Background: The ageing process not only increases the risk of coronary artery disease (CAD) but also complicates its diagnosis and treatment. It is therefore important to understand the newer concepts of cardiovascular ageing physiology as well as methods of predicting the outcomes of therapeutic options available for the elderly with severe CAD. Studies of atrioventricular (AV) ring or plane motion have attracted considerable interest in the last few years as a means of assessing ventricular and atrial function. As the displacement of AV rings towards the ventricular apex is a direct reflection of longitudinal fibre contraction, its measurement by echocardiography provides additional information regarding global and regional systolic and diastolic function. Left ventricular (LV) long axis amplitude of motion, referred to as mitral valve annular (MA) motion, is reduced in CAD and to some extent in the elderly as part of the normal ageing process. Objectives & Methods: The aim of the present study was two-fold. First, to investigate the relationship between the timing of MA motion and transmitral and pulmonary venous flow in healthy subjects, and to define the physiological significance of that relationship including its potential diagnostic utility. Second, to investigate the relationship between the clinical outcome and the behaviour of long axis function in patients with severe ischaemic LV dysfunction (SLVD) after percutaneous coronary angioplasty (PTCA). Transmitral early (E) and late (A) filling, and pulmonary venous flow reversal (Ar) were studied by Doppler echocardiography, while at the left lateral AV ring, the MA motion in early (Em) and late (Am) diastole were recorded by Doppler tissue imaging (DTI) and M-mode echocardiography. Results: Healthy subjects – In early diastole the onsets of LV filling (E) and relaxation (Em) were simultaneous, and peak Em preceded peak E by 26 msec in all age groups, constituting a time interval referred to as early diastolic temporal discordance (EDTD). Similarly, the onsets of Am, A and Ar were simultaneous at onset and began approximately 84 msec after the electrocardiographic P wave. Peak Am preceded peak A by 23 msec in the young and by 13 msec in the elderly, a time interval referred to as late diastolic temporal discordance (LDTD). Peak Ar, on the other hand, coincided with peak Am in all age groups. With increasing age and sequential prolongation of isovolumic relaxation time, the peaks of Am, Ar and A converged. This point of convergence is described as atrial mechanical alignment (AMA). Patients – MA total amplitude of motion, rates of shortening and lengthening were all reduced in patients with SLVD. At mid-term, 3-6 months after PTCA, there was improvement in all these variables. A pre-procedure long axis cut off value of ≥5 mm was associated with favourable symptomatic outcome. Overall angiographic success was 95.2%, and event-free survival was 78.4% at one month and declined steadily to 62.3% at one year with 2.5% mortality. Conclusions: EDTD, which reflects ventricular restoring forces (suction) is age independent while the narrowing of LDTD leading to AMA provides a novel method to identify healthy subjects at increased dependency on left atrial contraction for late diastolic filling. Peak atrial contraction (Am) coincides with peak Ar, thus the timing of regional atrial contraction by DTI can be used to estimate corresponding measurements of Ar, which is often difficult to image by transthoracic echocardiography. In patients with SLVD long axis total amplitude of at least 5 mm at the left MA suggests a significant potential for segmental function recovery after PTCA. Keywords: Echocardiography, Doppler tissue imaging, ageing, coronary disease, left ventricular dysfunction, atrial contraction, electromechanical function, coronary angioplasty.

