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  • Bladh, Marie (författare)
  • Birth Characteristics’ Impacton Future Reproduction and Morbidity Among Twins an dSingletons
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Globally, in both developed and developing countries, the twinning rates have increased since the early 70’s. A large proportion of twins are born preterm and/or small-for-gestational-age (SGA) and/or with a low birth weight. Several studies have been performed on the long-term effect of these non-optimal birth characteristics on future reproductive performance and morbidity. Yet, most studies exclude twins or higher order pregnancies and thus the findings are based on singleton pregnancies only.</p><p>The aim of the present thesis was therefore to investigate the impact of non-optimal birth characteristics in terms of preterm birth, small-for-gestational age, and low birth weight, on the reproductive pattern and morbidity among twins and singletons Furthermore, the present thesis attempted to establish whether twins and singletons were affected in the same manner.</p><p>The studies included in this thesis are prospective population-based register studies, including all men and women, alive and living in Sweden at age 13, who were born between 1973 and 1983 (1,000,037 singletons and 16,561 twins) for the first three studies with follow-up till the end of 2006 and 2009. The last study included all men and women, alive and living in Sweden at age 13, who were born between 1973 and 1993 (2,051,479 singletons and 39,726 twins) with follow-up till the end of 2012.</p><p>In general, twins were found less likely to reproduce between 13 and 33 years of age compared with singletons. Stratifying data by different birth characteristics, it was found that twins had a lower likelihood of reproducing on several different birth characteristics (appropriate-for-gestational-age, normal birth weight, low birth weight, term birth, preterm birth). However, twins born very preterm had an increased likelihood of reproducing compared with singletons born very preterm.</p><p>Not taking birth characteristics into account, twinning was associated with a higher degree of hospitalization. However, accounting for the diverging birth characteristics this difference diminished and for some diagnoses the relationship was reversed such that twins were actually less likely to be hospitalized compared with singletons.</p><p>In terms of the heritability of non-optimal birth characteristics singleton mothers born preterm were more predisposed to give birth to a child that was preterm while singleton mothers born SGA more often gave birth to a child either born preterm or SGA. Among twins this heritability was not as evident. The only difference observed was among twin mothers born SGA who were more likely to give birth to a child born SGA.</p><p>In the extended cohort comprising those born between 1973 and 1993, male and female twins were found to be less likely to become parents compared with singletons. No difference was found among women in terms of having a second child, while male twins were more likely to have a second child compared with male singletons. It was also found that the likelihood of becoming a first-time parent and second-time parent was positively associated with the number of siblings.</p>
  • Blomgran, Parmis, 1985- (författare)
  • Inflammation and tendon healing
  • 2017
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Tendons heal through three different overlapping phases; the inflammatory, proliferative and remodeling phase. Many studies have investigated what factors influence healing of tendons. However, little was known about inflammation and the immune cells present during Achilles tendon healing by the time this thesis started. We developed a flow cytometry method for our rat model of tendon healing, which enabled us to study different leukocyte subpopulations during Achilles tendon healing.</p><p>The general aim of this thesis was to understand more about inflammation and the immune cell populations present during tendon healing and how the immune cell composition changes during normal tendon healing. Moreover, we investigated how different factors that are known to influence tendon healing affected the composition of the immune cell population.</p><p>First, we described the immune cells during the time course of tendon healing focusing on different subpopulations of macrophages and T cells. Then, we studied how these cells were influenced by reduced mechanical loading. Mechanical loading prolonged the presence of M1 macrophages and delayed the switch to regulatory T cells and M2 macrophages compared to reduced mechanical loading. Next, the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the leukocyte composition revealed that, even though NSAIDs influence the mechanical properties of healing tendon, this effect was not mediated via changes in the leukocyte sub-populations during early and mid-time tendon healing. Further, the effect of corticosteroids during the inflammatory and remodeling phases of tendon healing was an improved healing of tendons and a reduction of CD8a T cells when corticosteroid was administered after the inflammatory phase. Lastly, we investigated if impairment of tendon healing by NSAIDs was related to mechanotransduction or microdamage during mechanical loading and showed that NSAIDs impair tendon healing by reducing the response to microdamage.