<p>Impaired endothelium-dependent vasodilation (EDV) is associated with atherosclerotic cardiovascular disease as well as several of its risk factors.</p><p>The aim of the present thesis was to investigate how lipids influence EDV in the vascular bed of the human forearm.</p><p>Apolipoprotein B was inversely associated with both EDV and endothelium-independent vasodilation (EIDV) in healthy subjects aged 20-69 years. HDL cholesterol was associated with the EDV to EIDV ratio (EFI). Small LDL particles and antibodies against oxidized LDL were not associated with endothelial vasodilatory function.</p><p>The EFI in young, healthy subjects was positively associated with alpha-linolenic acid proportion, but inversely associated with myristic acid in men only. Eicosapentaenoic acid was positively associated with EDV, whereas dihomo-gamma-linolenic acid was inversely associated with both EDV and EIDV in men. </p><p>Acute elevation of long-chain fatty acids with Intralipid^®/heparin infusion in young, healthy subjects impaired EDV after 2 h. This impairment could be prevented by co-infusing vitamin C, diclophenac or L-arginine. Acute elevation of both medium-chain and long-chain fatty acids during Structolipid^®/heparin infusion did not impair EDV.</p><p>An ordinary meal (34 E% fat) transiently attenuated EDV at 1 hour. No attenuation in EDV was observed after meals containing 20 and 3 E% fat. </p><p>These findings show that the endothelial vasodilatory function is associated with fatty acid profile in serum in the fasting state and during acute fatty acid elevation, as well as with apolipoprotein B and HDL cholesterol. Furthermore, lowering dietary fat content to 20 E% or less preserves endothelial vasodilatory function and might therefore protect against atherosclerosis.</p>

<p>Patients with systemic lupus erythematosus (SLE) have an activated type I interferon (IFN) system with an ongoing IFN-α synthesis. This may be caused by circulating immune complexes, consisting of anti-DNA antibodies (Abs) and DNA, with IFN-α inducing capacity. Produced IFN-α may be crucial in the pathogenesis, because this cytokine can break tolerance and promote autoimmunity.</p><p>In the present thesis, possible mechanisms of the IFN-α production in SLE were studied. To investigate whether IFN-α inducing material could be derived from apoptotic cells, IgG from SLE patients (SLE-IgG) were combined with apoptotic cells. This combination induced high IFN-α production in normal peripheral blood mononuclear cells (PBMC). The IFN-α induction was associated to presence of anti-RNP Abs, but not to anti-dsDNA Abs, indicating that two inducers could be active in SLE, one containing DNA and the other RNA.</p><p>Apoptotic cells and SLE-IgG exclusively activated the natural interferon producing cells (NIPC) and the IFN-α response was enhanced by type I IFN and inhibited by IL-10 and TNF-α. The IFN-α induction was dependent on FcγRII, because blocking this receptor reduced IFN-α production and NIPC were found to express FcγRIIa.</p><p>To further elucidate the role of different autoantibodies in the IFN-α induction, sera from patients with Sjögren´s syndrome (SS), containing autoantibodies to RNA binding proteins (SSA, SSB, RNP and/or Sm) were investigated. The combination of SS or SLE sera and apoptotic or necrotic cell material induced high IFN-α production in PBMC. RNA, but not DNA, was required for IFN-α induction, indicating that RNA and Abs to RNA-binding proteins form potent IFN-α inducing complexes.</p><p>The findings in this thesis can explain central mechanisms for the activation of NIPC in SLE, and perhaps also other autoimmune diseases. This activation is mediated by interferogenic immune complexes, and modulating the NIPC activation may be a novel therapeutic approach in SLE.</p>

<p>The objective of the dissertation was to study the cabin environment, and identify personal and environmental risk factors, associated with symptoms, and perception of cabin air quality. Another objective was to study if ban of smoking, and increased relative air humidity on intercontinental flights, could have a beneficial health effect. The studies were performed among Scandinavian cabin crew in one Airline Company. Office workers from the same company served as controls. Exposure differed between cruise and non-cruise conditions. Air humidity was very low during intercontinental flights (3-8%). Concentration of moulds, bacteria, formaldehyde, and ozone was low. Tobacco smoking increased respirable particles in the cabin air, from 3 to 49 mg/m3, and increased cotinine in urine. The ETS-exposure was highest in the aft part of the cabin. Symptoms and environmental complaints were more common among flight crew than office workers. We could identify personal factors of importance, and certain conditions that could be improved, to achieve a better cabin environment. There was an association between symptoms and environmental perceptions and work stress, lack of influence on working condition, and a history of atopy. After ban on smoking in aircraft, there was a decrease of ocular and general symptoms, and increased tear-film stability in aircrew. Air humidification reduced headache and ocular, nasal, and dermal dryness symptoms, increased tear-film stability, and increased nasal patency. Our result indicates that ETS and low air humidity are important environmental factors in aircraft, and that atopy, and work stress could be significant risk factors for symptoms and environmental perceptions.</p>