Traumatic brain injuries are common (hospitalization incidence: 250-300 per 100.000 inhabitants/year) and a great majority of these injuries (80-85%) are classified as mild traumatic brain injury (MTBI/concussion). Many patients with MTBI (20-80%) suffer from subsequent persistent and often disabling symptoms. In previous studies serum levels of biochemical markers of brain tissue damage (S-100B and neuron-specific enolase, NSE) have been propounded to serve as predictors of persisting symptoms.In the present studies serum concentrations of S-100B, NSE and cortisol in acute phase and post-concussion symptoms, post-traumatic stress-related symptoms, disabilities and life satisfaction one year after the trauma, were investigated in 88 patients (53 men and 35 women) with MTBI. Serum concentrations of S-100B and NSE were also assessed in elite players (n=54) of typical contact sports (ice-hockey and soccer), which are known to be high risk activities with respect to head injury. Basketball players (n=18) were used as a control group. A majority of patients with MTBI showed higher serum concentrations of S-100B, NSE and cortisol on admission compared with a second blood sample obtained about 7 hours later (p<0.001 for all analyses). Sequelae were common one year after the injury. Postconcussion symptoms were encountered in 45 % of the patients, stress-related symptoms in 17 % and disabilities in 48 %, but only 3 patients (4 %) were on sick-leave on follow-up due to the head trauma. There was a statistically significant negative correlation between the total score of life satisfaction and the total score of disability (r= -0.514, p<0.001). Symptoms on admission (dizziness, nausea) and S-100B were statistically significantly associated with disabilities (p<0.024, multiple logistic regression analysis). Nausea on admission was also statistically significantly associated with life satisfaction (p=0.004). A statistically significant association was found only for S-100B with early (0-1 week postinjury, p=0.008) and only for cortisol with late (more than 52 weeks post-injury, p=0.022) post-traumatic stress-related symptoms. Concentrations of S-100B after game were statistically significantly increased in comparison with the levels before game (soccer, p<0.001; ice-hockey, p<0.001; basketball (p<0.001). Concentrations of NSE were only raised after soccer play (p<0.001). Increases in S-100-B (post-game minus pre-game values) were correlated to the number of jumps in basketball play (r=0.706, p=0.002). For soccer, increases in S-100B were correlated to the number of headers (r=0.428, p=0.02) and to the number of acceleration/deceleration events other than heading (r=0.453, p=0.02). The findings provide support for the idea that injury of brain tissue is involved in the genesis of persisting disabilities and long-term changes of life satisfaction in MTBI. Since S-100B increases in serum were correlated to the number of headers and since soccer play also increased serum levels of NSE (in contrast to ice hockey and basketball), it seems that heading may have an impact on brain tissue. The studies have also shown that ordinary playing of the team sports in question (i.e. soccer, ice hockey and basketball) increases S-100B serum concentrations, which has to be taken into consideration when S-100B is used for the detection of injury of brain tissue in sportsmen with acute/overt head trauma during sport practice. An analysis of the biochemical markers of brain damage (in particular S-100B) may be an additional source of valuable information in the management of patients and sportsmen with MTBI. S-100B also seems to be promising for the prediction of impairments and disabilities after MTBI.

Impaired endothelium-dependent vasodilation (EDV) is associated with atherosclerotic cardiovascular disease as well as several of its risk factors. The aim of the present thesis was to investigate how lipids influence EDV in the vascular bed of the human forearm. 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. 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. 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. 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. 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.

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. 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. 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. 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. The presence of EBV was low in lymphomas in RA patients (12%).

We evaluated, in patients with ST-elevation myocardial infarction (STEMI) treated with thrombolytics, admission Troponin T (tnT), ST-segment resolution and admission N-terminal pro-brain natriuretic peptide (NT-proBNP) for early risk stratification as well as time delays and outcome in real life patients according to prehospital or in-hospital thrombolytic treatment. Also, baseline characteristics, treatments and outcome in patients enrolled in the ASSENT-2 trial in Sweden and in patients not enrolled were evaluated. TnT (n=881) and NT-proBNP (n=782) on admission and ST-resolution at 60 minutes (n=516) in patients from the ASSENT-2 and ASSENT-PLUS trials were analysed. Elevated levels of NT-proBNP and tnT on admission were both independently related to one-year mortality. However, when adding information on ST-resolution (</≥50%) 60 minutes after initiation of thrombolytic treatment, tnT no longer contributed independently to mortality prediction. High and low risk patients were best identified by a combination of NT-proBNP and ST-resolution at 60 minutes. We investigated consecutive STEMI patients included in the RIKS-HIA registry between 2001 and 2004, if they were ambulance transported and had received prehospital (n=1690) or in-hospital (n=3685) thrombolytic treatment. Prehospital diagnosis and thrombolysis reduced the time to thrombolysis by almost one hour, were associated with better left ventricular function and fewer complications and reduced the adjusted one-year mortality by 30% compared with in-hospital thrombolysis. Prospective data from the RIKS-HIA registry on STEMI patients treated with thrombolytics were linked to data on trial participants in the ASSENT-2 trial of thrombolytic agents and used for direct comparisons. Patients treated with thrombolytics and not enrolled in a clinical trial at trial hospitals (n=2048) had higher risk characteristics, more early complications and twice as high adjusted one-year mortality compared to those enrolled (n=729). One major reason for the difference in outcome appeared to be the selection of less critically ill patients to the trial.