</p><p>In conclusion, these studies show that inflammation plays an important role during Achilles tendon healing, and factors that influence healing can also alter the presence or polarization of immune cell populations. </p>
  • Blystad, Ida, 1972- (författare)
  • Clinical Applications of Synthetic MRI of the Brain
  • 2017
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Magnetic Resonance Imaging (MRI) has a high soft-tissue contrast with a high sensitivity for detecting pathological changes in the brain. Conventional MRI is a time-consuming method with multiple scans that relies on the visual assessment of the neuroradiologist. Synthetic MRI uses one scan to produce conventional images, but also quantitative maps based on relaxometry, that can be used to quantitatively analyse tissue properties and pathological changes. The studies presented here apply the use of synthetic MRI of the brain in different clinical settings.</p><p>In the first study, synthetic MR images were compared to conventional MR images in 22 patients. The contrast, the contrast-to-noise ratio, and the diagnostic quality were assessed. Image quality was perceived to be inferior in the synthetic images, but synthetic images agreed with the clinical diagnoses to the same extent as the conventional images.</p><p>Patients with early multiple sclerosis were analysed in the second study. In patients with multiple sclerosis, contrast-enhancing white matter lesions are a sign of active disease and can indicate a need for a change in therapy. Gadolinium-based contrast agents are used to detect active lesions, but concern has been raised regarding the long-term effects of repeated use of gadolinium. In this study, relaxometry was used to evaluate whether pre-contrast injection tissue-relaxation rates and proton density can identify active lesions without gadolinium. The findings suggest that active lesions often have relaxation times and proton density that differ from non-enhancing lesions, but with some overlap. This makes it difficult to replace gadolinium-based contrast agent injection with synthetic MRI in the monitoring of MS patients.</p><p>Malignant gliomas are primary brain tumours with contrast enhancement due to a defective blood-brain barrier. However, they also grow in an infiltrative, diffuse manner, making it difficult to clearly delineate them from surrounding normal brain tissue in the diagnostic workup, at surgery, and during follow-up. The contrast-enhancing part of the tumour is easily visualised, but not the diffuse infiltration. In studies three and four, synthetic MRI was used to analyse the peritumoral area of malignant gliomas, and revealed quantitative findings regarding peritumoral relaxation changes and non-visible contrast enhancement suggestive of non-visible infiltrative tumour growth.</p><p>In conclusion, synthetic MRI provides quantitative information about the brain tissue and this could improve the diagnosis and treatment for patients.</p>
  • Boij, Roland, 1952- (författare)
  • Aspects of inflammation, angiogenesis and coagulation in preeclampsia
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Preeclampsia is a major challenge to obstetricians, due to its impact on maternal and fetal morbidity and mortality and the lack of preventive and treatment strategies. The overall aim of this thesis is to increase the knowledge of the pathogenesis of preeclampsia including the role of inflammation, angiogenesis and coagulation, both locally at the fetomaternal interface and in the maternal circulation. Uncompensated maternal endothelial inflammatory responses to factors from stressed trophoblasts seem to be a major contributor to the syndrome, together with an imbalance in angiogenesis and an activated coagulation system. An increasing amount of data indicates an involvement of the immune system with defect tolerance to the conceptus as an integral part of the pathogenesis, at least in early-onset preeclampsia (EOP).