Primary Sjögren's syndrome (pSS) is a chronic inflammatory connective tissue disease of unknown etiology. The disease primarily involves salivary and lacrimal glands which results in oral and ocular dryness (sicca symptoms). A wide spectrum of extraglandular features from various organs may be seen. In this thesis, the frequency of psychiatric symptoms in women with primary Sjögren's syndrome was studied and an attempt was made to assess how these symptoms might influence their well being and quality of life. The main finding was that the women with pSS suffered significantly more often from symptoms of anxiety and depression when compared with age matched, healthy females and female patients with rheumatoid arthritis. The physical and mental well-being of the patients with pSS was significantly reduced compared to patient controls. The possible link of psychiatric symptoms to the altered function of the hypothalamic-pituitary-gonadal axis and adrenal androgen secretion was elucidated. Women with pSS have intact cortisol synthesis but reduced serum concentrations of dehydroepiandrosterone sulphate (DHEA-S) (p<0.05) and an increased cortisol/DHEA-S ratio (p<0.05), compared to healthy controls. These findings may reflect a constitutional or disease-meditated influence on adrenal steroid synthesis. Positive correlation was found between DHEA-S serum levels and quality of sexual life (p<0.01) and mental well-being (p<0.01) in women with pSS.

I avhandlingen analyseras betydelsen hos partiklarna "in", "ut", "upp" och "ner" då dessa fungerar som verbpartiklar och tillsammans med verbet bildar partikelverb. Analysen omfattar såväl semantiskt regelbundna som lexikaliserade partikelverb och söker finna förklaringar till partiklarnas polysemi. Undersökningen är korpusbaserad och materialet består av nästan 900 olika partikelverb representerade med över 5 100 belägg. Beskrivnings¬modellen bygger huvudsakligen på den kognitiva semantiken. Verbpartiklarna analyseras i olika kontexter i såväl det fysiska rummets domän som i andra domäner varvid utgångspunkten för analysen alltid är partiklarnas prototypiska (spatiala) betydelse. Undersökningen visar att verbpartiklarnas olika, till synes disparata, betydelser är motiverade av föreställningsscheman (VERTICAL AXIS schema) och deras transformationer (vertikal axel  horisontell axel), samt av metonymier (DELEN FÖR HELHETEN) och metaforer (CENTRUM IS UP). Partiklarnas betydelser är länkade till varandra genom familjelikhet och bildar ett nätverk. Partikelverb bildade med in, ut, upp och ner uppvisar vanligen en avgränsad aktionsart, men verbpartiklarna har i de allra flesta en mer specifik betydelse än enbart den perfektiva. Verbpartiklarna upp och in betecknar i regel riktningen mot centrum och har ofta positiva konnotationer medan verbpartiklarna ut och ner denoterar rörelsen mot periferin och snarare har negativa konnotationer. Den vertikala orienteringen tycks dominera svenskans strukturering av det fysiska rummets domän; en rörelse i förhållande till en vertikalt orienterad behållare (behållare utan tak) beskrivs med de vertikala partiklarna upp/ner och inte med behållarpartiklarna in/ut. I vissa få speciella kontexter kan de undersökta partiklarna signalera talarens perspektiv.

