<p>Kidney dysfunction increases cardiovascular disease (CVD) risk. The mechanisms for the risk increase seem to involve a combination of traditional and non-traditional CVD risk factors.</p><p>We studied renal dysfunction as CVD and mortality risk factor in middle-aged men free from diabetes and CVD. The risk for myocardial infarction (MI) and CVD mortality was increased by ~40% in the 16.5% of men with worse renal function, independent of other CVD risk factors.</p><p>Renal transplant dysfunction as CVD and mortality risk factor was also studied. Renal transplant dysfunction was a risk factor for mortality and for combined CVD endpoint. The risk by renal transplant dysfunction was independent of traditional CVD risk factors as well as transplantation-specific risk factors. Only moderate increase in serum creatinine resulted in mortality and CVD risk comparable to diabetes, older age and higher low density lipoprotein levels.</p><p>In haemodialysis patients, the effects of a dialysis session on non-traditional CVD risk factors were studied. A HD session reduced asymmetric dimethylarginine (ADMA) and homocysteine levels, as well as augmentation index (AIx). The change in AIx was related to ADMA plasma level change.</p><p>In patients with stage 3-5 chronic kidney disease (CKD), endothelium dependent vasodilation (EDV) was studied together with markers of oxidative stress and C-reactive protein (CRP). CRP was related to lipid peroxidation, while EDV was related to intracellular antioxidative capacity measured by reduced glutathione levels.</p><p>These studies demonstrate that mild to moderate renal dysfunction is independently associated with increased CVD risk in apparently healthy people, as well as in renal transplant recipients. The mechanisms by which renal dysfunction increases CVD risk are yet to be elucidated. We suggest that arterial stiffness could be reduced in haemodialysis patients by increasing nitric oxide bioavailability. In stage 3-5 CKD patients, improving intracellular antioxidative capacity may result in endothelial function improvement.</p>

<p>In this study, metastasizing serotonin-producing ileocaecal carcinoid tumours (MSPCs) were examined for biological characteristics that could be used to define clinically relevant subgroups within this patient population. Possible targets for new treatment options were also explored.</p><p>It was found that MSPCs share several biological characteristics such as expression of serotonin, tachykinins (TKs), chromogranin A, islet autoantigen-2 and connective tissue growth factor (CTGF). TKs and serotonin were demonstrated in the same endocrine tumours in the gut and lung. IA-2 expression was shown to be up-regulated in MSPCs, possibly in connection with active hormone secretion. CTGF expression was high in tumour areas adjacent to extensive stroma expressing alpha-smooth muscle actin. This indicated myofibroblast differentiation, which may be associated with fibrosis-related complications prevalent in patients with MSPCs. When compared with other endocrine tumours, MSPCs behaved as a relatively homogeneous group, though within the MSPC population several subgroups could be defined. Patients with tumours displaying either a solid growth pattern and/or a Ki67 index ≥1% had a less favourable prognosis than those who did not. Another group of patients, who had increased plasma TK concentrations, were more likely to suffer from severe diarrhea. This information should be considered when discussing clinical treatment and when undertaking tumour biological studies. New treatment possibilities, such as drugs that specifically target TK receptors and antibodies to CTGF, are also discussed.</p><p>In conclusion, MSPCs comprise a clinically relevant tumour group with similar biological features that are distinct from other endocrine tumours. Subgroups of patients within this patient category can be defined which may be relevant when establishing prognosis and when selecting future treatment modalities.</p>

<p>The cardiac troponins are the biochemical markers of choice for the diagnosis of acute myocardial infarction (AMI) and risk prediction in patients with acute coronary syndrome (ACS). In this thesis, the role of early serial cardiac troponin I (cTnI) testing was assessed in fairly unselected patient populations admitted because of chest pain and participating in the FAST II-study (n=197) and the FASTER I-study (n=380). Additionally, the importance of cTnI testing in stable post-ACS patients from the FRISC II-study (n=1092) was studied.</p><p>The analyses in chest pain patients demonstrate that cTnI is very useful for early diagnostic and prognostic assessment. cTnI allowed already 2 hours after admission the reliable exclusion of AMI and the identification of low-risk patients when ECG findings and a renal marker such as cystatin C were added as conjuncts. Other biomarkers such as CK-MB, myoglobin, NT-pro BNP or CRP did not provide superior clinical information. However, myoglobin may be valuable in combination with cTnI results for the early prediction of an impending major AMI when used as input variable for an artificial neural network. Such an approach applying cTnI results only may also furthermore improve the early diagnosis of AMI.</p><p>Persistent cTnI elevation > 0.01 μg/L was detectable using a high-sensitive assay in 26% of the stable post-ACS patients from the FRISC II-study. NT-pro BNP levels at 6 months were the most important variable independently associated to persistent cTnI elevation besides male gender, indicating a relationship between adverse left ventricular remodeling processes and cTnI leakage. Patients with persistent cTnI elevation had a considerable risk for both mortality and AMI during 5 year follow-up. </p><p>These analyses thus, confirm the value of cTnI for early assessment of chest pain patients and provide new and unique evidence regarding the role of cTnI for risk prediction in post-ACS populations.</p>

