Doctoral Theses /HS

Multiplex HLA-DR-DQ genotyping : for genetic epidemiology and clinica...
Lavant, Ewa : Malmö University. Faculty of Health and Society Doctoral Dissertation;2012:3 (2012)	DOCTORAL THESIS

English abstract:

The human leukocyte antigens (HLA) are highly polymorphic cell surface proteins encoded in the major histocompatibility complex (MHC) region on chromosome 6. The HLA system has been well known as transplantation antigens but the primary biological role of the HLA molecules is regulation of immune response by presenting peptide fragments to T-lymphocytes. As regulators of immune responses the HLA molecules are also of importance for susceptibility to several autoimmune and inflammatory diseases. Genotyping of these loci is therefore significant in research targeting the mechanisms of HLA associated diseases, in exploring new epidemiological associations between HLA and specific disease, and as a clinical tool for risk assessment for diseases with well defined associations. Although several commercial HLA genotyping methods are available, many require multiple steps, have low throughput and high cost. The aim of the work within this dissertation was to develop a robust, costeffective method for HLA-DRB1, -DQA1 and -DQB1 genotyping suitable for use in an epidemiological context and clinical investigation. The method was optimized with specific focus on risk alleles for type 1 diabetes mellitus and celiac disease, two autoimmune disorders with significant impact on public health. By combining PCR with sequence specific primers (PCR-SSP), product separation by capillary gel electrophoresis and fluorescence detection in the developed method, all three loci could be analyzed in a single step, resulting in low reagent cost and fast turnaround time. This in combination with the low total consumption of DNA template allows the method to be used in epidemiological studies. 10 A simplified version of the developed method is currently used for clinical risk assessment for celiac disease when histological and/or serologic results are ambiguous in investigated subjects or when a gluten-free diet has been initiated before diagnostic tests have been performed. The low cost of this newly developed method has enabled HLA typing as a tool in screening programs for high-risk groups, such as individuals with Down syndrome or type 1 diabetes, to preclude the risk for celiac disease and thus avoid periodic screening for auto-antibodies. This method is also used to analyze samples from children all over Sweden with newly diagnosed diabetes in the Better Diabetes Diagnosis project. The developed method was also used in two explorative association studies not related to type 1 diabetes or celiac disease. In one study the association between HLA-DRB1, -DQA1 and -DQB1 and acute myocardial infarction was investigated showing only weak associations. In the second study the HLA-DR-DQ haplotype effect on developing chronic pain after inguinal hernia surgery was explored demonstrating an HLA dependent risk of developing pain

Ewa Lavant HS muep.pdf (531.3Kb)

Interactions of Biopolymers and Metalcomplexes at Biological Interfaces
Hamit Eminovski, Jildiz : Malmö University Doctoral Dissertation;2011:3 (2011)	DOCTORAL THESIS

English abstract:

The present work concerns interaction between biopolymers at interfaces. Examples from real systems such as saliva and bacterial surfaces as well as model systems have been studied. Using atomic force microscopy (AFM), normal forces between the surface of the filamentous bacterium Microthrix parvicella and AFM-tips have been studied, before and after treatment with specific polyaluminium compounds used at wastewater treatment plants to control the growth of the bacterium. Measurements were performed using hydrophobized and hydrophilic tips in order to explore the interactive spectrum of the bacterium and also the changes of which, if any, on treatment with polyaluminium chloride. No preferential interaction was found to any of the tips. However, the studies revealed that long-range steric repulsion dominates the interaction on approach. It was also found that the steric repulsion is reduced by addition of polyaluminium compounds, indicating a compaction of the polymer layer on the surface of the bacterium. A mucin model system, i.e. Bovine Submaxillary Mucin (BSM), adsorbed at solid surfaces has been studied using ellipsometry and quartz crystal microbalance with dissipation (QCM-D). Using the optical method ellipsometry, time resolved data on the adsorbed amount per unit area and the average layer thickness of adsorbed BSM films were determined. From QCM-D measurements the Voigt mass per unit area and viscoelastic properties of an adsorbed BSM film (including coupled water) were determined. Combining these two methods the water content of BSM adsorbed at gold, hydrophobized, and hydrophilic silica surfaces was estimated. From the results structures for BSM adsorbed on gold, hydrophobized, and hydrophilic silica were proposed. Furthermore, effects by the addition of polyaluminium chloride of different hydrolysis ratio were investigated and compared to those of AlCl3 and a ferric chloride formulation. Hence, compaction of the BSM film was initiated at concentrations as low as 0.001 mM AlCl3. At higher concentrations, related to those used at wastewater treatment plants, addition of polyaluminium chloride formulations and AlCl3 induced an initial rapid decrease in thickness followed by an increase. An increasing adsorbed mass was also observed. Combining ellipsometry and QCM-D data it was determined that aluminium species precipitate in or on top of the pre-adsorbed BSM film and the ensemble swells over time. By rinsing the precipitate layer was removed, but with some fraction remaining associated to the film. The rate of removal was slow and proceeded over a period of tens of hours. Combining the data, the swelling of the precipitate was monitored and the water content calculated. It was obvious that the increase on adsorption and decrease on depletion is mainly related to swelling. The impact of surface characteristics was also investigated and surface charge influences in terms of electrostatic interactions between the surface and the cationic aluminium compound were inferred. Friction forces between hydroxyapatite surfaces coated with human whole salivary (HWS) films were measured and the friction coefficient of the salivary films was determined. Measurements were performed using AFM-colloidal probe using two hydroxyapatite spheres. The salivary film was found to show high compressibility and mechanical resistance. Treatment with an anionic surfactant, sodium dodecyl sulphate, however induced desorption and an irreversible structural change of the film.

