<p>Financial incentives have become important in health care all over the world. This thesis compares one council implementing a new payment system based on performance based reimbursement (PBR) with ten councils retaining an annual budget system. </p><p>The aim of this thesis was to study the effects of PBR on physicians’ attitudes and behaviours, that may affect the conditions for cost effective care. Aspects highlighted are efficiency, cost awareness, quality of care, professional autonomy and power, job satisfaction and leadership.</p><p>This thesis is based on data from seven studies, questionnaires, interviews and register based studies. One instrument, Incentive, Effectiveness, Environment (IEE) was developed within the framework of this thesis. It measures self-reported behavioural changes related to daily clinical work, judgements about work environment factors and the quality of care, and attitudes towards and existence of financial incentives.</p><p>Physicians in the council with PBR experienced a greater pressure to improve their efficiency and they did so. The average length of stay decreased more both in relative and absolute numbers. Much of the efficiency increase, however, seems to emanate from "running faster", not from working more rationally. Cost awareness increased in all councils studied although more so in the council with PBR. PBR was found to create a different financial incentive than an annual budget, stronger and more positive. Effects on quality of care were judged to be negative. Financial reductions were claimed to be the main reason for quality losses, but PBR was found to be more time consuming and therefore contributed to the negative outcome. Work environment factors, especially professional autonomy and power were judged to have deteriorated in all councils studied although more so in the council with PBR. Good leadership was shown to make a difference for quality of care as well as for professional autonomy and job satisfaction, regardless of context.</p><p>The results seem, at least partly, to depend on the new payment system, creating an increased efficiency pressure. Additional reasons discussed in this thesis are financial reductions, repeated organisational changes and a size effect.</p>

<p>Morbidity of asthma has increased over the world. The reasons for this increase have remained unclear. Studies in children have reported considerable East-West difference in the prevalence of atopy and respiratory allergies.</p><p>The aim of this thesis was to compare the prevalence and risk factors of respi-ratory symptoms, atopic sensitisation and bronchial hyperresponsiveness (BHR) in young adults in Estonia and Sweden. </p><p>Following the protocol of the European Community Respiratory Health Survey (ECRHS), two random population samples, 3000 from Tartu, Estonia, and 3600 from Uppsala, Sweden were investigated with postal questionnaires. Random sub samples and subjects with asthma-like complaints were subsequently interviewed, BHR was tested and serum samples analysed for total and specific IgE and eosinophil cationic protein (ECP). In a separate study two methacholine challenge methods, using either Spira Elektro2 or Mefar MB3 as dosimeters, were compared on 28 mild to moderate asthma patients.</p><p>Symptoms of asthma and hay fever were less common in Esto-nia than in Sweden, while respiratory symptoms in general were more common in Estonia. The prevalence of BHR was high and the prevalence of atopy and the levels of serum ECP were low in Tartu. The differences between the two centres in the prevalence of atopy and allergic rhinitis diminished with age, indicating a probable cohort effect. Current smoking was a dominant risk factor for BHR and for all respiratory symptoms, except attacks of asthma, both in Tartu and Uppsala. There was some difference between risk factors for BHR and atopy between Tartu and Uppsala, mostly of social and environmental origin. The low prevalence of hay fever and asthma in Tartu seemed to be partly explained by a lack of awareness of atopy and allergic diseases in the Estonian society. The estimated cumulative dose causing a 20% fall in FEV₁ was smaller and the decline of FEV₁ /log(dose) curve steeper, using the Spira, compared to the Mefar protocol.</p>

<p>Granulocyte adhesion and release of their granule proteins are key steps during selective accumulation of a certain cell to an inflammatory site. Eosinophils are specifically recruited to sites of allergic inflammation and parasitic infection, whereas neutrophil influx predominates in bacterial infection and rheumatoid arthritis. </p><p>A simple, reliable and convenient method was developed for the measurement of granulocyte adhesion and release of granule proteins by using the normal population of granulocytes. The design allows simultaneous quantitative assessment of eosinophil and neutrophil adhesion to proteins and degranulation. </p><p>Using this method, manganese ions (Mn²⁺) induced a higher level of eosinophil adhesion to fibronectin, fibrinogen and albumin as compared with neutrophils. PMA induced comparable levels of eosinophil and neutrophil adhesion. F-MLP stimulated a rapid, short-term adhesion of neutrophils to fibrinogen. </p><p>In the same conditions PMA alone stimulated a dose-dependent release of ECP from cells that adhered to both fibronectin and fibrinogen. Meanwhile, Mn²⁺ amplified the release of ECP induced by PMA. Furthermore, release of ECP was shown to be associated with cell death.</p><p>PMA, in combination with Mn²⁺, induced a marked release of ~ 80%of the intracellular content of lactoferrin and HNL in neutrophils. PMA or f-MLP alone induced 30-40% release of lactoferrin and HNL. A maximal release of MPO of 15-20% was obtained from neutrophils stimulated by PMA and Mn²⁺. Release of lactoferrin and HNL showed a significant negative relationship to the viability of cells.</p><p>Stimulated by PMA, eosinophils from pollen-atopic patients during early pollen season displayed a markedly enhanced adhesion and release of ECP of eosinophils compared with eosinophils from the references. Priming with IL-5 caused a significantly higher adhesion and release of ECP by eosinophils in response to PMA. GM-CSF priming enhanced eosinophil adhesion in response to PAF and PMA plus Mn²⁺, but did not enhance the release of ECP.</p><p>In conclusion, the assay allows a simple quantification of eosinophil and neutrophil adhesion, as well as degranulation by using the normal population of granulocytes. Cellular adhesion plays an important role in the regulation of both eosinophil and neutrophil degranulation, but adhesion and degranulation can be induced separately.</p>