<p>Hypoxia-reoxygenation (H-R) injury is an important clinical phenomenon in patients with coronary artery disease (CAD). Endothelial injury is a critical step in the initiation and progression of atherosclerosis. Therefore, endothelial and cardiomyocyte protection has been considered an effective step in prevention and treatment of CAD.</p><p>To investigate the cardioprotective effect of tocopherols, omega-3 fatty acid [eicosapentaenoic acid (EPA)] and transforming growth factor-β₁ (TGF-β₁) during H-R, calcium tolerant myocytes isolated from adult rats were cultured and subjected to hypoxia for 24 hrs followed by reoxygenation of 3 hrs. All strategies, including tocopherol preparations, EPA and TGF-β₁, showed attenuation of H-R-induced myocyte injury indicated by reduction of lactate dehydrogenase (LDH) release. Both a-tocopherol and a mixed- tocopherols (α-, γ-, and δ-) decreased the effects of H-R on iNOS expression and SOD activity in cultured myocytes. The mixed-tocopherols was more potent than a-tocopherol alone. EPA inhibited H-R-induced lipid peroxidation, MMP-1 expression and p38MAPK phosphorylation. TGF-β₁ blocked the increase in iNOS and PKB phosphorylation as well as the decrease in eNOS expression in cultured myocytes exposed to H-R.</p><p> To further investigate the protective effect of omega-3 fatty acids [docosahexaenoic acid (DHA) and EPA] and TGF-β₁, the cultured endothelial cells were exposed to oxidant injury mediated by oxidized low-density lipoprotein (ox-LDL). Ox-LDL markedly reduced TGF-β₁ release, increased the expression of TGF-β₁ receptors, upregulated the expression of adhesion molecules, P-selectin and ICAM-1, enhanced the adhesion of monocytes to endothelial cells, and decreased protein kinase B (PKB) activation. Both DHA and EPA blocked these effects of ox-LDL on endothelial cells. Exogenous recombinant TGF-β₁ also ameliorated ox-LDL-induced expression of adhesion molecules and monocytes adhesion, which were blocked by antibodies to the TGF-β₁ type 2, but not to the type 3 receptor.</p><p>These observations provide mechanistic insights into H-R and oxidant injury and tissue protection by three different strategies.</p>

<p>The human endometrium undergoes dramatic changes in morphology and function during the menstrual cycle. Recurrent angiogenesis (the formation of new blood vessels) is of utmost importance for oxygen supply and nourishment of the rapidly growing endometrial tissue. </p><p>The importance of some growth factors known to stimulate new blood vessel formation both in vivo and in vitro in non-uterine tissues, for endometrial angiogenesis, was studied. Further, the possible relationship between the patterns of expression of some angiogenic growth factors and bleeding disturbances during the use of a progestin-only intrauterine contraceptive device was analyzed. Different ways of determining changes in the endometrial vascular density during the menstrual cycle were also evaluated. </p><p>The expression of the angiogenic growth factors vascular endothelial growth factors (VEGF) A, B, C, and D, fibroblast growth factor 2 (FGF-2), and epidermal growth factor (EGF) and their receptors was analyzed using immunohistochemistry.</p><p>VEGF-A, -B and -C, FGF-2 and EGF and their receptors were all found to be expressed in normal human endometrium, especially in and/or around blood vessels, supporting the hypothesis that these peptides most probably contribute to the regulation of angiogenesis and blood vessel function in normal human endometrium.</p><p>There were differences in expression of some of the studied ligands and receptors in endometrium from users of an LNG-IUS with and without bleeding disturbances. We conclude that changes in the expression of these growth factors and receptors might be involved in the formation of fragile and dysfunctional blood vessels that subsequently give rise to bleeding disturbances.</p><p>The three different methods that were applied for calculating endometrial blood vessel density showed similar results and none of them indicated any significant changes during the menstrual cycle. Angiogenesis thus seems to occur mainly by blood vessel elongation and the angiogenic activity is probably related to changes in endometrial thickness and coiling of the spiral arteries.</p>

