| 11. |
- Andersson, Sara B. E., 1987-
(författare)
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Novel and refined small-scale approaches to determine the intrinsic dissolution rate of drugs
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many drugs are administered as crystalline particles compressed into tablets and taken orally. When the tablet reaches the gastrointestinal tract, it disintegrates and the drug particles dissolve in the gastrointestinal fluid. The dissolved molecules are absorbed across the intestinal membranes into the bloodstream to reach their target sites. Only dissolved molecules can be absorbed, and if a drug has low solubility and/or dissolution rate in gastrointestinal fluid, the drug absorption might be insufficient. Hence, knowing the solubility and dissolution behaviour of a potential drug candidate is necessary early in the drug development process. The aim of this thesis was to evaluate and refine different approaches for measuring and determining dissolution rate, as well as to develop novel in vitro small-scale dissolution methods. First, interlaboratory variability in determination of intrinsic dissolution rate (IDR) and apparent solubility (Sapp) was investigated using a miniaturized dissolution instrument. To minimize the interlaboratory variability, standardized protocols for both the experimental design and the data analyses were required, and a flow chart for performing standardized powder and disc IDR measurements was established. Next, as an alternative to the powder and disc methods, carefully dispersed suspensions were used to determine the IDR, and rapid and more controlled IDR measurements were obtained using suspensions with dispersed primary particles. From the suspension measurements, an IDR/Sapp ratio of the compounds were determined. This ratio can potentially be used to identify whether a compound is likely to show dissolution rate-limited absorption and hence is sensitive to particle size reduction. The final experiments used a single particle dissolution approach to determine the IDR at four different fluid velocities. Computational fluid dynamics (CFD) simulations were used to theoretically investigate the flow conditions and dissolution rates. Single particle dissolution measurements under well-defined conditions gave high-quality dissolution data. An IDR was determined within 5-60 minutes using particles with initial diameters of 37.5-104.6 μm. The single particle dissolution experiments were used to determine the thickness of the effective hydrodynamic boundary layer (heff). The heff values were also assessed by CFD simulations, and a good concordance between experimental and simulated heff values was obtained. The approaches presented in this thesis can be used to derive qualified knowledge about the dissolution properties of drugs with several potential applications in drug development, such as profiling of solid drugs, informed formulation decisions, assisting the modelling of drug dissolution and providing improved understanding of the in vivo-dissolution behaviour
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| 12. |
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| 13. |
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| 14. |
- Dini, Hoda, 1984-
(författare)
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As-cast AZ91D magnesium alloy properties : Effects of microstructure and temperature
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Today, there is an essential need for lightweight, energy-efficient, environmentally benign engineering systems, and this is the driving force behind the development of a wide range of structural and functional materials for energy generation, energy storage, propulsion, and transportation. These challenges have motivated the use of magnesium alloys for lightweight structural systems. Magnesium has a density of 1.74 g/cm3, which is almost 30% less than that of aluminium, one quarter of steel, and almost identicalto polymers. The ease of recycling magnesium alloys as compared to polymers makes them environmentally attractive, but their poor mechanical performance is the primary reason for the limited adoption of these alloys for structural applications.The Mg-Al-Zn alloy AZ91D exhibits an excellent combination of strength, die-castability, and corrosion resistance. However, its mechanical performance with regard to creep strength, for example, at evaluated temperatures is poor. Moreover, very little is known about the correlation between its mechanical properties and microstructural features. This thesis aims to provide new knowledge regarding the role played by microstructure in the mechanical performance of the magnesium alloy. The properties/performance of the material in relation to process parameters became of great interest during the investigation.An exhaustive characterisation of the grain size, secondary dendrite arm spacing (SDAS) distribution, and fraction of Mg17Al12 was performed using optical and electron backscatter diffraction (EBSD). These microstructural parameters were correlated to the offset yield point (Rp0.2), fracture strength, and elongation to failure of the material. It was proposed that the intermetallic phase, Mg17Al12, plays an important role in determining the mechanical and physical properties of the alloy in a temperature range of room temperature to 190°C by forming a rigid network of intermetallic. The presence of this network was confirmed by studying the thermal expansion behaviour of samples of the alloy containing different amounts of Mg17Al12.A physically based constitutive model with a wide validity range was successfully adapted to describe the flow stress behaviour of AZ91D with various microstructures. The temperature-dependent variables of the model correlated quite well with the underlying physics of the material. The model was validated through comparison with dislocation densities obtained using EBSD.The influence of high-pressure die-cast parameters on the distortion and residual stress of the cast components was studied, as were distortion and residual stress in components after shot peening and painting. Interestingly, it was found that intensification pressure has a major effect on distortion and residual stresses, and that the temperature of the fixed half of the die had a slight influence on the component's distortion and residual stress.
