| 1. |
- Ulfenborg, Benjamin, 1985-
(författare)
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Bioinformatics tools for discovery and evaluation of biomarkers : Applications in clinical assessment of cancer
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is a disease characterized by abnormal proliferation of cells in the body and ranks as the second leading cause of death worldwide. In order to improve cancer patient care, a major focus of cancer research is to discover biomarkers. A biomarker is a biological molecule found in tissues or body fluids and can be used to predict or assess disease states. The aim of this thesis is to develop bioinformatics tools for discovery and evaluation of novel biomarkers from high-throughput datasets.MicroRNAs (miRNAs) are short non-coding RNAs that function as negative regulators of gene expression. Dysregulation of miRNAs in cancer is frequently reported, making them interesting as biomarker candidates. GenoScan was developed for genome-wide discovery of miRNA-coding genes, as a first step in the identification of novel mi-RNA biomarkers.High-throughput technologies such as microarrays allow researchers to measure the expression of thousands of genes or miRNAs simultaneously. The Decision Trunk Classifier (DTC) algorithm has been developed to screen datasets from these experiments for biomarker candidates. When applied to a miRNA expression dataset for endometrial cancer (EC) samples vs. controls, a two-marker model with 98 % accuracy was generated. These miRNAs (hsa-miR-183-5p and hsa-miRPlus-C1070) are promising as biomarkers for EC screening.The miREC database was developed to store gene and miRNA data from curated expression profiling studies of EC, as well as gene-miRNA regulatory connections. Using gene-miRNA interaction networks from miREC, the roles of miRNAs in cancer hallmark acquisition can be clarified. To further support exploratory analysis of expression data, DTC was extended with partial least squares regression models. The resulting PLS-DTC algorithm can be used to gain deeper insights into the perturbation of biological processes and pathways.
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| 2. |
- Pejner, Margaretha Norell, 1958-
(författare)
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The bright side of life : support in municipal elderly home care
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Registered nurses in municipal elderly home care have in some occasionsdifficulties in identifying the patients’ needs and prioritize intervention inaccordance with the patients’ preferences, which is to obtain social and emotional support. The overall aim was to explore and describe which supportive interventions registered nurses use in municipal elderly home care settings and if it is in agreement with the patient’s preferences. Methods: A retrospective descriptive study (I ) were conducted and followed up by a qualitative approach with Grounded Theory as a method (II IV ). Sample to study; I , registered nurses (62) performed interventions to 6138 patients between 80- 109 years. II , 12 registered nurses, who performed 36 home visits to patients between 80- 102 years. III , 16 registered nurses. IV , 18 patients between 80- 96 years. Data was collected by; I , between 2004- 2008, during the months of April and October using a web- based form which was filled in by registered nurses. II , through nonparticipant observations when the registered nurse made a home visit. III and IV , using informal conversational interviews. Results: Combined, the four studies show that emotional support is important to a group of older patients because it helps them to experience serenity. Serenity is a state of relief and the moment required for the patient to be able to move forward in a dignify way. Patients lost or reduced ability to process their emotions makes so that they get stuck in a state, which fatigue them with additional experience of disease and illness. To get out of their state the patient uses the registered nurse as a reliever whose mission is to identify their needs and guide them into a state of serenity. Registered nurses on the other hand, makes priorities based on patients preferences. Registered nurses strengths was their profession that contributed to the patient's emotions became available to them. Weaknesses was registered nurses workload and lack of knowledge about the identification of emotions. Emotional support should be developed as a nursing intervention and be integrated as a part of nursing.
