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  • Public defence: 2016-12-07 13:00 MA121, Umeå
    Saarikko, Ted
    Umeå University, Faculty of Social Sciences, Department of Informatics.
    Saarikko, Ted
    Umeå University, Faculty of Social Sciences, Department of Informatics.
    An inquiry into the nature and causes of digital platforms2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    While the shape and nature of platforms varies across different instances, they pursue common ambitions such as reduction of risk, complexity, or transaction costs. Although initially theorised in industrial contexts, subsequent theorising regarding platform development, platform ecosystems, and platform strategy has drawn upon studies of high-tech industries in general and IT-based platforms in particular. While the inherent malleability of digitised data and digital technology offers possibilities, they also make it difficult to pin down the locus of a low-variety platform core. As such, one of the fundamental properties of digital platforms is rather mundane: to provide stability. With that in mind, this thesis pursues the following research question: How can a digital platform maintain stability for its stakeholders in the face of constant technical change? This thesis utilises affordance theory as a means to operationalise a relational view of digital platform, where stability is assessed in relation to stakeholders rather than technical persistence. This dissertation is based on an interpretive case study, primarily using qualitative data in the form of interviews gathered as part of two separate projects that varied both in scope and orientation. The thesis offers two main contributions. First, the idea of platform stability as derived from low-variety components that are persistent over time is difficult to apply in relation to digital platforms. Rather, we need to approach stability as a composite property, based on the ability of the platform to satisfy technical-, informational-, and social expectations. Hence, stability should not be considered as a fixed or absolute property, but rather a moving target. Second, this thesis suggests that the existing notion of (technical) coring needs to be complemented with information coring and social coring when applied to digital platforms. The proposed concept of information coring expresses the ability to hide complexity and present bottom-line results to the user in a comprehensible manner. Social coring refers to the idea of aligning technical integration and social integration in a platform. A relational perspective applied to digital platforms offers a possible avenue for theorising digital platforms as information systems artefacts rather than the dichotomous relationship between platform-as-architecture and platform-as-marketplace found in extant literature.

  • Public defence: 2016-12-08 10:00 Beteendevetarhuset Hörsal 1031, Umeå
    Lindster Norberg, Eva-Lena
    Umeå University, Faculty of Social Sciences, Department of Education.
    Lindster Norberg, Eva-Lena
    Umeå University, Faculty of Social Sciences, Department of Education.
    Hur ska du bli när du bli stor?: en studie i svensk gymnasieskola när entreprenörskap i skolan är i fokus2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The general aim of this thesis is to examine and explain how education fosters future citizens when Swedish upper secondary schools work actively with entrepreneurship in school. Toward this aim, two research questions are asked: How are students governed and how do students govern when focus is on entrepreneurship in school? How do teachers relate to entrepreneurship in school? The study took place in a school development program with a focus on teachers developing their abilities and working with entrepreneurship in schools. Four studies presented in four articles form the cornerstones of the thesis. The empirical data was collected during 2013– 2014 in three of the participating schools. Different methods were used. The first step was reading and analysing policy documents, followed by observations in the classrooms, interviews with the teachers with the help of performance maps, and interviews with the students in gendered focus groups. In total, 14 teachers and 90 students were involved in the study. The schools were geographically spread and represented both public and independent schools. For this study an abductive approach was used, which means that the empirical data were collected and first studied unbiased. Various theoretical models were chosen to find answers to the specific research questions; thus, a connection between the theory and the empirical data was made.

    The first article examines whether a citizen with entrepreneurial abilities is fostered in school when the concept of entrepreneurship has a place in the curriculum. This article also analyses the curriculum (Gy11) and more specifically what can be read under the heading The Task of the School. The main result from this study shows that students are emphasising entrepreneurial abilities over other abilities. The second article draws a comparison between John Dewey’s ideas of progressive education from the early 1900s and the teaching methods that have come to be advocated for developing student ́s entrepreneurial abilities. The main purpose of progressive education is to foster a democratic citizen; here I could observe that techniques for teaching entrepreneurship are comparable to progressive education, but the purpose is not the same. The purpose of entrepreneurship in school is primarily to foster individuals who are active and responsible for their own future.

    Michael Foucault's concept of governmentality is the focus of article three, which explores how students are governed and shaped when entrepreneurship in school is emphasised, and it explores whether boys and girls are governed in different ways. The analysis of the result indicated that the students were governed in three different ways in the three school contexts, and girls and boys were governed in different ways both among the schools and within the schools.

    The fourth article addresses how the teachers relate to entrepreneurship in schools in light of new reforms, marketization, more regulation and the demands of being an entrepreneurial teacher. The result shows three narratives: the cool teacher, the stressed teacher, and the frustrated teacher, each handling entrepreneurship in school in different ways.

    This thesis shows that the entrepreneur has come to be presented as a hero and entrepreneurship as a solution to cope with challenges—to the global economy, but also for coping with ourselves and our own lives. It also shows that fostering a democratic citizen is subordinate to fostering citizens with entrepreneurial abilities, as the regime of truth is to become the entrepreneur. The students are both governed and governing toward that direction. And even if teachers have different ways of approaching entrepreneurship in schools, the will to be the entrepreneurial teacher and to foster entrepreneurial citizens is clear. 

  • Public defence: 2016-12-09 10:15 Hörsal E, Humanisthuset, Umeå
    Skog, Frida
    Umeå University, Faculty of Social Sciences, Department of Sociology.
    Skog, Frida
    Umeå University, Faculty of Social Sciences, Department of Sociology.
    The Impact of Family Composition on Adult Earnings2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis addresses to what extent childhood family composition – the number of siblings and whether the parents live together, or whether there are non-parental adults and/or half-siblings in the household or not – contributes to variations in adult earnings. The theoretical perspective suggests that resources mediate the effect. While research has shown that siblings, as well as divorce and remarriage, are negatively linked to child outcomes, there are inconsistencies in previous literature. There has been debate over the unconfoundedness of previous studies, something that is handled here by analyzing large sets of representative data using a robust parameter. The longitudinal dataset used is based on Swedish administrative data and the cohorts analyzed are born in the beginning of the 1970s. The data structure is well suited for the assumptions underlying the semi-parametric method propensity score matching.

