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| 24. |
- Althini, Susanna
(författare)
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Experimental Studies of BMP Signalling in Neuronal Cells
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The developing nervous system depends largely on extracellular cues to shape its complex network of neurons. Classically, neurotrophins are known to be important mediators in this process. More recently, Bone Morphogenetic Proteins (BMPs), belonging to the Transforming Growth Factor beta (TGFβ) superfamily of secreted cytokines, have been shown to exert a wide range of effects, such as cellular growth, differentiation, survival and apoptosis, both in the developing and adult nervous system. They signal via serine/threonine kinase receptor essentially to the Smad pathway, which carries the signal to the nucleus where the transcription of target genes is regulated.This thesis investigates the functions of BMPs in the nervous system, using a set of different models. Firstly, a targeted deletion of GDF10 (BMP3b) in the mouse was established to evaluate the role of this growth/differentiation factor in the hippocampal formation, a brain area known to be involved in memory processing. Other members of the TGFβ superfamily likely compensate for the lack of GDF10, since no detectable alterations in hippocampal function or gene transcription profile have been found. Secondly, a mouse model was set up, with the aim to study impaired BMP-signalling in dopaminergic neurons. The tyrosine hydroxylase (TH) locus was used to drive the expression of dominant negative BMP receptors by means of bicistronic mRNAs. TH is the rate-limiting enzyme in the biosynthesis of catecholamine and the mice described, show a graded decrease of TH-activity resulting in severe to mild dopamine deficiency. The contribution of the dominant negative BMP receptors to the phenotype is however secondary to the apparent TH hypomorphism. The final theme of this thesis is the potentiating effects of BMPs on neurotrophin-induced neurite outgrowth as studied in explanted ganglia from chick embryos and in the rat phaeochromocytoma cell line PC12. A number of pharmacological inhibitors of intracellular signalling kinases were applied to the cultures in order to reveal the contribution of different pathways to the enhanced neurite outgrowth. We made the unexpected finding that inhibition of MEK signalling mimicked the potentiating effects of BMP stimulation in the chick system. The underlying mechanisms for the synergistic effects, however, are still an enigma.
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| 26. |
- Amin, Kawa
(författare)
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The relationship between inflammation and structural changes in the airways of the lower and upper respiratory tract : Studies in patients with asthma, Sjögren's syndrome, rhinitis and children with otitis media with effusion
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The pathophysiology of asthma, Sjögrens syndrome (SS), rhinitis, and otitis media with effusion (OME) in children has been extensively investigated in upper and lower respiratory tract, respectively, and shown to comprise structural changes in the airways and involvement of inflammatory cells. By comparing diseases that have bronchial hyperresponsivenses or mucosal inflammation as a common denominator, it may be possible to learn more about the mechanisms underlying inflammation in the upper and lower respiratory tract.With immunohistochemical techniques and a panel of monoclonal antibodies, inflammatory cells were identified and structural changes of the airway were quantitatively studied in the bronchial, nasal and middle ear mucosa and submucosa.The highest number of eosinophils and mast ceils in bronchial, nasal or middle ear biopsies was found in patients with atopic asthma (AA), perennial non-allergic rhinitis (PNAR) and children with OME. The number of the neutrophils was highest in SS, non-atopic asthma (NAA) and children with OME. The number of T lymphocytes in SS and AA was significantly higher than in NAA and healthy controls (HC). The degree of epithelial damage was higher in the AA group andin patients with perennial allergic rhinitis where the biopsy was taken within the pollen season (PARSEASON) group compared to the other patient groups. The tenascin- and Iaminin-positive layers in AA and SS were thicker than other groups. In AA, and PARSEASON a significant negative correlation was found between epithelial integrity and the count for eosinophils or neutrophils. The most pronounced epithelial damage was observed in patients with allergic rhinitis in areas characterized by an increased number of inflammatory cells. Eosinophils in asthmatic and PARSEASON patients and neutrophils in SS were found in the area of epithelial damage.This work has demonstrated a quantitatively different inflammatory profile in AA, NAA and SS, different profiles in perennial allergic and non-allergic rhinitis and a specific inflammatory profile in the middle ear of children with OME suggesting differences in the pathogenesis of respiratory tract diseases.
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| 27. |
- Amini, Rose-Marie, 1969-
(författare)
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Hodgkin Lymphoma : Studies of Advanced Stages, Relapses and the Relation to Non-Hodgkin Lymphomas
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The relationship between Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is not entirely elucidated and a clonal relation may be present more often than previously believed. Mechanisms of tumour progression and resistance to therapy are poorly understood.Between 1974 and 1994 all individuals in Sweden with both HL and NHL were identified. Thirty-two cases were studied using clinical, histopathological and immunohistochemical methods. The second lymphoma often appeared in an aggressive clinical form and a significant correlation between the expression of p53 and LMP-1 in the first and second lymphoma was demonstrated.The treatment outcome for 307 patients with advanced stages of HL, in an unselected population was in accordance with the treatment results of large centres world-wide. Some patients were successfully selected for a shorter chemotherapy-regimen without inferior treatment results.In 124 patients with relapse, the survival of those primarily treated with radiotherapy according to the National guidelines was in accordance with the survival of patients of initially advanced stages. A worse outcome was found for those who received both chemotherapy and radiotherapy initially, probably because of a higher frequency of bulky disease in this group. Immunohistochemical analysis of the tumour suppressor protein p53 and retinoblastoma protein (Rb) of paired samples at diagnosis and at relapse in 81 patients did not reveal any specific staining pattern affecting survival.A novel B-cell line (U-2932) was established from a patient with a diffuse large B-cell lymphoma previously treated for advanced stage and subsequent relapses of HL. An identical rearranged IgH gene was demonstrated in tumour cells from the patient and in U-2932. A p53 point mutation was detected and over-expression of the p53 protein was found. A complex karyotype with high-level amplifications of the chromosomal regions 18q21 and 3q27, i.e. the loci for bcl-2 and bcl-6 were demonstrated.
