| 1. |
- Boivie, Patrik, 1976-
(author)
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Cerebrovascular accidents associated with aortic manipulation during cardiac surgery
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Background: Despite the successful development in cardiac surgery, cerebrovascular accidents (CVA) remain a devastating complication. Aortic atherosclerosis has been identified as a major risk factor for CVA. The present thesis addresses this question in relation to aortic manipulation during cardiac surgery, being divided into a clinical (I-II) and an experimental part (III-V). Material and methods: Consecutive cardiac surgery cases (n=2641) were analyzed. Patients with CVA were extracted from a database designed to monitor clinical symptoms. Patient records were used to confirm clinical data and diagnosis. Subdivision was made into three groups: control subjects, immediate, and delayed CVA, being analyzed for neurological symptoms (I). Patients with CVA who also had been investigated with computer tomography (CT) (n=77) were further evaluated in terms of hemispheric and vascular distribution of lesions. The CT-findings were compared with CVA symptoms (II). An aortic perfusion model was developed using cadaver aorta onto which multiple cross-clamp manipulations were applied (III). Washout samples of perfusate were analyzed by computerized image processing and with subdivision into different particle spectra. The model was further developed with the introduction of intraluminal manipulation from cannula and intra-aortic filter (IV). A technique for macro-anatomic mapping of plaque distribution of cadaver thoracic aorta was developed (V). Variation in plaque density was analyzed in different anatomical segments, monitored by digital image analysis. Hazards associated with surgical manipulation were studied by superimposing cannulation and cross-clamp sites onto the aortic maps in a blinded fashion. Results: The incidence of immediate and delayed CVA was 3.0% and 0.9%, respectively. Aortic quality was a strongly associated with immediate but not delayed CVA. Left-sided symptoms of immediate CVA were significantly more frequent than of the contra-lateral side. Positive signs on CT were seen in 66% of the CVA patients. Right-hemispheric lesions were more frequent compared with the contra-lateral side and the middle-cerebral artery territory dominated. Aortic cross-clamping produced a substantial output of particulate matter. Manipulation by intra-aortic filter produced a significant washout of embolic particles that escaped the filter, although some particles were captured. Cannulation was an additional source of embolic material. In terms of plaque distribution was the anterior wall of the ascending part and arch of the aorta more affected than its posterior side. However, observing a plaque in the anterior wall of this aortic segment predicted to 83% a concomitant plaque in the posterior wall. Increased age correlated positively with plaque density. The theoretical chance of interfering with a plaque during cannulation and/or clamp positioning was 45.8%. Conclusions: Both CT scans and clinical symptoms confirmed that CVA after cardiac surgery had a right-hemispheric predominance. The perfusion model resulted in a profound output of material during cross-clamp maneuvers. The intra-aortic filter successfully collected particles but also generated embolic debris on its own. Aortic cannulation was an additional source of embolic debris. Plaques were frequently found in the cadaveric aorta, and there was a high risk of plaque interference during surgical manipulation. As expected, plaque density was age-dependent.
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| 2. |
- Chilkova, Olga, 1976-
(author)
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Functional and structural properties of eukaryotic DNA polymerase epsilon
- 2006
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Doctoral thesis (other academic/artistic)abstract
- In eukaryotes there are three DNA polymerases which are essential for the replication of chromosomal DNA: DNA polymerase alpha (Pol alpha), DNA polymerase delta (Pol delta) and DNA polymerase epsilon (Pol epsilon). In vitro studies of viral DNA replication showed that Pol alpha and Pol delta are sufficient for DNA replication on both leading and lagging DNA strands, thus leaving the function of Pol epsilon unknown. The low abundance and the reported protease sensitivity of Pol epsilon were holding back biochemical studies of the enzyme. The aim of this study was to characterize the structural and functional properties of eukaryotic Pol epsilon. We first developed a protocol for over-expression and purification of Pol epsilon from the yeast Saccharomyces cerevisiae. Pol epsilon consists of four subunits: Pol2 (catalytic subunit), Dpb2, Dpb3 and Dpb4. This four-subunit complex was purified to homogeneity by conventional chromatography and the subunit stoichiometry of purified Pol epsilon was estimated from colloidal coomassie-stained gels to be 1:1:1:1. The quaternary structure was determined by sedimentation velocity and gel filtration experiments. Molecular mass (371 kDa) was calculated from the experimentally determined Stokes radius (74.5 Å) and sedimentation coefficient (11.9 S) and was in good agreement with a theoretical molecular mass calculated for a heterotetramer (379 kDa). Analytical sedimentation equilibrium ultracentrifugation experiments supported the proposed heterotetrameric structure of Pol epsilon. By cryo-electron microscopy and single-particle image analysis we determined the structure of Saccharomyces cerevisiae Pol epsilon to 20-Å resolution. The four-subunit complex was found to consist of a globular domain, comprising the Pol2 subunit, flexibly connected to an elongated domain, including Dpb2, Dpb3 and Dpb4 subunits. We found that Pol epsilon requires a minimal length of 40 base pairs of primer-template duplex to be processive. This length corresponds to the dimensions of the elongated domain. To characterize the fidelity by which Pol epsilon synthesizes DNA, we purified wild type and exonuclease-deficient Pol epsilon. Wild type Pol epsilon synthesizes DNA with a very high accuracy. Analysis of the exonuclease-deficient Pol epsilon showed that Pol epsilon proofreads more than 90% of the errors made by its polymerase activity. Exonuclease-deficient Pol epsilon was shown to have a specific spectrum of errors not seen in other DNA polymerases: a high proportion of transversions resulting from T-dTTP, T-dCTP and C-dTTP mispairs. This unique error specificity and amino acid sequence alignment suggest that the structure of the polymerase active site of Pol epsilon differs from those of other members of B family DNA polymerases. With recombinant proteins and circular single-stranded DNA templates, we partially reconstituted DNA replication in vitro, in which we challenged Pol epsilon and Pol delta in side-by-side comparisons regarding functional assays for polymerase activity and processivity, as well as physical interactions with nucleic acids and PCNA. We found that Pol epsilon activity and “on-DNA” PCNA interactions are dependent on RPA-coated template DNA. By the surface plasmon resonance technique, we showed that Pol epsilon has a high affinity for DNA and low affinity for immobilized PCNA. By contrast, Pol delta was found to have low affinity for DNA and high affinity for PCNA. We suggest that a possible function of RPA is to regulate down the DNA synthesis through Pol epsilon, and that the mechanism by which Pol epsilon and Pol delta load onto the template is different due to different properties of the interaction with DNA and PCNA.
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| 3. |
- Werner, Thomas, 1971-
(author)
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Peptidoglycan recognition proteins in Drosophila melanogaster
- 2004
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Doctoral thesis (other academic/artistic)abstract
- The fruit fly Drosophila melanogaster is an excellent model organism to study the innate immune response, because insects and mammals share conserved features regarding the recognition and destruction of microorganisms and Drosophila is easily accessible to genetic manipulation. In my present study, I identified a new family of pattern recognition molecules for bacterial peptidoglycan in Drosophila, the Peptidoglycan Recognition Proteins (PGRP). This family of proteins is widespread in the animal kingdom, for instance there are 4 PGRP genes in humans with unknown function. So far, all tested PGRPs (from insects and mammals) have been shown to bind peptidoglycan. In Drosophila, we found and characterized 13 PGRP genes, which fall into two classes: Short PGRPs and Long PGRPs. To the short group belong PGRP-SA, SB1, SB2, SC1A, SC1B, SC2, and SD with short transcripts and predicted extracellular proteins. The long members are PGRP-LA, LB, LC, LD, LE, and LF with long transcripts and predicted intracellular and membrane spanning proteins. Transcripts from the 13 different PGRP genes are present in immune competent organs, and the majority are inducible by infection. The transcriptional regulation of the inducible PGRP genes occurs either via the imd/Relish or in some cases Toll/Dif pathway. My RNAi experiments in mbn-2 cells revealed that the peptidoglycan recognition protein PGRP-LC is a major activator of the imd/Relish pathway. In PGRP-LC deficient mbn-2 cells, Relish signalling is almost entirely blocked. However, the complex PGRP-LC gene generates three alternative splice forms, each of them carrying one of three possible PGRP domains, LCx, LCy, and LCa. I found that in the tissue culture system PGRP-LCa plays a specific role in the recognition of Gram-negative bacteria, while PGRP-LCx is crucial for the recognition of Gram-positive and Gram-negative bacteria, and peptidoglycan. Targeted mutagenesis of the PGRP-LCa isoform in vivo shows that the situation is more complicated than in the cell culture experiments. In conclusion, PGRPs constitute a highly diversified family of proteins, including key players of the innate immune response.
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| 4. |
- Antonsson, Åsa, 1972-
(author)
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Regulation of NF-κB by Calmodulin
- 2003
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Doctoral thesis (other academic/artistic)abstract
- 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.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.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.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.
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| 5. |
- Jonsson, Bertil, 1956-
(author)
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Interaction between humans and car seats : studies of occupant seat adjustment, posture, position, and real world neck injuries in rear-end impacts
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Background: The latest generation of rear-end whiplash protection systems, as found in the WHIPS Volvo and SAHR Saab, have reduced injury rates by almost 50% in comparison with the previous generation of seat/head restraint systems. Occupant behaviour, such as seated posture and seat adjustment settings, may affect the injury risk. Method: Five studies were conducted. Studie I was an injury outcome study based on insurance data. Studies II-IV investigated seat adjustment, occupant backset, and cervical retraction for drivers and occupants in different postures and positions in the car, during stationary and driving conditions. Study V compared the occupant data from studies II and III with a vehicle testing tool, the BioRID dummy, using the protocols of the ISO, RCAR, and the RCAR-IIWPG. Results: Female drivers and passengers had a threefold increased risk for medically-impairing neck injury in rear-end impacts, compared to males. Driver position had a double risk compared with front passenger seat position. Female drivers adjusted the driver seat differently to male drivers; they sat higher and closer to the steering wheel and with more upright back support. The volunteers also adjusted their seat differently to the ISO, RCAR, and RCAR-IIWPG protocol settings; both sexes sat further away from the steering wheel, and seat back angle was more upright then in the protocols. In stationary cars, backset was highest in the rear seat position and lowest in the front passenger seat position. Males had a larger backset than females. Cervical retraction decreased and backset increased for both sexes when posture changed from self-selected posture to a slouched posture. The BioRID II dummy was found to represent 96th percentile female in stature, and a 69th percentile female in weight in the volunteer group. Conclusions: Risks in car rear-end impacts differ by sex and seated position. This thesis indicates the need for a 50th percentile female BioRID dummy and re-evaluation of the ISO, RCAR, and RCAR-IIWPG protocols, and further development of new safety systems to protect occupants in rear-end impacts.
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| 6. |
- Li, ShuShun, 1963-
(author)
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Thrombospondin 1, an autocrine regulator in T cell adhesion and migration
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Lymphocytes, the principal cells of the immune system, perform the immune function throughout the body by their unique capacity to circulate in blood stream and lymphatic vessels and migrate in lymphoid and non-lymphoid tissues. The mechanisms regulating lymphocyte adhesion and migration, interactions with cells and components within the extracellular matrix are not fully understood. The aim of this work has been to elucidate molecular mechanisms governing T lymphocyte adhesion and migration by endogenous molecules. The studies presented in this thesis have shown that thrombospondin-1 (TSP-1) is expressed in T lymphocytes with a high turnover, manifested by variable cell surface expression, and is regulated by SDF-1a, adhesion to fibronectin and collagen type IV. The TSP-1 binding site of calreticulin (CRT), spanning amino acid 19-32, was shown to be a major triggering factor for T cell migration within a three-dimensional collagen type 1 matrix. The chemokine SDF-1a stimulated migration via a calreticulin-TSP-1 pathway. Endogenous calreticulin binding to the N-terminal domain of endogenous TSP-1 elicited a motogenic signal to the T cells through the C-terminal domain of TSP-1 and its cell surface receptor integrin-associated protein (IAP, CD47). Inhibition experiments of ligand binding of CD91 by receptor associated protein (RAP) and small interfering RNA technology indicated that CD91 is an important factor in TSP-1-mediated T cell adhesion and migration. These results unveil an autocrine mechanism of CRT-TSP-1-CD47-CD91 interaction for the control of T cell motility and migration within 3D extracellular matrix substrata. The data demonstrated that T cell adhesion and migration are sequential events governed by a series of interacting cell surface molecules comprising a CRT-TSP-1-CD47-CD91 pathway where endogenous TSP-1 functions as the hub. Ligation of the CD3/T cell antigen receptor complex determines T cell adhesion through this mechanism. CRT interaction with the N-terminal domain of TSP-1 elicits cytoplasmic spreading, and augments adhesion, while a counter-adhesive motogenic pathway, triggering interaction of the C-terminal domain of TSP-1, induces migration. CD91-dependent internalization of TSP-1 is a crucial event of this motogenic pathway. In conclusion, the studies provide a novel mechanism governing T cell adhesion and migration within extracellular matrix substrata.
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| 7. |
- Dahl, Lina, 1981-
(author)
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Stem cell function and organ development : analysis of Lhx2 function in hematopoietic stem cells and eye development
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- When a multicellular organism suffers damages to tissues/organs it heals itself by either substituting the lost cellular matrix by scar formation or by regenerating the lost tissue. Regeneration likely occurs by a recapitulation of the developmental process that formed the organ. Many processes regulating organ development are based on epithelial-mesenchymal interactions and a strict control of organ specific stem/progenitor cells. Elucidation of the molecular basis of these processes is therefore vital in order to develop novel therapies in regenerative medicine. The LIM homebox gene Lhx2 is interesting in this context since Lhx2 has been shown to be important for the formation of several organs by regulating epithelial-mesenchymal interactions and progenitor cell function. Targeted inactivation of Lhx2 leads to a lethal anemia due to malformed liver and severe neural abnormalities such as hypoplasia of the forebrain and anophtalmia. Thus, elucidation of the mechanisms of the function of Lhx2 in different organ systems would give important insights into the molecular mechanisms regulating epithelial-mesenchymal interactions and stem/progenitor cell function. To elucidate the function of Lhx2 in the hematopoietic system Lhx2 was initially expressed in hematopoietic progenitor cells derived from ES cells differentiated in vitro using retroviral vectors. This approach led to the generation of hematopoietic stem cell (HSC)-like cell lines suggesting that Lhx2 could impact HSC function. However neither the specificity nor the efficiency of the Lhx2-induced phenotype could be determined using this approach. To be able to elucidate the function of Lhx2 in the hematopoietic system, an ES cell line with inducible Lhx2 expression was generated. Lhx2 expression induces self-renewal of a distinct hematopoietic progenitor cell from which HSC-like cell lines were established. Down-regulation of Lhx2 in these HSC-like cell lines leads to a rapid loss of stem cell character, providing a good model to study the molecular function of Lhx2 in hematopoietic stem/progenitor cells. A global gene expression analysis was performed comparing the Lhx2+ stem cell population to the Lhx2- differentiated progeny. This approach identified genes putatively linked to self-renewal/differentiation of HSCs. A considerable proportion of the genes showed an overlapping gene expression pattern with Lhx2 expression in tissue of non-hematopoietic origin suggesting that Lhx2 function in stem/progenitor cells partly overlap with Lhx2 function during organ development. In order to define other Lhx2-dependent progenitor cell populations and to generate a tool to analyze the function of Lhx2 in organ development a new transgenic mouse model was generated. By using a specific part of the Lhx2 promoter to drive expression of Cre recombinase in vivo (Lhx2-Cre mice) we have been able to define the first eye committed progenitor cells in the forebrain. By using the Lhx2-Cre mice it will be possible to distinguish the function of genes during eye development from their function in the patterning of the forebrain e.g. the eye field transcription factors. Conditional inactivation of Lhx2 in these eye specific progenitor cells causes an immediate developmental arrest. The transgene is also active in Lhx2-/- embryonic forebrain, but re-expression of Lhx2 in Lhx2-/- progenitor cells only promote formation of retinal pigment epithelium cells. Analysis of genes expressed by the Lhx2+ stem cell population allowed us to define novel genes putatively linked to Lhx2 function in eye development. Thus, we have defined the progenitor cells in the forebrain committed to eye development and the expansion and patterning of these progenitors are dependent on Lhx2. Although commitment to eye development is Lhx2-independent, Lhx2 might be important for the acquisition of the oligopotent fate of these progenitor cells.
