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  • 751.
    Aghapournahr, Moharram
    et al.
    Arak Univ, Arak, Iran.
    Melkersson, Leif
    Linköping University, Department of Mathematics, Applied Mathematics. Linköping University, The Institute of Technology.
    COFINITENESS AND COASSOCIATED PRIMES OF LOCAL COHOMOLOGY MODULES2009In: Mathematica Scandinavica, ISSN 0025-5521, E-ISSN 1903-1807, Vol. 105, no 2, p. 161-170Article in journal (Refereed)
    Abstract [en]

    Let R be a noetherian ring, alpha an ideal of R such that dim R/alpha = 1 and M a finite R-module. We will study cofiniteness and some other properties of the local cohomology modules H-alpha(i)(M). For an arbitrary ideal alpha and an R-module M (not necessarily finite), we will characterize alpha-cofinite artinian local cohomology modules. Certain sets of coassociated primes of top local cohomology modules over local rings are characterized.

  • 752.
    Aghapournahr, Moharram
    et al.
    Teacher Training Univ, Fac Math Sci, Tehran 15614, Iran.
    Melkersson, Leif
    Linköping University, The Institute of Technology. Linköping University, Department of Mathematics, Applied Mathematics.
    Local cohomology and Serre subcategories2008In: Journal of Algebra, ISSN 0021-8693, E-ISSN 1090-266X, Vol. 320, no 3, p. 1275-1287Article in journal (Refereed)
    Abstract [en]

    The membership of the local cohomology modules H-a(n) (M) of a module M in certain Serre subcategories of the category of modules is studied from below (i < n) and from above (i > n). Generalizations of depth and regular sequences are defined. The relation of these notions to local cohomology are found. It is shown that the membership of the local cohomology modules of a finite module in a Serre subcategory in the upper range just depends on the support of the module. (C) 2008 Elsevier Inc. All rights reserved.

  • 753.
    Aghel Dawood, Menhel
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Obradovic, Dragan
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Guidelines for control equipment2013Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Detta examensarbete är utfört på ABB LV System som är en del av företaget ABB i Sverige. Detta är ett företag som bygger kontrollutrustning till kunder som befinner sig i många delar av världen. Vår uppgift var att sätta samman en pärm med riktlinjer för montörerna.

    Pärmen ska vara lättläst och samtidigt innehålla alla standarder samt viktig fakta som kan behövas vid byggandet av kontrollutrustning.

    Riktlinjerna som framställts ledde till att montörerna blev bättre uppdaterade om de senaste riktlinjerna och standarder som leder idag. Tack vara att montörerna nu har allt samlat i en lättläslig pärm blir ledtiderna kortare.

  • 754.
    Aghighi, Meysam
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Computational Complexity of some Optimization Problems in Planning2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Automated planning is known to be computationally hard in the general case. Propositional planning is PSPACE-complete and first-order planning is undecidable. One method for analyzing the computational complexity of planning is to study restricted subsets of planning instances, with the aim of differentiating instances with varying complexity. We use this methodology for studying the computational complexity of planning. Finding new tractable (i.e. polynomial-time solvable) problems has been a particularly important goal for researchers in the area. The reason behind this is not only to differentiate between easy and hard planning instances, but also to use polynomial-time solvable instances in order to construct better heuristic functions and improve planners. We identify a new class of tractable cost-optimal planning instances by restricting the causal graph. We study the computational complexity of oversubscription planning (such as the net-benefit problem) under various restrictions and reveal strong connections with classical planning. Inspired by this, we present a method for compiling oversubscription planning problems into the ordinary plan existence problem. We further study the parameterized complexity of cost-optimal and net-benefit planning under the same restrictions and show that the choice of numeric domain for the action costs has a great impact on the parameterized complexity. We finally consider the parameterized complexity of certain problems related to partial-order planning. In some applications, less restricted plans than total-order plans are needed. Therefore, a partial-order plan is being used instead. When dealing with partial-order plans, one important question is how to achieve optimal partial order plans, i.e. having the highest degree of freedom according to some notion of flexibility. We study several optimization problems for partial-order plans, such as finding a minimum deordering or reordering, and finding the minimum parallel execution length.

    List of papers
    1. Oversubscription planning: Complexity and compilability
    Open this publication in new window or tab >>Oversubscription planning: Complexity and compilability
    2014 (English)In: Proceedings of the Twenty-Eighth AAAI Conference on Artificial Intelligence, AI Access Foundation , 2014, Vol. 3, p. 2221-2227Conference paper, Published paper (Refereed)
    Abstract [en]

    Many real-world planning problems are oversubscription problems where all goals are not simultaneously achievable and the planner needs to find a feasible subset. We present complexity results for the so-called partial satisfaction and net benefit problems under various restrictions; this extends previous work by van den Briel et al. Our results reveal strong connections between these problems and with classical planning. We also present a method for efficiently compiling oversubscription problems into the ordinary plan existence problem; this can be viewed as a continuation of earlier work by Keyder and Geffner.

    Place, publisher, year, edition, pages
    AI Access Foundation, 2014
    National Category
    Computer and Information Sciences
    Identifiers
    urn:nbn:se:liu:diva-116727 (URN)2-s2.0-84908192348 (Scopus ID)9781577356790 (ISBN)
    Conference
    28th AAAI Conference on Artificial Intelligence, AAAI 2014, 26th Innovative Applications of Artificial Intelligence Conference, IAAI 2014 and the 5th Symposium on Educational Advances in Artificial Intelligence, EAAI 2014
    Available from: 2015-04-09 Created: 2015-04-02 Last updated: 2018-01-11
    2. Tractable Cost-Optimal Planning over Restricted Polytree Causal Graphs
    Open this publication in new window or tab >>Tractable Cost-Optimal Planning over Restricted Polytree Causal Graphs
    2015 (English)In: Proceedings of the Twenty-Ninth AAAI Conference on Artificial Intelligence, AAAI Press, 2015Conference paper, Published paper (Refereed)
    Abstract [en]

    Causal graphs are widely used to analyze the complexity of planning problems. Many tractable classes have been identified with their aid and state-of-the-art heuristics have been derived by exploiting such classes. In particular, Katz and Keyder have studied causal graphs that are hourglasses (which is a generalization of forks and inverted-forks) and shown that the corresponding cost-optimal planning problem is tractable under certain restrictions. We continue this work by studying polytrees (which is a generalization of hourglasses) under similar restrictions. We prove tractability of cost-optimal planning by providing an algorithm based on a novel notion of variable isomorphism. Our algorithm also sheds light on the k-consistency procedure for identifying unsolvable planning instances. We speculate that this may, at least partially, explain why merge-and-shrink heuristics have been successful for recognizing unsolvable instances.

    Place, publisher, year, edition, pages
    AAAI Press, 2015
    Series
    Proceedings of the AAAI Conference on Artificial Intelligence, ISSN 2159-5399, E-ISSN 2374-3468
    Keywords
    automated planning, causal graph, polynomial-time algorithm, cost-optimal planning, polytree
    National Category
    Computer Systems
    Identifiers
    urn:nbn:se:liu:diva-118729 (URN)978-1-57735-703-2 (ISBN)
    Conference
    29th AAAI Conference on Artificial Intelligence (AAAI-15), January 25–30, Austin, TX, USA
    Funder
    CUGS (National Graduate School in Computer Science)
    Available from: 2015-06-03 Created: 2015-06-03 Last updated: 2017-05-17
    3. Cost-optimal and Net-benefit Planning: A Parameterised Complexity View
    Open this publication in new window or tab >>Cost-optimal and Net-benefit Planning: A Parameterised Complexity View
    2015 (English)In: 24th International Joint Conference on Artificial Intelligence (IJCAI-15), IJCAI-INT JOINT CONF ARTIF INTELL, ALBERT-LUDWIGS UNIV FREIBURG GEORGES-KOHLER-ALLEE, INST INFORMATIK, GEB 052, FREIBURG, D-79110, GERMANY , 2015, p. 1487-1493Conference paper, Published paper (Refereed)
    Abstract [en]

    Cost-optimal planning (COP) uses action costs and asks for a minimum-cost plan. It is sometimes assumed that there is no harm in using actions with zero cost or rational cost. Classical complexity analysis does not contradict this assumption; planning is PSPACE-complete regardless of whether action costs are positive or non-negative, integer or rational. We thus apply parameterised complexity analysis to shed more light on this issue. Our main results are the following. COP is W[2]-complete for positive integer costs, i.e. it is no harder than finding a minimum-length plan, but it is para-NPhard if the costs are non-negative integers or positive rationals. This is a very strong indication that the latter cases are substantially harder. Net-benefit planning (NBP) additionally assigns goal utilities and asks for a plan with maximum difference between its utility and its cost. NBP is para-NP-hard even when action costs and utilities are positive integers, suggesting that it is harder than COP. In addition, we also analyse a large number of subclasses, using both the PUBS restrictions and restricting the number of preconditions and effects.

