Cortisol, the principal glucocorticoid secreted from the adrenal glands, is essential for life. Healthy cortisol levels are maintained through negative feedback on the central nervous system (CNS) – pituitary stimulatory apparatus which regulates production of adrenocorticotropin (ACTH) and contains a light–entrained intrinsic CNS driven diurnal rhythm. Cortisol participates in a regulatory mechanism where inflammatory cytokines stimulate cortisol release and cortisol in turn suppresses cytokine release. The effects of cortisol in inflammatory states include elevating blood pressure and metabolic regulation. This thesis contains three exploratory studies examining circulating cortisolaemia using the best available methodologies (total and free cortisol and corticosteroid-binding globulin (CBG)) in clinical states characterized by immune activation/ inflammation and altered blood pressure. These clinical states include: (1) septic shock, (2) hypertensive disorders of pregnancy and (3) obesity-induced hypertension. Prior to the studies described here, little was know about cortisolaemia in these common pathological states. Septic shock is a life threatening condition that complicates severe infection and is characterized by systemic inflammation and refractory hypotension. High plasma total cortisol levels and attenuated responses to synthetic ACTH stimulation are associated with increased mortality. The use of corticosteroids in septic shock has been highly controversial for decades, however recent trials have reported haemodynamic and survival benefits associated with the use of physiologic steroid replacement in patients with relative adrenal insufficiency (RAI) – currently defined as a total cortisol increment of 248 nmol/L or less following ACTH (250 μg) stimulation. However, CBG and albumin levels fall by around 50% with an increase in plasma free cortisol in critical illness. Hence, total cortisol may not reflect the biologically active free (unbound) cortisol, suggesting that standard assays for plasma cortisol (which measure total plasma cortisol) underestimate HPA axis activity. In this study, we have showed that plasma free cortisol is a better guide to circulating glucocorticoid activity in systemic infection than total cortisol. We have also validated the use of Coolens’ method in estimating free cortisol in systemic infection, using plasma total cortisol and CBG measurements as plasma free cortisol is not performed in clinical laboratories. Free cortisol measurement allows better categorization of RAI and non-RAI groups with a free cortisol increment of 110 nmol/L as cut-off. Moreover, we have shown that survivors of RAI have normal adrenocortical function on follow-up testing suggesting a lack of functional adrenal reserve rather than adrenal damage during critical illness. Larger randomized controlled trials will be required to redefine RAI using free cortisol measurements and relate that to clinical outcomes and responses to corticosteroid therapy. Nitric oxide (NO) is normally produced in the endothelium by the constitutive form of the NO synthase and this physiologic production is important for blood pressure regulation and blood flow distribution. Studies have shown that an overproduction of NO by the inducible form of NO synthase (iNOS) may contribute to the hypotension, cardiodepression and vascular hyporeactivity in septic shock. Clinical studies of non-selective inhibitors of the L-arginine nitric oxide pathway showed increased mortality from cardiovascular complications. However, glucocorticoids, which improve vasopressor sensitivity, may act by partially suppressing NO synthesis through selective direct inhibition of iNOS, and suppression of inflammatory cytokine synthesis. Hence, plasma nitrate/ nitrite (NOx) levels may provide a titratable end point to individualize glucocorticoid therapy in sepsis. The NOx study in this thesis showed that cortisol (total and free), CBG and NOx correlated to illness severity. Free cortisol, and to a lesser extent total cortisol, but not NOx levels, predicted septic shock. NOx levels were characteristically stable within individuals but inter-individual differences were only partly accounted for by illness severity or renal dysfunction. NOx levels correlated weakly with cortisol, did not relate to the need for vasopressors and were not suppressed by hydrocortisone treatment. Thus, NOx is not a suitable target for glucocorticoid therapy in septic shock. Pregnancy is the only sustained physiologic state of hypercortisolism in humans. A large body of data suggests that excessive foetal and prenatal glucocorticoid exposure leads to reduced birth weight and adverse health in offspring such as elevated blood pressure and insulin resistance. Pre-eclampsia and gamete donor pregnancies are associated with immune activation, elevated inflammatory cytokines as well as elevated blood pressure. Prior to the study described in this thesis however, there was no prospective data on maternal cortisolaemia in these complicated pregnancies. My study has demonstrated for the first time that there was a substantial fall in plasma CBG levels in the last few weeks of gestation with a corresponding rise in free cortisol in normal pregnancy, a finding obscured for methodological reasons in past studies. This free cortisol elevation in late pregnancy may facilitate organ maturation in the foetus and perhaps prepare the mother for the metabolic demands of labour. In pre-eclampsia and gestational hypertension, plasma CBG, total and free cortisol levels were lower in late third trimester; and in IUGR, plasma CBG levels were suppressed from 28 weeks gestation until delivery but with no significant difference in plasma total and free cortisol. Women with assisted reproduction using donor gametes/ embryos had significantly lower plasma CBG, total and free cortisol levels even in those with normal pregnancy outcomes. Low CBG may be due to reduced synthesis or enhanced inflammation-driven degradation. Low maternal cortisol may be due to a lack of placental corticotropin-releasing hormone, or reduced maternal ACTH, driving cortisol production. This unanticipated maternal hypocortisolism in complicated pregnancies may trigger precocious activation of the foetal HPA axis and could have implications for postnatal and adult health. Speculatively, since excess prenatal GCs increase HPA axis activity, we proposed that maternal hypocortisolism may predispose to the hypocortisolaemic state characterized by fatigue, pain and stress sensitivity, in offspring. The third state of immune/ inflammatory activation associated with blood pressure dysregulation studied in this thesis is obesity. The epidemiologic relationship between obesity and hypertension is widely recognised. Central obesity in particular has been associated with exaggerated HPA responses to stimuli. Studies of severe dieting and starvation resulted in hypercortisolism and a significant decrease in CBG. The HPA axis and the renin-angiotensin-aldosterone system (RAAS) have been implicated in the pathophysiology of obesity-induced hypertension. However, there is little data on the effect of moderate weight loss (30% caloric restriction) on adrenocortical function, and the relation of adrenal hormones to altered blood pressure with weight loss. In this study, measures of HPA axis and RAAS and blood pressure monitoring were performed in twenty-five obese subjects before and after a 12-week diet program (6000kJ/day). Short-term, moderate weight loss (mean 8.5 kg) was associated with a small reduction in blood pressure (mean arterial pressure 6 mmHg) and significantly reduced levels of aldosterone and renin but not cortisol levels. These findings suggest that aldosterone may have an important role in the blood pressure reduction with weight loss via a renin mediated mechanism, perhaps involving renal sympathetic tone. In contrast to severe caloric restriction, HPA axis activation does not occur with moderate weight loss. This suggests a threshold effect of weight loss on the HPA axis where greater caloric restriction is required for HPA stimulation, or a counterbalancing of central and direct adrenal effects on HPA axis function. Overall, these three exploratory studies have provided novel data on HPA axis function in systemic infection, pregnancy and in diet-induced weight loss. Each study offers a basis for further studies of HPA axis function in these disorders. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1289330 / Thesis(Ph.D.)-- School of Medicine, 2007.