Hamit Eminovski MUEP ny.pdf (861.3Kb)

Prevention of foot ulcers in patients with diabetes mellitus
Annersten Gershater, Magdalena (2011)	DOCTORAL THESIS

English abstract:

Amputation in patients with diabetes mellitus preceded by a foot ulcer is a serious complication. Patients with the highest risk of developing a foot ulcer are often found in home nursing settings. The overall aim was to focus on how registered nurses are working with prevention of foot ulcers in patients with diabetes mellitus in outpatient settings: - to identify factors related to short term outcome of foot ul-cers in patients treated in a multi-disciplinary system until healing was achieved. - to assess what was documented by registered nurses regarding diabetes care in a Swed-ish municipality’s home nursing service; to what extent nursing actions were planned for, performed and evaluated according to the goals of metabolic control, treatment and prevention of complications.- to explore registered nurses’ professional work with foot ulcer prevention in home nursing settings. - to explore whether participant driven group information has an impact on ulceration in a patient group with previ-ous diabetes foot ulcer. Study I used logistic regression analysis to identify factors related to outcome in a cohort of 2480 consecutive patients with diabetic foot ulcer at a multidisciplinary foot clinic. Results: Healed primarily: 65% (n=1617), 9% (n=250) after minor am-putation, 8% (n=193) after major amputation and 17% (n=420) died unhealed. Primary healing was related to co- morbidity, duration of diabetes, extent of periph-eral vascular disease and type of ulcer. In neuropathic ulcers, deep foot infection, site of ulcer and co-morbidity was related to amputation. In neuro-ischemic/ischemic ul-cers amputation was related to co morbidity, peripheral arterial disease and type of ulcer. Study II was a cross sectional assessment of all nursing records of patients with dia-betes (N=172) in a municipality’s home nursing setting and analyzed with manifest content analysis. Results: The overall standard of nursing records was insufficient. Evaluation of blood glucose was documented in 61% (n=105) of the records, weight was documented in 6% (n=10), blood pressure in 10% (n=17) and ongoing foot ul-cers were documented in 21% (n=36). Study III was a qualitative interview study of 15 registered nurses from four munici-palities, analyzed with manifest content analysis. Results: Registered nurses in home nursing settings worked mainly through health care assistants. The nurses used lead-ership and education as the main tools to enable the nursing process. They mainly relied on experience based competence. Study IV was a randomized controlled trial comparing participant driven education in group with standard information, in patients with diabetes and previous foot ul-cers. An interim analysis was made 6 months after intervention of 131 included pa-tients. Results: After 6 months follow up, 58% (n=57) of the 98 evaluated patients had not developed a new foot ulcer. There was no statistical difference between the two interventions. The most common reasons for ulceration were plantar stress ulcer and minor external trauma. Five patients had deceased and 10 had withdrawn con-sent to participate. Conclusion: Patients with diabetes and high risk of developing foot ulcer constitute a fragile group that needs special foot protective attention. This requires a well edu-cated staff in the home nursing organization. In the future patient education should target low risk patients.

MAG muep.pdf (1.433Mb)

What's neighbourhood got to do with it? : the influence of neighbourh...
Mellgren, Caroline : Faculty of Health and Society, Malmö University Malmö University Health and society Doctoral Dissertations;4 (2011)	DOCTORAL THESIS

English abstract:

The overarching aim of this thesis is to contribute to an increased understanding of how the neighbourhood context acts to influence individual reactions to crime. The general framework is that the social and physical make-up of residential neighbourhoods influences individuals, over and above individual background characteristics. Disorder is an important neighbourhood-level factor and its presence is more or less pronounced in different neighbourhoods. It acts as a sign of a general urban unease and has potential negative consequences for the individual as well as for the community at large. Four studies have been conducted each with its own specific objective. The first study reviews the Swedish crime survey literature in order to assess the national evidence for neighbourhood effects, paying special attention to methodological issues. Overall, the current literature provides mixed evidence for neighbourhood effects. Methodological issues were identified as obstacles to drawing general conclusions and specific areas that need improvement were identified. The second study examines the origins of disorder at the neighbourhood level and the relationship between disorder and crime. Two theory-driven models of the relationship between population density, disorder, and crime are tested alongside an examination of whether these models are equally applicable to data collected in two cities, Antwerp in Belgium and Malmö in Sweden. The results found some support for direct effects of disorder on crime in both settings, independent of structural variables. Some differences between the two settings were observed suggesting that the disorder-crime link may vary by setting. To further examine the influence of neighbourhood context, the role played by neighbourhood level disorder in relation to worry about criminal victimization has been tested in a multilevel model in the third study. Overall the hypotheses of the influence of both neighbourhood level and individually perceived disorder, in shaping individual worry were supported. Individual background explains most of the variance but neighbourhood context has independent effects on worry. Individual level perceived disorder mediated the effect of neighbourhood disorder on worry suggesting that the effect of context is indirect through its effect on individual perception. The fourth study investigates whether it is possible to identify any unique neighbourhood effects on the extent to which residents apply crime preventive strategies. Initially some of the total variance in the dependent variables was found to be situated between neighbourhoods. This indicates that the neighbourhood context may influence individuals’ willingness to take crime preventive action. As expected, individual characteristics explained a majority of this between-neighbourhood variance. An important finding is that the contextual variables appear to have different effects on different activities, highlighting the need to study different actions separately.

2043_12283 Mellgren muep.pdf (739.1Kb)

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