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  • Andersson, Ulrika, 1963- (författare)
  • Experimental studies in brain tumours with special regard to multidrug resistance and the ErbB-family
  • 2005
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Primary brain tumours, and especially the most common form malignant gliomas, usually display a pronounced resistance to other treatment modalities when surgery fails to cure. Growth factors, such as EGF and its receptor, frequently amplified and overexpressed in malignant gliomas, and factors associated with multidrug resistance have been suggested to at least partially explain the poor outcome. The aim of this thesis was to characterise factors in primary brain tumours associated with the development of resistance with focus on the epidermal growth factor receptor (ErbB) family, and multidrug resistance (MDR). Influences of irradiation on the expression and activity of P-glycoprotein (Pgp) in malignant gliomas was evaluated. The effects showed that irradiation increased the efflux activity of Pgp in rat brain vascular endothelial cells, but not in glioma cells. In the intracranial BT4C glioma model, Pgp was detected in the capillary endothelium in the tumour tissue but not in glioma cells. Expression of several factors coupled to MDR (Pgp, MRP1, LRP, and MGMT) in primary brain tumours were analysed and correlated to clinical data. In gliomas, Pgp and MRP1 were predominantly observed in capillary endothelium and in scattered tumour cells, whereas LRP occurred only in tumour cells. In meningiomas, expression of the analysed markers was demonstrated in the capillary endothelium, with a higher expression of Pgp and MRP1 in transitional compared to meningothelial meningiomas. A pronounced expression of MGMT was found independently of the histopathological grade or tumour type. Survival analysis indicated a shorter overall survival for patients suffering from low-grade gliomas with high expression of Pgp. To explore the importance of the epidermal growth factor receptor (EGFR), expression levels of the family members (EGFR, ErbB2-4) were analysed and their relations to various clinical parameters were evaluated in gliomas and meningiomas. In gliomas, the highest EGFR expression was observed in high-grade tumours, while ErbB4 expression was most pronounced in low-grade tumours. In meningiomas, expression of EGFR, ErbB2, and ErbB4 was observed in the majority of the tumours. An intriguing observation in low-grade gliomas was a significantly decreased overall survival for patients with high EGFR protein expression. The effects of different time schedules for administration of the selective EGFR inhibitor ZD1839 in relation to irradiation of glioma cells were analysed. The analyses showed a heterogeneity in the cytotoxic effects of ZD1839 between cell lines, and it was obvious that some of the cell lines showed sensitivity to ZD1839 despite no or low expression of EGFR. The study also demonstrated the importance of timing of ZD1839 administration when this agent is combined with irradiation. In conclusion, in order to enhance the efficacy of radiotherapy by various drugs in malignant gliomas it may be essential to inhibit drug efflux activity in endothelial cells and to deliver drugs in an optimal timing in relation to radiotherapy. The heterogeneity in expression of drug resistance markers, as well as the ErbB family reflects the complexity in classification of primary brain tumours, and indicates that subgroups of patients with low-grade gliomas expressing Pgp and EGFR might benefit from more aggressive and individualised treatment.
  • Andersson, Åsa, 1960- (författare)
  • B cell repertoire development in normal physiology and autoimmune disease
  • 1993
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The B cell repertoire in the neonatal immune system (IS) is characterised by reactivity towards self-components, including other immunoglobulin (Ig) V-regions. These properties have been suggested to be a requirement for the development of a normal immune system. DNA sequencing of two interacting Ig idiotypes, derived from neonatal, preimmune mice, demonstrated that such idiotypic connectivity is germ- line encoded and devoid of VDJ junctional diversity. The serum levels of the same Ig idiotypes were studied in normal mice and demonstrated that the expression in serum fluctuated over time in a pattern compatible with a complex dynamic system. In contrast, similar analyses in autoimmune mice or humans demonstrated fluctuations in Ig titers that differed significantly from the healthy individuals. These findings suggested that pathological autoimmunity may be associated with fundamental alterations in the dynamics of natural antibody (ab) expression. This was further investigated in the nonobese diabetic (NOD) mouse, an animal model for human Type I diabetes. Suppression of the early B cell development in the NOD mouse prevented the development of diabetes, suggesting a role for B cells/Igs in the development of diabetes in these mice. Furthermore, neonatal injections of polyclonal Ig preparations or single, monoclonal natural abs inhibited disease induction. The prevention of diabetes development by one such natural ab was demonstrated to be dependent on both the dose injected and the timing of administration. Studies of the B cell repertoire development in NOD mice, compared to normal mice, by DNA-sequence analyses of IgVH rearrangements utilising genes from the most D-proximal Vh family, Vh7183, supported the idea of an aberrant B cell repertoire in this mouse model. Thus, the adult NOD mouse retained a neonatal pattern of Vh7183 rearrangements. This pattern could, however, be "normalised" by neonatal injection of a natural antibody, previously demonstrated to prevent the development of T cell dependent autoimmunity in the NOD mouse.
