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Coming theses from other universities

  • Inflammatory Signaling Across the Blood-Brain Barrier and the Generation of Fever Author: Anna Eskilsson Link: Publication date: 2020-01-08 14:12

    Fever is a cardinal sign of inflammation and is evolutionary conserved. Fever is known to be beneficial during acute inflammation, but over time and if very high it can be detrimental. The signaling pathways by which fever is initiated by the brain and the peripheral mechanisms through which the temperature increase is generated were studied from several point of views. Fever is known to be dependent on prostaglandin E2 (PGE2) binding to its receptors in the median preoptic nucleus of the hypothalamus, which signals to the brainstem and through sympathetic nerves to heat conserving and heat producing effector organs. This thesis focuses on identifying the cells that produce the PGE2 critical for the fever response; showing where in the brain the critical PGE2 production takes place; demonstrating how peripheral inflammation activates these cells to produce PGE2; and finally, identifying the effector mechanisms behind the temperature elevation in fever. By using a newly developed specific antibody we showed that the enzyme responsible for the terminal step in the production of PGE2, microsomal prostaglandin E-synthase 1 (mPGES-1), is expressed in endothelial cells of brain blood vessels in mice where it is co-expressed with the enzyme cyclooxygenase-2 (Cox-2), which is known to be induced in these cells and to be rate limiting for the PGE2 production. The mPGES-1 enzyme was also expressed in several other cell types and structures which however did not express Cox-2, such as capillary-associated pericytes, astroglial cells, leptomeninges, and the choroid plexus. The role of the mPGES-1 in these other cells/structures remains unknown. Next, by using mice with selective deletion of Cox-2 in brain endothelial cells, we showed that local PGE2 production in deep brain areas, such as the hypothalamus, is critical for the febrile response to peripheral inflammation. In contrast, PGE2 production in other brain areas and the overall PGE2 level in the brain were not critical for the febrile response. Partly restoring the PGE2 synthesizing capacity in the anterior hypothalamus of mice lacking such capacity with a lentiviral vector resulted in a temperature elevation in response to an intraperitoneal injection of bacterial wall lipopolysaccharide (LPS). The data show that the febrile response is dependent on the local release of PGE2 onto its target neurons, possibly by a paracrine mechanism. Deletion of the receptor for the pyrogenic cytokine IL-6 on brain endothelial cells, but not on neurons or peripheral nerves, strongly attenuated the febrile response to LPS and reduced the induction of the Cox-2 expression in the hypothalamus. Furthermore, mice deficient of the IL- 6Rα gene in the brain endothelial cells showed a reduced SOCS3 mRNA induction, whereas IκB mRNA-levels were unaffected, suggesting that the IL-6 signaling occurs via STAT3 activation and not signaling through the transcription factor NF-κB. This idea was confirmed by the observation of attenuated fever in mice deficient of STAT3 in brain endothelial cells. These data show that IL-6, when endogenously released during systemic inflammation, is pyrogenic by binding to IL-6R on brain endothelial cells to induce prostaglandin synthesis in these cells. Finally, we demonstrate that mice with genetic deletion of uncoupling protein-1 (UCP-1), hence lacking functional brown adipose tissue, had a normal fever response to LPS, and that LPS caused no activation of brown adipose tissue in wild type mice. However, blocking peripheral cutaneous vasoconstriction resulted in a blunted fever response to LPS, suggesting that heat conservation, possibly together with shivering or non-shivering thermogenesis in the musculature, is responsible for the generation of immune-induced fever, whereas brown adipose tissue thermogenesis is not involved.  

  • Children living with Home Mechanical Ventilation - a double-edged existence : The everyday life experiences of the children, their siblings, parents and personal care assistants Author: Åsa Israelsson-Skogsberg Link: Publication date: 2020-01-08 08:59

    Aim: The overall aim of this thesis was to explore the everyday life experiences of living with Home Mechanical Ventilation (HMV) from the perspective of the children and their siblings, parents and personal care assistants.

    Methods: Study I describes the experiences of personal care assistants (PCA) working with a ventilator-assisted person at home, based on qualitative content analysis according to Elo and Kyngäs (2008), of 15 semi-structured interviews. Study II, using qualitative content analysis according to Graneheim and Lundman (2004), focuses on exploring everyday life experiences from the perspective of children and young people on HMV, by means of interviews with nine children and young people receiving HMV. Study III, using a phenomenological hermeneutical method, illuminates the everyday life experiences of siblings of children on HMV, based on ten interviews. Study IV explores HRQoL, family functioning and sleep in parents of children on HMV, based on self-reported questionnaires completed by 85 parents.

