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  • Antonsson, Åsa, 1972- (författare)
  • Regulation of NF-κB by Calmodulin
  • 2003
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Cells experience numerous external signals which they must respond to. Such signals arriving at the cell surface are transduced via various signal transduction pathways and often ultimately result in regulation of transcription. NF-κB is a family of transcription factors involved in the regulation of genes important for processes such as immune and inflammatory responses, cell growth, development and cell survival. NF-κB proteins are normally kept inactive in the cytoplasm due to masking of their nuclear localisation signal (NLS) by inhibitory IκB proteins. A large number of stimuli lead to the activation of IκB-kinase (IKK). Active IKK phosphorylates IκB and thereby labels it for ubiquitination and, subsequently, degradation by the proteasome. Liberated NF-κB enters the nucleus, where it takes part in the regulation of its target genes.</p><p>Calmodulin (CaM) is a ubiquitous Ca2+-binding protein which is considered to be the predominant intracellular Ca2+ sensor. CaM plays a major role in the Ca2+-dependent regulation of a wide variety of cellular processes, including transcription. CaM regulates transcription both indirectly through CaM-dependent kinases and phosphatases and directly through interaction with transcription factors.</p><p>CaM was found to bind directly and in a Ca2+-dependent fashion to the two NF-κB family members c-Rel and RelA. The CaM-NF-κB interactions were strongly enhanced by NF-κB activating stimuli and this enhancement was blocked by the addition of IκB, suggesting that c-Rel and RelA can bind CaM after their signal-induced release from IκB. Compared to wild-type c-Rel, CaM binding-deficient mutants were shown to exhibit an increased nuclear accumulation and transcriptional activity on Ca2+-regulated cytokine promoters. The results suggest that CaM can inhibit transport of c-Rel, but not of RelA, to the nucleus and thereby differentially regulate the activation of NF-κB proteins following cell stimulation. CaM was also found to affect NF-κB activity indirectly through the action of a CaM-dependent kinase (CaMK). Studies of the events leading to IκBα phosphorylation revealed that CaM and CaMKII inhibitors blocked phorbol ester induced activation of IKK. Furthermore, CaM and CaMKII inhibitors also blocked T cell receptor/CD3 induced IκBα degradation, and expression of an inhibitor-resistant derivative of the γ isoform of CaMKII caused the inhibitors lose their effect on phorbol ester induced IκBα degradation. Finally, expression of a constitutively active CaMKII resulted in the activation of NF-κB. These results identify CaMKII as a mediator of IKK activation, specifically in response to T cell receptor/CD3 and phorbol ester stimulation.</p><p>In conclusion, this thesis describes the identification of CaM as a dual regulator of NF-κB proteins, acting both directly and indirectly to affect the activity of this family of transcription factors.</p>
  • Appelblad, Micael, 1961- (författare)
  • Fat contamination of pericardial suction blood in cardiac surgery clinical and experimental studies in perspectives of transfusion logistics
  • 2006
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Introduction: During cardiac surgery aided by cardiopulmonary bypass (CPB) the autotransfusion of pericardial suction blood (PSB) is regarded mandatory to limit allogeneic blood exposure. PSB is however proposed as a source of lipid microemboli and to contribute to brain damage. This thesis addresses the logistics of allogeneic blood transfusion during coronary artery bypass grafting (CABG), the embolic potential of reinfused PSB, and means to reduce PSB fat contamination, investigated both clinically and experimentally.</p> <p>Methods: Study I) Patients undergoing CABG surgery (n=2469) were included in a database study. The magnitude of surgical bleeding versus blood transfusion was analyzed to extract a subgroup of patients (n=982) in whom transfusions were independent from bleeding. Study II) PSB and venous-blood samples were collected from patients undergoing routine CABG (n=20). The in vitro capillary-flow properties of blood subcomponents and the effects of routine screen filtration were tested. PSB fat contamination was evaluated by imprint microscopy. Study III) Heat extracted liquid human fat or soya oil were mixed with mediastinal drain blood (n=20) and incubated in a temperature controlled column, to evaluate spontaneous density separation of fat. Study IV) The findings from study-III were applied to develop a fat-reducing system (FRS) using two stacked compartments. The FRS was experimentally tested (n=12), with similar methods as in study-III, and clinically evaluated (n=10). A single-chamber blood bag (n=10) served as reference.