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| 8. |
- Aasa, Ulrika
(author)
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Ambulance Work : Relationships between occupational demands, individual characteristics and health-related outcomes
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Although musculoskeletal disorders (MSDs) and other health complaints are an occupational problem for ambulance personnel, there is a lack of knowledge regarding work-related factors associated with MSDs and other health complaints. The overall aim of this thesis was to investigate the relationships between occupational demands, individual characteristics and health-related outcomes among ambulance personnel. A random sample of 234 female and 953 male ambulance personnel participated in a national questionnaire survey on work-related factors, and musculoskeletal and other health complaints. Physical demands was associated with activity limitation due to neck-shoulder and low-back complaints among the female personnel. Among the male personnel, physical demands was associated with low-back complaints and activity limitation due to low-back complaints. Psychological demands was significantly associated with neck-shoulder complaints, sleeping problems, headache and stomach symptoms among both female and male ambulance personnel. Worry about work conditions was associated with musculoskeletal disorders and sleeping problems, headache and stomach symptoms. A local sample of 26 ambulance personnel was followed during a 24-hour work shift and for the next two work-free days. Subjective stress- and energy levels, and cortisol levels were measured at regular intervals, and heart rate was registered continuously by electrocardiogram (ECG). Autonomic reactivity to standardized tests before (pre-work) and at the end of the work shift (post-work) was also investigated. For the whole group, baseline values of heart rate were higher pre-work than post-work, but autonomic reactivity did not differ. Increased reactivity to the mental test, modest deviation in heart rate variability (HRV) pattern during the late night hours at work and higher morning cortisol values during work than during leisure time were observed in personnel with many health complaints, but not among their co-workers without or with few complaints. Ambulance personnel with many health complaints also reported higher psychological demands and tended to be more worried about work conditions. Heart rate (HR), lactate level (LL) and perceived exertion (RPE) were investigated in 17 female and 48 male ambulance personnel during a simulated standardized work task “carry a loaded stretcher”. The ambulance personnel had to carry the loaded stretcher (920 N) up and down three flights of stairs twice. The high physiological strain (HR, LL, RPE) for the male, and near or at maximal strain for the female ambulance personnel, implied the importance to identify what kind of physical capacity is most important for ambulance personnel. Therefore, the explained variance of developed fatigue by tests of cardiorespiratory capacity, muscular strength and endurance, and coordination was investigated. The results showed that VO2max and isometric back endurance were important predictors for development of fatigue when carrying a loaded stretcher. The influence of body size on the relationships between maximal strength and functional performance was investigated in a methodological study. The results confirm that the assessment of physical performance could be confounded by the body weight. Therefore, the models for explaining development of fatigue when carrying the loaded stretcher were adjusted for height and weight. Including height in the models significantly increased the explained variance of accumulated lactate among female, but not among male personnel. Lactate levels were higher among short compared to tall female personnel. Weight had no effect on any of the models. In conclusion, the national survey showed that self-reported physical demands was a risk factor of having MSDs, and that self-reported psychological demands and worry about work were important risk factors of having MSDs and other health complaints. Stress monitoring of ambulance personnel during work and leisure time showed that physiological and subjective stress markers did not show any differences between the 24-hour ambulance work shift and leisure time afterwards. However, ambulance personnel with many health complaints had certain physiological changes during the work shift in comparison with the next two work-free days. The physiological and subjective responses during carrying a loaded stretcher, especially among the female ambulance personnel, showed that female and male ambulance personnel could be exposed to internal exposures at different levels when performing the same work task. A better understanding of the relationships between occupational demands and health-related outcomes require further studies on age- and gender matched groups in long-term perspective studies.
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| 9. |
- Abraha Derbew, Atakelti, 1976-
(author)
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Bridging gaps in under-five child health : a comprehensive assessment of their social determinants and the health system performance in Tigray, Ethiopia
- 2024
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Doctoral thesis (other academic/artistic)abstract
- Background: Achieving the Sustainable Development targets related to child health necessitates a deep understanding of the multifaceted factors influencing their health.Aim: To comprehensively examine the social determinants of the access to, and quality of, child health services, and the performance of the health system in the region of Tigray.Methods: The study was conducted in six randomly selected rural districts of Tigray. The study employed focus group discussions and interviews (sub-study I), a retrospective case-control study (sub-study-II), a capture recapture method (sub-study III), and a two-stage mortality survey (sub-study IV).Results: Sub-study I: underscored a good knowledge on the causes and management of common childhood morbidity, and that the health posts were conveniently located and provided trusted services. However, several barriers to using health services were identified. These included cultural beliefs, seasonal mobility, economic constraints, limited decision-making power for women, and accessibility challenges.Sub-study II: Revealed that only 76% of eligible children born to HIV-positive mothers were tested, with 17% testing positive for HIV, and only 29% of them linked to anti-retroviral treatment.Sub-study III showed that the concordance correlation coefficient between the Family Folder data and the household survey for the total population, reproductive age women, and under-five year child population were all above 0.73, while they were close to zero for other child health parameters. Tracing and recording neonatal deaths, and the aggregation of data at various levels were the major operational challanges.Sub-study IV identified infectious diseases (52.9%), neonatal causes (35.6%), nutritional disorders (6.6%) and external causes (4.3%) as the major causes of child death. The cause for 76 (16.2%) children was indeterminate. Tracing neonatal deaths and logistical challenges, especially in remote areas were the major operational issues of conducting the mortality survey.Conclusion: In spite of the improvements in health literacy, access to cost-free reproductive, maternal, neonatal and child health services and improved utilization, various interrelated social determinants, including cultural beliefs, financial barriers and health system-related factors continue to hinder the optimal utilization of essential child health services. Moreover, the health system’s performance in the prevention of mother-to-child transmission of HIV and its effect in reducing mortality among exposed children is generally poor. Policymakers in the region should focus on tackling those social determinants, including the health system, to improve children´s health. The community health information system showed promising potential. However, the operational issue of capturing neonatal deaths adequately and the process by which community data can be aggregated upwards through the health system has to be improved. The study underscored the viability of implementing a cause-specific mortality survey using health extension workers, and the need to standardize data collection tools and logistics before implementation on a larger scale.
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| 10. |
- Abrahamsson, Pernilla, 1972-
(author)
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Methodological aspects on microdialysis sampling and measurements
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Background: The microdialysis (MD) technique is widely spread and used both experimentally and in clinical practice. The MD technique allows continuous collection of small molecules such as glucose, lactate, pyruvate and glycerol. Samples are often analysed using the CMA 600 analyser, an enzymatic and colorimetric analyser. Data evaluating the performance of the CMA 600 analysis system and associated sample handling are sparse. The aim of this work was to identify sources of variability related to handling of microdialysis samples and sources of error associated with use of the CMA 600 analyser. Further, to develop and compare different application techniques of the microdialysis probes both within an organ and on the surface of an organ. Material and Methods: Papers I and II are mainly in vitro studies with the exception of the No Net Flux calibration method in paper I where a pig model (n=7) was used to examine the true concentration of glucose and urea in subcutaneous tissue. Flow rate, sampling time, vial and caps material and performance of the analyser device (CMA 600) were examined. In papers III and IV normoventilated anaesthetised pigs (n=33) were used. In paper III, heart ischemia was used as intervention to compare microdialysis measurements in the myocardium with corresponding measurements on the heart surface. In paper IV, microdialysis measurements in the liver parenchyma were compared with measurements on the liver surface in association with induced liver ischemia. All animal studies were approved by the Animal Experimental Ethics Committee at Umeå University Sweden. Results: In paper I we succeeded to measure true concentrations of glucose (4.4 mmol/L) and Urea (4.1 mmol/L) in subcutaneous tissue. Paper II showed that for a batch analyse of 24 samples it is preferred to store microdialysis samples in glass vials with crimp caps. For reliable results, samples should be centrifuged before analysis. Paper III showed a new application area for microdialysis sampling from the heart, i.e. surface sampling. The surface probe and myocardial probe (in the myocardium) showed a similar pattern for glucose, lactate and glycerol during baseline, short ischemic and long ischemic interventions. In paper IV, a similar pattern was observed as in paper III, i.e. data obtained from the probe on the liver surface showed no differences compared with data from the probe in liver parenchyma for glucose, lactate and glycerol concentrations during baseline, ischemic and reperfusion interventions. Conclusion: The MD technique is adequate for local metabolic monitoring, but requires methodological considerations before starting a new experimental serie. It is important to consider factors such as flow rate, sampling time and handling of samples in association with the analysis device chosen. The main finding in this thesis is that analyses of glucose, lactate and glycerol in samples from the heart surface and liver surface reflect concentrations sampled from the myocardium and liver parenchyma, respectively.
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| 11. |
- Achour, Cyrinne, 1991-
(author)
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Canonical and non-canonical functions of METTL3 in breast cancer
- 2022
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Doctoral thesis (other academic/artistic)abstract
- Gene expression is spatially and temporally regulated at multiple levels. N6-methyladenosine (m6A) is the most prevalent internal modification in messenger RNA (mRNA) and long noncoding RNA (lncRNAs). m6A plays important roles in multiple cellular processes including stem cell pluripotency, adipogenesis, spermatogenesis, neurogenesis, circadian rhythm and development by modulating RNA splicing, export, stability, degradation and translation. Although aberrant m6A methylation has been reported in various types of cancer, the underlying molecular functions of METTL3, the solely catalytic subunit of the m6A-methylase complex, has yet to be defined.m6A has been recently identified in nascent pre-mRNA, and more specifically intronic m6A has been linked to exon skipping events. The occurrence of impaired alternative splicing (AS) is frequently found during the development of cancer. We performed transcriptome wide analysis in breast cancer cell lines and explored AS events. Our results define an AS signature for breast tumorigenesis. We found that METTL3 modulates AS directly through m6A deposition at the intron-exon junctions or indirectly by the m6A deposition in transcripts encoding for splicing factors and transcription factors. In particular, we show that MYC mRNA harbours the m6A mark, suggesting that METTL3 regulates AS indirectly via the regulation of MYC expression. Indeed, the targets of MYC overlapped with METTL3-associated AS events. Importantly, five of the AS events identified and validated in vitro, are linked to a worse prognosis in breast cancer patients. Additionally, we show that METTL3 enhances the breast cancer phenotype through a dual mechanism depending on its sub-cellular localization. We find that the canonical nuclear function of METTL3 decorates transcripts that are involved in cell proliferation and migration. We observe that METTL3 is highly expressed in the cytoplasmic compartment of breast cancer cells from patients. Remarkably, we uncover that the cytoplasmic METTL3 interacts with subunits of the exocyst, whose subunit EXOC7 has been linked to cell adhesion, migration and invasion. Notably, we show that breast cancer cell lines depleted of METTL3 display less gelatinase activity and invadopodia formation, supporting the role of METTL3 in cell invasion via exocytosis.m6A is a reversible modification, which can be demethylated by the erasers FTO and ALKBH5. Depletion of FTO has been shown to increase the level of m6A in mRNA, however recent studies have reported that FTO could demethylate N6,2´-O-dimethyladenosine (m6Am), adjacent to the 7-methylguanosine cap on mRNA. In the cellular model of colorectal cancer CRC1, depletion of FTO leads to a cancer stem cell phenotype and confers chemotherapy resistance. By performing m6A-RNA immunoprecipitation followed by sequencing (MeRIP), we show that knockdown of FTO in CRC1 cells does not affect the global level of m6A in mRNA but of m6Am level.
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| 12. |
- Adamo, Hanibal Hani, 1984-
(author)
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TINT Tumor Indicating Normal Tissue : new field of diagnostic biomarkers for prostate cancer
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Background: Prostate cancer is the most common cancer in Sweden. Due its highly variable behavior, multifocal nature, and insufficient diagnostic methods, prostate cancer is difficult to diagnose and prognosticate. Some patients have an aggressive lethal disease, but the majority of prostate cancer patients have slow-growing, non-lethal disease with long expected survival without treatment. Current diagnostic methods―serum levels of prostate-specific antigen (PSA) and histological grading of biopsied prostate tissue―often do not give the information required to be able to safely differentiate indolent tumors from potentially lethal ones. Many prostate cancers are difficult to detect by imaging, so tissue biopsy cannot be safely guided towards the tumor, and particularly not towards the most aggressive forms. To overcome this problem, multiple needle biopsies are taken from the organ, but biopsies are small and they sample less than 1% of the whole prostate. In this thesis, we explore the non-malignant prostate tissue adjacent to tumors, which is always sampled in biopsies, and we study adaptive changes in this tissue, which may provide new diagnostic and prognostic markers for prostate cancer. We have therefore proposed that this type of tissue should be termed TINT (Tumor Instructed/indicating Normal Tissue). Methods: In our studies, we used orthotopic rat prostate cancer models with tumors of different aggressiveness. We also used clinical materials from patients diagnosed with prostate cancer at transurethral resection (1975‒1990); the majority of these men were followed with watchful waiting. Analyses were performed with whole-genome expression array, quantitative real-time PCR, immunohistochemistry, and western blotting. Results: Using the animal model, we found that the presence of a tumor induces changes in gene expression in the surrounding tumor-bearing organ (TINT). The gene signature of TINT was linked to processes such as extracellular matrix organization, immune responses, and inflammation. We also showed that some of these adaptive TINT changes appear to be related to the aggressiveness and metastatic potential of the growing tumor, such as increases in macrophages, in mast cells, in vascular densities, and in vascular cell-proliferation. Some of these findings were confirmed by our observations in patient samples. We found that high staining of the extracellular matrix component hyaluronan in the stroma of the non-malignant prostate tissue was prognostic for short cancer-specific survival. We also found that an elevated proportion of C/EBP-beta positive epithelial cells in non-malignant (TINT) prostate tissue was associated with a good prognosis. Conclusions: Using animal experiments and patient samples, we showed that the presence of prostate cancer induces changes in the tumor-bearing organ, alterations associated with tumor aggressiveness, and that grading of these changes in TINT can be used to predict outcome in prostate cancer patients.
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| 13. |
- Adhikari, Deepak, 1978-
(author)
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Signaling pathways in the development of female germ cells
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Primordial follicles are the first small follicles to appear in the mammalian ovary. Women are born with a fixed number of primordial follicles in the ovaries. Once formed, the pool of primordial follicles serves as a source of developing follicles and oocytes. The first aim of this thesis was to investigate the functional role of the intra-oocyte signaling pathways, especially the phosphatidylinositol-3 kinase (PI3K) and mammalian target of rapamycin complex 1 (mTORC1) pathways in the regulation of primordial follicle activation and survival. We found that a primordial follicle remains dormant when the PI3K and mTORC1 signaling in its oocyte is activated to an appropriate level, which is just sufficient to maintain its survival, but not sufficient for its growth initiation. Hyperactivation of either of these signaling pathways causes global activation of the entire pool of primordial follicles leading to the exhaustion of all the follicles in young adulthood in mice. Mammalian oocytes, while growing within the follicles, remain arrested at prophase I of meiosis. Oocytes within the fully-grown antral follicles resume meiosis upon a preovulatory surge of leutinizing hormone (LH), which indicates that LH mediates the resumption of meiosis. The prophase I arrest in the follicle-enclosed oocyte is the result of low maturation promoting factor (MPF) activity, and resumption of meiosis upon the arrival of hormonal signals is mediated by activation of MPF. MPF is a complex of cyclin dependent kinase 1 (Cdk1) and cyclin B1, which is essential and sufficient for entry into mitosis. Although much of the mitotic cell cycle machinery is shared during meiosis, lack of Cdk2 in mice leads to a postnatal loss of all oocytes, indicating that Cdk2 is important for oocyte survival, and probably oocyte meiosis also. There have been conflicting results earlier about the role of Cdk2 in metaphase II arrest of Xenopus oocytes. Thus the second aim of the thesis was to identify the specific Cdk that is essential for mouse oocyte meiotic maturation. We generated mouse models with oocytespecific deletion of Cdk1 or Cdk2 and studied the specific requirements of Cdk1 and Cdk2 during resumption of oocyte meiosis. We found that only Cdk1 is essential and sufficient for the oocyte meiotic maturation. Cdk1 does not only phosphorylate the meiotic phosphoproteins during meiosis resumption but also phosphorylates and suppresses the downstream protein phosphatase 1, which is essential for protecting the Cdk1 substrates from dephosphorylation.