  • Andræ, Margareta, 1943- (författare)
  • Facing death physicians' difficulties and coping strategies in cancer care
  • 1994
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Even if the treatment of cancer has developed over the last decades 50% of the patients still die of their cancer. The doctor's way of dealing with his and his patient's anxiety must surely be of significance for the treatment the patient receives.In the first part of the thesis earlier studies of physicians' stress and ways of coping are reported. There is a lack of systematic studies which show how doctors working with cancer patients adjust to this work. The aim of this investigation is to study cancer doctors' difficulties and coping strategies. The theoretical frame of the study embraces parts of psychoanalytical theory and coping models, emphasizing that both unconscious and conscious psychological processes play their part in the coping process.The second, empirical part of the study includes 23 physicians strategically selected out of a population of physicians who work with institutional care and who have daily contact with adult cancer patients. The main method of data collection has been a series of recorded interviews. The focus of the interview was the physician's perception of how he reacts, thinks, talks and acts in different phases of the cancer disease. To illustrate the defence strategies of the interviewers, the projective percept-genetic test, the "Defence Mechanism Test" (DMT) is used. The "Structural Analysis of Social Behaviour" (SASB) has been used to study the doctors' self image.The results indicate that the stated difficulties deeply affect the doctor as a human being. The statements reflect conflicting feelings and wishes in relation to authority, conflicting feelings and wishes in relation to frightening and injuring, conflicting feelings and wishes in relation to intimacy/distance. Thirty themes of coping strategies frequently recur and they have been grouped into seven categories. Most of the doctors "seek knowledge" and support from scientific literature. The majority of them state that attempting to "solve a problem" is their main strategy. Most of the doctors "seek support " as a part of their coping strategy. An interesting observation is that the doctors to a higher extent "seek a relation" to their patients rather than to their colleagues. Almost one third use "denial of the severity of a situation" as their main strategy. All the doctors consciously or unconsciously use "diverting strategies", i.e. undertake tasks which are devoid of contact with patients, such as research and administration or other activities which allow them to avoid the patient. One third use "projective manoeuvres" but this is never a main strategy.In the third part of the study the credibility of the results and their pedagogical and practical implications are discussed.
  • Andréen, Lotta, 1961- (författare)
  • Allopregnanolone and mood studies of postmenopausal women during treatment with progesterone
  • 2006
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Introduction. Allopregnanolone and pregnanolone (neuroactive metabolites of progesterone) act as positive modulators of the GABAA receptor system which is the major inhibitory system in CNS. Contradictory results on the effect of GABAA receptor modulators are reported. Beneficial properties such as anaesthesia, sedation, and anxiolysis are reported as well as adverse, anxiogenic and aggressive effects. It has been suggested that GABAA receptor agonists have bimodal effects. Low concentrations increase an adverse, anxiogenic effect, whereas higher concentrations show beneficial, calming properties.Aims. To investigate if progesterone treatment induces adverse mood in postmenopausal women and if the severity in mood symptoms is related to progesterone, allopregnanolone or pregnanolone serum concentrations. To evaluate differences in steroid concentrations induced by different doses and routes of administration of progesterone.Methods. Two randomised, placebo-controlled, double-blind crossover studies of postmenopausal women were performed. Subjects were treated with estradiol continuously. Different doses of progesterone, given vaginally or orally, were added sequentially during the last 14 days of each treatment cycle. Daily symptom ratings were kept using a validated rating scale. Blood samples for progesterone, allopregnanolone and pregnanolone analyses were collected during each treatment cycle. A study regarding the pharmacokinetics after ingestion of low-dose oral progesterone was conducted with postmenopausal women. Blood samples for the analyses of progesterone, allopregnanolone and pregnanolone were collected and pharmacokinetic parameters were calculated.Results. Certain postmenopausal women on sequential HT with vaginal and oral progesterone experience mood deterioration during the progesterone phase while on a low dose of progesterone but not on higher doses or the placebo. Negative mood symptoms occurred when the serum concentration of allopregnanolone was similar to endogenous luteal phase levels, whereas lower and higher concentrations had no effect on mood. Pharmacokinetic analyses show that low-dose oral progesterone can be used as a prodrug to allopregnanolone when the aim is to achieve physiological concentrations of allopregnanolone.Conclusions. A bimodal association between allopregnanolone concentration and adverse mood is observed in postmenopausal women treated with progesterone. The addition of low-dose progesterone to estradiol induces adverse mood in postmenopausal women, whereas higher doses and placebo have no mood-deteriorating effect.