</p> <p>Results: Study I) A surgical bleeding of less than 400 mL showed no correlation to blood transfusion, although 64 of 982 patients still received allogeneic blood. The strongest predictors for this kind of transfusion were; female gender, weight ≤70 kg, CPB time ≥90 minutes, CPB temperature ≤32 ºC, and advanced age (P&lt;.001 - .038). Study II) The capillary-flow profile of PSB plasma was highly impaired compared to venous plasma (P&lt;.001). Conversely, blood-cell components showed no difference between PSB and venous blood. Routine screen filtration showed no ameliorating effect on capillary-flow resistance. Fat debris was detected on imprints in all PSB samples in contrast to venous plasma (P&lt;.05). Study III) After 10-min of incubation had 77% of added soya oil separated and found contained in the top 20% fraction of blood (P&lt;.001), aimed to be discarded. The density separation of human fat was less efficient compared to soya oil (P=.011). Fat also adsorbed to surface which was more pronounced at low temperature (P&lt;.001). The overall reduction of human fat was 70%. Study IV) PSB contained 1.5 mL fat suspended in 418 mL PSB. Of this fat was 24% surface-bound. Experimental analysis of the proposed FRS revealed an 83% fat-reduction which was clinically confirmed, suggesting 80% reduction (P=.001). The FRS also gave a small but significant erythrocyte-concentrating effect.</p> <p>Conclusions: Transfusion of allogeneic blood during CABG surgery appeared associated with an institutional, individual, and technical bias of an anticipated need and not only used to compensation for surgical bleeding. In part may this reflect a non-compliant CPB methodology and hemodilution. It was confirmed that PSB plasma contained fat, with a suggested embolic potential. Human fat was significantly reduced from mediastinal drain blood by spontaneous density separation and surface adsorption. The prototype FRS used for PSB incubation during CPB allowed an efficient fat reduction.</p>
  • Araya, Mesfin, 1954- (författare)
  • Postconflict internally displaced persons in Ethiopia mental distress and quality of life in relation to traumatic life events, coping strategy, social support, and living conditions
  • 2007
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Background: There are about 23.7 million internally displaced persons worldwide today, still living in the low-income countries. Ethiopia has for the past four decades been ravaged by war and famine. A lengthy civil war resulted in Eritrea, formerly a part of Ethiopia, becoming an independent state in 1991. This war led to displacement of one million people, and currently there are about 55000 internally displaced Ethiopians in Addis Ababa, most of them living in temporary shelters. A minority resettled in a small town Debre Zeit south east of Addis Ababa, dispersed in the community.</p> <p>Objectives: To study the consequences of trauma and extreme stress among these displaced persons.</p> <p>Methods: A random sample of 1200 displaced persons was selected from the Kaliti and Kore shelters of Addis Ababa, aged between 18 and 60 years. They were interviewed by internationally validated instruments which were translated into the Ethiopian official language Amharic. Information thus obtained covered sociodemographics, childhood trauma, traumatic life events, and mental distress as assessed by the SCL-90-R, the four domains of quality of life assessed by WHOQOL-BREF, coping strategies, perceived social support, and basic living conditions. A sample of 120 subjects from the displaced persons living in Debre Zeit was similarly evaluated. A study comparing prevalence rates and risk factors for PTSD in four postconflict, low-income countries (Algeria, Cambodia, Ethiopia, Gaza) was also undertaken.</p> <p>Results: Men, compared to women, reported significantly higher experience of trauma, higher perceived social support, and higher task-oriented coping. Women reported higher emotion-oriented coping. In both genders, emotion-oriented coping was correlated with higher trauma events, and task-oriented coping was correlated with higher perceived social support. Mental distress increased and quality of life decreased with age. Mental distress mediated the effects of most trauma in reducing quality of life, and some trauma reduced quality of life directly. Living conditions were also significantly related to quality of life. Coping strategies and perceived social support influenced mental distress and quality of life directly as well as indirectly by moderation, in part gender specific. Placement in the community setting of Debre Zeit gave a better quality of life compared to placement in the shelters of Addis Ababa. This difference was accounted for by the difference in living conditions, particularly protection from animals (rodents) and insects (mosquitoes), for three domains of quality of life. For domain 3 (social relationships), however, several further factors accounted for the difference, like marital status, ethnic belonging and coping strategy. The comparative study of 4 postconflict countries contributes to the theory that trauma may be the direct cause of the onset of PTSD but that a multiplicity of other adverse events determine the development of this disorder.</p> <p>Conclusions: Using the same assessment methods, a wide range of rates of symptoms of PTSD were found among 4 low-income populations who have experienced war, conflict, or mass violence. In the Ethiopian context we also found gender differences in the trauma background, coping strategies and perceived social support. Mental distress mediated much of the effects of trauma on quality of life. Coping strategies and perceived social support were significant moderators in this process.</p>
