| 1. |
- Law, Lucy, 1987-
(författare)
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Subclinical cardiovascular disease and health related quality of life in patients with radiographic axial spondyloarthritis
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Radiographic axial spondyloarthritis (r-axSpA) is a chronic inflammatory rheumatic disease predominantly affecting the axial skeleton. The global prevalence of r-axSpA is between 0.1-1.4%. The disease is associated with extra-musculoskeletal manifestations (EMMs) such as anterior uveitis (AU), as well as increased risk of cardiovascular disease (CVD)-related comorbidities such as atherosclerosis that significantly contribute to mortality and the burden of disease in patients with r-axSpA. The increased CVD risk is not fully explained by traditional CVD risk factors, and little is known about the difference in CVD risk profiles between the sexes. Moreover, the association of disease related variables and subclinical signs of CVD by ultrasound remain to be comprehensively investigated in a well-characterized and sex stratified patient cohort. Additionally, studies investigating factors related to health-related quality of life (HRQoL) in patients with r-axSpA acknowledge that r-axSpA patients have a lower HRQoL than the general population. However, constancy in study methods and comparison to general population controls, especially stratified by sex, are limited. Objectives: The global aim of this thesis was to explore novel methods relating to the evaluation, detection, and monitoring of factors contributing to the burden of CVD in patients with r-axSpA, and to increase knowledge about HRQoL. More specifically, to study the impact of r-axSpA on HRQoL (Paper 1) and identify novel ultrasound markers of subclinical CVD (Papers 2-4) in patients with r-axSpA, overall, stratified by sex, and compared to controls. Materials and methods: Paper 1: The Short Form-36 (SF-36) questionnaire was used to assess HRQoL in patients with r-axSpA from Western Sweden (n=210, females 42.4%). Each patient was compared to 5 age- and sex-matched persons from the SF-36 Swedish normative population database (n=1055). Papers 2-4: Ultrasound was used to (i) assess bilateral common carotid arterial (CCA) stiffness by calculation of b-stiffness index and circumferential 2D strain (Paper 2); (ii) measure mean bilateral carotid intima media thickness (cIMT) and investigate its relationship with biomarkers of inflammation (Paper 3); and (iii) assess the mean thickness of the epicardial adipose tissue (EAT) deposit and its associations with traditional CVD related risk factors (Paper 4). Papers 2-4 used a well characterized patient group from Northern Sweden (‘Backbone cohort’, n=155, female 31.0%). The control group for paper 2 included 46 age- and sex- matched persons from the local population, with no traditional CVD risk factors. The control group for papers 3 and 4, was derived from the Umeå region Swedish CArdioPulmonary bioImaging Study (SCAPIS) recall study (n= 400, females 51.0%). All results were presented stratified by sex. Uni- and multi-variate regression analysis methods were used to evaluate associations with disease and demographic variables. All studies were of cross-sectional design.Results: Paper 1: Patients exhibited significantly lower HRQoL compared to controls (P<0.001). Upon stratification by sex, both sexes scored significantly lower physical compared to the mental HRQoL scores. Multivariable logistic regression analysis found that patients with a longer disease duration, worse physical function (assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI), high disease activity (measured by the Ankylosing Spondylitis Disease Activity Score (ASDAS)), or who lived alone had significantly lower physical HRQoL. Lower mental HRQoL was associated with fatigue, high ASDAS and living alone. Some differences in sex were also found. Paper 2: Patients had higher mean bilateral CCA b-stiffness index, and lower 2D CCA circumferential strain, compared to controls. Multivariate linear regression analysis found that several disease related parameters, in addition to age, were related to 2D circumferential strain (R2 0.33), whereas only age was related to b-stiffness index (R2 0.19). Paper 3: Linear regression analysis, with various adjustment models, showed that patients had increased cIMT compared to controls. White blood cell (WBC)- and monocyte- count were the only inflammatory biomarkers associated with cIMT. This association was only seen in male patients and remained after adjustments. Paper 4: Mean EAT was thicker in r-axSpA patients overall and stratified by sex compared to controls. No difference in mean EAT was found between the sexes. There were borderline significant associations between EAT thickness and cholesterol levels in male patients.Conclusion: Patients with r-axSpA have decreased HRQoL and increased subclinical indicators of CVD compared to controls. By modifying factors, such as ASDAS-CRP and fatigue, HRQoL may be improved in patients with r-axSpA. Additionally, ultrasound methods are non-invasive, and easily obtainable, offering additional insights into the factors that influence the risk of CVD in r-axSpA patients. Although further studies are required to validate novel ultrasound methods, these techniques represent a powerful approach to non-invasively to detect, monitor, and help manage CVD related comorbidities.