Made available in DSpace on 2015-07-22T20:49:47Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-07-29. Added 1 bitstream(s) on 2015-08-11T03:26:28Z : No. of bitstreams: 1 Publico-345.pdf: 1277830 bytes, checksum: 6d2949e2d33e045cfec88a295d473e41 (MD5) / Associação Fundo de Incentivo à Psicofarmacologia (AFIP) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Alguns estudos pré-clínicos têm demostrado que eventos adversos na infância e adolescência representam um fator de vulnerabilidade para o surgimento de transtornos psiquiátricos na idade adulta, e que a redução da resiliência à eventos estressantes deve desempenhar um papel importante neste fenômeno. As manipulações em animais de laboratório, como a privação materna (PM) por 24 h durante o período de hiporresposividade ao estresse (PHRE), podem ser um instrumento útil para a compreensão de como os eventos no período precoce do desenvolvimento resultam em alterações comportamentais e da atividade do eixo Hipotálamo-Pituitária-Adrenal (HPA) na idade adulta. Alguns autores têm observado que a PM, quando imposta no 3° dia de vida (antes do início) ou no 11° dia (no vale) do PHRE, resulta em padrões de atividade do eixo HPA distintos. A PM no 3° dia induz à hiperatividade do eixo, enquanto que no 11° dia, resulta na hipoatividade, alterações estas observadas em animais jovens. Assim, os principais objetivos do presente trabalho foram os de estudar como a PM afetaria a atividade do eixo HPA durante o PHRE, e verificar se essas alterações teriam conseqüências duradouras. Os resultados mostraram que os efeitos da PM na liberação de ACTH mantiveram o mesmo padrão de atividade relatado na adolescência, ou seja, hiperresponsividade no grupo submetido à PM no 3o dia de vida e hiporresponsividade no grupo submetido à mesma manipulação no 11o dia de vida. No entanto, essa alteração não se refletiu na liberação da corticosterona (CORT), pois não se observou diferença na secreção deste hormônio entre os grupos. Além disso, a PM não alterou a liberação de CORT em resposta ao Teste de supressão à Dexametasona, indicando que não houve alterações no sistema de retroalimentação negativa no nível hipofisário do eixo HPA. A PM afetou o comportamento do tipo ansioso nos animais de ambos os grupos PM, sendo que tal alteração parece não ter sido mediada por mudanças na densidade do sítio benzodiazepínico do receptor GABAA. Os resultados indicaram que, embora a PM não leve a alterações permanentes na secreção da corticosterona, este pode ser um modelo animal interessante para se estudar o substrato neurobiológico que faz com que um evento adverso durante o desenvolvimento aumente a vulnerabilidade aos transtornos relacionados à ansiedade. / Adverse events in childhood have been associated to the development of psychopathologies, such as depression and anxiety disorders. In rats, stressful events during neonatal period, like 24h Maternal Deprivation (MD), may be an interesting tool to understand how stress during early life leads to changes in behavior and stress response in adulthood. According to some studies, MD on the 3rd day (MD 3-4) or 11th day (MD 11- 12) of life results in opposite changes in the activity of the Hypothalamus-Pituitary- Adrenal (HPA) axis, i.e., hyper and hyporresponsiveness, respectively. Since in human beings psychopathologies has been related to impairment in resilience to stress the aim of this work was to investigate whether MD leads to long lasting changes in HPA axis functioning and differential behavioral features in animal models of anxiety. The results obtained indicate that only the ACTH release presented the pattern we hypothesized. Conversely the corticosterone (CORT) plasmatic levels do not reflect this pattern. Moreover, MD did not affect the CORT release in response to the Dexamethasone Suppression Test, indicating that there are MD did not alter the negative feedback system. Although MD did not lead to convincing alteration to CORT levels it did change anxiety-like behavior in the group MD 11-12. However this behavioral change did not seem to be mediated by expression of benzodiazepine site in GABAA receptors. The results indicate that even though the MD procedure does not lead to consistent changes in the peripheral component of the HPA axis it could still be an interesting animal model to study the neurobiological underpinnings of how adverse events in early life increase the vulnerability to psychopathologies. / FAPESP: 2006/06415-4 / TEDE / BV UNIFESP: Teses e dissertações

