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- Gregers, Jannie, 1964-
(författare)
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Pharmacogenetic studies in childhood acute lymphoblastic leukaemia with primary focus on methotrexate
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Childhood acute lymphoblastic leukaemia is the most common type of cancer in children. Improvement in treatment has increased survival to approximately 85 per cent. Pharmacogenetics can influence the disposition of anticancer agents and can ideally be used as tool to further improve treatment based on the individual child’s pharmacogenetic profile.The hypothesis in this thesis was that polymorphisms in genes responsible for MTX influx (SLC19A1), efflux (ABCB1, studies with MTX monotherapy have demonstrated effect of variations in this gene) or other MTX pathways (ATIC, MTHFR and SHMT) could have impact on efficacy in childhood acute lymphoblastic leukaemia.The uptake of MTX and impact of SLC19A1 80G>A was investigated in vitro and showed that SLC19A1 80GG had decreased uptake in CD+ T cells and B cells caused by reduced capacity on receptor-to-receptor basis.In more than 500 patients the clinical effect of SLC19A1 80G>A genotype was evaluated and showed that patients with the SLC19A1 80AA had better survival, more bone marrow toxicity, but less liver toxicity than patients with SLC19A1 80GG or 80GA variants. Furthermore, it was demonstrated that SLC19A1 80G>A interacts with chromosome 21 copy number in the leukemic clone.The clinical impact of ABCB1 1199G>A, 1236C>T, 2677GT on the treatment was evaluated. Patients with either the 1199GA or the 3435CC variant had increased risk of relapse compared to patients with the 1199GG or 3435CT/TT variants, respectively. Toxicity was also affected by the ABCB1 polymorphisms.No association between polymorphisms in the ATIC, MTHFR and SHMT genes and outcome was seen. However the 677C>T and 1298 C>A in the MTHFR gene were associated with toxicity.The genotype frequencies between healthy donors and patients were compared, but no association to risk of developing cancer was seen in the investigated polymorphisms.The results in this thesis emphasise the importance of including pharmacogenetic markers in attempts to improve outcome and reduced side effects in childhood ALL.
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- Ewertzon, Mats, 1956-
(författare)
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Familjemedlem till person med psykossjukdom : bemötande och utanförskap i psykiatrisk vård
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focused on the situation of family members of persons with psychotic illness, particular on their experience of the approach of the healthcare professionals and of their feelings of alienation regarding the professional care of their family member. A further aim was to explore how siblings who have participated in a support group for siblings experienced their situation.A questionnaire was developed that enabled the aims of this thesis to be investigated (I). Seventy family members from various parts of Sweden participated, and data were collected via the questionnaire developed in study I (II-III). Thirteen siblings who previously had participated in a support group participated in follow-up focus groups interviews (IV).The questionnaire developed was shown to be reliable and valid in these studies (I). In many cases, the participants had experienced an approach from professionals that indicated that they did not experience openness, confirmation and cooperation, and that they felt powerless and socially isolated in relation to the care. There was also found to be a certain degree of association between how the participants experienced the approach and whether they felt alienation (II). The majority of the participants considered openness, confirmation, and cooperation to be important aspects of professional’s approach. The result also identified a low level of agreement between the participants’ experience and what they considered to be significant in the professional’s approach (III). The findings revealed the complexity of being a sibling of an individual with psychotic illness. Participating in a support group for siblings can be of importance in gaining knowledge and minimizing feelings of being alone (IV).Although the psychiatric care services in Sweden have been aware of the importance of cooperating with family members, the results indicated that there is a need for further research in this area.
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- Matsson, Elin, 1979-
(författare)
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In vivo Pharmacokinetics of Two New Thrombin Inhibitor Prodrugs : Emphasis on Intestinal and Hepatobiliary Disposition and the Influence of Interacting Drugs
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Biliary excretion is an important elimination route for many drugs and metabolites. For such compounds, it is important to know the extent of excretion and drug exposure in the bile, e.g., for the risk assessment of drug interactions, liver toxicity and the effects of genetic variants. In this thesis, duodenal aspiration of bile was performed in healthy volunteers and complemented with experiments in an in vivo model in pigs to increase the understanding of the intestinal and hepatobiliary disposition of two direct thrombin inhibitors. The compounds investigated, ximelagatran and AZD0837, are both prodrugs that require bioactivation to exert their pharmacological effect. Upon co-administration with erythromycin and ketoconazole, respectively, altered plasma exposure to ximelagatran and AZD0837 and their respective metabolites has been observed. The main objective of this thesis was to characterize the biliary excretion of the compounds, and investigate whether this elimination route explains the observed drug-drug interactions. High plasma-to-bile AUC ratios were observed, in particular for ximelagatran, its active metabolite melagatran, and AR-H067637, the active metabolite of AZD0837. These high ratios indicate the involvement of active transporters in the biliary excretion of the compounds, which is important since transporters constitute possible sites for drug interactions. The effects of erythromycin and ketoconazole on the plasma exposure of the prodrugs and metabolites were confirmed in both the pig and the clinical studies. The changes seen in plasma for ximelagatran and its metabolites were partly explained by reduced biliary clearance. Inhibited CYP3A4 metabolism likely caused the elevated plasma levels of AZD0837, whereas reduced biliary clearance was seen for AR-H067637 suggesting an effect on its excretion into bile. In summary, the studies led to mechanistic insights in the hepatobiliary disposition of ximelagatran and AZD0837, and demonstrate the value of combined clinical and animal studies for the investigation of the biliary drug excretion.
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- Nahar, Baitun
(författare)
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Effects of Food Supplementation and Psychosocial Stimulation on Growth and Development of Severely Malnourished Children : Intervention Studies in Bangladesh
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Early childhood malnutrition is a global public health problem with serious short- and long-term consequences. The aim of this thesis is to evaluate the effects of psychosocial stimulation (PS) with or without food supplementation (FS) on growth and development of severely malnourished children, quality of home environment, mother’s child-rearing practices and depressive symptoms. The study setting was Dhaka, Bangladesh, and the participants were severely malnourished children, aged 6-24 months, admitted at Dhaka Hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B). A hospital-based study was conducted in Nutrition Rehabilitation Unit of ICDDR,B hospital, where a control group (n=43) was studied initially, followed by an intervention group (n=54). All received standard nutrition rehabilitation care. The intervention group received daily group meetings and play sessions in the hospital, and was thereafter visited at home for 6 months. A community-based randomised trial was conducted including children (n=507) admitted at hospital for initial treatment of an acute infection, and thereafter assigned to PS, FS, PS+FS, clinic control or hospital control groups. PS was delivered at follow-up visits, fortnightly for 6 months at community clinics. FS included distribution of cereal-based food packets (150–300 kcal/day depending on age) for 3 months. All groups received standard medical care and micronutrient supplementation. In the hospital-based study, the intervention group had significantly higher scores in mental (p<0.001, effect size 0.52 SD) and motor development (p=0.047, effect size 0.37 SD), and weight (p=0.03, effect size 0.39 SD), after 6- months intervention. In the community-based trial, there was a significant effect of stimulation after six months of intervention on children’s mental development (group*session interaction p=0.037, effect size=0.37 SD) and weight (group*session interaction p=0.02, effect size=0.26 SD) but no effect on motor development or linear growth. The PS+FS and PS groups differed in total HOME score, two HOME subscales (maternal involvement and play materials), and in mother’s child- rearing practices scores but not in depressive symptoms. PS with or without FS had small improvement on children’s growth and development, quality of home environment and mother’s rearing-practices of severely malnourished children. More intensive interventions with longer duration are therefore recommended.
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