| 1. |
- Norda, Rut A C, 1948-
(författare)
-
Plasma as a Therapeutic Principle in Clinical Practice : With Special Reference to Sweden
- 2007
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The newly established Swedish Apheresis Registry makes it possible to do national inter-center comparisons. This study was undertaken to describe and analyze the use of therapeutic apheresis and the adverse effects in such therapy. The special case of plasma exchange as rescue therapy in multi-organ failure, including renal failure, was also studied. In Sweden, plasma for transfusion is prepared and stored to ensure rapid availability. Due to new EU legislation, validation of such plasma was performed. The analysis indicated that the use of therapeutic apheresis was in line with recommendations of other international societies. The frequency and types of adverse effects were comparable to those reported in other studies from analogous time periods. Compared with other countries, it appears that more therapeutic resources are available in Sweden and that there is a lower frequency of adverse effects in specific procedures. No fatalities were reported. The unique comparison of differences between centers regarding plasma exchange identified areas for further improvement.The study on plasma exchange as rescue therapy in severe sepsis or septic shock is the second largest reported. The result was promising, with a survival rate of 82%. The rapid availability of plasma for transfusion appears to be of clinical importance in patients with early coagulopathy and severe trauma but the present selection and storage procedures for plasma lead to a time-dependent increase of the number of units with cold-induced activation of the contact system and C1 inhibitor consumption before day 14. Improvements of plasma quality can be attained by using plasma from male donors only and by reducing the storage time from 14 to 7 days. Further studies are needed to define the role of plasma exchange in severe sepsis/septic shock, to evaluate the outcome of each patient’s treatment and to establish the indications for the transfusion of plasma.
|
|
| 2. |
|
|
| 3. |
- Lejon, Anna G.C. 1979-
(författare)
-
Ecosystem response to dam removal
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis aims to improve our understanding of how riverine ecosystems respond to dam removal. Riverine and particularly riparian ecosystems are among the most variable and important features of all landscapes. They connect landscape elements both longitudinally and laterally, and are governed by processes such as flooding, erosion and deposition that create dynamic, diverse and heterogeneous habitats. In fact, riparian zones are among the world’s most species-rich habitats. Worldwide there are millions of dams that fragment stream and river systems, regulate flows and degrade ecosystems. Dams impact freshwater, marine and terrestrial ecosystems and threaten biodiversity by disrupting organism movements and energy flows in the landscape. An important upstream effect of dams is inundation of habitats and development of new shorelines around impounded areas. Effects downstream of dams are mainly caused by changed hydrological regimes and retention of organic and inorganic materials in reservoirs, leading to reduced transport and dispersal of for example seeds to reaches downstream. The removal of dams create expectations that biota will eventually recover. We have studied a number of dam removal projects in Sweden. Our experimental results showed that following dam removal, newly exposed soils in former impoundments were rapidly colonized by pre-removal species. Their species richness increased slightly with time and their species composition indicated a slow change towards that in the reference site. In addition, the vegetation in formerly impounded areas showed a direction of change from lentic riparian plants (high proportion of aquatics) towards lotic ones, consisting of native perennials typical of free-flowing streams. We also found that the apprehensions that former impoundments would turn into pools of mud did not come true; in fact, a process towards more pristine channel morphology was observed. After removal there was erosion and downstream transport of sediment. We found only minor effects on macroinvertebrate communities. For example, a few species decreased over the years, suggesting that dam removal in itself might cause a temporary disturbance. This highlights the importance of long-term studies after dam removal, and also the importance of comparisons with pre-removal conditions and stretches unaffected by dams. Thorough documentation of executed dam removal projects and distribution of the results and experiences are tremendously important in the planning process of future decommissioning projects. Also, our experiences have taught us that in order to attain a successful dam removal it is important to involve stakeholders such as non-governmental organizations and local inhabitants in the process.
|
|
| 4. |
- Nilsson, Amalia C.