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| 28. |
- Anderberg, Ulla Maria
(författare)
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Fibromyalgia syndrome in women - a stress disorder? : Neurobiological and hormonal aspects
- 1999
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The FMS is almost exclusively a female disorder, as 90% of the patients struck by it are women. About 7% of all women in modern society have this disorder. The studies in this thesis demonstrated that variations in the female sex hormones over the menstrual cycle and in different hormonal states are important with respect to the severity of pain and other symptoms, global functioning and well being of FMS patients. The hormonal state is also of importance in the inter-connection with the monoaminergic systems, stress systems and pain processing systems. Besides the symptoms, this also appears as perturbed levels of neuropeptide Y (NPY), nociceptin and oxytocin in plasma.The importance of estrogen to pain processing peptides was shown in an animal study. In that study it was revealed that estrogen increase reduces pain sensitivity, and that estrogen is also able to change the levels of pain processing peptides such as substance P (SP) and met-enkephalin-Arg-Phe (MEAP) in certain brain areas, spinal cord and serum. It is suggested that stress may elicit pain through several neuroendocrinological mechanisms.All FMS patients scored higher than healthy women on mood and tension related symptoms, which is interpreted as an increased sensitivity and reaction to stress. FMS patients at the time of menstruation, and older, postmenopausal FMS patients were the most sensitive to these changes. The increased sensitivity to stress was also demonstrated in a personality study using the Temperament and Character Inventory (TCI), which showed that many female FMS patients are more anxious and worried and therefore also become easily fatigued.It is likely that development of the FMS is due to numerous biological events occurring in response to long-term stress. Women with stressful life experiences and anxious personality traits are probably more prone to develop this disorder, although various and sufficient stressful events of different origins can most likely lead to this disorder in any woman over the long run.
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| 29. |
- Andershed, Birgitta
(författare)
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Att vara nära anhörig i livets slut : Delaktighet i ljuset - delaktighet i mörkret
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of the present dissertation were: 1. To describe how the establishment of an inpatient hospice ward affected dying cancer patients' utilisation of care at a Medical Centre Hospital; 2. To analyse the involvement of the relative in the care of gravely ill cancer patients in different care cultures; 3. To analyse obstacles to and possibilities for relatives' involvement: 4. To develop a theoretical framework of understanding concerning the involvement of relatives. For the first aim, data was collected via register studies. The basic research design for the other aims was the hermeneutic method.The results show that during the first three years 315 patients died at the newly opened hospice ward. The year before the ward opened 82% of the cancer patients died in acute care compared with 59% during the third year of the hospice ward.The involvement of relatives in the patients' care was categorised into three main categories: "to know", " to be" and "to do". The studies show that the involvement can be described either as involvement in the light or involvement in the dark. Involvement in the light and in the dark illustrates relatives' understanding of the situation, their possibilities for involvement, and the attitude of the staff toward the relatives. Factors that promoted involvement in the light were a humanistic attitude of the staff, a stronger sense of coherence of relatives, an appropriate course of illness, and other available resources such as other relatives and one's own health.A surprising result was that the time between diagnosis and death was three months or less for 49% of 67 patients. In those cases where the course of illness was short there was no time to lose, and it was important that caring delays were avoided.The results from the substudies were summarised in five statements, which together form a theoretical framework of understanding for the involvement of relatives.
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| 30. |
- Andersson, Ann-Catrin, 1968-
(författare)
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Studies on Human Endogenous Retroviruses (HERVs) with Special Focus on ERV3
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Human endogenous retroviruses (HERVs) represent approximately 7% of the human genome. This investigation was focused on one particular HERV, ERV3, with the main purpose of characterising its gene expression patterns and genomic distribution of ERV3-like sequences. Furthermore, this careful expression study should provide insights into the biological role of HERVs. The impact of HERVs in health and disease is not yet clarified. ERV3 is expressed as three envelope (env) transcripts, of which two also contain a cellular gene, H-plk (human proviral linked Krüppel). ERV3 env expression was mainly investigated at the RNA level. The gene expression of two other HERVs, HERV-K and HERV-E was analysed and compared with ERV3 activity.Real-time PCRs were developed and in combination with in situ hybridisation, it was found that ERV3 is expressed in a tissue- and cell-specific way. High levels of ERV3 mRNA (up to six times over Histone3.3) were demonstrated in placenta, sebaceous glands, foetal and adult adrenal glands, brown adipose tissue, corpus luteum, pituitary gland, thymus and testis. In monocytic cells including both normal monocytes and malignant U-937 cells, elevated mRNA levels were observed after retinoic acid (RA)-induced differentiation. ERV3-encoded Env protein was detected in selected cases, one following RA-treatment. In addition, several new ERV3-like sequences were discovered in the human genome. ERV3 was found to have conserved open reading frames in contrast to other ERV3-like sequences in the human genome. This suggests that ERV3 may be involved in important cellular processes such as differentiation, cell fusion, immunomodulation and protection against infectious retroviruses. The developed techniques and obtained results will allow further studies of HERV expression to better correlate HERV activity to both normal development and disease.
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