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| 15. |
- Ekdahl, Christer, 1962-
(författare)
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Infective Endocarditis : aspects of pathophysiology, epidemiology, management and prognosis
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Infective endocarditis (IE) is a rare but complex disease that is fatal if untreated. With a modern combination of antimicrobial therapy and heart valve surgery, mortality is still 10-20 %. The structure of the endocarditis vegetation impedes the penetration of phagocytic cells such as monocytes and granulocytes. This leads to high bacterial counts inside the vegetation and the need for long treatment courses with a combination of intravenously administered bactericidal antibiotics.The aim of this thesis was to study the changes in epidemiology, management, and mortality at our hospital between 1980 and 2001, and to identify prognostic factors associated with mortality. To assess the issue of referral bias, differences between referred episodes and episodes from our local community were studied. Additional aims were to study the occurrence of the pro-chemotactic cytokines IL-8 and TNF-α in heart valves and vegetations during the active phase of IE, and to study the effect of the glycopeptide antibiotic vancomycin in dense staphylococcal cultures in vitro. As it is a rare and complex disease, management of IE is usually complicated for non-specialists. For this reason a computerised decision support system for IE was developed and evaluated.Between 1980 and 2001, the occurrence of Staphylococcus aureus IE and the use of early heart valve surgery increased significantly, regardless of whether the episodes were referred or of local origin. Glycopeptide antibiotics, mainly vancomycin, were used more frequently, especially among referred patients. Referred patients were younger, predominantly male, had more complications, and received surgical treatment more often than patients from our local community. The reason for the lower frequency of female patients in the referral cohort cannot be explained by more comorbidity or fewer complications. The differences between referred and local episodes seen in our study highlight the need for assessment and adjustment for referral bias in IE studies (Paper I).In six patients who needed early heart valve surgery, the largest numbers of IL-8-containing cells, and the greatest amount of inflammation, were seen in patients with short preoperative antimicrobial treatment courses. No such relationships were seen with respect to TNF-α-containing cells. The IL-8-containing cells and the inflammatory cells were predominantly scattered in the heart valve stroma or in the margin of the vegetation (Paper II). The primary effect of IL-8 is to stimulate chemotaxis of polymorphonuclear neutrophil granulocytes. This indicates that there is no deficiency of IL-8 in the area close to the vegetation as a cause of the localised agranulocytosis often present inside the vegetation.Our study revealed a need for computerised decision support systems (DSSs) in the field of IE, but to be used in clinical practice these DSSs need be part of knowledge bases covering larger domains (Paper IV). Some of our initial ideas described in Paper III, especially the use of Internet technology and the combination of rule-based advice and explanatory hypertext, will probably be included in these knowledge bases.In vitro, there is a rapid reduction of free vancomycin in broth containing dense staphylococcal cultures. Consequently, there is a simultaneous increase in broth MICs, particularly in high inocula, which is not caused by a development of resistance (Paper V). These findings need further evaluation in vivo, but indicate that the dosing regimen of vancomycin is of particular importance in staphylococcal infections with dense inocula, e.g. infective endocarditis.Diabetes mellitus and moderate to severe heart failure were independent risk factors for 6-month mortality in left-sided, Duke definite IE episodes, regardless of referral or local origin of the episodes. Early heart valve surgery had a positive impact on the 6-month mortality in the referral cohort of episodes, which may be due to referral bias (Paper VI).