    Results: PCAs working with a person with HMV experienced a complex work situation entailing a multidimensional responsibility. They badly wanted more education, support, and an organisation of their daily work that functioned properly. Children with HMV had the feeling that they were no longer sick, which included having plans and dreams of a future life chosen by themselves. However, at the same time, there were stories of an extraordinary fragility associated with sensitivity to bacteria, battery charges and power outages. The siblings' stories mirror a duality: being mature, empathetic, and knowledgeable while simultaneously being worried, having concerns, taking a lot of responsibility, being forced to grow up fast, and having limited time and space with one’s parents. Parents of children with HMV reported low HRQoL and family functioning in comparison with earlier research addressing parents of children with long-term conditions. One in four parents reported moderate or severe insomnia.

    Conclusion: Children receiving HMV may feel that they are fit and living an ordinary life, just like their healthy peers. At the same time the results of this thesis indicate that everyday life in the context of HMV is a fragile construct that in some respects resembles walking a tightrope. The fragility of the construct also affects the everyday lives of the families and the PCAs.

  • Physical activity among patients with cardiovascular disease : a predictor of hospital care utilisation and mortality in clinical work Author: Amanda Ek Link: Publication date: 2019-12-20 12:25

    Guidelines highlight the importance of physical activity (PA) in secondary prevention of cardiovascular disease (CVD) within the healthcare sector. Previous studies have mainly focused on the effects of PA at moderate-vigorous intensity performed within exercise-based cardiac rehabilitation (CR). However, only a minority of patients with CVD participate in exercise-based CR, and it is not known to what extent the guidelines for PA are implemented in clinical work. This leads to a knowledge gap in PA levels among patients with CVD, and the potential association of PA with hospital care utilisation and all-cause mortality. The overall aim of this thesis was to investigate PA and its importance for patients with CVD, and to what extent it is promoted during clinical work. The associations between self-rated PA level, changes in self-rated PA level, and sedentary time (SED) with hospital care utilisation and all-cause mortality were explored in three cohort studies (Studies I-III). Data were collected via questionnaires, medical records and national registers. Study I explored everyday PA, physical exercise and SED among patients with CVD (n=1148) prior to admittance to a cardiac ward at two of the hospitals in Stockholm. Studies II and III explored PA (of at least moderate intensity) post hospitalisation, and included 30 644 and 22 227 patients with myocardial infarction (MI), respectively, from the national SWEDHEART registry. Finally, in Study IV, healthcare professionals’ (n=251) stated importance and clinical work to promote healthy lifestyle habits (alcohol consumption, eating habits, physical activity, and smoking) were explored in a cross-sectional study. All healthcare professionals working on cardiac departments in two hospitals in Stockholm were included.

    The main findings were:

    • PA level (everyday PA, physical exercise, total PA level) and SED pre and post hospitalisation for cardiac events were found to be significant predictors of hospital care duration, readmission and mortality. The effects of high PA level and low SED did not differ between CVD diagnosis, sex, age, or comorbid states such as individuals with and without diabetes mellitus type II, kidney dysfunction, hypertension or dyslipidaemia.

    • There were no differences between individuals reporting a moderate or high level of PA or a medium or low level of SED, illustrating that “a little activity is better than nothing” and that the greatest health benefits would be achieved by increasing PA among the most inactive patients with CVD.

    • Changes in PA level during the first year post MI are important. Increased PA lowered the risk of mortality, and decreased PA increased the risk of mortality in patients post MI.

    • Healthcare professionals considered it important to promote lifestyle habits among patients within the healthcare sector in general, as well as in their own clinical work. However, there was a difference between stated importance and clinical practice as only a minority of healthcare professionals asked or provided counselling on healthy lifestyle habits. Our results indicated a relationship between promoting patients’ lifestyle habits in clinical work, and if they perceived clear organisational routines and objectives.

    In conclusion, the results of this thesis have a clinical impact. Firstly, asking patients on a cardiac department about their PA level and SED may identify individuals in need of behavioural changes. By identifying and supporting individuals who need to increase their PA level, clinicians may potentially decrease the utilisation of inpatient care and also lower the risk of all-cause mortality among individuals with a CVD diagnosis. Secondly, this information is of great predictive value, and PA can be seen as an additional marker of disease severity.