    Place, publisher, year, edition, pages
    IJCAI-INT JOINT CONF ARTIF INTELL, ALBERT-LUDWIGS UNIV FREIBURG GEORGES-KOHLER-ALLEE, INST INFORMATIK, GEB 052, FREIBURG, D-79110, GERMANY, 2015
    National Category
    Transport Systems and Logistics
    Identifiers
    urn:nbn:se:liu:diva-128181 (URN)000442637801080 ()9781577357384 (ISBN)
    Conference
    24th International Joint Conference on Artificial Intelligence (IJCAI-15), Buenos Aires, Argentina, Jul 25-31, 2015
    Funder
    CUGS (National Graduate School in Computer Science), 1054Swedish Research Council, 621- 2014-4086
    Available from: 2016-05-20 Created: 2016-05-20 Last updated: 2019-07-03Bibliographically approved
    4. A Multi-parameter Complexity Analysis of Cost-optimal and Net-benefit Planning
    Open this publication in new window or tab >>A Multi-parameter Complexity Analysis of Cost-optimal and Net-benefit Planning
    2016 (English)In: Twenty-Sixth International Conference on Automated Planning and Scheduling King's College, London June 12, 2016 – June 17, 2016 / [ed] Amanda Coles, Andrew Coles, Stefan Edelkamp, Daniele Magazzeni, Scott Sanner, AAAI Press, 2016, p. 2-10Conference paper, Published paper (Refereed)
    Abstract [en]

    Aghighi and Bäckström have previously studied cost-optimal planning (COP) and net-benefit planning (NBP) for three action cost domains: the positive integers (Z_+), the non-negative integers (Z_0) and the positive rationals (Q_+). These were indistinguishable under standard complexity analysis for both problems, but separated for COP using parameterised complexity analysis. With the plan cost, k, as parameter, COP was W[2]-complete for Z_+, but para-NP-hard for both Z_0 and Q_+, i.e. presumably much harder. NBP was para-NP-hard for all three domains, thus remaining unseparable. We continue by considering combinations with several additional parameters and also the non-negative rationals (Q_0). Examples of new parameters are the plan length, l, and the largest denominator of the action costs, d. Our findings include: (1) COP remains W[2]-hard for all domains, even if combining all parameters; (2) COP for Z_0 is in W[2] for the combined parameter {k,l}; (3) COP for Q_+ is in W[2] for {k,d} and (4) COP for Q_0 is in W[2] for {k,d,l}. For NBP we consider further additional parameters, where the most crucial one for reducing complexity is the sum of variable utilities. Our results help to understand the previous results, eg. the separation between Z_+ and Q_+ for COP, and to refine the previous connections with empirical findings.

    Place, publisher, year, edition, pages
    AAAI Press, 2016
    Keywords
    cost-optimal planning, parameterised complexity, numeric domains
    National Category
    Computer Systems
    Identifiers
    urn:nbn:se:liu:diva-136278 (URN)9781577357575 (ISBN)
    Conference
    Twenty-Sixth International Conference on Automated Planning and Scheduling (ICAPS-16), London, UK, June 12–17, 2016
    Available from: 2017-04-05 Created: 2017-04-05 Last updated: 2019-05-08Bibliographically approved
    5. Plan Reordering and Parallel Execution -- A Parameterized Complexity View
    Open this publication in new window or tab >>Plan Reordering and Parallel Execution -- A Parameterized Complexity View
    2017 (English)Conference paper, Published paper (Refereed)
    Abstract [en]

    Bäckström has previously studied a number of optimization problems for partial-order plans, like finding a minimum deordering (MCD) or reordering (MCR), and finding the minimum parallel execution length (PPL), which are all NP-complete. We revisit these problems, but applying parameterized complexity analysis rather than standard complexity analysis. We consider various parameters, including both the original and desired size of the plan order, as well as its width and height. Our findings include that MCD and MCR are W[2]-hard and in W[P] when parameterized with the desired order size, and MCD is fixed-parameter tractable (fpt) when parameterized with the original order size. Problem PPL is fpt if parameterized with the size of the non-concurrency relation, but para-NP-hard in most other cases. We also consider this problem when the number (k) of agents, or processors, is restricted, finding that this number is a crucial parameter; this problem is fixed-parameter tractable with the order size, the parallel execution length and k as parameter, but para-NP-hard without k as parameter.

    Place, publisher, year, edition, pages
    AAAI Press, 2017
    Keywords
    Partially ordered plan, Parameterized complexity, Complexity of planning, Plan reordering, Parallel plan execution
    National Category
    Computer Systems
    Identifiers
    urn:nbn:se:liu:diva-136279 (URN)
    Conference
    Thirty-First AAAI Conference on Artificial Intelligence (AAAI-17)
    Available from: 2017-04-05 Created: 2017-04-05 Last updated: 2017-05-17Bibliographically approved
  • 755.
    Aghighi, Meysam
    et al.
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Bäckström, Christer
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    A Multi-parameter Complexity Analysis of Cost-optimal and Net-benefit Planning2016In: Twenty-Sixth International Conference on Automated Planning and Scheduling King's College, London June 12, 2016 – June 17, 2016 / [ed] Amanda Coles, Andrew Coles, Stefan Edelkamp, Daniele Magazzeni, Scott Sanner, AAAI Press, 2016, p. 2-10Conference paper (Refereed)
    Abstract [en]

    Aghighi and Bäckström have previously studied cost-optimal planning (COP) and net-benefit planning (NBP) for three action cost domains: the positive integers (Z_+), the non-negative integers (Z_0) and the positive rationals (Q_+). These were indistinguishable under standard complexity analysis for both problems, but separated for COP using parameterised complexity analysis. With the plan cost, k, as parameter, COP was W[2]-complete for Z_+, but para-NP-hard for both Z_0 and Q_+, i.e. presumably much harder. NBP was para-NP-hard for all three domains, thus remaining unseparable. We continue by considering combinations with several additional parameters and also the non-negative rationals (Q_0). Examples of new parameters are the plan length, l, and the largest denominator of the action costs, d. Our findings include: (1) COP remains W[2]-hard for all domains, even if combining all parameters; (2) COP for Z_0 is in W[2] for the combined parameter {k,l}; (3) COP for Q_+ is in W[2] for {k,d} and (4) COP for Q_0 is in W[2] for {k,d,l}. For NBP we consider further additional parameters, where the most crucial one for reducing complexity is the sum of variable utilities. Our results help to understand the previous results, eg. the separation between Z_+ and Q_+ for COP, and to refine the previous connections with empirical findings.

  • 756.
    Aghighi, Meysam
    et al.
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Bäckström, Christer
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Cost-optimal and Net-benefit Planning: A Parameterised Complexity View2015In: 24th International Joint Conference on Artificial Intelligence (IJCAI-15), IJCAI-INT JOINT CONF ARTIF INTELL, ALBERT-LUDWIGS UNIV FREIBURG GEORGES-KOHLER-ALLEE, INST INFORMATIK, GEB 052, FREIBURG, D-79110, GERMANY , 2015, p. 1487-1493Conference paper (Refereed)
    Abstract [en]

    Cost-optimal planning (COP) uses action costs and asks for a minimum-cost plan. It is sometimes assumed that there is no harm in using actions with zero cost or rational cost. Classical complexity analysis does not contradict this assumption; planning is PSPACE-complete regardless of whether action costs are positive or non-negative, integer or rational. We thus apply parameterised complexity analysis to shed more light on this issue. Our main results are the following. COP is W[2]-complete for positive integer costs, i.e. it is no harder than finding a minimum-length plan, but it is para-NPhard if the costs are non-negative integers or positive rationals. This is a very strong indication that the latter cases are substantially harder. Net-benefit planning (NBP) additionally assigns goal utilities and asks for a plan with maximum difference between its utility and its cost. NBP is para-NP-hard even when action costs and utilities are positive integers, suggesting that it is harder than COP. In addition, we also analyse a large number of subclasses, using both the PUBS restrictions and restricting the number of preconditions and effects.

  • 757.
    Aghighi, Meysam
    et al.
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Bäckström, Christer
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Plan Reordering and Parallel Execution -- A Parameterized Complexity View2017Conference paper (Refereed)
    Abstract [en]

    Bäckström has previously studied a number of optimization problems for partial-order plans, like finding a minimum deordering (MCD) or reordering (MCR), and finding the minimum parallel execution length (PPL), which are all NP-complete. We revisit these problems, but applying parameterized complexity analysis rather than standard complexity analysis. We consider various parameters, including both the original and desired size of the plan order, as well as its width and height. Our findings include that MCD and MCR are W[2]-hard and in W[P] when parameterized with the desired order size, and MCD is fixed-parameter tractable (fpt) when parameterized with the original order size. Problem PPL is fpt if parameterized with the size of the non-concurrency relation, but para-NP-hard in most other cases. We also consider this problem when the number (k) of agents, or processors, is restricted, finding that this number is a crucial parameter; this problem is fixed-parameter tractable with the order size, the parallel execution length and k as parameter, but para-NP-hard without k as parameter.

  • 758.
    Aghighi, Meysam
    et al.
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Bäckström, Christer
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Jonsson, Peter
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Ståhlberg, Simon
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Analysing Approximability and Heuristics in Planning Using the Exponential-Time Hypothesis2016In: ECAI 2016: 22ND EUROPEAN CONFERENCE ON ARTIFICIAL INTELLIGENCE, IOS Press, 2016, Vol. 285, p. 184-192Conference paper (Refereed)
    Abstract [en]

    Cost-optimal planning has become a very well-studied topic within planning. Needless to say, cost-optimal planning has proven to be computationally hard both theoretically and in practice. Since cost-optimal planning is an optimisation problem, it is natural to analyse it from an approximation point of view. Even though such studies may be valuable in themselves, additional motivation is provided by the fact that there is a very close link between approximability and the performance of heuristics used in heuristic search. The aim of this paper is to analyse approximability (and indirectly the performance of heuristics) with respect to lower time bounds. That is, we are not content by merely classifying problems into complexity classes - we also study their time complexity. This is achieved by replacing standard complexity-theoretic assumptions (such as P not equal NP) with the exponential time hypothesis (ETH). This enables us to analyse, for instance, the performance of the h(+) heuristic and obtain general trade-off results that correlate approximability bounds with bounds on time complexity.

  • 759.
    Aghighi, Meysam
    et al.
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Bäckström, Christer
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Jonsson, Peter
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Ståhlberg, Simon
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, Faculty of Science & Engineering.
    Refining complexity analyses in planning by exploiting the exponential time hypothesis2016In: Annals of Mathematics and Artificial Intelligence, ISSN 1012-2443, E-ISSN 1573-7470, Vol. 78, no 2, p. 157-175Article in journal (Refereed)
    Abstract [en]

    The use of computational complexity in planning, and in AI in general, has always been a disputed topic. A major problem with ordinary worst-case analyses is that they do not provide any quantitative information: they do not tell us much about the running time of concrete algorithms, nor do they tell us much about the running time of optimal algorithms. We address problems like this by presenting results based on the exponential time hypothesis (ETH), which is a widely accepted hypothesis concerning the time complexity of 3-SAT. By using this approach, we provide, for instance, almost matching upper and lower bounds onthe time complexity of propositional planning.