    The findings show that family size impacts on adult earnings. However, this is not always of concern. For example, no effect of siblings is found in affluent families, and if siblings are closely spaced this results in better outcomes for children. Divorce and remarriage do not seem to lower the future earnings of children. Thus, this thesis shows that some of the most well-established patterns in the sociology of the family, namely the link between number of siblings and adult earnings, and between divorce/family re-formation and adult earnings, can be broken by resources.

  • Public defence: 2016-12-09 13:00 Sal E04, Umeå
    Olausson, Kristina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Olausson, Kristina
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Patient experiences of the radiotherapy process and treatment2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    Most cancer patients undergo external radiotherapy (RT) at some stage during their treatment trajectory. RT is often associated with unfamiliar procedures where the technical environment, side effects and interaction with staff seem to play a major role in the patient’s treatment experience. These experiences could sometimes lead to disruption of the treatment which may have negative consequences for the outcome. The overall aim of this thesis was to gain further knowledge about how patients experience RT and the related processes. Such knowledge is of vital importance when developing and improving care within a high-tech RT environment.

    Aim

    The overall aim of this thesis was to gain further knowledge about how patients experience RT and the related processes. Such knowledge is of vital importance when developing and improving care within a high-tech RT environment.

    Methods

    To gain further knowledge and understanding about patients experience of RT both quantitative (I, II, III) and qualitative (III, IV) methodology were used. The data in the thesis focused on patients undergoing external RT at different RT units in Sweden. Study I and II, focused on two regions, the northern region of Sweden and the region of Stockholm and Gotland.  Study III and IV were performed at eight different RT units in Sweden.

    Results

    In Study I, two types of topical agents (Calendula Weleda cream vs. Essex cream) were compared regarding reducing the risk of severe acute radiation skin reactions (ARSR). No difference in severe ARSR was found between the groups and the patients reported low levels of ARSR. In Study II, the influence of an RT unit’s psychosocial climate and treatment environment on cancer patients’ anxiety during external RT was evaluated. Data was collected (questionnaire) from 892 patients. The results showed that both the treatment environment and the psychosocial climate of the RT unit significantly impacted cancer patient anxiety levels. In Study III & IV, a questionnaire to measure the patient´s experience during external RT was developed and tested. The results showed that the RT Experience Questionnaire (RTEQ), with 23 items, was a tentatively valid and reliable instrument to measure how patients experience the RT process and the environment in the treatment room. In Study IV, written comments from the open-ended question “Is there anything else you want us to know?” in the preliminary RTEQ was analysed with qualitative content analysis. This data was abstracted into the following four major categories reflecting the experience of the RT process:  Experiences in the high tech RT environment; Understanding the RT procedures and side effects; Dealing with daily life during RT and The nurses’ role and performance.

    Conclusion

    The RT environment and the RT related processes seem to impact cancer patients, both physically and psychologically. A person-centered care approach, as well as attention to the design, both of the treatment process and the physical environment could significantly improve the patient experience and patient involvement. The results also highlight the importance of taking patient experiences into account when introducing new RT methods and techniques.

  • Public defence: 2016-12-09 13:00 Sal N320, Naturvetarhuset, Umeå
    Karalija, Amar
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Karalija, Amar
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Diagnostic and therapeutic strategies following spinal cord and brachial plexus injuries2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Traumatic injuries to the spinal cord and brachial plexus induce a significant inflammatory response in the nervous tissue with progressive degeneration of neurons and glial cells, and cause considerable physical and mental suffering in affected patients. This thesis investigates the effects of the antioxidants N-acetyl-cysteine (NAC) and acetyl-L- carnitine (ALC) on the survival of motoneurons in the brainstem and spinal cord, the expression of pro-apoptotic and pro-inflammatory cell markers, axonal sprouting and glial cell reactions after spinal hemisection in adult rats. In addition, a novel MRI protocol has been developed to analyse the extent of neuronal degeneration in the spinal cord. Rubrospinal neurons and tibial motoneurons were pre-labelled with the fluorescent tracer Fast Blue one week before cervical C3 or lumbar L5 spinal cord hemisection. The intrathecal treatment with the antioxidants NAC (2.4mg/day) or ALC (0.9 mg/day) was initiated immediately after injury using Alzet2002 osmotic mini pumps. Spinal cord injury increased the expression of apoptotic cell markers BAX and caspase 3, induced significant degeneration of rubrospinal neurons and spinal motoneurons with associated decrease in immunoreactivity for microtubule-associated protein-2 (MAP2) in dendritic branches, synaptophysin in presynaptic boutons and neurofilaments in nerve fibers. Immunostaining for the astroglial marker glial fibrillary acidic protein and microglial markers OX42 and ED1 was markedly increased. Treatment with NAC and ALC attenuated levels of BAX, caspase 3, OX42 and ED1 expression after 2 weeks postoperatively. After 4-8 weeks of continuous intratheca ltreatment, NAC and ALC rescued approximately half of the rubrospinal neurons and spinal motoneurons destined to die, promoted axonal sprouting, restored the density of MAP2 and synaptophysin immunoreactivity and reduced the microglial reaction. However, antioxidant therapy did not affect the reactive astrocytes in the trauma zone. The inflammation modulating properties of ALC were also studied using cultures of human microglial cells. ALC increased the microglial production of interleukin IL-6 and BDNF, thereby possibly mediating the anti-inflammatory and pro-regenerative effects shown in vivo. To study degeneration in the spinal cord following pre-ganglionic and post-ganglionic brachial plexus injuries, adult rat models of ventral root avulsion and peripheral nerve injury were used. A novel MRI protocol was employed and the images were compared to morphological changes found in histological preparations. Ventral root avulsion caused degeneration of dendritic branches and axonal terminals in the spinal cord, followed by significant shrinkage of the ventral horn. Extensive astroglial and microglial reactions were detected in the histological preparations. Peripheral nerve injury reduced the density of dendritic branches but did not cause shrinkage of the ventral horn. Quantitative analysis of MRI images demonstrated changes in the ventral horn following ventral root avulsion only, thus validating the developed MRI technique as a possible tool for the differentiation of pre-ganglionic and post-ganglionic nerve injuries.