We are unceasingly exposed to potentially harmful microorganisms. The battle against threatening infectious agents includes activation of both the innate and of the adaptive immune systems. Illness responses are elicited and include inflammation, fever, decreased appetite, lethargy and increased sensitivity to painful stimuli in order to defeat invaders. While many of these signs of disease are controlled by the central nervous system, it has remained an enigma how signals from the peripheral immune system reach the brain through its blood-brain barrier, which precludes macromolecules, including cytokines, from diffusing into the brain parenchyma. Previous findings indicate the existence of a pathway across the blood-brain barrier, which includes binding of the cytokine interleukin-1 (IL-1) to its receptor in the brain vessels, thereby inducing the production of the prostaglandin E2 (PGE2) synthesizing enzymes cyclooxygenase-2 (Cox-2) and microsomal prostaglandin E synthase-1 (mPGES-1), which ultimately synthesize PGE2. PGE2 subsequently binds to any of the four prostaglandin E2 (EP) -receptors. Previous results from our laboratory have suggested that this pathway plays a critical role in the febrile response to infectious stimuli. The present thesis aims at further investigating the molecular events underlying immune-to-brain signalling, with special emphasis on fever, hypothalamic-pituitary-adrenal (HPA) -axis activation and anorexia and their connection to signalling molecules of the cytokine and prostaglandin families, respectively. In paper I, the molecular processes linking the proinflammatory cytokine interleukin-6 (IL-6) and PGE2 in the febrile response were investigated. Both IL-6 and PGE2 have been shown to be critical players in the febrile response, although the molecular connections are not known, i.e. if IL-6 exerts its effects up- or downstream of PGE2. Mice deficient in IL-6 were unable to respond to bacterial lipopolysaccharide (LPS) with a febrile response, but displayed similar induction of Cox-2 and mPGES-1, and similar concentrations of PGE2 in the cerebrospinal fluid as wild-type mice. Paradoxically, the IL-6 deficient mice responded with a dose-dependent elevation of body temperature in response to intracerebroventricularly injected PGE2. Furthermore, IL-6 per se was not pyrogenic when injected peripherally in mice, and did not cause increased levels of PGE2 in cerebrospinal fluid. IL-6 deficient mice were not refractory to the action of PGE2 because of excess production of some hypothermia-producing factor, since administration of a Cox-2 inhibitor in LPS-challenged IL-6 deficient mice did not unmask any hypothermic response, and neutralization of tumor necrosis factor α (TNFα), associated with hypothermia, did not produce fever in LPS-challenged IL-6 deficient mice. These data indicate that IL-6 rather than exerting its effects up- or down-stream of PGE2 affects some process in parallel to PGE2, perhaps by influencing the diffusion and binding of PGE2 onto its target neurons. In papers II and III, we injected the proinflammatory cytokine IL-1β in free-fed wild-type mice, in mice with a deletion of the gene encoding mPGES-1, or in mice deficient in the EP1, EP2 and EP3. Food intake was continuously measured during their active period, revealing that mPGES-1 deficient mice were almost completely resistant to anorexia induced by IL-1β. However, all of the investigated EP receptor deficient mice exhibited a normal profound anorexic response to IL-1β challenge, suggesting that the EP4 is the critical receptor that mediates IL-1β-induced anorexia. We also investigated the role of mPGES-1 in anorexia induced by lipopolysaccharide (LPS) in mPGES-1 deficient mice. The profound anorexic response after LPS-challenge was similar in mPGES-1 deficient and wild-type mice. To further investigate the anorectic behaviour after LPS injection, we pre-starved the animals for 22 hours before injecting them with LPS. In this paradigm, the anorexia was less profound in mPGES-1 knock-out mice. Our results suggest that while the inflammatory anorexia elicited by peripheral IL-1β seems largely to be dependent on mPGES-1-mediated PGE2 synthesis, similar to the febrile response, the LPS-induced anorexia is independent of this mechanism in free-fed mice but not in pre-starved animals. In papers IV and V, the role of prostanoids for the immune-induced HPA-axis response was investigated in mice after genetic deletion or pharmacological inhibition of prostanoid-synthesizing enzymes, including Cox-1, Cox-2, and mPGES-1. The immediate LPS-induced release of ACTH (adrenocorticotropic hormone and corticosteroids was critically dependent on Cox-1 derived prostanoids and occurred independently of Cox-2 and mPGES-1 derived PGE2. In contrast, the delayed HPA-axis response was critically dependent on immune-induced PGE2, synthesized by Cox-2 and mPGES-1, and occurred independently of Cox-1 derived enzymes. In addition, in the mPGES-1 deficient mice, the synthesis of CRH hnRNA and mRNA was decreased in the paraventricular nucleus of the hypothalamus after LPS-challenge, indicating that the delayed hormone secretion was mediated by PGE2-induced gene-transcription of CRH in the hypothalamus. The expression of the c-fos gene and Fos protein, an index of synaptic activation, was maintained in the paraventricular nucleus and its brainstem afferents both after unselective and Cox-2 selective inhibition as well as in Cox-1, Cox-2, and mPGES-1 knock-out mice. This suggests that the immune-induced neuronal activation of autonomic relay nuclei occurs independently of prostanoid synthesis and that it is insufficient for eliciting stress hormone release.

