The endothelium plays an important part in blood flow regulation by producing the vasodilatory substance nitric oxide (NO). Various studies have shown that commonly accepted risk factors for coronary heart disease, such as hypertension, diabetes, hypercholesterolemia, smoking and mental stress impair endothelium-derived vasodilation by the NO-pathway. This thesis focuses on the effects of mental stress on the endothelium. Furthermore, the effects of epinephrine (E) and norepinephrine (NE) and blockades of adrenergic receptors were studied in the forearm in young healthy subjects. Different blockades were given locally in the forearm, not affecting general hemodynamics. β-adrenoceptor blockade impaired endothelium-dependent vasodilation (EDV), while α-adrenoceptor blockade and neurogenic blockade caused a general vasodilation which was not endothelium dependent. Neuropeptide Y did not seem to influence blood flow in the resting forearm. A short period of mental stress induced by an arithmetic task, impaired EDV in the forearm. This negative effect could be blocked by β-adrenergic, but not α-adrenergic receptor blockade. Local infusions of E and NE in the human forearm induced vasodilation and vasoconstriction, respectively. As both EDV and endothelium-independent vasodilation were affected by both E and NE, the two catecholamines did not seem to affect vascular tone by an endothelium-specific mechanism. Both cold pressure stress and mental stress induced impairments in flow-mediated vasodilation (FMD) when normalised for the degree of hyperemic blood flow. These findings give us new insights in how mental stress and sympathetic activation affects the endothelium and how the negative effects can be prevented.

In this thesis, different aspects of the insulin resistance syndrome in relation to plasminogen activator inhibitor-1 (PAI-1) activity are investigated in a longitudinal population-based study. Participants were men investigated at ages 50 and 70 with follow-up data on mortality. High PAI-1 activity was associated with low insulin sensitivity, high concentrations of serum triglycerides, high body mass index and high waist/hip ratio, independently of each other and of potential confounders. Low birth weight predicted high blood pressure, insulin resistance, truncal obesity and high PAI-1 activity but not the abdominal obesity or dyslipidaemia present in the insulin resistance syndrome. Increased physical activity level between 50 and 70 years of age, in the absence of active intervention, was associated with improved glucose, insulin, proinsulin and lipoprotein metabolism. Insulin and proinsulin seemed to be important factors that mediate much of the association between a sedentary lifestyle and increased risk of cardiovascular disease. The reported dietary intake of both mono- and polyunsaturated fatty acids was positively associated with PAI-1 activity, whereas saturated fatty acid intake displayed no association. The associations present between PAI-1 activity and the fatty acid proportions in serum cholesterol esters were partly influenced by factors related with the insulin resistance syndrome. This thesis provides further knowledge to the epidemiological view of the interrelations of the insulin resistance syndrome, PAI-1, birth weight, and lifestyle factors as physical activity and dietary habits. PAI-1 is a part of the insulin resistance syndrome and is associated both with modifiable and non-modifiable factors related with this syndrome.

Vitamin A and metabolites (retinoids) are crucial for normal epidermal maturation. Physiological effects are mediated by retinoic acid (RA) that activates nuclear retinoic acid receptors (RARs) in complexes with retinoid X receptors (RXRs), resulting in altered gene transcription. Psoriasis is a common disease with unknown etiology. Lesions display inflammation, hyperproliferation, and disturbed epidermal maturation. Treatments include topical or oral synthetic retinoids that allegedly bind to and activate the RARs. The mRNA expression of retinoid receptors RARα/γ and RXRα was studied in normal and psoriatic skin samples. RARα and RXRα were significantly reduced in psoriatic plaques as compared to non-lesional and normal skin. In situ immunofluorescence detection revealed altered distribution patterns of the receptor proteins in lesional skin. All three receptor proteins were more intensely detected in the lower half of the epidermis but were significantly reduced in the superficial epidermis compared to both normal and non-lesional skin. In order to evaluate the retinoid signaling system in psoriatic lesions, we compared the effect of topical RA on the expression of the cellular RA-binding protein II (CRABPII) in psoriatic and normal skin. CRABPII was induced by RA on mRNA and protein level in non-lesional and normal skin but not in lesional skin, where the basal expression of CRABPII was already up-regulated. Changes in retinoid signaling during keratinocyte differentiation in vitro were studied by measuring retinoid receptor and RAR-ligand levels. Exposure to differentiation-inducing levels of calcium, phorbol myristate acetate (PMA) or interferon-γ (IFNγ) led to increased RAR-ligand levels but PMA and IFNγ caused receptor protein loss due to increased proteasomal degradation. Since an increased IFNγ level is a hallmark of psoriatic inflammation, this might be a cause of altered retinoid signaling in lesional epidermis. Conclusion: Keratinocyte differentiation is accompanied by alterations in the retinoid signaling system. In psoriatic lesions, this system appears to be dysfunctioning due to reduced retinoid receptor levels, which might be an important event in the pathogenesis of the disease.