  • Aripaka, Karthik, 1986- (författare)
  • Studies on the biological functions of interaction between components in Wnt, TGF-β and HIF pathways for cancer progression
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Cancer is a disease that involves aggressive changes in the genome and aberrant signals between the living cells. Signalling pathways such as TGF-β (Transforming growth factor-β), Wnt, EGF (epidermal growth factor) and HIF (Hypoxia-inducible factor) evolved to regulate growth and development in mammals. These factors are also implicated for tumorigenesis due to failure or aberrant expression of components in these pathways. Cancer progression is a multistep process, and these steps reflect genetic alterations driving the progressive transformation of healthy human cells into highly malignant derivatives. Many types of cancers are diagnosed in the human population, such as head &amp; neck, cervical, brain, liver, colon, prostate, uterine, breast, and renal cell cancer.</p><p>Prostate cancer is the second most common cancer and one of the foremost leading cancer-related deaths in men in the world. Aberrant Wnt3a signals promote cancer progression through the accumulation of β-Catenin. In the first paper, we have elucidated intriguing functions for Tumour necrosis factor receptor-associated factor 6 (TRAF6) as a coregulatory factor for the expression of Wnt-target genes which was confirmed <em>in vivo</em> by using CRISPR/Cas9 genomic editing, in zebrafish. Our data suggest that Wnt3a promotes TRAF6 interaction with Wnt components, and TRAF6 is required for gene expression of β-Catenin as well as for the Wnt-ligand co-receptor LRP5. From the <em>in vivo</em> studies, we elucidated positive regulation of TRAF6, which is crucial for survival and development of zebrafish. This study identifies TRAF6 as an evolutionary conserved co-regulatory protein in the Wnt pathway that also promotes the progression of prostate and colorectal cancer due to its positive effects on Wnt3a signalling.</p><p>Hypoxia is a condition due to O<sub>2</sub> deprivation, and Hypoxia-inducible factors (HIF) transcription factors are responsible for the maintenance of oxygen homeostasis in living cells. Irregularities in these HIF transcription factors trigger pathological cellular responses for initiation and progression of malignant cancers. Renal cell carcinoma, malignant cancer arising in renal parenchyma and renal pelvis and, hypoxia plays a vital role in its progression. In the second paper, we have investigated the clinicopathological relevance of several hypoxic and TGF-β component proteins such as HIF-1α/2α/3α, TGF-β type 1 receptor (ALK5-FL) and the intracellular domain of ALK5 (ALK5-ICD), SNAI1 and PAI-1 with patient survival in clear cell renal cell carcinoma (ccRCC). We showed that HIF-2α associated with low cancer-specific survival. HIF-2α and SNAI1 positively correlated with ALK5-ICD, pSMAD2/3, PAI-1 and SNAI1 with HIF-2α; HIF-1α positively correlated with pSMAD2/3. Further, under normoxic conditions, our data suggest that ALK5 interacts with HIF-1α and HIF-2α, and promotes their expression and target genes such as GLUT1 and CA9, in a VHL dependent manner through its kinase activity. These findings shed light on the critical aspect of cross-talk between TGF-β signalling and hypoxia pathway, and also the novel finding of an interaction between ALK5 and HIF-α might provide a more in-depth understanding of mechanisms behind tumour progression</p><p>In the third paper, an ongoing study, we investigated the role of HIF-3α in the progression of Renal cell carcinoma and its association with the components of TGF-β and HIF pathways. We have observed increased levels of HIF-3α in ccRCC and pRCC (papillary renal cell carcinoma) which are associated with advanced tumour stage, metastasis and larger tumours. Also, we found HIF-3α show a significant positive association with pro-invasive gene SNAI1, which is a crucial regulator of epithelial to mesenchymal transition. TRAF6 an E3 ligase known to be a prognostic marker in RCC and we observed HIF-3α associates with TRAF6.</p>
  • Árnadóttir, Guðrún, 1955- (författare)
  • Measuring the impact of body functions on occupational performance validation of the ADL-focused occupation-based neurobehavioral evaluation (A-ONE)