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| 2. |
- Holmgren, Anders, 1956-
(författare)
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Metabolic risk markers and relative survival in patients with aortic stenosis requiring surgery
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Aortic stenosis (AS) is the most common valve disorder requiring surgery in developed countries. The etiology of AS is only partly known. Identification of new biomarkers in prospective studies could lead to novel insights in the etiology of AS, and possibly lead to improved clinical management. Long term observed survival after aortic valve surgery has improved over the last decades despite an ageing population presenting with more comorbidities. Whether this is reflected in improved relative survival is not known. We evaluated if biomarkers associated prospectively with AS requiring surgery, and if these associations differed between genders, time to surgery and the presence of coronary artery disease (CAD). We also assessed long term observed and relative survival after aortic valve surgery with and without concomitant coronary artery by-pass surgery (CABG).Methods and results: Study I: We prospectively studied the impact of lipoprotein (a)(Lp[a]) and apolipoproteins (Apo) in subgroups of AS. During a 20-year period, 336 patients with prior participation in large population-based surveys in northern Sweden were operated due to AS plus CABG when indicated. For each case two referents were matched. Data from the baseline survey were collected and included data on cardiovascular risk factors, health history, measurements of anthropometry, blood pressure, blood glucose and blood lipid levels were retrieved. Data from pre- and perioperative assessments were also collected. The presence of CAD was determined from the coronary angiogram. Elevated levels of Lp(a) and an elevated Apo B/Apo A 1 ratio were independently associated with future surgery for AS, but only in patients with concomitant CAD (OR 1.29, 95 % CI 1.07-1.55 and 1.43, 95 % CI 1.16-1.76 respectively). Study II: The same patient cohort as in study I was used. A panel of 92 cardiovascular candidate proteins were analysed with the multiplex proximity extension assay in samples obtained at baseline. Six circulating proteins (growth differentiation factor 15[GDF-15], galectin-4, von Willebrand factor [vWF], interleukin 17 receptor A, transferrin receptor protein 1, and proprotein convertase subtilisin/kexin type 9, [PCSK9]) were associated with future surgery for AS in patients with concurrent CAD (ORs ranged from 1.25 to 1.37 per SD increase in the protein signal). In the validation study with 106 additional cases, the association of all but one, (interleukin 17 receptor A), of these proteins were replicated in patients with AS and concurrent CAD but not in those without concurrent CAD. Study III: In the same patient cohort as in study I and II we evaluated if troponin T (TnT) and C-reactive protein (CRP) associated prospectively with future surgery for AS. TnT was independently associated with surgery for AS in patients both with (OR 1.22, 95 % CI 1.02-1.46) and without concomitant CAD (1.39, 95% CI 1.05-1.84). CRP was not associated with surgery for AS (OR 1.06, 95 % CI 0.92-1.23). Study IV: 4970 patients between 2005 and 2016 from three Swedish heart surgery centres, undergoing aortic valve replacement (AVR) due to either AS or aortic regurgitation in conjunction with CABG when indicated, were followed up. All-cause mortality, as well as both observed and relative survival, was analysed with focus on age, sex, type of valve prosthesis and the impact of concomitant CABG. Median follow-up was 4.7 years (2.3-7.6). 30-day mortality was 2.3 %. Long-term survival with 30-day mortality excluded was 96.6 %, 82.7 %, 57.6 % after 1, 5 and 10 years respectively. Relative survival rates (adjusting for the background mortality in the general Swedish population based on age, sex and year) were 99.6 %, 99.5 % and 90.6 % after 1, 5 and 10 years respectively. Age had a negative influence on observed survival (p<0.001) but was associated with better relative survival (relative mortality rate [RMR] 0.74, 95 % CI 0.71 - 0.77). Women had a lower observed mortality than men (p<0.001) but a lower relative survival (RMR 1.17, 95 % CI 1.02-1.35). Combined surgery (AVR+CABG) was not significantly associated with higher mortality (p=0.43) in a multivariable adjusted analysis. The presence of bicuspid morphology was associated with lower observed mortality compared with tricuspid valve, and a relative survival matching that in the general population.Conclusion: I. Plasma levels of Lp(a) and the Apo B/Apo A 1 ratio were independently associated with future surgery for AS but only in patients with concomitant CAD. This finding suggests that patients with AS have different phenotypes and may open a new avenue of research on targeted risk factor interventions in this population. II. Five circulating proteins – GDF-15, galectin-4, vWF, transferrin receptor protein 1, and PCSK9 – were associated with the need for aortic valve surgery several years later. The role of these proteins should be investigated in future studies. III. Elevated plasma levels of TnT were independently associated with future surgery for AS, irrespective of the presence of concomitant CAD, which could indicate that the myocardium is subject to mechanical stress already in the subclinical stage of AS. This may be used as a clinical tool for identification of patients with subclinical AS who could benefit from early intervention. Elevated CRP levels did not associate with future AVR. IV. Relative survival following AVR was particularly good in the elderly matching that in the general population underlining the benefits of aortic valve surgery in properly selected patients. Women had decreased relative survival compared to men. This should be explored in future studies. Adding CABG to an AVR procedure was not associated with increased risk. Bicuspid valve morphology was associated with lower observed mortality compared with tricuspid valve morphology, and with a relative survival matching that of the general population.