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| 14. |
- Adjeiwaah, Mary, 1980-
(author)
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Quality assurance for magnetic resonance imaging (MRI) in radiotherapy
- 2017
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Licentiate thesis (other academic/artistic)abstract
- Magnetic resonance imaging (MRI) utilizes the magnetic properties of tissues to generate image-forming signals. MRI has exquisite soft-tissue contrast and since tumors are mainly soft-tissues, it offers improved delineation of the target volume and nearby organs at risk. The proposed Magnetic Resonance-only Radiotherapy (MR-only RT) work flow allows for the use of MRI as the sole imaging modality in the radiotherapy (RT) treatment planning of cancer. There are, however, issues with geometric distortions inherent with MR image acquisition processes. These distortions result from imperfections in the main magnetic field, nonlinear gradients, as well as field disturbances introduced by the imaged object. In this thesis, we quantified the effect of system related and patient-induced susceptibility geometric distortions on dose distributions for prostate as well as head and neck cancers. Methods to mitigate these distortions were also studied.In Study I, mean worst system related residual distortions of 3.19, 2.52 and 2.08 mm at bandwidths (BW) of 122, 244 and 488 Hz/pixel up to a radial distance of 25 cm from a 3T PET/MR scanner was measured with a large field of view (FoV) phantom. Subsequently, we estimated maximum shifts of 5.8, 2.9 and 1.5 mm due to patient-induced susceptibility distortions. VMAT-optimized treatment plans initially performed on distorted CT (dCT) images and recalculated on real CT datasets resulted in a dose difference of less than 0.5%. The magnetic susceptibility differences at tissue-metallic,-air and -bone interfaces result in local B0 magnetic field inhomogeneities. The distortion shifts caused by these field inhomogeneities can be reduced by shimming. Study II aimed to investigate the use of shimming to improve the homogeneity of local B0 magnetic field which will be beneficial for radiotherapy applications. A shimming simulation based on spherical harmonics modeling was developed. The spinal cord, an organ at risk is surrounded by bone and in close proximity to the lungs may have high susceptibility differences. In this region, mean pixel shifts caused by local B0 field inhomogeneities were reduced from 3.47±1.22 mm to 1.35±0.44 mm and 0.99±0.30 mm using first and second order shimming respectively. This was for a bandwidth of 122 Hz/pixel and an in-plane voxel size of 1×1 mm2. Also examined in Study II as in Study I was the dosimetric effect of geometric distortions on 21 Head and Neck cancer treatment plans. The dose difference in D50 at the PTV between distorted CT and real CT plans was less than 1.0%.In conclusion, the effect of MR geometric distortions on dose plans was small. Generally, we found patient-induced susceptibility distortions were larger compared with residual system distortions at all delineated structures except the external contour. This information will be relevant when setting margins for treatment volumes and organs at risk. The current practice of characterizing MR geometric distortions utilizing spatial accuracy phantoms alone may not be enough for an MR-only radiotherapy workflow. Therefore, measures to mitigate patient-induced susceptibility effects in clinical practice such as patient-specific correction algorithms are needed to complement existing distortion reduction methods such as high acquisition bandwidth and shimming.
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| 15. |
- af Bjerkén, Sara, 1979-
(author)
-
On dopamine neurons : nerve fiber outgrowth and L-DOPA effects
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Parkinson’s disease is a disorder mainly characterized by progressive degeneration of dopamine producing neurons in the substantia nigra of the midbrain. The most commonly used treatment strategy is to pharmacologically restore the lost function by the administration of the dopaminergic precursor L-DOPA. Another treatment strategy is to replace the degenerated neurons with immature fetal ventral mesencephalic tissue, or ultimately stem cell-derived tissue. Grafting trials have, however, revealed poor reinnervation capacity of the grafts, leaving much of the striata dopamine-denervated. An additional drawback is the upcoming of dyskinesia (involuntary movements), a phenomenon also observed during L-DOPA treatment of Parkinson’s disease patients. Attempts to characterize nerve fiber formation from dopamine neurons have demonstrated that the nerve fibers are formed in two morphologically diverse outgrowth patterns, one early outgrowth seen in the absence of astrocytes and one later appearing outgrowth seen in co-existence with astrocytes. The overall objective of this thesis has been to study the dopaminergic outgrowth including guidance of nerve fiber formation, and to look into the mechanisms of L-DOPA-induced dyskinesia. The first paper in this thesis characterizes the different outgrowth patterns described above and their relation to different glial cells. The study demonstrated the two different outgrowth patterns to be a general phenomenon, applying not only to dopamine neurons. Attempts of characterization revealed no difference of origin in terms of dopaminergic subpopulations, i.e. A9 or A10, between the outgrowth patterns. Furthermore, the “roller-drum” technique was found optimal for studying the dual outgrowth sequences. The second and the third paper also utilized the “roller-drum” technique in order to promote both patterns of neuronal fiber formation. The effects of glial cell line-derived neurotrophic factor (GDNF) on the formation of dopamine nerve fibers, was investigated. Cultures prepared from gdnf knockout mice revealed that dopaminergic neurons survive and form nerve fiber outgrowth in the absence of GDNF. The dopaminergic nerve fibers exhibited an outgrowth pattern consistent with that previous observed in rat. GDNF was found to exert effect on the glial-associated outgrowth whereas the non-glial-associated was not affected. Astrocytic proliferation was inhibited using cytosine β-D-arabinofuranoside, resulting in reduced glial-associated outgrowth. The non-glial-associated dopaminergic outgrowth was on the other hand promoted, and was retained over longer time in culture. Furthermore, the non-glial-associated nerve fibers were found to target the fetal frontal cortex. Different developmental stages were shown to promote and affect the outgrowths differently. Taken together, these data indicate and state the importance of astrocytes and growth factors for neuronal nerve fiber formation and guidance. It also stresses the importance of fetal donor age at the time for transplantation. The fourth and fifth studies focus on L-DOPA dynamics and utilize in vivo chronoamperometry. In study four, 6-OHDA dopamine-depleted rats were exposed to chronic L-DOPA treatment and then rated as dyskinetic or non-dyskinetic. The electrochemical recordings demonstrated reduced KCl-evoked release in the intact striatum after chronic L-DOPA treatment. Time for maximal dopamine concentration after L-DOPA administration was found to be shorter in dyskinetic animals than in non-dyskinetic animals. The serotonergic nerve fiber content in the striatum was evaluated and brains from dyskinetic animals were found to exhibit significantly higher nerve fiber density compared to non-dyskinetic animals. Furthermore, the mechanisms behind the conversion of L-DOPA to dopamine in 6-OHDA dopamine-depleted rats were studied. Local administration of L-DOPA in the striatum increased the KCl-evoked dopamine release in the intact striatum. Acute application of L-DOPA resulted sometimes in a rapid conversion to dopamine, probably without vesicle packaging. This type of direct conversion is presumably occurring in non-neuronal tissue. Furthermore, KCl-evoked dopamine releases were present upon local application of L-DOPA in the dopamine-depleted striatum, suggesting that the conversion to dopamine took place elsewhere, than in dopaminergic nerve fibers. In conclusion, these studies state the importance of astrocytes for neuronal nerve fiber formation and elucidate the complexity of L-DOPA conversion in the brain.
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| 16. |
- Ahlm, Kristin, 1956-
(author)
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Traffic and drowning incidents with emphasis on the presence of alcohol and drugs
- 2014
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Doctoral thesis (other academic/artistic)abstract
- Worldwide, fatal traffic injuries and drowning deaths are important problems. The aim of this thesis was to investigate the cirumstances of fatal and non-fatal traffic injuries and drowning deaths in Sweden including analysis of the presence of alcohol and drugs, which are considered to be major risk factors for these events. Data where obtained from the database of National Board of Forensic Medicine.In the first study, we investigated 420 passenger deaths from 372 crashes during 1993-1996. There were 594 drivers involved. In total, 21% of the drivers at fault were alcohol positive compared to 2% of drivers not at fault (p<0.001) (Paper I). During 2004-2007, crashes involving 56 fatally and 144 non-fatally injured drivers were investigated in a prospective study from Northern Sweden (Paper II). The drivers were alcohol positive in 38% and 21%, respectively. Psychoactive drugs were found in 7% and 13%, respectively. Benzodiazepines, opiates and antidepressants were the most frequent drugs found in drivers. Illict drugs were found 9% and 4% respectively, with tetrahydrocannabinol being the most frequent of these drugs (Paper II).We investigated 5,125 drowning deaths in Sweden during 1992-2009 (Paper III). The incidence decreased on average by about 2% each year (p<0.001). Unintentional drowning was most common (50%). Alcohol was found in 44% of unintentional, 24% of intentional, and 45% of undetermined drowning deaths. Psychoactive substances were detected in 40% and benzodiazepines were the most common substance. Illicit drugs were detected in 10%. Of all drowning deaths, a significantly higher proportion females commited suicide compared with males (55% vs. 21%, p<0.001). Suicidal drowning deaths (n=129) in Northern Sweden were studied further in detail (Paper IV). of these, 53% had been hospitalized due to a psychiatric diagnosis within five years prior to the suicide. Affective and psychotic disorders were the most common psychiatric diagnoses. Almost one third had performed a previous suicide attempt. One fourth had committed suicide after less than one week of discharge from hospital. Alochol was found in 16% and psychoactive drugs in 62% of these cases, respectively. In conclusion, alcohol and psychoactive drugs are commonly detected among injured drivers and drowning victims, and probably play a role in these events. Most of the individuals that tested positive for alcohol and high blood concentrations, indicating alochol dependence or abuse. This association warrants futher attention when planning future prevention.
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| 17. |
- Ahmed Hassan Ahmed, Osama, 1972-
(author)
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Rift Valley fever : challenges and new insights for prevention and control using the “One Health” approach
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Rift Valley fever (RVF) is an emerging viral zoonosis that causes frequent outbreaks in east Africa and on the Arabian Peninsula. The likelihood of RVF global expansion due to climate change and human anthropogenic factors is an important issue. The causative agent, RVF virus, is an arbovirus that is transmitted by several mosquito species and is able to infect a wide range of livestock as well as people. The infection leads to mass abortions and death in livestock and a potentially deadly hemorrhagic fever in humans. RVF has severe socio-economic consequences such as animal trade bans between countries, disruption of food security, and economic disaster for farmers and pastoralists as well as for countries. Human behavior such as direct contact with infected animals or their fluids and exposure to mosquito bites increases the risk for contracting the disease.To better understand the challenges associated with RVF outbreaks and to explore prevention and control strategies, we used the One Health approach. The local community had to be involved to understand the interaction between the environment, animals, and humans. We focused on Sudan, Saudi Arabia, and Kenya. First, we systematically reviewed the literature and then we performed cross sectional community-based studies using a special One Health questionnaire. Climatic and remote sensing data were used in combination with statistics to develop a sub-region predictive model for RVF.For both Saudi Arabia and Sudan, the ecology and environment of the affected areas were similar. These areas included irrigation canals and excessive rains that provide an attractive habitat for mosquito vectors to multiply. The surveillance systems were unable to detect the virus in livestock before it spread to humans. Ideally, livestock should serve as sentinels to prevent loss of human lives, but the situation here was reversed. Differences between countries regarding further spread of RVF was mainly determined by better economic and infrastructure resources.In Sudan, there was a lack of knowledge and appropriate practices at the studied community regarding RVF disease symptoms and risk factors for both animals and humans. The community was hesitant in notifying the authorities about RVF suspicion in livestock due to the lack of a compensation system. The perceived role of the community in controlling RVF was fragmented, increasing the probability of RVF transmission and disease.In Kenya, our study found that better knowledge about RVF does not always translate to more appropriate practices that avoid exposure to the disease. However, the combination of good knowledge, attitudes, and practices may explain why certain communities were less affected. Strategies to combat RVF should consider socio-cultural and behavioral differences among communities. We also noticed that RVF outbreaks in Kenya occurred in regions with high livestock density exposed to heavy rains and wet soil fluxes, which could be measured by evapotranspiration and vegetation seasonality variables. We developed a RVF risk map on a sub-regional scale. Future outbreaks could be better managed if such relevant RVF variables are integrated into early warning systems.To confront RVF outbreaks, a policy is needed that better incorporates ecological factors and human interactions with livestock and environment that help the RVF pathogen spread. Early detection and notification of RVF is essential because a delay will threaten the core of International Health Regulations (IHR), which emphasizes the share of information during a transboundary disease outbreak to avoid unnecessary geographical expansion.
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| 18. |
- Al-Alawi, Kamila, 1974-
(author)
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Team-based approach in the management of diabetes at primary health care level in Muscat, Oman : challenges and opportunities
- 2019
-
Doctoral thesis (other academic/artistic)abstract
- Introduction: The growth of type 2 diabetes is considered an alarming epidemic in Oman. The efficient team-based approach to diabetes management in primary health care is an essential component for providing ideal diabetic care. This thesis aimed to explore the current situation related to team-based management of type 2 diabetes in public Primary Health Care Centres (PHCCs) under the Ministry of Health (MOH) in Oman, including the various challenges associated with diabetes management and the most preferable Human Resources for Health (HRH) management mechanism, and to examine how this could be optimized from provider and patient perspectives.Materials and methods: The entire project was conducted in Muscat Governorate and was based on one quantitative and three qualitative studies. In the quantitative study, 26 public PHCCs were approached through cross-sectional study. The core diabetes management team recommended by the MOH for PHCCs in Oman was explored in terms of their competencies, values, skills, and resources related to the team-based approach to diabetes management. For the qualitative studies, five public purposely-selected PHCCs were approached. The diabetes consultations conducted by the core members and other supportive members involved in diabetes management were observed and later the Primary Health Care Providers (PHCPs) were interviewed. The different approaches explored challenges related to diabetes management and the most preferable HRH mechanism by PHCPs. Seven type 2 diabetes patients with different gender, employment status, and education were consequently interviewed to explore their perceptions towards the current diabetes management service and their opinions towards nurse-led clinics.Results: The survey provided significant and diverse perceptions of PHCPs towards their competencies, values, skills, and resources related to diabetes management. Physicians considered themselves to have better competencies than nurses and dieticians. Physicians also scored higher on team-related skills and values compared with health educators. In terms of team-related skills, the difference between physicians and nurses was statistically significant and showed that physicians perceived themselves to have better skills than nurses. Confusion about the leadership concept among PHCPs with a lack of pharmacological, technical, and human resources was also reported. The observations and interviews with PHCPs disclosed three different models of service delivery at diabetes management clinics. The challenges explored involved PHCCs’ infrastructure, nurses’ knowledge, skills, and non-availability of technical and pharmaceutical support. Other challenges that evolved into the community were cultural beliefs, traditions, health awareness, and public transportation. Complete implementation of task-sharing mechanisms within the team-based approach was selected by all PHCPs as the most preferable HRH mechanism. The selection was discussed in the context of positive outcomes, worries, and future requirements. The physicians stated that nurses’ weak contribution to the team within the selected mechanism could be the most significant aspect. Other members supported the task-sharing mechanism between physicians and nurses. However, type 2 diabetes patients’ non-acceptance of a service provided by the nurses created worries for the nurses. The interviews with type 2 diabetes patients disclosed positive perceptions towards the current diabetes management visits; however, opinions towards nurse-led clinics varied among the patients.Conclusions and recommendations: The team-based approach at diabetes management clinics in public PHCCs in Oman requires thoughtful attention. Diverse presence of the team members can form challenges during service delivery. Clear roles for team members must be outlined through a solid HRH management mechanism in the context of a sharp leadership concept. Nurse-led clinics are an important concept within the team; however, their implementation requires further investigation. The concept must involve clear understandings of independence and interdependence by the team members, who must be educated to provide a strong gain for team-based service delivery.