(författare)
-
A Lighter Shade of Dark : Exploring the Value Adding and Value Subtracting Effects of Headquarters Attention and Involvement in Subsidiary Activities
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Headquarters of multinational corporations are presented with a diverse range of stimuli that influences the issues that they pay attention to and ultimately get involved in. However, headquarters have to prioritize since their attention and resources are limited, and they cannot pay attention to all issues and get equally involved in all subsidiaries. To stand out and attract attention and involvement, subsidiaries can use different issue selling tactics to present headquarters with issues that are strategically important to the subsidiary. While headquarters can add value to their subsidiaries by paying attention and getting involved in subsidiary activities, there is also a risk of headquarters making different prioritizations than the subsidiaries, and instead subjecting them to misguided involvement and value subtraction. Existing research tends to assume that the more attention a subsidiary receives, the better off it will be. However, I reevaluate this assumption, and complement existing research by examining how subsidiaries experience headquarters attention and involvement, and the effects on subsidiary activities.Data were collected at the subsidiary level, using interviews and a survey to capture the subsidiary perspective of headquarters attention and involvement. More specifically, 115 interviews were conducted with subsidiary managers of European MNCs based in Japan, and survey data was collected from 93 Japanese subsidiaries of European MNCs. The empirical findings highlight circumstances under which headquarters attention and involvement can add or subtract value from subsidiary activities. Furthermore, subsidiaries can highlight strategic issues during their issue selling efforts to attract headquarters involvement that has a beneficial impact on subsidiary activities. I extend the parenting literature by developing an attention-based parenting typology and showing how misaligned priorities risk exposing subsidiaries to value subtraction rather than value added during headquarters involvement. This thesis also contributes to elaborating on the attention-based view by exploring mixed types and levels of attention, as well as circumstances under which negative attention can be perceived as beneficial and value adding by subsidiaries.By incorporating the attention-based view with the parenting literature and issue selling, this thesis extends our understanding of the headquarters-subsidiary relationship, highlights circumstances under which subsidiaries appreciate attention and involvement, and shows a darker side of headquarters’ parenting in which subsidiaries risk experiencing value subtraction.
|
|
| 5. |
- Nilsson, Emma C, 1979-
(författare)
-
Cellular receptors for viruses with ocular tropism
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Several viruses from different virus families are known to cause ocular infections, e.g. members of the Adenoviridae, Picornaviridae and the Herpesviridae families. These infections are spread by contact and in the case of adenoviruses (Ads) and picornaviruses they are also highly contagious. The ocular infections caused by Ads and picornaviruses are called epidemic keratoconjunctivitis (EKC) and acute hemorrhagic conjunctivitis (AHC), respectively. Historically, EKC is caused mainly by three types of Ads from species D: Ad8, Ad19 and Ad37. The infection is characterized by keratitis and conjunctivitis but also involves pain, edema, lacrimation and blurred vision. AHC is caused mainly by two types of picornaviruses: coxsackievirus A24v (CVA24v) and enterovirus 70 (EV70), and is characterized by pain, redness, excessive tearing, swelling and subconjunctival hemorrhages. In addition, blurred vision, keratitis, malaise, myalgia, fever, headache and upper respiratory tract symptoms can also be experienced. Both infections are problematic in many parts of the world, affecting millions of people every year. Despite the great need, the only treatment available today is supportive treatment; no antiviral drugs are available to combat these common viral infections. Ad37 has previously been reported to use sialic acid (SA) as its cellular receptor. Since there is no antiviral treatment available against EKC we wanted to evaluate the inhibitory effect of SA-based antiviral compounds on Ad37 binding to and infection of ocular cells. We found that multivalent compounds consisting of SA linked to a globular carrier molecule, in this case human serum albumin, efficiently blocked Ad37 binding and infection at low concentrations. Further attempts were then made to improve the effect by chemically modifying SA monosaccharides. However, no enhanced inhibitory effect was accomplished and the conclusion was that the best inhibitors are based on unmodified SA. We next hypothesized that development of efficient SA-based binding inhibitors may require detailed knowledge about the structure of the SA-containing receptor. Using a battery of biological and biochemical experiments, including glycan array, binding and infection assays, X-ray crystallography and surface plasmon resonance (SPR); we identified a specific glycan involved in the binding and infection of Ad37. This glycan turned out to be a branched, di-SA-containing motif corresponding to the glycan motif of the ganglioside GD1a. However, the ganglioside itself did not function as a cellular receptor, as shown by a number of binding and infection assays. Instead, the receptor consisted of one or more glycoproteins that contain the GD1a glycan motif. This glycan docked with both its SAs into the trimeric Ad37 knob resulting in a very strong interaction as compared to most other protein-glycan interactions. Hopefully, this finding will aid development of more potent inhibitors of Ad37 binding and infection. The receptor for CVA24v, one of the main causative agents of AHC, has been unknown until now. We showed that this ocular virus, like Ad37, is also able to use SA as a receptor on corneal cells but not on conjunctival cells. This suggested that CVA24v may use two different receptors. As for Ad37, the receptor used by CVA24v on corneal cells also appears to be one or more sialic acid-containing glycoproteins. We believe that these findings may be a starting point for design and development of candidate drugs for topical treatment of AHC.
