Introduction: Chronic hepatitis B (CHB) is a viral infection that can lead to development of fibrosis and hepatocellular carcinoma (HCC). Several factors affecting disease progression have been reported, such as sex and region of origin. Liver stiffness and fibrosis can be evaluated using transient elastography. The degree of fibrosis is an important parameter when deciding if treatment and HCC surveillance is indicated. Aim1) To compare patients with CHB according to sex and region of origin regarding the parameters liver stiffness, presence of significant fibrosis, hepatitis B e antigen (HBeAg) positivity, frequency of elevated alanine aminotransferase (ALT) levels and HCC surveillance.2) To identify factors associated with significant liver fibrosis. Methods: 410 patients with a registered doctor’s visit 2015–2018 at the Department of Infectious Diseases at Örebro University Hospital were included. A systematic review of medical records was performed and groups (women-men, regions of origin) were compared. Multivariate logistic regression was used to identify factors associated with significant fibrosis. Results: Men had significantly higher liver stiffness values, higher presence of significant fibrosis, and were more frequently under HCC surveillance compared to women. No other significant differences were found regarding the studied parameters, neither related to sex, nor to region of origin. Factors associated with significant fibrosis were: male sex, elevated ALT levels and hepatitis D virus (HDV) co-infection. Conclusions: Men had a higher frequency of significant fibrosis compared to women. Factors associated with significant fibrosis were male sex, elevated ALT values and HDV co-infection.

The insulin resistance syndrome [INSR] is associated with increased cardiovascular risk and affects up to 25% of the Australian population. The mechanism underlying the relationship between the INSR and increased cardiovascular risk is controversial. We postulated that perturbations in the renin-angiotensin system [RAS] and endothelium-derived NO may be implicated in the development of early vascular changes in the INSR. Repeated measurements of arterial stiffness [using digital photoplethysmography] and haemodynamic parameters in response to vasoactive medications were used to demonstrate the functional expression of angiotensin II [Ang II] receptors and NO synthase [NOS]. Ang II acts via two main receptor sub-types: the Ang II type 1 [AT1] and Ang II type 2 [AT2] receptors. The AT1 receptor is central to the development of arterial stiffness and endothelial dysfunction. The role of AT2 receptors in humans is controversial but is postulated to counter-act AT1 receptor mediated effects in diseased vascular beds. We demonstrated increased AT1 and AT2 receptor-mediated effects in small to medium-sized arteries of subjects with early INSR [Chapter 6]. In addition, functional expression of AT2 receptors in adult insulin resistant humans [Chapter 5], but not in healthy volunteers [Chapter 4] was demonstrated. AT1 receptor blockade in subjects with early INSR resulted in improvements in vascular function, with a consequent functional down-regulation of AT2 receptors [Chapter 7]. Functional NOS expression was demonstrated to be increased in subjects with early INSR compared with healthy controls [Chapter 6]. This was postulated to be a homeostatic response to counteract early vascular changes in subjects with early INSR. AT1 receptor blockade in these subjects reduced functional NOS expression [Chapter 8]. In conclusion, patients with early INSR represent a model of early disease where early intervention may be able to reverse the process incited by the initial exposure to multiple cardiovascular risk factors. Early vascular changes in these individuals are mediated at least in part, by increased AT1 receptor activity and/or expression, and may be detected by changes in arterial stiffness indices and non-invasive vascular reactivity studies. There is a compensatory increase in AT2 receptor and NOS expression/activity to counter-act these vascular changes.

The insulin resistance syndrome [INSR] is associated with increased cardiovascular risk and affects up to 25% of the Australian population. The mechanism underlying the relationship between the INSR and increased cardiovascular risk is controversial. We postulated that perturbations in the renin-angiotensin system [RAS] and endothelium-derived NO may be implicated in the development of early vascular changes in the INSR. Repeated measurements of arterial stiffness [using digital photoplethysmography] and haemodynamic parameters in response to vasoactive medications were used to demonstrate the functional expression of angiotensin II [Ang II] receptors and NO synthase [NOS]. Ang II acts via two main receptor sub-types: the Ang II type 1 [AT1] and Ang II type 2 [AT2] receptors. The AT1 receptor is central to the development of arterial stiffness and endothelial dysfunction. The role of AT2 receptors in humans is controversial but is postulated to counter-act AT1 receptor mediated effects in diseased vascular beds. We demonstrated increased AT1 and AT2 receptor-mediated effects in small to medium-sized arteries of subjects with early INSR [Chapter 6]. In addition, functional expression of AT2 receptors in adult insulin resistant humans [Chapter 5], but not in healthy volunteers [Chapter 4] was demonstrated. AT1 receptor blockade in subjects with early INSR resulted in improvements in vascular function, with a consequent functional down-regulation of AT2 receptors [Chapter 7]. Functional NOS expression was demonstrated to be increased in subjects with early INSR compared with healthy controls [Chapter 6]. This was postulated to be a homeostatic response to counteract early vascular changes in subjects with early INSR. AT1 receptor blockade in these subjects reduced functional NOS expression [Chapter 8]. In conclusion, patients with early INSR represent a model of early disease where early intervention may be able to reverse the process incited by the initial exposure to multiple cardiovascular risk factors. Early vascular changes in these individuals are mediated at least in part, by increased AT1 receptor activity and/or expression, and may be detected by changes in arterial stiffness indices and non-invasive vascular reactivity studies. There is a compensatory increase in AT2 receptor and NOS expression/activity to counter-act these vascular changes.