</p><p>We showed that a single administration of human preeclampsia serum in pregnant IL-10<sup>−/−</sup> mice induced the full spectrum of preeclampsia-like symptoms including hypoxic injury in uteroplacental tissues and endotheliosis in maternal kidneys. Importantly, preeclampsia serum, as early as 12 to 14 weeks of gestation, disrupted cross talk between trophoblasts and endothelial cells in an<em> in vitro</em> model of endovascular activity (Tube formation test). These results indicate that preeclamptic sera can be used to better understand the pathophysiology and to predict the disorder. Preeclampsia has been associated with increased inflammation, aberrant angiogenesis and activated coagulation, but their correlation and relative contribution are unknown. We found that markers for all these mechanisms were independently associated with preeclampsia. Cytokines, chemokines, and complement factors seem all to be part of a Th1-associated inflammatory reaction in preeclampsia, more pronounced in EOP than in late-onset preeclampsia (LOP), in line with a more homogeneous pathogenesis in EOP as based on placental pathology. In women with intrauterine growth restriction (IUGR), with an anticipated pathologic placentation, only differences in levels for sFlt-1 and PlGF were found in comparison with mothers without IUGR. Thus, sFlt-1 and PlGF seem to be indicators of placental pathology, while other biomarkers might also reflect maternal endothelial pathology. Chemokines, in contrast to cytokines, may prove to be useful markers in preeclampsia.</p><p>A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Utilizing recent advances in flow cytometry phenotyping, we found no major alterations in circulating Treg numbers in preeclamptic women compared with normal pregnant and non-pregnant women. However, preeclampsia was associated with increased fractions of CTLA-4<sup>+</sup> and CCR4<sup>+</sup> cells within Treg subpopulations, which is in line with a migratory defect of Treg cells, and potentially associated with a reduced number of suppressive Treg cells at the fetomaternal interface. As we found that corticosteroid treatment affected the results, it should be accounted for in studies of EOP. Chemokines are supposed to be part of the immune adaptation in pregnancy. We found a decreased expression of CCL18  (Th2/Tregassociated), in trophoblasts from preeclamptic compared to normal pregnant women, indicating a local regulatory defect in preeclampsia, in line with our finding of a possible migratory defect of circulating Treg cells. Due to increased expression of CCL20 (Th17) and CCL22 (Th2) in first trimester placenta and increased circulating levels of CXCL10 (Th1) and CCL20 (Th17) in third trimester preeclamptic women, we suggest that CCL20 and CCL22 may be important for implantation and early placentation while in third trimester of a preeclamptic pregnancy CXCL10 and CCL20 mainly mirror maternal increased endothelial inflammation and aberrant angiogenesis. In summary, we found that preeclampsia is associated with increased inflammation, aberrant angiogenesis and activated coagulation, caused by placental factors in maternal peripheral circulation, more pronounced in the early-onset form of preeclampsia. It also appears that there is a defective modulation of the immune system in preeclamptic pregnancies. The results provide a better understanding of the pathogenesis of preeclampsia and have given suggestions to predictive markers for preeclampsia in the future.</p>
  • Bojmar, Linda (författare)
  • Metastatic Mechanisms in Malignant Tumors
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The ultimate cause of cancer related deaths is metastasis. This thesis is about three of the main human cancers; breast, colorectal and pancreatic cancer, that together account for more than 25% of the cancer-related deaths worldwide. The focus of the thesis is the spread of cancer, metastasis, and the aim was to investigate mechanisms that can be of importance for this process. We analyzed patient samples to validate the role of epithelialto-mesenchymal transition in vivo and found regulations of many related factors. However, these changes tend to fluctuate along the metastatic process, something which makes targeting complicated. We, moreover, focused on the influence of the tumor microenvironment for metastatic spread. In pancreatic cancer, the stroma constitutes the main part of many tumors. We analyzed the crosstalk between tumor and stromal cell and focused on the mediating inflammatory factor interleukin-1 (IL-1) and regulation of microRNAs. The results showed that the most commonly mutated factor in pancreatic cancer, KRAS, associates with the expression of IL-1 and subsequent activation of stromal cells. Blocking KRAS signaling together with IL-1 blockage give a more pronounced effect on in vitro proliferation and migration of cancer cells and suggests the use of a combination therapy. The cancer-associated activation of the stroma was found to be related to changes in microRNA expression. microRNA was analyzed separately in epithelial cells and stromal cells after microdissection of matched samples of primary and secondary tumors of breast and colorectal cancers. miR-214 and miR-199a were upregulated in stroma associated with progressive tumors and in pancreatic cancer