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Background: Among the instruments commonly used by occupational therapists working in the area of rehabilitation of persons with neurological disorders are evaluations of both occupation, such as activities of daily living (ADL), and body functions. While persons with neurological diagnoses typically have symptoms that represent diminished neurobehavioral functions, the resulting pattern of neurobehavioral impairments affecting ADL performance often differs among diagnostic groups. Usually, neurobehavioral impairments are evaluated in a context that is separate from and not natural for ADL task performance. The A-ONE is a unique instrument that can be used to evaluate both ADL performance (ADL scale) and, in the natural context of the ADL task performance, the underlying neurobehaviors that cause diminished ADL task performance among persons with neurological disorders (Neurobehavioral scale). The scales of the instrument are of ordinal type, and in their existing form, do not have measurement properties. Measurement properties are a requirement of evidence-based and quality assured rehabilitation services.</p><p>The overall aim of this doctoral study was to further develop and validate the A-ONE. This included (a) internal validation to explore the potential for converting the ordinal scales of the instrument to interval scales, (b) examination of which of the neurobehavioral items would be most beneficial and clinically useful for constructing a new Neurobehavioral Impact (NBI) scale for evaluating persons with different neurological diagnoses, and (c) exploration of whether persons with right and left cerebrovascular accidents (RCVA, LCVA) differ in mean NBI measures.</p><p> Methods: This thesis is comprised of four studies which all contribute in different ways to the validation of the scales of the A-ONE. In the first three studies, Rasch analyses, a widely accepted modern test theory methodology, was used to examine internal validity of the scales and the reliability of the A-ONE measures. In the fourth study, ANCOVA was used to explore between group differences, and Pearson correlation coefficients were used to explore relations between person measures from the different A-ONE scales.</p><p>Results: The first study of 209 persons diagnosed with CVA and dementia provided support for converting the ordinal ADL scale to an interval scale that has potential to be used to measure change in ADL performance over time. The second and third studies, including 206 and 422 persons respectively, indicated that it is possible to construct several unidimensional versions of a new NBI scale from the neurobehavioral items of the instrument, each with different item content and hierarchical item structure. Further, some of these NBI scales could be used across different diagnostic groups. When exploring differences between 215 persons with RCVA and LCVA on the NBI scale developed for CVA, results of the ANCOVA (with ADL ability as a covariate) indicated that there is no significant difference between groups in their mean NBI measures, despite known differences in patterns of neurobehavioral impairments.</p><p>Conclusions: The results of this thesis indicate that the A-ONE, although developed by traditional psychometric methods for the purpose of providing useful information for intervention planning, now also has the potential to be used to measure change and compare diagnostic groups. This additional feature will likely enhance both clinical and research potential of the instrument. In order to make the results of the study accessible for clinicians, conversion tables need to be developed.</p>
  • Arnadottir, Solveig, 1968- (författare)
  • Physical activity, participation and self-rated health among older community-dwelling Icelanders a population-based study
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Background:</strong> The main objective of this study was to investigate older people’s physical activity, their participation in various life situations, and their perceptions of their own health. This included an exploration of potential influences of urban versus rural residency on these outcomes, an evaluation of the measurement properties of a balance confidence scale, and an examination of the proposed usefulness of the International Classification of Functioning, Disability and Health (ICF) as a conceptual framework to facilitate analysis and understanding of selected outcomes.</p><p><strong>Methods:</strong> The study design was cross-sectional, population-based, with random selection from the national register of one urban and two rural municipalities in Northern Iceland. There were 186 participants, all community-dwelling, aged 65 to 88 years (mean = 73.8), and 48% of the group were women. The participation rate was 79%. Data was collected in 2004, in face-to-face interviews and through various standardized assessments. The main outcomes were total physical activity; leisure-time, household, and work-related physical activity; participation frequency and perceived participation restrictions; and self-rated health. Other assessments represented aspects of the ICF body functions, activities, environmental factors and personal factors. Moreover, Rasch analysis methods were applied to examine and modify the Activities-specific Balance Confidence (ABC) scale and the ICF used as a conceptual framework throughout the study.