The overall aim of this thesis was to study knowledge, attitudes and experience of emergency contraceptive pills among women and providers. Both quantitative and qualitative methods were used. Focus-group interviews were conducted with teenage-girls (I) and with women who had purchased ECP without prescription (IV). Self-administered waiting-room questionnaires were administered to women presenting for induced abortion in three large hospitals (II, III), and after the deregulation of ECP, a postal questionnaire was sent to pharmacy staff and nurse-midwives in three counties in mid-Sweden (V). Overall, women showed high basic awareness of ECP although specific knowledge such as the level of effectiveness, time-frames and how the method works was lacking. Approval of the method was high and most women were positive to use the method if they needed. Contradictory views as to whether ECP undermines contraceptive behavior were expressed. As many as 43% of women requesting induced abortion had a history of one or more previous abortions. Among the abortion applicants, one out of five, 22%, had previously used ECP and 3% had used it to prevent the current pregnancy. Media and friends were the two most common sources of information on ECP. Half of the women, 52%, were positive to having ECP prescription-free. Those women who had purchased ECP in a pharmacy without prescription, appreciated this possibility, and the major benefits expressed were time saving aspects. No severe side-effects were reported. The women's experiences of interaction with pharmacy staff were both positive and negative. The importance of up-to-date information about ECP and the OTC-availability from the health care providers was emphasized. Both pharmacy staff and nurse-midwives had positive attitudes towards ECP and the OTC availability. Of pharmacy staff, 38% reported that they referred women to nurse-midwives/gynecologists for further counseling and follow-ups. The need for increased communication and collaboration between pharmacies and local family planning clinics was reported by both study groups with suggestions of regular meetings for information and discussions. The results suggest that ECP is still underused and that more factual information is needed before the method is becoming a known, accepted and integrated back-up method to the existing family planning repertoire. Longitudinal research to assess the long-term effects of ECP is needed.

Autoimmune mechanisms and genetic susceptibility contribute to the pathogenesis of primary Sjögren’s syndrome and SLE. These chronic systemic autoimmune diseases have many serological and clinical features in common and have an impact on daily life. The studies in this thesis aim to elucidate their autoimmune mechanisms, define susceptibility genes and evaluate effects of androgen supplement on health-related quality of life. Autoantibodies against α-fodrin, a widely distributed cytoskeletal protein, were detected at similar frequencies in sera from patients with primary and secondary Sjögren’s syndrome and SLE. Consequently, testing for antibodies against α-fodrin would not add diagnostic value compared to conventional serological analysis and does not discriminate between these diseases. The type I interferon (IFN) system was found to be activated in primary Sjögren’s syndrome. IFN-α containing cells were detected in minor salivary gland biopsies, while sera from patients with primary Sjögren’s syndrome induced IFN-α production in the presence of apoptotic and necrotic cell material. This ability of sera correlated with the presence of antibodies against RNA-binding proteins and IFN-α production was dependent on RNA in immune complexes. The natural interferon producing cells/plasmacytoid dendritic cells (NIPC/PDC) were the IFN-α producers and blocking of FcγRIIa inhibited the production. Single nucleotide polymorphisms (SNPs) in two genes in the type I IFN signalling pathway, those for tyrosine kinase 2 and interferon regulatory factor 5, were strongly associated with SLE in a Swedish, Finnish and Icelandic population. The minor allele frequencies were lower in SLE patients than in healthy controls. These SNPs may decrease the function of the type I IFN system, thereby conferring protection against SLE. Supplementation with dehydroepiandrosterone (DHEA) in glucocorticoid treated women with SLE led to mild improvements in health-related quality of life in respect of mental well-being and sexuality, whereas physical well-being was unaffected.