<p>Angiogenesis is defined as the formation of new capillary blood vessels from pre-existing ones. This process involves several steps including: migration, proliferation and differentiation of endothelial cells into blood vessels. Angiogenesis is initiated by binding of specific growth factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), to their cell surface receptors. Shb is a ubiquitously expressed adaptor protein with the ability to bind several tyrosine kinase receptors. My aim has been to identify the role of Shb in FGF- and VEGF-signalling in endothelial cells. Shb was found to be phosphorylated in a Src-dependent manner upon both FGF- and VEGF-stimulation. This was confirmed using fibroblasts overexpressing temperature sensitive v-Src. Furthermore, Shb-induced cell spreading on collagen of immortalised brain endothelial (IBE) cells was also Src-dependent. FGF stimulation led to a direct association between Shb and FAK, which was mediated by the phosphotyrosine binding domain of Shb. IBE cells overexpressing wild-type or R522K Shb (inactive SH2 domain) displayed increased FAK activation on collagen.</p><p>The SH2-domain of Shb was found to bind to tyrosine 1175 in the VEGFR-2 in a phosphotyrosine dependent manner using PAE cells expressing VEGFR-2. Furthermore, by use of siRNA, Shb knock-down experiments revealed that Shb regulates FAK activity, cellular migration and stress fiber formation in response to VEGF stimulation of VEGFR-2. In summary, Shb binds to both FGFR-1 and VEGFR-2 and regulates the activity of FAK and thereby stress fiber formation and cellular migration, which are necessary for formation of new blood vessels. IBE cells with an inactive SH2 domain of Shb displayed disorganised formation of tubular structures in the tube formation assay, while overexpression of wild-type Shb led to accelerated tubular morphogenesis.</p><p>Taken together, my data show that the adaptor protein Shb plays an important role in the process angiogenesis, in response to angiogenic tyrosine kinase receptors, by interacting with FAK and regulating spreading, stress fiber formation and cellular migration.</p>

<p>This thesis evaluates the use of Fourier Transform Infrared Spectroscopy (FTIR) as an approach to the increasingly difficult air sampling challenges within the field of occupational and environmental hygiene. The application of FTIR is exemplified by the assessment of emissions from and exposures in the sawmill and pellet industries. </p><p>Open path FTIR was applied in the sawsheds and the terpene levels were monitored for several days. Traditional adsorbent sampling was used to evaluate the FTIR measurements. The volatile emissions from wood pellets were investigated in warehouses and in domestic storage rooms. </p><p>The installation of open path FTIR in the harsh sawmill environment proved useful, however, attention must be paid to vibrations, beam blockage and limited sensitivity. Adsorbent sampling showed good agreement with open path FTIR. The uncontrolled airflows in sawsheds caused significant underestimation of emission rates. By the use of FTIR and a tracer gas a more accurate estimate was obtained. The total emission from processing of Scots pine was estimated to 660 g/m³ of roundwood under bark, and can amount to 700 tons annually from a large sawmill.</p><p>Hexanal (111±32 mg/m³) and CO (56±4mg/m³) were recorded in pellet warehouses. Storage of wood pellets constitutes a potential occupational and domestic health hazard. Experiments from kiln drying of lumber show that the emissions of hexanal and carbon monoxide are not limited to wood pellets but are caused by general degradation processes of wood, facilitated by drying at elevated temperature. This is the first published report where low-temperature emission of carbon monoxide from wood materials is described. </p><p>The FTIR method is a significant advancement in measurement technology. The retrieved data offers unparalleled information. It offers robust, convenient and efficient monitoring of gases over extended periods. FTIR spectroscopy should be considered a standard technique within the field of occupational and environmental hygiene.</p>

<p><i>Objectives.</i> To study the prevalence of musculoskeletal symptoms among farmers as compared to rural referents and to evaluate the effects of physical work exposures, psychosocial factors, lifestyle and comorbidity.</p><p><i>Material and methods.</i> A cross-sectional population-based survey of 1013 farmers and 769 matched referents was performed. Data on various symptoms, consultations and sick leave and information on primary health care and hospital admissions were obtained along with information on physical workload, psychosocial factors and lifestyle. </p><p><i>Results.</i> The farmers reported higher lifetime prevalence of symptoms from hands and forearms, low back and hips as compared to the referents. However, the farmers did not seek medical advice more often than the referents, and they reported significantly fewer sick leaves. After adjustment for the influence of physical work exposure, farmers still had a excess rate of low back pain (LBP) and hip symptoms as compared with the referents, while a lower rate of neck-shoulder symptoms was revealed. Several of the psychosocial variables were associated with LBP but the difference in LBP prevalence between farmers and referents could only be explained to some extent. LBP was associated with musculoskeletal symptoms other than LBP and with chest discomfort, dyspepsia, symptoms from mucous membranes, skin problems, work-related fever attacks, and primary care for digestive disorders. Presence of both respiratory and digestive disorders doubled the LBP prevalence.</p><p><i>Conclusions.</i> Symptoms from hips and low back were more frequent among farmers than among referents, but farmers did not seek more health care and reported fewer sick leaves than referents. Physical work exposure and psychosocial factors did not explain the differences in low back and hip symptoms between the two groups. Significant associations between LBP and digestive and respiratory disorders might indicate that these disorders may have etiological factors in common.</p>

