2. Ethical values in caring encounters on a geriatric ward from the next of kin´s perspective: An interview study
Open this publication in new window or tab >>Ethical values in caring encounters on a geriatric ward from the next of kin´s perspective: An interview study
2010 (English)In: International Journal of Nursing Practice, ISSN 1322-7114, E-ISSN 1440-172X, Vol. 16, no 1, p. 20-26Article in journal (Refereed) Published
##### Abstract [en]

The aim of this study was to identify and describe the governing ethical values that next of kin experience in interaction with nurses who care for elderly patients at a geriatric clinic. Interviews with fourteen next of kin were conducted and data were analysed by Constant comparative analysis. Four categories were identified: Receiving, showing respect, facilitating participation and showing professionalism. These categories formed the basis of the core category: “Being amenable”, a concept identified in the next of kin’s description of the ethical values that they and the elderly patients perceive in the caring encounter. Being amenable means that the nurses are guided by ethical values; taking into account the elderly patient and the next of kin. Nurses’ focusing on elderly patients’ well-being as a final criterion affects the next of kin and their experience of this fundamental condition for high quality care seems to be fulfilled.

Wiley, 2010
##### Keywords
Ethical values, geriatric wards, grounded theory, nursing ethics, next of kin
##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-51737 (URN)10.1111/j.1440-172X.2009.01805.x (DOI)000274177000004 ()
##### Note

On the day of the defence day the status of this article was: Manuscript. This is the author’s version of the following article: Lise-Lotte Jonasson, Per-Erik Liss, Björn Westerlind and Carina Berterö, Ethical values in caring encounters on a geriatric ward from the next of kin´s perspective: An interview study, 2010, International Journal of Nursing Practice, (16), 1, 20-26. which has been published in final form at: http://dx.doi.org/10.1111/j.1440-172X.2009.01805.x Copyright: Blackwell Publishing Ltd http://eu.wiley.com/WileyCDA/Brand/id-35.html

Available from: 2009-11-16 Created: 2009-11-16 Last updated: 2017-12-12Bibliographically approved
3. Corroborating indicates nurses’ ethical values in a geriatric ward
Open this publication in new window or tab >>Corroborating indicates nurses’ ethical values in a geriatric ward
##### Abstract [en]

Aim. The aim of the study was to identify nurses’ ethical values, which become apparent through their behavior in the interactions with older patients in caring encounters at a geriatric clinic.

Background. Descriptions of ethics in caring practice are a problem since they are vague compared with the four principles of autonomy, beneficence, non-maleficence, and justice.

Methods. A Grounded Theory methodology was used. In total, 65 observations and follow-up interviews with 20 nurses were conducted, and data were analysed by constant comparative analysis.

Findings. Three categories were identified: showing consideration, connecting, and caring for. These categories formed the basis of the core category: ―Corroborating‖. In corroborating the focus is on the person in need of integrity and self-determination, that is, the autonomy principle. A similar concept was earlier described in regard to confirming. Corroborating deals more with support and interaction. It is not enough to be kind and show consideration, i.e. to benefit someone; nurses must also connect and care for the older person, i.e. demonstrate nonmaleficence, in order to corroborate that person.

Conclusion. The findings of this study can improve the ethics of nursing care. There is a need for research on development of a high standard of nursing care to corroborate the older patients in order to maintain their autonomy, beneficence and non-maleficence. The principal of justice was not specifically identified as a visible nursing action. However, all older patients received treatment, care and reception in an equivalent manner.

##### Keywords
Ethical values, geriatric wards, grounded theory, nursing ethics, nurses’ behaviour, nursing
##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-67875 (URN)
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2013-09-12Bibliographically approved
4. Empirical and normative ethics: a synthesis relating to the care of older patients
Open this publication in new window or tab >>Empirical and normative ethics: a synthesis relating to the care of older patients
2011 (English)In: Nursing Ethics, ISSN 0969-7330, E-ISSN 1477-0989, Vol. 18, no 6, p. 814-824Article in journal (Refereed) Published
##### Abstract [en]

The aim of this study was to synthesize the concepts from empirical studies and analyze, compare and interrelate them with normative ethics. International Council of nurses (ICN) and the Health and Medical Service Act are normative ethics. Five concepts were used in the analysis; three from the grounded theory studies and two from the theoretical framework on normative ethics. A simultaneous concept analysis resulted in five outcomes; interconnectedness, interdependence, corroboratedness, completeness and good care are all related to the empirical perspective of the nurse’s interaction with the older patient, and the normative perspective, i.e. that found in ICN code and SFS law. Empirical ethics and normative ethics are intertwined according to the findings of this study. Normative ethics are supporting documents for nurses as professionals and by extension also beneficial for older patients.

##### Place, publisher, year, edition, pages
Sage Publications, 2011
##### Keywords
Empirical ethics, Normative ethics, ICN code, Health and Medical Service Act, Beneficence, Nurse
##### National Category
Medical and Health Sciences Nursing
##### Identifiers
urn:nbn:se:liu:diva-67876 (URN)10.1177/0969733011405875 (DOI)000297476000007 ()
Available from: 2011-05-02 Created: 2011-05-02 Last updated: 2017-12-11Bibliographically approved
• 7.
Linköping University, Department of Electrical Engineering, Vehicular Systems. Linköping University, The Institute of Technology.
A DAE Formulation for Multi-Zone Thermodynamic Models and its Application to CVCP Engines2009Doctoral thesis, comprehensive summary (Other academic)

In the automotive area there are ever increasing demands from legislators and customers on low emissions and good fuel economy. In the process of developing and investigating new technologies, that can meet these demands, modeling and simulation have become important as standard engineering tools. To improve the modeling process new concepts and tools are also being developed.