  • Angelin, Martin, 1976- (författare)
  • Travel – a risk factor for disease and spread of antibiotic resistance
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • As international travel is rapidly increasing, more people are being exposed to potentially more antibiotic resistant bacteria, a changed infectious disease epidemiology, and an increased risk of accidents and crime. Research-based advice is needed to adequately inform travellers about these risks. We studied travellers who sought advice from the Travel Medicine Clinic at the Department of Infectious Diseases, Umeå University Hospital, as well as university students from Umeå, Stockholm, and Gothenburg travelling abroad for study, research, and clinical exchange programs.From retrospective data at the Travel Medicine Clinic, we found that pre-existing health problems were rare among travellers from Umeå seeking pre- travel health advice and vaccinations. In addition, we found that the travel destination and the sex of the traveller affected vaccination levels. Although hepatitis A is endemic to both Thailand and Turkey, compared to travellers to Thailand few travellers to Turkey visited the clinic for hepatitis A vaccination. The data also revealed that more women than men were vaccinated against Japanese encephalitis despite comparable trips.A prospective survey study showed that travellers felt that the pre-travel health advice they received was helpful. Two-thirds of the travellers followed the advice given although they still fell ill to the same extent as those who were not compliant with the advice. Factors outside the control of travellers likely affect the travel-related morbidity. Compared to older travellers, younger travellers were less compliant with advice, fell ill to a greater extent, and took greater risks during travel.In a prospective survey study, we found that healthcare students had higher illness rates and risk exposure when abroad compared to students from other disciplines. This difference was mainly due to the fact that healthcare students more often travelled to developing regions during their study period abroad. When abroad, half of all students increased their alcohol consumption and this was linked to an increased risk of theft and higher likelihood of meeting a new sex partner.The healthcare students participating in the survey study also submitted stool samples before and after travel. These samples were tested for the presence of antibiotic resistance, both by selective culturing for ESBL-PE (Extended-Spectrum Beta-Lactamase Producing Enterobacteriaceae) as well as by metagenomic sequencing. About one-third (35%) of the students became colonised by ESBL-PE following their study abroad. The strongest risk factor for colonisation was travel destination; for example, 70% of students who had travelled to India became colonised. Antibiotic treatment during travel was also a significant risk factor for colonisation.The stool samples from a subset of study subjects were analysed using metagenomic sequencing. From this we learned that although the majority of resistance genes in the gut microbiome remained unchanged following travel, several clinically important resistance genes increased, most prominently genes encoding resistance to sulphonamide, trimethoprim, and beta-lactams. Overall, taxonomic changes associated with travel were small but the proportion of Proteobacteria, which includes several clinically important bacteria (e.g., Enterobacteriaceae), increased in a majority of the study subjects.Clearly, there are risks associated with international travel and these risks include outside factors as well as the personal behaviour of travellers. We believe our results can be used to develop better pre-travel advice for tourists as well as university students studying abroad resulting in safer travel.