A avaliação do ventrículo esquerdo (VE) é uma das principais contribuições da ecocardiografia no estudo da função cardíaca e inclui a mensuração dos diâmetros da cavidade e espessura das paredes em diástole e sístole. O estudo por meio do modo M tem sido usado como padrão para a realização da mensuração e para o cálculo de índices sistólicos, mas o modo bidimensional também é utilizado para este fim. As medidas podem ser adquiridas a partir de dois planos de imagem: transversal e longitudinal. A definição de intervalos de confiança para valores normais de VE permite a identificação de remodelamento ventricular, concêntrico ou excêntrico, decorrente de doenças cardiovasculares ou sistêmicas. Assim sendo, o objetivo deste estudo foi comparar as medidas ecocardiográficas desta câmara obtidas pelos seguintes métodos: modo M em corte transversal, modo M em corte longitudinal, modo bidimensional em corte transversal e modo bidimensional em corte longitudinal. Adicionalmente, estudou-se o comportamento do efeito do peso e do sexo nos métodos mencionados. Foram selecionados 40 cães adultos da raça Pastor Alemão sem alterações cardiovasculares. A realização do ecocardiograma de cada animal inclui os quatro métodos descritos acima, de acordo com o recomendado pela literatura. Foram pesquisados os efeitos do corte e do método, bem como a influência do peso e do sexo, sobre cada medida estudada, linear ou derivada. O peso apresentou correlação com todas as medidas lineares de VE em pelo menos um dos métodos, mas não com fração de encurtamento (FE) e fração de ejeção (FEj). Utilizando-se a análise univariada, verificou-se que machos apresentaram todas as medidas estudadas significativamente maiores que fêmeas em pelo menos um dos métodos, exceto FE e FEj, cujos valores não foram diferentes entre os sexos. Observou-se efeito isolado do corte apenas sobre diâmetro diastólico final do ventrículo esquerdo (DdFVE), com medidas maiores obtidas no corte transversal, e mudança de comportamento do sexo nos cortes com influência significativa do peso sobre septo interventricular em diástole (SIVd). Houve efeito isolado do modo sobre os índices de função sistólica FE e FEj, com valores maiores fornecidos pelo modo M. O peso teve efeito isolado positivo sobre parede livre de ventrículo esquerdo em diástole (PLVEd), exceto no modo M em corte transversal e (diâmetro sistólico final de ventrículo esquerdo (DsFVE). O sexo, retirada a influência do peso, teve efeito isolado apenas sobre DdFVE, com machos apresentando valores significativamente maiores que fêmeas em ambos os cortes no modo bidimensional. Os resultados Os resultados mostram que há risco de erro de interpretação quando valores normais de referência, gerados a partir de determinado método, são utilizados para a avaliação de um paciente examinado por técnica de mensuração diversa, especialmente quando se obtém resultados nos limites superior ou inferior de normalidade. / Left ventricle (LV) evaluation is one of the most important contributions of echocardiography in the assessment of cardiac function. It includes measurements of internal diameter and wall thickness at end-diastole and end-sistole of this chamber. M Mode echocardiography has been widely used for measuring linear dimensions and quantifying systolic function, but bidimensional mode is also used with the same purpose. The LV measurement can be derived from transverse or longitudinal images of the heart. The establishment of normal confidence intervals of LV dimensions allows identification of concentric or excentric ventricular remodeling process secondary to cardiovascular and systemic diseases. The aim of this study was to compare LV measurements obtained from four methods: M mode in short-axis, M mode in long-axis, bidimensional mode in short-axis and bidimensional mode in long-axis view of the heart. In addition the effect of weight and gender over measures was studied in the methods mentioned above. Forty adult German Shepherds without cardiovascular diseases were selected. The echocardiogram of each animal included the four described methods, according previous referenced recommendations. The effects of axis and mode as well as weight and gender were studied for each linear or derived LV measure. Weight correlated with all linear LV measures at least in one method, but not with ejection fraction (EF) and shortening fraction (SF). All LV measures of males were greater than those of females at least in one method, except for EF and SF, which did not differ between sexes. Isolated effect of the axis was observed only for LV end diastolic diameter (LVEDD), with greater values obtained from short-axis views. The combined effect of axis, gender and weight was identified in interventricular septal end diastolic thickness. There was isolated effect of mode over EF and SF, with greater measures derived from bidimensional mode methods. Weight had isolated significant positive effect over LV enddiastole posterior wall thickness in all methods, except from M mode performed in short axis, and LV end-sistolic diameter. Gender had isolated effect only over LVEDD, males showing greater values than females in bidimensional mode in short and long axis. Professionals should be aware of the possibility of erroneous interpretation when using data obtained by a different method of that used in the patient exam as reference, mainly for the values situated in inferior and superior limits of confidence intervals.