A formulation of a differential algebraic equation (DAE) that can be used for simulation of multi-zone in-cylinder models is extended and analyzed. Special emphasis is placed on the separation between thermodynamic state equations and the thermodynamic properties. This enables implementations with easy reuse of model components and analysis of simulation results in a structured manner which gives the possibility to use the formulation in a large number of applications. The introduction and depletion of zones are handled and it is shown that the DAE formulation has a unique solution as long as the gas model fulfills a number of basic criteria. Further, an example setup is used to validate that energy, mass, and volume are preserved when using the formulation in computer simulations. In other words, the numerical solution obeys the thermodynamic state equation and the first law of thermodynamics, and the results are consistent and converge as tolerances are tightened. As example applications, the DAE formulation is used to simulate spark ignited SI and Diesel engines as well as simple control volumes and 1-dimensional pipes. It is thus shown that the DAE formulation is able to adapt to the different requirements of the SI and Diesel engine models.

An interesting application is the SI engine with continuously variable cam phasing (CVCP), which is a technology that reduces the fuel consumption. It influences the amount of air and residual gases in the engine in a non trivial manner and this SI application is used to evaluate three control oriented models for cylinder air charge and residual mass fraction for a CVCP-engine both for static and transient conditions. The models are: a simple generalized flow restriction model created with physical insight and two variants of a model that is based on an energy balance at intake valve closing (IVC). The two latter models require measurement of cylinder pressure and one also requires an air mass flow measurement. Using the SI model as reference it is shown that transients in cam positions have a large impact on air charge and residual mass fraction, and the ability of the models to capture these effects is evaluated. The main advantages of the generalized flow restriction model are that it is simple and does not require measurement of the cylinder pressure but it is also the model with the largest errors for static operating points and highest sensitivity in transients. The two models that use an energy balance at IVC both handle the transient cycles well. They are, however, sensitive to the temperature at IVC. For static cycles it is therefore advantageous to use the model with air mass flow measurement since it is less sensitive to input data. During transients however, if the external measurement is delayed, it is better to use the model that does not require the air mass flow.

The conclusion is that the DAE formulation is a flexible, robust, tool, and that it is well suited for multi-zone in-cylinder models as well as models for manifolds and pipes outside the cylinder.

1. Control Oriented Modeling of the Gas Exchange Process in Variable Cam Timing Engines
Open this publication in new window or tab >>Control Oriented Modeling of the Gas Exchange Process in Variable Cam Timing Engines
2006 (English)In: SAE Technical Paper 2006-01-0660, SAE , 2006Conference paper, Published paper (Refereed)
##### Abstract [en]

Variable cam timing engines pose new questions for engine control system designers. The cam timing directly influences cylinder air charge and residual mass fraction. Three models that predict residual mass fraction are investigated for a turbocharged dual independent Variable Cam Timing (VCT) engine. The three models (Fox et. al. 1993, Ponti et. al. 2002, and Mladek et. al. 2000) that all have real time capabilities are evaluated and validated against data from a crank angle based reference model. None of these models have previously been validated to cover this engine type. It is shown that all three models can be extended to dual independent VCT engines and that they also give a good description of the residual gas fraction. However, it is shown that the two most advanced models, based on a thermodynamic energy balance, are very sensitive to the model inputs and proper care must therefore be taken when these models are used

SAE, 2006
##### National Category
Engineering and Technology
##### Identifiers
urn:nbn:se:liu:diva-18306 (URN)
Available from: 2009-05-18 Created: 2009-05-18 Last updated: 2018-01-30Bibliographically approved
2. Control Oriented Gas Exchange Models for CVCP Engines and their Transient Sensitivity
Open this publication in new window or tab >>Control Oriented Gas Exchange Models for CVCP Engines and their Transient Sensitivity
2007 (English)In: Oil & gas science and technology, ISSN 1294-4475, E-ISSN 1953-8189, Vol. 62, no 4, p. 573-584 Article in journal (Refereed) Published
##### Abstract [en]

The paper analyzes a set of control oriented models for the gas exchange phase in engines with continuously variable cam phasing (CVCP). These models describe the mass flow of fresh gases and the residual gases caught in the cylinder during the gas exchange phase. Simulations with CVCP transients are also performed to analyze the models performance during transients.

IFP, 2007
##### National Category
Engineering and Technology
##### Identifiers
urn:nbn:se:liu:diva-18307 (URN)10.2516/ogst:2007041 (DOI)
Available from: 2009-05-18 Created: 2009-05-18 Last updated: 2018-01-30Bibliographically approved
• 8.
Linköping University, Department of Medical and Health Sciences, Health and Society. Linköping University, Faculty of Health Sciences.
A Data-Rich World: Population‐based registers in healthcare research2007Doctoral thesis, comprehensive summary (Other academic)

Advances and integration of information and communication technologies into healthcare systems offer new opportunities to improve public health worldwide. In Sweden, there are already unique possibilities for epidemiological research from registers because of a long tradition of centralized data collection into population-based registers and their allowance for linkage. The growing efficiency of automated digital storage provides growing volumes of archived data that increases the potential of analyses further.

The purpose of this thesis can be divided into two parallel themes: illustrations and discussions of the use and usefulness of population-based registers on the one hand, and specific research questions in epidemiology and healthcare research on the other. The research questions are addressed in separate papers.

From the Swedish Cancer Registry, 25 years of incidence data on testicular cancer was extracted for a large cohort. Record linkage to survey data on serum cholesterol showed a highly significant positive association, suggesting that elevated serum cholesterol concentration is a risk factor for testicular cancer. Since the finding is the first of its kind and because of wide confidence intervals further studies are needed to confirm the association.

Östergötland County council’s administra-tive database (the Care Data Warehouse in Östergötland (CDWÖ)) provided data for preva-lence estimations of four common chronic diseases.