  • Anticona Huaynate, Cynthia, 1983- (författare)
  • Lead exposure in indigenous children of the Peruvian Amazon seeking the hidden source,venturing into participatory research
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Introduction. In 2006, a Peruvian environmental agency reported the presence of elevated blood lead levels (BLLs) in indigenous communities of the Corrientes river basin. This is a territory in the Peruvian Amazon where oil activity has been associated with serious environmental effects, with impact on an ongoing social conflict. This PhD project aimed to determine the lead sources, risk factors and pathways in children of these communities and to suggest control and prevention strategies. Given the arguments attributing the lead source to the oil activity pollution, the second objective was to clarify any potential connection between the two. This project was conducted by a collaborative research partnership with the regional health authorities and the community-based organization. The third objective was to characterize the challenges, facilitating factors and the lessons learned from the research process.Methods. Two epidemiological studies were conducted. Study I (2009) was carried out in three communities and study II (2010) in six communities with different levels of exposure to oil activity. The participants were children 0–17 years old. Data collection included: determination of BLLs, hemoglobin levels and anthropometric indicators, a risk factor questionnaire, an environmental assessment and a risk map. Data analysis included univariate, bivariate and multivariate logistic regression. Data for the third objective came from field notes, documents, interviews and a process of collective reflection.Results. Study I (n= 221) found no significant difference in the geometric mean(GM) BLLs between the communities exposed and not exposed to oil activity. Older age and being a boy were found as risk factors for BLLs ≥ 10 μg/dL. In study II (n= 346), age stratified logistic regression models indicated that children 0–3 years whose mothers had BLLs ≥ 10 μg/dL, children 0–6 years who played with pieces of lead and children 7–17 years who fished 3 times or more per weekor chewed pieces of lead to manufacture fishing sinkers had a significant increased risk of having BLLs ≥ 10 μg/dL. Children who lived in communities near oil battery facilities also had a significant increased risk of having BLLs ≥ 10 μg/dL. In both studies, environmental samples showed lead concentrations below reference levels. The challenges and facilitating factors identified focused on five interrelated themes: i) mutual trust, ii) multiple agendas, iii) equal participation, iv) competing research paradigms and v) complex and unexpected findings.Conclusions. Metal lead appeared to be the main source of exposure. Playing with pieces of lead and chewing pieces of lead to construct fishing sinkers appeared to be pathways of exposure for children aged 0–6 years and 7–17 years, respectively. Mothers’ BLLs > 10 μg/dL was a risk factor for BLLs > 10 μg/dL in children aged 0–3 years. Living in a community with high exposure to oil activity was a risk factor for BLLs > 10 μg/dL. The identified connection with oil activity was the proximity of communities to oil battery facilities and thus greater access to lead from cables and other industrial waste. Despite the numerous challenges, participatory research appears to be the most appropriate approach for this type of context. The study findings led us to recommend:i) a comprehensive community-based lead control and prevention plan,ii) the introduction of substitute non-harmful material(s) for fishing sinkers and iii) secure containment of the oil company’s waste deposits.
  • Antonsson, Helena, 1962- (författare)
  • Interaktion i särskilt boende för personer med utvecklingsstörning och utmanande beteende
  • 2013
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Bakgrund: Många personer med utvecklingsstörning har kommunikativa svårigheter och har därför behov av att utveckla olika sätt att kommunicera för att kunna förstå andra och göra sig förstådda. Svårigheter i kommunikationen påverkar interaktionen mellan personer med utvecklingsstörning och deras vårdare. Detta ställer höga krav på vårdare att kunna tolka och förstå den enskilda individens sätt att uttrycka önskningar och behov. På samma sätt riskerar vårdares budskap att missförstås. Om vårdaren misslyckas att förstå den boendes kommunikation och vice versa, kan det leda till situationer med utmanande beteende exempelvis i form av vägran, verbal eller fysisk aggressivitet.Syfte: Det övergripande syftet med avhandlingen är att studera interaktion mellan vuxna personer med utvecklingsstörning och vårdare i gruppbostäder, samt att studera effekter av en utbildningsintervention för vårdare som arbetar i gruppbostäder.Metod: Avhandlingens samtliga delstudier har genomförts i gruppbostäder för personer med utvecklingsstörning bland boende och vårdare i ett län i norra Sverige. I studie I insamlades data kring 556 personer med utvecklingsstörning. I studie II och III deltog 16 vårdare och 11 personer med utvecklingsstörning. I studie IV deltog 7 vårdare. Studie I bygger på personalens skattningar av funktionsnivåer och förekomst av begränsningsåtgärder. I Studie II och III utgörs data av videoobservationer och narrativa intervjuer. I