The accumulation of eosinophil granulocytes (EOS) at sites of inflammation is a common feature of astma, allergic rhinitis and inflammatory bowel disease. The aim of the present investigation was to study the mechanisms involved in this accumulation. Bronchoalveolar lavage (BAL) fluid obtained from patients with birch-pollen allergy lavaged during season exhibited increased eosinophil chemotactic activity compared with pre-season BAL fluid from the same patients. We identified IL-5, IL-8 and RANTES as the main eosinophil chemotactic agents in the BAL fluid. Only EOS from allergic donors responded to IL-8. IL-2 inhibited albumin-stimulated eosinophil migration towards buffer or chemoattractants. EOS from allergic subjects were less sensitive to this inhibition than EOS from normal subjects, and in vitro priming of the EOS with IL-5 prevented the inhibitory effect of IL-2. We therefore hypothesise that IL-2 acts as an autocrine regulator of EOS migration, and that this inhibitory effect may be down-regulated in allergy, resulting in increased migration of EOS towards chemotactic factors. The stimulation of eosinophil migration by albumin is mediated by PI3 kinase. Decreased expression of CD49d and CD49f caused by albumin may decrease the adhesiveness of the EOS, which in turn may facilitate migration. We found a higher chemotactic activity in perfusion fluids from patients with ulcerative colitis than from control patients. The chemotactic activity correlated with the concentrations of eosinophil granule proteins in the perfusion fluids. IL-5 and TNF-α were identified as two of the chemotactic agents in the perfusion fluid that were inhibited by steroid treatment. Agents with steroid-insensitive chemotactic activity remain to be identified.

Otitis media with effusion (OME) is the major form of chronic relapsing inflammatory disease of the middle ear, constitutes the most common diagnosis for children under 15 years old and is the major cause of auditory dysfunction in pre-school children. OME is a disease more commonly found in allergic children. These studies sought to investigate the inflammatory response in the middle ear of patients and test the hypothesis that an allergic-like response might occur in the ear. Atopy was diagnosed by standard in vitro tests. Immunochemical techniques used to study classic allergic rhinitis and asthma were extrapolated to the evaluation of OME children whose effusion persisted beyond 2 months. Not only eosinophil cationic protein (ECP), tryptase, CD3-positive and IL-5 producing cells, but also myeloperoxidase (MPO) was found in middle ear fluid and/or mucosa in the majority of patients with OME and atopy. Initially, levels of ECP, MPO, and tryptase were measured in effusions from 97 random OME patients whose atopic status was determined by in vitro testing to 12 inhalants and 5 foods. The response of eosinophils, neutrophils and mast cells in the middle ear was distinctly different between atopic and non-atopic patients (p<0.001) with higher levels of the cell markers in the atopic group of patients. This suggested that 1) perhaps OME was predominantly a disease of atopics and that 2) they differed in their response from non-atopics. Tryptase was measured in middle ear effusions from 38 patients with OME, 94.7% of whom were atopic by in vitro testing. Tryptase was elevated only in the effusion of atopic patients as compared to 5 controls (p<0.01). Biopsies stained histochemically for tryptase showed evidence of mast cells in the mucosa and submucosa from 6 of 8 OME ears but absent in 4 normals. Middle ear biopsies, embedded in a plastic resin to improve the structural preservation, from 5 patients with OME and 5 normals were evaluated for the presence of eosinophils and neutrophils with monoclonal antibodies against 4 specific granule proteins. Eosinophils and neutrophils were present in the mucosa and mucus in significantly higher numbers than in the control group. In an effort to determine whether the middle ear itself might be involved in allergic disease, evidence that some of the cells, mediators and cytokines associated specifically with a Th-2 response were sought for in the middle ear mucosa of these children. Middle ear biopsies from 7 atopic patients with OME and 4 controls demonstrated the presence of activated eosinophils, CD-3+ T cells and IL-5 mRNA cells only in the mucosa from atopic OME children. Conclusion: Effusion and mucosal biopsies containing ECP, tryptase, and/or IL-5 mRNA cells, CD3+ T cells, eosinophils, and mast cells indicate that many of the mediators and cells essential to the production of a Th-2 immune mediated response are present in ears with chronic effusion. The increased levels of MPO in atopic patients further suggest that the general inflammatory response to putative inciting agents such as bacterial and viral products may be altered in atopy. These studies support the hypothesis that the exaggerated inflammation within the middle ear associated with most cases of OME is possibly the result of an atopic response within the middle ear itself.