The prevalence rate agreed very well with previous estimates for diabetes and fairly well with those for asthma. For hypertension and chronic obstructive pulmonary disease, the observed rates were lower than previous prevalence estimates. Data on several consecutive years covering all healthcare levels are needed to achieve valid prevalence estimates.

CDWÖ data was also used to analyse the impact of diabetes on the prevalence of ischemic heart disease. Women had higher diabetes/non-diabetes prevalence rate ratios across all ages. The relative gender difference remained up to the age of 65 years and thereafter decreased considerably.

The age-specific direct healthcare cost of diabetes was explored using data from the CDWÖ, the county council’s Cost Per Patient database and the Swedish Prescribed Drug Register. The cost per patient and the relative magnitude of different cost components varied considerably by age, which is important to consider in the future planning of diabetes management.

The Cancer Registry was established mainly as a basis for epidemiological surveillance and research, exemplified in this thesis by a study on testicular cancer. In contrast, the newly established and planned healthcare databases in different Swedish counties are mainly for managerial purposes. As is shown in this thesis, these new databases may also be used to address problems in epidemiology and healthcare research.

1. Serum cholesterol and testicular cancer incidence in 45 000 men followed for 25 years
Open this publication in new window or tab >>Serum cholesterol and testicular cancer incidence in 45 000 men followed for 25 years
2005 (English)In: British Journal of Cancer, ISSN 0007-0920, Vol. 92, no 9, p. 1785-1786Article in journal (Refereed) Published
##### Abstract [en]

In a 25-year follow-up study of 44 864 men with measured serum cholesterol levels, the testicular cancer hazard ratios for the serum cholesterol categories 5.7–6.9 and ≥7.0 mmol l-1 vs the reference category (<5.7 mmol l-1) were 1.3 and 4.5, respectively; P-value for trend=0.005. This highly significant association suggests that high-serum cholesterol is a risk factor for testicular cancer.

##### Keywords
epidemiology, testicular neoplasm, cholesterol
##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-12757 (URN)10.1038/sj.bjc.6602539 (DOI)
Available from: 2007-11-06 Created: 2007-11-06 Last updated: 2011-02-03
2. Estimating disease prevalence using a population-based administrative healthcare database
Open this publication in new window or tab >>Estimating disease prevalence using a population-based administrative healthcare database
2007 (English)In: Scandinavian Journal of Public Health, ISSN 1403-4948, Vol. 35, no 4, p. 424-431Article in journal (Refereed) Published
##### Abstract [en]

Aims: In Östergötland County, Sweden, all data on hospital care and primary healthcare (PHC) have been entered in a diagnosis-related administrative database since 1999. This database was used to estimate the prevalence of four chronic diseases and to examine the capture of data in PHC, outpatient hospital care, and inpatient hospital care, considered in different time frames.

Methods: A case-finding algorithm identified patients with at least one healthcare contact involving a diagnosis of diabetes, hypertension, asthma, or chronic obstructive pulmonary disease (COPD) in 1999—2003. Prevalence rates were calculated as the ratio of the number of identified patients alive to the total number of inhabitants on 31 December 2003 (n~415,000).

Results: Prevalence rates were 4.4% for diabetes, 10.3% for hypertension, 4.5% for asthma, and 1.2% for COPD. For all four diagnoses, the proportions of patients identified on only one healthcare level were greatest for PHC, reaching rates of 23%, 68%, 53%, and 48%, respectively. The cases identified solely in PHC comprised larger proportions of women and patients over the age of 65 years. Considering the proportion of patients identified in 2003 in relation to the total five-year period gave values of 71%, 50%, 38%, and 58%, respectively, for the four diagnoses.

Conclusions: The administrative healthcare databases in Sweden today can be important tools in epidemiological research. However, data on several consecutive years and both PHC and hospital data are needed to achieve valid prevalence estimates.

##### Keywords
Asthma, COPD, diabetes mellitus, epidemiology, healthcare, hypertension, inpatients, prevalence, primary outpatients, registries
##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-12758 (URN)10.1080/14034940701195230 (DOI)
Available from: 2007-11-06 Created: 2007-11-06 Last updated: 2009-05-19
3. Age and Gender Differences in the Impact of Diabetes on the Prevalence of Ischemic Heart Disease: a Population-Based Register Study
Open this publication in new window or tab >>Age and Gender Differences in the Impact of Diabetes on the Prevalence of Ischemic Heart Disease: a Population-Based Register Study
2008 (English)In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 79, no 3, p. 497-502Article in journal (Refereed) Published
##### Abstract [en]

Objective: To explore age and gender differences in the impact of diabetes on the prevalence of ischemic heart disease (IHD) in a defined population.

Methods: Data were obtained from an administrative health care register covering a population of about 415 000. The study included all patients aged 45-74 years diagnosed between 1999-2003 with IHD (n=11 311) and diabetes (n=10 364) by physicians at all primary health care centres (PHCs) and out- and inpatient clinics at all hospitals in the county of Östergötland, Sweden.

Results: In the 45-54 year-old age group, diabetes was associated with an increase in IHD prevalence equivalent to ageing about 20 years in women and 10 years in men. The diabetes/nondiabetes IHD prevalence rate ratio (IPR) decreased with age in both men and women (trend p-values < 0.001). The IPR was higher among women than men in each age group, though the female relative excess decreased from 75% higher in the 45-54 year-old age group to 33% higher in the 65-74 year-old age group (trend p-value = 0.018).

Conclusions: The relative gender difference in the impact of diabetes on IHD in younger middle-aged patients remained up to the age of 65 years, decreasing considerably thereafter.