Epidermolysis bullosa simplex (EBS) and epidermolytic ichthyosis (EI) are rare skin fragility diseases characterized by intra-epidermal blistering due to autosomal dominant-negative mutations in basal (KRT5 or KRT14) and suprabasal (KRT1 or KRT10) keratin genes,  respectively. Despite vast knowledge in the disease pathogenesis, the pathomechanisms are not fully understood, and no effective remedies exist. The purpose of this work was to search for keratin gene mutations in EBS patients, to develop in vitro models for studying EBS and EI, and to investigate novel pharmacological approaches for both diseases. We identified both novel and recurrent KRT5 mutations in all studied EBS patients but one which did not show any pathogenic keratin mutations. Using cultured primary keratinocytes from EBS patients, we reproduced a correlation between clinical severity and cytoskeletal instability in vitro. Immortalized keratinocyte cell lines were established from three EBS and three EI patients with different phenotypes using HPV16-E6E7. Only cell lines derived from severely affected patients exhibited spontaneous keratin aggregates under normal culture conditions. However, heat stress significantly induced keratin aggregates in all patient cell lines. This effect was more dramatic in cells from patients with a severe phenotype. In organotypic cultures, the immortalized cells were able to differentiate and form a multilayered epidermis reminiscent of those observed in vivo. Addition of two molecular chaperones, trimethylamine N-oxide dihydrate (TMAO) and sodium 4-phenylbutyrate (4-PBA), reduced the keratin aggregates in both stressed and unstressed EBS and EI keratinocytes, respectively. The mechanism of action of TMAO and 4-PBA was shown to involve the endogenous chaperone system (Heat shock proteins e.g. Hsp70). Besides, MAPK signaling pathways also seemed to be incriminated in the pathogenesis of EBS. Furthermore, depending on which type of keratin is mutated, 4-PBA up-regulated Hsp70 and KRT4 (possibly compensating for mutated KRT1/5), and down-regulated KRT1 and KRT10, which could further assist in protecting EBS and EI cells against stress. In conclusion, novel and recurrent pathogenic keratin mutations have been identified in EBS. Immortalized EBS and EI cell lines that functionally reflect the disease phenotype were established. Two pharmacologic agents, TMAO and 4-PBA, were shown to be promising candidates as novel treatment of heritable keratinopathies in this in vitro model.

Neuroendocrine tumors (NET´s) are often characterized by overproduction of peptide hormones. In spite of pronounced clinical symptoms, the tumor lesions can be small and difficult to detect. The general aim of this thesis was to investigate, in vitro and in vivo, some of the potential monoamine pathways present in NET´s, using radiolabeled tracers for positron emission tomography (PET), with the intention to explore the value of PET-imaging in the management of NET´s. We used the 11C-labeled serotonin precursor 5-hydroxy tryptophan (HTP) as the tracer for imaging of NET´s. More than 95% of the subjects displayed a high tracer uptake on PET and tumor detection rate with PET was higher in >50% of the patients compared both to computed tomography (CT) and somatostatin receptor scintigraphy (SRS). The primary tumor was imaged by PET in 84% (16/19), compared to 47% and 42% for SRS and CT, respectively. Tumor visibility was better with PET due to a higher tumor-to-background ratio and a better spatial resolution. There was a strong correlation (r = .907) between changes in urinary-5-hydroxy indole acetic acid and changes in transport rate of 11C-5-HTP during treatment, indicating the use of PET in treatment monitoring of NET´s. Pretreatment with carbidopa decreased the urinary radioactivity concentration four-fold and significantly (p<0.001) increased the tumor tracer uptake. This greatly improved image interpretation and tumor lesion detection. A screening for expression of monoamine pathways in NET´s revealed a high in vitro binding of the monoamineoxidase-A ligand harmine to tumor sections. PET examinations with 11C-harmine could visualize tumors in all patients, including non-functioning endocrine pancreatic tumors (EPT´s). Finally, the in vitro turnover and in vivo distribution of the amino acids glutamate, glutamine and aspartate was investigated. Limited uptake in vivo indicates the lack of utility for these substances as PET-tracers for imaging and characterization of NET´s.