<p>Ultraviolet radiation (UVR) is a major risk factor for development of skin cancer. UVR-induced DNA damage and a dysfunctional p53 protein are important steps in the development of squamous cell carcinoman in human skin (SCC). The aim of the present investigation was to analyze incidence trends of SCC in Sweden, quantify the risk of second primary cancer after SCC and further analyze the effects of UVR and p53 protein in human skin <i>in vivo</i> and <i>in vitro</i>. The effect of photoprotection by sunscreens was also evaluated. </p><p>We found that the age-standardized incidence rate of SCC in Sweden increased substantially in both men and women during the period 1961-1995, especially in men and at chronically sun-exposed skin sites. Patients with SCC are also at increased risk of developing new primary cancers, especially in the skin, squamous cell epithelium, hematopoietic tissues and respiratory organs. In experimental studies <i>in vivo</i> and <i>in vitro</i> in human skin we observed that repair of UV-induced DNA damage appears to be more efficient in chronically sun-exposed skin despite a less uniform p53 response. Non-sun- exposed skin is more homogeneous with respect to the epidermal p53 response. Keratinocytes in skin exposed frequently to the sun may be prone to react more easily to cytotoxic stress. Two different modalities of photoprotection significantly reduced the amount of DNA damage and the number of p53-positive cells. In addition, we demonstrated that a well-defined system for <i>in vitro</i> culture of explanted skin provides an excellent alternative to <i>in vivo</i> experiments. </p><p>In conclusion, this study has increased our knowledge of SCC epidemiology in Sweden and of the effects of artificial and solar UVR and sunscreens on chronically sun-exposed and non-sun-exposed sites, respectively, of human skin.</p>

<p>Antitumour properties of the cyanoguanidine CHS 828 and analogues were discovered in 1997. CHS 828 is presently in clinical phase I/II trials. This thesis encompasses in vitro studies of the kinetics and mode of cell death induced in the human cell line U-937 GTB, by CHS 828 and the standard antitumour drug etoposide.</p><p>Etoposide induces apoptosis in U-937 GTB within 4 h. The cells exhibited apoptotic morphology, including condensed and fragmented nuclei and formation of apoptotic bodies, activation of caspase 3 and 8, and DNA fragmentation, visualised by TdT-mediated dUTP nick end-labelling (TUNEL).</p><p>CHS 828 induced few and weak signs of apoptosis. Metabolic activity was the only parameter affected during the first 24 h of exposure. After ~30 h, proliferation (DNA synthesis) and protein synthesis ceased, and viability started to decrease towards 10% at 72 h. Morphology and ultrastructure of dying/dead cells showed predominant necrosis. The decrease in viability was postponed by protein synthesis inhibition or maintenance of ATP levels by 3-aminobenzamide. In addition, 3-aminobenzamide switched morphology towards apoptosis. </p><p>Continuous co-exposure to CHS 828 and etoposide resulted in impressive cell kill synergy in U-937 GTB cells at effect levels of 30-70%. Pre-exposure to CHS 828 for 18 h or more, on the other hand, resulted in diminished cell kill and inability to activate the apoptotic machinery upon etoposide stimulation, evaluated by morphology and caspase activity.</p><p>In summary, CHS 828 induced cell death is predominantly non-apoptotic, does not involve caspases and can be postponed by maintained protein synthesis and ATP levels.</p>