The insulin resistance syndrome [INSR] is associated with increased cardiovascular risk and affects up to 25% of the Australian population. The mechanism underlying the relationship between the INSR and increased cardiovascular risk is controversial. We postulated that perturbations in the renin-angiotensin system [RAS] and endothelium-derived NO may be implicated in the development of early vascular changes in the INSR. Repeated measurements of arterial stiffness [using digital photoplethysmography] and haemodynamic parameters in response to vasoactive medications were used to demonstrate the functional expression of angiotensin II [Ang II] receptors and NO synthase [NOS]. Ang II acts via two main receptor sub-types: the Ang II type 1 [AT1] and Ang II type 2 [AT2] receptors. The AT1 receptor is central to the development of arterial stiffness and endothelial dysfunction. The role of AT2 receptors in humans is controversial but is postulated to counter-act AT1 receptor mediated effects in diseased vascular beds. We demonstrated increased AT1 and AT2 receptor-mediated effects in small to medium-sized arteries of subjects with early INSR [Chapter 6]. In addition, functional expression of AT2 receptors in adult insulin resistant humans [Chapter 5], but not in healthy volunteers [Chapter 4] was demonstrated. AT1 receptor blockade in subjects with early INSR resulted in improvements in vascular function, with a consequent functional down-regulation of AT2 receptors [Chapter 7]. Functional NOS expression was demonstrated to be increased in subjects with early INSR compared with healthy controls [Chapter 6]. This was postulated to be a homeostatic response to counteract early vascular changes in subjects with early INSR. AT1 receptor blockade in these subjects reduced functional NOS expression [Chapter 8]. In conclusion, patients with early INSR represent a model of early disease where early intervention may be able to reverse the process incited by the initial exposure to multiple cardiovascular risk factors. Early vascular changes in these individuals are mediated at least in part, by increased AT1 receptor activity and/or expression, and may be detected by changes in arterial stiffness indices and non-invasive vascular reactivity studies. There is a compensatory increase in AT2 receptor and NOS expression/activity to counter-act these vascular changes.

Les microtubules sont des composants structuraux de cellules et gouvernent des fonctions cellulaires essentielles telles que les mitoses et le transport des vésicules. Ils sont composés de deux sous-unités non identiques (tubulines α et β), formant un dimère, et sont arrangés de sorte à former une structure tubulaire de 20nm de diamètre. Généralement, ils sont constitués de 13 ou 14 protofilaments arrangés en spirale. Les liaisons longitudinales entre dimères sont plus rigides et fortes que les liaisons latérales. Aussi, les microtubules sont des structures fortement anisotropes. Dans ces travaux de thèse, nous avons pour but de définir l'ensemble des coefficients élastique qui permet de reproduire leur comportement atomistique ainsi que de rendre compte de leur réponse mécanique selon des chemins de chargement variés. En négligeant la discontinuité hélicoïdale souvent observée, un microtubule est représenté par une structure triangulaire de dimères à partir desquels un volume élémentaire représentatif est défini. Un potentiel harmonique est utilisé pour décrire les interactions entre dimères voisins. A partir de l'estimation des constantes élastiques et de l'utilisation de la méthode proposée par Arslan et Boyce (2006) -alors pour analyser le comportement mécanique d'un réseau triangulaire de spectrines composant les membranes des globules rouges-, un modèle continu de comportement mécanique est présenté pour reproduire le comportement des parois des microtubules. Un modèle numérique éléments finis est ensuite créé pour modéliser le comportement d'un microtubule dans sa globalité. Des éléments coques sont utilisés pour reproduire les fines parois des microtubules. Les propriétés du modèle éléments finis sont ajustées à partir des résultats du modèle présenté ainsi qu'aux données expérimentales provenant de la littérature. La rigidité de flexion calculée au cours de simulation des tests de flexion 3 points est en accord avec les valeurs de la littérature. Ces tests révèlent les mécanismes de déformation en fonction de la longueur utile du tube utilisé: Flexion et cisaillement locaux de la paroi gouvernent la déformation pour de "petits" tubes. Pour des longueurs "moyennes" le cisaillement et la flexion du tube prédominent. Enfin, dans le cas de tubes "longs", la déformation est uniquement associée aux effets de flexion. Ces résultats témoignent de l'influence de l'anisotropie du tube sur la réponse observée selon différents mode de sollicitation. Ils permettent également d'expliquer l'évolution de la rigidité de flexion avec la longueur utile du tube, comme reportée dans la littérature. Enfin, des micrographes montrent la propension des extrémités des microtubules à diverger radialement -"à boucler"-. Une telle géométrie est causée par des instabilités propres aux microtubules et implique un état précontraint. Un «modèle d'interactions» est alors proposé de manière à considérer un état précontraint et ainsi reproduire la cinétique des instabilités des microtubules au cours de la polymérisation/dépolymérisation.