  • 760.
    Aghighi, Meysam
    et al.
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, The Institute of Technology.
    Jonsson, Peter
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, The Institute of Technology.
    Oversubscription planning: Complexity and compilability2014In: Proceedings of the Twenty-Eighth AAAI Conference on Artificial Intelligence, AI Access Foundation , 2014, Vol. 3, p. 2221-2227Conference paper (Refereed)
    Abstract [en]

    Many real-world planning problems are oversubscription problems where all goals are not simultaneously achievable and the planner needs to find a feasible subset. We present complexity results for the so-called partial satisfaction and net benefit problems under various restrictions; this extends previous work by van den Briel et al. Our results reveal strong connections between these problems and with classical planning. We also present a method for efficiently compiling oversubscription problems into the ordinary plan existence problem; this can be viewed as a continuation of earlier work by Keyder and Geffner.

  • 761.
    Aghighi, Meysam
    et al.
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, The Institute of Technology.
    Jonsson, Peter
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, The Institute of Technology.
    Ståhlberg, Simon
    Linköping University, Department of Computer and Information Science, Software and Systems. Linköping University, The Institute of Technology.
    Tractable Cost-Optimal Planning over Restricted Polytree Causal Graphs2015In: Proceedings of the Twenty-Ninth AAAI Conference on Artificial Intelligence, AAAI Press, 2015Conference paper (Refereed)
    Abstract [en]

    Causal graphs are widely used to analyze the complexity of planning problems. Many tractable classes have been identified with their aid and state-of-the-art heuristics have been derived by exploiting such classes. In particular, Katz and Keyder have studied causal graphs that are hourglasses (which is a generalization of forks and inverted-forks) and shown that the corresponding cost-optimal planning problem is tractable under certain restrictions. We continue this work by studying polytrees (which is a generalization of hourglasses) under similar restrictions. We prove tractability of cost-optimal planning by providing an algorithm based on a novel notion of variable isomorphism. Our algorithm also sheds light on the k-consistency procedure for identifying unsolvable planning instances. We speculate that this may, at least partially, explain why merge-and-shrink heuristics have been successful for recognizing unsolvable instances.

  • 762.
    Aghili, Mohammed
    Linköping University, Department of Computer and Information Science.
    Jämförelse av aggregeringswebbdelar i MOSS 20072010Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    En typisk funktion på startsidan till många webbportaler är den webbdel som presenterar exempelvis desenaste blogginläggen, nyheterna eller händelserna som har lagts till på webbplatsen. Dessa funktioner ärkända som aggreggeringswebbdelar. Eftersom startsidan är den sida som besöks mest jämfört med alla andrawebbsidor i portalen innebär det i sin tur att denna funktion utnyttjas väldigt ofta.Detta arbete syftar till att finna ett antal olika metoder som kan användas för att uppnå denna funktion ochatt ta reda på hur väl dessa webbdelar presterar.Denna rapport presenterar både de olika metoder som fanns och resultaten på en systematisk testning avdessa. Resultaten av testerna presenteras på ett överskådligt sätt.Slutligen dras slutsatser angående resultaten. Resultaten förespråkar inte en specifik metod, den metod somlämpar sig bäst för varje enskild sammanhang avgörs till största del av andra faktorer såsom frekvens avbesökare eller ändringar på innehållet som metoden söker igenom.

  • 763.
    Agholme, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
    Wnt signaling and metaphyseal bone healing2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis relates to some new aspects on the regulation of bone healing. In the last few years, Wnt-signaling has been shown to play a central role in bone biology. As well as being involved in bone maintenance and repair, Wnt-signaling has been presented as one of the key pathways through which bone responds to mechanical load. Two secreted extracellular inhibitors of Wnt-signaling, sclerostin and dickkopf-1 are potent negative regulators of bone formation.

    Using a rat fracture model we investigated how metaphyseal bone healing is influenced by changes in Wnt-signaling.

    Antibodies were used to suppress levels of sclerostin and dickkopf-1, and thereby increase Wnt-signaling. Primarily, we investigated if those antibody treatments lead to improved bone healing. Also, we investigated if the response was coupled to the loading conditions of the bone.

    Our findings suggest that suppression of either sclerostin or dickkopf-1 leads to increased bone formation and improved bone healing. Apart from just having an effect on healing, the treatment also improved bone formation in other parts of the skeleton. Depending on the loading conditions, the effects were different. Dickkopf-1 appeared to have a stronger effect on bone volume density in unloaded bone, implying a role mainly in mechano-transduction, while sclerostin had similar effect in both loaded and unloaded bone. To confirm these findings, we studied how the expression of several Wnt-related genes changed due to trauma and unloading in metaphyseal bone. We found that trauma led to upregulation of most of the genes with the largest effect seen in the unloaded bone. In untraumatized bone, there was mainly an effect on the sclerostin gene.

    In conclusion, antibodies against sclerostin and dickkopf-1 appear to be able to improve metaphyseal bone healing. There appear to be some differences in how the effect of the two antibodies manifests itself, especially if the loading conditions of the bone are altered. These findings suggest a potential for clinical use to shorten fracture healing time.

    List of papers
    1. Sclerostin Antibody Treatment Enhances Metaphyseal Bone Healing in Rats
    Open this publication in new window or tab >>Sclerostin Antibody Treatment Enhances Metaphyseal Bone Healing in Rats
    Show others...
    2010 (English)In: JOURNAL OF BONE AND MINERAL RESEARCH, ISSN 0884-0431, Vol. 25, no 11, p. 2412-2418Article in journal (Refereed) Published
    Abstract [en]

    Sclerostin is the product of the SOST gene Loss of-function mutations in the SOST gene result in a high bone-mass phenotype demonstrating that sclerostin is a negative regulator of bone mass Primarily expressed by osteocytes in bone sclerostin is reported to bind the LRP5/6 receptor thereby antagonizing canonical Wnt signaling and negatively regulating bone formation We therefore investigated whether systemic administration of a sclerostin neutralizing antibody would increase the regeneration of traumatized metaphyseal bone in rats Young male rats had a screw inserted in the proximal tibia and were divided into six groups given 25 mg/kg of sclerostin antibody or control twice a week subcutaneously for 2 or 4 weeks In four groups, the screws were tested for pull out strength At the time of euthanasia a similar screw also was inserted in the contralateral tibia and pull-out tested immediately Sclerostin antibody significantly increased the pull out force by almost 50% compared with controls after 2 and 4 weeks Also the screws inserted at the time of euthanasia showed increased pull out force Micro-computed tomography (mu CT) of the remaining two groups showed that the antibody led to a 30% increase in bone volume fraction in a region surrounding the screw There also was a general increase in trabecular thickness in cancellous bone Thus as measured by the amount of bone and its mechanical resistance the sclerostin antibody increased bone formation during metaphyseal repair but also in untraumatized bone

    Place, publisher, year, edition, pages
    American Society for Bone and Mineral Research, 2010
    Keywords
    bone formation;implants;bone repair;sclerostin;antibody
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-62733 (URN)10.1002/jbmr.135 (DOI)000284133500016 ()20499342 (PubMedID)
    Available from: 2010-12-03 Created: 2010-12-03 Last updated: 2011-10-10
    2. The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions
    Open this publication in new window or tab >>The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions
    2011 (English)In: BONE, ISSN 8756-3282, Vol. 48, no 5, p. 988-996Article in journal (Refereed) Published
    Abstract [en]

    The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unclear how it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, mu CT and histology were used for evaluation. The animals were injected with either 10 mg/kg Dkk1-ab or saline every 14 days for 14, 28, or 42 days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28 days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botulinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233%. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction.

    Place, publisher, year, edition, pages
    Elsevier Science B.V., Amsterdam., 2011
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-68352 (URN)10.1016/j.bone.2011.02.008 (DOI)000289879900005 ()
    Note
    Original Publication: Fredrik Agholme, Hanna Isaksson, Stuart Kuhstoss and Per Aspenberg, The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions, 2011, BONE, (48), 5, 988-996. http://dx.doi.org/10.1016/j.bone.2011.02.008 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/ Available from: 2011-05-20 Created: 2011-05-20 Last updated: 2011-10-10
    3. Anti-sclerostin antibody and mechanical loading appear to influence metaphyseal bone independently in rats
    Open this publication in new window or tab >>Anti-sclerostin antibody and mechanical loading appear to influence metaphyseal bone independently in rats
    Show others...
    2011 (English)In: Acta Orthopaedica, ISSN 1745-3674, Vol. 82, no 5, p. 628-632Article in journal (Refereed) Published
    Abstract [en]

    Background and purpose: Sclerostin is produced by osteocytes and is an inhibitor of bone formation. Thus, inhibition of sclerostin by a monoclonal antibody increases bone formation and improves fracture repair. Sclerostin expression is upregulated in unloaded bone and is downregulated by loading. We wanted to determine whether an anti-sclerostin antibody would stimulate metaphyseal healing in unloaded bone in a rat model.

    Methods: 10-week-old male rats (n = 48) were divided into 4 groups, with 12 in each. In 24 rats, the right hind limb was unloaded by paralyzing the calf and thigh muscles with an injection of botulinum toxin A (Botox). 3 days later, all the animals had a steel screw inserted into the right proximal tibia. Starting 3 days after screw insertion, either anti-sclerostin antibody (Scl-Ab) or saline was given twice weekly. The other 24 rats did not receive Botox injections and they were treated with Scl-Ab or saline to serve as normal-loaded controls. Screw pull-out force was measured 4 weeks after insertion, as an indicator of the regenerative response of bone to trauma.

    Results: Unloading reduced the pull-out force. Scl-Ab treatment increased the pull-out force, with or without unloading. The response to the antibody was similar in both groups, and no statistically significant relationship was found between unloading and antibody treatment. The cancellous bone at a distance from the screw showed changes in bone volume fraction that followed the same pattern as the pull-out force.

    Interpretation: Scl-Ab increases bone formation and screwfixation to a similar degree in loaded and unloaded bone.