<p>In patients with unstable coronary artery disease, this study evaluated the degree of inflammation and coagulation activity, relations to myocardial cell damage, prognosis, and influences of randomisation to 72 h infusion with three different doses of inogatran, a direct thrombin inhibitor (n=904), or unfractionated heparin (n=305). </p><p>Anticoagulant treatment effects were evaluated with aPT time. In inogatran treated patients with aPT times ≥ 44 s (median), the 7-days event rate - death, myocardial infarction or refractory angina – was 11.6 %, compared to 6.6 % with aPT times < 44 s (p=0.01). Higher aPT times was related to improved outcome during heparin treatment.</p><p>Markers of inflammation, i.e. fibrinogen and C-reactive protein (CRP), and coagulation, i.e. prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT), soluble fibrin (SF) and D-dimer were analysed in serial samples (n=320). High fibrinogen, F1+2 and D-dimer levels persisted at 30 days. Patients with myocardial damage, detected by elevated troponin, had higher levels of all markers except TAT.</p><p>Ischemic events occurred at 30 days in 17 % of patients with high (pre-treatment top tertile) and 8.5 % of patients with lower fibrinogen levels (p=0.03), while high CRP levels only were related to increased mortality. At 30 days, patients with high compared to low pre-treatment levels of TAT or SF had 40 % lower event rate. Patients with early decreased compared to raised F1+2 or TAT levels during treatment had 50 % lower 30-days event rate (p<0.05). </p><p>Conclusions: The aPT time is an inappropriate indicator of antithrombotic efficacy. The raise in fibrinogen in the acute phase is sustained, and indicates risk of thrombosis and new ischemic events. The pronounced CRP elevation is transient, but associated with increased mortality. Higher coagulation activity may identify patients with a thrombotic condition as the major cause of instability, who are best responders to anticoagulant therapy. However, reactivation of coagulation activity with raised risk of ischemic events is a concern at cessation of treatment.</p>

<p>The aims of this thesis are threefold: (1) To investigate cancer patients’ satisfaction with and utilisation of an Individual Psychological Support (IPS) intervention. (2) To evaluate the effects of Individual Support (IS), comprising IPS combined with Intensified Primary Health Care and Nutritional Support, on psychological distress and quality of life during the first year after diagnosis. (3) To explore to what extent aspects of quality of life and emotional functioning one year after diagnosis can be predicted by medical, psychological and socio-demographic factors at diagnosis. The analyses are based on data from the Support-Care-Rehabilitation project, using a prospective randomised design to compare four conditions: (1) Individual Support (IS) starting at diagnosis, (2) Group Rehabilitation (GR) starting three months later, (3) a combination of IS and GR, and (4) Standard Care (SC). The study sample consisted of patients newly diagnosed with breast cancer, colorectal cancer, gastric cancer or prostate cancer. A total of 481 patients were randomised and followed for 24 months.</p><p>The IPS was an individually tailored, problem-focused intervention based on psychosocial oncology and cognitive behaviour therapy. Half of the patients receiving IPS had more than 2 sessions. Patients reporting that they had problems to address received more IPS sessions and reported more benefits of the intervention. Receiving an extensive medical treatment, young age, and not having someone besides the family to rely on in times of difficulties increased the odds of receiving tree or more sessions of IPS. The IS had limited impact on psychological distress and quality of life in intention-to-treat analyses. Additional analyses with stratification for baseline anxiety and/or depression levels suggested that for IS patients with higher levels of anxiety and/or depression, these problems continued to diminish below those of Control patients during the first year after diagnosis.</p><p>Linear regression models were used to explore, one year after diagnosis, quality of life aspects indicative of rehabilitation needs. High levels of baseline anxiety and / or depressive symptoms were associated with lower levels of Emotional Functioning, and high self-rated well-being was associated with higher levels of Emotional Functioning. Extensive medical treatment and presence of comorbid conditions during the year before diagnosis predicted a low Global Quality of Life, whereas self-rated wellbeing predicted a high Global Quality of Life. Advanced disease, one or more comorbid conditions and high age were found to be associated with lower levels of Physical Functioning. A high level of activities outside the home during the year before diagnosis and high self-rated wellbeing were predictive of a better Physical Functioning. </p><p>In conclusion, a large proportion of cancer patients offered IPS in conjunction with diagnosis and primary treatments seized this opportunity to discuss their situation, and perceived the experience as beneficial. Thus, offering newly diagnosed cancer patients these psychosocial support services may facilitate their situation.</p>