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| 16. |
- Karlsson, Peter S.
(författare)
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Issues of incompleteness, outliers and asymptotics in high dimensional data
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis consists of four individual essays and an introduction chapter. The essays are in the field of multivariate statistical analysis of High dimensional data. The first essay presents the issue of estimating the inverse covariance matrix alone and when it is used within the Mahalanobis distance in High-dimensional data. Three types of ridge-shrinkage estimators of the inverse covariance matrix are suggested and evaluated through Monte Carlo simulations. The second essay deals with incomplete observations in empirical applications of the Arbitrage Pricing Theory model and the interest is to model the underlying covariance structure among the variables by a few common factors. Two possible solutions to the problem are considered and acase study using the Swedish OMX data is conducted for demonstration. In the third essay the issue of outlier detection in High-dimensional data is treated. A number of point estimators of the Mahalanobis distance are suggested and their properties are evaluated. In the fourth and last essay the relation between the second central moment of a distribution to its first raw moment is considered in an financial context. Three possible estimators are considered and it is shown that they are consistent even when the dimension increases proportionally to the number of observations.
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| 17. |
- Kunz, Barbara, 1980-
(författare)
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Kind words, cruise missiles and everything in between : A neoclassical realist study of the use of power resources in U.S. policies towards Poland, Ukraine and Belarus 1989–2008
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This study intends to explain why the United States led entirely different policies towards Poland, Ukraine and Belarus under circumstances where realist theory would predict otherwise. Realism being an “environment based theory”, it would indeed predict a state to lead highly similar foreign policies under identical conditions. Yet, within the overall context of managing unipolarity, the US has clearly led different policies toward these three countries from the demise of the Soviet Union to the end of the second Bush Administration (i.e., in the years 1989 to 2008). In seeking to explain that puzzle, this study follows a path hitherto neglected by neoclassical realist scholarship: a strong emphasis on the bilateral dimension in all foreign policies. Poland, Ukraine and Belarus are friendly, undecided and non-friendly states, respectively, as seen from a Washington perspective. What type of power resources seems appropriate in addressing them is likely to depend on this status. The study subsequently shows that different types of power resources or “base values” underlie the various foreign policy tools employed with respect to the studied countries. For that reason, it argues that perceptions of states’ friend, non-friend or undecided statuses should be considered an element of the missing link neoclassical realists identified between states’ power resources and their foreign policy output.
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| 18. |
- Lindroos, Hillevi Lina, 1976-
(författare)
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Studies of Genome Diversity in Bartonella Populations : A journey through cats, mice, men and lice
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bacteria of the genus Bartonella inhabit the red blood cells of many mammals, including humans, and are transmitted by blood-sucking arthropod vectors. Different species of Bartonella are associated with different mammalian host species, to which they have adapted and normally do not cause any symptoms. Incidental infection of other hosts is however often followed by various disease symptoms, and several Bartonella species are considered as emerging human pathogens.In this work, I have studied the genomic diversity within and between different Bartonella species, with focus on the feline-associated human pathogen B. henselae and its close relatives, the similarly feline-associated B. koehlerae and the trench-fever agent B. quintana which is restricted to humans.In B. henselae, the overall variability in sequence and genome content was modest and well correlated, suggesting low levels of intra-species recombination in the core genome. The variably present genes were located in the prophage and the genomic islands, which are also absent from B. quintana and B. koehlerae, indicating multiple independent excision events. In contrast, diversity of genome structures was immense and probably associated with rearrangements between the repeated genomic islands located around the terminus of replication, possibly to avoid the host’s immune system. In both B. henselae and the mouse-associated species B. grahamii a large portion of the chromosome was manifold amplified in long-time cultures and packaged into phage particles, allowing for different recombination rates for different chromosomal regions.In B. quintana, diversity was studied by sequencing non-coding spacers. The low variability might be due to the recent emergence of this species. Surprisingly, also this species displayed high variability in genome structures, despite its lack of repeated sequences.The results indicate that genome rearrangements and gain or loss of mobile elements are major mechanisms of evolution in Bartonella.
