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- Alimohammadi, Mohammad, 1978-
(författare)
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Molecular Targets in Autoimmune Polyendocrine Syndrome Type1 and Their Clinical Implications
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Autoimmune diseases occur when the immune system attacks and destroys healthy body tissue. Autoimmunity is known to cause a wide range of disorders, and is suspected to be responsible for many more. Most autoimmune disorders are chronic and cause severe morbidity for the patients, and are also costly for society. A majority of these disorders are today considered as complex diseases with incompletely known etiology. Hence, model systems for studying the pathogenesis of autoimmunity are important to unravel its causes. Autoimmune Polyendocrine Syndrome Type 1 (APS-1), (OMIM 240300), is a rare autoimmune disorder. Patients with APS-1 progressively develop multiple organ-specific autoimmune lesions involving both endocrine and non endocrine tissues. Typical autoimmune disease components in APS-1 are hypoparathyroidism, Addison’s disease, vitiligo, alopecia and type 1 diabetes. The gene preventing APS-1 has been identified and designated Autoimmune Regulator (AIRE). It has been shown that mutations of AIRE cause loss of tolerance to self-structures, resulting in organ-specific autoimmunity. Although APS-1 is a rare syndrome occurring mainly in genetically isolated populations, the disease components of APS-1 are, in isolated forms, not unusual in the general population and affect many patients. Hence, APS-1 is an attractive model disease for studies of molecular mechanisms underlying organ-specific autoimmunity. This thesis concerns investigations in which two novel autoantigens are identified in APS-1 and used in serological diagnosis of the disease. NALP5, is identified as a parathyroid autoantigen - an important finding since autoimmune hypoparathyroidism is one of the cardinal symptoms of APS-1. Additionally, KCNRG is identified as a bronchial autoantigen in APS-1 patients with respiratory symptoms. Finally, studies that compare the immune response in APS-1 patients and the mouse model for APS-1 are presented.
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- Alvehus, Malin, 1975-
(författare)
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Obesity-associated inflammation in adipose tissue
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Excess body fat, particularly in the visceral depot, is linked to increased mortality and morbidity, including the development of diseases such as type 2 diabetes, cardiovascular disease, and cancer. Chronic low-grade inflammation in adipose tissue may be a key mediator of obesity-associated diseases. Importantly, specific pro-inflammatory cytokines have been shown to influence adipose tissue function and could therefore be a link to metabolic disorders. Circulating cytokine levels may also be increased in obesity and metabolic diseases. However, although fat distribution and inflammation are clearly linked to metabolic disorders, inflammatory gene expression in the different abdominal adipose depots has not been investigated in detail. The menopausal transition is followed by a centralization of body fat and increased adiposity. Notably, inflammatory changes in fat during the menopausal transition have not been characterized. Finally, there is a lack of studies investigating the long-term effects of weight loss on low-grade inflammation. The aim of this thesis was to characterize differences between fat depots and investigate putative changes in low-grade inflammation in adipose tissue and circulation following menopause or weight loss. Materials & Methods: The expression of inflammation-related genes was investigated in abdominal adipose tissue depots obtained from women with varying adiposity, before and after menopause or weight loss induced by surgery or dietary intervention. Circulating cytokine levels were analyzed using immunoassays. Results: Visceral fat displayed a distinct and adverse inflammatory profile compared with subcutaneous adipose tissues, and the higher gene expression in visceral fat was associated with adiposity. Postmenopausal women exhibited a higher expression of pro-inflammatory genes than premenopausal women that associated with central fat accumulation. There was also a menopause-related increase in circulating cytokine levels in postmenopausal women. After surgery-induced weight loss, there was a dramatic reduction in inflammatory gene expression followed by increased insulin sensitivity. We observed no alterations in circulating cytokine levels. Long-term dietary intervention, associated with weight loss, had favorable effects on inflammation in both adipose tissue and serum. Conclusion: Fat accumulation is linked to low-grade inflammation in abdominal adipose tissue. The unique inflammatory pattern of visceral fat suggests a distinct role in adipose tissue inflammation that is aggravated with increasing adiposity. In postmenopausal women, the adverse adipose inflammatory profile was associated with central fat accumulation, while higher circulating cytokine levels correlated with menopausal state/age. Our data from severely obese women undergoing surgery-induced weight loss clearly supports a link between adipose inflammation and insulin resistance. The long-term beneficial effects of weight loss were also demonstrated by the improved inflammatory profile after dietary intervention. In summary, excess body fat is clearly linked to adipose tissue inflammation. Long-term weight loss is accompanied by improved metabolic profile and reduced low-grade inflammation in fat.
