Familial amyloidotic polyneuropathy (FAP), found in the northernmost counties in Sweden, is a rare, lethal and inherited amyloidosis. The disease is caused by mutated transthyretin (TTR). The mutation is characterized by an exchange of valine for methionine at position 30 (ATTRVal30Met). FAP is characterised by progressive polyneuropathy affecting both the peripheral and autonomic nervous system (ANS). Cardiac arrhythmia and autonomic disturbances are common as well as gastrointestinal symptoms: such as constipation and diarrhoea. Today, orthotopic liver transplantation (LTx) is the only treatment to stop the progression of FAP. The rationale for this is because 95% of TTR is synthesized by the liver, a liver transplantation should abolish the production of new mutated amyloidogenic TTR. The first liver transplantation for FAP was performed in Sweden 1990. Heart complications and autonomic disturbances are common in FAP patients both before and after liver transplantation. The aim of the present study was three-fold: to determine whether liver transplantation affects the natural course of cardiac arrhythmias and cardiac autonomic function; to predict the risk of ventricular arrhythmias; and to elucidate heart rate variability (HRV) patterns by power spectrum analysis and Poincaré plots. In total, ninety-seven Swedish FAP patients were included in the studies. The patients underwent 24-hours electrocardiography (Holter) recordings, and/or signal averaged electrocardiography (SAECG) and heart rate variability. The study showed that many patients developed cardiac arrhythmias and conduction disturbances after LTx. Approximately 25 percent of patients were pacemaker treated after LTx. The SAECG recordings disclosed that many FAP patients had ventricular late potentials (LP) compared with healthy subjects, and that LP were associated with nonsustained ventricular arrhythmia. Analyses of heart rate variability (HRV) showed reduced autonomic function in the majority of patients. Some patients had high HRV with broadband power spectra and Poincaré graphs with a fan or complex pattern. These novel findings could be an indicator of ECG abnormalities (subtle atrial arrhythmia) in FAP patients instead of reflecting normal cardiac autonomic modulation. The HRV studies also showed that LTx preserves cardiac autonomic function in FAP. In conclusion, cardiac arrhythmias, late potentials and reduced heart rate variability were common in Swedish patients with FAP, whether they underwent liver transplantation or not. The absence of LP may indicate a low risk for ventricular tachycardia in FAP patients.

Lipoprotein lipase (LPL) hydrolyses blood lipids at the vascular endothelium. This action makes fatty acids available for tissue metabolic requirements. LPL is anchored to the endothelium by electrostatic forces and may act as a bridge connecting lipoproteins to cell surfaces. Clusters of positively charged amino acid residues in LPL interact with anionic groups on oligosaccharides covering the cell surfaces. Heparin competes with cell surface oligosaccharides for binding to LPL. Interaction of LPL with soluble and cell surface- ound oligosaccharides influences the activity and catabolism of the enzyme. LPL has a dual role in the development of atherosclerosis. Hydrolysis of lipoproteins by LPL contributes to clearance of lipids from plasma, resulting in an anti-atherogenic lipid profile. On the other hand, trough its bridging function, LPL contributes to lipoprotein retention at the endothelium and in the connective tissue of the artery wall. Furthermore LPL may stimulate uptake of lipoproteins in cells, converting them to foam cells. In this way LPL is considered to be proatherogenic. We have investigated the effects caused by a synthetic heparin analogue, RG-13577, developed for treatment of tumors by anti-angiogenesis theraphy (Paper I) and by heparin (Paper II) on the turnover and biological role of LPL. The variation of LPL activity in kidney among animal species was studied in Paper III. Localization of LPL in healthy and atherosclerotic human arteries in relation to two other heparin-binding proteins (extracellular superoxide dismutase and apolipoprotein B) was studied in Paper IV.

<p>Fysisk aktivitet hos äldre är viktig för att förebygga sjukdom samt för att upprätthålla självständighet och en bra livskvalitet. Fysisk aktivitet går att mäta med instrument, såsom accelerometer eller att skatta med skattningsskalor. Syftet med detta arbete var att undersöka om den fysiska aktiviteten är korrelerad med den fysiska funktionsförmågan och om fysisk aktivitet bestämd med accelerometri går att prediktera med skattningsskalor. I studien inkluderades totalt 27 patienter som opererats för höftfraktur. 14 av dessa var kvinnor med medelåldern 80 år (62-94) och 13 var män med medelåldern 82 år (73-94). För att mäta aktiviteten användes accelerometern ActiGraph GT1M. Resultatet visade ett måttligt, förväntat samband mellan uppmätt fysisk funktion och uppmätt fysisk aktivitet. Resultaten talar för att det inte är möjligt att använda skattningsskalor för att få en rättvisande bild av den habituella fysiska aktiviteten hos äldre personer som nyligen opererats för höftfraktur. Det verkar därför vara bättre att mäta den fysiska aktiviteten än att skatta den.</p>