##### Place, publisher, year, edition, pages
Institutionen för medicin och hälsa, 2008
##### Keywords
aging, coronary disease, diabetes mellitus, prevalence, sex differences
##### National Category
Social Sciences
##### Identifiers
urn:nbn:se:liu:diva-11241 (URN)10.1016/j.diabres.2007.10.009 (DOI)
##### Note
Original publication: Ann-Britt E. Wiréhn, Carl Johan Östgren and John M. Carstensen, Age and Gender Differences in the Impact of Diabetes on the Prevalence of Ischemic Heart Disease: a Population-Based Register Study, 2008, Diabetes Research and Clinical Practice, (79), 3, 497-502. http://dx.doi.org/10.1016/j.diabres.2007.10.009. Copyright: Elsevier B.V., http://www.elsevier.com/Available from: 2008-03-12 Created: 2008-03-12 Last updated: 2017-12-13
4. Age-specific direct health care costs attributable to diabetesin a Swedish population: a register-based analysis
Open this publication in new window or tab >>Age-specific direct health care costs attributable to diabetesin a Swedish population: a register-based analysis
2008 (English)In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 25, no 6, p. 732-737Article in journal (Refereed) Published
##### Abstract [en]

Aims: The aim of this population-based study was to explore the age-specific additional direct healthcare cost for patients with diabetes compared with the non-diabetic population.

Methods: In 1999-2005, patients with diabetes in the Swedish county of Östergötland (n = 20 876) were identified from an administrative database. Cost data on the healthcare expenditure in primary healthcare, out-patient hospital care and in-patient care for the entire county population (n = ∼415 000) in 2005 were extracted from a cost per patient (CPP) database, which includes information on all utilized healthcare resources in the county. Data on drug sales were obtained from the Swedish Prescribed Drug Register.

Results: The cost per person was 1.8 times higher in patients with diabetes than in the non-diabetic population, 7.7 times higher in children and 1.3 times higher in subjects aged > 75 years. The additional cost per person for diabetes was €1971; €3930 and €1367, respectively, for children and subjects aged > 75 years. The proportion of total additional diabetes costs attributable to in-patient care increased with age from 25 to 50%; in-patient care was the most expensive component at all ages except in children, for whom visiting a specialist was most expensive. The diabetes-related segment of the total healthcare cost was 6.6%, increasing from 2.0% in children to 10.3% in the age group 65-74 years, declining to 6.2% in the oldest age group.

Conclusions: The direct medical cost of diabetes varies considerably by age. Knowledge about the influence of age on healthcare costs to society will be important in future planning of diabetes management.

##### Keywords
Diabetes, Economics, Healthcare delivery, Prevalence, Registers
##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-12760 (URN)10.1111/j.1464-5491.2008.02444.x (DOI)
Available from: 2007-11-06 Created: 2007-11-06 Last updated: 2017-12-14
• 9.
Linköping University, Department of Clinical and Experimental Medicine, Division of Speech language pathology, Audiology and Otorhinolaryngology. Linköping University, Faculty of Medicine and Health Sciences.
A Finite Element Model of the Human Head for Simulation of Bone-conducted Sound2018Doctoral thesis, comprehensive summary (Other academic)

Bone conduction is usually understood as the hearing sensation based on the vibrations of the skull bone and surrounding tissues. The fact that vibration of the skull bones can result in a sound percept has been known for a long time. However, it is difficult to give a general definition of BC sound. Normally, BC sound is described as the sound energy transmitted through the body (comprising the solid and fluid parts) then the outer, middle and inner ear are involved and finally produce a perception of sound.

Even if BC sound perception has been studied for more than a century, the whole pattern of BC sound transmission is still not complete. There are limitations for experimental investigation of BC sound, such as the complexity of experimental manipulations and individual differences between subjects resulting in difficult to interpret outcomes. One way to overcome some of those issues is the use of a simulation model for BC sound. However, until now, the published models are unable to provide a holistic response of BC sound in the human. Therefore, the primary aim of this thesis is to develop a finite element model that could simulate BC sound transmission in the human. Based on cryosectional images of a female, the LiUHead was developed as a FE model of the human head with the structure and material properties of real human. Most the structures and tissues which could contribute to the BC transmission were included in the LiUHead. The simulation results of the LiUHead agreed with experimental data obtained in both cadaver heads and live humans.

After the development and validation of the LiUHead, the model was used to investigate BC sound.  Since BC sound is transmitted in and between the tissues, the power transmission of BC sound was investigated in the LiUHead in the frequency domain. When the stimulation was applied on the surface of the skull at the mastoid position, the results of the simulations show that, as the name suggest, the skull bone dominants the BC sound transmission. The soft tissues and cartilages are as the second most important media of the BC sound while the skull interior is the least important for the BC transmission. Moreover, according to the power flux in the skull, the BC vibrations are mainly concentrated at the skull base. Other important transmission pathways are located at the occipital bone at the posterior side of the head, but the power transmitted over the face, forehead and vertex is minor. There is power interaction between the skull bone and skull interior near the stimulation position but the transmission of sound power through the brain seem to be minimal. Since the power or energy is difficult to measure in an experimental setting, this investigation gave unique knowledge about BC sound transmission in the head and the interaction between the tissues.

As a common application for BC sound, bone-conduction devices are used to stimulate the hearing and is a method for hearing loss rehabilitation. Nowadays many different kinds of BCDs are available. However, most studies failed to compare the different types of BCDs in the same conditions as well as between several BCDs as it is not possible to compare several BCDs within the same subject due to the implantation required for several BCDs. The model gives a unique opportunity to evaluate various BCDs in the same head. Eight different BCDs, including four kinds of skin-drive BCDs, three kinds of direct-drive BCDs, and one in-the-mouth device, were applied to the LiUHead and the simulation results were evaluated. The results proved that the direct-drive BCDs and the in-the-mouth device gave similar vibration responses at the cochlea. At low frequencies, the skin-drive BCDs had similar or even better cochlear responses than the direct-drive BCDs. However, the direct-drive BCDs gave stable responses at mid-frequencies and gave higher responses than the skin-drive BCDs at high frequencies. These results are beneficial evaluating and for designing and improving current BCDs.