|
|
| 6. |
- Nilsson, Gunnel, 1950-
(författare)
-
Zopiclone degradation in biological samples : Characteristics and consequences in forensic toxicology
- 2014
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bio-analytical results are influenced by in vivo factors such as genetics, pharmacological and physiological conditions and in vitro factors such as specimen composition, sample additives and storage conditions. Zopiclone (ZOP) is a short-acting hypnotic drug (Imovane®) used for treatment of insomnia. ZOP is metabolized by three major pathways; oxidation to the active zopiclone N-oxide (ZOPNO), demethylation to the inactive N-desmethylzopiclone (NDZOP) and oxidative decarboxylation to other inactive metabolites. ZOP is increasingly being encountered in forensic cases and is a common finding in samples from drug-impaired drivers, users of illicit recreational drugs, victims of drug facilitated sexual assaults and forensic autopsy cases. ZOP is a notoriously unstable analyte in biological matrices and analytical results depend on pre-analytical factors, such as storage time and temperature. The overall aim of this thesis was to investigate the stability of ZOP and the factors of importance for degradation during storage in biological samples and to identify consequences for interpretation of results in forensic toxicology.In paper I, different stability tests in spiked samples were performed including short-term, longterm, freeze-thaw and processed stability. Analyses of ZOP were performed by gas chromatography with nitrogen phosphorous detection and ZOP concentrations were measured at selected time intervals. The degradation product 2-amino-5-chloropyridine (ACP) was identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The stability investigations showed a very poor short-term storage stability of ZOP.Therefore, in paper II, the influence of pre-analytical conditions was further investigated in dosed subjects. Whole blood from volunteers was obtained before and after oral administration of Imovane®. In this study, the influence from physiological factors such as drug interactions, matrix composition and plasma protein levels were minimized. The results showed that ZOP was stable in whole blood for only one day at room temperature, one week in a refrigerator and at least three months frozen in authentic as well as in spiked whole blood. The rapid degradation of ZOP at ambient temperature can cause an underestimation of the true concentration and consequently flaw the interpretation. However, by also analyzing the degradation product ACP the original concentration of ZOP may be estimated.In papers III and IV, two LC-MS-MS methods were validated for the quantitation of ACP, ZOP and NDZOP in blood and ACP, ZOP, NDZOP and ZOPNO in urine. These methods were used in a controlled pharmacokinetic study where whole blood and urine were obtained after oral administration of Imovane®. Samples of blood and urine were aliquoted, analyzed and stored under different conditions and the formation of ACP was monitored. Additionally, at each studied time point the pH of the blood and urine samples was measured using i-STAT® system. The results showed that ACP was formed in equimolar amounts to the degradation of ZOP and its metabolites.In urine samples, the formation of ACP occurred at elevated pH or temperature and mirrored the degradation of ZOP, NDZOP and ZOPNO. The high concentrations of metabolites, which also degraded to ACP, made it impossible to estimate the original ZOP concentration.The results from analysis of blood samples containing ACP were also used to develop mathematical models to estimate the original ZOP concentration. Both models showed strong correlation to the original ZOP concentration (r=0.960 and r=0.955) with p<0.01. This study showed that the equimolar degradation of ZOP and NDZOP to ACP could be used to estimate the original concentration of ZOP in blood samples.Absence of ACP in the blood or urine samples analysed strongly suggests that degradation has not occurred and that the measured concentration of ZOP is reliable. For proper interpretation in forensic cases, it is strongly recommended that ZOP and its metabolites as well as ACP are included in the analysis.