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| 3. |
- Jacobson, Sofie, 1961-
(författare)
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Severe sepsis : epidemiology and sex-related differences in inflammatory markers
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background. Sepsis is a syndrome associated with high mortality rates, substantial morbidity and high costs of care. The incidents of sepsis is reported to be high and controversy exists whether gender affect severity or outcome. Little is known about factors determining susceptibility for developing the syndrome and severity of the syndrome once developed. Early detection and adequate antibiotic administration are the mainstay of treatment and means to identify patients with particular high risk of adverse outcome are desirable. There are data to suggest that the course of sepsis and outcome from the syndrome may be influenced by inherited differences in the immunological response among humansAims: Paper I: Assess incidence and outcome for ICU-treated sepsis patients in this region; Paper II: Assess if there are gender differences related to characteristics, aspects of treatment or outcome in sepsis in this region. Paper III: Assess the association of baseline levels of leptin and adiponectin and future sepsis event, and association of these adipokines in the cute phase and sepsis severity and outcome. Paper IV: Assess association of baseline levels of mannose-binding lectin (MBL) and future sepsis event, and MBL levels in the acute phase in relation to sepsis severity and outcome.Results. Paper I: Overall ICU mortality rate was 25%, while the ICU mortality for patients with septic shock was 58% in this retrospective single university hospital cohort analysis. Cardiovascular disease and diabetes were the most prevalent comorbidities among patients who died during hospital stay. Paper II: No gender-related differences in mortality or length of stay was found in this prospective single center observational study. Differences in aspects of treatment were related to differences in site of infection. Men had more often infections in skin and skin-structures, whereas women more often had abdominal infections. Early organ dysfunction assessed as SOFA score at admission was a stronger predictor for hospital mortality for women than for men. The discrepancy was related to the SOFA coagulation-sub score. Paper III: In this nested case-referent study hyperleptinemia at baseline predicted a first-ever sepsis event, even after adjustment for BMI and other cardiovascular risk factors. Hyperleptinemia in the acute sepsis phase was associated with reduced risk of in-hospital death in men, but associated with increased risk of in-hospital death in women. Paper IV: In the same matched cohort as in Paper III high baseline levels of MBL predicted a first ever sepsis event. High MBL levels in the acute phase or an increase from baseline to the acute phase associate with increased in-hospital death in women but not in men. Low MBL levels was not identified as a risk for acute sepsis or in-hospital death.Conclusions. Mortality from severe sepsis is high, equally affecting men and women. There are differences in patient characteristics and inflammatory markers, which associate with in-hospital mortality differentially in men and women. Aspects of gender should be mandatory, and genetic analysis are desired in future sepsis research.