The ultimate goal of this thesis is to provide a computational model for BC sound that can be used for evaluation of BC sound transmission. This was accomplished by the LiUHead that gave results comparable to experimental data and enabled investigations that cannot easily be conducted in experiments.

1. A Three-Dimensional Finite-Element Model of a Human Dry Skull for Bone-Conduction Hearing
Open this publication in new window or tab >>A Three-Dimensional Finite-Element Model of a Human Dry Skull for Bone-Conduction Hearing
2014 (English)In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, Vol. 2014, no 519429Article in journal (Refereed) Published
##### Abstract [en]

A three-dimensional finite-element (FE) model of a human dry skull was devised for simulation of human bone-conduction (BC) hearing. Although a dry skull is a simplification of the real complex human skull, such model is valuable for understanding basic BC hearing processes. For validation of the model, the mechanical point impedance of the skull as well as the acceleration of the ipsilateral and contralateral cochlear bone was computed and compared to experimental results. Simulation results showed reasonable consistency between the mechanical point impedance and the experimental measurements when Youngs modulus for skull and polyurethane was set to be 7.3 GPa and 1 MPa with 0.01 and 0.1 loss factors at 1 kHz, respectively. Moreover, the acceleration in the medial-lateral direction showed the best correspondence with the published experimental data, whereas the acceleration in the inferior-superior direction showed the largest discrepancy. However, the results were reasonable considering that different geometries were used for the 3D FE skull and the skull used in the published experimental study. The dry skull model is a first step for understanding BC hearing mechanism in a human head and simulation results can be used to predict vibration pattern of the bone surrounding the middle and inner ear during BC stimulation.

##### Place, publisher, year, edition, pages
Hindawi Publishing Corporation, 2014
##### National Category
Clinical Medicine
##### Identifiers
urn:nbn:se:liu:diva-112658 (URN)10.1155/2014/519429 (DOI)000344143300001 ()25243148 (PubMedID)
##### Note

Funding Agencies|European Union [600933]

Available from: 2014-12-05 Created: 2014-12-05 Last updated: 2018-04-09
2. The development of a whole-head human finite-element model for simulation of the transmission of bone-conducted sound
Open this publication in new window or tab >>The development of a whole-head human finite-element model for simulation of the transmission of bone-conducted sound
2016 (English)In: Journal of the Acoustical Society of America, ISSN 0001-4966, E-ISSN 1520-8524, Vol. 140, no 3, p. 1635-1651Article in journal (Refereed) Published
##### Abstract [en]

A whole head finite element model for simulation of bone conducted (BC) sound transmission was developed. The geometry and structures were identified from cryosectional images of a female human head and eight different components were included in the model: cerebrospinal fluid, brain, three layers of bone, soft tissue, eye, and cartilage. The skull bone was modeled as a sandwich structure with an inner and outer layer of cortical bone and soft spongy bone (diploe) in between. The behavior of the finite element model was validated against experimental data of mechanical point impedance, vibration of the cochlear promontories, and transcranial BC sound transmission. The experimental data were obtained in both cadaver heads and live humans. The simulations showed multiple low-frequency resonances where the first was caused by rotation of the head and the second was close in frequency to average resonances obtained in cadaver heads. At higher frequencies, the simulation results of the impedance were within one standard deviation of the average experimental data. The acceleration response at the cochlear promontory was overall lower for the simulations compared with experiments but the overall tendencies were similar. Even if the current model cannot predict results in a specific individual, it can be used for understanding the characteristic of BC sound transmission in general. (C) 2016 Acoustical Society of America.

##### Place, publisher, year, edition, pages
ACOUSTICAL SOC AMER AMER INST PHYSICS, 2016
##### National Category
Vehicle Engineering
##### Identifiers
urn:nbn:se:liu:diva-133011 (URN)10.1121/1.4962443 (DOI)000386932500026 ()27914383 (PubMedID)
##### Note

Funding Agencies|European Union [600933]; Incheon Nation University (International Cooperative) Research Grant

Available from: 2016-12-08 Created: 2016-12-07 Last updated: 2018-03-20
• 10.
Linköping University, Department of Science and Technology, Visual Information Technology and Applications (VITA). Linköping University, The Institute of Technology.
A Framework for the Coordination of Complex Systems’ Development2003Doctoral thesis, monograph (Other academic)

This study is about the coordination of complex systems’ development. A Framework has been designed and deployed by the author in the development practice of Ericsson, a major supplier of telecommunication systems on the global market. The main purpose of the study is to investigate the impacts on coordination from the Framework. The development projects are very large and subject to turbulent market conditions. Moreover, they have many participants (often several thousand), have tight time constraints and are distributed to many design centres all over the world. In these projects, coordination of the development is of crucial importance. The Framework is grounded in a tentative theory called the Activity Domain Theory, which in turn is based on the praxis philosophy. In this theory the interaction between the individual and her environment is mediated by signs. Coordination is conceived as a particular activity domain which provides coordination to the development projects. The coordination domain is gradually constructed by the actors in this domain by iteratively refining a conceptual model, a process model, a transition model, a stabilizing core and information system support. In this process individual knowledge, shared meaning and organizational artefacts evolve in a dialectical manner. The Framework has been introduced in the Ericsson development practice over a period of more than ten years. Between 1999 and 2002 approximately 140 main projects and sub-projects at Ericsson have been impacted by the Framework. These projects were distributed to more than 20 different development units around the world and were carried out in a fiercely turbulent environment. The findings indicate that the Framework has had a profound impact on the coordination of the development of the most complex nodes in the 3rd generation of mobile systems. The knowledge contributions include an account for the history of the Framework at Ericsson and an identification of elements which contribute to successful outcomes of development projects.