  • Public defence: 2016-12-12 10:00 Hörsal 1031, Norra Beteendevetarhuset, Umeå
    Ivanov, Sergej
    Umeå University, Faculty of Arts, Department of language studies.
    Ivanov, Sergej
    Umeå University, Faculty of Arts, Department of language studies.
    A Transnational Study of Criticality in the History Learning Environment2016Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This study examines conceptions of criticality and its instruction in the History learning environ- ment in Sweden, Russia, and Australia as evidenced in one sample upper secondary class in each country. To achieve this, data were collected at macro, micro and meso levels. At the macro level, elements of curriculum theory were used to analyse the policy framework provided to develop students’ criticality in the upper secondary History classroom and to identify the conceptions of criticality as manifested in the policy documents. At the micro level, a content-based, thematic analysis was used to examine how the teachers and student focus groups conceptualise criticality and the ways of its teaching and learning. At the meso level, the conceptions of criticality and its instruction modes identified in the policy documents and interviews were used to analyse the class- room data collected in the selected classes.

    The combined findings from the three levels of analysis provide a transnational account of criticality and its instruction. They suggest that criticality is conceptualised as a generic skill of questioning at the overarching curriculum level, whereas it is reconceptualised as a discipline- specific skill at the subject level. Discipline-specific conceptions include criticality as source criti- cism, as meaning making from historical evidence, as questioning historical narratives, and as educating for citizenship. The findings indicate that the visionary criticality objectives of the curricula might be obstructed at other policy levels and by the interviewees’ conceptions of criticality as well as the classroom practicalities.

    Based on the transnational findings, it is proposed that harmonisation between the curriculum contents and time allocation might contribute to the promotion of narrative diversity. As argued in the study, narrative diversity is a prerequisite for criticality as questioning historical narratives. To nurture this form of criticality, the policy makers might consider a shift of attention towards the lower stages of schooling that could equip upper secondary students with necessary background knowledge. Further, harmonisation between the teaching objectives and learning outcomes of basic History courses might help avoid excluding certain groups of students from receiving criticality instruction on unclear grounds. This might ensure the equity of education with regard to criticality instruction for all upper secondary students, as required in the national curricula in Sweden, Russia and Australia. 

  • Public defence: 2016-12-12 13:00 N 320, Umeå
    Arnesson, Daniel
    Umeå University, Faculty of Social Sciences, Department of applied educational science. Forskarskolan i Pedagogiskt arbete.
    Arnesson, Daniel
    Umeå University, Faculty of Social Sciences, Department of applied educational science. Forskarskolan i Pedagogiskt arbete.
    PISA i skolan: hur lärare, rektorer och skolchefer förhåller sig till internationella kunskapsmätningar2016Doctoral thesis, monograph (Other academic)
    Abstract [en]

    This thesis addresses the local reception and use in Sweden of the major international large scale assessments (ILSAs) of student performance: Programme for International Student Assessment (PISA), Trends in International Mathematics and Science Study (TIMSS), Progress in International Reading Literacy Study (PIRLS) and International Civic and Citizenship Education Study (ICCS). The aim is to describe and analyze how Swedish teachers, principals and school directors interpret and possibly use ILSAs in their professional practice. ILSA is treated here as a new idea or a new social technology defining what constitutes good (or bad) education. The theoretical framework combines a top-down perspective provided by Rogers’ (2003) Diffusion of Innovation theory, and a complementary, more critical Policy Enactment approach (Ball et al. 2012), stressing the import-ance of context and local actors’ perspectives. Empirically, the thesis is based on 40 semi-structured interviews carried out in the 2011-2012 school year with teachers, principals and municipal school directors in five municipalities and 12 compulsory schools, selected to cover diverse municipalities, schools, and respondents.

    The respondents perceive ILSAs as valid evaluations of the Swedish school system. Most think it is important to compare results of different nations, although ILSA is not expected to cover the whole curriculum. Most interviewees are aware that Swedish ILSA results have been declining for years and perceive an urgent need to reverse this trend. However, few of the directors, principals or teachers believe that Swedish schools are in a deep crisis, as described in Swedish media. The participants frequently regard schools as primary determinants of ILSA results, and few blame family, socio-economic, cultural and contextual factors for the Swedish decline in ILSA rankings. There are significant differences between the three occupational groups in their reception and use of ILSA. Municipal school directors who are very well-informed emphasize the influence of ILSA on their local development efforts. Principals and teachers say that ILSAs have had modest direct effects on their work, but they argue that poor Swedish results in international assessments have had indirect effects, for instance by prompting the introduction of a new national curriculum.

  • Public defence: 2016-12-14 13:00 N460, Naturvetarhuset, Umeå
    Nyström, Robin
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Nyström, Robin
    Umeå University, Faculty of Science and Technology, Department of Applied Physics and Electronics.
    Particle emissions from residential wood and biodiesel combustion2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Emissions from anthropogenic combustion sources, such as vehicles and biomass combustion, contribute significantly to ambient particulate matter (PM) both on a local and global scale. Exposure to ambient PM and air pollution in general is linked to a variety of different health effects and it has been estimated that as many as 2.1 million premature deaths each year, due to cardiopulmonary disease and lung cancer, are caused by the changes in anthropogenic air pollution since pre-industrial times. There is today still a lack of information regarding the emissions of different specific particulate emission components, e.g. soot, polycyclic aromatic hydrocarbons (PAHs), oxy-PAHs combined with details about the behaviour of different fuels under varying combustion conditions. The overall objective of this work was to provide new knowledge regarding physical and chemical properties of PM from solid and liquid biofuels, which are important for the viewpoint of human health and atmospheric pollution. This was achieved by experimental studies of the combustion of biomass using a residential wood stove and by introducing biodiesel to an off-road engine, thereby investigating two major emission sources for PM and gaseous emissions.

    From the two papers regarding biodiesel included in this thesis, it can be concluded that the introduction of the biodiesel, and potentially other renewable fuels, can in a considerable way change the exhaust particle emissions. This could have implications for the assessment of exhaust from engines running on biodiesel fuels, especially when introducing biodiesel in existing and older engines.

    The results from the wood combustion research performed showed some important considerations regarding both specific particle properties and the influences of different burning conditions and fuels. One major finding, based on several of the included studies, was that a proper operation of a wood stove is of major importance to avoid unfavourable burning condition and elevated emissions of soot and organic particles, regardless of the wood species used. Some specific occasions during the burning phases in batch wise wood combustion were also identified as important for the overall emissions. The results from this research has given new specific insights into the emissions from wood stoves and should be of relevance for both technological development of residential appliances, emission testing/certification, information to users and legislation.