stroma we could show that their expression alters the activation of stromal cells and thereby the growth and migratory ability of associated pancreatic tumor cells. In  breast and colorectal cancers we found several common microRNAs to be up- or downregulated in line with progression. We could show that one of these candidates, miR-18a, had a prognostic value in metastatic breast cancer. To further develop these studies we analyzed this microRNA in circulating microvesicles, i.e. exosomes, and investigated their role in the preparation of a pre-metastatic niche. MicroRNAs are stable biomarkers in the circulation, especially protected in exosomes, which can moreover specifically deliver their message to recipient cells. These studies facilitate the understanding of metastatic behavior and suggest new targets to stop cancer metastasis.</p>
  • Boknäs, Niklas, 1979- (författare)
  • Studies on interfaces between primary and secondary hemostasis
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Our conceptual understanding of hemostasis is still heavily influenced by outdated experimental models wherein the hemostatic activity of platelets and coagulation factors are understood and studied in isolation. Although perhaps convenient for researchers and clinicians, this reductionist view is negated by an ever increasing body of evidence pointing towards an intimate relationship between the two phases of hemostasis, marked by strong interdependence. In this thesis, I have focused on factual and proposed interfaces between primary and secondary hemostasis, and on how these interfaces can be studied.</p><p>In my first project, we zoomed in on the mechanisms behind the well-known phenomenon of thrombin-induced platelet activation, an important event linking secondary to primary hemostasis. In our study, we examined how thrombin makes use of certain domains for high-affinity binding to substrates, called exosite I and II, to activate platelets via PAR4. We show that thrombin-induced platelet activation via PAR4 is critically dependent on exosite II, and that blockage of exosite II with different substances virtually eliminates PAR4 activation. Apart from providing new insights into the mechanisms by which thrombin activates PAR4, these results expand our knowledge of the antithrombotic actions of various endogenous proteins such as members of the serpin superfamily, which inhibit interactions with exosite II. Additionally, we show that inhibition of exosite II could be a feasible pharmacological strategy for achieving selective blockade of PAR4.</p><p>In my second project, we examined the controversial issue of whether platelets can initiate the coagulation cascade by means of contact activation, a hypothesis which, if true, could provide a direct link between primary and secondary hemostasis. In contrast to previous results, our findings falsify this hypothesis, and show that some of the erroneous conclusions drawn from earlier studies can be explained by inappropriate experimental models unsuitable for the study of plateletcoagulation interfaces.</p><p>My third project comprised an assessment of the methodological difficulties encountered when trying to measure the ability of platelets to initiate secondary hemostasis by the release of microparticles expressing tissue factor. Our study shows that the functional assays available for this purpose are highly susceptible to error caused by artificial contact activation. These results could help to improve the methodology of future research and thus pave the way for new insights into the roles of tissue factor-bearing microparticles in the pathophysiology of various thrombotic disorders.</p><p>From a personal perspective, my PhD project has been a fascinating scientific odyssey into the largely unexplored interfaces between primary and secondary hemostasis. Looking forward, my ambition is to continue our work exploring platelet-coagulation interactions and to translate these insights into clinically meaningful information, which may someday improve the treatment of patients with bleeding and/or thrombosis.</p>
  • Bolic Baric, Vedrana (författare)
  • Support in school and the occupational transition process Adolescents and young adults with neuropsychiatric disabilities