|
|
| 7. |
|
|
| 8. |
- Nilsson, Peter, 1970-
(författare)
-
Conjugated polyelectrolytes : conformation sensitive optical probes for the recording of biological processes
- 2005
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The physical properties of conjugated polymers can be utilized for a wide range of biosensors. For instance, the conformational flexibility fouud in conjugated polyelectrolytes, allows direct connection between the geometry of chains and the resulting electronic structure and optical processes, since the extension of the π-conjugated system is distorted by conformational changes of the polyelectrolyte backbone. The biosensors presented in this thesis are utilizing conformational changes of conjugated polyelectrolytes for the detection of biomolecular processes, such as biospecific interactions and conformational changes of biomolecules. The methodology have been used for the detection of DNA-hybridization, single nucleotide polymorphism (SNP) in DNA, conformational alterations of synthetic peptides, conformational alterations of Calmodulin and binding of Ca2+-activated Calmodulin (CaM) to Calcineurin, and amyloid fibril formation of amyloidogenic proteins.The method is based on non-covalent assembly of a conjugated polyelectrolyte and a biomolecule of interest. Upon exposure to a second biomolecule recognizing the first biomolecule or a conformational change of the first biomolecule, a conformational alteration of the polyelectrolyte backbone and a change in the electronic properties of the polyelectrolyte occurs, and these alterations can be detected by a change of the absorption or the fluorescence from the polyelectrolyte. Hence, conjugated polyelectrolytes can be used as novel conformation sensitive optical probes for the detection of several biological processes. The biomolecular interaction or the conformational changes of the biomolecule are reflected as an alteration of the geometry and the electronic structure of the bouud polyelectrolyte chains and are detected by absorption and emission. The present mechanism may be used for detection of a variety biomolecular processes, and the simplicity and the diversity of this methodology make it suitable for making inexpensive protein- and DNA-chips for rapid detection of biomolecular recognition.
|
|
| 9. |
- Otten, Volker T C, 1973-
(författare)
-
The Uncemented Cup in Total Hip Arthroplasty : stability, Wear and Osteolysis
- 2019
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Artificial hip joint replacement has undergone tremendous development in the past 100 years. In the beginning, complications, such as infection and early loosening, were the rule rather than the exception. Today, complications of any sort are rare during the first decade after the operation. Artificial hip joint replacement has been chosen as the "Operation of the Century" and has dramatically improved the quality of life of millions of patients. Unfortunately, in the long-term, prosthesis loosening due to pathological bone resorption (osteolysis) around the prosthesis is still common. Traditionally, the prosthesis is anchored in the bone with bone cement (Plexiglas). However, since this cementation method was suspected to cause late loosening, alternative methods, such as the implantation of so-called uncemented prostheses, have been developed and are being increasingly applied. Because the early movement of a prosthesis (migration) increases the risk of loosening, uncemented cups are often augmented with additional screws. The mechanisms regulating the early and late loosening of uncemented cups are not fully established. Wear particles from the artificial joint and intermittent fluid pressure on the bone appear to accelerate or even cause bone loss and can eventually lead to loosening of the prosthesis. Therefore, screw holes in the uncemented cup have been suspected to be a risk factor.Aims: We have studied whether the additional augmentation of modern uncemented cups with screws, pegs or hydroxyapatite increases the long-term stability, affects the wear rate, influences the development of osteolysis, or has any impact on the risk of cup revision. Furthermore, we investigated whether computed tomography (CT), which is needed to detect osteolysis around the prosthesis, could also be used in the follow-up of migration studies without losing significant precision compared to radiostereometry (RSA), which is the gold standard for these measurements.Patients and Methods: In studies I-III, we evaluated 48 hips (45 patients) randomized to receive cups with or without augmentation. As part of the 14-year follow-up with conventional radiographs of the pelvis, two pairs of stereo radiographs and a CT scan were obtained. Migration and wear were measured by RSA. The volume and type of osteolysis were determined on CT. Furthermore, we calculated the precision and limit of agreement of RSA and CT to compare these two modalities as tools for migration measurements.In study IV, we compared the risk of cup revision