The overall aim of this thesis is to investigate health-related quality of life (HRQoL), anxiety and depression in patients with endocrine gastrointestinal (GI) tumours. Patient as well as staff perceptions were assessed. HRQoL was studied with the EORTC QLQ-C30, and anxiety and depression with the Hospital Anxiety and Depression Scale. In addition, patient perceptions of the importance of and satisfaction with selected HRQoL aspects were investigated. Semi-structured interviews with open-ended questions were conducted to identify disease- and treatment-related distress, what constitutes a good quality of life and strategies to "keep a good mood" among these patients. Patients reported a relatively good HRQoL and low levels of anxiety and depression. However, they reported a lower HRQoL than could be expected for healthy people of similar age and gender. Staff gave a more pessimistic view of patient satisfaction with HRQoL aspects than did patients, and staff did not accurately judge individual patients' levels of anxiety and depression. Importance>satisfaction discrepancies for HRQoL aspects may identify patients with a low quality of life. HRQoL, anxiety and depression did not change substantially during the first year of treatment. Categories identified through content analysis of interview data concerning distress and quality of life were referred to physical, emotional or social dimensions. Identified strategies to "keep a good mood" were classified as Internal or External. Most categories of distress that were identified are covered by the EORTC QLQ-C30 and/or the HADS, but some additional emotional and social aspects of distress emerged from the interview data. Receiving good care was identified as a strategy to "keep a good mood". This result indicates a possible and potentially important relation between the quality of care and patient HRQoL.

The main purpose of the present study was to obtain an in-depth understanding of what the final phase of life was like for a group of gravely ill and dying cancer patients, with focus on autonomy, dependency and quality of life. The specific aims were to: 1) describe the patients' autonomy and how the attitudes of relatives and staff promoted/hindered patient participation in decision-making, 2) describe how the patients assessed their quality of life in two care cultures, 3) describe how members of the care team prognosticated the patients' remaining survival time, and 4) investigate continuity of care site in two different care cultures during the patients' final month of life. The theoretical framework consisted of Weisman's concept of an appropriate death, and an ethical perspective based on a dialogical ethic and truthfulness. The study comprised 56 consecutively selected adult cancer patients. Data was collected via retrospective interviews with relatives, quality of life assessments by the patients, prognoses/motivations from members in the care team, and register data on the utilisation of forms of care. Both qualitative and quantitative methods were used. Four categories respecting autonomy were found; the dying patients exercised their autonomy as self-determiners, co-determiners, delegators and nonparticipators. The co-determiners and delegators practised "shared autonomy" in interaction with relatives and staff, and a dialogue characterised by truthfulness was typical of the interplay. In the assessment of quality of life, half of the patients assessed themselves as satisfied/somewhat satisfied with their situation. The "cognitive-" and "emotional functioning" differed least from that of a normal population, while "physical-", "role functioning" and "global health status/quality of life" differed most. The prognosticated and the actual remaining survival time were in agreement for 19/51 patients (± 0.5 months). Some resistance to prognosticating emerged. The members of the care team used different forms of knowledge to motivate their prognostication. Continuity in terms of care site was fairly high for the majority of dying patients. To a great extent, organisational and structural factors determined the choice of care form.

Autoimmune polyendocrine syndrome type I (APS) is a monogenous, recessively inherited disease characterised by endocrine and non-endocrine autoimmune manifestations. One fifth of APS I patients suffer from periodic intestinal dysfunction with varying degrees of malabsorbtion, steatorrhea and constipation. Alopecia areata is found in one third of APS I patients. By immunoscreening human cDNA libraries derived from normal human duodenum and scalp with APS I sera, we identified tryptophan hydroxylase (TPH) as an intestinal autoantigen and tyrosine hydroxylase (TH) as a dermal autoantigen. Forty-eight percent (38/80) of the APS I patients had TPH antibodies (Ab) and 44% (41/94) showed TH immunoreactivity. No reactivity against TPH or TH was seen in healthy controls. TPH-Abs showed a statistically significant correlation with gastrointestinal dysfunction (p<0.0001) and TH-Abs were significantly correlated to alopecia (p=0.02). TPH-Ab positive APS I sera specifically immunostained TPH containing enterochromaffin cells in normal duodenal mucosa. In affected mucosa a depletion of the TPH containing EC cells was seen. In enzyme inhibition experiments TPH and TH activity in vitro was reduced by adding APS I sera. TPH and TH together with phenylalanine hydroxylase (PAH) constitute the group of pteridine dependent hydroxylases. These are highly homologous enzymes involved in the biosynthesis of neurotransmitters. Immunoprecipitation of PAH expressed in vitro showed that 27% (25/94) of APS I patients had antibodies reacting with PAH, but no associations with clinical manifestations was observed. An immunocompetition assay showed that the PAH reactivity reflects a cross-reactivity with TPH. In conclusion, we have identified TPH and TH as intestinal and dermal autoantigens in APS I, coupled to gastrointestinal dysfunction and alopecia. We have also demonstrated immunoreactivity against PAH in APS I patient sera reflecting a cross-reactivity with TPH.