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| 4. |
- Parks, Luke
(författare)
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Development of directed-evolution methods utilizing combinatorial protein libraries in Escherichia coli
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Directed evolution using combinatorial protein libraries is a tremendously powerful technique for the generation of proteins with new or improved properties. A key aspect in such techniques is the link between individual protein variants and their corresponding genetic information. To provide this link, the most successful combinatorial protein engineering methods employ microorganisms, such as bacteriophages, bacteria or yeast for the production and display of libraries. This thesis focuses on the development and application of new directed evolution methods utilizing the bacterium Escherichia coli (E. coli), for the engineering of affinity proteins and proteases.The first study aimed to engineer the substrate specificity of a protease from tobacco etch virus (TEV). For this purpose, a novel method was devised based on expression of intracellular protease libraries, and employed a reporter fusion protein consisting of amyloid β peptide fused to the N-terminus of enhanced green fluorescent protein (EGFP). Variants were screened for proteolytic activity on co-expressed target substrate by means of fluorescence-activated cell sorting (FACS). After three rounds of FACS, a set of TEV protease variants were enriched that exhibited improved proteolytic activity on the novel substrate.Studies two to four describe the development of an E. coli surface expression system that was explored for directed evolution applications. The method is based on display of recombinant proteins on the outer membrane via fusion to a bacterial autotransporter, adhesin involved in diffuse adherence I (AIDA-I). The second study focused on the optimization of the surface display system and its application to directed evolution. In this effort, several affinity protein classes were evaluated for surface display via AIDA-I in a panel of E. coli strains. Results showed that smaller and less complicated affibody molecules were displayed at high levels, while more complex proteins, such as antibody fragments, varied in their performance and functioned best in certain engineered strains. A mock affibody library was used to develop a high-throughput magnetic-assisted cell sorting (MACS) protocol for enrichment of binders from very large libraries.In the third and fourth study, the new E. coli display method combined with the MACS protocol was evaluated for generation of new affibody molecules.In the third study, a large naïve affibody library (>1.5×1011 members) was constructed, displayed on E. coli and characterized. The performance of the method and library was evaluated by selection of binders against two cancer-associated targets, tumor-associated calcium signal transducer 2 (TROP-2) and lymphocyte-activation gene 3 (LAG-3). MACS and FACS were performed, with flow cytometry assessment between rounds to monitor enrichment. Both selections produced high affinity binders to their respective targets.In the fourth study, a maturation library was constructed for improving the properties of an affibody molecule toward the renal cell carcinoma biomarker carbonic anhydrase IX (CAIX). Selections included stringent off-rate procedures and yielded variants with improved affinities and folding stability compared to previously reported binders.In summary, the work in this thesis demonstrate the potential of E. coli-based directed evolution methods for selection of new proteins with altered or improved properties.
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| 5. |
- Shimanda, Panduleni Penipawa, 1989-
(författare)
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Rheumatic heart disease in Namibia : evaluating the burden and the cost-effectiveness of a preventive strategy
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Rheumatic Heart Disease (RHD) is a neglected public health problem, which is most prevalent in low-and middle-income countries. It affects over 460 million people and causes about 390,000 deaths annually, predominantly children, young adults, and women. This thesis aimed to assess the burden of Rheumatic Heart Disease in Namibia and to evaluate the cost-effectiveness of a preventive strategy.Methods: Data was obtained from primary and secondary sources in four distinct studies. The first study analysed the RHD outpatient and inpatient data from 2010-2020. The second employed a cross-sectional survey, incorporating a questionnaire with the EQ-5D-5L tool, to assess the health-related quality of life and healthcare usage pre- and post-RHD diagnosis. A systematic review was conducted in the third study synthesising preventive interventions, while the fourth study used a Markov model to evaluate the cost-effectiveness of a secondary prevention strategy in Namibia.Results: The clinical RHD prevalence was estimated at 28 per 100,000 cases. From the survey, 83 RHD patients participated, predominantly women (77%) and primarily young adults aged 20-29 (41%). The majority (84%) had received surgical treatment. Notably, there was a significant increase in mean QALY from 0.773 pre-diagnosis to 0.941 post-diagnosis (p<0.001). The systematic review underscored the effectiveness of school and nurse-led prevention programmes. The health economic evaluation demonstrated that echocardiographic RHD screening was cost-effective, with an Incremental Cost-Effectiveness Ratio of N$ 28,516.75 per QALY gained, which falls below Namibia’s GDP per capita.Conclusions: The findings highlight a significant gap in RHD data, particularly in high-endemic regions like Sub-Saharan Africa, emphasising the need for enhanced data quality and surveillance. The effectiveness of school-based and community-led programmes is apparent, but the scarcity of data from diverse regions limits a comprehensive understanding of optimal prevention strategies. Echocardiographic screening is identified as a feasible component of RHD secondary prevention in Africa, pointing towards a policy need for improved surveillance and data quality. Future research should investigate the impact of various interventions on RHD incidence and prevalence.