    Place, publisher, year, edition, pages
    Taylor and Francis, 2011
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-71284 (URN)10.3109/17453674.2011.625539 (DOI)
    Available from: 2011-10-10 Created: 2011-10-10 Last updated: 2014-10-17Bibliographically approved
    4. Wnt gene expression during metaphyseal bone healing under different load conditions
    Open this publication in new window or tab >>Wnt gene expression during metaphyseal bone healing under different load conditions
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Bone Wnt signalling has been presented as one of the key pathways through which bone responds to mechanical load. This pathway is also active during the healing process after bone trauma. Bone healing can be improved by pharmacological modulation of Wnt signalling. We investigated how the expression of several Wntrelated genes changed due to trauma and unloading in metaphyseal bone.

    20 male rats had one hind limb unloaded by intramuscular Botox injections. In half of the animals a hole was drilled bilaterally in the proximal tibia. After 7 days, a cylindrical biopsy was taken from the bone surrounding the hole and at a corresponding site in animals without trauma. The biopsies were analyzed for the mRNA expression of Wnt1, Wnt3a, Wnt4, Wnt5a, Wnt5b, Sost, Dkk1, Dkk2, Sfrp1, Sfrp4, Lrp5, Lrp6, Wisp1, Wif1 and Wnt10b.

    Trauma led to upregulation of most of the studied genes. This effect was most evident in unloaded bone, where 8 genes were upregulated, among them Wnt receptors, ligands and inhibitors. Unloading increased the expression of Sost in untraumatized bone, but did not significantly influence the other genes.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-71285 (URN)
    Available from: 2011-10-10 Created: 2011-10-10 Last updated: 2011-10-10Bibliographically approved
  • 764.
    Agholme, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
    Andersson, Therese
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Tengvall, P
    University of Gothenburg.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Local bisphosphonate release versus hydroxyapatite coating for stainless steel screw fixation in rat tibiae2012In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 23, no 3, p. 743-752Article in journal (Refereed)
    Abstract [en]

    Implant fixation in bone can be improved by a coating that delivers bisphosphonates locally, or by a hydroxyapatite (HA) coating. In this study, we compared these different types of coatings. For mechanical testing, 30 rats were assigned into three groups, and similar screws were implanted bilaterally in the proximal tibiae. The rats received screws that were either uncoated, coated with nano-crystalline hydroxyapatite or coated with a bisphosphonate releasing protein matrix. After 4 weeks, one screw was subjected to pull-out testing, and the contra-lateral one to torsion testing. For morphology, 30 rats were assigned to similar treatment groups, but received only one screw each. Bisphosphonates enhanced the pull-out force by 41% (P = 0.02) compared to controls, HA increased the pull-out force although not significantly. Conversely, HA increased the maximal torque by 64% (P = 0.02). Morphometry showed higher bone volume around bisphosphonate screws in comparison to HA-coated screws (P andlt; 0.001) and controls (P andlt; 0.001). The results suggest that bisphosphonates improve fixation by increasing the amount of surrounding bone, whereas HA mainly improves bone to implant attachment.

  • 765.
    Agholme, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Linköping University, Faculty of Health Sciences.
    Andersson, Therese
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Tengvall, Pentti
    University of Gothenburg.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
    A win for bisphosphonates? Comparison between local bisphosphonate release and hydroxyapatite coating for screw fixation in rats in BONE, vol 46, issue , pp S67-S672010In: BONE, Elsevier Science B.V., Amsterdam. , 2010, Vol. 46, p. S67-S67Conference paper (Refereed)
    Abstract [en]

    n/a

  • 766.
    Agholme, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Linköping University, Faculty of Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
    Experimental results of combining bisphosphonates with allograft in a rat model2009In: Journal of Bone and Joint Surgery - Series B, ISSN 0301-620X, Vol. 91, no 5, p. 670-675Article in journal (Refereed)
    Abstract [en]

    Soaking bone grafts in a bisphosphonate solution before implantation can prevent their resorption and increase the local bone density in rats and humans. However, recent studies suggest that pre-treatment of allografts with bisphosphonate can prevent bone ingrowth into impaction grafts. We tested the hypothesis that excessive amounts of bisphosphonate would also cause a negative response in less dense grafts. We used a model where nonimpacted metaphyseal bone grafts were randomised into three groups with either no bisphosphonate, alendronate followed by rinsing, and alendronate without subsequent rinsing, and inserted into bone chambers in rats. The specimens were evaluated histologically at one week, and by histomorphometry and radiology at four weeks. At four weeks, both bisphosphonate groups showed an increase in the total bone content, increased newly formed bone, and higher radiodensity than the controls. In spite of being implanted in a chamber with a limited opportunity to diffuse, even an excessive amount of bisphosphonate improved the outcome. We suggest that the negative results seen by others could be due to the combination of densely compacted bone and a bisphosphonate. We suggest that bisphosphonates are likely to have a negative influence where resorption is a prerequisite to create space for new bone ingrowth.

  • 767.
    Agholme, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Linköping University, Faculty of Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Orthopaedic Centre, Department of Orthopaedics Linköping.
    Reduced serum serotonin impairs metaphyseal repair in rats in BONE, vol 46, issue , pp S67-S672010In: BONE, Elsevier Science B.V., Amsterdam. , 2010, Vol. 46, p. S67-S67Conference paper (Refereed)
    Abstract [en]

    n/a

  • 768.
    Agholme, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Wnt signaling and orthopedics, an overview2011In: ACTA ORTHOPAEDICA, ISSN 1745-3674, Vol. 82, no 2, p. 125-130Article in journal (Refereed)
    Abstract [en]

    Wnt signaling is a ubiquitous system for intercellular communication, with multiple functions during development and in homeostasis of the body. It comprises several ligands, receptors, and inhibitors. Some molecules, such as sclerostin, appear to have bone-specific functions, and can be targeted by potential drugs. Now, ongoing clinical trials are testing these drugs as treatments for osteoporosis. Animal studies have also suggested that these drugs can accelerate fracture healing and implant fixation. This brief overview focuses on currently available information on the effects of manipulations of Wnt signaling on bone healing.

  • 769.
    Agholme, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
    Isaksson, Hanna
    Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
    Kuhstoss, Stuart
    Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, USA.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    The effects of Dickkopf-1 antibody on metaphyseal bone and implant fixation under different loading conditions2011In: BONE, ISSN 8756-3282, Vol. 48, no 5, p. 988-996Article in journal (Refereed)
    Abstract [en]

    The secreted protein Dickkopf-1 (Dkk1) is an antagonist of canonical Wnt signaling, expressed during fracture healing. It is unclear how it is involved in the mechanical control of bone maintenance. We investigated the response to administration of a Dkk1 neutralizing antibody (Dkk1-ab) in metaphyseal bone under different loading conditions, with or without trauma. In this three part experiment, 120 rats had a screw or bone chamber inserted either unilaterally or bilaterally in the proximal tibia. Mechanical (pull-out) testing, mu CT and histology were used for evaluation. The animals were injected with either 10 mg/kg Dkk1-ab or saline every 14 days for 14, 28, or 42 days. Antibody treatment increased bone formation around the screws and improved their fixation. After 28 days, the pull-out force was increased by over 100%. In cancellous bone, the bone volume fraction was increased by 50%. In some animals, one hind limb was paralyzed with Botulinum toxin A (Botox) to create a mechanically unloaded environment. This did not increase the response to antibody treatment with regard to screw fixation, but in cancellous bone, the bone volume fraction increased by 233%. Thus, the response in unloaded, untraumatized bone was proportionally larger, suggesting that Dkk1 may be up-regulated in unloaded bone. There was also an increase in thickness of the metaphyseal cortex. In bone chambers, the antibody treatment increased the bone volume fraction. The results suggest that antibodies blocking Dkk1 might be used to stimulate bone formation especially during implant fixation, fracture repair, or bone disuse. It also seems that Dkk1 is up-regulated both after metaphyseal trauma and after unloading, and that Dkk1 is involved in mechano-transduction.

  • 770.
    Agholme, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
    Isaksson, Hanna
    Department of Applied physics, University of Eastern Finland, Kuopio, Finland.
    Li, Xiaodong
    Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
    Ke, Hua Zhu
    Metabolic Disorders, Amgen Inc., Thousand Oaks, CA, USA.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Anti-sclerostin antibody and mechanical loading appear to influence metaphyseal bone independently in rats2011In: Acta Orthopaedica, ISSN 1745-3674, Vol. 82, no 5, p. 628-632Article in journal (Refereed)
    Abstract [en]

    Background and purpose: Sclerostin is produced by osteocytes and is an inhibitor of bone formation. Thus, inhibition of sclerostin by a monoclonal antibody increases bone formation and improves fracture repair. Sclerostin expression is upregulated in unloaded bone and is downregulated by loading. We wanted to determine whether an anti-sclerostin antibody would stimulate metaphyseal healing in unloaded bone in a rat model.

    Methods: 10-week-old male rats (n = 48) were divided into 4 groups, with 12 in each. In 24 rats, the right hind limb was unloaded by paralyzing the calf and thigh muscles with an injection of botulinum toxin A (Botox). 3 days later, all the animals had a steel screw inserted into the right proximal tibia. Starting 3 days after screw insertion, either anti-sclerostin antibody (Scl-Ab) or saline was given twice weekly. The other 24 rats did not receive Botox injections and they were treated with Scl-Ab or saline to serve as normal-loaded controls. Screw pull-out force was measured 4 weeks after insertion, as an indicator of the regenerative response of bone to trauma.

    Results: Unloading reduced the pull-out force. Scl-Ab treatment increased the pull-out force, with or without unloading. The response to the antibody was similar in both groups, and no statistically significant relationship was found between unloading and antibody treatment. The cancellous bone at a distance from the screw showed changes in bone volume fraction that followed the same pattern as the pull-out force.

    Interpretation: Scl-Ab increases bone formation and screwfixation to a similar degree in loaded and unloaded bone.