Two computationally fast fluid mechanical models for vertical axis turbines are the streamtube and the vortex model. The streamtube model is the fastest, allowing three-dimensional modeling of the turbine, but lacks a proper time-dependent description of the flow through the turbine. The vortex model used is two-dimensional, but gives a more complete time-dependent description of the flow. Effects of a velocity profile and the inclusion of struts have been investigated with the streamtube model. Simulations with an inhomogeneous velocity profile predict that the power coefficient of a vertical axis turbine is relatively insensitive to the velocity profile. For the struts, structural mechanic loads have been computed and the calculations show that if turbines are designed for high flow velocities, additional struts are required, reducing the efficiency for lower flow velocities.Turbines in channels and turbine arrays have been studied with the vortex model. The channel study shows that smaller channels give higher power coefficients and convergence is obtained in fewer time steps. Simulations on a turbine array were performed on five turbines in a row and in a zigzag configuration, where better performance is predicted for the row configuration. The row configuration was extended to ten turbines and it has been shown that the turbine spacing needs to be increased if the misalignment in flow direction is large.A control system for the turbine with only the rotational velocity as input has been studied using the vortex model coupled with an electrical model. According to simulations, this system can obtain power coefficients close to the theoretical peak values. This control system study has been extended to a turbine farm. Individual control of each turbine has been compared to a less costly control system where all turbines are connected to a mutual DC bus through passive rectifiers. The individual control performs best for aerodynamically independent turbines, but for aerodynamically coupled turbines, the results show that a mutual DC bus can be a viable option.Finally, an implementation of the fast multipole method has been made on a graphics processing unit (GPU) and the performance gain from this platform is demonstrated.

Transdisciplinary research in general, and stress research in particular, requires an efficient integration of methodological knowledge of all involved academic disciplines, in order to obtain conclusions of incremental value about the investigated constructs. From a psychologist’s point of view, biochemistry and quantitative neuroendocrinology are of particular importance for the investigation of endocrine stress systems (i.e., the HPA axis, and the SNS). Despite of their fundamental role for the adequate assessment of endocrine activity, both topics are rarely covered by conventional psychological curriculae. Consequently, the transfer of the respective knowledge has to rely on other, less efficient channels of scientific exchange. The present thesis sets out to contribute to this exchange, by highlighting methodological issues that are repeatedly encountered in research on stress-related endocrine activity, and providing solutions to these issues. As outlined within this thesis, modern stress research tends to fall short of an adequate quantification of the kinetics and dynamics of bioactive cortisol. Cortisol has gained considerable popularity during the last decades, as its bioactive fraction is supposed to be reliably determinable from saliva and is therefore the most conveniently obtainable marker of HPA activity. However, a substantial fraction of salivary cortisol is metabolized to its inactivated form cortisone by the enzyme 11β-HSD2 in the parotid glands, which is likely to restrict its utility. Although the commonly used antibody-based quantification methods (i.e. immunoassays) might “involuntarily” qualify this issue to some degree (due to their inherent cross-reactivity with matrix components that are structurally-related to cortisol; e.g., cortisone), they also cause differential within-immunoassay measurement bias: Salivary cortisone has (as compared to salivary cortisol) a substantially longer half-life, which leads to an overestimation of cortisol levels the more time has passed since the onset of the prior HPA secretory episode, and thus tends to distort any inference on the kinetics of bioactive cortisol. Furthermore, absolute cortisol levels also depend on the between-immunoassay variation of antibodies. Consequently, raw signal comparisons between laboratories and studies, which are favorable as compared to effect comparisons, can hardly be performed. This finding also highlights the need for the long-sought standardization of biochemical measurement procedures. The presumably only way to circumvent both issues is to rely on quantification of ultrafiltrated