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| 19. |
- Al-Amiry, Bariq, 1976-
(author)
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Radiological measurements in total hip arthroplasty
- 2018
-
Doctoral thesis (other academic/artistic)abstract
- Every year, about 1 million patients worldwide and 20000 patients in Sweden undergo total hip arthroplasty (THA). This type of operation is considered a successful, safe and cost-effective procedure to regain mobility and restore hip joint function in patients suffering from severe hip joint disease or trauma. The main goals of the operation are to relief the pain, improve quality of life (QoL) and to restore the biomechanical forces around the hip with appropriate femoral offset (FO), leg length and proper component position and orientation. The radiographic preoperative planning and postoperative evaluation of these parameters require good validity, interobserver reliability and intraobserver reproducibility. Most patients are satisfied after THA, although this treatment still has its complications. About 10 % of THA patients report persistent pain and suboptimal functional outcome and QoL at long-term follow-up. The absolute number of dissatisfied patients is expected to rise given the increase in the annual number of THA performed. Therefore, every effort should be made to investigate factors that possibly influence THA outcome. The data available about the influence of preoperative radiological severity and symptom duration of OA on the outcome of THA are scarce and contradictory. Further studies even needed to evaluate the effect of obesity on post-operative THA radiological measurements
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| 20. |
- Alanentalo, Tomas, 1978-
(author)
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Optical projection tomography based 3D-spatial and quantitative assessments of the diabetic pancreas
- 2008
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Doctoral thesis (other academic/artistic)abstract
- The gastrointestinal tract comprises a number of digestive organs including the stomach and pancreas. The stomach is involved in the digestion and short term storage of food while the pancreas is a mixed endocrine and exocrine gland which provides the body with hormones and enzymes essential for nutritional utilisation. The pancreas consists of three different cell lineages, acinar, ductal and endocrine cells. The endocrine cells, organised in the islets of Langerhans, are scattered throughout the exocrine parenchyma and regulate blood glucose levels by production of hormones such as glucagon and insulin. The Nkx family of homeodomain proteins controls numerous processes during development. Previous studies have identified two members belonging to the Nkx6 subfamily of Nkx proteins, Nkx6.1 and Nkx6.2. We have described the cloning and embryonic expression pattern of Nkx6.3. All three members of the Nkx6 gene family were shown to be expressed in partially overlapping domains during the development of the gastrointestinal tract and the central nervous system. Nkx6.2 was also identified as a transient marker for pancreatic exocrine cells. Analysing gene expression patterns and morphological features in tissues and organs is often performed by stereologic sampling which is a labour-intensive two dimensional approach that rely on certain assumptions when calculating e.g. β-cell mass and islet number in the pancreas. By combined improvements in immunohistochemical protocols, computational processing and tomographic scanning, we have developed a methodology based on optical projection tomography (OPT) allowing for 3D visualisation and quantification of specifically labelled objects within intact adult mouse organs. In the pancreas, this technique allows for spatial and quantitative measurements of total islet number and β-cell mass. We have further developed a protocol allowing for high resolution regional analyses based on global OPT assessments of the pancreatic constitution. This methodology is likely to facilitate detailed cellular and molecular analysis of user defined regions of interest in the pancreas, at the same time providing information on the overall disease state of the gland. Type 1 diabetes mellitus (T1D) can occur at any age and is characterized by the marked inability of the pancreas to secrete insulin due to an autoimmune destruction of the insulin producing β-cells. Information on the key cellular and molecular events underlying the recruitment of lymphocytes, their infiltration of the islets of Langerhans and consequent β-cell destruction is essential for understanding the pathogenesis of T1D. Using the developed methodology we have recorded the spatial and quantitative distribution of islet β-cells and infiltrating lymphocytes in the non obese diabetic (NOD) mouse model for T1D. This study shows that the smaller islets, which are predominantly organised in the periphery of the organ, are the first to disappear during the progression of T1D. The larger islets appear more resistant and our data suggest that a compensatory proliferative process is going on side by side with the autoimmune-induced β-cell destruction. Further, the formation of structures resembling tertiary lymphoid organs (TLOs) in areas apparently unaffected by insulitis suggests that local factors may provide cues for the homing of these lymphocytes back to the pancreas.
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| 21. |
- Albertsson, Pontus, 1958-
(author)
-
Occupant casualties in bus and coach traffic : injury and crash mechanisms
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Background: The relevance of conducting this thesis is evident by the fact that bus and coach casualties have been “stubbornly stable” in Europe recent years and a need for investigating if a similar trend could be found in Sweden is therefore obvious. It was also important to add new knowledge to the bus and coach research in Sweden, since many areas were scarcely addressed. Aims: To describe bus and coach occupants’ injuries, crash and injury mechanisms generated in a traffic environment based on data from the medical sector. Additional aims were to investigate the injury reducing effect of a 3-point belt, the effect of cross-winds, and crucial factors in the emergency- and rescue response. Material and methods: Injury data analyses were based on a complete ten-year medical data set from a catchment-area with about 130,000 inhabitants. A number of crash studies with the scope in different crash phases were conducted by applying and elaborating the Haddon matrix as a framework. An additional framework, Protocol for Major Incidents was used in order to investi-gate the emergency- and rescue response to a severe coach crash. Results: Between the first and second five-year period, the incidence of injured in non-crash in-cidents was increased by 24%. In non-crash incidents, 54% were injured; 2/3 while alighting from a bus or coach. The pre-crash factor cross-wind, in addition to vehicle design, vehicle speed and road friction, was investigated in ten crashes. It was confirmed that cross-wind, in relation to vehicle speed and slippery road conditions, needs more attention. The importance of goods load-ing and passengers’ position in the bus, was indicated by the fact that a displacement of the cen-tre of mass rearwards with 10% increased the necessary coefficient of friction with, on average 45%, which in many cases corresponded to dry road conditions. Three Swedish rollover crashes were analysed with regard to the injury outcome, mechanisms and the possible injury reduction for occupants using a safety belt. A considerable increase in safety for occupants belted with 3-point belts was shown through limiting interior contacts, occupant interaction and the possibility of ejection. Crucial post-crash factors in the emergency- and rescue response showed that ordi-nary ways of working and equipment are not always useful and proper equipment for lifting a coach body is essential in the case of a rollover. Finally, the communication between the hospitals is important, and the telephone systems may be overloaded by calls from worried relatives and media. Conclusions: In non-crash events: Non-crash events constitute a majority of all bus and coach casualties with a high proportion of elderly female occupants among the MAIS 2+ injury cases. Boarding and, especially alighting causes many injuries to the lower extremities. In the pre-crash phase: Cross-winds do affect the safety of buses and coaches and requires more at-tention. Seat belt usage among bus and coach occupants has to be increased. In the crash phase: Rollover and ejection are the major causes behind serious and fatal injuries to bus and coach occupants, consequently, retentive glazing, pillars or rails need more attention. An upgrade from 2-point seat belts to 3-point seat belts yields an increase in the estimated injury re-duction from approximately 50% up to 80% for the MAIS 2+ casualties in a rollover crash. In the post-crash phase: In order to be able to lift a coach body proper equipment originated from experience and development is essential in a rescue operation of a crashed bus or coach. Fur-thermore, to improve the emergency response inside crashed coaches proper methods originated from experience need to be developed. Euro NBAP: Based on the results and conclusions generated in this thesis, a European New Bus and Coach Assessment Programme is suggested, which would provide bus and coach occupants with a assessment programme similar to the Euro NCAP.
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| 22. |
- Alenius Dahlqvist, Jenny, 1972-
(author)
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Heart rate variability and pacemaker treatment in children with Fontan circulation
- 2019
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Doctoral thesis (other academic/artistic)abstract
- Background: Fontan surgery is performed in children with univentricular heart defects. Arrhythmias are frequent complications, occasionally requiring pacemaker treatment. Previous data regarding indications and risk factors for pacemaker treatment in Fontan patients is limited and conflicting. Heart rate variability (HRV) reflects autonomous nervous activity controlling the sinus node and has been associated with tachyarrhythmias in both adults and children, as well as in adults with sinus node dysfunction (SND).Aim: To study HRV, arrhythmia and pacemaker treatment in children with Fontan circulation— with the purpose of contributing to the reduction of long term complications in this patient group.Methods: We have retrospectively reviewed pacemaker therapy in all Swedish patients who underwent Fontan surgery from 1982 to 2017 (n=599). We have also analysed HRV from 24-hour Holter ECG recordings in 112 children with Fontan circulation and in children with univentricular heart defects before bidirectional Glenn (BDG) procedure (n=47), before and on completion of Fontan surgery (n=47 and 45 respectively). Analysis was performed by power spectral analysis and Poincaré method, and results compared with healthy controls. Furthermore, HRV was analysed in Fontan patients who later required a pacemaker due to severe SND. Results were compared with Fontan patients who had SND, without indication for pacemaker treatment, with patients with Fontan circulation without SND and healthy controls. In addition we evaluated the possibility to analyse arrhythmias and HRV in 27 Fontan children using intermittent ECG recordings with a handheld devices at home during a 14-day period.Results: After a mean follow-up of 12 years, 13% (78/599) of patients with Fontan circulation had received a pacemaker. Patients operated with the extracardiac conduit (EC) had a significantly lower prevalence of pacemaker implantation (6%) than patients with a lateral tunnel (LT) (17%). The most common pacemaker indication in patients with Fontan circulation was SND (64%). Children with Fontan circulation showed significant reductions in several HRV parameters, compared with controls. No significant differences were found between patients operated with LT versus EC (paper I). After BDG the RR interval and SD2 (representing changes in heart rate over 24-hours) significantly increased compared to pre-BDG. Compared with healthy controls, patients post-BDG, had significantly longer RR intervals and reduced overall HRV. PHF (reflecting parasympathetic control of the heart) was significantly reduced after TCPC as compared to before (paper II). Fontan patients with SND showed significantly elevated SD2 (representing changes in heart rate over 24-hours), somewhat reduced in patients that later required a pacemaker (Paper V). Handheld ECG analysis revealed frequent ventricular extra systoles in one patient and episodes of supraventricular tachycardia in another. Seven Fontan patients showed reduced HRV recorded with the handheld device over a 14-day period (paper III).Conclusions: Overall HRV was reduced in patients with univentricular heart defects during the different surgical stages of Fontan surgery, compared to healthy controls. HRV was reduced in both patients with LT and EC with no significant difference between them. After BDG heart rate was significantly reduced as compared to before. PHF, reflecting the parasympathetic innervation of the heart was reduced after as compared to before TCPC. Pacemaker treatment is commonly needed in patients with Fontan circulation, and SND was the most prevalent indication for implantation. The prevalence of Fontan patients requiring pacemaker treatment was significantly lower in patients with EC. HRV analysis can contribute to management when following-up patients with Fontan circulation.
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| 23. |
- Alenius, Gerd-Marie, 1957-
(author)
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A Clinical and Genetic Study of Psoriatic Arthritis
- 2003
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Doctoral thesis (other academic/artistic)abstract
- Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. PsA has a heterogeneous pattern, expressed by different manifestations such as mild mono-oligoarthritis or very severe, erosive and destructive polyarthritis. Measurable inflammatory activity is not always prominent. The aetiology is unknown but genetic factors are believed to be of importance. The pattern of inheritance is proposed to be polygenic. The aim of this study was to estimate the prevalence of joint and axial manifestations, characterise the disease in relation to inflammatory and genetic markers, and to identify disease susceptibility gene(s) for PsA in patients from northern Sweden. All patients from the city of Umeå (n=276), selected from a community and hospital based psoriasis register (n=1737) at the Dept of Dermatology, were invited to a prevalence study. Two hundred-two patients were examined and 97 (48%) had inflammatory manifestations such as peripheral arthritis, axial disease, undifferentiated spondylarthropathy (uSpA) and enthesopathies. Of the 67 patients (33 %) with peripheral arthritis and/or axial disease, 30 were not previously diagnosed. The association of clinical manifestations and potential markers of aggressive joint disease with HLA associations were analysed in 88 patients with PsA. We were not able to confirm findings of other groups reporting strong association with several HLA-antigens. The prevalence of HLA-B17, B37 and B62 was increased compared with controls, but the strongest predictive factors among our patients for an aggressive disease, in a multiple logistic analysis, were polyarthritic disease and distal interphalangeal engagement. In order to investigate for disease susceptibility genes, five genetic loci were analysed with microsatellites and single nucleotide polymorphisms in an association study of 120 patients with PsA. There was a significant association with the TNFB locus on chromosome 6p but not with any other loci examined; 1q21 (PSORS4), 3q21 (PSORS5), 8q24 and CTLA4. When stratifying for the TNFB alleles the association was confined to allele 123. In a subgroup of patients who were HLA-typed (n=83), we were not able to verify linkage disequilibrium with the TNFB allele 123 and the HLA antigens; B17, B27, B37, B62 or Cw*0602. The presence of renal abnormalities was evaluated as a manifestation of systemic inflammation in 73 patients with PsA. Renal abnormalities defined as decreased creatinine-clearance (≤ mean - 2SD) and/or urinary albumin >25 mg/24 h was found in 23% of the patients. The predictive factors for renal abnormalities was inflammatory activity (ESR > 25 mm/h and/or CRP >15 mg/L) indicating a systemic effect in some of the patients. In conclusion, we found high prevalence of inflammatory manifestations in patients with psoriasis. There was no strong association between PsA and HLA antigens and predictive factors for aggressive disease were polyarthritic disease and DIP joint engagement. The TNFB locus was associated with PsA and there were no linkage disequilibrium with the HLA antigens B17, B27, B62 or Cw*0602. There were evidence for systemic effects as renal abnormalities in patients with PsA and measurable inflammatory activity.
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| 24. |
- Aléx, Lena
(author)
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Äldre människors berättelser om att bli och vara gammal tolkade utifrån genus- och etnicitetsperspektiv
- 2007
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Doctoral thesis (other academic/artistic)abstract
- The overall aim of the five studies that make up this thesis is to elucidate constructions of being old from the perspectives of gender and ethnicity. One of the studies uses quantitative data and four use qualitative data.The sample in study I consisted of 125 participants from the Umeå 85+ study, aged 85 to 103 years old, who were able to use Likert scales in responding to questions. Studies II and III involved content analysis of interviews with old persons scoring on the extremes of the resilience scale. In study IV, interviews with nine Sami women were analysed using grounded theory. In study V, four interview situations were subjected to discourse analysis.Study I showed statistically significant correlations between the scales measuring resilience, sense of coherence, purpose in life and self-transcendence. These scales were supposed to measuring a common dimension, which is here interpreted as “inner strength”. There was a significant correlation between women’s “inner strength” and perceived mental health.The femininities found were associated with “being connected”, “being an actor”, “living in the shadow of others” and “being alienated”. The masculinities found were associated with “being in the male centre”, “striving to maintain the male facade” and “being related”. The femininity associated with “being an actor” and the masculinity associated with “being in the male centre” were pronounced in those participants assessed as having high resilience.Old Sami woman were found to be balancing within various discourses, including being a reindeer owner versus not owning reindeer, being Sami versus being Swedish, speaking in Sami versus speaking in Swedish, dreaming about the past versus looking to the future, being equal to men versus living in the shadow of the male herders, and changing for survival versus striving to retain uniqueness as a Sami.Study V revealed that shifts in power between the interviewer and the interviewed can be related to the discourses of age, gender, education, body, ethnicity and ideology.This thesis presents a complex picture of what it means to be among the oldest old. The ageing, gendered and ethicised selves cannot be seen as socially and culturally fixed. For the women, the femininity expressed in “being connected” involved being satisfied, content and having positive relationships. “Being an actor” involved a stress on the person’s own strength and own choices. The femininities experienced as “living in the shadow of others” and “being alienated” generated narratives about dissociation and loneliness. For the men, it seemed important to relate to themselves and to other men. However, the masculinity expressed in “being related” involved an alternative form of masculinity, focusing on the importance of daily work, new relationships, and reflecting on the meaning of life. The Sami women showed strength in being able to position themselves between various discourses, but their narratives also showed tender sadness when they spoke of their longing for the past and for their mother tongue. The reflection on how narratives are constructed by both the interviewed and the interviewer in relation to their access to various discourses of age, gender, education, ethnicity and ideology in different interview situations can be important for increasing awareness of the role of these discourses. Various ways of constructing femininities and masculinities must be studied if we are to avoid ageism developing in society. Analyzing and reflecting on the importance of age, gender and ethnicity from a constructivist perspective may reduce stereotypical descriptions of the oldest old.