<p>Hypertension is common and constitutes an increased risk of morbidity and mortality of cardiovascular disease. Antihypertensive treatment will reduce this risk; the individual patient's response to treatment, however, is difficult to predict.</p><p>Patients with hypertension and left ventricular hypertrophy were randomized to monotherapy with either the angiotensin II type 1 receptor antagonist irbesartan or the beta-adrenoreceptor blocker atenolol, and followed for three months. The aim was to determine whether gene polymorphisms in the renin-angiotensin-aldosterone system were related to the response to treatment.</p><p>The ACE II genotype was associated with the most pronounced diastolic blood pressure response, while the aldosterone synthase (CYP11B2) -344 TT genotype showed the greatest systolic blood pressure response. The angiotensinogen 174 TM genotype showed the most pronounced regression in left ventricular mass, independent of the change in blood pressure. These associations were exhibited only in response to treatment with the angiotensin II type 1 receptor antagonist irbesartan.</p><p>In a sample of apparently healthy subjects, those with both the D allele and the angiotensinogen 174 TM variant in combination showed a decreased endothelium-dependent vasodilation.</p><p>These results suggest that the response to antihypertensive treatment is associated with polymorphisms in the genes reflective of the pathophysiological pathway the drug targets. The present study is an encouragement for future investigation, such as large scale studies of multiple polymorphisms and combinations thereof in an attempt to identify a panel of genotypes that can be used as a predictor of an individual patient's response to anithypertensive treatment.</p>

<p>Cardiovascular disease (CVD) is the major cause of death in patients with chronic renal failure (CRF). Endothelial function and oxidative stress (OS) have previously been shown to be important in the pathogenesis of CVD. In this thesis, the endothelium-dependent vasodilatation (EDV) and OS were investigated in the patients with CRF. Also the influence of L-arginine, erythropoietin and diclofenac on EDV were evaluated in patients with CRF. </p><p>Patients with CRF were found to be characterized by a defect EDV even after correction for traditional cardiovascular risk factors. This impairment was related to the degree of renal failure. </p><p>Measurement of OS markers in CRF patients demonstrated that these patients were in a state of OS compared to healthy controls. The most informative indices to evaluate the degree of OS in CRF were: oxidized glutathione (GSSG) level, ratio between oxidized and reduced glutathione (GSSG/GSH ratio), lag phase of lipoprotein fraction (LPF) and baseline diene conjugation level of LPF. </p><p>Simultaneously investigated OS markers and EDV demonstrated a relationship between OS and EDV in patients with CRF. EDV was positively correlated with total antioxidative activity, reduced glutathione (GSH) and lag phase of LDL. </p><p>Local infusion of L-arginine as a substrate for nitric oxide synthesis and diclofenac as an inhibitor of cyclooxygenase-derived vasoconstrictive agents augmented EDV in patients CRF. In contrast, the erythopoietin treatment (both acute and long-term) impaired EDV in CRF patients. </p><p>In conclusion, patients with CRF have increased levels of OS markers and impaired endothelial vasodilatory function. These factors may be important with respect to the high morbidity and mortality of CVD found in patients with CRF. One possible mechanism to reduce CVD in patients with CRF is to improve endothelial function and eliminate OS. Locally administrated L-arginine and diclofenae improved EDV but erythropoietin administration impaired EDV in patients with CRF. </p>

<p>In 101 patients with ST-elevation myocardial infarction treated with streptokinase the additional effects of lmw-heparin (dalteparin) were investigated. The prognostic value of troponin-T (TnT) was elucidated and the development of myocardial damage was investigated with Positron Emission Tomography (PET).</p><p>Dalteparin tended to provide a higher rate of TIMI grade 3 flow in the infarct-related artery at 24 h compared to placebo. In patients with signs of early reperfusion there was a higher rate of TIMI grade 3 flow in the dalteparin group compared to placebo. There were significantly fewer patients with ischemic episodes at 6-24 h in the dalteparin compared to placebo group.</p><p>The increase in coagulation activity was attenuated in the dalteparin group. There was a tendency to more ischemic episodes and lower frequency of TIMI grade 3 flow in patients with persistent elevation of coagulation activity at 18 h. Among deceased patients the coagulation activity was significantly higher than in survivors. </p><p>The association between elevated TnT on admission and long-term mortality might be explained by longer delay, episodes of chest pain during the last 24 h, less non-invasive signs of reperfusion at 90 minutes, and lower patency in the infarct-related artery at 24 h. </p><p>Eight patients were investigated with PET at 3h, 24 h and after 3 weeks. PET outlines the infarct region with reduced perfusion and metabolism. The oxidative metabolism in the infarct region at 3 h correlated with the water-Perfusable Tissue Fraction (PTF) and its improvement over time.</p><p>Dalteparin seems to improve maintenance of coronary patency, which can be explained by attenuation of the increased coagulation activity. Elevated TnT level on admission is associated with a worse outcome, which can partly be explained by less successful fibrinolytic treatment. PET investigations might to be a useful method in future trials evaluating new agents in the treatment of acute myocardial infarction.</p>