</p><p><strong>Results:</strong> The total <em>physical activity</em> score was the same for urban and rural people and the largest proportion of the total physical activity behavior was derived from the household domain. Rural females received the highest scores of all in household physical activity and rural males were more physically active than the others in the work-related domain. However, leisure-time physical activity was more common in urban than rural communities. A physically active lifestyle, urban living, a higher level of cognition, younger age, and fewer depressive symptoms were all associated with more <em>frequent participation</em>. Rural living and depressive symptoms were associated with <em>perceived participation restrictions.</em> Moreover, perceived participation restrictions were associated with not being employed and limitations in advanced lower extremity capacity. Both fewer depressive symptoms and advanced lower extremity capacity also increased the likelihood of better <em>self-rated health</em>, as did capacity in upper extremities, older age, and household physical activity. Rasch rating scale analysis indicated a need to modify the ABC to improve its psychometric properties. The modified ABC was then used to measure <em>balance confidence</em> which, however, was found not to play a major role in explaining participation or self-rated health. Finally, the <em>ICF</em> was useful as a conceptual framework for mapping various components of functioning and health and to facilitate analyses of their relationships.</p><p><strong>Conclusions:</strong> The results highlighted the commonalities and differences in factors associated with participation frequency, perceived participation restrictions, and self-rated health in old age. Some of these factors, such as advanced lower extremity capacity, depressive symptoms, and physical activity pattern should be of particular interest for geriatric physical therapy due to their potential for interventions. While the associations between depressive symptoms, participation, and self-rated health are well known, research is needed on the effects of advanced lower extremity capacity on participation and self-rated health in old age. The environment (urban versus rural) also presented itself as an important contextual variable to be aware of when working with older people’s participation and physically active life-style. Greater emphasis should be placed on using Rasch measurement methods for improving the availability of quality scientific measures to evaluate various aspects of functioning and health among older adults. Finally, a coordinated implementation of a conceptual framework such as ICF may further advance interdisciplinary and international studies on aging, functioning, and health.</p>
  • Arnerlöv, Conny, 1952- (författare)
  • Prediction of prognosis in human breast cancer a study on clinicopathologic and cytometric prognostic factors
  • 1991
  • Ingår i: digitalisering@umu. - Umeå : Umeå universitet.
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>This study was undertaken to evaluate some important prognostic factors in human breast cancer. The prognostic value of accepted clinicopathological factors such as the presence of axillary lymph node métastasés, histologic grade, clinical and pathological stage was confirmed.</p><p>In a cohort of stage T3,T4,M0 breast cancer with 91 patients (paper I) DNA ploidy by static cytometry (SCM) turned out to be the most important prognostic factor. In a cohort of stage T2,M0 breast cancer with 99 patients (paper III) the presence of involved axillary nodes and low histologic grade were independent prognostic factors. According to life-table analyses DNA ploidy by flow cytometty (FCM) and SCM were significant prognostic predictors for survival but S-phase fraction (SPF) was not. The significant discrimination between euploid and aneuploid tumours was seen also among the node-negative patients. In a patient material with 158 tumours of predominantly low stages (73% T0,T1, papers IV and V) and calculated mammographie tumour volume doubling time (DT) DNA ploidy by FCM gave no significant prognostic information. A computer program was used to calculate SPF from the histograms obtained by FCM. SPF with a cut-off value of 7.5% between tumours with high and low proliferation rate was a highly significant and independent prognostic factor for survival. The other independent prognostic predictors were low histologic grade, the presence of involved axillary nodes and stage II and III <em>(versus</em> stage I).</p><p>DT values for 158 patients (papers IV and V) varied between 0.6 and 65.8 months (mean 10.9 months) and 11 tumours showed no growth at all between mammographies. The median value of 9.0 months was chosen as cut-off point between slow and fast growing tumours. The prognostic power of DT was however low, and the difference between slow and fast growing tumours was significant only for distant disease-free survival. Seventy-one of the 158 tumours were detected by mammographie screening. The screening detected carcinomas with predominantly long DT:s were discovered at an early stage and showed favourable characteristics concerning DNA ploidy and SPF.