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| 25. |
- Aliashkevich, Alena, 1990-
(author)
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Molecular mechanisms and biological consequences of the production of non-canonical D-amino acids in bacteria
- 2021
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Doctoral thesis (other academic/artistic)abstract
- Most bacteria possess a vital net-like macromolecule – peptidoglycan (PG). PG encases bacteria around the cytoplasmic membrane to withstand the high internal turgor pressure and thereby protect the cell from bursting. In addition, PG is a major morphological determinant of bacteria being both required and sufficient to maintain cell shape. During cell growth PG hydrolysis and synthesis are tightly controlled to keep proper cell shape and integrity at all times. Given the essentiality of PG for bacterial growth and survival, the synthesis of this polymer is a major target of many natural and synthetic antibiotics (e.g. penicillins, glycopeptides).For a long time, PG composition was considered to be conserved and static, however it’s now being recognized as a dynamic and plastic macromolecule. The structure and chemistry of PG is influenced by a myriad of environmental cues that include interkingdom/interspecies interactions. Recently, it was found that a wide set of non-canonical D-amino acids (D-amino acids different from D-Ala and D-Glu, NCDAAs) are produced and released to the extracellular milieu by diverse bacteria. In Vibrio cholerae these NCDAAs are produced by broad-spectrum racemase enzyme (BsrV) and negatively regulate PG synthesis through their incorporation into PG. We have shown that in addition to D-Met and D-Leu, which were reported previously, V. cholerae also releases high amounts of D-Arg, which inhibits a broader range of phylogenetically diverse bacteria. Thus, NCDAAs affect not only the producer, but might target other species within the same environmental niche. However, in contrast to D-Met, D-Arg targets cell wall independent pathways. We have shown that non-proteinogenic amino acids also can be racemized by Bsr. A plant amino acid L-canavanine (L-CAN) is converted into D-CAN by a broad-spectrum amino acid racemase (BSAR) of the soil bacterium Pseudomonas putida and subsequently released to the environment. D-CAN gets highly incorporated into the PG of Rhizobiales (such as Agrobacterium tumefaciens, Sinorhizobium meliloti) thereby affecting the overall PG structure, bacterial morphogenesis and growth fitness. We found that detrimental effect of D-CAN in A. tumefaciens can be suppressed by a single amino acid substitution in the cell division PG transpeptidase penicillin-binding protein 3a (PBP3a). Rhizobiales are a polar-growing species that encode multiple LD-transpeptidases (LDTs), enzymes that normally perform PG crosslinking, but that can also incorporate NCDAAs into termini of the PG peptides. As these species incorporate high amounts of D-CAN in their PG, we hypothesized that LDTs might represent the main path used by NCDAAs to edit A. tumefaciens’ PG and cause their detrimental effects. Therefore, we decided to further explore the significance of LDT proteins for growth and morphogenesis in A. tumefaciens. While in the Gram-negative model organism E. coli LDT proteins are non-essential under standard laboratory conditions, we found that A. tumefaciens needs at least one LDT for growth out of the 14 putative LDTs encoded in its genome. Moreover, clustering the LDT proteins based on their sequence similarity revealed that A. tumefaciens has 7 LDTs that are exclusively present among Rhizobiales. Interestingly, the loss of this group of LDTs (but not the rest) leads to reduced growth, lower PG crosslinkage and rounded cell phenotype, which suggests that this group of Rhizobiales- specific LDTs have a major role in maintaining LD-crosslinking homeostasis, which in turn is important for cell elongation and proper shape maintenance in A. tumefaciens.
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| 26. |
- Alvehus, Malin, 1975-
(author)
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Obesity-associated inflammation in adipose tissue
- 2012
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Doctoral thesis (other academic/artistic)abstract
- Background: Excess body fat, particularly in the visceral depot, is linked to increased mortality and morbidity, including the development of diseases such as type 2 diabetes, cardiovascular disease, and cancer. Chronic low-grade inflammation in adipose tissue may be a key mediator of obesity-associated diseases. Importantly, specific pro-inflammatory cytokines have been shown to influence adipose tissue function and could therefore be a link to metabolic disorders. Circulating cytokine levels may also be increased in obesity and metabolic diseases. However, although fat distribution and inflammation are clearly linked to metabolic disorders, inflammatory gene expression in the different abdominal adipose depots has not been investigated in detail. The menopausal transition is followed by a centralization of body fat and increased adiposity. Notably, inflammatory changes in fat during the menopausal transition have not been characterized. Finally, there is a lack of studies investigating the long-term effects of weight loss on low-grade inflammation. The aim of this thesis was to characterize differences between fat depots and investigate putative changes in low-grade inflammation in adipose tissue and circulation following menopause or weight loss. Materials & Methods: The expression of inflammation-related genes was investigated in abdominal adipose tissue depots obtained from women with varying adiposity, before and after menopause or weight loss induced by surgery or dietary intervention. Circulating cytokine levels were analyzed using immunoassays. Results: Visceral fat displayed a distinct and adverse inflammatory profile compared with subcutaneous adipose tissues, and the higher gene expression in visceral fat was associated with adiposity. Postmenopausal women exhibited a higher expression of pro-inflammatory genes than premenopausal women that associated with central fat accumulation. There was also a menopause-related increase in circulating cytokine levels in postmenopausal women. After surgery-induced weight loss, there was a dramatic reduction in inflammatory gene expression followed by increased insulin sensitivity. We observed no alterations in circulating cytokine levels. Long-term dietary intervention, associated with weight loss, had favorable effects on inflammation in both adipose tissue and serum. Conclusion: Fat accumulation is linked to low-grade inflammation in abdominal adipose tissue. The unique inflammatory pattern of visceral fat suggests a distinct role in adipose tissue inflammation that is aggravated with increasing adiposity. In postmenopausal women, the adverse adipose inflammatory profile was associated with central fat accumulation, while higher circulating cytokine levels correlated with menopausal state/age. Our data from severely obese women undergoing surgery-induced weight loss clearly supports a link between adipose inflammation and insulin resistance. The long-term beneficial effects of weight loss were also demonstrated by the improved inflammatory profile after dietary intervention. In summary, excess body fat is clearly linked to adipose tissue inflammation. Long-term weight loss is accompanied by improved metabolic profile and reduced low-grade inflammation in fat.
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| 27. |
- Amani, Paul Joseph, 1975-
(author)
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Does health insurance contribute to improving responsiveness of the health system? : the case of elderly in rural Tanzania
- 2022
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Doctoral thesis (other academic/artistic)abstract
- Background: Financing healthcare in Tanzania has for years depended on out-of-pocket payments. This mechanism has been criticized as being inefficient, contributing to inequity and high cost as well as denying access to healthcare to those most in need, including the elderly in rural areas. Health insurance (HI) was recently introduced as an instrument to enable equitable access to healthcare and thus to improve the responsiveness of the health system. Even though health insurance is expected to bring benefits to those who are insured, there is a lack of specific studies in the country looking at the role of HI in facilitating the health system responsiveness among vulnerable populations of remote areas.Aim: The aim of this thesis is to understand if and how health insurance contributes to improving the responsiveness of the healthcare system among the elderly in rural Tanzania. Methods: Four interrelated sub-studies (2 quantitative and 2 qualitative) were conducted in Igunga and Nzega districts of Tabora region between July 2017 and December 2018. The first two sub-studies are based on a household survey using an adapted version of the World Health Organization’s Study on Global Ageing and Adult Health questionnaire. Elderly people aged 60 years and above who had used both outpatient and inpatient healthcare three and twelve months prior to the study, respectively, were interviewed. Whereas in sub-study 1 the focus was to investigate the role of health insurance status on facilitating access to healthcare, sub-study 2 assessed the relationship between health insurance and the health system responsiveness domains. In sub-study 3, interviews with healthcare providers were carried out to capture their perspective regarding the functioning of the health insurance. In the final sub-study 4, focus group discussions with elderly were conducted in order to explore their experience of healthcare, depending on their health insurance status. Crude and adjusted logistic and quantile regression models were applied to analyse the association between health insurance and access to healthcare (sub-study 1) and responsiveness (sub-study 2), respectively. For both sub-studies 3 and 4, qualitative content analysis was used to analyse the data.Results: Sub-studies 1 and 2 involved a total of 1899 insured and uninsured elderly, while sub-studies 3 and 4 included 8 health providers and 78 elderlies respectively. Sub-study 1 showed that about 45% of the elderly were insured and HI ownership improved access and utilization of healthcare, both outpatient and inpatient services. In sub-study two, however, health insurance was associated with a lower responsiveness of the healthcare system. In general, all six domains: cleanliness, access, confidentiality, autonomy, communication, and prompt attention were rated high, but three were of concern: waiting time; cleanliness; and communication. Sub-study 3 uncovered several challenges coexisting alongside the provision of insurance benefits and thus contributing to a lower responsiveness. These included shortage of human resources and medical supplies, as well as operational issues related to delays in funding reimbursement. In sub-study 4, the elderly revealed that HI did not meet their expectations, it failed to promote equitable access, provided limited-service benefits and restricted use of services within residential areas. Conclusion: While HI seems to increase the access to and use of healthcare services by the elderly in rural Tanzania, a lower responsiveness by the healthcare system among the insured elderly was reported. Long waiting times, limited-service benefits, restricted use of services within schemes, lack of health workforce in both numbers and skills as well as shortage of medical supplies were important explanations for the lower responsiveness. The results of this thesis, while supporting the national aim of expanding HI in rural areas, also exposed several weaknesses that require immediate attention. There is a need to, first, review the insurance policy to improve its implementation, expand the scope of services coverage, and where possible, to introduce cross-subsidization between the publicly owned schemes; additionally, improvements in the healthcare infrastructure, increasing the number of qualified health workforce and the availability of essential medicines and laboratory services, especially at the primary healthcare facilities, should be prioritized and further investments allocated.
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| 28. |
- Anderl, Ines, 1973-
(author)
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Activation of the Cellular Immune Response in Drosophila melanogaster Larvae
- 2015
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Doctoral thesis (other academic/artistic)abstract
- During the last 40 years, Drosophila melanogaster has become an invaluable tool in understanding innate immunity. The innate immune system of Drosophila consists of a humoral and a cellular component. While many details are known about the humoral immune system, our knowledge about the cellular immune system is comparatively small. Blood cells or hemocytes constitute the cellular immune system. Three blood types have been described for Drosophila larvae. Plasmatocytes are phagocytes with a plethora of functions. Crystal cells mediate melanization and contribute to wound healing. Plasmatocytes and crystal cells constitute the blood cell repertoire of a healthy larva, whereas lamellocytes are induced in a demand-adapted manner after infection with parasitoid wasp eggs. They are involved in the melanotic encapsulation response against parasites and form melanotic nodules that are also referred to as tumors.In my thesis, I focused on unraveling the mechanisms of how the immune system orchestrates the cellular immune response. In particular, I was interested in the hematopoiesis of lamellocytes.In Article I, we were able to show that ectopic expression of key components of a number of signaling pathways in blood cells induced the development of lamellocytes, led to a proliferative response of plasmatocytes, or to a combination of lamellocyte activation and plasmatocyte proliferation.In Article II, I combined newly developed fluorescent enhancer-reporter constructs specific for plasmatocytes and lamellocytes and developed a “dual reporter system” that was used in live microscopy of fly larvae. In addition, we established flow cytometry as a tool to count total blood cell numbers and to distinguish between different blood cell types. The “dual reporter system” enabled us to differentiate between six blood cell types and established proliferation as a central feature of the cellular immune response. The combination flow cytometry and live imaging increased our understanding of the tempo-spatial events leading to the cellular immune reaction.In Article III, I developed a genetic modifier screen to find genes involved in the hematopoiesis of lamellocytes. I took advantage of the gain-of-function phenotype of the Tl10b mutation characterized by an activated cellular immune system, which induced the formation blood cell tumors. We screened the right arm of chromosome 3 for enhancers and suppressors of this mutation and uncovered ird1.Finally in Article IV, we showed that the activity of the Toll signaling pathway in the fat body, the homolog of the liver, is necessary to activate the cellular immune system and induce lamellocyte hematopoiesis.
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| 29. |
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| 30. |
- Andersson, Anne, 1966-
(author)
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Long-term side effects after treatment of Hodgkin's lymphoma
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Background Long-term side effects associated with the treatment of Hodgkin’s lymphoma (HL) have frequently been reported during the last decades. Studies have shown increased mortality in HL survivors. Following Hodgkin’s lymphoma, second malignancies (SM) and cardiovascular disease (CVD) are the most common causes of death in individuals treated for HL. This study investigates the incidence of side effects such as SM, CVD and infections in a cohort diagnosed with HL in Sweden between 1965 and 1995. In addition, this study identifies covariate risk factors for late side effects in order to develop strategies that prevent morbidity and mortality in HL survivors. Methods Using the Swedish Cancer Registry (SCR) at the National Board of Health and Welfare and the Multi-Generation Registry at Statistics (MGR) Sweden, we identified 6946 individuals diagnosed with HL between the years 1965 and 1995, and their first degree relatives (FDR) (n=17 858). In addition we identified the malignancies and inpatient care for CVD and infections for the HL cohort and their FDR. The standard incidence ratio (SIR) was calculated for the risk of SM, CVD and infections. For SM and CVD the risk also was stratified and calculated for family history of disease. The Swedish Hodgkin Intervention and Prevention study (SHIP), a prospective study, invited 702 individuals treated for HL at the age of 45 years or younger and who were treated in the region of Skåne, Uppsala or Umeå. The participants completed a questionnaire and were invited to an out-patient visit to an oncologist with clinical examination and blood tests. Any pathological findings were referred for further investigation. Results An increased risk for SM in HL long-term survivors was observed and seems to increase with the number of FDRs with cancer. There was also an increased risk for inpatient care due to congestive heart failure (CHF) and coronary artery disease (CAD). A family history of CHF and CAD further increased the risk for these diseases. The risk for inpatient care due to infections was increased and remained increased after 20 years or longer. The risk for infections was associated with splenectomy and hypothyroidism. Radiotherapy was an independent risk factor for cardiovascular disease in the cohort of the prospective study. ConclusionLong-term survivors from HL have an increased risk for developing late side effects such as SM, CVD and infections. Since many HL patients are young and the cure rate from the disease is high, it is of great importance to offer focused surveillance programs to selected individuals who are at high risk, e.g. individuals who received radiotherapy as part of their treatment and who have other known risk factors for cardiovascular disease such as hypertension, hypercholesterolemia, family history and smoking.
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| 31. |
- Andersson, Britta, 1979-
(author)
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Manipulation of potassium ion fluxes to induce apoptosis in lung cancer cells
- 2007
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Doctoral thesis (other academic/artistic)abstract
- Apoptosis is a special form of cell death that if non-functional may lead to diseases such as cancer. A reduction of the intracellular potassium ion (K+) content is necessary for activating enzymes important for the execution of apoptosis. Pharmacological modulation of K+ fluxes to reduce intracellular K+ in cancer cells might therefore force the cells into apoptosis and decrease tumour cell mass. Human malignant pleural mesothelioma (MPM) is a form of cancer often caused by asbestos exposure. Although asbestos has been banned in the Western World, the incidence of MPM is expected to increase. Cisplatin is the first-line chemotherapy for MPM, but acquired resistance to the drug is a clinical problem. This thesis is mainly based on work with the human malignant pleural mesothelioma cell line (P31 wt) and a cisplatin-resistant sub-line (P31 res). The aim was to first characterize K+ fluxes in P31 wt and P31 res cells, and then manipulate them in order to reduce intracellular K+ and induce apoptosis with K+ manipulation alone or in combination with cisplatin. Characterization of K+ fluxes in P31 wt cells showed that: 1) ouabain, a digitalis-like drug, and specific blocker of the Na+, K+, ATPase pump, effectively inhibited K+ uptake, 2) bumetanide, a diuretic, and an inhibitor of the Na+, K+, 2Cl-¬-cotransporter, had a transient effect on K+ uptake, and 3) the antifungal drug amphotericin B stimulated K+ efflux. In order to determine intracellular K+ content, the potassium-binding fluorescent probe PBFI-AM was used in a 96-well plate assay. After a 3-h incubation with ouabain, with or without bumetanide, combined with amphotericin B, the intracellular K+ content was reduced in P31 wt cells but not in P31 res cells. Ouabain induced apoptosis in both P31 wt and P31 res cells. P31 res cells were sensitized to cisplatin by ouabain, since 10 mg/L cisplatin in combination with ouabain induced about the same percentage of apoptotic cells as 40 mg/L cisplatin. Apoptosis was executed via caspase-3 activation in both P31 wt and P31 res cells. Amphotericin B enhanced ouabain-induced apoptosis in P31 wt cells via caspase-9 activation, with increased caspase-3 activation and DNA fragmentation as consequences. Ouabain-induced apoptosis in P31 res cells was executed via increased expression of pro-apoptotic Bak. The combination of cisplatin with ouabain and amphotericin B was stressful to both P31 wt and P31 res cells, since SAPK/JNK a known factor in stress-induced apoptosis was activated. In conclusion, K+ flux manipulation with clinical used drugs can induce apoptosis per se and also enhance cisplatin-induced apoptosis in P31 wt and P31 res cells.