<p>Postmenopausal estrogen therapy, initiated early in the menopause, seems to protect against development of atherosclerosis and cardiovascular diseases. This thesis concerns studies of artery wall thickness and arterial stiffness estimated by noninvasive ultrasound techniques in long-term estrogen treated postmenopausal women who initiated therapy at the time of the menopause.</p><p>A noninvasive 25 MHz high-frequency ultrasound technique was validated in the imaging of superficial arteries by using an animal model. Ultrasound estimates of the artery wall layers obtained <i>in vivo</i> in the pig were compared to <i>ex-vivo</i> histomorphometry. Valid estimates of total artery wall and media thickness were found for the most superficial arteries. Adventitia thickness was underestimated and intima thickness overestimated in this animal model when non-atherosclerotic vessels were imaged.</p><p>To validate the clinical usefulness of separately estimating the artery wall layers in the human, the carotid artery wall was imaged in elderly subjects. Separate estimates of intima thickness, media thickness and intima/media ratio differed significantly between subjects with and without atherosclerosis and CVD, indicating that this noninvasive high-frequency ultrasound method might be a strong tool in monitoring changes in artery wall morphology associated with aging and development of atherosclerosis.</p><p>The investigation of intima thickness, media thickness and intima/media ratio of the carotid and femoral arteries in long-term estrogen treated postmenopausal women showed a maintenance of a thin intima and a preservation of media thickness and intima/media ratio at values similar to those obtained in women of fertile age. By comparing estrogen-users with age-matched postmenopausal nonusers, long-term estrogen therapy initiated at the time of the menopause seemed to counteract the increase in intima and decrease in media thickness associated with aging and development of atherosclerosis. The preservation of the artery wall morphology into older age might be a mechanism for the well-documented cardioprotective effects of estrogen when therapy is initiated early after menopause. However, long-term estrogen therapy showed no substantial effects on the age-related changes in arterial stiffness estimated at the aorta, carotid and femoral arteries, suggesting that any long-term cardioprotective effect that estrogen therapy may have is unlikely to be mediated by an impact on arterial stiffness. </p>

<p>Patients with rheumatoid arthritis (RA) are at increased risk of developing malignant lymphoma, although details about this association remain unclear. The aims of this thesis were to investigate risk factors for lymphoma in patients with RA and to characterize these lymphomas regarding subtype, presence of Epstein-Barr virus (EBV), clinical manifestations and prognosis. </p><p>The Swedish hospital discharge register and the cancer register were used to identify RA patients with lymphoma. Two case-control studies were performed, one smaller including RA patients with lymphoma hospitalised in Uppsala health care region 1964-1983 (n=41) and one larger study of hospitalised RA patients with lymphoma in Sweden 1964-1995 (n=378). RA patients from the same cohorts, but without lymphoma, were matched as controls. Medical records for cases and controls were scrutinized for exposure information. The lymphoma tissues were reclassified according to the WHO classification, and presence of EBV was analysed by EBER in situ hybridisation.</p><p>The most important risk factor for lymphoma development was high RA disease activity. No association was determined between treatment with traditional disease modifying drugs, non-steroidal anti-inflammatory drugs, aspirin, peroral and intra-articular corticosteroids and lymphoma risk. Diffuse large B-cell lymphoma (DLBCL) was more frequent in RA patients than in lymphoma patients in the general population and displayed stronger association with RA disease activity than other lymphoma subtypes. RA patients with DLBCL had increased extranodal involvement and more advanced lymphoma stage at presentation than DLBCL patients in general, and the prognosis was poor. </p><p>A further subdivision of DLBCL into germinal centre (GC) and non-GC subtypes by the expression patterns of CD10, bcl-6 and IRF-4 showed a predominance of the non-GC subtype. This suggested peripheral activated B-cells as the cells of origin in these lymphomas. </p><p>The presence of EBV was low in lymphomas in RA patients (12%). </p>