  • Public defence: 2016-12-15 09:00 Hörsal B Unod T9, Umeå
    Parween, Saba
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Parween, Saba
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Diabetes in 3D: β-cell mass assessments in disease models & evaluation of SPECT based imaging2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Diabetes is a rapidly growing disease with 415 million affected adults worldwide. The pancreatic endocrine cells, most importantly the insulin producing β-cells, play an important role in regulating blood glucose homeostasis. Type 1 diabetes (T1D) is characterized by the inability of the pancreas to secrete sufficient amounts of insulin due to autoimmune destruction of insulin producing β-cells. Type 2 diabetes (T2D) on the other hand is characterized by defects in insulin secretion and insulin sensitivity. Alterations in the β-cell mass (BCM) and/or function play a major role in the development and progression of the disease. Understanding BCM dynamics in disease models is therefore a key aspect for better interpretation of research results. In this thesis, we have used optical projection tomography (OPT) as a tool to evaluate a non-invasive imaging modality for β-cell scoring and to study disease dynamics in frequently used animal models for T1D and T2D.

    The possibility to monitor BCM in vivo would radically improve our competence in studying the pathogenesis of diabetes and in therapeutic interventions. Single photon emission computed tomography (SPECT) is a widely used technique that has become a promising approach to monitor changes in BCM in vivo. A key issue for using this approach is to evaluate the β-cell specificity and read out of the utilized radiotracers. This is most commonly performed by conventional stereological approaches, which rely on the extrapolation of 2D data. We developed a protocol for SPECT-OPT multimodal imaging that enables rapid and accurate cross evaluation of SPECT based assessments of BCM. While histological determination of islet spatial distribution was challenging, SPECT and OPT revealed similar distribution patterns of the radiotracer 111In-exendin-3 and insulin positive β-cell volumes respectively between different pancreatic lobes, both visually and quantitatively. We propose SPECT-OPT multimodal imaging as an accurate and better approach for validating the performance of β-cell radiotracers.

    The leptin deficient ob/ob mouse is a widely used model for studies of metabolic disturbances leading to T2D, including obesity and insulin resistance. By OPT imaging we created the first 3D-spatial and quantitative account of BCM distribution in this model. We observed a previously unreported degree of cystic lesions in hypertrophic islets, that were occupied by red blood cells (RBCs) and/or fibrin mesh. We propose that these lesions are formed by a mechanism involving the extravasation of RBCs/plasma due to increased blood flow and islet vessel instability. Further, our data indicate that the primary lobular compartments of the ob/ob pancreas have different potentials for expanding their β-cell population. Unawareness of these characteristics of β-cell expansion in ob/ob mice presented in this study may significantly influence ex vivo and in vivo assessments of this model in studies of β-cell adaptation and function. The tomographic data, on which this study was based, will be made publically available as a resource to the research community for the planning and interpretation of research involving this model.

    There are limited studies on early metabolic and functional changes of BCM in the settings of T1D. In order to assess initial metabolic alterations in BCM before the onset of diabetes, we characterized congenic diabetes prone Bio-breeding (BB) DR.lyp/lyp rats, a widely used model for T1D diabetes. We observed lower acute insulin response, reduced islet blood flow and a significant reduction in the BCM of small and medium sized islets at a very early stage (40 days), i.e. before insulitis and development of diabetes. Underlying changes in islet function may be a previously unrecognized factor of importance in the development of T1D.

    The full text will be freely available from 2017-12-15 00:00
  • Public defence: 2016-12-15 13:00 KB3A9, Umeå
    Yelhekar, Tushar
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Yelhekar, Tushar
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Chloride Homeostasis in Central Neurons2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The overall aim of the present thesis is to clarify the control of intracellular chloride homeostasis in central neurons, because of the critical role of chloride ions (Cl) for neuronal function. Normal function of the central nervous system (CNS) depends on a delicate balance between neuronal excitation and inhibition. Inhibition is, in the adult brain, most often mediated by the neurotransmitter γ-aminobutyric acid (GABA). GABA may, however, in some cases cause excitation. GABA acts by activating GABA type A receptors (GABAARs), which are ion channels largely permeable to Cl. The effect of GABAAR-mediated neuronal signaling - inhibitory or excitatory - is therefore mainly determined by the Cl gradient across the membrane. This gradient varies with neuronal activity and may be altered in pathological conditions. Thus, understanding Cl regulation is important to comprehend neuronal function. This thesis is an attempt to clarify several unknown aspects of neuronal Cl regulation. For such clarification, a sufficiently sensitive method for measuring the intracellular Cl concentration, [Cl]i, is necessary. In the first study of this thesis, we examined two electrophysiological methods commonly used to estimate [Cl]i. Both methods, here called the interpolation and the voltage-ramp method, depend on an estimate of the Cl equilibrium potential from the current-voltage relation of GABA- or glycine-evoked Cl currents. Both methods also provide an estimate of the membrane Cl conductance, gCl. With a combination of computational and electrophysiological techniques, we showed that the most common (interpolation) method failed to detect changes in [Cl]i and gCl during prolonged GABA application, whereas the voltage-ramp method accurately detected such changes. Our analysis also provided an explanation as to why the two methods differ. In a second study, we clarified the role of the extracellular matrix (ECM) for the distribution of Cl across the cell membrane of neurons from rat brain. It was recently proposed that immobile charges located within the ECM, rather than as previously thought cation-chloride transporter proteins, determine the low [Cl]i which is critical to GABAAR-mediated inhibition. By using electrophysiological techniques to measure [Cl]i, we showed that digestion of the ECM decreases the expression and function of the neuron-specific K+ Cl cotransporter 2 (KCC2), which normally extrudes Cl- from the neuron, thus causing an increase in resting [Cl]i. As a result of ECM degradation, the action of GABA may be transformed from inhibitory to excitatory. In a third study, we developed a method for quantifying the largely unknown resting Cl (leak) conductance, gCl, and examined the role of gCl for the neuronal Cl homeostasis. In isolated preoptic neurons from rat, resting gCl was about 6 % of total resting conductance, to a major part due to spontaneously open GABAARs and played an important role for recovery after a high Cl load. We also showed that spontaneous, impulse-independent GABA release can significantly enhance recovery when the GABA responses are potentiated by the neurosteroid allopregnanolone. In a final commentary, we formulated the mathematical relation between Cl conductance, KCC2-mediated Cl extrusion capacity and steady-state [Cl]i. In summary, the present thesis (i) clarifies how well common electrophysiological methods describe [Cl]i and gCl, (ii) provides a novel method for quantifying gCl in cell membranes and (iii) clarifies the roles of the ECM, ion channels and ion transporters in the control of [Cl]i homeostasis and GABAAR-mediated signaling in central neurons. 