The main purpose of this thesis was to apply the WHO and NHS palliative care approach to dementia care. Thirty-one staff-members in mid-Sweden (studies I and II) and 20 next-of- kin (study IV) were interviewed. In study III, 316 staff-members from dementia care and 121 staff-members from palliative cancer care responded to a questionnaire about family support. The interviews were tape-recorded and analysed with a qualitative phenomenographic (I and II) and a hermeneutic approach (IV). The questionnaires (III) were analysed using qualitative and quantitative content analysis. The staff-members stated almost unanimously that daily leadership was lacking, and consequently clear goal formulations and care planning were rare (I). Proper teamwork between the doctor and the staff who worked on a daily basis with the patients was absent (I). With respect to existential issues, education and staff discussions were lacking (II). The staff were at a loss concerning how to deal with these issues. Nevertheless, these issues are central to family-members who have to deal with an existential crisis (IV). Important questions emerged about obligation and guilt, faithfulness, responsibility, and paying back what you once received. Existential isolation could be identified e.g. in the reversal of roles experienced as "being a parent to your parent" and in the burden of "visiting a living dead person". There were no routines for bereavement visits. The type of support suggested for dementia family members is partly similar to support in palliative cancer care, but it also differs in other respects such as feelings of guilt because the early signs of the disease are misunderstood, the need for respite because of the long trajectory of dementia diseases, and the occurrence of anticipatory grief because in the late phase family members can no longer make any contact at all with the patient (III). A palliative approach can improve the quality of life for the dementia patient and for the family. It can be used as a basis for a clear goal formulation. Some of the suggestions listed in this thesis for improving the quality of care are more a reflection of the need for a change in attitudes rather than the need for substantial budget increases.

Heart failure and left ventricular dysfunction are major causes of morbidity and mortality. In this thesis, metabolic, hormonal, genetic and prognostic aspects of echocardiographically determined left ventricular function were investigated in a fairly large longitudinal population-based study of men. The participants were examined both at age 50 and 70 years and were followed for mortality using the national cause-of-death registry. Several factors associated with the insulin resistance syndrome predicted left ventricular systolic dysfunction independent of myocardial infarction, hypertension, diabetes and the use of cardiovascular medication after twenty years follow-up. Plasma levels of N-terminal atrial natriuretic peptide (N-ANP) were significantly increased in men with left ventricular dysfunction in comparison to healthy men. However, the diagnostic accuracy was poor due to the extensive overlapping between the groups. Relations between a haplotype of the novel hUNC-93B1 gene and the E/A-ratio were found and validated in separate samples of the cohort. Myocardial performance index (a Doppler derived index of combined left ventricular systolic and diastolic function) and left ventricular ejection fraction were found to be predictors for cardiovascular mortality independent of traditional cardiovascular risk factors in a longitudinal analysis with a mean follow-up of seven years. In conclusion, this thesis showed that left ventricular function is influenced by metabolic, hormonal and genetic factors and that echocardiographic measurements of left ventricular function, such as the myocardial performance index, are strong independent risk factors for cardiovascular mortality in elderly men.

Defects in insulin secretion and insulin action are the major abnormalities in the development of Type 2 diabetes. Hyperinsulinemia is a risk marker for Type 2 diabetes and according to some, but not in all studies also for coronary heart disease (CHD). Conventional insulin assays measure immunoreactive insulin including proinsulin-like molecules. Proinsulin and insulin measured by specific methods, insulin sensitivity measured by the euglycemic insulin clamp and early insulin response after a glucose challenge give more detailed information and may be better estimates of true risk for Type 2 diabetes and CHD. This study examined relationships between proinsulin, insulin, insulin secretion and insulin sensitivity for the development of Type 2 diabetes and CHD. The investigation of the prognostic significance of proinsulin and insulin for the development of Type 2 diabetes and CHD was performed in prospective studies of 50-year and 70-year-old men in a population-based cohort. The results indicated, that increased proinsulin concentrations, was a marker of increased risk for Type 2 diabetes independent of measurements of insulin secretion and insulin sensitivity whereas insulin was not. Proinsulin was shown to be a predictor for CHD mortality and morbidity, respectively, independent of conventional risk factors, whereas insulin was not. Insulin sensitivity measured by the gold standard euglycemic insulin clamp at age 70 was a predictor of CHD morbidity, independently of established risk factors. In summary, these data provide evidence that an increased concentration of proinsulin and not an elevated plasma insulin level per se, that constitutes the association with Type 2 diabetes and CHD and that insulin resistance per se, is associated with CHD risk. / Defekter i insulinsekretionen och insulinkänsligheten i målorganen för insulin är de huvudsakliga orsakerna till utvecklandet av typ-2 diabetes. Förhöjd insulinhalt i blodet indikerar nedsatt känslighet för insulin och är en riskmarkör för typ-2 diabetes men också för hjärt-kärlsjukdom enligt vissa studier. Konventionella insulinmätmetoder är ospecifika och mäter immunoreaktivt insulin som förutom insulin också innehåller ett förstadium till insulin, proinsulin. Proinsulin och specifikt insulin, insulinkänslighet bestämd med hyperglykemisk insulin clamp teknik och tidigt insulinsvar vid sockerbelastning ger en bättre och mer detaljerad och precis information. Dessa variabler kan därför utgöra en bättre prediktor för typ-2 diabetes och hjärt-kärlsjukdom. I denna avhandling har proinsulin, specifikt insulin, tidigt insulinsvar vid sockerbelastning och insulinkänslighet jämförts med varandra som prediktorer för utvecklandet av typ-2 diabetes och hjärt-kärlsjukdom. Två studier har omfattat risken för diabetes och två studier risken för hjärt-kärlsjukdom. Män i medelåldern respektive i högre ålder har studerats. Studierna har utförts i en populations-baserad grupp, en kohort som har sitt ursprung i en stor hälsoundersökning som genomfördes i Uppsala 1970 till 1973. Resultaten visar att proinsulin, i motsats till specifikt insulin, är en riskmarkör för utveckling av typ 2 diabetes, oberoende av insulinkänslighet och tidigt insulinsvar vid sockerbelastning. Vidare har visats att proinsulin i motsats till specifikt insulin är en riskmarkör för död respektive sjuklighet i hjärt-kärlsjukdom, oberoende av de kända riskfaktorerna rökning, högt blodtryck och förhöjt kolesterol. Slutligen har visats att insulinkänsligheten i sig är en riskmarkör för hjärt-kärlsjuklighet oberoende av ovanstående riskfaktorer förutom proinsulin. Sammanfattningsvis visar resultaten i avhandlingen att det snarare är proinsulinhalten och inte insulinnivån i blodet som står för de observerade sambanden med typ 2 diabetes och hjärt-kärlsjukdom. Nedsatt känslighet för insulin i sig är förenat med ökad risk för hjärt-kärlsjukdom.