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| 3. |
- Kozlowski, Piotr, 1969-
(författare)
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Prognostic factors, treatment and outcome in adult acute lymphoblastic leukemia : Population-based studies in Sweden
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute lymphoblastic leukemia (ALL) has poor prognosis in older/elderly adults and in high-risk/relapsed disease. Recommended treatment of ALL was evaluated (study I-IV). Data was obtained from the Swedish Acute Leukemia registries and from patient records.I. We assessed ALL relapse treatment and outcome in 76 patients aged 15-65 years (y). Complete remission (CR) was achieved in 50/71 patients (70%). Of them, 29 underwent allogeneic hematopoietic stem cell transplantation (hSCT). Five year overall survival (OS) was 15%, but close to 50% in 19 patients <35y after hSCT.II. We studied outcome of treatment with the Hyper-CVAD protocol in 19 of 24 patients with T-ALL aged 18-72y. CR was reached in 89%, but 5y leukemia-free survival was only 29%, and 20% in 15 patients not transplanted in CR1. Six patients received hSCT in CR2. Finally, 5y OS in all 19 patients was 47%. The only negative prognostic factor found was age ≥35y.III. We evaluated minimal residual disease (MRD) monitoring in 35 patients with Philadelphia (Ph) negative B-ALL aged 46-79y and treated with the ABCDV protocol. The CR rate was 91%. MRD was measured by flow cytometry in 73% in CR1 (MRD1) and omitted in those >70y or with high-risk ALL. Five patients received hSCT (only one due to MRD). Five year OS in the whole cohort was 47%. Continuous CR but not OS was improved in patients with MRD1 <0.1 %.IV. We studied 155 patients with ALL (Ph+ in 35%) aged 55-85y and treated with remission induction/palliation (124/31). Both, intensive, and palliative treatment resulted in the CR rates of 70/83/16% and 3y OS of 26/32/3%. OS was negatively influenced by age and platelet count ≤35×109/L (but not Ph+). OS was not enhanced by introduction of an age-adapted protocol.We concluded that intensive treatment with subsequent allogeneic hSCT is the most reasonable option in younger patients with ALL recurrence (I). Hyper-CVAD has low relapse-preventing efficacy (II). MRD guided intensification is probably feasible in only a minority of older patients (III). Prognosis in elderly ALL is poor, but no longer impaired by Ph+ (IV).
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| 4. |
- Kumawat, Ashok Kumar, 1982-
(författare)
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Adaptive immune response in the intestinal mucosa of microscopic colitis patients
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Microscopic colitis (MC) is a chronic diarrhoeal disease of unknown aetiology, comprising collagenous colitis (CC) and lymphocytic colitis (LC). The nature of the adaptive local immune responses in the mucosa of MC patients is however far from elucidated. The present study investigates phenotypic and functional characteristics of the adaptive local immune responses in the colonic mucosa of these patients.Our immunohistochemistry and flow cytometry studies (Paper I & II) demonstrated increased frequencies of CD8+ T cells in the colonic epithelium and lamina propria of both LC and CC patients compared to controls, whereas the frequencies of CD4+ T cells were unaltered or reduced. Our flow cytometry data revealed increased local activation of both CD4+ and CD8+ T cells in the lamina propria as well as the intraepithelial compartment of CC and LC patients compared to controls, demonstrated as increased proportions of these cells expressing the active/memory marker CD45RO and the proliferation marker Ki67.Analysis of recent thymic emigrants by measuring T cell receptor excision circle (TREC) levels in the colonic mucosa of CC and LC patients revealed reduced TRECs levels in these patients compared to controls (Paper III). These results suggests that the observed increased numbers of T cells in the mucosa of CC and LC patients is due to the expansion of local resident T cells rather than direct recruitment of recent thymic emigrants to the mucosa.Molecular analysis of T helper (Th) cell and cytotoxic T lymphocyte (Tc) mucosal cytokines at messenger and protein levels in the colonic biopsies from CC and LC patients demonstrated a mixed Th17/Tc17 and Th1/Tc1 mucosal cytokine profile and revealed significant differences in the mucosal cytokine levels in CC and LC patients compared to controls (Paper IV).Finally, we have set up an in vitro model to investigate how the colonic milieu affects the activation and differentiation of T lymphocytes (Paper V). Our preliminary data indicate increased production of both pro inflammatory and antiinflammatory cytokines by peripheral blood T cells in the presence of soluble factors from the inflamed colonic mucosa of CC patients compared to controls.
