<p>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. </p><p>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.</p><p>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.</p><p>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.</p><p>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. </p><p>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.</p>

<p>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.</p>

<p>Reduced performance of the left ventricle to eject blood – left ventricular systolic dysfunction (LVSD) – is a common predecessor of the heart failure syndrome. With or without symptoms, LVSD is associated with a poor prognosis. However, with adequate treatment, the development or progression of symptoms, the need for hospitalisation and mortality can all be reduced. In the present work, the occurrence of LVSD was evaluated by echocardiography in a community-based sample of 75-year-old men and women (n = 433). LVSD was a common condition, with a prevalence rate of 6.8%. In nearly half the participants with LVSD, there was no clinical evidence of heart failure.</p><p>Community-based screening for asymptomatic LVSD has been proposed as a strategy to reduce the incidence of heart failure. Because of the high costs and low availability, echocardiography is not a suitable screening tool. The plasma concentration of B-type natriuretic peptide (BNP) has been the most advocated screening tool. Another alternative is the standard 12-lead electrocardiogram (ECG). Both the ECG and BNP were effective in excluding LVSD in our 75-year-old community-based sample. However, compared with BNP, the ECG had considerably better specificity. In screening for LVSD, BNP had a diagnostic value in addition to the ECG, but only in individuals with abnormal ECGs.</p><p>The left ventricular ejection fraction (LVEF) measured by echocardiography is a well-established index for describing left ventricular systolic function. The wall motion index (WMI) and the amplitude of mitral annulus motion (MAM) are suggested as alternative echocardiographic methods. Compared with MAM, the WMI had a more favourable agreement with the LVEF in our 75-year-old participants. Nonetheless, MAM was a strong predictor of mortality. MAM predicted the risk of all-cause and cardiac mortality independently of other risk factors. In addition, when it came to cardiac mortality, the predictive ability of MAM was independent of the LV function measured as the WMI.</p>

<p>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.</p><p>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. </p><p>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. </p>

<p>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 <i>in vitro</i> 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 <i>in vitro</i> 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.</p><p>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.</p>

<p>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. </p>

<p>This thesis studied environmental factors in relation to asthma and respiratory symptoms among schoolchildren in two countries. In Sweden, 1014 pupils (5-14 year) in 8 schools participated. Wheeze was reported by 7.8%, current asthma by 5.9%, doctor-diagnosed asthma by 7.7%, cat allergy by 6.8% and dog allergy by 4.8%. Current asthma was less common among those consuming more fresh milk and fish. Doctor-diagnosed asthma was less common among those consuming olive oil. Cat, dog and horse allergens were common in settled dust and related to respiratory symptoms. Pupils consuming butter and fresh milk had less respiratory symptoms in relation to allergen exposure. In schools with increased levels of microbial volatile organic compounds and selected plasticizers (Texanol and TXIB) asthma and respiratory symptoms were more common.</p><p>In Korea, 2365 pupils (9-11 year) in 12 schools participated (96%). In total, wheeze was reported by 8.0%, current asthma by 5.7%, doctor-diagnosed asthma by 5.4%, cat allergy by 2.6% and dog allergy by 4.9%. Contamination of dog and mite (<i>Dermatophagoides farinae</i>) allergen was common while cat allergen was uncommon. Remodelling, changing floor and building dampness at home were positively associated with asthma and respiratory symptoms. The strongest associations were found for floor dampness. Indoor/outdoor concentration of NO₂, formaldehyde and ultrafine particles (UFP) at schools were positively associated with asthma and respiratory symptoms. </p><p>When comparing Sweden and Korea, Korean pupils had more breathlessness and asthma but reported less cat and pollen allergy. Swedish schools had CO₂-levels below 1000 ppm, while most Korean schools exceeded this standard. Since both home and school environment may affect pupil’s asthma and respiratory symptoms, air quality should be an important health issue. Moreover, changes in dietary habits may be beneficial to decrease asthma and allergies. Furthermore, interaction between diet and environment needs to be further investigated.</p>

