Mechanisms of glucocorticoid programmed disease

Substantial epidemiological evidence correlates low weight or thinness at birth with increased risk of disease in later life; notably insulin resistance, hypertension and ischaemic heart disease. This concept of intrauterine life events having permanent influences upon later health has been termed 'programming'. Whilst the molecular mechanisms linking these effects are unknown, overexposure of the foetus to glucocorticoids has been implicated. Treating pregnant rats with dexamethasone (DEX), a synthetic glucocorticoid commonly used in obstetric practice, results in offspring born of low weight, who subsequently develop adulthood hypertension, glucose intolerance and insulin resistance. Whilst prenatal DEX-programmed glucose intolerance is associated with permanently increased hepatic activity of a key gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK), mechanisms underlying the programming of hypertension remain unidentified. DEX-programmed hypertension occurs in both sexes, whilst hyperglycaemia/hyperinsulinaemia has only been demonstrated in male offspring. Principally, this thesis investigates the role of the renin-angiotensin (RAS), and sympathetic nervous systems (SNS) in determining programmed hypertension, and seeks to determine whether programming effects are sexually dimoiphic. ft further examines the impact of dietary manipulations, and environmental noise stress, on prenatally-treated offspring phenotypes.DEX administration in the last week of gestation reduces offspring birth weight and programmes adult cardiovascular and metabolic physiology in a sex specific manner. In male offspring, prenatal glucocorticoid exposure programmes elevated basal circulating corticosterone, elevated PEPCK activity, and produces adulthood post-glucose hyperglycaemia and hyperinsulinaemia. Whilst in female offspring, prenatal DEX programmes elevated hepatic angiotensinogen mRNA expression, elevated plasma angiotensinogen and renin activity, and produces hypertension, when measured by tail-cuff plethysmography.A 4-fold reduction in dietary sodium intensifies this RAS dysregulation in female DEX-treated offspring; however this does not exacerbate their programmed blood pressure phenotype. Conversely, the lower sodium diet results in hypertension in prenatally vehicle treated animals, and supports a role for both the HPA and RAS in mediating this. Furthermore, acute exposure to the lower sodium diet is sufficient to cause glucose intolerance and insulin resistance in female adult rats, irrespective of their prenatal treatment.Unlike previous studies, offspring blood pressure was subsequently assessed with radiotelemetry, which is unmarred by any stress artefact. We now show that prenatal DEX-treated male and female offspring actually display lower basal blood pressure in adulthood; with the commonly expected hypertensive phenotype only being noted when these offspring are subjected to any stressor, regardless of its apparent banality. Moreover, DEX-treated offspring sustain this stress-induced hypertension for longer. These hypertensive responses are mediated by alterations in the responsivity of the sympathetic nervous system, being ameliorated by the inhibition of catecholamine synthesis, and further exaggerated by the promotion of systemic catecholamine release. Additionally, we demonstrate that DEX-treated offspring display greater sensitivity to various vasoconstrictors in the isolated mesenteric vasculature.Finally, perinatal exposure of pregnant rats to environmental noise pollution results in vehicle-treated offspring with a phenotype analogous to prenatal DEXtreated offspring i.e. lower birth weight, hypercorticosteronaemia, hypertension, and features of the insulin resistance syndrome. Conversely, exposure of DEX-treated offspring to the same perinatal noise stressors does not appear to further influence their phenotype. Therefore, perinatal stress produces a similar phenotype to prenatal glucocorticoid over-exposure.These findings demonstrate that in utero over-exposure to glucocorticoids actually results in stress-induced hypertension, and support a role for both RAS and SNS in mediating this. Furthermore, it appears that the programming of cardiovascular physiology may reflect distinct processes in each gender, whilst the programming of metabolic physiology is male specific

Smartphone Adoption amongst Chinese Youth during Leisure-based Tourism: Challenges and Opportunities.

With the spread of Information communications technology (ICT) in China, the tourism industry has come to recognize the importance of examining the factors that influence adoption of smartphones during leisure-based tourism among Chinese youth, a vital segment in what the world’s greatest domestic, inbound, and outbound 10 tourism market will be by 2020. Using data collected from undergraduate students at a university in China, this study, based on the technology acceptance model (TAM) and theory of reasoned action (TRA), found that an extended model can predict travelers' intentions. A detailed profile of Chinese youth and their smartphone usage is provided, and the managerial implications of increased adoption of Internet-capable smart- 15 phones during leisure-based tourism are also explored

Symposium Introduction: Persuasion in Civil Rights Advocacy

In April of 2015, the Michigan State Law Review and the Research, Writing, and Advocacy program of Michigan State University College of Law collaborated to host a symposium devoted to the topic of Persuasion in Civil Rights Advocacy. This intersection of the fields of law, persuasive strategies, and social justice provided a wide-ranging discussion of topics that should be of interest to practicing lawyers as well as to members of the legal academy

The assessment of size in fossil felidae

Estimations of body size in fossil vertebrates depend on establishing the relationships between body mass, overall length or some measure of stature and measurements taken on skeletal elements in living relatives or close proxies. However, most osteological collections lack information on body size for individual specimens, and published investigations usually fa11 back on summary data derived from the literature to plot against measurements taken directly on the skeletal material. The utility of such approaches beyond very general indications of size is open to question. In an effort to reduce these problems we attempt to establish some objective basis for using skeletal elements for the purpose of size estimation in the larger Felidae of the genus Panthera, using data for the jaguar, Panthera onca. We show that cranial length offers a good indication of overall size in the living animal, and that various other cranial dimensions correlate closely with that measurement, while individual teeth, despite their frequent occurrence in assemblages, show a looser relationship and therefore appear less useful for size estimations of fossil material than has been thought.Las estimaciones de la talla corporal en vertebrados fósiles depende de las relaciones establecidas entre el peso corporal, la longitud total o alguna medida de estatura tomada de los elementos esqueléticos de animales actuales emparentados o muy afines. Sin embargo, en muchas colecciones osteológicas falta información sobre la talla corporal de los ejemplares, de forma que las investigaciones publicadas usualmente recurren a datos sintetizados de la literatura que se relacionan con medidas tomadas directamente del material esquelético. La utilidad de estas aproximaciones más allá de indicaciones generales sobre la talla es discutible. En un esfuerzo de minimizar estos problemas intentamos establecer bases objetivas para el uso de los elementos esqueléticos con el propósito de estimar la talla de los grandes Felidae del género Panthera, utilizando los datos obtenidos del jaguar, Panthera onca. Se muestra que la longitud craneal ofrece una buena indicación de la talla total en los animales actuales, y que otras dimensiones craneales se correlacionan estrechamente con esta medida, mientras que los dientes aislados, a pesar de su hallazgo frecuente en las asociaciones fósiles, muestra una menor correlación y por lo tanto es menos útil para la estimación de la talla en formas fósiles de lo que anteriormente se había pensado

Keeping it Agile: The Internationalisation Decision for The Agile Executive

This case focuses on The Agile Executive, a company looking for new market opportunities to expand their business in several possible European markets. This case is also an exercise case for students to practice their knowledge from the perspective of strategic management, branding, marketing & sales, conducting market research and the development of feasible marketing entry strategies, all based on clear use of robust criteria, aligning with the core competences, resources and capabilities of the organisation. This case can be divided into sub-cases that could focus on answering the questions of how to enter or expand in a target European market, which market to enter, how to position and brand the organisation, all based on a clear strategic analysis of the core competences of The Agile Executive