The overall aim of this thesis was to evaluate the outcome when treating children for displaced femoral fractures with external fixation. In a consecutive and prospective study during the period 1993-2000, 96 children aged 3-15 years with 98 displaced femoral fractures were treated with external fixation and early mobilisation. The mean age was 8.1 years, the mean hospital stay was 8.7 days and the mean treatment time was 61 days. All fractures healed. Minor complications included pin tract infections (18%), clinical insignificant malunions, heterotopic ossification and two re-reductions. Major complications (6%) included two re-fractures after significant trauma and three plastic deformations after premature fixator removal leading to an osteotomy. Radiological evaluation was performed up to one year for the whole group and for a subgroup up to two years. The evaluation showed that malunions were few and prone to remodelling almost completely. Although the fractures were fixated without shortening, as recommended earlier, the overgrowth was far less than expected. Isokinetic muscle strength was measured in both hamstrings and quadriceps in 31 of the patients and compared with 31 matched children without previous injury to the legs. Early mobilisation seems to prevent residual muscle weakness previously shown after treatment with traction or cast for femoral fractures in children. A cost analysis was performed, comparing three different treatment modalities of femoral shaft fractures: traction in hospital, traction in hospital/at home and external fixation. The analysis included both total medical costs and costs for the care provider. The most important factors were days spent at the hospital and the sick leave for the care provider. Treatment that can minimise these factors will contribute strongly to a lowering of health care costs. Conclusion: External fixation of displaced femoral fractures in children can be used as standard treatment in children aged 3-15 years. The treatment provides satisfactory results with a low rate of major complications. Early mobilisation seems to prevent residual muscle weakness. The treatment reduce the number of days in hospital and the number of days of sick leave for the care provider and contributes strongly to lowering health care costs.

This dissertation has two parts. Firstly, satisfaction with life as a whole and with 10 life domains (using an instrument termed LiSat-11 with 6-graded scales) is described in a nationally representative sample aged 18-64 years (n: 2,533) and is related to some socio-demographic circumstances. Secondly, vocationally disabled people (n: 109) at an employability institute are prospectively followed in order to determine their life satisfaction and to identify early predictors of vocational rehabilitation outcome. <u>Main results</u>: Gender independently, 70 % of the national sample were satisfied with life as a whole (were happy). The ten domains formed a 4-factor pattern: ”Closeness, Health, Spare time, Provision”. Seven domains were sizeable predictors of overall life satisfaction. In a complex manner socio-demographics were predictive of (gross levels) all LiSat-11 items. Main predictors were perceived health, immigrant status and educational level. Generally, the vocational rehabilitees had low LiSat-11 levels except for the closeness items. They had relatively poor background resources (low “sense of coherence“ level) for successful coping. Whereas a positive rehabilitation outcome was accompanied by increases in several LiSat-11 aspects, only satisfaction with the vocational situation was clearly responsive. Three early predictors of outcome were identified: belief in vocational return, educational level and sense of coherence. <u>In summary</u>: Besides providing reference values for the LiSat-11 instrument, this dissertation demonstrates that different socio-demographic factors influence different areas of concern (domains) in 18- to 64-year-old Swedes. In turn, satisfaction derived from different areas heavily influences level of overall life satisfaction. Moreover, the vocational rehabilitees generally seemed to be predisposed to being poor copers, possibly a major background of low levels of many LiSat-11 aspects. The identified set of predictors of the outcome of vocational rehabilitation emphasizes a need for focusing on psycho-social aspects within vocational rehabilitation.