Small wind turbines that operate in low-wind environments are prone to suffer performance degradation as they often fail to accelerate to a steady, power-producing condition. The behaviour during this process is called “starting behaviour” and it is the subject of this present work. This thesis evaluates potential benefits that can be obtained from the improvement of starting behaviour, investigates, in particular, small wind turbine starting behaviour (both horizontal- and vertical-axis), and presents aerofoil performance characteristics (both steady and unsteady) needed for the analysis. All of the investigations were conducted using a new set of aerodynamic performance data of six aerofoils (NACA0012, SG6043, SD7062, DU06-W-200, S1223, and S1223B). All of the data were obtained at flow conditions that small wind turbine blades have to operate with during the startup - low Reynolds number (from 65000 to 150000), high angle of attack (through 360◦), and high reduced frequency (from 0.05 to 0.20). In order to obtain accurate aerodynamic data at high incidences, a series of CFD simulations were undertaken to illustrate effects of wall proximity and to determine test section sizes that offer minimum proximity effects. A study was carried out on the entire horizontal-axis wind turbine generation system to understand its starting characteristics and to estimate potential benefits of improved starting. Comparisons of three different blade configurations reveal that the use of mixed-aerofoil blades leads to a significant increase in starting capability. The improved starting capability effectively reduces the time that the turbine takes to reach its power-extraction period and, hence, an increase in overall energy yield. The increase can be as high as 40%. Investigations into H-Darriues turbine self-starting capability were made through the analogy between the aerofoil in Darrieus motion and flapping-wing flow mechanisms. The investigations reveal that the unsteadiness associated with the rotor is key to predicting its starting behaviour and the accurate prediction can be made when this transient aerofoil behaviour is correctly modelled. The investigations based upon the analogy also indicate that the unsteadiness can be exploited to promote the turbine ability to self-start. Aerodynamically, this exploitation is related to the rotor geometry itself.