blood cortisol by mass-spectrometric methods. Being partly related to biochemical considerations with research on HPA activity, a second topic arises concerning the operationalization of the construct itself: In contrast to the simple outcome measures like averaged reaction times, inclined stress researchers can only indirectly infer on the sub-processes being involved in HPA activity from longitudinally sampled hormone concentrations. HPA activity can be quantified either by (a) discrete-time, or by (b) continuous-time models. Although the former is the most popular and more convenient approach (as indicated by the overly frequent encounter of ANOVAs and trapezoidal AUC calculations in the field of psychobiological stress research), most discrete time models form rather data-driven, descriptive approaches to quantify HPA activity, that assume the existence of some endocrine resting-state (i.e., a baseline) at the first sampling point and disregard any mechanistic hormonal change occurring in between all following sampling points. Even if one ignores the fact, that such properties are unlikely to pertain to endocrine systems in general, many generic discrete time models fail to account for the specific structure of endocrine data that results from biochemical hormone measurement, as well as from the dynamics of the investigated system. More precisely speaking, cortisol time series violate homoscedasticity, residual normality, and sphericity, which need to be present in order to enable (mixed effects) GLM-based analyses. Neglecting these prerequisites may lead to inference bias unless counter-measures are taken. Such counter-measures usually involve alteration of the scale of hormone concentrations via transformation techniques. As such, a fourth-root transformation of salivary cortisol (being determined by a widely used, commercially available immunoassay) is shown to yield the optimal tradeoff for generating homoscedasticity and residual normality simultaneously. Although the violation of sphericity could be partly accounted for by several correction techniques, many modern software packages for structural equation modeling (e.g., Mplus, OpenMX, Lavaan) also offer the opportunity to easily specify more appropriate moment structures via path notation and therefore to relax the modeling assumptions of GLM approaches to the analysis of longitudinal hormone data. Proceeding from this reasoning, this thesis illustrates how one can additionally incorporate hypotheses about HPA functioning, and thus model all relevant sub-processes that give rise to HPA kinetics and dynamics. The ALT modeling framework being advocated within this thesis, is shown to serve well for this purpose: ALT modeling can recover HPA activity parameters, which are directly interpretable within a physiological framework, that is, distinct growth factors representing the amount of secreted cortisol and velocity of cortisol elimination can serve to interpret HPA reactivity and regulation in a more unambiguous way, as compared to GLM effect measures. For illustration of these advantages on a content level, cortisol elimination after stress induction was found to be elevated as compared to its known pharmacokinetics. While the mechanism behind this effect requires further investigation, its detection would obviously have been more difficult upon application of conventional GLM methods. Further extension of the ALT framework allowed to address a methodological question, which had previously been dealt with by a mere rule of thumb; what’s the optimal threshold criterion, that enables a convenient but comparably accurate classification of individuals whose HPA axis is or is not activated upon encountering a stressful situation? While a rather arbitrarily chosen baseline-to-peak threshold of 2.5 nmol/L was commonly used to identify episodes of secretory HPA activity in time series of salivary cortisol concentrations, a reanalysis of a TSST meta- dataset by means of ALT mixture modeling suggested that this 2.5 nmol/L criterion is overly conservative with modern biochemical measurement tools and should be lowered according to the precision of the utilized assay (i.e., 1.5 nmol/L). In sum, parametric ALT modeling of endocrine activity can provide a convenient alternative to the commonly utilized GLM-based approaches that enables the inference on and quantification of distinct HPA components on a theoretical foundation, and thus to bridge the gap between discrete- and continuous-time modeling frameworks. The implementation of the outlined modeling approaches by the respective statistical syntaxes and practical guidelines being derived from the comparison of cortisol assays mentioned above, are provided in the appendix of the present thesis, which will hopefully help stress researchers to directly quantify the construct they actually intend to assess.