Serum levels of eosinophil granule proteins namely ECP, EPO and EPX, which are stored in the matrix of specific granules, were shown to correlate with the course of disease in disorders involving eosinophils. The concentration of eosinophil proteins in serum is the result of their release in vivo and ex vivo during the sampling procedure. Generally, eosinophils release the content of their specific granules in three ways: exocytosis, piecemeal degranulation (PM) or cytolysis. Which of them is operating in circulating eosinophils has not yet been defined. The aim of this thesis was to study the mechanisms of granule protein release from blood eosinophils in respect of protein subcellular localization and cell ultrastructure. In patients with bacterial infections, serum levels of ECP but not EPO increased, while in patients with viral infections both proteins remained within the range of healthy controls. G-CSF is a cytokine involved in the response mechanism to bacterial but not viral infections. Administration of G-CSF to healthy subjects induced an elevation of eosinophil numbers and a preferential increase of serum EPX and ECP in comparison to EPO. The model of PM consists of the stepwise transportation of specific granule contents from the granules towards the plasma membrane. We observed that administration of G-CSF to healthy subjects and the allergen exposure of allergic subjects during the pollen season, caused changes in the ultrastructure of eosinophil specific granules such as loosening of the matrix, granule matrix lucency and ragged losses of their core. Similar alterations of morphology had been previously described for eosinophils undergoing PM. ECP, EPX and EPO were localized not only in the specific granules but also in extra-granular compartments as shown both by immuno electron microscopy and subcelular fractionations, An extra-granular EPX compartment was present in healthy as well as in allergic and in hypereosinophilic subjects, and there were no significant differences in its size between the groups. The size of the extra-granular compartments of ECP and EPO was increased in allergics during the season, and these compartments were clearly separate from that of EPX. Results of this show the differential mobilization ofgranule proteins in blood stream eosinophils serum and indicates PM as its mechanism.

In this thesis the oxidative metabolism by blood eosinophils from birch pollen allergic subjects was studied and compared to that by eosinophils from healthy controls, during and out of the pollen season. The effects and mechanisms of in vitro IL-5 priming on blood eosinophils were investigated and compared to the effects of in vivo priming during pollen exposure. The main findings of this work were that the oxidative metabolism by blood eosinophils taken from pollen allergic subjects is reduced during the pollen season. The eosinophils taken from asymptomatic allergics have a reduced capacity to produce oxygen free radicals as compared to non-allergic controls. The oxidative metabolism by blood eosinophils from allergic subjects is primed in vivo during the pollen season, as compared to the healthy controls and as compared to out of season. IL-5 primed the oxidative metabolism by eosinophils from allergic subjects in a similar way as eosinophils from healthy controls, both during and out of pollen exposure. The total and tyrosine phosphorylation patterns obtained were identical in eosinophils from allergic subjects and non-allergic controls during the pollen season. Spontaneous phosphorylation was the same in both groups and different from that after IL-5 priming. The oxidative metabolism of blood eosinophils is composed of different stages. The initial stage, measured as the t½rises of the CL curves, is an indication of the state of priming of the cell, while the end stage, measured as the peaks of the CL curves, is an estimate of the total radical production by the cells. IL-5 priming affected these two stages differently and the two stages are regulated by different signal transduction pathways and IL-5 priming causes a by-passing of MEK. In conclusion, in this thesis it is shown that blood eosinophils from allergic subjects are primed in vivo during exposure to their allergen. This in vivo priming leads on one hand to a reduced oxidative metabolism during the pollen season, but also to a faster onset of radical production as a response to certain stimuli. Our data do not provide any evidence of IL-5 involvement in the in vivo priming of blood eosinophils from allergic patients during pollen exposure.

This study evaluated the use of multi-lead ST-monitoring in the early assessment of patients with suspected or confirmed unstable coronary artery disease (UCAD). At continuous 12-lead ECG (c12ECG), the definition of an ischemic episode as a transient ST-deviation ¡Ý0 for at least 1 minute resulted in a good observer agreement (kappa=0.72) and an acceptable incidence of postural ST-changes. When c12ECG was performed from admission and for 12 hours in 630 patients with suspected UCAD, 16% had ischemic episodes. At 30 days, patients with episodes had a higher risk of cardiac death or myocardial infarction (MI) (10% vs. 1.5%). In a multivariate analysis, troponin T¡Ý0.10¦Ìg/l and presence of ischemic episodes were independent predictors of cardiac death or MI. When ST-monitoring and troponin T status were combined, patients could be divided into a low-, intermediate-, and high-risk group with 1%, 4% and 12% risk for cardiac death or MI at 30 days of follow up. As a part of a multicenter trial, including patients with UCAD, 1016 patients underwent ST-monitoring with c12ECG or continuous vectorcardiography (cVCG). Ischemia was detected in 32% and 35%, respectively. When the groups with ischemia were compared, the groups were similar with respect to several clinical variables. Thus, these methods identify the same high-risk population. Of the 629 patients treated non-invasively with extended treatment of low-molecular- weight heparin (LMWH) or placebo, 34% had ischemic episodes. In this group at 3 months, patients administered LMWH had a significantly lower risk of death, MI, or revascularization than patients treated with placebo (35.2% vs. 53.4%). In patients without transient ischemic episodes, the outcome in the LMWH and placebo group was similar. Thus, multi-lead monitoring provides important prognostic information early after admission in this population, and seems to identify patients who benefit most from extended antithrombotic treatment.