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| 6. |
- Tossavainen, Erik, 1977-
(författare)
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In the hands of ohm : hemodynamic aspects in pulmonary hypertension
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Congestive heart failure (CHF) is one of the most challenging diseases in terms of health care demand and mortality, in the western world. Despite major breakthroughs in the fields of diagnosis and treatment over the three last decades, the management of CHF still remains challenging.CHF is defined as inability of the heart to supply sufficient blood flow to meet the needs of the body. This definition however, may be an oversimplification of a complex pathophysiological process since patients with overt CHF may have normal, or even supernormal cardiac output at the expense of increased filling pressures, which subsequently leads to the development of post capillary pulmonary hypertension (PH). In the presence of advanced CHF, clinical signs and symptoms are obvious at rest. However, the majority of affected individuals do not experience any discomfort at rest and may demonstrate normal findings when assessed. Small increases in systemic blood pressure and or venous return, caused by activity may result in severe elevation of filling pressures if left ventricular compliance is significantly decreased. This example highlights the need to perform cardiac investigations during stress to provoke symptoms. Increased pulmonary vascular resistance (PVR), commonly found in pre-capillary PH, is a condition that shares many symptoms with CHF, and is also associated with poor prognosis. Even though the disease is located within the lung vessels, it is highly important and challenging task differentiating pre- and post-capillary PH. Since treatment differs considerably and may be detrimental in case of misdiagnosis, additional sensitive and reliable screening methods are crucial to aid in differentiation.Methods: Out of the four studies included in this thesis, three were conducted solely at Norrland’s University Hospital, while patients in the third study were recruited and examined at Uppsala Akademiska Hospital. All included patients had idiopathic dyspnea and were admitted for right heart catheterization (RHC), which is gold standard with regards to hemodynamics. Echocardiographic examinations were performed simultaneously with RHC, except in the Uppsala study, wherein echocardiography were performed within 3 days to the RHC.Echo-Doppler derived pulmonary artery acceleration time (PAcT) is an easily assessed parameter, indicating elevated pulmonary artery systolic pressure (PASP) and pulmonary artery resistance (PVR). PAcT was tested as a screening method for identification and differentiation of pre and post- capillary PH in a cohort of 56 patients (study 1).The ability to calculate PVR non-invasively, using novel echocardiographic measurements, was made by replacing the invasive pressure and flow components that constitutes the foundation of the PVR = (mean pulmonary artery pressure – Pulmonary capillary wedge pressure (PCWP)) /cardiac output), with novel echocardiographic measurements. PVR = mPAP-Chemla – Left atrial strain rate during atrial systole (LASRa) / Cardiac Output-Echo (study 2).Invasively measured left ventricular filling pressure in response to passive leg lifting, and its ability to predict pathological increase in left ventricular filling pressures during supine bicycling, was tested in a population of 85 patients with normal left ventricular ejection fraction (LVEF) and suspicion of CHF based on NT-proBNP levels alone were investigated (Study 3).Finally, an evaluation of standard and novel Doppler echocardiographic parameters, potentially useful in identifying patients who may develop increased filling pressures during passive leg lifting (PLL), was carried out (study 4).Results:Study 1: PAcT correlated negatively with pulmonary artery systolic pressure (PASP) (r = -0.60, p < 0.001) and PVR (r = -0.57, p < 0.001). PAcT of <90 ms had a sensitivity of 84% and a specificity of 85% in identifying patients with PVR ≥ 3.0 WU. Regardless of normal or elevated left sided filling pressures, PAcT differed significantly in patients with normal, compared to those with elevated levels of, PVR (p < 0.01). A significant difference was also found on comparison of the PAcT/PASP ratio (p < 0.01), with a lower ratio among patients with PVR ≥ 3.0. WU.Study 2: We prospectively used Doppler and 2D echocardiography in 46 patients with sinus rhythm which revealed that left atrial strain rate during atrial systole (LASRa) had the highest significant positive correlation with PCWP (r2 = 0.65, P < 0.001). By adopting a linear line of best-fit, LASRa may therefore be substituted for PCWP. Subsequently, LASRa was substituted into the PVR equation. This novel echocardiographically derived PVR calculation, significantly correlated with RHC generated PVR values (r2 = 0.69, P < 0.001) and minor drift (+0.1WU) when assessed by Bland Altman analysis.Study 3: Only 22% (11/51) of patients with elevated NT-proBNP had PCWP above normal levels at rest. However, in response to PLL, 47% of