Approximately 1 in 6 infants are born prematurely each year. Typically, these infants spend 25 days in the Neonatal Intensive Care Unit (NICU) where they experience 10-18 painful and inflammatory procedures each day. Remarkably, pre-emptive analgesics and/or anesthesia are administered less than 30% of the time. Unalleviated pain during the perinatal period is associated with permanent decreases in pain sensitivity, blunted cortisol responses and high rates of neuropsychiatric disorders. To date, the mechanism(s) by which these long-term changes in stress and pain behavior occur, and whether such alterations can be prevented by appropriate analgesia at the time of injury, remains unclear. We have previously reported in rats that inflammation experienced on the day of birth permanently upregulates central opioid tone, resulting in a significant reduction in adult pain sensitivity. However, the impact on early life pain on anxiety- and stress-related behavior and HPA axis regulation is not known. Therefore the goal of this dissertation was to determine the long-term impact of a single neonatal inflammatory pain experience on adult anxiety- and stress-related responses. Neuroanatomical changes in stress-associated neurocircuits were also examined. As the endogenous pain control system and HPA axis are in a state of exaggerated developmental plasticity early in postnatal life, and these systems work in concert to respond to noxious or aversive stimuli, this dissertation research aimed to answer the following questions: (1) Does neonatal injury produce deficits in adult stress-related behavior and alter stress-related neuroanatomy through an opioid-dependent mechanism? (2) Does neonatal injury alter receptor systems regulating the activation and termination of the stress response in adulthood? (3) Are stress- and pain-related neurotransmitters altered within the first week following early life pain? (4) Is early activation of the pain system necessary for the long-term changes in anxiety- and stress-related behavior? Together these studies demonstrate the degree, severity and preventability of the long-term deficits in stress responding associated with a single painful experience early in life. The goal of this research is to promote change in the treatment of infant pain in the NICU to reduce long-term sensory and mental health complications associated with prematurity.

Arbetets syfte är att göra en aktualiserad framställning av ämnet trädkult. En viktig del av syftet har också varit att göra en mera heltäckande materialgenomgång än tidigare studier. Framställningen kommer huvudsakligen att beröra den fornskandinaviska religionen men utblickar kommer att bli nödvändiga för att komplettera materialet. Således kommer även kontinentalgermanska och samiska områden att beröras, kontinentalgermanskt område något utförligare, samiskt område i form av ett exempel. Visserligen kommer arbetet i mycket att ha karaktären av en betraktelse. Som sådan blir den resonerande såtillvida att då någon källa har redovisats och/eller den i respektive fall eventuelle forskaren har fått lägga dit sina aspekter kommer jag att i vissa fall ha små reflektioner att tillägga. Trots detta vill jag ändå som tillägg sätta en traditionell frågeställning eftersom inget uppsatsarbete borde undvika att söka besvara åtminstone någon eller några frågor. De frågor den här uppsatsen kommer att söka besvara blir: <ul type="disc">Kan en koppling mellan myt och rit påvisas? Finns det möjlighet att påvisa ett mikro-, makrokosmiskt förhållande? Fanns det maktlegitimerande skäl för kultplatsen?