  • Public defence: 2016-12-16 09:00 Room 135, Family Medicine, Building 9A, Umeå
    Godefay Debeb, Hagos
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Godefay Debeb, Hagos
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Maternal Mortality Then, Now, and Tomorrow: The Experience of Tigray Region, Northern Ethiopia2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Abstract

    Background: Maternal mortality is one of the most sensitive indicators of the health disparities between poorer and richer nations. It is also one of the most difficult health outcomes to measure reliably. In many settings, major challenges remain in terms of both measuring and reducing maternal mortality effectively. This thesis aims to quantify overall levels, identify specific causes, and evaluate local interventions in relation to efforts to reduce maternal mortality in Tigray Region, Northern Ethiopia, thereby providing a strong empirical basis for decision making by the Tigray Regional Health Bureau using methods that can be scaled at national level.

     

    Methods: This study employed a combination of community-based study designs to investigate the level and determinants of maternal mortality in six randomly selected rural districts of Tigray Region. A census of all households in the six districts was conducted to identify all live births and all deaths to women of reproductive age occurring between May 2012 and September 2013. Pregnancy-related deaths were screened through verbal autopsy with the data processed using the InterVA-4 model, which was used to estimate Maternal Mortality Ratio. To identify independent determinants of maternal mortality, a case-control study using multiple logistic regression analysis was done, taking all pregnancy-related deaths as cases and a random sample of geographical and age matched mothers as controls. Uptake of ambulance services in the six districts was determined retrospectively from ambulance logbooks, and the trends in pregnancy-related death were analyzed against ambulance utilization, distance from nearest health center, and mobile network coverage at local area level. Lastly, implementation of the Family Folder paper health register, and its potential for accurately capturing demographic and health events, were evaluated using a capture-recapture assessment.

     

    Results: A total of 181 deaths to women of reproductive age and 19,179 live births were documented from May 2012 to April2013. Of the deaths, 51 were pregnancy-related. The maternal mortality ratio for Tigray region was calculated at 266 deaths per 100,000 live births (95% CI 198-350), which is consistently lower than previous “top down” MMR estimates. District–level MMRs showed strong inverse correlation with population density (r2 = 0.86). Direct obstetric causes accounted for 61% of all pregnancy–related deaths, with hemorrhage accounting for 34%. Non-membership in the voluntary Women’s Development Army (AOR 2.07, 95% CI 1.04-4.11), low husband or partner involvement during pregnancy (AOR 2.19, 95% CI 1.14-4.18), pre-existing history of other illness (AOR 5.58, 95% CI 2.17-14.30), and never having used contraceptives (AOR 2.58, 95% CI 1.37-4.85) were associated with increased risk of maternal death in a multivariable regression model. In addition, utilization of free ambulance transportation service was strongly associated with reduced MMR at district level. Districts with above-average ambulance utilization had an MMR of 149 per 100,000 LB (95% CI: 77-260) compared with 350 per 100,000 (95% CI: 249-479) in districts with below average utilization. The Family Folder implementation assessment revealed some inconsistencies in the way Health Extension Workers utilize the Family Folders to record demographic and health events.

     

    Conclusion: This work contributes to understanding the status of and factors affecting maternal mortality in Tigray Region. It introduces a locally feasible approach to MMR estimation and gives important insights in to the effectiveness of various interventions that have been targeted at reducing maternal mortality in recent years.

  • Public defence: 2016-12-16 09:00 E04, Umeå
    Song, Jie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Song, Jie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Non-canonical TGFb signaling pathways in prostate cancer2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Prostate cancer is the second leading cause of cancer-related death in men in the Western world. Deregulation of transforming growth factor β (TGFβ) signaling pathway is frequently detected in prostate cancer and contributes to tumor growth, migration, and invasion. In normal tissue and the early stages of cancer, TGFβ acts as a tumor suppressor by regulating proliferation, differentiation, and apoptosis. In later stages of cancer, TGFβ acts as a tumor promoter by inducing angiogenesis, tumor invasion, and migration. Thus, it is important to investigate the molecular mechanisms behind the tumor-promoting effects of TGFβ, which is the topic of this thesis.

     

    The tumor necrosis factor receptor–associated factor 6 (TRAF6) controls non-canonical TGFβ signals due to its enzymatic activity, causing polyubiquitination of the cell membrane–bound, serine/threonine kinase TGFβ type I receptor (TβRI) and its subsequent cleavage in the extracellular domain by tumor necrosis factor a–converting enzyme (TACE) in a protein kinase C ζ (PKCζ)-dependent manner. TRAF6 also recruits the active g-secretase complex to the TβRI, resulting in a second cleavage in the transmembrane region and the liberation of the TβRI intracellular domain (TβRI-ICD), which enters the nucleus, where it associates with the transcriptional co-regulator p300. In Paper I, the aim was to elucidate by which mechanisms TβRI-ICD enters the nucleus. We found that the endocytic adaptor protein APPL1 interacts with TβRI and PKCζ. APPL proteins are required for TβRI translocation from endosomes to the nucleus via microtubules in a TRAF6-dependent manner. Moreover, APPL proteins are important for TGFβ-induced cell invasion, and high levels of APPL1 are detected by immunohistochemistry in prostate cancer. Finally, we demonstrated that the APPL1–TβRI complex visualized with the in situ proximity ligation assay (PLA) correlates with Gleason score, indicating that it might be a novel prognostic marker for aggressive prostate cancer. In Paper II, the aim was to explore by which mechanisms TGFβ causes activation of the AKT pathway, which regulates migration and therapy resistance of cancer cells. We found that the E3 ligase activity of TRAF6 induces Lys63-linked polyubiquitination of p85α upon TGFβ stimulation, resulting in plasma membrane recruitment, Lys63-linked polyubiquitination, and subsequent activation of AKT. Moreover, the TRAF6 and PI3K/AKT pathway were found to be crucial for the TGFβ-induced migration. Importantly, we demonstrated, by PLA, a correlation between Lys63-linked polyubiquitination of p85α and aggressive prostate cancer in tissue sections from patients with prostate cancer. In Paper III, the aim was to investigate the mechanisms for TGFβ-induced activation of PKCζ and the role of PKCζ in tumor regression. We found that TRAF6 caused Lys63-linked polyubiquitination of PKCζ. By using two novel chemical compounds that inhibit PKCζ, we demonstrated that PKCζ is crucial for prostate cancer cell survival and invasion. In Paper IV, the aim was to investigate further the target genes for the nuclear TβRI-ICD-APPL1 complex identified in Paper I. We provide evidence that APPL proteins and the TGFβ signaling pathway are important for cell proliferation. In summary, the results reported in this thesis suggest the potential usefulness of the identified signaling components of the tumor-promoting effects of TGFβ as drug targets and biomarkers for aggressive prostate cancer. 