• 11.
Linköping University, Department of Computer and Information Science, RTSLAB - Real-Time Systems Laboratory. Linköping University, The Institute of Technology.
A Generic Principle for Enabling Interoperability of Structured and Object-Oriented Analysis and Design Tools2003Doctoral thesis, monograph (Other academic)

In the 1980s, the evolution of engineering methods and techniques yielded the object-oriented approaches. Specifically, object orientation was established in software engineering, gradually relieving structured approaches. In other domains, e.g. systems engineering, object orientation is not well established. As a result, different domains employ different methods and techniques. This makes it difficult to exchange information between the domains, e.g. passing systems engineering information for further refinement to software engineering. This thesis presents a generic principle for bridging the gap between structured and object-oriented specification techniques. The principle enables interoperability of structured and object-oriented analysis and design tools through mutual information exchanges. Therefore, the concepts and elements of representative structured and object-oriented specification techniques are identified and analyzed. Then, a metamodel for each specification technique is created. From the meta-models, a common metamodel is synthesized. Finally, mappings between the meta-models and the common meta-model are created. Used in conjunction, the meta-models, the common meta-model and the mappings enable tool interoperability through transforming specification information under one meta-model via the common meta-model into a representation under another metamodel. Example transformations that illustrate the proposed principle using fragments of an aircraft’s landing gear specification are provided. The work presented in this thesis is based on the achievements of the SEDRES (ESPRIT 20496), SEDEX (NUTEK IPII-98-6292) and SEDRES-2 (IST 11953) projects. The projects strove for integrating different systems engineering tools in the forthcoming ISO-10303-233 (AP-233) standard for systems engineering design data. This thesis is an extension to the SEDRES / SEDEX and AP-233 achievements. It specifically focuses on integrating structured and modern UML based object-oriented specification techniques which was only performed schematically in the SEDRES / SEDEX and AP-233 work.

• 12.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
A molecular approach to insulin signalling and caveolae in primary adipocytes2007Doctoral thesis, comprehensive summary (Other academic)

The prevalence of type II diabetes is increasing at an alarming rate due to the western world lifestyle. Type II diabetes is characterized by an insulin resistance distinguished by impaired glucose uptake in adipose and muscle tissues. The molecular mechanisms behind the insulin recistance and also the knowledge considering normal insulin signalling in fat cells, especially in humans, are still unclear.

Insulin receptor substrate (IRS) is known to be important for medating the insulin-induced signal from the insulin receptor into the cell. We developed and optimized a method for transfection of primary human adipocytes by electroporation. By recombinant expression of proteins, we found a proper IRS to be crucial for both mitogenic and metabolic signalling in human adipocytes. In human, but not rat, primary adipocytes we found IRS1 to be located at the plasma membrane in non-insulin stimulated cells. Insulin stimulation resulted in a two-fold increase of the amount of IRS1 at the plasma membrane in human cells, compared with a 12-fold increase in rat cells. By recombinant expression of IRS1 we found the species difference between human and rat IRS1 to depend on the IRS proteins and not on properties of the host cell.

The adipocytes function as an energy store, critical for maintaining the energy balance, and obesity strongly correlates with insulin resistance. The insulin sensitivity of the adipocytes with regard to the size of the cells was examined by separating small and large cells from the same subject. We found no increase of the GLUT4 translocation to the plasma membrane following insulin stimulation in the large cells, whereas there was a two-fold increase in the small cells. This finding supports the idea of a causal relationship between the enlarged fat cells and reduced insulin sensitivity found in obese subjects.

The insulin receptor is located and functional in a specific membrane structure, the caveola. The morphology of the caveola and the localization of the caveolar marker proteins caveolin-1 and -2 were examined. Caveolae were shown to be connected to the exterior by a narrow neck. Caveolin was found to be located at the neck region of caveolae, which imply importance of caveolin for maintaining and sequestering caveolae to the plasma membrane.

In conclusion, the transfection technique proved to be highly useful for molecular biological studies of insulin signal transduction and morphology in primary adipocytes.

1. Expression of a mutant IRS inhibits metabolic and mitogenic signalling of insulin in human adipocytes
Open this publication in new window or tab >>Expression of a mutant IRS inhibits metabolic and mitogenic signalling of insulin in human adipocytes
2004 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, Vol. 221, no 1-2, p. 1-8Article in journal (Refereed) Published
##### Abstract [en]

Adipose tissue is a primary target of insulin, but knowledge about insulin signalling in human adipocytes is limited. We developed an electroporation technique for transfection of primary human adipocytes with a transfection efficiency of 15% ± 5 (mean ± S.D.). Human adipocytes were co-transfected with a mutant of IRS-3 (all four potential PI3-kinase binding motifs mutated: IRS-3F4) and HA-tagged protein kinase B (HA-PKB/Akt). HA-PKB/Akt was immunoprecipitated from cell lysates with anti-HA antibodies, resolved with SDS-PAGE, and immunoblotted with phospho-specific antibodies. We found that IRS-3F4 blocked insulin stimulation of HA-PKB/Akt phosphorylation and in further analyses also translocation of recombinant HA-tagged glucose transporter to the plasma membrane. IRS-3F4 also blocked insulin-induced activation of the transcription factor Elk-1. Our results demonstrate the critical importance of IRS for metabolic as well as mitogenic signalling by insulin. This method for transfection of primary human adipocytes will be useful for studying insulin signalling in human adipocytes with molecular biological techniques.