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The overall aim of this thesis was to describe and explore the experiences of support in school of adolescents and young adults with neuropsychiatric disabilities. Furthermore, the aim was to explore support that influences the occupational transition to upper secondary school, further education and work. The two first studies investigated computer use in educational activities and during leisure activities by adolescents with attention deficit hyperactivity disorder (ADHD). Study II also aimed to explore how traditional leisure activities and Internet activities interrelate among adolescents with ADHD. In Studies I and II data was collected using a questionnaire focusing on information and communication technology (ICT) use in school and leisure. Adolescents with ADHD (n = 102) aged 12-18 years were compared with adolescents with physical disabilities (Study I) and adolescents from the general population (Studies I and II). In Study III the aim was to describe the experiences of support at school among young adults with AS and ADHD, and to explore what support they, in retrospect, described as influencing learning. Study IV aimed to describe the occupational transition process to upper secondary school, further education and/or work and to explore what support influenced the process from the perspectives of young adults with AS or ADHD. Studies III (n=13) and IV (n=15) used qualitative semi-structured interviews with young adults with AS or ADHD, aged 18-30 years and were analysed using hermeneutics according to Gadamer.</p><p>The findings of Study I showed that students with ADHD reported significantly less frequent use of computers for almost all educational activities compared with students with physical disabilities and students from the general population. They reported low satisfaction with computer use in school and a desire to use computers more often and for more activities in school compared with students with physical disabilities. Study II showed that Internet activities among adolescents with ADHD during leisure, tended to focus on online games. Furthermore, analysis demonstrated that Internet activities were broadening leisure activities among adolescents with ADHD, rather than being a substitute for traditional leisure activities. Study III found that young adults with AS or ADHD experienced difficulties at school that included academic, social, and emotional aspects, all of which influenced learning. Support addressing difficulties with academic performance was described as insufficient and only occasionally provided in school. In conclusion, support for learning among students with AS or ADHD needs to combine academic and psychosicial support. The findings of Study IV identified three different pathways following compulsory school. Support influencing the occupational transition process included: occupational transition preparation in compulsory school, practical work experience in a safe environment, and support beyond the workplace. Support from community-based day centres was described both as an important step towards work in the regular labour market, as well as being too far away from the regular labour market.</p><p>In conclusion, this thesis revealed that support in school among students with AS or ADHD needs to combine academic and psychosocial support. Despite being regarded as facilitating learning, individuals with ADHD or AS reported limited computer and Internet use in school. Based on the results it is suggested that Internet activities may provide adolescents with neuropsychiatric disabilities with new opportunities for social interaction and educational activities. On the basis of the results it is suggested that the occupational transition process should be viewed as a longitudinal one, starting in compulsory school and continuing on until young adults obtain and are able to remain in work or further education. This thesis revealed that extended transition planning, inter-service collaboration and support from communitybased day centres were aspects of the environment that influenced the occupational transition process.</p>
  • Boman, Andrea, 1978- (författare)
  • Lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The pre-symptomatic stage of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) occurs several decades before the clinical onset. Changes in the lysosomal network, i.e. the autophagosomal, endosomal and lysosomal vesicular system, are among the first alterations observed. There are currently no treatments to slow or cure neurodegenerative diseases, and there is a great need for discovery of treatment targets in cellular pathways where pathology pre-dates the neuronal death. It is also crucial to be able to diagnose neurodegenerative diseases earlier, both to enable early intervention treatment and aid in selecting clinical trial populations before the patient has widespread pathology.</p><p>This thesis aims at investigating the potential of lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease.</p><p>A targeted search for lysosomal network proteins was performed in cerebrospinal fluid (CSF) from AD patients, and seven proteins: early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), lysozyme, microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were elevated. The levels of EEA1, LAMP-1, LAMP-2, LC3, lysozyme and Rab3 were also measured in CSF from parkinsonian syndrome patients: PD, clinically diagnosed 4-repeat tauopathy, pathologically confirmed corticobasal degeneration (CBD) and pathologically confirmed progressive supranuclear palsy (PSP) patients. LAMP-1 and LAMP-2 were decreased in PD. LC3 and lysozyme levels were increased in 4-repeat tauopathy patients. EEA1 was decreased and lysozyme increased in PSP, and LAMP-1, LAMP-2, LC3 and lysozyme were increased in CBD. The lysosomal network proteins had different CSF protein profiles in all the parkinsonian syndromes, as well as in AD. It should be emphasized that only a select few of the lysosomal network proteins were observed to be changed, rather than a general change in lysosomal network proteins, which implicates the involvement of these seven proteins in specific pathological processes. The most interesting candidates, LAMP-2 and lysozyme, were selected for further study for their involvement in the pathology of AD.</p><p>Lysozyme was found to co-localise with Aβ plaques in AD patients and overexpression prolonged survival and improved the activity in a <em>Drosophila</em> model of AD. Lysozyme was found to alter the aggregation pathway of Aβ<sub>1-42</sub>, to counteract the formation of toxic Aβ species and to protect from Aβ<sub>1-42 </sub>induced cell toxicity. Aβ<sub>1-42</sub> in turn was found to increase the expression of lysozyme in both neuronal and glial cells. These data suggest that lysozyme levels rise in AD as a compensatory response which is protective against Aβ associated toxicity.</p><p>LAMP-2 mRNA and protein were found increased in brain areas relevant for AD pathology and various cellular models showed complex involvement of LAMP-2 in Aβ related pathology, with extensive crosstalk between LAMP-2 and Aβ. Exposure to oligomeric Aβ<sub>1-42 </sub>caused an upregulation of LAMP-2 and in turn, overexpression of LAMP-2 caused a reduction in secreted levels of Aβ<sub>1-42</sub>, as well as changing the generation pattern of Aβ and affecting clearance and secretion of Aβ<sub>1-42</sub>. These data indicate that the increased levels of LAMP-2 in AD could be an attempt to regulate Aβ generation and secretion.</p><p>In summary, this thesis reports that utilising lysosomal network proteins as biomarkers and novel therapeutic targets for neurodegenerative diseases holds great promise.</p>
  • Borgestig, Maria (författare)
  • The impact of gaze-based assistive technology on daily activities in children with severe physical impairments
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Aim:</strong> The aim of the thesis was to investigate the impact of gaze-based assistive technology on daily activities in children with severe physical impairments and without speech. The objectives were to develop and pilot a gaze-based assistive technology intervention (GAT intervention) at home and in school for these children and to understand its impact on daily activities as experienced by their parents.</p><p><strong>Methods:</strong> Study I was a pilot study in which the basic components that were developed for the intervention were evaluated for students with physical impairments. The study aimed at improving the use of computers as assistive technology (AT) in school. Based on the findings in Study I, the GAT intervention was developed. The GAT intervention aimed at implementing gaze-based AT in daily activities. It consisted of two parts; having access to gaze-based AT and having access to services from a multi professional communication team during nine to ten months. Studies II-IV concerned gazebased AT for children with severe physical impairments without speech who participated in the GAT intervention. The participants were ten children (ages 1-15) (Studies II, III), and their parents (Study IV). Studies II and III had longitudinal designs and children were followed during 15-20 months with repeated measurements before, after and at follow-up. In Study II children’s repertoire of computer activities, extent of use, and goal attainment with gaze-based AT was evaluated, as well as parents’ satisfaction with the AT and with services. In Study III children’s eye gaze performance when using gaze-based AT was examined. In Study IV, parents were interviewed twice with the aim of  exploring their experiences of children’s gaze-based AT use in daily life. In Study IV a hermeneutical approach was used.</p><p><strong>Results:</strong> The findings of Study I showed that the basic components of intervention improved the use of computers in school. Study II showed an increased repertoire of computer activities with the gazebased AT, maintained use in daily activities for all at follow up, and that all children attained goals for gaze-based AT use in daily activities. Parents were satisfied with the gaze-based AT, and with the services in the GAT intervention. In study III, nine children improved in eye gaze performance over time when using the gaze-based AT in daily activities. Study IV revealed that children’s gaze-based AT usage in daily activities made a difference to parents since the children demonstrated agency, and showed their personality and competencies by using gaze-based AT, and for the parents this opened up infinite possibilities for the child to do and learn things. Overall, children’s gaze-based AT usage provided parents with hope of a future in which their children could develop and have influence in life.