Background: Financial constraints challenge evidence of the effectiveness of dermatological inpatient management. Objective: To evaluate the effectiveness of hospitalization in atopic dermatitis and psoriasis regarding initial and sustained benefits. Methods: Prospective study on adults with psoriasis vulgaris (n = 22) and atopic dermatitis (n = 14). At admission, discharge, and 3 months after discharge, validated outcomes of objective and subjective disease severity were assessed by trained investigators. Results: Hospitalization resulted in substantial benefit in quality of life and clinical disease severity. Looking at mean scores, the observed benefit appeared stable until 3-month follow-up. The analysis of individual patient data revealed significant changes in disease severity between discharge and 3-month follow-up with some patients relapsing, others further improving. Reasons for hospitalization and treatment performed were not related to sustained benefit. Conclusions: In psoriasis vulgaris and atopic dermatitis, hospitalization effectively improved quality of life and clinical disease severity. Further research should focus on prognostic factors for sustained improvement. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Chronic neck-shoulder pain is associated with impairments of proprioception and motor control. Thus, assessment of proprioceptive and motor function may be powerful tools both for research and clinical practice. However, insufficient knowledge of certain features of human sensorimotor control hampers both development and interpretation of results of clinically relevant tests. For example, evidence is lacking which proprioception submodalities are reflected in common tests of proprioception. For testing motor function, a better understanding of the control of goal directed arm movements is needed. The purpose of the thesis was to gain further insights into the sensorimotor control of the upper limb in healthy subjects, with implications for clinical testing. The main aims were: (1) to study relationships of outcomes of different tests of shoulder proprioception and (2) to study control strategies in bimanual pointing tasks by analysis of the structure of joint angle variability with the Uncontrolled Manifold (UCM) method. Correlations between proprioceptive acuity in different variants of ipsilateral position-matching and velocity-discrimination were studied. The main finding was that two uncorrelated mechanisms based either on perception of position or movement might underlie perception of limb location in ipsilateral position-matching. The results provided important information for interpretation of common and development of novel tests of shoulder proprioception. The structure of joint angle variance was computed with respect to several task variables during bimanual pointing. Joint angle variability was decomposed in variance affecting and not affecting a task variable. The results showed that the variance in joint space was structured according to the predictions of the UCM hypothesis. It was also shown that the arms were united into one synergy to significantly larger degree than joints within each arm were united into single-arm synergies. It was concluded that the UCM approach might quantify components of motor variability during repetitive motor tasks.

Objectives. To describe the prevalence of asthma in a mid-Swedish region and measure the detection rate of asthma in primary care. To compare clinical outcomes for adolescents with asthma in primary care or in paediatric care and to perform a clinical validation in children with airway, nose and skin symptoms. Material and methods. A questionnaire survey of respiratory symptoms and disease in an adult population and an investigation of the occurrence of clinically detected asthma in primary care. A cross-sectional study comparing management, asthma control and quality of life in adolescents. The last study was a nested case-control study with a clinical validation of reported allergic symptoms in children. Results. The prevalence of asthma in the adult population was 8%. The clinical prevalence of asthma in primary care was 2%. The detection rate was higher in primary health care centres with asthma clinics, as compared to primary care without such clinics. In adolescents with asthma there was no difference in clinical outcomes between primary care and paediatric care. The validation study showed a high correlation between assigned cases and disease. Conclusions. Asthma is a common disease where the majority of cases are managed in primary care. Many cases are, however, not diagnosed and the detection rate becomes a quality care indicator. The study of adolescents confirms that proactive care can be further improved regardless of whether their management is in primary or paediatric care. The nested case-control design is suitable to suggest causational risk factors for asthma and for prediction of allergic disease development.