studie IV användes flera datainsamlingsmetoder i en mixed method design med både vårdarnas skattningar, med hjälp av instrument och semi-strukturerade intervjuer. Analys av materialet i studie II, III och IV har gjorts med kvalitativ innehållsanalys och i studie I och IV har data analyserats statistiskt.Resultat: I studie I framkom att av 556 boende hade 99 (18%) varit föremål för fysiska begränsningsåtgärder under den senaste veckan. Av dessa 99 hade nästan alla varit föremål för mer än en typ av begränsningsåtgärd. Den vanligaste begränsningsåtgärden var bälte i stol (74%). Användningen av begränsningsåtgärder var relaterade både till fysiska funktionsnedsättningar och till beteende.I studie II reflekterade vårdare över videoinspelad interaktion där vårdarna medverkat, både framgångsrik och misslyckad interaktion. Exempel på framgångsrik interaktion var att förstå tecken, kunna möta behov och hantera situationer med utmanande beteenden. Vårdarna reflekterade över att framgångsrik interaktion ledde till säkerhet, trygghet och självförtroende hos de boende. Vårdarna reflekterade även över de konsekvenser misslyckad interaktion fick i form av irritation, aggression och våld från de boende.I studie III studerades videoinspelad interaktion mellan 11 personer med utvecklingsstörning och 16 av deras vårdare. Verbal och icke-verbal interaktion identifierades. Fyra inspelade situationer valdes ut för att belysa framgångsrikt samspel. Resultatet visade att framgångsrikt samspel mellan personer med utvecklingsstörning och deras vårdare bland annat bygger på möjligheten att bekräfta varandra, dela vardagshändelser, ge tid och utrymme och på att använda ett kongruent och tydligt språk.I studie IV utvärderades effekterna av en web-baserad utbildningsintervention, vars syfte var att förbättra interaktionen mellan personer med utvecklingsstörning och vårdare samt att därmed reducera förekomsten av situationer med utmanande beteende. Resultatet visade att vårdarna hade förbättrat sin förmåga att hantera situationer med utmanande beteende och att förekomsten av utmanande beteende minskat. Vårdarna beskrev att den web-baserade utbildningen upplevts givande och möjlig att ta del av parallellt med arbetet.Slutsats: Fysiska begränsningsåtgärder förekommer i gruppbostäder för personer med utvecklingsstörning. Användningen av begränsningsåtgärder kan vara relaterade både till fysiska funktionsnedsättningar och till beteenden i samspelet mellan brukare och vårdare. Vårdare upplever användningen av fysiska begränsningsåtgärder svår och tröttande. Brott i kommunikationen mellan personer med utvecklingsstörning och deras vårdare kan leda till försvårad interaktion med risk för situationer med utmanande beteenden. När vårdare är framgångsrika i interaktionen med personer med utvecklingsstörning ger det tillfredsställelse både för de boende och vårdarna. Vårdarna upplever dock ofta hjälplöshet och osäkerhet i relation till hantering av situationer med utmanande beteende och efterfrågar utbildning. Web-baserad utbildning om interaktion med personer med utvecklingsstörning och utmanande beteende har i vår studie visat sig ge lovande effekter och bör vara möjlig att utveckla för både introduktion av nyanställda vårdare och för kompetensutveckling bland mer erfaren personal.
  • Appelblad, Micael, 1961- (författare)
  • Fat contamination of pericardial suction blood in cardiac surgery clinical and experimental studies in perspectives of transfusion logistics
  • 2006
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Introduction: During cardiac surgery aided by cardiopulmonary bypass (CPB) the autotransfusion of pericardial suction blood (PSB) is regarded mandatory to limit allogeneic blood exposure. PSB is however proposed as a source of lipid microemboli and to contribute to brain damage. This thesis addresses the logistics of allogeneic blood transfusion during coronary artery bypass grafting (CABG), the embolic potential of reinfused PSB, and means to reduce PSB fat contamination, investigated both clinically and experimentally.Methods: Study I) Patients undergoing CABG surgery (n=2469) were included in a database study. The magnitude of surgical bleeding versus blood transfusion was analyzed to extract a subgroup of patients (n=982) in whom transfusions were independent from bleeding. Study II) PSB and venous-blood samples were collected from patients undergoing routine CABG (n=20). The in vitro capillary-flow properties of blood subcomponents and the effects of routine screen filtration were tested. PSB fat contamination was evaluated by imprint microscopy. Study III) Heat extracted liquid human fat or soya oil were mixed with mediastinal drain blood (n=20) and incubated in a temperature controlled column, to evaluate spontaneous density separation of fat. Study IV) The findings from study-III were applied to develop a fat-reducing system (FRS) using two stacked compartments. The FRS was experimentally tested (n=12), with similar methods as in study-III, and clinically evaluated (n=10). A single-chamber blood bag (n=10) served as reference.Results: Study I) A surgical bleeding of less than 400 mL showed no correlation to blood transfusion, although 64 of 982 patients still received allogeneic blood. The strongest predictors for this kind of transfusion were; female gender, weight ≤70 kg, CPB time ≥90 minutes, CPB temperature ≤32 ºC, and advanced