With the advantage of modern high speed computers, there has been an increased interest in the use of first-principles based computational approaches for the aerodynamic modeling of horizontal axis wind turbine (HAWT). Since these approaches are based on the laws of conservation (mass, momentum, and energy), they can capture much of the physics in great detail. The ability to accurately predict the airloads and power output can greatly aid the designers in tailoring the aerodynamic and aeroelastic features of the configuration. First-principles based analyses are also valuable for developing active means (e.g., circulation control), and passive means (e.g., Gurney flaps) of reducing unsteady blade loads, mitigating stall, and for efficient capture of wind energy leading to more electrical power generation. In this present study, the aerodynamic performance of a wind turbine rotor equipped with circulation enhancement technology (trailing edge blowing or Gurney flaps) is investigated using a three-dimensional unsteady viscous flow analysis. The National Renewable Energy Laboratory (NREL) Phase VI horizontal axis wind turbine is chosen as the baseline configuration. Prior to its use in exploring these concepts, the flow solver is validated with the experimental data for the baseline case under yawed flow conditions. Results presented include radial distribution of normal and tangential forces, shaft torque, root flap moment, surface pressure distributions at selected radial locations, and power output. Results show that good agreement has been for a range of wind speeds and yaw angles, where the flow is attached. At high wind speeds, however, where the flow is fully separated, it was found that the fundamental assumptions behind this present methodology breaks down for the baseline turbulence model (Spalart-Allmaras model), giving less accurate results. With the implementation of advanced turbulence model, Spalart-Allmaras Detached Eddy Simulation (SA-DES), the accuracy of the results at high wind speeds are improved. Results of circulation enhancement concepts show that, at low wind speed (attached flow) conditions, a Coanda jet at the trailing edge of the rotor blade is effective at increasing circulation resulting in an increase of lift and the chordwise thrust force. This leads to an increased amount of net power generation compared to the baseline configuration for moderate blowing coefficients. The effects of jet slot height and pulsed jet are also investigated in this study. A passive Gurney flap was found to increase the bound circulation and produce increased power in a manner similar to the Coanda jet. At high wind speed where the flow is separated, both the Coanda jet and Gurney flap become ineffective. Results of leading edge blowing indicate that a leading edge blowing jet is found to be beneficial in increasing power generation at high wind speeds. The effect of Gurney flap angle is also studied. Gurney flap angle has significant influence in power generation. Higher power output is obtained at higher flap angles.

This thesis introduces a design optimization methodology that is based on minimizing the Cost of Energy (COE) of a Horizontal Axis Wind Turbine (HAWT) that is to be operated at a specific wind site. In the design methodology for the calculation of the Cost of Energy, the Annual Energy Production (AEP) model to calculate the total energy generated by a unit wind turbine throughout a year and the total cost of that turbine are used. The AEP is calculated using the Blade Element Momentum (BEM) theory for wind turbine power and the Weibull distribution for the wind speed characteristics of selected wind sites. For the blade profile sections, either the S809 airfoil profile for all spanwise locations is used or NREL S-series airfoil families, which have different airfoil profiles for different spanwise sections, are used,. Lift and drag coefficients of these airfoils are obtained by performing computational fluid dynamics analyses. In sample design optimization studies, three different wind sites that have different wind speed characteristics are selected. Three scenarios are generated to present the effect of the airfoil shape as well as the turbine power. For each scenario, design optimizations of the reference wind turbines for the selected wind sites are performed the Cost of Energy and Annual Energy Production values are compared.

This work focuses on modeling, parameter estimation, and real-time position control of a two axis Gimbaled Mirror System (GMS) which is designed and manufactured to move an IR spot generated by an Infra Red Scene Generator System (IRSGS) in two orthogonal axes (elevation and azimuth) within the IR scene which is also generated by the IRSGS. Mathematical models of the GMS, the control system, and the disturbance torque originated from the movements of Flight Motion Simulator (FMS), on which the IRSGS will be mounted, are constructed using MATLAB&reg / /Simulink&reg / and MATLAB/Simulink/SimMechanics&reg / . Parameter estimations of the GMS and control system elements are achieved using MATLAB/Simulink Parameter Estimation Tool&reg / . The controller tuning is performed using the developed mathematical models in MATLAB/Simulink environment. Optimized digital PID controllers are implemented in the real-time control system. Performances of the controllers for both GMS axes are evaluated by both real system tests and simulation runs / and the results of these runs are compared. Controller performances under the effect of disturbances are analyzed by using the mathematical models developed in the MATLAB/ Simulink environment.