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| 5. |
- Sundin, Per-Ola, 1971-
(författare)
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A life-course approach to chronic kidney disease : risks and consequences
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Successful primary prevention of chronic kidney disease (CKD) relies on understanding the pathways leading to established disease, including how they extend over the life-course. Projects in this thesis examine risk factors for CKD and consequences of impaired kidney function from a life-course perspective using routinely collected health-data in Swedish registers and research cohort data from the United Kingdom.The main findings regarding risk factors for CKD are, that markers of health and development determined at conscription assessment in adolescence, independently predict diagnosis of end-stage renal disease in middle age. We also identified a persistent increased risk of CKD following hospital admission with pneumonia in adulthood with highest magnitude risks in years immediately following infection, but still statistically significantly raised more than 15 years after the pneumonia episode. Our main findings relevant to predicting the consequences of impaired kidney function are that creatinine and cystatin C used clinically to estimate kidney function (estimated glomerular filtration rate, eGFR) have associations with increased mortality risk independent of GFR measured with an exogenous filtration marker (mGFR). If cystatin C and creatinine are combined, adding mGFR does not improve mortality risk prediction. Another important finding is that moderately reduced eGFR is only associated with a statistically significant increased mortality risk among individuals in the lowest third of the distribution of grip strength in a general population sample followed for 4-5 years, after adjustment for potential confounding factors.These results highlight the importance of adopting a life-course perspective when studying risk factors for CKD, since these associations can extend over different stages in the life-course. When assessing increased mortality risk associated with measures of GFR, combining cystatin and creatinine improves risk prediction. Potential effect modification across subgroups, including by grip strength, should be considered.
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| 6. |
- Vidlund, Mårten, 1968-
(författare)
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Glutamate for metabolic intervention in coronary surgery : with special reference to the GLUTAMICS-trial
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Myocardial ischemia is a major cause of postoperative heart failure and adverse outcome in coronary artery bypass graft surgery (CABG). Conventional treatment of postoperative heart failure with inotropic drugs may aggravate underlying ischemic injury. Glutamate has been claimed to increase myocardial tolerance to ischemia and promote metabolic and hemodynamic recovery after ischemia. The aim of this work was to investigate if intravenous glutamate infusion given in association with CABG for acute coronary syndrome can reduce mortality and prevent or mitigate myocardial injury and postoperative heart failure. We also wanted to assess neurological safety issues, as a concern with the use of glutamate is that it may act as an excitotoxin under certain conditions.A metabolic strategy for perioperative care was assessed in an observational study on 104 consecutive patients with severe left ventricular dysfunction undergoing CABG. Based on encouraging clinical results, unsurpassed in the literature, the GLUTAMICS-trial was initiated. 861 patients undergoing CABG for acute coronary syndrome were randomly allocated to blinded intravenous infusion of L-glutamicacid solution or saline. The primary endpoint was a composite of postoperative mortality (≤30 days), perioperative myocardial infarction and left ventric ular heart failure in association with weaning from cardiopulmonary bypass. Secondary endpoints included neurological safety issues, degree of myocardial injury,postoperative hemodynamic state, use of circulatory support and cardiac mortality.The event rate was lower than anticipated and the primary endpoint did not differ significantly between the groups. Regarding secondary endpoints there were significant differences compatible with a beneficial effect of glutamate on post-ischemic myocardial recovery. The putative effect of glutamate infusion was seen in more ischemic patients (CCS class IV) and in patients with evident or anticipated LV-failure on weaning from CPB. No evidence for increased incidence of clinical or subclinical neurological injury was found. In conclusion, intravenous glutamate infusion is safe in the dosages employed and could provide a novel and important way of promoting myocardial recovery after ischemic injury.