This master's thesis deals with design of equatorial fork mount for astronomical telescope. The issue of space object watching equipment is deeply analysed. The enclosures of analysis are used in design project. Important aspects are accuracy of motion and high resolution of mount. These parameters are compared with series manufactured equatorial mounts.

The dissertation work focuses on the design and optimization of the castings and foundry technology and the production a particular model for the casting. The technology proposal and the pattern set building in 3D using CAD system. The casting simulation in CAE MAGMAsoft® system and evaluation of the proposed casting technology. Production of the pattern using CAD/CAM software and CNC machine tools with a focus on 3-axis and 5-axis machining. The economic benefits for the company.

Single photon emission tomography (SPECT) data from myocardial perfusion imaging (MPI) are normally displayed as a set of three slices orthogonal to the left ventricular (LV) long axis for both ECG-gated (GSPECT) and non-gated SPECT studies. The total number of slices presented for assessment depends on the size of the heart, but is typically in excess of 30.  A requirement for data presentation is that images should be orientated about the LV axis; therefore, a set of radial slice would fulfill this need. Radial slices are parallel to the LV long axis and arranged diametrically. They could provide a suitable alternative to standard orthogonal slices, with the advantage of requiring far fewer slices to adequately represent the data. In this study a semi-automatic method was developed for displaying MPI SPECT data as a set of radial slices orientated about the LV axis, with the aim of reducing the number of slices viewed, without loss of information and independent on the size of the heart. Input volume data consisted of standard short axis slices orientated perpendicular to the LV axis chosen at the time of reconstruction.  The true LV axis was determined by first determining the boundary on a central long axis slice, the axis being in the direction of the y-axis in the matrix. The skeleton of the myocardium were found and the true LV axis determined for that slice. The angle of this axis with respect to the y-axis was calculated. The process was repeated for an orthogonal long axis slice. The input volume was then rotated by the angles calculated. Radial slices generated for presentation were integrated over a sector equivalent to the imaging resolution (1.2 cm); assuming the diameter of the heart is about 8cm then non-gated data could be represented by 20 radial slices integrated over an 18 degree section. Gated information could be represented with four slices spaced at 45 intervals, integrated over a 30 degree sector.

Posttraumatic stress disorder (PTSD) is a trauma-related disorder that may develop in response to traumatic or stressful events. Dysfunction of the Hypothalamic-Pituitary-Adrenal (HPA) axis has been implicated in the disorder. Studies support such dysfunction as being a consequence of PTSD, rather than a precursor. However, most studies of the HPA are either cross-sectional or have been carried out in adults. The aim of the present study was to identify whether HPA dysregulation interacts with stressful experiences to increase the likelihood of developing PTSD symptoms in a community-recruited sample of healthy adolescent girls. Adolescent girls (N = 550) and one of their parents participated. Adolescents’ clinical symptoms were assessed at baseline and at a nine month follow-up. Saliva samples were collected from all adolescent participants at waking, 30 minutes after waking, and 8 pm on 3 consecutive days. Flattened diurnal slope of cortisol at baseline was associated with increased PTSD symptoms nine months later. Baseline cortisol awakening response (CAR) per se was not prospectively related to developing PTSD symptoms, but its interactions with stressful experience was associated with elevated PTSD symptoms at follow-up. Effects were small and need to be replicated in samples with more severe stressors, as well as more clinical levels of PTSD. Nevertheless, findings suggest that dysregulated basal HPA functioning may be involved in the development of PTSD symptoms.

Recent research shows, that gut microbiome can influence various functions of the organism and is able to communicate with the brain. The data also show that changes in the composition of gut microbiome can influence behavior and stress reactions and vice versa, psychological state of the organism can cause changes in gut microbiome. The aim of this master's thesis was to examine changes of HPA activation and local metabolism of glucocorticoids caused by stress in the presence or absence of gut microbiome. We therefore used germ-free mice and studied the effect of stress in pituitary, adrenal gland, colon and spleen. We found that, stress has different impact on gene expression in adrenal gland, colon and spleen in the presence or absence of gut microbiome. In contrast, there wasn't any significant effect of stress on pituitary in germ free mice and their conventionaly colonized counterparts.

The aim of this thesis is the design of the rotary tilting table controlled the fourth and fifth axis for CNC centrum.První part includes the search for pivotally tilting tables. The second part includes the choice of technical paremetrů pivotally tilting table for selected CNC center, design of possible options , selection of appropriate options, design of the selected option.