  • 771.
    Agholme, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
    Li, Xiaodong
    Amgen Inc.
    Isaksson, Hanna
    University of Eastern Finland.
    Zhu Ke, Hua
    Amgen Inc.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Sclerostin Antibody Treatment Enhances Metaphyseal Bone Healing in Rats2010In: JOURNAL OF BONE AND MINERAL RESEARCH, ISSN 0884-0431, Vol. 25, no 11, p. 2412-2418Article in journal (Refereed)
    Abstract [en]

    Sclerostin is the product of the SOST gene Loss of-function mutations in the SOST gene result in a high bone-mass phenotype demonstrating that sclerostin is a negative regulator of bone mass Primarily expressed by osteocytes in bone sclerostin is reported to bind the LRP5/6 receptor thereby antagonizing canonical Wnt signaling and negatively regulating bone formation We therefore investigated whether systemic administration of a sclerostin neutralizing antibody would increase the regeneration of traumatized metaphyseal bone in rats Young male rats had a screw inserted in the proximal tibia and were divided into six groups given 25 mg/kg of sclerostin antibody or control twice a week subcutaneously for 2 or 4 weeks In four groups, the screws were tested for pull out strength At the time of euthanasia a similar screw also was inserted in the contralateral tibia and pull-out tested immediately Sclerostin antibody significantly increased the pull out force by almost 50% compared with controls after 2 and 4 weeks Also the screws inserted at the time of euthanasia showed increased pull out force Micro-computed tomography (mu CT) of the remaining two groups showed that the antibody led to a 30% increase in bone volume fraction in a region surrounding the screw There also was a general increase in trabecular thickness in cancellous bone Thus as measured by the amount of bone and its mechanical resistance the sclerostin antibody increased bone formation during metaphyseal repair but also in untraumatized bone

  • 772.
    Agholme, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Macias, Brandon
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Hamang, Matt
    Lilly Research Labs, IN USA .
    Lucchesi, Jonathan
    Lilly Research Labs, IN USA .
    Adrian, Mary D.
    Lilly Research Labs, IN USA .
    Kuhstoss, Stuart
    Lilly Research Labs, IN USA .
    Harvey, Anita
    Lilly Research Labs, IN USA .
    Sato, Masahiko
    Lilly Research Labs, IN USA .
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Efficacy of a Sclerostin Antibody Compared to a Low Dose of PTH on Metaphyseal Bone Healing2014In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 32, no 3, p. 471-476Article in journal (Refereed)
    Abstract [en]

    We compared the effect of a sclerostin antibody to that of a clinically relevant dose of parathyroid hormone (PTH) in a rat model for metaphyseal bone healing. Screws of steel or poly methyl methacrylate (PMMA) were inserted bilaterally into the proximal tibia of young male rats. During 4 weeks the animals then received injections of either phosphate buffered saline (control), sclerostin antibody (25mg/kg, twice weekly) or PTH (5 mu g/kg, daily). The healing response around the screws was then assessed by mechanical testing and X-ray microtomography (mu CT). To distinguish between effects on healing and general effects on the skeleton, other untraumatized bone sites and serum biomarkers were also assessed. After 4 weeks of treatment, PTH yielded a 48% increase in screw pull-out force compared to control (p=0.03), while the antibody had no significant effect. In contrast, the antibody increased femoral cortical and vertebral strength where PTH had no significant effect. mu CT showed only slight changes that were statistically significant for the antibody mainly at cortical sites. The results suggest that a relatively low dose of PTH stimulates metaphyseal repair (screw fixation) specifically, whereas the sclerostin antibody has wide-spread effects, mainly on cortical bone, with less influence on metaphyseal healing.

  • 773.
    Agholme, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
    Sandberg, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences.
    Aspenberg, Per
    Linköping University, Department of Clinical and Experimental Medicine, Orthopaedics and Sports Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Orthopaedics in Linköping.
    Wnt gene expression during metaphyseal bone healing under different load conditionsManuscript (preprint) (Other academic)
    Abstract [en]

    Bone Wnt signalling has been presented as one of the key pathways through which bone responds to mechanical load. This pathway is also active during the healing process after bone trauma. Bone healing can be improved by pharmacological modulation of Wnt signalling. We investigated how the expression of several Wntrelated genes changed due to trauma and unloading in metaphyseal bone.

    20 male rats had one hind limb unloaded by intramuscular Botox injections. In half of the animals a hole was drilled bilaterally in the proximal tibia. After 7 days, a cylindrical biopsy was taken from the bone surrounding the hole and at a corresponding site in animals without trauma. The biopsies were analyzed for the mRNA expression of Wnt1, Wnt3a, Wnt4, Wnt5a, Wnt5b, Sost, Dkk1, Dkk2, Sfrp1, Sfrp4, Lrp5, Lrp6, Wisp1, Wif1 and Wnt10b.

    Trauma led to upregulation of most of the studied genes. This effect was most evident in unloaded bone, where 8 genes were upregulated, among them Wnt receptors, ligands and inhibitors. Unloading increased the expression of Sost in untraumatized bone, but did not significantly influence the other genes.

  • 774.
    Agholme, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    The involvement of degradation pathways and neuron-to-neuron transmission in Alzheimer’s disease2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Although the vast majority of Alzheimer’s disease (AD) cases are of the sporadic type, mutations causing the familial form have been the focus of AD research for decades. The disease is pathologically characterised by β-amyloid (Aβ) and tau protein aggregates in neuritic plaques and neurofibrillary tangles. Furthermore, it is known that AD pathology spreads throughout the brain, most often along the same anatomical pattern. However, so far no cause for the sporadic form of the disease has been found. Accumulation of protein aggregates as well as decreased activity of the protein degradation systems, lysosomes and proteasomes, is found in diseased brains. This indicates that defective degradation contributes to sporadic AD.

    The aim of this thesis was to develop an improved neuronal model, and study the effects of decreased proteasome function on tau phosphorylation and axonal transport. In addition, the effects on Aβ accumulation and generation upon proteasome inhibition were investigated. Finally, the possibility that intracellularly accumulated Aβ oligomers could be transferred from one neuron to another was tested.

    Differentiation of human SH-SY5Y neuroblastoma cells in an extracellular matrix gel, using a set of neurotrophic factors, resulted in cells with neuronal phenotype, expressing neuron specific markers and all six adult isoforms of tau. Within this neuronal model, we found that reduced proteasome activity inhibited neuritic transport, and caused tau phosphorylation in a c-Jun and ERK 1/2 dependent manner. Using proteasome inhibition in APP overexpressing cells, we found an autophagy dependent intralysosomal Aβ accumulation, together with elevation of intra- and extracellular concentrations of Aβ. Autophagy inhibition protected the cells from the toxicity induced by decreased proteasome activity. Finally, we could, as the first group, show that Aβ can be directly transferred from one neuron to another through connected neurites. Furthermore, accumulation of Aβ in the endo-lysosomal compartment of receiving cells caused toxicity and neurodegeneration.

    We believe that cells not able to degrade accumulated Aβ, due to increased generation or reduced degradative capacity, instead tries to clear its content through transfer to connected neurons. If not properly degraded in the receiving cell, this can accelerate AD pathology and cause neuritic and neuronal degeneration spreading throughout the brain. Increasing the activity of the degradative systems, or inhibiting transmission of Aβ between neurons could therefore be novel treatments for AD.

    List of papers
    1. An In Vitro Model for Neuroscience: Differentiation of SH-SY5Y Cells into Cells with Morphological and Biochemical Characteristics of Mature Neurons
    Open this publication in new window or tab >>An In Vitro Model for Neuroscience: Differentiation of SH-SY5Y Cells into Cells with Morphological and Biochemical Characteristics of Mature Neurons
    Show others...
    2010 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 20, no 4, p. 1069-1082Article in journal (Refereed) Published
    Abstract [en]

    Neuroscience, including research on Alzheimers disease, is hampered by the lack of suitable in vitro models to study the human nervous system. To counteract this, many attempts to differentiate cell lines into more neuron-like cells have been performed, resulting in partial expression of neuronal features. Furthermore, it has been reported that neuroblastoma cell lines lack mature isoforms of tau. Our aim was to develop an improved in vitro model, generating sustainable cells with morphology and biochemistry of human, mature neurons. To obtain cells with neuronal differentiation and function, we investigated the effect of combining three-dimensional culturing of SH-SY5Y cells in extracellular matrix (ECM) gel with several factors reported to have neuro-differentiating effects. This resulted in cells with apparent neuronal morphology with long, extensively branched neurites. Further investigation revealed expression of several neurospecific markers including synapse protein Sv2 and nuclear marker NeuN, as well as the presence of synapses and axonal vesicle transport. In addition, these cells expressed mature tau isoforms, and tau protein expression was significantly increased compared to undifferentiated cells, reaching levels found in adult human brain. In conclusion, we found that pre-treatment with retinoic acid followed by ECM gel culturing in combination with brain derived neurotrophic factor, neuregulin beta(1), nerve growth factor, and vitamin D-3 treatment generated sustainable cells with unambiguous resemblance to adult neurons. These cells also expresses adult splicing forms of tau with neuronal localization, making this cellular in vitro model useful in many areas of neuroscience research, particularly the Alzheimers disease field.

    Place, publisher, year, edition, pages
    Ios Press, 2010
    Keywords
    Alzheimers disease; differentiation; in vitro model; neuroblastoma; tau
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-58227 (URN)10.3233/JAD-2010-091363 (DOI)000279539500012 ()
    Note
    Original Publication: Lotta Agholme, Tobias Lindström, Katarina Kågedal, Jan Marcusson and Martin Hallbeck, An In Vitro Model for Neuroscience: Differentiation of SH-SY5Y Cells into Cells with Morphological and Biochemical Characteristics of Mature Neurons, 2010, Journal of Alzheimer's Disease, (20), 4, 1069-1082. http://dx.doi.org/10.3233/JAD-2010-091363 Copyright: Ios Press http://www.iospress.nl/ Available from: 2010-08-10 Created: 2010-08-09 Last updated: 2017-12-12
    2. Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease
    Open this publication in new window or tab >>Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease
    Show others...
    2014 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 58, p. 29-39Article in journal (Refereed) Published
    Abstract [en]

    Alzheimer’s disease (AD) is characterized by accumulation of two misfolded and aggregated proteins, β-amyloid and hyperphosphorylated tau. Both cellular systems responsible for clearance of misfolded and aggregated proteins, the lysosomal and the proteasomal, have been shown to be malfunctioning in the aged brain and more so in AD patients. This malfunction could be the cause of β-amyloid and tau accumulation, eventually aggregating in plaques and tangles. We have investigated how decreased proteasome activity affects AD related pathophysiological changes of microtubule transport and stability, as well as tau phosphorylation. To do this, we used our recently developed neuronal model where human SH-SY5Y cells obtain neuronal morphology and function through differentiation. We found that exposure to low doses of the proteasome inhibitor MG-115 caused disturbed neuritic transport, together with microtubule destabilization and tau phosphorylation. Furthermore, reduced proteasome activity activated several kinases implicated in AD pathology, including JNK, c-Jun and ERK 1/2. Restoration of the microtubule transport was achieved by inhibiting ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun reversed the proteasome inhibition-induced tau phosphorylation. Taken together, this study suggests that a decrease in proteasome activity can, through activation of c-Jun and ERK 1/2, result in several events contributing to AD pathology. Restoring proteasome function or inhibiting ERK 1/2 and c-Jun could therefore be used as novel treatments against AD.