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| 7. |
- Walldén, Jakob, 1968-
(författare)
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The influence of opioids on gastric function : experimental and clinical studies
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Efter operation och anestesi får patienter ofta en negativ påverkan på magsäck och tarmar. Illamående och kräkningar är ett stort problem och många har svårt att komma igång med intag av föda och normal tarmfunktion då magsäcken och tarmarna ”står stilla”. Flera faktorer bidrar- bl.a. smärtan, det kirurgiska traumat och de läkemedel vi ger i samband med anestesin. Av de senare är opioider, d.v.s morfin och morfinliknande läkemedel, starkt bidragande. I detta avhandlings- arbete har opioiders effekter på magsäckens motilitet studerats. Med ett absorptionstest (paracetamolmetoden) studerades hos frivilliga hur opioiden remifentanil påverkar magsäckstömning och om kroppspositionen har betydelse för tömningshastigheten ut i tarmen. Remifentanil fördröjde magsäcks-tömningen och under pågående opioid behandling hade kroppspositionen ingen större betydelse, vilket det däremot hade under kontrollförsöken. Med samma metod jämförde vi hos patienter två anestesimetoder och studerade magsäcks-tömning direkt efter en operation. Ingen skillnad kunde påvisas mellan en opioidbaserad och en opioidfri anestesi, men inom respektive grupp var det en stor variation i magsäckstömning mellan individerna. Med en barostat studerades tonus i övre delen av magsäcken. Hos hälften av de frivilliga orsakade remifentanil en ökning av tonus och hos den andra hälften en minskning av tonus. Vidare undersöktes hos en grupp patienter opioiden fentanyls påverkan på den elektriska aktiviteten i magsäcken. Med en elekroga-strograf (EGG) registrerades de långsamma elektriska vågor som koordinerar muskelrörelserna i magsäcken. Hos hälften av de undersökta påverkades aktiviteten av fentanyl med en sänkt vågfrekvens eller upphörande av vågor, medan aktiviteten var opåverkad hos den övriga hälften. För att finna en förklaring till variationen gjordes genetiska analyser av genen för opioidreceptorn hos de undersökta i barostat och EGG studierna. Variationer i genomet, s.k. polymorfism, var inte associerad till utfallen i studierna. Studierna har visat på att opioider har en uttalad effekt på magsäckens motilitet och att den varierar kraftigt mellan individer. Polymorfism i genen för opioid- receptorn förklarade inte skillnaden mellan individer. Direkt efter operation bidrar sannolikt andra faktorer än anestesimetod till det variabla utfallet i magsäckstömning.
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| 8. |
- Zakrisson, Ann-Britt, 1955-
(författare)
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Management of patients with chronic obstructive pulmonary disease in primary health care : a study of a nurse-led multidisciplinary programme of pulmonary rehabilitation
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to modify and evaluate effects, as well as todescribe experiences of a nurse-led multidisciplinary programme of pulmonaryrehabilitation in primary health care for patients with chronicobstructive pulmonary disease (COPD) and their next of kin.Interviews were performed with 12 COPD nurses about their experiencesof patient education (I). Forty-nine patients participated in the interventiongroup and 54 in the control group in a quasi-experimentalstudy which investigated the effects of the programme on functional capacity,quality of life and exacerbation frequency during one year (II).Interviews were performed related to the experiences of 20 patients whohad participated in the six-week programme (III) and the experiences of20 next of kin to the patients that had participated (IV).The results showed that COPD nurses fluctuated between security andinsecurity in patient education and were in need of support, time, structureand collaboration to develop their patient education (I). In Study IIthere were no differences between the groups with regard to functionalcapacity and quality of life, but the number of exacerbations decreased inthe intervention group and increased in the control group (II). The patientsin study III had allowed themselves to live at their own pace followingthe programme but a constant fear was present in spite of the programme(III). Next of kin in Study IV had a life that remained overshadowedby illness but there were positive outcomes of the programme aslong as two years afterwards. The next of kin also had constant fear,however (IV).In conclusion, the six week programme brought about results in changingeveryday life. Nevertheless, all lived in the shadow of fear and uncertaintyin spite of the programme. More research is needed to address therequirements of COPD nurses, patients and next of kin.
