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- Dahlin, Anna, 1979-
(författare)
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The CpG island methylator phenotype in colorectal cancer : studies on risk and prognosis
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Colorectal cancer (CRC) is the second most common malignancy in developed countries. The mortality is high, with nearly half of patients dying from the disease. The primary treatment of CRC is surgery, and decisions about additional treatment with chemotherapy are based mainly on tumor stage. Novel prognostic markers that identify patients at high risk of recurrence and cancer-related death are needed. The development of CRC has been described in terms of two different pathways; the microsatellite instability (MSI) and chromosomal instability (microsatellite stable, MSS) pathway. More recently, the CpG island methylator phenotype (CIMP), characterized by frequent DNA hypermethylation, has been described as an alternative pathway of tumorigenesis. The event of DNA methylation is dependent on one-carbon metabolism, in which folate and vitamin B12 have essential functions. The purpose of this thesis was to study CIMP in CRC. The specific aims were to investigate the potential role of components of one-carbon metabolism as risk factors for this subgroup of tumors, and the prognostic importance of CIMP status, taking into consideration important confounding factors, such as MSI and tumor-infiltrating T cells. Methods CRC cases and referents included in the Northern Sweden Health and Disease Study (NSHDS, 226 cases and 437 referents) and CRC cases in the Colorectal Cancer in Umeå Study (CRUMS, n=490) were studied. Prediagnostic plasma concentrations of folate and vitamin B12 were analyzed in NSHDS. In both study groups, CIMP status was determined in archival tumor tissue by real-time quantitative PCR using an eight-gene panel (CDKN2A, MLH1, CACNA1G, NEUROG1, RUNX3, SOCS1, IGF2 and CRABP1). MSI screening status and the density of tumor-infiltrating T cells were determined by immunohistochemistry. Results An inverse association was found between plasma concentrations of vitamin B12 and rectal, but not colon, cancer risk. We also found a reduced risk of CIMP-high and CIMP-low CRC in study subjects with the lowest levels of plasma folate. We found that patients with CIMP-low tumors in both NSHDS and CRUMS had a poorer prognosis compared with CIMP-negative, regardless of MSI screening status. We also found that MSS CIMP-high patients had a poorer prognosis compared with MSS CIMP-negative. The density of tumor-infiltrating T cells and CIMP status were both found to be independent predictors of CRC patient prognosis. A particularly poor prognosis was found in patients with CIMP-low tumors poorly infiltrated by T cells. In addition, the density of T cells appeared to be more important than MSI screening status for predicting CRC patient prognosis. Conclusion Rather than being one disease, CRC is a heterogeneous set of diseases with respect to clinico-pathological and molecular characteristics. We found that the association between risk and plasma concentration of vitamin B12 and folate depends on tumor site and CIMP status, respectively. Patient prognosis was found to be different depending on CIMP and MSI screening status, and the density of tumor-infiltrating T cells.
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| 2. |
- Hammam, Tag, 1961-
(författare)
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Electrical and Frictional Performance of Tin-Coated Contacts Exposed to Wear and Fretting Corrosion
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The complexity of electronic systems in vehicles is rapidly increasing, and as a consequence, the long-term reliability of automotive connectors has become an important issue. The aims of this thesis have been: 1. to characterize the friction, wear and electrical properties of tin coatings, 2. to achieve an improved fundamental understanding of the deterioration processes caused by wear and fretting corrosion, 3. to propose improvements of tin coatings systems for electrical connectors. The required insertion force has a significant impact on the design and the cost of a connector. A reduced insertion force can be achieved by reduced contact load and/or reduced tin coating thickness, but this will increase the risk of fretting corrosion. Wear during the insertion stroke is essential in order to wipe off the non-conductive oxide layer. However, a thin tin layer may become worn off after only a few insertion strokes. The rider will then partly slide on the hard intermetallic compound formed between the substrate and the residual tin. Due to the restricted wear when sliding on the intermetallic compound more oxide will be formed during sliding than is removed and consequently the electrical contact resistance will increase. Two semi-empirical models are proposed, the first describing the contact resistance when the rider plows the free tin layer, and the second describing the contact resistance increase due to oxidation when the rider slides on the intermetallic compound. Two novel methods to improve the performance of pre-tinned material were evaluated. The first involves the use of a lubricant in combination with a textured surface, to improve the supply of lubricant into the contact spot. The second involves the addition of small amounts of a preferential oxidation additive to the tin. This increases the possibility of achieving a cold-welded contact spot, which results in an ultimately stable connection.