</p><p><strong>Conclusions:</strong> This thesis shows that these children with severe physical impairments and without speech acquired sufficient gaze control skills to use gaze-based AT for daily activities in the home and at school. The gaze-based AT had a positive impact on performing activities, for example, play activities and communication- and interaction-related activities. For the parents, children’s gaze-based AT usage made a difference since it shaped a hope of a better future for their children, where they can develop and gain influence in their future life. Furthermore, the children continued to perform daily activities with gaze-based AT over time. This finding suggests that key persons were provided with sufficient knowledge and skills to support children in maintained use of gaze-based AT after withdrawal of the services provided in the GAT intervention.</p>
  • Bratengeier, Cornelia, 1983- (författare)
  • Mechanisms of mechanically induced Osteoclastogenesis in a novel <em>in vitro</em> model for bone implant loosening
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Total joint arthroplasty is the primary intervention in the treatment of end-stage osteoarthritis. Despite the high success rate, in some patients, the replacement will fail during their lifetime requiring a revision of the implant. These revisions are strenuous for the patient and costly for health care. Joint replacement at a younger age, in combination with a more active lifestyle, increases the need for an early revision of the joint prosthesis. The main reason for revision surgeries is aseptic loosening, a condition where the prosthesis is loosening due to bone degradation at the peri-prosthetic interface in the absence of infections. The most well-established pathological mechanism for aseptic loosening is related to wear particles, generated from different parts of the prosthesis that will trigger bone degradation and bone loss. In addition, early micromotions of the prosthesis and resulting local pressurized fluid flow in the peri-prosthetic interface (supraphysiological loading) have also been identified as a cause for aseptic loosening. However, it remains unknown what cells are the primary responders to supraphysiological loading, and what underlying physical, cellular and molecular mechanism that triggers osteoclast differentiation and osteolysis.</p><p>In this thesis, we intended to shed light on three currently unknown aspects of mechanical loading-induced peri-prosthetic osteolysis, leading to aseptic loosening of orthopedic prostheses: (1)Which cells are the primary responder to supraphysiological loading? (2)What characteristics of the mechanical stimulus induce an osteo-protective or osteo-destructive response? (3)Which cellular mechano-sensing mechanisms are involved in an osteo-destructive response?</p><p>We successfully implemented supraphysiological mechanical loading, mimicking the periprosthetic pressurized fluid flow around a loosening implant, in an <em>in vitro </em>model for bone implant loosening. Using this model, we uncovered the involvement of mesenchymal stem cells and myeloid progenitor cells (monocytes) in mechanical loading-induced peri-prosthetic osteolysis. Applying supraphysiological loading on cells from patients undergoing primary hip arthroplasty, successfully validated the <em>in vitro </em>model for the use of cells of human origin. We further identified in murine myeloid progenitor cells that a combination of high loading amplitude (3.0±0.2Pa), prolonged active loading duration per cycle (duty cycle 22%-50%), and rapid alterations in minimum/maximum values of the loading profile (square wave) is necessary to induce an osteo-destructive response. Further, the loading-induced ATP release and subsequent activation of the P2X7 receptor was essential for the release of soluble factors modulating osteoclastogenesis.</p><p>In conclusion, we expect that the proposed new <em>in vitro </em>model is a helpful tool to further advance the knowledge in aseptic loosening, by uncovering the mechanoresponsive cellular mechanism to supraphysiological mechanical loading. The identification of the respondent cells in mechanical loading-induced prosthetic loosening gives the opportunity to deliver targeted treatment strategies. Furthermore, identifying the physical parameters that define the shift towards an osteo-destructive response emphasizes the importance of the prosthetic design and surgical technique to reduce mechanical loading-induced bone degradation around a prosthesis.</p>
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