    Place, publisher, year, edition, pages
    Elsevier, 2014
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-81339 (URN)10.1016/j.mcn.2013.11.001 (DOI)000331853600004 ()
    Available from: 2012-09-12 Created: 2012-09-12 Last updated: 2017-12-07Bibliographically approved
    3. Amyloid-β Secretion, Generation, and Lysosomal Sequestration in Response to Proteasome Inhibition: Involvement of Autophagy
    Open this publication in new window or tab >>Amyloid-β Secretion, Generation, and Lysosomal Sequestration in Response to Proteasome Inhibition: Involvement of Autophagy
    Show others...
    2012 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 31, no 2, p. 343-358Article in journal (Refereed) Published
    Abstract [en]

    The proteasome is important for degradation of worn out and misfolded proteins. Decreased proteasome activity has been implicated in Alzheimer's disease (AD). Proteasome inhibition induces autophagy, but it is still unknown whether autophagy is beneficial or deleterious to AD neurons, as the autophagosome has been suggested as a site of amyloid-β (Aβ) generation. In this study, we investigated the effect of proteasome inhibition on Aβ accumulation and secretion, as well as the processing of amyloid-β protein precursor (AβPP) in AβPPSwe transfected SH-SY5Y neuroblastoma cells. We show that proteasome inhibition resulted in autophagy-dependent accumulation of Aβ in lysosomes, and increased levels of intracellular and secreted Aβ. The enhanced levels of Aβ could not be explained by increased amounts of AβPP. Instead, reduced degradation of the C-terminal fragment of AβPP (C99) by the proteasome makes C99 available for γ-secretase cleavage, leading to Aβ generation. Inhibition of autophagy after proteasome inhibition led to reduced levels of intracellular, but not secreted Aβ, and tended to further increase the C99 to AβPP ratio, supporting involvement of the autophagosome in Aβ generation. Furthermore, proteasome inhibition caused a reduction in cellular viability, which was reverted by inhibition of autophagy. Dysfunction of the proteasome could cause lysosomal accumulation of Aβ, as well as increased generation and secretion of Aβ, which is partly facilitated by autophagy. As a decrease in cellular viability was also detected, it is possible that upregulation of autophagy is an unsuccessful rescue mechanism, which instead of being protective, contributes to AD pathogenesis.

    Place, publisher, year, edition, pages
    I O S Press, 2012
    Keywords
    AβPP processing, Alzheimer’s disease, amyloid- peptide, autophagy, cell death, LC-3, lysosome, p70S6K, proteasome
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-81340 (URN)10.3233/JAD-2012-120001 (DOI)000307377300011 ()22555375 (PubMedID)
    Note

    funding agencies|foundations of Engqvist, Wiberg, Hedlund, Osterman, and Stohne||Gustav V and Queen Victorias Foundation||Swedish Alzheimers foundation||Ostergotland County Council||Swedish Research Council||

    Available from: 2012-09-12 Created: 2012-09-12 Last updated: 2017-12-07Bibliographically approved
    4. Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of beta-Amyloid
    Open this publication in new window or tab >>Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of beta-Amyloid
    Show others...
    2012 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 26, p. 8767-8777Article in journal (Refereed) Published
    Abstract [en]

    Alzheimers disease (AD) is the major cause of dementia. During the development of AD, neurofibrillary tangles progress in a fixed pattern, starting in the transentorhinal cortex followed by the hippocampus and cortical areas. In contrast, the deposition of beta-amyloid (A beta) plaques, which are the other histological hallmark of AD, does not follow the same strict spatiotemporal pattern, and it correlates poorly with cognitive decline. Instead, soluble A beta oligomers have received increasing attention as probable inducers of pathogenesis. In this study, we use microinjections into electrophysiologically defined primary hippocampal rat neurons to demonstrate the direct neuron-to-neuron transfer of soluble oligomeric A beta. Additional studies conducted in a human donor-acceptor cell model show that this A beta transfer depends on direct cellular connections. As the transferred oligomers accumulate, acceptor cells gradually show beading of tubulin, a sign of neurite damage, and gradual endosomal leakage, a sign of cytotoxicity. These observations support that intracellular A beta oligomers play a role in neurodegeneration, and they explain the manner in which A beta can drive disease progression, even if the extracellular plaque load is poorly correlated with the degree of cognitive decline. Understanding this phenomenon sheds light on the pathophysiological mechanism of AD progression. Additional elucidation will help uncover the detailed mechanisms responsible for the manner in which AD progresses via anatomical connections and will facilitate the development of new strategies for stopping the progression of this incapacitating disease.

    Place, publisher, year, edition, pages
    SOC NEUROSCIENCE, 2012
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-79695 (URN)10.1523/JNEUROSCI.0615-12.2012 (DOI)000305890700003 ()
    Available from: 2012-08-13 Created: 2012-08-13 Last updated: 2018-01-25
  • 775.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Getting rid of intracellular Aβ- loss of cellular degradation leads to transfer between connected neurons2014In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 20, no 15, p. 2458-2468Article in journal (Refereed)
    Abstract [en]

    The sporadic, late onset form of Alzheimers disease (AD) shares pathological hallmarks with the familial form; however, no clear reason for increased beta-amyloid (A beta) generation has been found in the former. It has long been speculated that the late onset form of AD is caused by reduced degradation and/or clearance of A beta. Indeed, both intracellular degradation systems, the proteasomal and lysosomal systems, have been shown to be defective in AD. Reduced proteasome activity increases levels of intracellular and secreted A beta. Furthermore, accumulation of improperly degraded A beta in the lysosomes causes lysosomal disruption and cell death. We recently showed that oligomeric A beta can be transmitted from one neuron to another, which causes neurotoxicity. In both the donating and receiving cells, A beta accumulates in the endo-lysosomal compartment. It is possible that ineffective degradation of A beta causes its transfer to neighboring neurons, thereby spreading AD pathology. This review summarizes the data underlying the idea of reduced A beta clearance and subsequent A beta spread in AD, and also suggests new therapeutic methods, which are aimed at targeting the degradation systems and synaptic transfer. By enhancing degradation of intracellular accumulated A beta, it can be possible to remove it and avoid A beta-induced neurodegeneration without disturbing the endogenously important pool of secreted A beta. Additionally, drugs targeted to inhibit the spread of intracellular toxic A beta aggregates may also be useful in stopping the progression of pathology, without affecting the level of A beta that normally occurs in the brain.

  • 776.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Benedikz, Eirikur
    Department of Neurobiology, Division of Neurodegeneration, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Amyloid-β Secretion, Generation, and Lysosomal Sequestration in Response to Proteasome Inhibition: Involvement of Autophagy2012In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 31, no 2, p. 343-358Article in journal (Refereed)
    Abstract [en]

    The proteasome is important for degradation of worn out and misfolded proteins. Decreased proteasome activity has been implicated in Alzheimer's disease (AD). Proteasome inhibition induces autophagy, but it is still unknown whether autophagy is beneficial or deleterious to AD neurons, as the autophagosome has been suggested as a site of amyloid-β (Aβ) generation. In this study, we investigated the effect of proteasome inhibition on Aβ accumulation and secretion, as well as the processing of amyloid-β protein precursor (AβPP) in AβPPSwe transfected SH-SY5Y neuroblastoma cells. We show that proteasome inhibition resulted in autophagy-dependent accumulation of Aβ in lysosomes, and increased levels of intracellular and secreted Aβ. The enhanced levels of Aβ could not be explained by increased amounts of AβPP. Instead, reduced degradation of the C-terminal fragment of AβPP (C99) by the proteasome makes C99 available for γ-secretase cleavage, leading to Aβ generation. Inhibition of autophagy after proteasome inhibition led to reduced levels of intracellular, but not secreted Aβ, and tended to further increase the C99 to AβPP ratio, supporting involvement of the autophagosome in Aβ generation. Furthermore, proteasome inhibition caused a reduction in cellular viability, which was reverted by inhibition of autophagy. Dysfunction of the proteasome could cause lysosomal accumulation of Aβ, as well as increased generation and secretion of Aβ, which is partly facilitated by autophagy. As a decrease in cellular viability was also detected, it is possible that upregulation of autophagy is an unsuccessful rescue mechanism, which instead of being protective, contributes to AD pathogenesis.

  • 777.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in the East of Östergötland, Department of Geriatrics.
    Lindström, Tobias
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Kågedal, Katarina
    Linköping University, Department of Neuroscience and Locomotion, Pathology. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    An In Vitro Model for Neuroscience: Differentiation of SH-SY5Y Cells into Cells with Morphological and Biochemical Characteristics of Mature Neurons2010In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 20, no 4, p. 1069-1082Article in journal (Refereed)
    Abstract [en]

    Neuroscience, including research on Alzheimers disease, is hampered by the lack of suitable in vitro models to study the human nervous system. To counteract this, many attempts to differentiate cell lines into more neuron-like cells have been performed, resulting in partial expression of neuronal features. Furthermore, it has been reported that neuroblastoma cell lines lack mature isoforms of tau. Our aim was to develop an improved in vitro model, generating sustainable cells with morphology and biochemistry of human, mature neurons. To obtain cells with neuronal differentiation and function, we investigated the effect of combining three-dimensional culturing of SH-SY5Y cells in extracellular matrix (ECM) gel with several factors reported to have neuro-differentiating effects. This resulted in cells with apparent neuronal morphology with long, extensively branched neurites. Further investigation revealed expression of several neurospecific markers including synapse protein Sv2 and nuclear marker NeuN, as well as the presence of synapses and axonal vesicle transport. In addition, these cells expressed mature tau isoforms, and tau protein expression was significantly increased compared to undifferentiated cells, reaching levels found in adult human brain. In conclusion, we found that pre-treatment with retinoic acid followed by ECM gel culturing in combination with brain derived neurotrophic factor, neuregulin beta(1), nerve growth factor, and vitamin D-3 treatment generated sustainable cells with unambiguous resemblance to adult neurons. These cells also expresses adult splicing forms of tau with neuronal localization, making this cellular in vitro model useful in many areas of neuroscience research, particularly the Alzheimers disease field.