##### Keywords
Insulin, Transfection, Human, Adipocytes, Protein kinase B, Elk-1
##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-14538 (URN)10.1016/j.mce.2004.04.011 (DOI)000222854100001 ()
Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2013-10-22Bibliographically approved
2. Cell surface orifices of caveolae and localization of caveolin to the necks of caveolae in adipocytes
Open this publication in new window or tab >>Cell surface orifices of caveolae and localization of caveolin to the necks of caveolae in adipocytes
2003 (English)In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 14, no 10, p. 3967-3976Article in journal (Refereed) Published
##### Abstract [en]

Caveolae are noncoated invaginations of the plasma membrane that form in the presence of the protein caveolin. Caveolae are found in most cells, but are especially abundant in adipocytes. By high-resolution electron microscopy of plasma membrane sheets the detailed structure of individual caveolae of primary rat adipocytes was examined. Caveolin-1 and -2 binding was restricted to the membrane proximal region, such as the ducts or necks attaching the caveolar bulb to the membrane. This was confirmed by transfection with myc-tagged caveolin-1 and -2. Essentially the same results were obtained with human fibroblasts. Hence caveolin does not form the caveolar bulb in these cells, but rather the neck and may thus act to retain the caveolar constituents, indicating how caveolin participates in the formation of caveolae. Caveolae, randomly distributed over the plasma membrane, were very heterogeneous, varying in size between 25 and 150 nm. There was about one million caveolae in an adipocyte, which increased the surface area of the plasma membrane by 50%. Half of the caveolae, those larger than 50 nm, had access to the outside of the cell via ducts and 20-nm orifices at the cell surface. The rest of the caveolae, those smaller than 50 nm, were not open to the cell exterior. Cholesterol depletion destroyed both caveolae and the cell surface orifices.

##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-14539 (URN)10.1091/mbc.E03-01-0050 (DOI)
Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2017-12-13
3. Human, but not rat, IRS1 targets to the plasma membrane in both human and rat primary adipocytes
Open this publication in new window or tab >>Human, but not rat, IRS1 targets to the plasma membrane in both human and rat primary adipocytes
2007 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 363, no 3, p. 840-845Article in journal (Refereed) Published
##### Abstract [en]

Adipocytes are primary targets for insulin control of metabolism. The activated insulin receptor phosphorylates insulin receptor substrate-1 (IRS1), which acts as a docking protein for downstream signal mediators. In the absence of insulin stimulation, IRS1 in rat adipocytes is intracellular but in human adipocytes IRS1 is constitutively targeted to the plasma membrane. Stimulation of adipocytes with insulin increased the amount of IRS1 at the plasma membrane 2-fold in human adipocytes, but >10-fold in rat adipocytes, with the same final amount of IRS1 at the plasma membrane in cells from both species. Cross-transfection of rat adipocytes with human IRS1, or human adipocytes with rat IRS1, demonstrated that the species difference was due to the IRS1 protein and not the cellular milieus or posttranslational modifications. Chimeric IRS1, consisting of the conserved N-terminus of rat IRS1 with the variable C-terminal of human IRS1, did not target the plasma membrane, indicating that subtle sequence differences direct human IRS1 to the plasma membrane.

##### Keywords
Insulin receptor substrate; Human; Rat; Insulin; Plasma membrane; Signaling; Transfection; Caveolae
##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-14540 (URN)10.1016/j.bbrc.2007.09.065 (DOI)
Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2017-12-13
4. Insulin-induced GLUT4 translocation to the plasma membrane is blunted in large compared with small primary fat cells isolated from the same individual
Open this publication in new window or tab >>Insulin-induced GLUT4 translocation to the plasma membrane is blunted in large compared with small primary fat cells isolated from the same individual
2007 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 50, no 8, p. 1716-1722Article in journal (Refereed) Published
##### Abstract [en]

Aims/hypothesis: Several studies have suggested that large fat cells are less responsive to insulin than small fat cells. However, in these studies, large fat cells from obese individuals were compared with smaller fat cells from leaner participants, in effect making it impossible to draw conclusions about whether there is a causal relationship between fat cell size and insulin sensitivity. We hypothesised that small fat cells might be more insulin-responsive than large adipocytes when obtained from the same individual.

Materials and methods: We developed a method of sorting isolated primary human fat cells by using nylon filters of two different pore sizes. The cells were stained to visualise DNA, which allowed discrimination from artefacts such as lipid droplets. The sorted cells were left to recover overnight, since we had previously demonstrated that this is necessary for correct assessment of insulin response.

Results: We found similar amounts of the insulin receptor (IR), IRS-1 and GLUT4 when we compared small and large adipocytes from the same volunteer by immunoblotting experiments using the same total cell volume from both cell populations. Activation of IR, IRS-1 and Akt1 (also known as protein kinase B) by insulin was similar in the two cell populations. However, immunofluorescence confocal microscopy of plasma membrane sheets did not reveal any increase in the amount of GLUT4 in the plasma membrane following insulin stimulation in the large fat cells, whereas we saw a twofold increase in the amount of GLUT4 in the small fat cells.

Conclusions/interpretation: Our results support a causal relationship between the accumulation of large fat cells in obese individuals and reduced insulin responsiveness.

##### Keywords
Adipocyte, GLUT4, Human, Insulin, Insulin receptor, Insulin resistance, IRS-1, Primary fat cell
##### National Category
Medical and Health Sciences
##### Identifiers
urn:nbn:se:liu:diva-14541 (URN)10.1007/s00125-007-0713-1 (DOI)
Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2017-12-13Bibliographically approved
• 13.
Linköping University, Department of Biomedical Engineering, Medical Informatics. Linköping University, The Institute of Technology.
A Multidimensional Filtering Framework with Applications to Local Structure Analysis and Image Enhancement2008Doctoral thesis, comprehensive summary (Other academic)

Filtering is a fundamental operation in image science in general and in medical image science in particular. The most central applications are image enhancement, registration, segmentation and feature extraction. Even though these applications involve non-linear processing a majority of the methodologies available rely on initial estimates using linear filters. Linear filtering is a well established cornerstone of signal processing, which is reflected by the overwhelming amount of literature on finite impulse response filters and their design.