</p><p>FCM was a rapid and reliable method for DNA analysis with a better prognostic discrimination between euploid and aneuploid groups than SCM (papers II and III).</p><p>SPF, DNA ploidy and histologic grade are significantly correlated to one another but show no strong correlation to the presence of axillary lymph node métastasés. There is also a significant correlation between DT on one hand and DNA ploidy and SPF on the other hand.</p><p>In conclusion the classic prognostic factors are still valuable. DNA ploidy as a single prognostic factor seems to have a relatively low prognostic power and seems to be of limited clinical value. SPF is a highly significant prognostic predictor for breast cancer of low stage, but the clinical value is not defined.</p>
  • A'roch, Roman, 1959- (författare)
  • Left ventricular function's relation to load, experimental studies in a porcine model
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Background:</strong> Loading conditions are recognized to influence ventricular function according to the Starling relationship for length/stretch and force.  Many modern echocardiographic parameters which have been announced as describing ventricular function and contractile status, may be confounded by uncontrolled and unmeasured load.  These studies aimed to measure the relation between four differ­ent types of assessments of ventricular dysfunction and degrees of load.  Study examined the ‘myo­cardial performance index’ (MPI).  Study II examined long axis segmental mechanical dyssynchrony.  Study III examined tissue velocities, and Study IV examined ventricular twist.  All studies aimed to describe the relation of these parameters both to load and to inotropic changes.</p> <p><strong>Methods</strong>:  In anesthetized juvenile pigs, left ventricular (LV) pressure and volume were measured continuously and their relationship (LVPVR) was analysed.  Preload alterations were brought about by inflation of a balloon tipped catheter in the inferior vena cava (IVCBO).  Inotropic interventions were brought about by either an overdose of anesthetic (combine intravenous pentobarbital and inhaled isoflurane, Study I), or beta blocker and calcium channel blocker given in combination (Stud­ies III and IV).  In one study (II), global myocardial injury and dysfunction was induced by endotoxin infusion.  MPI measurements were derived from LVPVR heart cycle intervals for isovolumic contrac­tion and relaxation as well as ejection time.  Long axis segmental dyssynchrony was derived by ana­lyzing for internal flow and time with segmental dyssynchronous segment volume change during systole, hourly before and during 3 hours of endotoxin infusion.  Myocardial tissue velocities were measured during IVCBO at control, during positive and then later negative inotropic interventions.  The same for apical and base circumferential rotational velocities by speckle tracking.  Load markers (including end-diastolic volume) were identified for each beat, and the test parameters were analysed together with load for a relation.  The test parameters were also tested during single apneic beats for a relation to inotropic interventions.</p> <p><strong>Results:</strong> MPI demonstrated a strong and linear relationship to both preload and after-load, and this was due to changes in ejection time, and not the isovolumic intervals.  Long axis segmental dyssyn­chrony increased during each hour of endotoxin infusion and global myocardial injury.  This dysyn­chrony parameter was independent of load when tested by IVCBO. Peak systolic velocities were strongly load-independent, though not in all the inotropic situations and by all measurement axes.  Peak systolic strain was load-dependent, and not strongly related to inotropic conditions.  Peak sys­tolic LV twist and untwist were strongly load-dependent.</p> <p><strong>Conclusions:</strong> MPI is strongly load-dependent, and can vary widely in value for the same contractile status if the load is varied.  Mechanical dyssynchrony measures are load-independen in health and also in early global endotoxin myocardial injury and dysfunction.  Peak sytole velocities are a clinically robust parameter of LV regional and global performance under changing load, though peak systolic strain seems to be load-dependent.  Left ventricular twist and untwist are load-dependent in this pig model.</p>
  • Arvidsson, Sandra, 1986- (författare)
  • Cardiac function in hereditary transthyretin amyloidosis an echocardiographic study