age (P<.001 - .038). Study II) The capillary-flow profile of PSB plasma was highly impaired compared to venous plasma (P<.001). Conversely, blood-cell components showed no difference between PSB and venous blood. Routine screen filtration showed no ameliorating effect on capillary-flow resistance. Fat debris was detected on imprints in all PSB samples in contrast to venous plasma (P<.05). Study III) After 10-min of incubation had 77% of added soya oil separated and found contained in the top 20% fraction of blood (P<.001), aimed to be discarded. The density separation of human fat was less efficient compared to soya oil (P=.011). Fat also adsorbed to surface which was more pronounced at low temperature (P<.001). The overall reduction of human fat was 70%. Study IV) PSB contained 1.5 mL fat suspended in 418 mL PSB. Of this fat was 24% surface-bound. Experimental analysis of the proposed FRS revealed an 83% fat-reduction which was clinically confirmed, suggesting 80% reduction (P=.001). The FRS also gave a small but significant erythrocyte-concentrating effect.Conclusions: Transfusion of allogeneic blood during CABG surgery appeared associated with an institutional, individual, and technical bias of an anticipated need and not only used to compensation for surgical bleeding. In part may this reflect a non-compliant CPB methodology and hemodilution. It was confirmed that PSB plasma contained fat, with a suggested embolic potential. Human fat was significantly reduced from mediastinal drain blood by spontaneous density separation and surface adsorption. The prototype FRS used for PSB incubation during CPB allowed an efficient fat reduction.
  • Araya, Mesfin, 1954- (författare)
  • Postconflict internally displaced persons in Ethiopia mental distress and quality of life in relation to traumatic life events, coping strategy, social support, and living conditions
  • 2007
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Background: There are about 23.7 million internally displaced persons worldwide today, still living in the low-income countries. Ethiopia has for the past four decades been ravaged by war and famine. A lengthy civil war resulted in Eritrea, formerly a part of Ethiopia, becoming an independent state in 1991. This war led to displacement of one million people, and currently there are about 55000 internally displaced Ethiopians in Addis Ababa, most of them living in temporary shelters. A minority resettled in a small town Debre Zeit south east of Addis Ababa, dispersed in the community.Objectives: To study the consequences of trauma and extreme stress among these displaced persons.Methods: A random sample of 1200 displaced persons was selected from the Kaliti and Kore shelters of Addis Ababa, aged between 18 and 60 years. They were interviewed by internationally validated instruments which were translated into the Ethiopian official language Amharic. Information thus obtained covered sociodemographics, childhood trauma, traumatic life events, and mental distress as assessed by the SCL-90-R, the four domains of quality of life assessed by WHOQOL-BREF, coping strategies, perceived social support, and basic living conditions. A sample of 120 subjects from the displaced persons living in Debre Zeit was similarly evaluated. A study comparing prevalence rates and risk factors for PTSD in four postconflict, low-income countries (Algeria, Cambodia, Ethiopia, Gaza) was also undertaken.Results: Men, compared to women, reported significantly higher experience of trauma, higher perceived social support, and higher task-oriented coping. Women reported higher emotion-oriented coping. In both genders, emotion-oriented coping was correlated with higher trauma events, and task-oriented coping was correlated with higher perceived social support. Mental distress increased and quality of life decreased with age. Mental distress mediated the effects of most trauma in reducing quality of life, and some trauma reduced quality of life directly. Living conditions were also significantly related to quality of life. Coping strategies and perceived social support influenced mental distress and quality of life directly as well as indirectly by moderation, in part gender specific. Placement in the community setting of Debre Zeit gave a better quality of life compared to placement in the shelters of Addis Ababa. This difference was accounted for by the difference in living conditions, particularly protection from animals (rodents) and insects (mosquitoes), for three domains of quality of life. For domain 3 (social relationships), however, several further factors accounted for the difference, like marital status, ethnic belonging and coping strategy. The comparative study of 4 postconflict countries contributes to the theory that trauma may be the direct cause of the onset of PTSD but that a multiplicity of other adverse events determine the development of this disorder.Conclusions: Using the same assessment methods, a wide range of rates of symptoms of PTSD were found among 4 low-income populations who have experienced war, conflict, or mass violence. In the Ethiopian context we also found gender differences in the trauma background, coping strategies and perceived social support. Mental distress mediated much of the effects of trauma on quality of life. Coping strategies and perceived social support were significant moderators in this process.