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| 32. |
- Andersson, Christopher, 1987-
(author)
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Regulatory pathways and virulence inhibition in Listeria monocytogenes
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Listeria monocytogenes is a rod-shaped Gram positive bacterium. It generally exist ubiquitously in nature, where it lives as a saprophyte. Occasionally it however enters the food chain, from where it can be ingested by humans and cause gastro-intestinal distress. In immunocompetent individuals L. monocytogenes is generally cleared within a couple of weeks, but in immunocompromised patients it can progress to listeriosis, a potentially life-threatening infection in the central nervous system. If the infected individual is pregnant, the bacteria can cross the placental barrier and infect the fetus, possibly leading to spontaneous abortion.The infectivity of L. monocytogenes requires a certain set of genes, and the majority of them is dependent on the transcriptional regulator PrfA. The expression and activity of PrfA is controlled at several levels, and has traditionally been viewed to be active at 37 °C (virulence conditions) where it bind as a homodimer to a “PrfA-box” and induces the expression of the downstream gene.One of these genes is ActA, which enables intracellular movement by recruiting an actin polymerizing protein complex. When studying the effects of a blue light receptor we surprisingly found an effect of ActA at non-virulent conditions, where it is required for the bacteria to properly react to light exposure.To further study the PrfA regulon we tested deletion mutants of several PrfA-regulated virulence genes in chicken embryo infection studies. Based on these studies we could conclude that the chicken embryo model is a viable complement to traditional murine models, especially when investigating non-traditional internalin pathogenicity pathways. We have also studied the effects of small molecule virulence inhibitors that, by acting on PrfA, can inhibit L. monocytogenes infectivity in cell cultures with concentrations in the low micro-molar range.
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| 33. |
- Andersson, Charlotta, 1976-
(author)
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Significance of Wilms’ tumor gene 1 as a biomarker in acute leukemia and solid tumors
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Wilms’ tumor gene 1 (WT1) is a zinc finger transcriptional regulator with crucial functions in embryonic development. Originally WT1 was described as a tumor suppressor gene, but later studies have shown oncogenic properties of WT1 in a variety of tumors. Because of its dual functions in tumorigenesis, WT1 has been described as a chameleon gene. In this thesis, the significance of WT1 as a biomarker was investigated in acute myeloid leukemia (AML), clear cell renal cell carcinoma (ccRCC), ovarian carcinoma (OC) and childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL).Previous studies have suggested that expression of WT1 is a potential marker for detection of minimal residual disease (MRD) in AML. We aimed to define expression of WT1 as an MRD marker in AML. In adult AML patients, we found that a reduction of WT1 expression in bone marrow (≥ 1-log) detected less than 1 month after diagnosis was associated with an improved overall survival (OS) and freedom from relapse (FFR). In peripheral blood, a reduction of WT1 expression (≥ 2-log) detected between 1 and 6 months after treatment initiation was associated with an improved OS and FFR.WT1 harbor pathogenic genetic variants in a considerable proportion of AML and T-lymphoblastic leukemia (T-ALL), but mutations have not been reported in BCP-ALL. We aimed to evaluate the clinical impact of WT1 mutations and single nucleotide polymorphisms (SNPs) in BCP-ALL. Pathogenic mutations in the WT1 gene were rarely seen in childhood BCP-ALL. However, five WT1 SNPs were identified. In survival analyses, WT1 SNP rs1799925 was found to be associated with worse OS, indicating that WT1 SNP rs1799925 may be a useful marker for clinical outcome in childhood BCP-ALL. We also explored whether WT1 mutations and SNPs in ccRCC could be used as biomarkers for risk and treatment stratification. We therefore examined whether SNPs or mutations in WT1 were associated with WT1 expression and clinical outcome. Sequencing analysis revealed that none of the previously reported WT1 mutations were found in ccRCC; however, we identified six different WT1 SNPs. Our data suggest that pathogenic WT1 mutations are not involved in ccRCC, and the prognostic significance of WT1 SNPs in ccRCC is considerably weak. However, a favorable OS and disease-specific survival were found in the few cases harboring the homozygous minor allele.OC has a poor prognosis, and early effective screening markers are lacking. Serous OCs are known to express the WT1 protein. Overexpressed oncogenic proteins can be considered potential candidate antigens for cancer vaccines and T-cell therapy. It was therefore of great interest to investigate whether anti-WT1 IgG antibody (Ab) measurements in plasma could serve as biomarkers of anti-OC response. We found limited prognostic impact, but the results indicated that anti-WT1 IgG Ab measurements in plasma and WT1 staining in tissue specimens could be potential biomarkers for patient outcome in the high-risk subtypes of OCs.In conclusion, the results of this thesis indicate that WT1 gene expression can provide information about MRD of patients with AML, and WT1 SNP rs1799925 may be used as a biomarker for predicting clinical outcome in childhood BCP-ALL. In ccRCC, the prognostic significance of WT1 SNPs is weak and limited to the subgroup of patients that are homozygous for the minor allele. In OCs anti-WT1 IgG Ab measurement in plasma and WT1 staining in tissue specimens could possibly be used as biomarkers for predicting patient outcome in the high-risk subtypes of OCs.
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| 34. |
- Andersson, Emma, 1978-
(author)
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Human adenoviruses : new bioassays for antiviral screening and CD46 interaction
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Adenoviruses are common pathogens all over the world. The majority of the population has at some point been infected with an adenovirus. Although severe disease can occur in otherwise healthy individuals an adenovirus infection is most commonly self limited in these cases. For immunocompromised individuals however, adenoviruses can be life-threatening pathogens capable of causing disseminated disease and multiple organ failure. Still there is no approved drug specific for treatment of adenovirus infections. We have addressed this using a unique whole cell viral replication reporter gene assay to screen small organic molecules for anti-adenoviral effect. This RCAd11pGFP-vector based assay allowed screening without any preconceived idea of the mechanism for adenovirus inhibition. As a result of the screening campaign 2-[[2-(benzoylamino)benzoyl]amino]-benzoic acid turned out to be a potent inhibitor of adenoviral replication. To establish a structure-activity relationship a number of analogs were synthesized and evaluated for their anti-adenoviral effect. The carboxylic acid moiety of the molecule was important for efficient inhibition of adenovirus replication.There are 54 adenovirus types characterized today and these are divided into seven species, A-G. The receptors used by species B and other adenoviruses are not fully characterized. CD46 is a complement regulatory molecule suggested to be used by all species B types and some species D types but this is not established. We have designed a new bioassay for assessment of the interaction between adenoviruses and CD46 and investigated the CD46-binding capacity of adenovirus types indicated to interact with CD46. We concluded that Ad11p, Ad34, Ad35, and Ad50 clearly bind CD46 specifically, whereas Ad3p, Ad7p, Ad14, and Ad37 do not.CD46 is expressed on all human nucleated cells and serves as a receptor for a number of different bacteria and viruses. Downregulation of CD46 on the cell surface occurs upon binding by some of these pathogens. We show that early in infection Ad11p virions downregulate CD46 upon binding to a much higher extent than the complement regulatory molecules CD55 and CD59.These findings may lead to a better understanding of the pathogenesis of adenoviruses in general and species B adenoviruses in particular and hopefully we have discovered a molecule that can be the basis for development of new anti-adenoviral drugs.
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| 35. |
- Andersson-Evelönn, Emma, 1983-
(author)
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DNA methylation as a prognostic marker in clear cell Renal Cell Carcinoma
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma worldwide. Metastatic ccRCC is correlated to poor prognosis whereas non-metastatic disease has a 5-year survival rate up to 90%. Due to increased accessibility to different types of diagnostic imaging the frequency of metastatic ccRCC at diagnosis has decreased since the beginning of the 21st century. This has led to an earlier detection of primary tumors before patients present symptoms. However, 20-30% of the non-metastatic patients at diagnosis will progress and metastasize within five years of primary nephrectomy. Identifying patients at high risk of tumor progression at an early stage after diagnosis is of importance to improve outcome and survival. Currently, in Sweden, the Mayo scoring system is used to divide tumors into low, intermediate or high risk for tumor progression.DNA methylation has been associated with tumor development and progression in different malignancies. In this thesis, Illumina Infinium HumanMeth27 BeadChip Arrays and Human Meth450K BeadChip Arrays have been used to evaluate the relationship between methylation and clinicopathological variables as well as ccRCC outcome in 45 and 115 patients.Our studies identified an association between higher level of promoter-associated DNA methylation and clinicopathological variables in ccRCC. There was a significant stepwise increase of average methylation from tumor-free tissue, via non-metastatic tumors to metastatic disease. Cluster analysis divided patients into two distinct groups that differed in average methylation levels, TNM stage, Fuhrman nuclear grade, tumor size, survival and tumor progression. We also presented two prognostic classifiers for non-metastatic tumors; the promoter methylation classifier (PMC) panel and the triple classifier. The PMC panel divided tumors depending on the methylation level, PMC low or PMC high, with significantly worse prognosis in the PMC high group. This data was verified in an independent, publically available cohort. The triple classifier was created using a combination of clinicopathological variables, previously identified CpGs biomarkers and a novel cluster analysis approach (Directed Cluster Analysis). The triple classifier had a higher specificity compared to the clinically used Mayo scoring system and predicted tumor progression with higher accuracy at a fixed sensitivity.The identification of two epigenetic classifiers that predicted outcome in non-metastatic ccRCC further establishes the role of DNA methylation as a prognostic marker. This knowledge can contribute to identification of patients with a high risk of tumor progression and can be of importance in the decision regarding adjuvant treatment post-nephrectomy.
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| 36. |
- Andersson, Gustav, 1983-
(author)
-
Influences of paratendinous innervation and non-neuronal substance P in tendinopathy : studies on human tendon tissue and an experimental model of Achilles tendinopathy
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- Pain of the musculoskeletal system is one of the most common reasons for people seeking medical attention, and is also one of the major factors that prevent patients from working. Chronic tendon pain, tendinopathy, affects millions of workers world-wide, and the Achilles tendon is an important structure often afflicted by this condition. The pathogenesis of tendinopathy is poorly understood, but it is thought to be of multifactoral aetiology. It is known that tendon pain is often accompanied not only by impaired function but also by structural tissue changes, like vascular proliferation, irregular collagen organisation, and hypercellularity, whereby the condition is called tendinosis. In light of the poor knowledge of tendinosis pathophysiology and recent findings of a non-neuronal signalling system in tendon tissue, the contributory role of neuropeptides such as substance P (SP) has gained increased interest. SP, known for afferent pain signalling in the nervous system, also has multiple efferent functions and has been described to be expressed by non-neuronal cells. As pain is the most prominent symptom of tendinopathy, the focus of the studies in this thesis was the innervation patterns of the tissue ventral to the Achilles tendon (i.e. the tissue targeted in many contemporary treatment methods) as well as the distribution of SP and its preferred receptor, the neurokinin-1 receptor (NK-1R), in the tendon tissue itself. It was hereby hypothesised that the source of SP affecting the Achilles tendon might be the main cells of the tendon tissue (the tenocytes) as well as paratendinous nerves, and that SP might be involved in tendinosis- development. The studies were conducted, via morphological staining methods including immunohistochemistry and in situ hybridisation, on tendon biopsies from patients suffering from Achilles tendinosis and on those from healthy volunteers. The hypothesis of the thesis was furthermore tested using an experimental animal model (rabbit) of Achilles tendinopathy, which was first validated. The model was based on a previously established overuse protocol of repetitive exercise. In the human biopsies of the tissue ventral to the Achilles tendon, there was a marked occurrence of sympathetic innervation, but also sensory, SP-containing, nerve fibres. NK-1R was expressed on blood vessels and nerve fascicles of the paratendinous tissue, but also on the tenocytes of the tendon tissue proper itself, and notably more so in patients suffering from tendinosis. Furthermore, the human tenocytes displayed not only NK-1R mRNA but also mRNA for SP. The animal model was shown to produce objectively verified tendinosis-like changes, such as hypercellularity and increased vascularity, in the rabbit Achilles tendons, after a minimum of three weeks of the exercise protocol. The contralateral leg of the animals in the model was found to be an unreliable control, as bilateral changes occured. The model furthermore demonstrated that exogenously administered SP triggers an inflammatory response in the paratendinous tissue and accelerates the intratendinous tendinosis-like changes such that they now occur after only one week of the protocol. Injections of saline as a control showed similar results as SP concerning hypercellularity, but did not lead to vascular changes or pronounced paratendinous inflammation. In summary, this thesis concludes that interactions between the peripheral sympathetic and sensory nervous systems may occur in Achilles tendinosis at the level of the ventral paratendinous tissue, a region thought to be of great importance in chronic tendon pain since many successful treatments are directed toward it. Furthermore, the distribution of NK-1R:s in the Achilles tendon described in these studies gives a basis for SP, whether produced by nerves mainly outside the tendon or by tenocytes within the tendon, to affect blood vessels, nerve structures, and/or tendon cells, especially in tendinosis patients. In light of this and of previously known SP-effects, such as stimulation of angiogenesis, pain signalling, and cell proliferation, the proposed involvement of SP in tendinosis development seems likely. Indeed, the animal model of Achilles tendon overuse confirms that SP does induce vascular proliferation and hypercellularity in tendon tissue, thus strengthening theories of SP playing a role in tendinosis pathology.
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| 37. |
- Andersson, Henrik, 1972-
(author)
-
A microarray analysis of the host response to infection with Francisella tularensis
- 2006
-
Doctoral thesis (other academic/artistic)abstract
- Francisella tularensis is a gram-negative bacterium that is the cause of the serious and sometimes fatal disease, tularemia, in a wide range of animal species and in humans. The response of cells of the mouse macrophage cell line J774 to infection with Francisella tularensis LVS was analyzed by means of a DNA microarray. It was observed that the infection conferred an oxidative stress upon the target cells and many of the host defense mechanisms appeared to be intended to counteract this stress. The infection was characterized by a very modest inflammatory response. Tularemia caused by inhalation of F. tularensis subspecies tularensis is one of the most aggressive infectious diseases known. We used the mouse model to examine in detail the host immune response in the lung. After an aerosol challenge all mice developed clinical signs of severe disease, showed weight loss by day four of infection, and died the next day. Gene transcriptional changes in the mouse lung samples were examined on day one, two, and four of infection. Genes preferentially involved in host immune responses were activated extensively on day four but on day one and two, only marginally or not at all. Several genes upregulated on day four are known to depend on IFN-gamma or TNF-alpha for their regulation. In keeping with this finding, TNF-alpha and IFN-gamma levels were found to be increased significantly in bronchoalveolar lavage on day four. We undertook an analysis of the transcriptional response in peripheral blood during the course of ulceroglandular tularemia by use of Affymetrix microarrays. Samples were obtained from seven individuals at five occasions during two weeks after the first hospital visit and convalescent samples three months later. In total 265 genes were differentially expressed. The most prominent changes were noted in samples drawn on days 2-3 and a considerable proportion of the upregulated genes appeared to represent an IFN-gamma-induced response and also a pro-apoptotic response. Genes involved in the generation of innate and acquired immune responses were found to be downregulated, presumably a pathogen-induced event. A logistic regression analysis revealed that seven genes were good predictors of the early phase of tularemia. Recently, a large number of methods for the analysis of microarray data have been proposed but there are few comparisons of their relative performances. We undertook a study to evaluate established and novel methods for filtration, background adjustment, scanning, and censoring. For all analyses, the sensitivities at low false positive rates were observed together with a bias measurement. In general, there was a trade off between the analyses ability to identify differentially expressed genes and their ability to obtain unbiased estimators of the desired ratios. A commonly used standard analysis using background adjustment performed poorly. Interestingly, the constrained model combining data from several scans resulted in high sensitivities. For experiments where only low false discovery rates are acceptable, the use of the constrained model or the novel partial filtration method are likely to perform better than some commonly used standard analyses.