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- Andersson, Jonas, 1969-
(författare)
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Adipose tissue as an active organ : blood flow regulation and tissue-specific glucocorticoid metabolism
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Despite advances in the treatment of atherosclerosis, cardiovascular disease is the leading cause of death worldwide. With the population getting older and more obese, the burden of cardiovascular disease may further increase. Premenopausal women are relatively protected against cardiovascular disease compared to men, but the reasons for this sex difference are partly unknown. Redistribution of body fat from peripheral to central depots may be a contributing factor. Central fat is associated with hyperlipidemia, hyperglycemia, hypertension, and insulin resistance. Two possible mediators of these metabolic disturbances are tissue-specific production of the stress hormone cortisol and adipose tissue blood flow (ATBF). The aim of this thesis was to determine the adipose tissue production of cortisol by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and to investigate the regulation of ATBF. Materials and Methods: Cortisol release was estimated by labeled cortisol infusions and tissue-specific catheterizations of subcutaneous and visceral adipose tissue (VAT) in men. We investigated ATBF by 133Xe-washout and its relation to autonomic activity, endothelial function, adipose tissue distribution, and adipokines in different groups of women. We further investigated the effect of two diets and of weight loss on ATBF in women. Results: We demonstrated significant cortisol release from subcutaneous adipose tissue in humans. Splanchnic cortisol release was accounted for entirely by the liver. Cortisol release from VAT (to the portal vein) was not detected. ATBF decreased according to increasing weight and postmenopausal status, and the level of blood flow was associated with nitric oxide (NO) activity and autonomic activity. ATBF was also highly associated with leptin levels and both subcutaneous adipose tissue and VAT areas. After 6 months of diet and weight reduction, a significant difference in ATBF was observed between diet groups. Conclusions: Our data for the first time demonstrate the contributions of cortisol generated from subcutaneous adipose tissue, visceral tissues, and liver by 11β-HSD1. ATBF is linked to autonomic activity, NO activity, and the amount of adipose tissue (independent of fat depot). Postmenopausal overweight women exhibited a loss of ATBF flexibility, which may contribute to the metabolic dysfunction seen in this group. Weight loss in a diet program could not increase the ATBF, although there were ATBF differences between diet groups. The results will increase understanding of adipose tissue biology and contribute to the development of treatment strategies targeting obesity and obesity-related disorders.
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- Andersson, Therése, 1978-
(författare)
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Estrogen and Glucocorticoid Metabolism
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Cardiovascular disease (CVD) is the leading cause of death among women in Sweden. The risk of CVD increases rapidly after the menopause. A major contributing factor may be the redistribution of adipose tissue, from the peripheral to central depots, associated with menopause. This change in body composition is commonly attributed to declining estrogen levels but may also be affected by tissue-specific alterations in exposure to other steroid hormones, notably glucocorticoids – mainly cortisol in humans. Indeed, adipose tissue-specific overexpression of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) induces central obesity, insulin resistance and hypertension in mice. Interestingly, estrogen may regulate this enzyme. The aim of this thesis was to investigate putative links between estrogen and glucocorticoid activation by 11βHSD1. Materials and Methods: 11βHSD1 expression and/or activity in adipose tissue and liver, and adipose estrogen receptor α and β (ERα and ERβ) gene expression, were investigated in lean pre- and postmenopausal women and ovariectomized rodents with and without estrogen supplementation. In lean women measures of 11βHSD1 were correlated to risk markers for CVD. The association between adipose 11βHSD1 and ER mRNA expression was investigated in both lean women and rats and in an additional cohort of obese premenopausal women. In vitro experiments with adipocyte cell lines were used to explore possible pathways for estrogen regulation of 11βHSD1. Results: Subcutaneous adipose tissue transcript levels and hepatic activity of 11βHSD1 were higher in postmenopausal vs. premenopausal women. In rodents, estrogen treatment to ovariectomized rats decreased visceral adipose tissue 11βHSD1, resulting in a shift towards higher subcutaneous (vs. visceral) 11βHSD1 mRNA expression/activity. Increased adipose and hepatic 11βHSD1 were associated with increased blood pressure and a disadvantageous blood lipid profile in humans. We found significant positive associations between 11βHSD1 and ERβ transcript levels in adipose tissue. The in vitro experiments showed upregulation of 11βHSD1 mRNA expression and activity with estrogen or ERβ-agonist treatment at low (corresponding to physiological) concentrations. Conclusions: Our studies show for the first time increased local tissue glucocorticoid activation with menopause/age in women. This may contribute to an increased risk of CVD. Estrogen treatment in rodents induces a shift in 11βHSD1 activity towards the subcutaneous adipose tissue depots, which may direct fat accumulation to this metabolically “safer” depot. The in vitro studies suggest that low-dose estrogen treatment upregulates 11βHSD1 via ERβ. In summary, estrogen - glucocorticoid metabolism interactions may be key in the development of menopause-related metabolic dysfunction and in part mediate the beneficial effects of postmenopausal estrogen treatment on body fat distribution.
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Att lära en företagsekonom att tänka
- 2014. - 1
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Samlingsverk (redaktörskap) (övrigt vetenskapligt/konstnärligt)abstract
- Här beskriver åtta högskolelärare i företagsekonomi egenupplevda undervisningssituationer utifrån vilka de, med hjälp av pedagogiska och filosofiska teorier, undersöker och reflekterar över sin praktiska kunskap.Vad kan dessa lärares redogörelser och reflektioner säga oss om universitetslärarens arbetssituation? Hur gör de för att lösa de problematiska situationer som uppstår? Hur kommer det sig att de lyckas få studenter med vitt skilda förväntningar, varierande bakgrunder och förutsättningar och med olika grader av motivation, att lära sig nya sätt att tänka och att med tiden utvecklas till självständiga yrkesutövare?
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