patients developed elevated PCWP, and the majority of this 47% subsequently developed pathological pressure levels while performing supine cycling exercise. Thus, the likelihood of developing high LVFPs during exercise could be determined by PLL, with a sensitivity and specificity of 90%.Study 4: At rest, left atrial volume indexed to body mass index (BMI) (LAVI) and mitral deceleration time (DT) were independently related to PCWP during PLL. However, during PLL univariate regression analysis revealed LASRa (β = -0.77, P <0,001) and E/LVSRe (β = 0.47, P < 0,021) most related to PCWPPLL. Multiple regression analysis fortified LASRa and E/LVSRe as relevant independent parameters useful in the assessment of filling pressure during PLL.Conclusion: A PAcT < 90ms is strongly suggestive of increased PVR (>3.0 WU). Based on study 1, there is clear evidence suggesting that these findings apply irrespective of LVFPs. PAcT can potentially serve as a rapid screening tool for estimation of PVR, however, is not useful if the exact level of PVR is required. In this case, an established PVR calculation method is preferred, and could be performed with higher precision by inclusion of echocardiography derived LASRa as a surrogate measure of PCWP. Insufficient LV compliance results in the inability to cope with increased cardiac preload. Nt-proBNP is secreted when the myocardium is stretched, however only a small portion of patients within the CHF group (study 3) had a high PCWP at rest. Nearly half of the study population with elevated NT-proBNP showed increased PCWP during PLL, which is indicative of underlying ventricular stiffness. By performing this preload increasing maneuver, patients predisposed to developing high filling pressure during supine cycling could be identified with high sensitivity and specificity. Echocardiography, in comparison with RHC, is more accessible, safer and requires less resources and time, thus is an appealing option in the quest to identify additional, non-invasive methods reflective of invasive pressures, which could be useful in the assessment of filling pressure during different loading conditions. LAVI at rest, LASRa and E/LVSRe during PLL, proved independently related to PCWP during PLL.
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| 7. |
- Andersson, Jonas, 1969-
(författare)
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Adipose tissue as an active organ : blood flow regulation and tissue-specific glucocorticoid metabolism
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Despite advances in the treatment of atherosclerosis, cardiovascular disease is the leading cause of death worldwide. With the population getting older and more obese, the burden of cardiovascular disease may further increase. Premenopausal women are relatively protected against cardiovascular disease compared to men, but the reasons for this sex difference are partly unknown. Redistribution of body fat from peripheral to central depots may be a contributing factor. Central fat is associated with hyperlipidemia, hyperglycemia, hypertension, and insulin resistance. Two possible mediators of these metabolic disturbances are tissue-specific production of the stress hormone cortisol and adipose tissue blood flow (ATBF). The aim of this thesis was to determine the adipose tissue production of cortisol by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and to investigate the regulation of ATBF. Materials and Methods: Cortisol release was estimated by labeled cortisol infusions and tissue-specific catheterizations of subcutaneous and visceral adipose tissue (VAT) in men. We investigated ATBF by 133Xe-washout and its relation to autonomic activity, endothelial function, adipose tissue distribution, and adipokines in different groups of women. We further investigated the effect of two diets and of weight loss on ATBF in women. Results: We demonstrated significant cortisol release from subcutaneous adipose tissue in humans. Splanchnic cortisol release was accounted for entirely by the liver. Cortisol release from VAT (to the portal vein) was not detected. ATBF decreased according to increasing weight and postmenopausal status, and the level of blood flow was associated with nitric oxide (NO) activity and autonomic activity. ATBF was also highly associated with leptin levels and both subcutaneous adipose tissue and VAT areas. After 6 months of diet and weight reduction, a significant difference in ATBF was observed between diet groups. Conclusions: Our data for the first time demonstrate the contributions of cortisol generated from subcutaneous adipose tissue, visceral tissues, and liver by 11β-HSD1. ATBF is linked to autonomic activity, NO activity, and the amount of adipose tissue (independent of fat depot). Postmenopausal overweight women exhibited a loss of ATBF flexibility, which may contribute to the metabolic dysfunction seen in this group. Weight loss in a diet program could not increase the ATBF, although there were ATBF differences between diet groups. The results will increase understanding of adipose tissue biology and contribute to the development of treatment strategies targeting obesity and obesity-related disorders.