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| 38. |
- Andersson, Johanna, 1990-
(author)
-
Idiopathic normal pressure hydrocephalus : epidemiology and diagnostics
- 2021
-
Doctoral thesis (other academic/artistic)abstract
- Idiopathic normal pressure hydrocephalus (iNPH) is a progressive neurological condition characterized by a deterioration of gait, cognition, and continence. The diagnosis is based on a combination of enlarged ventricles seen in neuroimaging, with typical clinical findings. iNPH often affects elderly individuals (i.e., over the age of 65). Shunt insertion is the only available treatment, with an improvement rate of up to 80%.The prevalence has previously been reported to be between 0.5 and 3% among individuals over age 65. However, most previous studies have been conducted on hospital-based materials, and there is a lack of epidemiological studies based on the general population. One of the challenges of diagnosing iNPH is that there are no common, widely accepted diagnostic criteria. There are currently two different diagnostic guidelines: the American-European guidelines and the Japanese ones, which makes it harder to compare different studies.The aim of this thesis was to determine the prevalence of iNPH in population-based materials and to evaluate the differences between the diagnostic guidelines. Furthermore, we wanted to assess the quality of life and depressive symptoms among individuals with iNPH compared to those without. In addition, we assessed longitudinal changes in the clinical and radiological findings of iNPH.We asked 1,000 individuals aged 65 and older to participate in the study by answering a questionnaire containing typical iNPH symptoms. We invited all participants who had marked at least two symptoms on the questionnaire for further investigation, in addition to a randomly selected group with fewer than two symptoms. A total of 168 participants underwent clinical examinations and computed tomography (CT) of the brain. We followed up with the same cohort two years later with repeated testing, with the addition of questionnaires on depressive symptoms and quality of life. A total of 122 individuals remained in the 2-year follow-up cohort. The clinical examinations included an iNPH-specific grading scale for symptoms and neurological examinations.The prevalence of iNPH for those 65 years and older was 3.7% according to the American-European guidelines and 1.5% according to the Japanese guidelines. The prevalence was higher for those over age 80, with no differences between the sexes. Furthermore, participants with iNPH had more depressive symptoms and lower quality of life than those without iNPH. Radiological findings and symptoms progressed slightly over two years, and those with symptom deterioration had an even higher degree of radiological progress compared to those with stationary or improved symptoms.This thesis shows that iNPH is fairly common in a normal population of elderly individuals. There is disagreement between the current diagnostic guidelines, which underscores the need for revisions, preferably into one common diagnostic system. In this thesis, individuals with iNPH had a lower functional status, more depressive symptoms, and lower quality of life than those without iNPH.Moreover, iNPH progresses slightly in both symptoms and radiological signs over two years, which underlines the value of clinical follow-up for asymptomatic individuals with radiological signs of iNPH. Finally, iNPH is probably underdiagnosed and an important diagnosis to consider in an elderly person with gait and balance impairments.
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| 39. |
- Andersson, Jonas, 1977-
(author)
-
Inflammation and lifestyle in cardiovascular medicine
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- Despite major advances in the treatment and prevention of atherosclerosis the last several decades, cardiovascular disease still accounts for the majority of deaths in Sweden. With the population getting older, more obese and with rising numbers of diabetics, the cardiovascular disease burden may increase further in the future. The focus in cardiovascular disease has shifted with time from calcification and narrowing of arteries to the biological processes within the atherosclerotic plaque. C-reactive protein (CRP) has emerged as one of many proteins that reflect a low grade systemic inflammation and is suitable for analysis as it is more stable and easily measured than most other inflammatory markers. Several large prospective studies have shown that CRP is not only an inflammatory marker, but even a predictive marker for cardiovascular disease. C-reactive protein is associated with several other risk factors for cardiovascular disease including obesity and the metabolic syndrome. Our study of twenty healthy men during a two week endurance cross country skiing tour demonstrated a decline in already low baseline CRP levels immediately after the tour and six weeks later. In a study of 200 obese individuals with impaired glucose tolerance randomised to a counselling session at their health care centre or a one month stay at a wellness centre, we found decreased levels of CRP in subjects admitted to the wellness centre. The effect remained at one, but not after three years of follow-up. In a prospective, nested, case-referent study with 308 ischemic strokes, 61 intracerebral haemorrhages and 735 matched referents, CRP was associated with ischemic stroke in both uni- and multivariate analyses. No association was found with intracerebral haemorrhages. When classifying ischemic stroke according to TOAST criteria, CRP was associated with small vessel disease. The CRP 1444 (CC/CT vs. TT) polymorphism was associated with plasma levels of CRP, but neither with ischemic stroke nor with intracerebral haemorrhage. A study on 129 patients with atrial fibrillation was used to evaluate whether inflammation sensitive fibrinolytic variables adjusted for CRP could predict recurrence of atrial fibrillation after electrical cardioversion. In multivariate iv models, lower PAI-1 mass was associated with sinus rhythm even after adjusting for CRP and markers of the metabolic syndrome. In conclusion, lifestyle intervention can be used to reduce CRP levels, but it remains a challenge to maintain this effect. CRP is a marker of ischemic stroke, but there are no significant associations between the CRP1444 polymorphism and any stroke subtype, suggesting that the CRP relationship with ischemic stroke is not causal. The fibrinolytic variable, PAI-1, is associated with the risk of recurrence of atrial fibrillation after electrical cardioversion after adjustment for CRP. Our findings suggest a pathophysiological link between atrial fibrillation and PAI-1, but the relation to inflammation remains unclear.
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| 40. |
- Andersson, Jonas, 1975-
(author)
-
Ion recombination in liquid ionization chambers : development of an experimental method to quantify general recombination
- 2013
-
Doctoral thesis (other academic/artistic)abstract
- An experimental method (the two-dose-rate method) for the correction of general recombination losses in liquid ionization chambers has been developed and employed in experiments with different liquids and radiation qualities. The method is based on a disassociation of initial and general recombination, since an ionized liquid is simultaneously affected by both of these processes.The two-dose-rate method has been compared to an existing method for general recombination correction for liquid ionization chambers, and has been found to be the most robust method presently available.The soundness of modelling general recombination in liquids on existing theory for gases has been evaluated, and experiments indicate that the process of general recombination is similar in a gas and a liquid. It is thus reasonable to employ theory for gases in the two-dose-rate method to achieve experimental corrections for general recombination in liquids. There are uncertainties in the disassociation of initial and general recombination in the two-dose-rate method for low applied voltages, where initial recombination has been found to cause deviating results for different liquids and radiation qualities.Sensitivity to ambient electric fields has been identified in the microLion liquid ionization chamber (PTW, Germany). Experimental data may thus be perturbed if measurements are conducted in the presence of ambient electric fields, and the sensitivity has been found to increase with an increase in the applied voltage. This can prove to be experimentally limiting since general recombination may be too severe for accurate corrections if the applied voltage is low.
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| 41. |
- Andersson, Kennet, 1979-
(author)
-
Assessment of cerebrospinal fluid system dynamics : novel infusion protocol, mathematical modelling and parameter estimation for hydrocephalus investigations
- 2011
-
Doctoral thesis (other academic/artistic)abstract
- Patients with idiopathic normal pressure hydrocephalus (INPH) have a disturbance in the cerebrospinal fluid (CSF) system. The treatment is neurosurgical – a shunt is placed in the CSF system. The infusion test is used to assess CSF system dynamics and to aid in the selection of patients that will benefit from shunt surgery. The infusion test can be divided into three parts: a mathematical model, an infusion protocol and a parameter estimation method. A non-linear differential equation is used to mathematically describe the CSF system, where two important parameters are the outflow conductance (Cout) and the Pressure Volume Index (PVI). These are used both for clinical and research purposes. The analysis methods for the non-linear CSF system have limited the infusion protocols of presently used infusion investigations. They come with disadvantages such as long investigation time, no estimation of PVI and no measure of the reliability of the estimates.The aim of this dissertation was to develop and evaluate novel methods for infusion protocols, mathematical modelling and parameter estimation methods for assessment of CSF system dynamics.The infusion protocols and parameter estimation methods in current use, constant pressure infusion (CPI), constant infusion and bolus infusion, were investigated. The estimates of Cout were compared, both on an experimental set-up and on 20 INPH patients. The results showed that the bolus method produced a significantly higher Cout than the other methods. The study suggested a method with continuous infusion for estimating Cout and emphasized that standardization of Cout measurement is necessary.The non-linear model of the CSF system was further developed. The ability to model physiological variations that affect the CSF system was incorporated into the model and it was transformed into a linear time-invariant system. This enabled the use of methods developed for identification of such systems. The underlying model for CSF absorption was discussed and the effect of baseline resting pressure (Pr) in the analysis on the estimation of Cout was explored using two different analyses, with and without Pr.A novel infusion protocol with an oscillating pressure pattern was introduced. This protocol was theoretically better suited for the CSF system characteristics. Three new parameter estimation methods were developed. The adaptive observer was developed from the original non-linear model of the CSF system and estimated Cout in real time. The prediction error method (PEM) and the robust simulation error (RSE) method were based on the transformed linear system, and they estimated both Cout and PVI with confidence intervals in real time. Both the oscillating pressure pattern and the reference CPI protocol were performed on an experimental set-up of the CSF system and on 47 hydrocephalus patients. The parameter estimation methods were applied to the data, and the RSE method produced estimates of Cout that were in good agreement with the reference method and allowed for an individualized and considerably reduced investigation time.In summary, current methods have been investigated and a novel approach for assessment of CSF system dynamics has been presented. The Oscillating Pressure Infusion method, which includes a new infusion protocol, a further developed mathematical model and new parameter estimation methods has resulted in an improved way to perform infusion investigations and should be used when assessing CSF system dynamics. The advantages of the new approach are the pressure-regulated infusion protocol, simultaneous estimation of Cout and PVI and estimates of reliability that allow for an individualized investigation time.
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| 42. |
- Andersson, Karin
(author)
-
Prefibrillar oligomeric Transthyretin mutants - amyloid conformation, toxicity and association with Serum amyloid P component
- 2005
-
Doctoral thesis (other academic/artistic)abstract
- Amyloidoses represent a heterogeneous group of diseases characterized by abnormal protein metabolism leading to extracellular deposition of fibrillar, proteinaceous amyloid in various tissues and organs of the body. To date more than 20 different proteins have been linked to diseases with amyloid depositions, of which Alzheimer’s disease and the prion-associated diseases are the most well known. Despite the origin of protein in the amyloid, the fibrils share some common biochemical and biophysical properties such as a diameter of 8-13 nm, a β-pleated sheet secondary structure packed in an ordered crystal-like way, Congo red and thioflavin binding with characteristic spectroscopic patterns and decoration of the fibrils with Serum amyloid P component and glycoseaminoglycans.The plasma protein transthyretin (TTR) is associated with familial amyloidosis with polyneuropathy (FAP) and senile systemic amyloidosis (SSA). FAP is a lethal, autosomal inherited disorder caused by point mutations in the TTR-gene. More than 80 different mutations have been associated with amyloid formation and linked to FAP. The interpretation is that amino acid replacements at different sites of the polypeptide lead to reduced stability. Mutant TTR were constructed that have a strong tendency to self-aggregate under physiological conditions. The precipitates were shown to be amyloid by staining with thioflavin T and Congo red. As the mutants were sensitive to trypsin cleavage compared to plasma TTR, we suggest that the mutants represent amyloid precursors or that they may share structural properties with intermediates on a pathway leading to amyloid deposition. Monoclonal antibodies were generated that exclusively recognize the amyloidogenic folding of TTR providing direct biochemical evidence for a structural change in amyloidogenic intermediates. Two cryptic epitopes were mapped to a domain of TTR, where most mutations associated with amyloidosis occur and is proposed to be displaced at the initial phase of amyloid formation. Amyloidogenic intermediates of TTR were shown to induce a toxic, free radical dependent, response in cultured neuroblastoma cells. Morphological studies revealed a correlation between toxicity (apoptosis) and the presence of immature amyloid suggesting that mature full-length fibrils represent an inert end stage, which might serve as a rescue mechanism.Serum amyloid P component (SAP) is a highly conserved plasma glycoprotein universally found associated with amyloid depositions independently of protein origin. SAP’s role in amyloid formation is contradictory since both inhibition and promotion of aggregation have been shown in the case of fibril formation from the Aβ peptide of Alzheimer’s disease. Amyloidogenic prefibrils of TTR were shown to bind SAP and no interference with aggregation was detected. SAP co-localize in patches with mutant TTR on the surface of neuroblastoma cells and prevent apoptosis induced by mutant TTR and Aβ peptide, while several other molecules known to decorate amyloid fibrils were without effect.
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| 43. |
- Andersson, Liselott, 1961-
(author)
-
Implications of psychiatric disorders during pregnancy and the postpartum period - A population-based study
- 2004
-
Doctoral thesis (other academic/artistic)abstract
- Background: Depressive and anxiety disorders are common health problems, affecting women at least twice as often as men. Although some studies have been made on pregnant women or, especially, in the postpartum period, most of these studies have been performed on small samples, mainly specific risk groups such as teenage mothers, women of low socioeconomic status and certain ethnic groups. Also, there is a lack of studies on antenatal and postpartum depression and/or anxiety using diagnostic criteria adhering to the Diagnostic and Statistical Manual of Mental disorders, fourth edition (DSM-IV). Aims and methods: The aims were to estimate the point prevalence of mood, anxiety and eating disorders, based on DSM-IV criteria, in an unselected population during the second trimester of pregnancy, and to assess the obstetric and neonatal outcome, as well as the health care consumption during pregnancy, delivery and the early postpartum period among women with a psychiatric disorder, compared to healthy subjects. Finally, we aimed to investigate depression and anxiety, and associated maternal characteristics and events through pregnancy and the postpartum period in the same group of women. The Primary Care Evaluation of Mental Disorders (PRIME-MD) was used for assessment of psychiatric disorders during the second trimester of pregnancy and three to six months after delivery. From October 2nd, 2000, to October 1st, 2001 all women attending the second trimester routine ultrasound-screening at two different hospitals in northern Sweden (at Umeå University Hospital and at Sunderby Central Hospital) were approached for participation in the study. After delivery, data were extracted from the medical records of the mothers and their offspring to evaluate obstetric and neonatal outcome. Three to six months after delivery, the women who had an antenatal depression and/or anxiety were contacted for an assessment using the PRIME-MD. The same procedure was made in a control group, consisting of 500 women, randomly selected among those who did not have any psychiatric diagnosis according to the PRIME-MD investigation during the second trimester of pregnancy. Results and conclusions: Of the 1555 women in the study population, 220 (14.1%) had one or more PRIME-MD diagnoses. Living single, low socioeconomic status, smoking, multiparity and a body mass index of 30 or more were significantly associated with a psychiatric diagnosis in the second trimester of pregnancy. Women with antenatal depression and/or anxiety more often suffered from nausea and vomiting during pregnancy were more often on sick leave, and they visited their obstetrician more often than healthy subjects, specifically because of fear of childbirth and premature contractions. Also, they were more commonly delivered by elective caesarean section, had an increased use of epidural analgesia and reported a longer self-experienced duration of labor. Severe complications of pregnancy, delivery, and the early postpartum period were not affected by antenatal depression and/or anxiety. There was no significant difference in neonatal outcome depending on antenatal depressive or anxiety disorder. Fewer cases of depressive and/or anxiety disorders were prevalent postpartum, but there was a significant shift from a majority of sub-threshold diagnoses during pregnancy to full DSM-IV diagnoses during the postpartum period. Previous psychiatric disorder and living singly were significantly associated with both a new-onset and a postpartum continuation/recurrence of depression and/or anxiety. Postpartum continuation/recurrence of a psychiatric disorder was additionally associated with smoking, obesity, and adverse obstetric events.
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| 44. |
- Andersson, Marie, 1962-
(author)
-
Immunopathogenesis of relapsing fever borreliosis
- 2008
-
Doctoral thesis (other academic/artistic)abstract
- Relapsing fever (RF) is caused by different species of Borrelia transmitted by soft ticks or by the human body louse. Illness is characterized by reappearing peaks of high concentrations of spirochetes in blood, concordant with fever peaks separated by asymptomatic periods. Neuroborreliosis is one of the most severe manifestations of RF borreliosis. To understand the immune response during early RF, we analyzed immune cells in brain and kidney of mice infected with B. crocidurae during the acute infection. Our results indicate that brain defense is comprised primarily of innate immune cells. Despite the infiltration of innate immune cells, Borrelia was not completely eradicated. A failure of the host brain to clear the bacteria may give the pathogen a niche where it can persist. Using our mouse model, we revealed that Borrelia duttonii could persist in the mouse brain for up to 270 days, without being present in the circulation. The infection was silent with no change in host gene expression, and the spirochetes could re-enter the circulation after immunosuppression. We propose that the brain is used by the pathogen to evade host immunity and serves as a possible natural reservoir for B. duttonii, a spirochete that has rarely been found in any mammalian host other than man. Borrelia-induced complications during pregnancy have been reported, and are especially common in RF. In our established mouse model of gestational RF, we could show that the fetuses suffered from severe pathology and growth retardation, probably as a consequence of placental destruction. We could also show trans-placental transmission of the bacteria leading to neonatal RF. Surprisingly, pregnant dams had a lower bacterial load and less severe disease, showing that pregnancy has a protective effect during RF. We have used the gestational RF model to investigate host factors favoring disease resolution. Because the spleen is the primary organ responsible for trapping and removing blood-borne pathogens, we have compared temporal changes in spleen immune cell populations and cytokine/chemokine induction during the infection. Spleens of pregnant mice had earlier neutrophil infiltration, as well as faster and higher production of pro-inflammatory mediators. This rapid, robust response suggests a more effective host defense. Thus, an enhanced pro-inflammatory response during pregnancy imparts a distinct advantage in controlling the severity of relapsing fever infection.