  • Aripaka, Karthik, 1986- (författare)
  • Studies on the biological functions of interaction between components in Wnt, TGF-β and HIF pathways for cancer progression
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Cancer is a disease that involves aggressive changes in the genome and aberrant signals between the living cells. Signalling pathways such as TGF-β (Transforming growth factor-β), Wnt, EGF (epidermal growth factor) and HIF (Hypoxia-inducible factor) evolved to regulate growth and development in mammals. These factors are also implicated for tumorigenesis due to failure or aberrant expression of components in these pathways. Cancer progression is a multistep process, and these steps reflect genetic alterations driving the progressive transformation of healthy human cells into highly malignant derivatives. Many types of cancers are diagnosed in the human population, such as head & neck, cervical, brain, liver, colon, prostate, uterine, breast, and renal cell cancer.Prostate cancer is the second most common cancer and one of the foremost leading cancer-related deaths in men in the world. Aberrant Wnt3a signals promote cancer progression through the accumulation of β-Catenin. In the first paper, we have elucidated intriguing functions for Tumour necrosis factor receptor-associated factor 6 (TRAF6) as a coregulatory factor for the expression of Wnt-target genes which was confirmed in vivo by using CRISPR/Cas9 genomic editing, in zebrafish. Our data suggest that Wnt3a promotes TRAF6 interaction with Wnt components, and TRAF6 is required for gene expression of β-Catenin as well as for the Wnt-ligand co-receptor LRP5. From the in vivo studies, we elucidated positive regulation of TRAF6, which is crucial for survival and development of zebrafish. This study identifies TRAF6 as an evolutionary conserved co-regulatory protein in the Wnt pathway that also promotes the progression of prostate and colorectal cancer due to its positive effects on Wnt3a signalling.Hypoxia is a condition due to O2 deprivation, and Hypoxia-inducible factors (HIF) transcription factors are responsible for the maintenance of oxygen homeostasis in living cells. Irregularities in these HIF transcription factors trigger pathological cellular responses for initiation and progression of malignant cancers. Renal cell carcinoma, malignant cancer arising in renal parenchyma and renal pelvis and, hypoxia plays a vital role in its progression. In the second paper, we have investigated the clinicopathological relevance of several hypoxic and TGF-β component proteins such as HIF-1α/2α/3α, TGF-β type 1 receptor (ALK5-FL) and the intracellular domain of ALK5 (ALK5-ICD), SNAI1 and PAI-1 with patient survival in clear cell renal cell carcinoma (ccRCC). We showed that HIF-2α associated with low cancer-specific survival. HIF-2α and SNAI1 positively correlated with ALK5-ICD, pSMAD2/3, PAI-1 and SNAI1 with HIF-2α; HIF-1α positively correlated with pSMAD2/3. Further, under normoxic conditions, our data suggest that ALK5 interacts with HIF-1α and HIF-2α, and promotes their expression and target genes such as GLUT1 and CA9, in a VHL dependent manner through its kinase activity. These findings shed light on the critical aspect of cross-talk between TGF-β signalling and hypoxia pathway, and also the novel finding of an interaction between ALK5 and HIF-α might provide a more in-depth understanding of mechanisms behind tumour progressionIn the third paper, an ongoing study, we investigated the role of HIF-3α in the progression of Renal cell carcinoma and its association with the components of TGF-β and HIF pathways. We have observed increased levels of HIF-3α in ccRCC and pRCC (papillary renal cell carcinoma) which are associated with advanced tumour stage, metastasis and larger tumours. Also, we found HIF-3α show a significant positive association with pro-invasive gene SNAI1, which is a crucial regulator of epithelial to mesenchymal transition. TRAF6 an E3 ligase known to be a prognostic marker in RCC and we observed HIF-3α associates with TRAF6.
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