<p>Information about dynamic tire properties has always been important for drivers of wheel driven vehicles. With the increasing amount of systems in modern vehicles designed to measure and control the behavior of the vehicle information regarding dynamic tire properties has grown even more important.</p><p>In this thesis a number of methods for modeling and estimating dynamic tire properties have been implemented and evaluated. The more general issue of estimating model parameters in linear and non-linear vehicle models is also addressed.</p><p>We conclude that the slope of the tire slip curve seems to dependent on the stiffness of the road surface and introduce the term combined stiffness. We also show that it is possible to estimate both longitudinal and lateral combined stiffness using only standard vehicle sensors.</p>

<p>Prostate cancer is the most common type of cancer in men in Europe and the USA. Some prostate tumours are regarded as stiffer than the surrounding normal tissue, and therefore it is of interest to be able to reliably measure prostate tissue stiffness. The methods presently used to detect prostate cancer are inexact, and new techniques are needed. In this licentiate thesis resonance sensor technology, with its ability to measure tissue stiffness, was applied to normal and cancerous prostate tissue.</p><p>A piezoelectric transducer element in a feedback system can be set to vibrate at its resonance frequency. When the sensor element contacts an object a change in the resonance frequency is observed, and this feature has been utilized in sensor systems to describe physical properties of different objects. For medical applications it has been used to measure stiffness variations due to various pathophysiological conditions.</p><p>An impression-controlled resonance sensor system was used to quantify stiffness in human prostate tissue in vitro using a combination of frequency change and force measurements. Measurements on prostate tissue showed statistically significant (p < 0.001) and reproducible differences between normal healthy tissue and tumour tissue when using a multivariate parameter analysis. Measured stiffness varied in both the normal tissue and tumour tissue group. One source of variation was assumed to be related to differences in tissue composition. Other sources of error could be uneven surfaces, different levels of dehydration of the prostates, and actual differences between patients.</p><p>The prostate specimens were also subjected to morphometric measurements, and the sensor parameter was compared with the morphology of the tissue with linear regression. In the probe impression interval 0.5–1.7 mm, the maximum coefficient of determination was R2 ≥ 0.60 (p < 0.05, n = 75). An increase in the proportion of prostate stones (corpora amylacea), stroma, or cancer in relation to healthy glandular tissue increased the measured stiffness. Cancer and stroma had the greatest effect on the measured stiffness. The deeper the sensor was pressed, the greater, i.e., deeper, volume it sensed.</p><p>It is concluded that prostate cancer increases the measured stiffness as compared with healthy glandular tissue, but areas with predominantly stroma or many stones could be more difficult to differentiate from cancer. Furthermore, the results of this study indicated that the resonance sensor could be used to detect stiffness variations in human prostate tissue in vitro, and especially due to prostate cancer. This is promising for the development of a future diagnostic tool for prostate cancer.</p>