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| 45. |
- Andersson, Nina, 1976-
(author)
-
Cerebrospinal fluid infusion methods : development and validation on patients with idiopathic normal pressure hydrocephalus
- 2007
-
Doctoral thesis (other academic/artistic)abstract
- Cerebrospinal fluid (CSF) infusion tests can be used to estimate the dynamic properties of the CSF system. Idiopathic normal pressure hydrocephalus (INPH) is a syndrome signified by a disturbance to the CSF system, where the cause is unknown and the diagnosis is difficult to determine. As an aid in identifying patients with INPH who will improve after shunt surgery, infusion tests are commonly used to determine the outflow conductance (Cout), or outflow resistance (Rout=1/Cout), of the CSF system. The tests are also used to determine shunt function in vivo. The general aim of this thesis was to develop and validate CSF infusion methods, to investigate the dynamics of the CSF system. The methods should be applicable to patients with INPH, to aid in the quest to further improve the diagnosis and management of this syndrome.An existing mathematical model describing the dynamics of the CSF system was further developed. The characteristics of the model were verified and the effect of expanding intracranial air on the intracranial pressure (ICP) was simulated. The simulations supported the recommendation to maintain sea-level pressure during air ambulance transportation of patients with suspected intracranial air.A recently developed infusion apparatus was evaluated, on an experimental model as well as on a patient material. The repetitiveness in estimating Cout was found to be good. A statistically significant difference was found between the repeated Cout estimations in the patient group, indicating that there might have been a small physiological change introduced during the infusion test. A parameter, ∆Cout, was proposed and evaluated. It proved to reflect the reliability of individual Cout investigations in a clinically useful way, as well as to provide easily interpreted information.An adaptive algorithm for assessment of Cout was developed and evaluated on a patient group. The new algorithm was shown to reduce the investigation time, from 60 minutes, by 14.3 ± 5.9 minutes (mean ± SD), p<0.01, without reducing the reliability of the estimated Cout below clinically relevant levels.The relationship between ICP and CSF outflow was studied in a group of patients investigated for INPH. It was found that in the range of moderate increase from baseline pressure, the assumption of a pressure independent Rout was confirmed (p=0.5). However, at larger pressure increments, the relationship had a non-linear tendency (p<0.05). This indicates that the traditional view of a pressure independent Rout might have to be questioned in the region where ICP exceeds baseline pressure too much.Infusion tests can be performed in different ways, where three main categories may be distinguished. The bolus infusion method was compared to the constant pressure and constant flow infusion methods, on an experimental model as well as on a patient material. When physiological pressure fluctuations were added to the model, significant differences were found in the determination of Cout in the range of clinical importance, i.e. low Cout (p<0.05). The finding was supported by the patient investigations, the difference was however not significant.With the application of the new methods developed in this thesis, and the increased knowledge concerning relationships between CSF dynamic parameters, the CSF infusion test was further improved with the ability to increase measurement reliability in a reduced time. This constitutes a good basis to perform a large multi-centre study with the main goal to determine the predictive value of the parameter Cout.
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| 46. |
- Andersson, Sofia, 1972-
(author)
-
Vård i livets slutskede på särskilt boende för äldre personer : närstående och vårdpersonals skattade och berättade erfarenheter
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Bakgrund I Europa, blir det allt vanligare att äldre personer dör på särskilt boende i stället för på sjukhus. Särskilda boenden spelar därför en viktig roll när det gäller vård i livets slutskede. Målet med palliativ vård för personer med livshotande sjukdom och deras närstående är att öka livskvaliteten och lindra lidande. Strukturerade vårdplaner såsom Liverpool Care Pathway for care of the dying (LCP) kan vara ett sätt att öka vårdkvaliteten. Det saknas dock forskning om vård i livets slutskede på särskilda boenden när en strukturerad vårdplan har använts.Syfte Det övergripande syftet med avhandlingen var att beskriva vård i livets slutskede på särskilt boende för äldre personer utifrån närstående och vårdpersonals skattade och berättade erfarenheter.Metod Avhandlingen baseras på två kvantitativa (I, II) och två kvalitativa (III, IV) studier. Studie I baseras på frågeformuläret Views of Informal Carers – Evaluation of Services (VOICES) som har besvarats av närstående (n = 189) efter att en anhörig har dött. Data har därefter analyserats med beskrivande och jämförande statistik. Studie II baseras på data om alla förväntade dödsfall (n = 22 855) som registrerats i Svenska palliativregistret (SPR). Dödsfallsenkäten har besvarats av vårdpersonal och svaren har sedan analyserats med beskrivande statistik och univariat och multipel logistisk regressionsanalys. Studie III baseras på fokusgruppsintervjuer och enskilda intervjuer med vårdpersonal. Studie IV baseras på enskilda intervjuer med närstående. Data från studie III och IV har analyserats med hjälp av kvalitativ innehållsanalys.Resultat Resultatet i studie I visar att majoriteten av de närstående skattade att den äldre personen fick tillräcklig hjälp såväl med personlig vård (78,5 %) som med sjukvård (93,0 %) de sista tre dagarna i livet. De närstående (86,2 %) rapporterade att de var informerade om att det var sannolikt att den äldre personen skulle avlida och majoriteten (94,1 %) av de äldre hade avlidit på önskad plats. Resultatet visade dock på hög förekomst av smärta (46,5 %) och andnöd (55,9 %). Det var ingen skillnad mellan åldersgrupperna när det gällde smärta men de äldre < 85 år hade signifikant högre förekomst av andnöd (70,6 %) jämfört med de äldre äldre, ≥ 85 år, (47,5 %). De äldre, < 85 år, hade signifikant oftare symtomlindring för andnöd (53,1 %) jämfört med äldre äldre, ≥ 85 år, (31,8 %).Resultatet i studie II visar hög förekomst av smärta (68,8 %) och ångest (44,0 %). Faktorer associerade med symtomlindring av smärta, illamående, ångest och andnöd var dels att validerat smärtskattningsinstrument hade använts, dels att munhälsan var bedömd. Starkast samband var det mellan symtomlindring av tre symtom (smärta, andnöd och ångest) och att injektioner var förskrivna vid behov.Resultatet i studie III visar att vårdpersonalen upplevde sig tryggare efter implementeringen av LCP genom att de hade fått ett gemensamt förhållningssätt, kände stöd att skräddarsy vården utifrån den döende personens individuella behov, kände stöd att involvera närstående i beslut och i vården samt hade blivit mer medvetna om vårdmiljön.Resultatet i studie IV visar att närstående upplevde sig tryggare i en välbekant och varm atmosfär, att vara kontra inte vara involverad i vård i livets slutskede och att bli tröstade genom att bevittna vårdpersonalens strävan att lindra lidande.Konklusion Resultatet från studierna i den här avhandlingen pekar på hög vårdkvalitet i livets slutskede på särskilt boende genom god omvårdnad, men resultatet pekar också mot förekomst av inadekvat symtomlindring och hög förekomst av smärta, andnöd och ångest de sista dagarna i livet. Det framkom ett tydligt samband mellan ordinerade injektioner vid behov och symtomlindring av smärta, illamående och ångest. Resultatet indikerar även vikten av att använda smärtskattningsinstrument och göra munhälsobedömningar för symtomlindring vid vård i livets slutskede. Således kan ett sätt att öka vårdkvaliteten för döende personer vara att det finns ordinerade injektionsläkemedel vid behov mot vanliga symtom, att använda validerade smärtskattningsinstrument och att göra munhälsobedömningar. Det framkom också att användandet av en standardiserad vårdplan såsom LCP kan vara ett sätt att förbättra vården för de äldre personerna i livets slutskede. Såväl vårdpersonalen som de närstående upplevde stöd av den struktur för bedömningar och vårdaktiviteter som LCP ger. Vårdpersonalen upplevde också stöd i att involvera närstående i vården och i vårdrelaterade beslut.
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| 47. |
- Andersson, Therese, 1983-
(author)
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Acute Pulmonary Embolism : not just an acute condition after all
- 2022
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Doctoral thesis (other academic/artistic)abstract
- Background: Acute pulmonary embolism (PE) is the third most common cardiovascular disease following myocardial infarction and stroke. Despite diagnostic improvements, the diagnosis of PE is still associated with many difficulties, as the symptoms of an acute PE are nonspecific. Even though an acute PE is associated with a high short-term mortality, less attention has been given to long-term mortality. In addition, the clinical course following an acute PE may be accompanied by substantial morbidity, and one feared complication is chronic thromboembolic pulmonary hypertension (CTEPH), a progressive pulmonary vasculopathy. In addition to CTEPH, increasing evidence suggests that a large proportion of patients report persistent functional impairment several years after an acute PE. Recently, the term chronic thromboembolic pulmonary disease (CTEPD) has been proposed for those with remaining symptoms and signs of residual thrombotic material in the pulmonary arteries. Methods and Results: A nation-wide Swedish cohort of all patients (n= 5793) diagnosed with an acute PE in 2005 was identified. The incidence of PE was 0.6/1000 person-years, and during a 4-year follow-up, the mortality was more than doubled compared with an age- and sex-matched control group. We found that the acute PE associated with multiple comorbidities, and with cardiovascular diseases in particular. All surviving patients in 2007 (n=3510) were invited to answer a questionnaire regarding dyspnea and related comorbidities. We demonstrated a substantially higher prevalence of both exertional dyspnea (53.0% vs. 17.3%) and wake-up dyspnea (12% vs. 1.7%) in patients compared to controls from the Northern Sweden MONICA study. Furthermore, PE associated independently with dyspnea in a multivariable analysis. Through a manual review of approximately 10 % of the patient’s medical records, a positive predictive value of 79% was found for the PE diagnosis. Post-PE patients with remaining dyspnea and/or previously known risk factors for CTEPH development were referred for blood sampling and levels of N-terminal (NT)-prohormone (pro) brain-type natriuretic peptide (BNP) were determined. Thereafter, they were referred to their local hospital for a pulmonary ventilation/perfusion (V/Q) scintigraphy and echocardiography. Approximately 45% of the V/Q-scans showed perfusion defects and 27 % of echocardiographies showed signs of pulmonary hypertension. In total, 24 cases of CTEPH were identified, resulting in a prevalence of 0.4 % (95 % confidence interval 0.2 %–0.6 %). Conclusion: An acute PE is a serious event, associated with decreased survival, multiple comorbidities, frequent dyspnea, and pathological investigational findings. The term CTEPD seems reasonable as it captures that this is a disease of the pulmonary vasculature, and that pharmacological and surgical interventions used for CTEPH may be useful. Regardless, proper follow-up after acute PE is essential for timely identification of patients in need of appropriate investigations and care.
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| 48. |
- Andersson, Therése, 1978-
(author)
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Estrogen and Glucocorticoid Metabolism
- 2010
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Doctoral thesis (other academic/artistic)abstract
- Background: Cardiovascular disease (CVD) is the leading cause of death among women in Sweden. The risk of CVD increases rapidly after the menopause. A major contributing factor may be the redistribution of adipose tissue, from the peripheral to central depots, associated with menopause. This change in body composition is commonly attributed to declining estrogen levels but may also be affected by tissue-specific alterations in exposure to other steroid hormones, notably glucocorticoids – mainly cortisol in humans. Indeed, adipose tissue-specific overexpression of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) induces central obesity, insulin resistance and hypertension in mice. Interestingly, estrogen may regulate this enzyme. The aim of this thesis was to investigate putative links between estrogen and glucocorticoid activation by 11βHSD1. Materials and Methods: 11βHSD1 expression and/or activity in adipose tissue and liver, and adipose estrogen receptor α and β (ERα and ERβ) gene expression, were investigated in lean pre- and postmenopausal women and ovariectomized rodents with and without estrogen supplementation. In lean women measures of 11βHSD1 were correlated to risk markers for CVD. The association between adipose 11βHSD1 and ER mRNA expression was investigated in both lean women and rats and in an additional cohort of obese premenopausal women. In vitro experiments with adipocyte cell lines were used to explore possible pathways for estrogen regulation of 11βHSD1. Results: Subcutaneous adipose tissue transcript levels and hepatic activity of 11βHSD1 were higher in postmenopausal vs. premenopausal women. In rodents, estrogen treatment to ovariectomized rats decreased visceral adipose tissue 11βHSD1, resulting in a shift towards higher subcutaneous (vs. visceral) 11βHSD1 mRNA expression/activity. Increased adipose and hepatic 11βHSD1 were associated with increased blood pressure and a disadvantageous blood lipid profile in humans. We found significant positive associations between 11βHSD1 and ERβ transcript levels in adipose tissue. The in vitro experiments showed upregulation of 11βHSD1 mRNA expression and activity with estrogen or ERβ-agonist treatment at low (corresponding to physiological) concentrations. Conclusions: Our studies show for the first time increased local tissue glucocorticoid activation with menopause/age in women. This may contribute to an increased risk of CVD. Estrogen treatment in rodents induces a shift in 11βHSD1 activity towards the subcutaneous adipose tissue depots, which may direct fat accumulation to this metabolically “safer” depot. The in vitro studies suggest that low-dose estrogen treatment upregulates 11βHSD1 via ERβ. In summary, estrogen - glucocorticoid metabolism interactions may be key in the development of menopause-related metabolic dysfunction and in part mediate the beneficial effects of postmenopausal estrogen treatment on body fat distribution.
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| 49. |
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| 50. |
- Andersson, Ulrika, 1963-
(author)
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Experimental studies in brain tumours : with special regard to multidrug resistance and the ErbB-family
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Primary brain tumours, and especially the most common form malignant gliomas, usually display a pronounced resistance to other treatment modalities when surgery fails to cure. Growth factors, such as EGF and its receptor, frequently amplified and overexpressed in malignant gliomas, and factors associated with multidrug resistance have been suggested to at least partially explain the poor outcome. The aim of this thesis was to characterise factors in primary brain tumours associated with the development of resistance with focus on the epidermal growth factor receptor (ErbB) family, and multidrug resistance (MDR). Influences of irradiation on the expression and activity of P-glycoprotein (Pgp) in malignant gliomas was evaluated. The effects showed that irradiation increased the efflux activity of Pgp in rat brain vascular endothelial cells, but not in glioma cells. In the intracranial BT4C glioma model, Pgp was detected in the capillary endothelium in the tumour tissue but not in glioma cells. Expression of several factors coupled to MDR (Pgp, MRP1, LRP, and MGMT) in primary brain tumours were analysed and correlated to clinical data. In gliomas, Pgp and MRP1 were predominantly observed in capillary endothelium and in scattered tumour cells, whereas LRP occurred only in tumour cells. In meningiomas, expression of the analysed markers was demonstrated in the capillary endothelium, with a higher expression of Pgp and MRP1 in transitional compared to meningothelial meningiomas. A pronounced expression of MGMT was found independently of the histopathological grade or tumour type. Survival analysis indicated a shorter overall survival for patients suffering from low-grade gliomas with high expression of Pgp. To explore the importance of the epidermal growth factor receptor (EGFR), expression levels of the family members (EGFR, ErbB2-4) were analysed and their relations to various clinical parameters were evaluated in gliomas and meningiomas. In gliomas, the highest EGFR expression was observed in high-grade tumours, while ErbB4 expression was most pronounced in low-grade tumours. In meningiomas, expression of EGFR, ErbB2, and ErbB4 was observed in the majority of the tumours. An intriguing observation in low-grade gliomas was a significantly decreased overall survival for patients with high EGFR protein expression. The effects of different time schedules for administration of the selective EGFR inhibitor ZD1839 in relation to irradiation of glioma cells were analysed. The analyses showed a heterogeneity in the cytotoxic effects of ZD1839 between cell lines, and it was obvious that some of the cell lines showed sensitivity to ZD1839 despite no or low expression of EGFR. The study also demonstrated the importance of timing of ZD1839 administration when this agent is combined with irradiation. In conclusion, in order to enhance the efficacy of radiotherapy by various drugs in malignant gliomas it may be essential to inhibit drug efflux activity in endothelial cells and to deliver drugs in an optimal timing in relation to radiotherapy. The heterogeneity in expression of drug resistance markers, as well as the ErbB family reflects the complexity in classification of primary brain tumours, and indicates that subgroups of patients with low-grade gliomas expressing Pgp and EGFR might benefit from more aggressive and individualised treatment.
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