between 10,371 uncemented cups with and 12,354 without screw holes, using data from the Swedish Hip Arthroplasty Register.Results: Study I: Cup stability was equally good regardless of cup augmentation. The mean wear rate of the cup liner was high, at 0.21 mm/year, with no significant difference between the groups.Study II: The limit of agreement between CT and RSA was 1.15°, 1.51°, and 0.70° for rotation and 0.46, 0.43, and 0.52 mm for translation. These results were within the described normal 99% confidence limits for precision in RSA: 0.3° to 2° for rotation and 0.15 to 0.6 mm for translation.Study III: Osteolysis of some degree was visible in all 48 hips on CT. We found three different types of osteolytic lesions: type 1A, absent trabecular bone and a sclerotic border around the lesion; type 1B, absent trabecular bone and no sclerotic border; and type 2, reduced radiodensity and reduced trabecular number. Cups with screw holes were surrounded with larger osteolytic lesions, and osteolysis around these cups was more likely to be a type 1A lesion.Study IV: Cups without screw holes showed a decreased risk of cup revision (implant exchange or removal) due to any reason at both 2 years (adjusted hazard ratio, HR: 0.6, confidence interval, CI: 0.5-0.8) and 10 years (HR: 0.7, CI: 0.5- 0.9). However, for aseptic loosening, there was no significant difference between cups with and without screw holes, with an implant survival rate of 99.9% (CI: 99.8-99.9) at 2 years and 99.1% (CI: 98.6-99.7) at 10 years.Conclusion: Uncemented cups augmented with screws, pegs, or hydroxyapatite do not have improved long-term stability compared with cups with press-fit only. Unsealed screw holes in uncemented cups appear to be a risk factor for the development of larger osteolytic lesions. CT showed three different types of osteolytic lesions. The risk of aseptic loosening for modern uncemented cup designs is very low, and cups without additional augmentation do not have an increased revision rate. In contrast, the risk of cup revision for any reason was higher for cups with screw holes. CT can be used for migration studies for the longitudinal evaluation of patients with tantalum markers with precision comparable to that of RSA.
|
|
| 10. |
- Sörme, Pernilla, et al.
(författare)
-
Design and Synthesis of Galectin Inhibitors
- 2003
-
Ingår i: Recognition of Carbohydrates in Biological Systems, Part B: Specific Applications (Methods in Enzymology; 263). - 0121822664 ; 363, s. 157-169
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Galectins, a lectin family, have shown binding affinities towards b-galactosides. Galectins have been proposed to be involved in a wide range of functions like for example, cell growth, adhesion, migration, chemo taxis and apoptosis. They have also been associated with various cancer types. However, the detailed functions of galectins are still very much unknown. High affinity inhibitors towards the galectins would thus be of value as research tools, as well as possible future pharmaceutical agents. Existing inhibitors have undesirable properties, for example high molecular weight and instability. This thesis concerns the synthesis of small high affinity galectin inhibitors. A previously published X-ray structure of galectin-3 together with LacNAc revealed an extended binding pocket close to 3´-C of the galactoside residue. Filling this pocket with additional chemical entities was hypothesized to allow for further interactions and hence creating higher affinity ligands as compared to the naturally occurring ligand. The hypothesis was probed by substituting the 3´-hydroxyl group on the galactose unit of LacNAc with an amine, which enables the introduction of functional groups under mild reaction conditions. We synthesised a collection of more than 60 LacNAc derivatives with various functional groups at 3´-C of the galactose unit. The measurements of inhibitor potencies towards galectins were made in a novel fluorescence polarisation (FP) assay, which is a solution phase method, as well as a general technique that do not need major re-optimisation to enable the study of other galectins. Hence, it enabled us to study the panel of synthetic inhibitors towards galectin-1, -3 and –4. Selective and high affinity inhibitors were discovered, which is of value as often more than one galectin is present in one and the same system. We found that aromatic amides in particular showed high affinity towards galectin-3. In addition, the X-ray structure of one of the best inhibitors (Kd 0.9 mM) revealed that Arg-144 on galectin-3 had moved 3.5 Å to enable a face-to-face stacking interaction with a 4-methoxy-2,3,5,6-tetrafluorobenzamido substituent. The best inhibitor synthesised as of yet, carried a 2-naphthamido functionality at 3´of the galactose residue. This inhibitor had a Kd of 0.3 mM, which the strongest binding affinity achieved as compared to any monovalent inhibitor. It shows over 200 times higher affinity towards galectin-3 than the unfunctionalised LacNAc.
|
|