Urinary incontinence is a prevalent condition; nevertheless few women seek professional help. One aim of this study was to investigate all women aged 18-70 years in a Swedish community regarding (a) the prevalence rate and risk factors of urine leakage and (b) the quality of life for women with and without urine leakage, for women with stress incontinence versus urge incontinence, and for women with urine leakage who had or had not sought help. A second aim was to study all women aged 18-46 years from the same population four years later regarding (a) the quality of life and natural history of urine leakage, (b) why some women with persistent urine leakage seek help and others do not, and (c) how they deal with their urine leakage. Every fourth woman aged 18-70 years was found to have urine leakage. The number of women with urine leakage increased with increasing age, the number of deliveries, the presence of urinary tract infection, and the use of oestrogen substitutions. Women with urine leakage had a lower quality of life in all eight dimensions of the SF-36 as compared with women without urine leakage. Furthermore, in women with urge incontinence the quality of life was lower compared with women with stress incontinence in all dimensions of the SF-36. Women with urine leakage who had sought help had lower quality of life in seven of eight SF-36 dimensions as compared with women with urine leakage who had not sought help. At the four-year follow-up the quality of life had deteriorated in five of eight SF-36 dimensions in women aged 18-46 years with persistent urine leakage as compared with women with persistent continence. The mean annual incidence and remission rates of urine leakage were on the same low level (4%). Most women with slight or moderate long-term urine leakage had not sought professional help, largely because they considered their leakage a minor problem. Pelvic floor exercises was the most commonly used management method for all participants.

The overall aim of the present thesis was three-fold. The overall aim of the present thesis was three-fold. The first was to study occupational performance in individuals with severe mental disorders and their experiences of occupational therapy, the second to study experienced burden of family caregivers and the third to test the validity and the homogeneity of assessment tools in this area. The samples consisted of individuals with severe mental disorders participating in organised occupations (n= 112), occupational therapy records (n=64), occupational therapists working in mental health care (n=7) and family caregivers of individuals with severe mental disorders (n=256). Data were collected by questionnaires, structured and narrative interviews, observations and occupational therapy records. Individuals with severe mental disorders reported problems related to leisure and work activities and the occupational therapists recorded problems concerning how to organise and structure occupational performance. Individuals functioning on a high cognitive level experienced problems related to work and productive activities. Participation in occupational therapy strengthened their confidence in their own ability. The "Experience of Occupational Performance Questionnaire" (EOPQ) was developed from data on the experiences of women participating in occupational therapy. A principal component analysis gave seven factors with acceptable homogeneity. There is a need for assessment tools to evaluate occupational therapy. The EOPQ represents an attempt to fulfil this need. Family caregivers experienced limitations of daily activities as a burden. The ability to perform daily activities was studied from three perspectives, the individuals’, the occupational therapists’, and the experienced burden of the family caregivers. These perspectives are complementary and thus necessary for planning and implementation of individually adapted occupational therapy as well as for the evaluation of outcomes.