The overall aim was to study and gain knowledge about what it means to live with muscular dystrophy and to study rehabilitation from the patient's perspective, among adults with muscular dystrophy in three Swedish counties: Örebro, Östergötland and Norrbotten. The thesis comprises two qualitative and three quantitative studies. Thirty interviews about illness experience were subjected to content analysis and 37 interviews about perceived support in rehabilitation were analysed according to phenomenological guidelines. Data were also collected by the Assessment of Problem-focused Coping (APC), the ADL Staircase, the Self-report ADL, the Mental Adjustment to Cancer Scale, the Sickness Impact Profile, the Psychosocial well-being questionnaire and the Quality of Life Profile. The APC was developed for assessment of problem-focused coping and also covers questions concerning the extent to which activities are experienced as problems and satisfaction with activities. The result shows that the experience of illness is largely similar in the three diagnostic groups (proximal MD, Myotonic muscular dystrophy, Myopathia distalis tarda hereditaria). The persons reported many restrictions of everyday activities, most often in mobility and transportation. Over half were dependent on other people in activities of daily living, and the illness was experienced mainly as having negative consequences for everyday life. A lower quality of life may be partly explained by a reduced capacity for activities. Problem-focused coping was used only to a limited extent, and 'Fighting spirit' was the dominant coping strategy. Rehabilitation was experienced as very valuable, particularly the education about the muscle disease, technical aids, grants and physical training. Over a five-year period, disability and quality of life of the study participants deteriorated significantly, and the dependence on other people increased.

This thesis describes the use of a new technology, the Cytosensor® microphysiometer, in the in vitro evaluation of cytotoxic drugs, using the lymphoma cell line U-937 GTB and primary cultures of tumour cells from patients as model systems. The method was specifically applied to study the metabolic effects of the novel cyanoguanidine N-(6-(4-chlorophenoxy)hexyl)-N’-cyano-N’’-4-pyridylguanidine, CHS 828, currently in phase I/II clinical trials. The Cytosensor® measures metabolic effects as changes in the rate of extracellular acidification of cells exposed to a drug by perfusion. A number of standard cytotoxic drugs were found to produce typical and reproducible acidification response patterns during observation times up to 20 h. There seemed to be a relationship between a decrease in acidification and cytotoxicity, measured in the fluorometric microculture cytotoxicity assay (FMCA), after 20-24 h of continuous drug exposure. In U-937 cells, CHS 828 induced a cytotoxic effect characterised by a steep concentration-response relationship followed by a plateau. After 24 h of incubation the DNA and protein synthesis were turned off. CHS 828 was found to produce a rapid and prolonged increase in extracellular acidification and lactate production similar to that of the structurally related mitochondrial inhibitor m-iodobenzylguanidine (MIBG). The CHS 828 induced acidification was observed in cell lines as well as in cells from various tumour types from patients and probably originates from increased glycolytic flux. The effects may be secondary to block of oxidative phosphorylation in the mitochondria, but the relevance of the early acidification is not clear. CHS 828 seemed to induce a late, at approximately 15 h, inhibition of the glycolysis followed by loss of ATP and subsequent cell death. After exposure to MIBG the loss of ATP and cell death occurred earlier and in parallel. The effects of CHS 828 were not found to resemble those of the structurally related polyamine biosynthesis inhibitor methylglyoxal-bis(guanyl-hydrazone) (MGBG). Thus, CHS 828 may represent a new and, thus, interesting mode of cytotoxic action worthwhile for further development. In combinatory studies, a synergistic interaction was demonstrated between CHS 828 and the non-toxic drug amiloride. Additive-to-synergistic effects were also seen between CHS 828 and the bioreductive cytotoxic drug mitomycin C. In U-937 cells as well as in tumour cells from patients, CHS 828 demonstrated synergistic interactions in combination with melphalan and etoposide. It is concluded that measurement in the Cytosensor® microphysiometer of early cellular metabolic changes is a feasible and potentially valuable complement to more conventional methods used in the evaluation of anticancer agents.