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| 19. |
- Mahajan, Mayank
(författare)
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Evolution of cellular complexity and other remarkable features in Gemmataceae : Complex bacterial lineages defy prokaryotic trends
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bacteria of the family Gemmataceae belong the phylum Planctomycetes and are remarkable because of their complex cellular architectures, previously considered to be traits exclusive to eukaryotes. This thesis provides clues to the atypical cell envelope, the enhanced radiotolerance and the amazing cellular complexity of these bacteria.A comparative genomics study of these bacteria revealed massive duplications and new combinations of structural domains that are highly abundant in eukaryotes but rare in bacteria. These domains are known to facilitate signalling and protein interactions. The proteins of these bacteria also contain long regions with no predicted domains. On average, eukaryotic proteins are longer and more disordered than prokaryotic proteins. Intriguingly, the length and fraction of disordered regions in proteins of some bacteria are higher than in many other prokaryotes, and these bacteria also have complex lifestyles. Many bacteria in the Planctomycetes, including the Gemmataceae, are among these few bacteria. This suggests that there is no sharp boundary between prokaryotes and eukaryotes with respect to protein length and domain composition patterns, as previously thought.A bioinformatics analysis revealed the loss of genes for the peptidoglycan cell wall in some lineages of the Planctomycetes. Loss of the gene for the FtsZ protein, the major cell division protein in bacteria, may have facilitated the evolution of budding in the Planctomycetales and led to the gradual loss of the cell wall and cell division gene cluster. These changes may have enabled the expansion of the inner membrane and triggered adaptive changes in conserved membrane proteins and transport systems. The loss of the peptidoglycan cell wall may also explain the altered cell morphology. A subcellular proteomics study showed that the DNA replication and repair proteins are associated with the cell envelope, which supports the cell factory model of DNA replication.T. immobilis, which has the simplest genome of all members of the Gemmataceae, was found to be naturally competent and most suitable for transformation experiments. T. immobilis was transformed to produce mutants in which the gene for DdrA, a double stranded break DNA repair protein, has been inactivated. The DdrA-null mutant showed a major loss in radiotolerance.
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| 20. |
- Nilsson, Pia
(författare)
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Price Formation in Real Estate Markets
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis includes an introductory chapter and four individual papers. The papers are held together by concepts associated with price formation in real estate markets, differentiated goods and the local character of land and housing markets. The first two papers focus on the markets for land and agricultural property and the two succeeding studies on housing markets. The first study examines regional variations of Swedish agricultural land prices. The associated empirical model follows the form of earlier literature in testing the influence of expected returns from the current agricultural use of land and the potential for non-agricultural use on prices. The use of market transacted land and the inclusion of decoupled income support to farmers, among a set of agricultural and non-agricultural factors, distinguishes this study from earlier empirical work.The second paper relates to the first by its focus on decoupled income support, but here the analysis extends to the micro level and to the study of price formation in the market for agricultural property. The study applies a spatial multilevel model to study variations in price determinants across and within local and regional markets.The third paper is devoted to the analysis of housing prices and their relation to open landscape amenities. The spatial analysis employs two geographical databases containing single-family home sales and preserved open spaces. In order to address the local character of urban housing markets and intraurban heterogeneity in amenity valuations the study applies a geographically weighted regression approach.The last paper focuses on the market for second homes with a particular emphasis on urban-rural interrelations. The paper is motivated by a growing demand for natural amenities and by the awareness that urban areas are becoming increasingly attractive markets for second homes.
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