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| 8. |
- Andersson, Therese, 1983-
(författare)
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Acute Pulmonary Embolism : not just an acute condition after all
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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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| 9. |
- Arnqvist, Johan, 1985-
(författare)
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Mean Wind and Turbulence Conditions in the Boundary Layer above Forests
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- As wind turbines have grown, new installation areas become possible. Placing wind turbines in forested landscapes introduce uncertainties to the wind resource estimation. Even though close-to-canopy processes have been studied intensively during the last thirty years, the focus has mostly been on exchange processes and the height span of the studies has been below the rotor of a modern wind turbine.This thesis contains analysis of new measurements from a 138 m high tower in a forested landscape. The previous knowledge of near-canopy processes is extended to the region above the roughness sublayer. It is shown that above the roughness sublayer, the surface layer behaves as over low vegetation, and Monin-Obukhov similarity is shown to hold for several variables. However, in stable stratification, effects that could be linked to the boundary layer depth are shown to be present in the measurements. These include wind turning with height, the behaviour of the turbulence length scale and the curvature of the wind profile.Two new analytical models are presented in the thesis. One is a flux-profile expression in the roughness sublayer, which allows for analytical integration of the wind gradient. The model suggests that the roughness-sublayer effect depends on stratification and that the aerodynamic roughness length changes with stability. A decrease of roughness length in stable stratification is confirmed with a new method to determine the roughness length using measurements from the 138 m tower.The other model determines the spectral tensor in stable stratification using analytical solution to the rapid distortion equations for stratified shear flow, with homogeneous stratification and shear. By using a formulation for the integration time of the distortions of an isotropic spectrum, a model is derived which provides the cross spectra of velocity and temperature at any two given points in space.Finally the existence of waves in the wind over forests is investigated and it is concluded that the Kelvin-Helmholtz instability can create waves which are coherent in time and exist over the entire height span of wind turbine rotors. Linear wave theory is shown to be able to explain certain features of the waves.
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| 10. |
- Bergsten, Ulrika, 1966-
(författare)
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Patients' and healthcare providers' experiences of the cause, management and interaction in the care of rheumatoid arthritis
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aim: The overall aim of this thesis was to explore and describe patients’ and healthcare providers’ experiences of the causes, management and interaction in the care of rheumatoid arthritis (RA). Method: The thesis is based on four studies. Studies I and II contain data from an epidemiologic project involving patients who were recently diagnosed with RA. The patients answered an open-ended question about their conception of the cause of their RA (Study I). Qualitative data from 38 patients were analysed using the phenomenographic approach in order to identify variation in conceptions. The results of Study I formed the basis for categorizing the conceptions of 785 patients in the search for patterns of background factors (Study II). Study III aimed to explore how patients experienced their management of RA in everyday life. Data were collected by interviews with 16 patients and analysed according to Grounded Theory (GT). In study IV, the aim was to explore healthcare providers’ experiences of their interaction with patients’ management of RA. Data were collected by interviews with 18 providers representing different professions and analysed using GT. Findings: Patients’ conceptions of the cause of their RA revealed new aspects from the patient perspective that can complement pathogenetic models. Two descriptive categories emerged: consequences beyond personal control and overloaded circumstances, which included six categories of conceptions (Study I). The most common conceptions of the cause of RA were unexpected effects of events followed by work and family-related stress (Study II). Background factors that influenced the conceptions of the cause were age, sex and educational level. Patient management of RA involved using personal resources together with grasping for support from others in their striving for a good life. When linking these aspects together, four ways of management emerged: mastering, struggling, relying and being resigned (Study III). Healthcare providers’ experiences of their interaction with patients’ management shed light upon the important issue of delivering knowledge and advice. The providers’ attitudes constituted one cornerstone and patients’ responses the other. The providers reported that the interaction led to different outcomes: completed delivery, adjusted delivery and failed delivery. Conclusions: The findings contribute new knowledge from both patients’ and healthcare providers’ perspectives, which could be used to develop a more person-centred approach in rheumatology care. Person-centred care involves taking patients’ beliefs and values into account in addition to creating a trusting relationship between patient and provider. A successful person-centred approach requires an organisation that supports the person-centred framework.
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