The overall aim of this thesis was to describe (1) needs for occupational therapy among persons with self-perceived activity limitations and/or participation restrictions due to long-term/recurrent pain, and (2) treatment interventions in occupational therapy to meet demonstrated needs. The Liss’ model for assessing health care needs was used as a structural scheme. A randomly selected sample (n=10,000) from the Swedish general population aged 18-58 years was the foundation for the study population with and without pain. In addition, occupational therapists were included (n=109). Data collection was made by postal questionnaires. The results showed a prevalence of 26 % and an incidence rate of 0.07. Demographic characteristics of the sample were female gender, ages 40-58 years and fewer years of education than those without pain. Pain in shoulders/lower back of searing/aching/gnawing character was the most frequently reported. A majority of the respondents reported affective/emo-tional effects of pain mainly of depressive character and they had previously been on sick leave due to pain. Women reported higher frequencies of self-perceived activity limitations/ participation restrictions due to pain, more difficulties with intermediate ADL, perceived higher job demands and had longer sick leave than men. Men perceived poorer social support than did women. Needs for occupational therapy were reported mainly as a consequence of activity and temporal imbalance. High health care consumers reported higher frequencies of needs/problems than did low health care consumers. The main goals and interventions suggested by occupational therapists to meet the needs in pain management focused on increased knowledge of handling daily occupations with the purpose to reduce pain, maintain competence/improve performance of home maintenance, reduce consequences of pain and increase knowledge how to handle effects of pain.

Cardiovascular risk in primary hyperparathyroidism (HPT) is controversial, and studies mainly from Europe associate HPT with increased cardiovascular morbidity and mortality. Cardiovascular morphology and function were evaluated prospectively in 31 consecutive HPT patients (mean serum calcium 2.97±0.04) and randomly enrolled controls matched for age and sex. Patients were re-examined at normocalcemia about one year after parathyroidectomy. HPT patients showed an operatively reversible disturbance in endothelial vasodilatory function that seemed unrelated to an early sign of atherosclerosis, i.e. thickness of carotid artery intima-media complex. Acute hypercalcemia in healthy subjects induced a similar impairment in endothelial function, which suggests a dependence on biochemical rather than structural vascular changes in HPT. Echocardiography showed left ventricular diastolic dysfunction and supernormal systolic performance being reversed after operation. Left ventricular mass tended to be irreversibly increased. During exercise HPT patients exhibited greater rise in systolic blood pressure compared to controls and an increased number of premature ventricular beats. This indicated increased work load and a propensity for fatal cardiac events. Following surgery, an improvement with less pronounced ST-segment depression was seen. 24-hour ambulatory blood pressure monitoring showed irreversibly increased levels despite maintained diurnal rhythm, while 24-hour heart rate variability analysis displayed blunted nocturnal increase of low and very low frequency bands that was corrected postoperatively. Parathyroidectomy seems to alleviate most of the cardiovascular disturbances in HPT, except for hypertension. This is consistent with the normalised longevity in HPT treated with parathyroidectomy and supports active treatment of HPT.

Atrial fibrillation is a common disease. With pharmacological therapy most patients with atrial fibrillation have moderate or little symptoms, but a number of patients have severely symptomatic disease. This study evaluates two new non-pharmacological therapies for atrial fibrillation, the Maze procedure and atrial overdrive pacing. In the patients planned for Maze surgery the quality of life, assessed with the SF-36 questionnaire, was very low before the operation. The quality of life was markedly improved 6 and 12 months after the Maze operation, and was comparable to values of the general Swedish population. In the patients with sinus rhythm before surgery, the atrial size and transport function was assessed with echocardiography, and the autonomic balance was assessed with heart rate variability (HRV). The sizes of both atria were reduced and the transmitral early filling / atrial filling (E/A) ratio was increased at 6 months after the operation compared to before. A progressive increase of the E/A ratio was seen during the 24 months follow-up period, indicating a progressive decline of the left atrial transport function. All components of HRV, including the parameters expressing sympathetic and parasympathetic modulation, were markedly decreased early after the Maze procedure compared to before. Late after the operation all components of HRV were still markedly depressed. This is interpreted as a partial autonomic denervation of the heart Single-site right atrial overdrive pacing with two different levels of overdriving was compared with no pacing in patients with paroxysmal atrial fibrillation in a cross-over study. Overdrive pacing reduced the median number of episodes of atrial fibrillation with 50% compared to no pacing. There was no difference between medium rate overdrive pacing and high rate overdrive pacing.