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| 3. |
- Jänes, Arthur, 1970-
(författare)
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Parastomal hernia : clinical studies on definitions and prevention
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of the studies was to evaluate the short and long term effects on the development of parastomal hernia and stoma complications of a prophylactic prosthetic mesh placed in a sublay position at the index operation. Also the purpose was to validate a definition of parastomal hernia at clinical examination and a method and a definition of parastomal hernia at CT-scan. In the first two studies 27 patients were randomized to a conventional stoma or to a stoma with the addition of a partly absorbable low weight large pore mesh in sublay position. Patients were examined after one and five years. After five years the rate of parastomal hernia was 80% with a conventional stoma and 14% with the addition of a mesh. A prophylactic mesh did not increase the rate of complications. In the third study a prophylactic mesh was intended at stoma formation in 93 consecutive patients in routine surgery. In 75 patients provided with a mesh the rate of parastomal hernia after one year was 13%. Complication rates were not increased in 19 severely contaminated wounds. In the fourth study 27 patients with ostomies were examined by tree surgeons and parastomal hernia was defined as any protrusion in the vicinity of the stoma. CT-scans with patients examined in the supine and prone positions were assessed by three radiologists. Herniation was then defined as any intra abdominal content protruding beyond peritoneum or the presence of a hernia sac. Kappa was 0.85 for surgeons and 0.85 for radiologists with CT-scan in the prone position. Kappa was 0.80 for surgeons and radiologists collectively, with CT-scan in the prone position. Four parastomal hernias detected at CT-scan in the prone position could not be detected in the supine position. A parastomal hernia diagnosed at clinical examination was always detected at CT-scan in the prone position. Conclusions: A prophylactic mesh placed in a sublay position at the index operation reduces the rate of parastomal hernia without increasing the rate of complications. Parastomal hernia should at clinical examination be defined as any protrusion in the vicinity of the stoma with the patient straining in the supine and erect positions. At CT-scan, with the patient examined in the prone position, herniation should be defined as any intra abdominal content protruding beyond peritoneum or the presence of a hernia sac.
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| 4. |
- Ställvik, Olof, 1975-
(författare)
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Domarrollen : Rättsregler, yrkeskultur och ideal
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The role of judges has not previously been systematically analyzed in Swedish legal research. Rather, legal scholarship has focused on the role of courts as institutions in the legal system. This is despite the fact that legal education in Sweden is often said to be focused on the methods used by judges when dealing with cases. The aim of this dissertation is to consider the professional position of judges in Sweden by applying an interdisciplinary approach. This is done by combining the legal and constitutional notions of judicial independence with theories on professionalization and de-professionalization. Empirically the investigation is based on a constitutional and historical analysis as well as in-depth interviews with eighteen Swedish judges, thereby taking a broad methodological approach. The main conclusion is that actual judicial independence can not be attained solely by legal means and instruments. In fact, legal culture (as defined by the Finnish legal scholar Kaarlo Tuori) and judicial culture (as in professional culture) are more important for the existence of judicial independence than legal rules alone. Thus, professional values are often a more important guarantee of judicial integrity, professionalism and good judgment than constitutional or legal rules. However, legal rules can be a gauge as to how judicial independence is valued and ascertained in a specific legal culture. In Sweden, the judicial professional culture has been closely linked to the executive branch of government since the early 17th century. From a constitutional perspective, this raises questions concerning the independence of the judiciary vis-à-vis the executive and, perhaps more importantly, how judges perceive themselves and their role in the larger context of the Swedish legal order and legal culture. Are judges thus the agent of the executive, the protector of civil rights, the arbitrator of disputes, or something else? Furthermore, some recent developments in administrative management have put courts and judges under pressure. Often labeled New Public Management, these tendencies have conveyed a greater focus on the economic efficiency of public management, including auditing, management by objectives, and decentralization. This focus on management and economic efficiency threatens to infringe on professional autonomy and thus on judicial independence. However, this development is somewhat countered by other developments in Swedish legal culture, notably the influence of European human rights and community law.