It is well known that the outcome of teaching and learning in higher education is often unsatisfactory. Earlier studies have shown that medical students often have a surface approach to their studies and that misconceptions of fundamental physiological phenomena are common. The aim of this thesis is to support educational practice in medicine, particularly in medical physiology. The thesis can be categorised as subject matter-specific education research, which means that questions about teaching and learning are closely linked to the subject studied. The researcher should be well acquainted with the subject in question. The subject area dealt with in this thesis is physiological phenomena related to cardiovascular pressure-flow relations. The thesis consists of studies of 3-dimensional intra cardiac pressure-flow phenomena in the heart (studies 1 and 2) and studies of how students conceive of and develop an understanding of physiological phenomena related to blood pressure and blood pressure regulation (studies 3 and 4). Flow in the left atrium as well as inflow-patterns to the left ventricle were studied. The 3-dimensional method elucidates vortical flow phenomena which were previously unknown. The findings could contribute to increasing physicians and technicians understanding of flow phenomena in the diagnosis and assessment of heart disease and to the further development of diagnostic methods. In the studies of learning and understanding of physiological phenomena, the findings point to new aspects of a deep approach to learning, which have to do with the students’ ability to change perspective and adopt a variety of learning strategies to a phenomenon (Moving) versus a tendency to hold on to one explanatory model (Holding). The study also investigates the students’ ability to identify and apply fundamental physiological principles as well as how they conceive of the importance of detailed knowledge for understanding of physiology. The findings point to differences in the students’ conceptions of physiological principles. A problemising approach, which includes not only causally described relations, indicates a more complex conception of physiological phenomena. The study shows aspects of understanding which are seldom assessed in examinations. The findings indicate a connection between the students’ approaches to learning and the quality of their understanding of fundamental physiological principles. In the thesis, teaching interventions are proposed in order to stimulate dynamic learning and a learning environment where students are not afraid to challenge their conceptions in order to acquire a rich and nuanced picture of physiological phenomena.

<p>In order to examine the usefulness of the multi breath helium dilution method (MB) it was compared to the single breath helium dilution method (SB) and body plethysmography (BP). Residual volume (RV), total lung capacity (TLC) and vital capacity (VC) were measured in seventeen subjects with obstructive (11) or restrictive (6) lung disease and four normal subjects.</p><p>With information from professional literature and current periodicals, advantages and disadvantages with all three methods were compared. ANOVA and Student's t-test were performed on the measurement results.</p><p>The results of the statistical tests tell us there are differences among the methods in the group of obstructive patients. They also reveal a notable difference between the MB and SB methods when measuring the same parameter. In addition, it was noted that none of the existing sets of prediction equations fulfill the requirements established on high quality lung function testing.</p><p>Although a thorough evaluation of the reproducibility of the method is still required, it appears to be a viable alternative to body plethysmography. We claim that measuring the above mentioned static lung volumes with only the single breath helium dilution method cannot be considered a satisfactory practice.</p>

<p>Det finns tillfällen då kliniskt uppmätta blodtryck inte återger patientens allmänna blodtryckssituation och kardiovaskulära belastning, vid dessa tillfällen är det möjligt att låta patienten genomgå noninvasiv blodtrycksmätning under till exempel ett dygn. Reproducerbarheten för denna metod har visat sig vara överlägsen blodtrycksmätningen som utförs på klinik. Syftet med denna studie var att undersöka metodens reproducerbarhet genom att se om det fanns någon systematisk skillnad i resultatet första gången undersökningen jämförs med andra gången, samt om det fanns någon systematisk skillnad mellan en helgdag och en vardag. 20 stycken försökspersoner genomförde två stycken randomiserade ambulatoriska blodtrycksmätningar, en på en vardag och en på en helgdag. Resultatet visar en god överensstämmelse mellan 24 timmars blodtrycksmätning utfört vid två olika tillfällen. Diastoliskt blodtryck under en helgdag är sannolikt lägre än under en vardag. En eventuell skillnad i blodtryck mellan det första och andra mättillfället är dock så liten att den ej kan påvisas i denna studie, detta gäller även eventuell skillnad i systoliskt blodtryck mellan en vardag och en helgdag.</p>