  • Public defence: 2016-12-16 09:00 Hörsal F, Humanisthuset, Umeå
    Bohm, Ingela
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    Bohm, Ingela
    Umeå University, Faculty of Social Sciences, Department of Food and Nutrition.
    “We’re made of meat, so why should we eat vegetables?”: food discourses in the school subject home and consumer studies2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background

    Food has many different functions. On a physical level, it is needed to survive and to maintain health, but it also has many social, psychological, and emotional meanings. For example, food is used to build relationships, to mark hierarchies, to celebrate holidays, and to influence mood and self-image. Different foods have different cultural meanings, and people are socialized from an early age to recognize and utilize their symbolic value.

    One arena where food occupies a central position is the Swedish school subject Home and Consumer Studies (HCS), which focuses on both the physical and the psychosocial dimensions of food-related health. Since these dimensions are not always compatible, the aim of this dissertation was to explore how students and teachers of HCS use big ‘D’ Discourses to talk about and handle food, with a special focus on vegetables, meat, vegetarian food, and sweet foods.

    Methods

    Fifty-nine students and five teachers were observed, recorded, and in some cases video-taped. Participants’ talk about vegetables, meat, vegetarian food, and sweet foods was transcribed verbatim and analysed for big ‘D’ Discourses.

    Results

    Students mostly based their choice of vegetables on sensory and cultural Discourses. Some vegetables were mandatory and others were optional, depending on whether or not they were part of a recipe or a cultural tradition. The health Discourse was only used if a specific assignment demanded it, and was closely tied to the evaluation Discourse.

    Contrary to the sometimes optional status of vegetables, meat was seen as central in the sensory, cultural, health, and social Discourses. Therefore the reduction of meat could be problematic. It was regarded as simultaneously healthy and unhealthy, and it could elicit disgust, but whenever participants talked about decreasing meat consumption, its centrality was invoked as a counterargument.

    As an extension of this, vegetarian food was seen as ‘empty’, deviant, and an unattainable ideal. Access to vegetarian food was limited for meat-eaters, and vegetarians were othered in both positive and negative ways. When vegetarian food was cooked during lessons, it was constructed as something out of the ordinary.

    Sweet foods could be viewed as a treasure, as something dangerous and disgusting, or as an unnecessary extra. Home-made varieties were seen as superior. Sweet foods gave social status to both students and teachers, and they could be traded or given away to mark relationships and hierarchies, but also withheld and used to police others.

    Conclusion

    In summary, two powerful potential opposites met in the HCS classroom: the Discourses of normality (sensory, cultural, and social Discourses), and the Discourses of responsibility (health and evaluation). Normality could make physically healthy food choices difficult because of participants’ social identity, the conflicted health Discourse, and too-strict ideals. On the other hand, some people were excluded from normality itself, notably vegetarians, who were seen as deviant eaters, and teachers, who had to balance state-regulated goals in HCS against local norms.

    To counteract such problems, teachers can 1) focus on sensory experiences, experimental cooking methods, and already popular foods, 2) challenge normality by the way they speak about and handle different types of food, 3) make cooking and eating more communal and socially inclusive, 4) explore the psychosocial dimension of health on the same level as the physical dimension, and 5) make sure they do not grade students’ cultural backgrounds, social identities, or taste preferences. This might go some way towards empowering students to make informed choices about food and health. However, scant resources of things like time, money, and equipment limit what can be achieved in the subject.

  • Public defence: 2016-12-16 10:00 Major Groove, Biomedicinhuset, Byggnad 6L, Umeå
    Avican, Ummehan
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Avican, Ummehan
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Twin-arginine translocation in Yersinia: the substrates and their role in virulence2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Pathogenic Yersinia cause a manifold of diseases in humans ranging from mild gastroenteritis (Y. pseudotuberculosis and Y. enterocolitica) to pneumonic and bubonic plague (Y. pestis), while all three have a common virulence strategy that relies on a well-studied type III secretion system and its effector proteins to colonize the host and evade immune responses. However, the role of other protein secretion and/or translocation systems in virulence of Yersinia species is not well known. In this thesis, we sought to investigate the contribution of twin-arginine translocation (Tat) pathway and its secreted substrates to the physiology and virulence of Y. pseudotuberculosis. Tat pathway uniquely exports folded proteins including virulence factors across the cytoplasmic membranes of bacteria. The proteins exported by Tat pathway contain a highly conserved twin-arginine motif in the N-terminal signal peptide. We found that the loss of Tat pathway causes a drastic change of the transcriptome of Y. pseudotuberculosis in stationary phase at environmental temperature with differential regulation of genes involved in virulence, carbon metabolism and stress responses. Phenotypic analysis revealed novel phenotypes of the Tat-deficient strain with defects in iron acquisition, acid resistance, copper oxidation and envelope integrity, which we were partly able to associate with the related Tat substrates. Moreover, increased glucose consumption and accumulation of intracellular fumarate were observed in response to inactivation of Tat pathway implicating a generic effect in cellular physiology. We evaluated the direct role of 22 in silico predicted Tat substrate mutants in the mouse infection model and found only one strain, ΔsufI, exhibited a similar degree of attenuation as Tat-deficient strain. Comparative in vivo characterization studies demonstrated a minor defect for ΔsufI in colonization of intestinal tissues compared to the Tat-deficient strain during early infection, whereas both SufI and TatC were required for dissemination from mesenteric lymph nodes and further systemic spread during late infection. This verifies that SufI has a major role in attenuation seen for the Tat deficient strain both during late infection and initial colonization. It is possible that other Tat substrates such as those involved in iron acquisition and copper resistance also has a role in establishing infection. Further phenotypic analysis indicated that SufI function is required for cell division and stress-survival. Transcriptomic analysis revealed that the highest number of differentially regulated genes in response to loss of Tat and SufI were involved in metabolism and transport. Taken together, this thesis presents a thorough analysis of the involvement of Tat pathway in the overall physiology and virulence strategies of Y. pseudotuberculosis. Finally, we propose that strong effects in virulence render TatC and SufI as potential targets for development of novel antimicrobial compounds