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p><strong>Background: </strong>Hereditary transthyretin amyloidosis (ATTR) is a lethal disease in which misfolded transthyretin (TTR) proteins accumulate as insoluble aggregates in tissues throughout the body. A common mutation is the exchange of valine to methionine at place 30 (TTR V30M), a form endemically found in the northern parts of Sweden. The main treatment option for ATTR amyloidosis is liver transplantation as the procedure halts production of mutated transthyretin. The disease is associated with marked phenotypic diversity ranging from predominant cardiac complications to pure neuropathy. Two different types of fibril composition – one in which both fragmented and full-length TTR are present (type A) and one consisting of only full-length TTR (type B) have been suggested to account for some phenotypic differences. Cardiac amyloidosis is associated with increased myocardial thickness and the disease could easily be mistaken for other entities characterised by myocardial thickening, such as sarcomeric hypertrophic cardiomyopathy (HCM). The aims in this thesis were to investigate echocardiographic characteristics in Swedish ATTR amyloidosis patients, and to identify markers aiding in differentiating ATTR heart disease from HCM. Another objective was to examine the impact of fibril composition and sex on the phenotypic variation in amyloid heart disease.</p><p><strong>Methods: </strong>A total of 122 ATTR amyloidosis patients that had undergone thorough echocardiographic examinations were included in the studies. Analyses of ventricular geometry as well as assessment of systolic and diastolic function were performed, using both conventional echocardiographic methods and speckle tracking technique. ECG analysis was conducted in study I, allowing measurement of QRS voltage. In study I and study II ATTR patients were compared to patients with HCM. In addition, 30 healthy controls were added to study II.</p><p><strong>Results: </strong>When parameters from ECG and echocardiography were investigated, the results revealed that the combination of QRS voltage &lt;30 mm (&lt;3 mV) and an interventricular/posterior wall thickness quotient &lt;1.6 could differentiate cardiac ATTR amyloidosis from HCM. Differences in degree of right ventricular involvement were also demonstrated between HCM and ATTR amyloidosis, where ATTR patients displayed a right ventricular apical sparing pattern whereas the inverse pattern was found in HCM. Analysis of fibril composition revealed increased LV wall thickness in type A patients compared to type B, but in addition type A women displayed both lower myocardial thickness and more preserved systolic function as compared to type A males. When cardiac geometry and function were evaluated pre and post liver transplantation in type A and B patients, significant deterioration was detected in type A but not in type B patients after liver transplantation.</p><p><strong>Conclusions: </strong>Increasing awareness of typical cardiac amyloidotic signs by echocardiography is important to reduce the risk of delayed diagnosis. Our classification model based on ECG and echocardiography could aid in differentiating ATTR amyloidosis from HCM. Furthermore, the apical sparing pattern found in the right ventricle may pose another clue for amyloid heart disease, although it requires to be studied further. Furthermore, we disclosed that type A fibrils, male sex and increasing age were important determinants of increased myocardial thickness. As type A fibril patients displayed rapid cardiac deterioration after liver transplantation other treatment options should probably be sought for this group of patients.</p>
  • Asayesh, Amir, 1977- (författare)
  • Spleno-pancreatic development assessed by 3D molecular imaging
  • 2007
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>The development of different organs and tissues along the gastrointestinal tract, including the pancreas, depends on signalling between the endoderm and the adjacent mesenchyme. The Nkx gene Bapx1 is involved in spatial control of organ-positioning in the spleno-pancreatic region, and deficiency in this gene results in unacceptable proximity of the splenic mesenchyme to the pancreas. This permits agitating signals from the splenic mesenchyme to induce an in vivo (and in vitro) transformation of pancreatic epithelium to a cystic structure with gut like features. Also, wild type splenic mesenchyme is competent to induce a similar transformation. These findings illustrate the importance for strict control of organ positioning during spleno-pancreatic development.</p> <p>Several growth factors and receptors involved in pancreatic development are activated by protease processing. Some of these growth factors have been implicated as substrates for members of the A Disintegrin And Metalloprotease (ADAM) family. The ADAMs 9, 10, and 17 are expressed during pancreatic development and in the adult pancreas, suggesting a possible role for these ADAMs in pancreatic development and function.</p> <p>Animal model systems are widely used to investigate gene function during development and disease. However, spatial, molecular, and quantitative phenotype screening in animals is a time consuming effort. Optical Projection Tomography is a 3-dimensional imaging technique that, in combination with improvements in sample preparation and computer processing, can be used to visualize and quantify characteristics of intact adult mouse organs such as the total β-cell content in the pancreas.</p>
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