Standard techniques for multidimensional filtering are computationally intense. This leads to either a long computation time or a performance loss caused by approximations made in order to increase the computational efficiency. This dissertation presents a framework for realization of efficient multidimensional filters. A weighted least squares design criterion ensures preservation of the performance and the two techniques called filter networks and sub-filter sequences significantly reduce the computational demand.

A filter network is a realization of a set of filters, which are decomposed into a structure of sparse sub-filters each with a low number of coefficients. Sparsity is here a key property to reduce the number of floating point operations required for filtering. Also, the network structure is important for efficiency, since it determines how the sub-filters contribute to several output nodes, allowing reduction or elimination of redundant computations.

Filter networks, which is the main contribution of this dissertation, has many potential applications. The primary target of the research presented here has been local structure analysis and image enhancement. A filter network realization for local structure analysis in 3D shows a computational gain, in terms of multiplications required, which can exceed a factor 70 compared to standard convolution. For comparison, this filter network requires approximately the same amount of multiplications per signal sample as a single 2D filter. These results are purely algorithmic and are not in conflict with the use of hardware acceleration techniques such as parallel processing or graphics processing units (GPU). To get a flavor of the computation time required, a prototype implementation which makes use of filter networks carries out image enhancement in 3D, involving the computation of 16 filter responses, at an approximate speed of 1MVoxel/s on a standard PC.

1. On Geometric Transformations of Local Structure Tensors
Open this publication in new window or tab >>On Geometric Transformations of Local Structure Tensors
##### Identifiers
urn:nbn:se:liu:diva-13022 (URN)
Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2010-01-13
2. Estimation of Non-Cartesian Local Structure Tensor Fields
Open this publication in new window or tab >>Estimation of Non-Cartesian Local Structure Tensor Fields
2007 (English)In: Image Analysis: 15th Scandinavian Conference, SCIA 2007, Aalborg, Denmark, June 10-14, 2007 / [ed] Bjarne Kjær Ersbøll, Kim Steenstrup Pedersen, Springer Berlin/Heidelberg, 2007, Vol. 4522/2007, p. 948-957Conference paper, Published paper (Refereed)
##### Abstract [en]

In medical imaging, signals acquired in non-Cartesian coordinate systems are common. For instance, CT and MRI often produce significantly higher resolution within scan planes, compared to the distance between two adjacent planes. Even oblique sampling occurs, by the use of gantry tilt. In ultrasound imaging, samples are acquired in a polar coordinate system, which implies a spatially varying metric.

In order to produce a geometrically correct image, signals are generally resampled to a Cartesian coordinate system. This paper concerns estimation of local structure tensors directly from the non-Cartesian coordinate system, thus avoiding deteriorated signal and noise characteristics caused by resampling. In many cases processing directly in the warped coordinate system is also less time-consuming. A geometrically correct tensor must obey certain transformation rules originating from fundamental differential geometry. Subsequently, this fact also affects the tensor estimation. As the local structure tensor is estimated using filters, a change of coordinate system also change the shape of the spatial support of these filters. Implications and limitations brought on by sampling require the filter design criteria to be adapted to the coordinate system.

##### Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2007
##### Series
Lecture Notes in Computer Science, ISSN 0302-9743, E-ISSN 1611-3349 ; 4522
##### National Category
Signal Processing
##### Identifiers
urn:nbn:se:liu:diva-13023 (URN)10.1007/978-3-540-73040-8_96 (DOI)000247364000096 ()978-3-540-73039-2 (ISBN)978-3-540-73040-8 (ISBN)
##### Conference
15th Scandinavian Conference, SCIA 2007, Aalborg, Denmark, June 10-14, 2007
Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2018-02-15Bibliographically approved
3. Efficient 3-D Adaptive Filtering for Medical Image Enhancement
Open this publication in new window or tab >>Efficient 3-D Adaptive Filtering for Medical Image Enhancement
2006 (English)In: 3rd IEEE International Symposium on Biomedical Imaging: Nano to Macro, 2006., IEEE , 2006, p. 996-999Conference paper, Published paper (Refereed)
##### Abstract [en]

Tensor based orientation adaptive filtering, an explicit methodology for anisotropic filtering, constitutes a flexible framework for medical image enhancement. The technique features post-filtering steerability and allows user interaction and direct control over the high-frequency contents of the signal. A new class of filters for local structure analysis together with filter networks significantly lowers the complexity to meet the requirements of computation time for clinical use, while maintaining accuracy. In this paper the technique is applied to low-dose CT-images, magnetic resonance angiography and T2-weighted MRI.

IEEE, 2006
##### Series
International Symposium on Biomedical Imaging. Proceedings, ISSN 1945-7928
##### National Category
Engineering and Technology
##### Identifiers
urn:nbn:se:liu:diva-13024 (URN)10.1109/ISBI.2006.1625088 (DOI)000244446000252 ()0-7803-9576-X (ISBN)
##### Conference
3rd IEEE International Symposium on Biomedical Imaging: Nano to Macro, 6-9 April 2006, Arlington, VA, USA
Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2014-01-31Bibliographically approved
4. Approximate Spectral Factorization for Design of Efficient Sub-Filter Sequences
Open this publication in new window or tab >>Approximate Spectral Factorization for Design of Efficient Sub-Filter Sequences
2008 (English)Manuscript (preprint) (Other (popular science, discussion, etc.))
##### National Category
Engineering and Technology
##### Identifiers
urn:nbn:se:liu:diva-13025 (URN)
Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2015-06-02
5. Filter Networks for Efficient Estimation of Local 3-D Structure
Open this publication in new window or tab >>Filter Networks for Efficient Estimation of Local 3-D Structure