  • Public defence: 2016-12-16 10:00 Lilla hörsalen, Umeå
    Hedström, Per
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Hedström, Per
    Umeå University, Faculty of Science and Technology, Department of Ecology and Environmental Sciences.
    Climate change impacts on production and dynamics of fish populations2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Ongoing climate change is predicted to increase water temperatures and export of terrestrial dissolved matter (TDOM) to aquatic ecosystems influencing ecosystem productivity, food web dynamics and production of top consumers. Ecosystem productivity is mainly determined by the rates of primary production (GPP) in turn controlled by nutrients, light availability and temperature, while temperature alone affect vital rates like consumption and metabolic rates and maintenance requirements of consumers. Increased level of TDOM causes brownification of water which may cause light limitation in algae and decrease GPP and especially so in the benthic habitat. Temperature increase has a been suggested to increase metabolic rates of consumers to larger extent than the corresponding effect on GPP, which suggest reduced top consumer biomass and production with warming.

    The aim of this thesis was to experimentally study the effects of increased temperature and TDOM on habitat specific and whole ecosystem GPP and fish densities and production. In a replicated large-scale pond experiment encompassing natural food webs of lotic ecosystems I studied population level responses to warming and brownification in the three- spined stickleback (Gasterosteus aculeatus).

    Results showed overall that warming had no effect on whole ecosystem GPP, likely due to nutrient limitation, while TDOM input decreased benthic GPP but stimulated pelagic GPP. In fish, results first of all suggested that recruitment in sticklebacks over summer was negatively affected by warming as maintenance requirements in relation to GPP increased and thereby increased starvation mortality of young-of-the-year (YOY) sticklebacks. Secondly, brownification increased mortality over winter in YOY as the negative effect on light conditions likely decreased search efficiency and caused lower consumption rates and starvation over winter in sticklebacks. Third, seasonal production of YOY, older, and total stickleback production was negatively affected by warming, while increased TDOM caused decreased YOY and total fish production. The combined effect of the two was intermediate but still negative. Temperature effects on fish production were likely a result of increased energy requirements of fish in relation to resource production and intake rates whereas the negative effect of TDOM likely was a result of decreased benthic resource production. Finally, effects of warming over a three-year period caused total fish density and biomass and abundance of both mature and old fish to decrease, while proportion of young fish increased. The main cause behind the strong negative effects of warming on fish population biomass and changes in population demographic parameters were likely the temperature driven increased energy requirements relative to resource production and cohort competition.

    The results from this thesis suggest that predicted climate change impacts on lentic aquatic ecosystems will decrease future densities and biomass of fish and negatively affect fish production and especially so in systems dominated by benthic resource production.

  • Public defence: 2016-12-16 13:00 Hörsal B, målpunkt A, 9 trappor, Umeå
    Franklin, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Franklin, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stromal components and micro-RNAs as biomarkers in pancreatic cancer2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background Pancreatic ductal adenocarcinoma (PDAC) patients have the poorest 5-year survival rates of all cancer forms. It is difficult to diagnose at early disease stages, tumour relapse after surgery is common, and current chemotherapies are ineffective. Carbohydrate antigen 19-9 (Ca 19-9), the only clinically implemented PDAC biomarker, is insufficient for diagnostic and screening purposes.

    PDAC tumours are characterised by a voluminous stroma that is rich in extracellular matrix (ECM) molecules such as collagens, hyaluronan (HA) and matricellular proteins. These stromal components have been suggested to promote PDAC cell migration, proliferation, evasion of apoptosis and chemotherapy resistance. Those events are mediated via interactions with adhesion receptors, such as integrins and CD44 receptors expressed on cancer cell surfaces.

    Micro-RNAs (miRNA) post-transcriptionally regulate gene expression in health and disease. At the time of PDAC diagnosis, miRNA levels are altered both in plasma and tumour tissue. Before PDAC diagnosis, tissue miRNA levels are altered in precursor lesions, raising the possibility that plasma miRNAs might aid in early detection.

    In this thesis, it is hypothesised that stromal components and miRNAs can serve as tissue or blood based biomarkers in PDAC. The aims are: (1) to characterise the expression of stromal components and their receptors in normal and cancerous tissue; (2) to find potential stroma-associated tissue and blood-based biomarkers for diagnosis and prognosis estimates; (3) to determine the cellular effects of type IV collagen (Col IV) in PDAC; (4) to determine if plasma miRNAs that are altered in manifest PDAC can be used to diagnose PDAC earlier.

    Methods The expression patterns of Col IV, Col IV-binding integrin subunits (α1, α2, β1), Endostatin, Osteopontin (OPN) and Tenascin C (TNC) were analysed in frozen PDAC and normal pancreatic tissue. A tissue microarray (TMA) was constructed using formalin-fixed, paraffin-embedded primary tumours and lymph node metastases. The TMA was used to study the expression levels and associations with survival of the standard CD44 receptor (CD44s), its variant isoform 6 (CD44v6), HA, OPN and Col IV. Circulating levels of HA, Col IV, Endostatin, OPN and TNC were measured in PDAC patients and healthy individuals, and compared with conventional tumour markers (Ca 19-9, CEA, Ca 125 and TPS). The functional roles of Col IV were studied in PDAC cell lines by: (1) growth on different matrices (2) blocking Col IV binding integrin subunits, (3) blocking the Col IV domains 7s, CB3 and NC1, and (4) by down regulation of PDAC cell synthesis of Col IV using siRNA transfection. Plasma miRNAs alterations were screened for in samples from patients with manifest disease, using real-time quantitative PCR (RT-qPCR). To find early miRNA alterations, levels of those miRNAs that were altered at diagnosis were measured in prediagnostic plasma samples.