Despite advances, stroke remains the largest cause of disability and fourth leading cause of death in the United States. The relationship between changes in human vasculature (atherosclerosis and arteriosclerosis) prior to clinical incident, and other risk factors for stroke remains unclear. This dissertation represents work towards the identification of imaging biomarkers for vascular change, focusing on ultrasound to characterize persons at risk, including differences among race/ethnic groups. This research contained three distinct projects. The first goal was to determine if changes within ultrasonographic measures of carotid vasculature could be found across race/ethnic groups after adjustment for risk factors. The second was to determine if those same measures were related to changes in cerebral white matter known to be associated with ongoing cerebrovascular disease; we compared ultrasound to an MRI marker of subclinical vascular disease, white matter hyperintensity volume (WMHV). Finally, we sought to investigate a known and well-studied ultrasound marker for atherosclerosis, carotid intima-medial thickness, with those same MRI markers of subclinical vascular disease (WMHV). All studies were conducted within an on-going multiethnic cohort that has been followed since 1990, The Northern Manhattan Study. The population is comprised of persons who self-identify as Hispanic (52%), Black (24%), or White (21%), with less than 3% identified as “race/other.” We found race/ethnic differences in carotid arterial stiffness and diameter; carotid diameter increases with age among Hispanics, but not among blacks or whites. A significant correlation was also found between diastolic diameter and subclinical vascular disease, and this relationship was also increased among Hispanics; neither black race nor white race was associated with corresponding increases in both MRI white matter hyperintensity and diastolic diameter. Finally, using a surrogate marker for atherosclerosis, carotid intima-medial thickness (cIMT), we document for the first time, positive associations between cIMT and WMHV. There are important developments still to be made in the field of vascular risk. Use of inexpensive and non-invasive ultrasound technology to approximate ongoing cerebrovascular disease could lead to better understanding of the effect of known risk factors, and could help stroke risk assessment and treatment modification.

This thesis presents numerical predictions for the leakage and direct stiffness coefficients of pocket damper seals. Modifications made to earlier flow-prediction models are discussed. Leakage and static pressure measurements on straight-through and diverging configurations of eight-bladed and twelve-bladed seals were used for code validation and for calculation of seal discharge coefficients. Higher than expected leakage rates were measured in the case of the twelve-bladed seal, while the leakage rates for the eight-bladed seals were predicted reasonably accurately. Results are presented for shake tests conducted on the seals at pressures of up to 1000 Psi (6.90 MPa). Test variables included pressure drop across the seals and rotor speed. The experimentally obtained stiffness coefficients are compared to results of a rotordynamic damper seal code, which uses the corrected mass flow-rate calculation method. Results show that the code under-predicts the magnitude of the seal's stiffness for most test cases. However, general trends in the frequency dependency of the direct stiffness are more accurately predicted. The expectation of high values of negative stiffness in diverging seals is confirmed by the results, but the frequency at which the sign of the stiffness becomes positive is considerably lower than is predicted. In addition to presenting high-pressure test data, this thesis also attempts to provide some insight into how seal parameters can be modified to obtain desired changes in seal stiffness.

The present series of in vivo experiments in healthy subjects, were performed to investigate wall stiffness in peripheral vessels and how this modality adapts to iterative increments or sustained reductions in local intravascular pressures. Vascular stiffness was measured as changes in arterial and venous diameters, and in arterial flow, during graded increments in distending pressures in the vasculature of an arm or a lower leg. In addition, effects of intravascular pressure elevation on flow characteristics in veins, and on limb pain were elucidated. Arteries and veins were stiffer (i.e. pressure distension was less) in the lower leg than in the arm. The pressure-induced increase in arterial flow was substantially greater in the arm than in the lower leg, indicating a greater stiffness in the arterioles of the lower leg. Prolonged reduction of intravascular pressures in the lower body, induced by 5 wks of sustained horizontal bedrest (BR), decreased stiffness in the leg vasculature. BR increased pressure distension in the tibial artery threefold and in the tibial vein by 86 %. The pressure-induced increase in tibial artery flow was greater post bedrest, indicating reduced stiffness in the arterioles of the lower leg. Intermittent increases of intravascular pressures in one arm (pressure training; PT) during a 5-wk period decreased vascular stiffness. Pressure distension and pressure-induced flow in the brachial artery were reduced by about 50 % by PT. PT reduced pressure distension in arm veins by 30 to 50 %. High intravascular pressures changed venous flow to arterial-like pulsatile patterns, reflecting propagation of pulse waves from the arteries to the veins either via the capillary network or through arteriovenous anastomoses. High vascular pressures induced pain, which was aggravated by BR and attenuated by PT; the results suggest that the pain was predominantly caused by vascular overdistension. In conclusion, vascular wall stiffness constitutes a plastic modality that adapts to meet demands imposed by a change in the prevailing local intravascular pressure. That increased intravascular pressure leads to increased arteriolar wall stiffness supports the notion that local pressure load may serve as a “prime mover” in the development of vascular changes in hypertension. / medicine doktorsexamen QC 20101109