This study examined relationships between 24-hour ambulatory BP and components of the insulin resistance syndrome, and investigated the prognostic significance of 24-hour BP for cardiovascular morbidity in a longitudinal population-based study of 70-year-old men. The findings indicated, that a reduced nocturnal BP fall, nondipping, was a marker of increased risk primarily in subjects with diabetes. A low body mass index and a more favourable serum fatty acid composition at age 50 predicted the development of white-coat as opposed to sustained hypertension over 20 years. Furthermore, cross-sectionally determined hypertensive organ damage at age 70 was detected in sustained hypertensive but not in white-coat hypertensive subjects. In a prospective analysis, 24-hour ambulatory pulse pressure and systolic BP variability at age 70 were strong predictors of subsequent cardiovascular morbidity, independently of office BP and other established risk factors. Isolated ambulatory hypertension, defined as having a normal office BP but increased daytime ambulatory BP, was associated with a significantly increased incidence of cardiovascular events during follow-up. Hypertension constitutes part of the insulin resistance syndrome, and is a common and powerful risk factor for cardiovascular disease in elderly. Blood pressure (BP) measured with 24-hour ambulatory monitoring gives however more detailed information and may be a better estimate of the true BP than conventional office BP. In summary, these data provide further knowledge of 24-hour ambulatory BP and associated metabolic risk profile, and suggest that the prognostic value of 24-hour ambulatory BP is superior to conventional BP in an elderly population.

The prevalence of respiratory symptoms and diseases like asthma and chronic obstructive pulmonary disease (COPD), seem to have increased the last decades. The reason for the increase in asthma related symptoms and allergy is uncertain. Some, but not all, of this increase might be ascribed to lowered threshold for use of the diagnosis by medical doctors, change in diagnostic criteria, and increased awareness of symptoms in the population. Studies have indicated that increased prevalence might be explained by a reduction during the last decades in exposure to environmental factors in infancy, These factors are supposed to stimulate the change from Th-2 to TH-1 helper cells (hygiene hypothesis), but even low level of allergen exposure seems to contribute to increase in risk for allergy. The increase in COPD in developed countries is closely related to the smoking pattern during the last two to four decades, and the increased therefore, is mainly seen in women. Further, studies have indicated that women are more vulnerable for the deleterious effects of tobacco smoking than men are; if this is true the current smoking pattern with increased female smoking, is worrying. / Paper 1 reprinted with kind permission of Journal of Epidemiology and Community Health. Papers 2 and 3 reprinted with kind permission of European Respiratory Society Journals Ltd. Paper 4 reprinted with kind permission of John Wiley and Sons Limited.

Enterovirus (EV) infections have been associated with the pathogenesis of Type 1 Diabetes (T1D). However, the pathway(s) by which EV may induce or accelerate diabetes is not well understood. The purpose of this thesis was to obtain new information on the mechanism by which EV infections, with different strains of EV, could cause damage to the insulin-producing β-cells in isolated human islets and in a rat insulin-producing cell line (RINm5F). Infection with EV strains isolated from T1D patients revealed replication/cell destruction in human islets and EV-like particles in the cytoplasm of the β-cell and infection with the isolates affected the release of insulin in response to glucose stimulation as early as three days post infection, before any decrease in cell viability was observed. A decrease in the induction/secretion of the chemokine RANTES in human islets during EV infection was also detected. When islets were cultured with nicotinamide (NA) the secretion of RANTES was increased irrespectively if the islets were infected or not. In addition, the degree of virus-induced cytolysis of human islets was reduced by NA, suggesting an antiviral effect of NA. Infection with EV strains revealed permissiveness to islet-derived cells. All EV strains used for infection were able to replicate in the RIN cell clusters (RCC) but not in the RIN cells that were cultured as a monolayer. This might be due to the differences in expression of the Coxsackie-adenovirus receptor (CAR), which only could be detected on the RCC. Infection of RCC with a CBV-4 strain did not affect cell viability and did not induce nitric oxide (NO) production alone or with the addition of IFN-γ. This was in contrast to the results obtained with synthetic dsRNA, poly(IC), which induced NO, suggesting that synthetic dsRNA does not mimic enteroviral intermediate dsRNA. During analyses performed with the samples from a family where the mother and one son where diagnosed with T1D on the same day, the results showed that the whole family had a proven EV infection at the time diagnosis. To conclude, the ability of EV strains to replicate in RIN cells is dependent on the growth pattern of the cells and this may be due to the upregulation and/or changed expression pattern of CAR in these cells. In the RIN cells, contrary to artificial dsRNA, viral dsRNA does not induce NO. The isolated EV virus strains used were able to infect and affect human pancreatic islets in vitro. The chemokine RANTES is reduced during an EV infection of human pancreatic islets and NA causes upregulation of RANTES in infected and uninfected islets.