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| 5. |
- Testorf, Martin, 1972-
(författare)
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Melanophores : cell biophysics and sensor applications
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis deals with studies of melanophores and melanosomes by means of a physical approach. Melanophores are pigment cells that give the black colour to many vertebrates, e.g. fishes, frogs, and reptiles. Covering large areas of the skin, these cells are approximately 0.1 mm in diameter, and they contain black pigment granules called melanosomes.The geometry and the electric charge of isolated melanosomes were two physical properties that were studied. The electric charge was measured by electrophoresis and was found to be (-1.7 ± 0.2)·10-16 Coulomb in average. The geometry of melanosomes was measured using Scanning Force Microscopy, SFM, and resulted in an ellipsoidal shape with an average major diameter of 840 ± 20 nm.Under nervous and hormonal control, melanophores rearrange the intracellular melanosomes from a scattered distribution, called dispersed, to a state where all melanosomes are accumulated in the cell centre, called the aggregated state. In this way, melanophores change from black towards transparent. This gives an animal the ability to change not only between being pale or dark, but also between different colours by using melanophores to cover and uncover the colours of different types of pigment cells from underlying layers.The volume of melanosomes was measured with SFM. This study resulted in a difference of 18% when individual melanosomes from aggregated and dispersed melanophores were measured separately.Magnetic field exposure of melanophores has been reported to affect the aggregation. However, contradicting results are presented in the literature. To clarify the possible effect of magnetic fields on melanophores, experiments by aggregating fish melanophores under exposure to strong (8 and 14 Tesla), homogenous, static magnetic fields were carried out. Both the magnetic field-induced Lorentz force on the charged melanosomes and the reorientation of the cytoskeleton were considered as possible explanations of any effects. Whenfield experiments were compared to control experiments with zero field, no difference in aggregation levels were found. However, a more irregular speed of aggregation was seen in the 8 Tesla field than in the control experiments.A theoretical model was developed to explain switch-like responses in biological systems. A switch-like response to a graded stimulation was sometimes seen in the case of melanophores but was shown not to have a very large so-called Hill coefficient. The model is simple in its approach. It may be applied to general phenomena and is based on the assumption of a simultaneous desorption of an activator (agonist; substrate molecule; ... ) and an inactivator (antagonist, inhibitor; ... ) caused by a collision or interaction between two effector molecules (e.g. receptors or enzymes).Melanosomes are also found in the human body and have a remarkably capacity to bind other molecules. A well-established forensic application of this is to detect (illegal) drugs that have bound to melanosomes in hair shafts. So far this application is only qualitative. This thesis includes a characterisation of the binding of flunitrazepam to melanin. Flunitrazepam is the active substance of Rohypnol, which is a sedative that is illegal in several countries and sometimes called the "date-rape-drug".Melanophores are excellent model systems for studies of cellular phenomena. Moreover, melanophores are also interesting in sensing aspects. The change from black to transparent is a highly visible response to substances in their surroundings and has previously been the measurand in melanophore-based biosensors. The physical approach of these studies of melanophores also had the objective of evaluating new biosensor solutions.
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| 9. |
- Öhberg, Fredrik, 1969-
(författare)
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Biomechanical methods and error analysis related to chronic musculoskeletal pain
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background Spinal pain is one of humanity’s most frequent complaints with high costs for the individual and society, and is commonly related to spinal disorders. There are many origins behind these disorders e.g., trauma, disc hernia or of other organic origins. However, for many of the disorders, the origin is not known. Thus, more knowledge is needed about how pain affects the neck and neural function in pain affected regions. The purpose of this dissertation was to improve the medical examination of patients suffering from chronic whiplash-associated disorders or other pain related neck-disorders. Methods A new assessment tool for objective movement analysis was developed. In addition, basic aspects of proprioceptive information transmission, which can be of relevance for muscular tension and pain, are investigated by studying the coding of populations of different types of sensory afferents by using a new spike sorting method. Both experiments in animal models and humans were studied to accomplish the goals of this dissertation. Four cats where were studied in acute animal experiments. Mixed ensembles of afferents were recorded from L7-S1 dorsal root filaments when mechanical stimulating the innervated muscle. A real-time spike sorting method was developed to sort units in a multi-unit recording. The quantification of population coding was performed using a method based on principal component analysis. In the human studies, 3D neck movement data were collected from 59 subjects with whiplash-associated disorders (WAD) and 56 control subjects. Neck movement patterns were identified by processing movement data into parameters describing the rotation of the head for each subject. Classification of neck movement patterns was performed using a neural network using processed collected data as input. Finally, the effect of marker position error on the estimated rotation of the head was evaluated by computer simulations. Results Animal experiments showed that mixed ensembles of different types of afferents discriminated better between different muscle stimuli than ensembles of single types of these afferents. All kinds of ensembles showed an increase in discriminative ability with increased ensemble size. It is hypothesized that the main reason for the greater discriminative ability might be the variation in sensitivity tuning among the individual afferents of the mixed ensemble will be larger than that for ensembles of only one type of afferent. In the human studies, the neural networks had a predictivity of 0.89, a sensitivity of 0.90 and a specificity of 0.88 when discriminating between control and WAD subjects. Also, a systematic error along the radial axis of the rigid body added to a single marker had no affect on the estimated rotation of the head. Conclusion The developed spike sorting method, using neural networks, was suitable for sorting a multiunit recording into single units when performing neurophysiological experiments. Also, it was shown that neck movement analysis combined with a neural network could build the basis of a decision support system for classifying suspected WAD or other pain related neck-disorders.
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