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| 9. |
- Ahlstrand, Rebecca, 1973-
(författare)
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Effects of anasthesia on esophageal sphincters
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The esophageal sphincters constitute the anatomical protection against pulmonary aspiration. The aim of this thesis was to study the esophageal sphincters and how they are affected by different components of emergency anesthesia using high-resolution solid-state manometry.The effect of propofol (0.3 mg/kg) was studied in young and elderly volunteers. Propofol can be given as an anxiolytic agent for manometric studies of the lower esophageal sphincter (LES) without affecting the results. However, propofol is not recommended for studies of the upper esophageal sphincter (UES).The effects of cricoid pressure (CP) and peripheral pain were studied in awake volunteers, with and without remifentanil infusion (5 ng/ml). Pain did not affect pressure in the LES, but CP or remifentanil induced a significant decrease in LES pressure. However, neither CP nor remifentanil affected the barrier pressure (LES-intra gastric pressure). When CP was applied during ongoing remifentanil infusion, no further decrease in LES pressure was measured. CP induced high pressures in the area of the UES independent of remifentanil infusion, indicating that CP is effective in preventing gastroesophageal regurgitation.Barrier pressure was also studied in anesthetized patients after rocuronium (0.6 mg/kg) administration and no decrease was measured. In addition, alfentanil (20 μ/kg) added during anesthesia induction with propofol did not decrease the barrier pressure.In conclusion, CP seems to be effective in preventing regurgitation and does not affect barrier pressure. Muscle relaxation with rocuronium does not risk gastro-esophageal integrity. In addition, opioids can be integrated, even during emergency anethesia, without increasing the risk for pulmonary aspiration.
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| 10. |
- Andersson, Tommy, 1970-
(författare)
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Atrial fibrillation and cause of death, sex differences in mortality, and anticoagulation treatment in low-risk patients
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Atrial fibrillation (AF) is the most common arrhythmia but information on cause of death in patients with AF is sparse, and whether individuals at low risk of cerebral infarction (CVL) should receive antico-agulant medication is controversial. Studies of sex differences with respect to mortality risk have shown conflicting results.Methods: Data were obtained from Swedish National Registers. In Study I, there were 272 186 AF patients and matched controls and in Studies II and III, 9519 AF patients and no other diagnosis and matched controls. Study IV compared treatment with warfarin to no treatment in 48 433 patients with AF. Hazard ratio (HR) was calculated with 95% confidence intervals and outcome rates as number per 1000 person-years.Results: Ischemic heart disease (IHD) was the most common underlying cause of death and was present in 40.2% of AF patients at a HR of 1.7 (1.4-2.1). CVL/stroke was a cause of death in 13.1%, HR 2.7 (1.8-4.0). Among underlying and contributing causes of death, the most common diagnoses were IHD in 43.5%, HR 1.7 (1.4-2.0) and heart failure in 33.1%, HR 2.9 (2.2-3.7). The HRs for mortality in females with AF in age categories ≤65, 65-74, and 75-85 were 2.15, 1.72, and 1.44, and for males 1.76, 1.36, and 1.24. The rates of mortality in females with AF in age categories 55-64, 65-74, and 75-85 were 6.2, 20.7, and 57.3, and for males 8.5, 27.3, and 64.5. In patients 65-74 years, females with a CHA2DS2-VASc score of 2, and males with a score of 1 receiving warfarin treatment showed a significantly reduced risk of cerebral infarc-tion/stroke, HR 0.46 (0.25-0.83) for females and for males, HR 0.39 (0.21-0.73).Conclusions: Most common causes of death in AF patients were CVL/stroke, heart failure, and IHD. HR of mortality in patients with AF was higher in females than in males but absolute risk was higher in males with AF compared to females with AF. Anticoagulant therapy was benefi-cial in patients ≥65 years, regardless of the CHA2DS2-VASc score.
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