The aim was to study the prevalence of asthma, eczema, allergy and respiratory symptoms among pupils in Shanxi province, China, in relation to home and school environment and outdoor air pollution. In one study there was a low prevalence of self-reported asthma, eczema and pollen or pet allergy among pupils (9-20y). Rural childhood and consumption of fruit and fish were negatively associated with asthma or allergy, while current urban residency and consumption of hamburgers tended to be risk factors. In another study in junior high school pupils, similar low prevalence of asthma and allergy was found. Compared with pupils at the same age in Uppsala, Sweden, asthma and allergy were less common while daytime attacks of breathlessness were more common in Chinese pupils. Parental asthma or allergy was a predictor of asthma symptoms. Factors in the home environment such as new floor, new furniture and ETS exposure were risk factors for asthma symptoms. Crowdedness, dust amount, CO2, temperature and air humidity were negatively associated with respiratory symptoms. Microbial chemical components like muramic acid and ergosterol, markers for bacteria and fungi, were negatively associated with wheeze or daytime attacks of breathlessness. The associations with endotoxin varied depending on the length of 3-hydroxy fatty acids of the lippopolysaccharides (LPS). Among outdoor air pollutants, SO2 and formaldehyde were positively associated with asthma symptoms or respiratory infections. In addition, indoor SO2, NO2 and formaldehyde were positively associated with asthma symptoms and respiratory infections. In conclusion, rural childhood and dietary factors can be protective for asthma and allergy. ETS and chemical emissions from new material at home can be risk factors for asthmatic symptoms. In the school environment, factors of indoor origin seemed to be generally protective for respirator symptoms while factors of outdoor origin seemed to be risk factors.

In this thesis, chitosan, a biocompatible polysaccharide that has been approved as a food additive was selected as a platform for the development of safe, efficient non-viral gene delivery systems to mammalian cells. Previously, chitosan-based gene formulations had been generally associated with high molecular weight chitosans, which were poorly characterised in terms of molecular weight distribution and degree of acetylation. Therefore, in order to improve the properties of chitosan-based gene formulations, the research associated with this thesis focused on establishing the structure-property relationships of well-defined, low molecular weight chitosans (chitosan oligomers) as delivery systems for nucleic acids (pDNA and siRNA) in vitro and after lung administration in vivo. pDNA dissociated more easily from chitosan oligomers than from conventional high molecular weight chitosans, resulting in a faster onset and higher levels of in vivo gene expression, comparable to those mediated by polyethyleneimine (PEI), one of the most efficient non-viral delivery systems. Coupling of a trisaccharide branch to the chitosan oligomers so as to target extracellular lectins resulted in a significant improvement in transfection efficiency because of enhanced cellular uptake and colloidal stability. In contrast to pDNA, longer linear chitosan oligomers were required to form physically-stable nanoparticles with siRNA that mediated efficient, sustained gene silencing in vitro. Finally, the use of an optimised catheter device for the nebulisation of small volumes of pDNA formulations resulted in improved dose precision and lung distribution in vivo compared with conventional intratracheal instillation. In conclusion, chitosan oligomers are interesting and viable alternatives to other non-viral gene delivery systems.