  • 778.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Geriatric Medicine in Norrköping.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Domert, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine in Linköping.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease2014In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 58, p. 29-39Article in journal (Refereed)
    Abstract [en]

    Alzheimer’s disease (AD) is characterized by accumulation of two misfolded and aggregated proteins, β-amyloid and hyperphosphorylated tau. Both cellular systems responsible for clearance of misfolded and aggregated proteins, the lysosomal and the proteasomal, have been shown to be malfunctioning in the aged brain and more so in AD patients. This malfunction could be the cause of β-amyloid and tau accumulation, eventually aggregating in plaques and tangles. We have investigated how decreased proteasome activity affects AD related pathophysiological changes of microtubule transport and stability, as well as tau phosphorylation. To do this, we used our recently developed neuronal model where human SH-SY5Y cells obtain neuronal morphology and function through differentiation. We found that exposure to low doses of the proteasome inhibitor MG-115 caused disturbed neuritic transport, together with microtubule destabilization and tau phosphorylation. Furthermore, reduced proteasome activity activated several kinases implicated in AD pathology, including JNK, c-Jun and ERK 1/2. Restoration of the microtubule transport was achieved by inhibiting ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun reversed the proteasome inhibition-induced tau phosphorylation. Taken together, this study suggests that a decrease in proteasome activity can, through activation of c-Jun and ERK 1/2, result in several events contributing to AD pathology. Restoring proteasome function or inhibiting ERK 1/2 and c-Jun could therefore be used as novel treatments against AD.

  • 779.
    Agic, Haris
    Linköping University, Department of Medical and Health Sciences, Health and Society. Linköping University, Faculty of Health Sciences.
    Hope Rites: An Ethnographic Study of Mechanical Help-Heart Implantation Treatment2012Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This thesis is about cultural aspects of advanced medical technology for treating end-stage heart failure. New medical technologies like mechanical help-hearts save lives, but they also bring new uncertainties, risks, and challenges. Based on nine months of ethnographic field work in a Swedish academic hospital, this study examines the ways of managing uncertainties of end-stage heart failure and of high-tech treatment, and also how these practices tie into the shared understandings of life-threatening chronic illness, the body, and medical technology’s role.

    This study draws on anthropological discussions of healing rituals as an analytical tool to make sense of social and cultural dimensions of mechanical help-heart implantation treatment. Viewed as a ritual, this treatment creates and maintains hope as a virtue through which possibilities of new medical technology are justified as culturally approved ways of handling the uncertainties of severe heart failure and mechanical help-heart treatment. Ultimately, even when treatment is regarded as successful, the patients may be saved but are never really ‘cured’ and remain, thus, permanently tied to the world of medicine. This new mode of existence is characterized by paradoxical permanent transit between uncertainty and hope.

  • 780.
    Agmell, M.
    et al.
    Lund University, Sweden.
    Ahadi, A.
    Lund University, Sweden.
    Zhou, J. M.
    Lund University, Sweden.
    Peng, Ru
    Linköping University, Department of Management and Engineering, Engineering Materials. Linköping University, Faculty of Science & Engineering.
    Bushlya, V.
    Lund University, Sweden.
    Stahl, J. -E.
    Lund University, Sweden.
    Modeling subsurface deformation induced by machining of Inconel 7182017In: Machining science and technology, ISSN 1091-0344, E-ISSN 1532-2483, Vol. 21, no 1, p. 103-120Article in journal (Refereed)
    Abstract [en]

    Traditionally, the development and optimization of the machining process with regards to the subsurface deformation are done through experimental method which is often expensive and time consuming. This article presents the development of a finite element model based on an updated Lagrangian formulation. The numerical model is able to predict the depth of subsurface deformation induced in the high- speed machining of Inconel 718 by use of a whisker-reinforced ceramic tool. The effect that the different cutting parameters and tool microgeometries has on subsurface deformation will be investigated both numerically and experimentally. This research article also addresses the temperature distribution in the workpiece and the connection it could have on the wear of the cutting tool. The correlation of the numerical and experimental investigations for the subsurface deformation has been measured by the use of the coefficient of determination, R-2. This confirms that the finite element model developed here is able to simulate this type of machining process with sufficient accuracy.

  • 781. Agmell, Mathias
    et al.
    Ahadi, A
    Zhou, J M
    Peng, Ru
    Linköping University, Department of Management and Engineering, Engineering Materials. Linköping University, Faculty of Science & Engineering.
    Bushlya, Volodymyr
    Stahl, J-E
    Modeling Subsurface Deformation Induced by Machining of Inconel 7182017In: Machining science and technology, ISSN 1091-0344, E-ISSN 1532-2483, Vol. 21, no 1, p. 103-120Article in journal (Refereed)
    Abstract [en]

    Traditionally, the development and optimization of the machining process with regards to the subsurface deformation are done through experimental method which is often expensive and time consuming. This article presents the development of a finite element model based on an updated Lagrangian formulation. The numerical model is able to predict the depth of subsurface deformation induced in the high- speed machining of Inconel 718 by use of a whisker-reinforced ceramic tool. The effect that the different cutting parameters and tool microgeometries has on subsurface deformation will be investigated both numerically and experimentally. This research article also addresses the temperature distribution in the workpiece and the connection it could have on the wear of the cutting tool. The correlation of the numerical and experimental investigations for the subsurface deformation has been measured by the use of the coefficient of determination, R2. This confirms that the finite element model developed here is able to simulate this type of machining process with sufficient accuracy.

  • 782.
    Agmell, Simon
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    Dekker, Marcus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, Faculty of Science & Engineering.
    IR-Based Indoor Localisation and Positioning System2019Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [en]

    This thesis presents a prototype beacon-based indoor positioning system using IR-based triangulation together with various inertial sensors mounted onto the receiver. By applying a Kalman filter, the mobile receivers can estimate their position by fusing the data received from the two independent measurement systems. Furthermore, the system is aimed to operate and conduct all calculations using microcontrollers. Multiple IR beacons and an AGV were constructed to determine the systems performance.

    Empirical and practical experiments show that the proposed localisation system is capable centimeter accuracy. However, because of hardware limitation the system has lacking update frequency and range. With the limitations in mind, it can be established that the final sensor-fused solution shows great promise but requires an extended component assessment and more advanced localisation estimations method such as an Extended Kalman Filter or particle filter to increase reliability.

  • 783.
    Agnafors, Marcus
    Linköping University, Department of Culture and Communication. Linköping University, Faculty of Arts and Sciences.
    A Critical Comment on Collste2011In: Public Health Ethics, ISSN 1754-9973, E-ISSN 1754-9981, Vol. 4, no 2, p. 203-205Article in journal (Other academic)
    Abstract [en]

    This article claims that the account of specification as a way to solve conflicts between rights, suggested by Göran Collste, is unsatisfactory. It is argued that specification is not a solution on its own, but is better described as a remedy in response to a political failure.

  • 784.
    Agnafors, Marcus
    Linköping University, Department of Culture and Communication, Arts and Humanities. Linköping University, Faculty of Arts and Sciences.
    A Secular State?2010In: Identity and pluralism : ethnicity, religion and values / [ed] Göran Collste, Linköping: LiU-Tryckk , 2010, p. 80-102Chapter in book (Other academic)
  • 785.
    Agnafors, Marcus
    Linköping University, Department of Culture and Communication, Arts and Humanities. Linköping University, Faculty of Arts and Sciences. Lunds universitet.
    Bör den liberala staten privilegiera religion i samhället?2013In: Tidskrift för politisk filosofi, ISSN 1402-2710, Vol. 17, no 3, p. 1-21Article in journal (Other academic)
    Abstract [sv]

    Det anses ofta att en liberal stat måste förhålla sig neutral till religiösa element i samhället. Att bryta mot neutralitetskravet och därmed privilegiera religiösa element i samhället är uteslutet, hävdas det, eftersom ett sådant privilegierande skulle innebära att man medvetet gynnar en grupp uppfattningar om det goda livet – vilket skulle vara synnerligen icke-liberalt.

    I den här artikeln ifrågasätts det neutralitetskrav som åläggs den liberala staten. Istället försvaras idén att en liberal stat i vissa fall kan ha en prima facie skyldighet att privilegiera vissa religiösa element i samhället. I artikeln presenteras tre villkor som måste vara uppfyllda för att ett avsteg från neutralitetskravet ska vara rättfärdigat.

    Efter en kortare diskussion om den relevanta empiriska forskningen konkluderas att en liberal stat i vissa fall är berättigad att privilegiera religiösa element i samhället utan att därmed kompromissa med sin liberala status.

  • 786.
    Agnafors, Marcus
    Linköping University, Department of Culture and Communication, Arts and Humanities. Linköping University, Faculty of Arts and Sciences.
    Introduktion2013In: Varför inte Socialism? och Om den egalitära rättvisans valuta / [ed] G. A. Cohen, Daidalos, 2013Chapter in book (Other (popular science, discussion, etc.))
  • 787.
    Agnafors, Marcus
    Linköping University, Department of Culture and Communication. Linköping University, Faculty of Arts and Sciences.
    Justice among Us: A Philosophical Analysis of Michael Walzer’s Theory of Justice2010Doctoral thesis, monograph (Other academic)
    Abstract [en]

    The American philosopher Michael Walzer has been regarded as one of the most influential theorists in the field of distributive justice since the publication of Spheres of Justice in 1983. However, despite the popularity, his theory is often misunderstood or said to suffer from serious shortcomings.