<p>Chronic obstructive pulmonary disease (COPD) is in up to 90 % of all cases caused by</p><p>smoking. COPD often has negative effects on circulation, effects that first and foremost can be</p><p>observed as respiratory insufficiency. Reduced function of the right ventricle of the heart is</p><p>common in patients suffering from chronic obstructive pulmonary disease, especially if they</p><p>also have hypoxemi; insufficient levels of oxygen in blood or tissue. The incidence of this</p><p>cardiac complication reduces the survival time. It is possible in chronic obstructive pulmonary</p><p>disease that the pressure in the pulmonary circulation gradually increases resulting in</p><p>pulmonary hypertension followed by a slow adaptation of the right ventricle by hypertrophy of</p><p>the myocardium.</p><p>To investigate a correlation between COPD and pulmonary hypertension COPD patients</p><p>were subjected to spirometry and ultrasound on heart.</p><p>Of 14 examined patients 5 had developed pulmonary hypertension. A correlation between</p><p>obstruction in the COPD- patients and an increase in left ventricular diameter was found.</p><p>DLCO (diffusion capacity) of the lungs is directly connected to PA (pulmonary arterial</p><p>pressure). The lower DLCO, the higher risk to develop pulmonary hypertension. However, we</p><p>could not find a significant correlation between COPD and pulmonary hypertension in this</p><p>study even if most patients had a decreased DLCO.</p>

Allergic asthma is an inflammatory disease of the airways and is characterized by eosinophilic inflammation and increased airway reactivity. In the studies presented in this thesis, lung mechanics and measurements of airway reactivity were assessed in anaesthetized tracheostomized mice by using an animal ventilator (flexiVent®). A forced oscillation technique makes it possible to measure of both airway and tissue mechanics with a potential to distinguish between central and peripheral airways. The results of the experiments on lung mechanics imply that it is important to understand how altered lung mechanics can affect the airway physiology in order to assess the relevance of different animal models of asthma. We have investigated the effects of changing different components of the lung mechanical measurements, such as administering bronchoconstrictive agents via inhalation or intravenously and implementing deep inhalation in animals with airway inflammation. We have also investigated the relation between airway inflammation and oxidative stress. We found that the formation and time-course of F2-isoprostanes, a marker of oxidative stress, and tissue damage were associated with the degree of inflammation and with the degree of heterogeneous airway airflow. Finally we wished to investigate the hypothesis that nitric oxide (NO) may interact with glucocorticoid (GC) treatment because we see a potential for finding new strategies to increase the therapeutic effect in poor responders or patients resistant to GC treatment. NO plays a central role in physiological regulation of the airway function, and is involved in asthma. We found that the concomitant administration of NO and GC attenuated the airway reactivity more than either treatment alone. In conclusion, with the information presented in this thesis, we hope to contribute to the development of better experimental tools and to improved understanding of murine models of asthma for investigating and understanding the underlying pathophysiology of asthma.

Echocardiography is a well established technique when evaluating the size and function of the heart. One of the most common ways to measure the size of the right ventricle (RV) is to measure the RV outflow tract 1(RVOT1). Several ways to measure RVOT1 are described in the literature.These ways were compared with echocardiography on 27 healthy subjects.The result showed significant differences in RVOT1, depending on the way it was measured, concluding that the same site, method and body positionshould be used when comparing RVOT1 in the same subject over time.One parameter to evaluate the RV diastolic function (RVDF) is to measure the RV isovolumetric relaxation time (RV-IVRT), a sensitive marker ofRV dysfunction. There are different ways to measure this. In this thesis two ways of measuring RV-IVRT and their time intervals were compared in 20 patients examined with echocardiography. There was a significant difference between the two methods indicating that they are not measuring the same interval.Another way to assess the RVDF is to measure the maximal early diastolicvelocity (MDV) in the long-axis direction. MDV can be measured bydifferent methods, hence 29 patients were examined and MDV was measured according to two methods. There was a good correlation but a poor agreement between the two methods meaning that reference values cannot be used interchangeably.Takotsubo cardiomyopathy is characterized by apical wall motion abnormalities without coronary stenosis. The pathology of this condition remains unclear. To evaluate biventricular changes in systolic long-axisfunction and diastolic parameters in the acute phase and after recovery, 13 patients were included and examined with echocardiography at admission and after recovery. The results showed significant biventricular improvementof systolic long-axis function while most diastolic parameters remainedunchanged.