    Results High tissue expression of both the standard CD44 receptor (CD44s) and its variant isoform CD44v6 as well as low expression of stromal OPN were associated with poor survival. In addition, high CD44s and low OPN predicted poor survival independent of established prognostic factors.

    Circulating Col IV, Endostatin, OPN, TNC and HA were increased in preoperative samples from PDAC patients. Preoperatively, higher levels of serum-HA and plasma-Endostatin were associated with shorter survival. Postoperatively, higher levels of Col IV, Endostatin and OPN were associated with shorter survival. On the contrary, only one of the conventional tumour markers was associated with survival (Ca 125).

    Col IV stimulated PDAC cell proliferation and migration and inhibited apoptosis in vitro, dependent on the collagenous domain (CB3) of Col IV and the Col IV binding integrin subunit β1. Reduced endogenous Col IV synthesis inhibited these effects, suggesting that PDAC cells synthesise Col IV to stimulate tumour-promoting events via a newly discovered autocrine loop.

    15 miRNAs were altered in early stage PDAC patients and the combination of these markers outperformed Ca 19-9 in discriminating patients from healthy individuals. However, none of the miRNAs were altered in prediagnostic samples, suggesting that plasma miRNA alterations appear late in the disease course.

    Conclusions Up regulated stromal components in PDAC tumours are detectable in blood samples and are potential diagnostic and prognostic biomarkers in PDAC. High circulating levels of Col IV, Endostatin, OPN and HA predict poor survival, as well as high expression of CD44s and CD44v6 and low expression of OPN in tumour tissue. PDAC cells synthesise Col IV, which forms BM-like structures close to cancer cells and promote tumour progression in vitro via an autocrine loop. Several plasma-miRNAs are altered in PDAC, but are not useful for early discovery. 

  • Public defence: 2016-12-21 09:00 Hörsal D Unod T 9, Umeå
    Jashari, Haki
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jashari, Haki
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    The effect of pressure afterload due to aortic coarctation on left ventricular function in children2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background:

    Coarctation of the aorta (CoA) is a congenital heart disease which represents a narrowing of the proximal descending aorta, hence increasing pressure afterload to the left ventricle (LV). Conventional treatment of native CoA is surgical repair, however potential recurrence or other related complications e.g. aortic rupture, heart failure and cerebrovascular events are common. Thus, lifelong follow-up of these patients is required. Echocardiography is the most patient’s friendly method to evaluate CoA and in particular its effect on LV function. Moreover, the novel speckle tracking echocardiography (STE) is an important method to assess subclinical LV dysfunction, a technique that promises better evaluation of LV function in these patients.

    The aims of this thesis were to review the literature on LV function in children with CoA using myocardial deformation imaging technologies, hence, to better understand the current knowledge and vagueness of the scientific evidence. We also aimed to study the effect of early CoA repair on the structure and function of LV and ascending aorta. In addition, we wished to establish in a meta-analysis format normal values of speckle tracking derived strain and strain rate values.

    Methods:

    Study 1. We have systematically searched the PubMed, and studies that fulfilled the inclusion criteria were critically analyzed and presented on a narrative form.

    Study 2 and 3. In addition to conventional echocardiographic measures of LV and ascending aorta, we measured longitudinal strain and strain rate of the LV using a vendor independent software, TomTec. We have also measured the aorto-septal angle (AoSA). Data was compared with normal healthy controls.

    Study 4. Electronic databases were systematically searched and suitable studies were meta analyzed using Comprehensive meta-analysis version 3 software.

    Results:

    Study 1. In 7/4945 included articles, 123 and 76 patients with congenital aortic stenosis (CAS) and CoA were reported, respectively. Normal conventional LV function, with subclinical myocardial dysfunction were reported in all studies before intervention. After intervention, a consistent improvement of myocardial deformation parameters was documented, even though not reaching normal values.

    Study 2. In 21 patients with CoA, LV function significantly improved after intervention (p <0.001), however normal values were not reached even at medium-term follow-up (p = 0.002). Medium-term longitudinal strain correlated with pre intervention LV ejection faction (EF) (r = 0.58, p = 0.006). Medium-term subnormal values were more frequently associated with Bicuspid aortic valve (BAV) (33.3% vs. 66.6%; p <0.05).

    Study 3. AoSA was abnormally wide before intervention, in particular at peak ejection in the descending aorta (p <0.0001), and correlated with CoA pressure gradient. After intervention, AoSA normalized and significantly correlated with the increase of LV cavity function and overall LV deformation parameters.

    Study 4. In a meta-analysis of 28/282 studies including 1192 subjects, strain and strain rate values were established. Longitudinal strain normal mean values varied from -12.9 to -26.5 (mean, -20.5; 95 % CI, -20.0 to -21.0). Normal mean values of circumferential strain varied from -10.5 to -27.0 (mean, -22.06; 95 % CI, -21.5 to -22.5). Radial strain normal mean values varied from 24.9 to 62.1 (mean, 45.4; 95 % CI, 43.0 to 47.8). Meta-regression showed LV end-diastolic diameter as a significant determinant of variation of longitudinal strain. Longitudinal systolic strain rate was significantly determined by age and radial strain was influenced by the type of vendor used.

    Conclusion:

    The systematic review showed subclinical LV dysfunction in children with CoA before and after correction. However, since most of the patients were operated at an older age and had preserved LV EF, the effect of early intervention on LV function was only speculated. Our children with CoA who were operated at an earlier age showed LV subclinical dysfunction even at medium- term after intervention while the AoSA returned to normal shortly after intervention. Lower longitudinal strain values were found in patients with LV dysfunction (LV EF <50%) before intervention and BAV. Finally, normal range values for strain and strain rate have been established and seem to be influenced by patients’ age, LV end-diastolic diameter and vendor used.