    The aim of the dissertation is to present and defend a clearer and stronger version of Walzer’s theory of distributive justice. After a brief sketch of Walzer’s early works, in which important concepts were introduced and developed, the mature theory is analysed. By subjecting the key areas of Walzer’s theory to a critical and reconstructive philosophical analysis, a stronger and more detailed account is gained. Important ideas and concepts such as community, consent, interpretation, social meanings, complex equality and minimal morality are discussed, criticised and revised in order to strengthen the theory. In addition, a comparison is made between John Rawls’s method of wide reflective equilibrium and Walzer’s interpretative method; it is argued that the methods of the two philosophers exhibit considerable similarities.

  • 788.
    Agnafors, Marcus
    Linköping University, Department of Culture and Communication, Arts and Humanities. Linköping University, Faculty of Arts and Sciences.
    Michael Sandel: What Money Can’t Buy: The Moral Limits of Markets2014In: Tidskrift för politisk filosofi, ISSN 1402-2710, Vol. 18, no 1, p. 37-44Article, book review (Other academic)
  • 789.
    Agnafors, Marcus
    Lund University, Sweden.
    Quality of Government and the Treatment of Immigrants2013In: Ecumenical Review Sibiu / Revista Ecumenica Sibiu, ISSN 2065-5940, Vol. 5, no 1, p. 25-41Article in journal (Refereed)
    Abstract [en]

    Normative questions concerning the treatment of immigrants can be approached from various perspectives: consequentialistic, deontological, fairness-based, rectificatory, or similar. In this paper, the implications of the idea of quality of government for the treatment of immigrants are examined. It is argued that an acceptable definition of quality of governance includes a principle of beneficence, which prescribes a beneficial treatment of immigrants whenever laws and policies allow. The principle, which is not novel in itself, is presented in a more specified form and is provided with a philosophical justification.

  • 790.
    Agnafors, Marcus
    Lund University, Sweden.
    Quality of Government: Toward a More Complex Definition2013In: American Political Science Review, ISSN 0003-0554, E-ISSN 1537-5943, Vol. 107, no 3, p. 433-445Article in journal (Refereed)
    Abstract [en]

    Concepts such as “quality of government” and “good governance” refer to a desired character of the exercise of public authority. Recently the interest in good governance, the quality of government, and similar concepts has increased considerably. However, despite this increasing interest and use, an adequate definition of the concept of quality of government has proved difficult to find. This article criticizes recent attempts at such a definition and proposes an alternative, more complex definition that includes moral content and also encompasses a plurality of values and virtues at its core. An acceptable definition of the quality of governance must be consistent with the demands of a public ethos, the virtues of good decision making and reason giving, the rule of law, efficiency, stability, and a principle of beneficence. The article describes these components in detail and the relations among them.

  • 791.
    Agnafors, Marcus
    Lund University, Sweden.
    Reassessing Walzer’s social criticism2012In: Philosophy & Social Criticism, ISSN 0191-4537, E-ISSN 1461-734X, Vol. 38, no 9, p. 917-937Article in journal (Refereed)
    Abstract [en]

    It is often argued that Michael Walzer's theory of social criticism, which underpins his theory of justice, is not much of a theory at all, but rather an impressionistic collection of historical anecdotes. Contrary to this perception, I argue that Walzer's method can be accurately described as a version of John Rawls' well-known method of wide reflective equilibrium. Through a systematic comparison it can be shown that the two methods are strikingly similar. This implies that, far from the critics' claim, Walzer's method can be described as a philosophically sophisticated method. This also adds credibility to Walzer's views on politics and justice.

  • 792.
    Agnafors, Marcus
    Linköping University, Department of Culture and Communication. Linköping University, Faculty of Arts and Sciences.
    The Ethics of Free Soloing2010In: Climbing: because it's there / [ed] Stephen E. Schmid, Wiley-Blackwell, 2010, p. 158-168Chapter in book (Other (popular science, discussion, etc.))
  • 793.
    Agnafors, Marcus
    Lund University, Sweden .
    When Do We Share Moral Norms?2012In: Journal of Value Inquiry, ISSN 0022-5363, E-ISSN 1573-0492, Vol. 46, no 3, p. 303-315Article in journal (Refereed)
  • 794.
    Agnafors, Sara
    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)
    Abstract [en]

    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.

    List of papers
    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.
    Show others...
    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
    National Category
    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
    Show others...
    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

    National Category
    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
    Show others...
    2016 (English)Manuscript (preprint) (Other academic)
    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
    National Category
    Psychiatry
    Identifiers
    urn:nbn:se:liu:diva-124208 (URN)
    Available from: 2016-01-22 Created: 2016-01-22 Last updated: 2016-01-22Bibliographically approved
  • 795.
    Agnafors, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Bladh, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Svedin, Carl Göran
    Linköping University, Department of Clinical and Experimental Medicine, Barnafrid. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Child and Adolescent Psychiatry in Linköping.
    Sydsjö, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Mental health in young mothers, single mothers and their children2019In: BMC Psychiatry, ISSN 1471-244X, E-ISSN 1471-244X, Vol. 19, article id 112Article in journal (Refereed)
    Abstract [en]

    Background: Parenthood is a life transition that can be especially demanding for vulnerable individuals. Young maternal age and maternal single status have been reported to increase the risk for adverse outcomes for both mother and child. The aim of this study was to investigate the effect of young maternal age and maternal single status on maternal and child mental health and child development at age 3. Methods: A birth-cohort of 1723 mothers and their children were followed from birth to age 3. Sixty-one mothers (3.5%) were age 20 or younger, and 65 (4.0%) reported single status at childbirth. The mothers filled out standardized instruments and medical information was retrieved from the standardized clinical assessment of the children at Child Welfare Centers, (CWC). Results: Young maternal age was associated with symptoms of postpartum depression whereas single status was not. Young mothers were more prone to report internalizing and externalizing problems in their children, while there was no association between single status and child behavioral problems. No differences were seen on child development (CWC scores). School drop-out was, however, a more influential factor on depressive symptoms postpartum than maternal age. Conclusion: Young mothers are at increased risk for symptoms of postpartum depression which indicates the need for attention in pre- and postnatal health care programs. Single mothers and their children were not found to be at increased risk for adverse outcomes. The importance of schooling was demonstrated, indicating the need for societal support to encourage adolescents to remain in school.

  • 796.
    Agnafors, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Child and Adolescent Psychiatry. Linköping University, Faculty of Health Sciences.
    Comasco, Erika
    Division of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Bladh, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Sydsjö, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Dekeyser, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Oreland, Lars
    Division of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Svedin, Carl Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Effect of gene, environment and maternal depressive symptoms on pre-adolescence behavior problems - a longitudinal study.2013In: Child and Adolescent Psychiatry and Mental Health, ISSN 1753-2000, E-ISSN 1753-2000, Vol. 7, no 1, p. 10-Article in journal (Refereed)
    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.

  • 797.
    Agnafors, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Svedin, Carl Göran
    Linköping University, Department of Clinical and Experimental Medicine, Barnafrid. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Child and Adolescent Psychiatry in Linköping.
    Oreland, Lars
    Uppsala University, Sweden.
    Bladh, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Comasco, Erika
    Uppsala University, Sweden.
    Sydsjö, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    A Biopsychosocial Approach to Risk and Resilience on Behavior in Children Followed from Birth to Age 122017In: Child Psychiatry and Human Development, ISSN 0009-398X, E-ISSN 1573-3327, Vol. 48, no 4, p. 584-596Article in journal (Refereed)
    Abstract [en]

    An increasing prevalence of mental health problems calls for more knowledge into factors associated with resilience. The present study used multiple statistical methodologies to examine a biopsychosocial model of risk and resilience on preadolescence behavior. Data from 889 children and mothers from a birth cohort were used. An adversity score was created by combining maternal symptoms of depression, psychosocial risk and childrens experiences of life events. The proposed resilience factors investigated were candidate genetic polymorphisms, child temperament, social functioning, and maternal sense of coherence. The l/ l genotype of the serotonin transporter linked polymorphic region was associated with lower internalizing scores, but not mainly related to the level of adversity. An easy temperament was associated with resilience for children exposed to high adversity. Social functioning was found to be promotive independent of the risk level. The results support a multiple-level model of resilience indicating effects, though small, of both biological and psychosocial factors.

  • 798.
    Agnafors, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Svedin, Carl Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Child and Adolescent Psychiatry in Linköping.
    Oreland, Lars
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Bladh, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Comasco, Erika
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Sydsjö, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    A biopsychosocial approach to risk and resilience on behavior in children followed from birth to age twelve2016Manuscript (preprint) (Other academic)
    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.

  • 799.
    Agnafors, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sydsjö, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Comasco, Erika
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Bladh, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    Oreland, Lars
    Department of Neuroscience, Uppsala University, Uppsala, Sweden.
    Svedin, Carl Göran
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Child and Adolescent Psychiatry in Linköping.
    Early predictors of behavioural problems in pre-schoolers: a longitudinal study of constitutional and environmental main and interaction effects2016In: BMC Pediatrics, ISSN 1471-2431, E-ISSN 1471-2431, Vol. 16Article in journal (Refereed)
    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

  • 800.
    Agnafors, Sara
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Child and Adolescent Psychiatry. Linköping University, Faculty of Health Sciences.
    Sydsjö, Gunilla
    Linköping University, Department of Clinical and Experimental Medicine, Obstetrics and gynecology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center of Paediatrics and Gynaecology and Obstetrics, Department of Gynaecology and Obstetrics in Linköping.
    deKeyser, Linda
    Linköping University, Department of Clinical and Experimental Medicine, Child and Adolescent Psychiatry. Linköping University, Faculty of Health Sciences.
    Göran Svedin, Carl
    Linköping University, Department of Clinical and Experimental Medicine, Child and Adolescent Psychiatry. Linköping University, Faculty of Health Sciences.
    Symptoms of Depression Postpartum and 12 years Later-Associations to Child Mental Health at 12 years of Age2013In: Maternal and Child Health Journal, ISSN 1092-7875, E-ISSN 1573-6628, Vol. 17, no 3, p. 405-414Article in journal (Refereed)
    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.

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