Coming theses from other universities
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Microvascular Function Assessment after Mastectomy and Radiation Therapy in Breast Cancer Patients : From Methodology to Clinical Application
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-203080
Post-mastectomy radiotherapy (PMRT) is an important part of the treatment of breast cancer. It reduces the risk of recurrence and improves overall survival. Scaring and fibrotization of the skin and subcutaneous tissue of the chest wall or remaining breast are among its side-effects. These late side-effects of PMRT may in turn affect skin microcirculation and oxygenation, although this connection is not completely established. In patients that later require breast reconstruction, it is difficult as a plastic surgeon to evaluate if the microcirculatory changes have been affected by PMRT, and how such effects should have an impact on the choice of reconstructive method. In the work presented in this thesis, laser speckle contrast imaging (LSCI), laser-doppler flowmetry (LDF) and diffuse reflectance spectroscopy (DRS) have been used with a strong vasodilator, methyl nicotinate (MN) to study the microcirculatory changes after PMRT.
In studies I and II, we aimed to find the optimal concentration of MN and its main mechanisms of action. In healthy volunteers, the microvascular response to different concentrations of MN was evaluated on the forearm using LSCI. It was found that a concentration of 20 mmol/l resulted in a quick vasodilatory response with a long plateau phase, minimal tissue edema and no non-responders. In study II, we utilized locally administered drugs to block the three main pathways responsible for skin vasodilation. Subsequently, we provoked the skin with MN and assessed its effect with LSCI. From this study we could conclude that MN’s mechanism of action is largely mediated by prostaglandins and partly by local sensory nerves.
In study III, we examined the skin microcirculatory response in breast cancer patients before, immediately after, and at two and six months following unilateral PMRT, using the contralateral breast as a control. A significant increase in basal skin perfusion and perfusion after application of MN was observed on the irradiated chest wall immediately after RT compared to the contralateral breast and compared to before RT. At six months after RT, there was no longer a difference in basal skin perfusion or after application of MN in the irradiated chest wall compared to the contralateral breast and compared to before RT was given. The results from this study concluded that skin perfusion in the irradiated chest wall had returned to normal when measured six months after RT.
In study IV, the late effects on skin microvascular function were studied in women who had undergone mastectomy and PMRT several years prior to the study. Skin perfusion and oxygen saturation was measured with white light diffuse reflectance spectroscopy (DRS) combined with Laser Doppler Flowmetry (LDF) before and after application of MN on the irradiated chest wall with the contralateral non-irradiated breast as control. In this study we found that skin perfusion and oxygenation in the breast are affected several years after radiotherapy and that our method could be a valuable clinical tool prior to deciding surgical procedures after PMRT.
To conclude, MN can be topically applied to the skin to reliably assess microvascular function and the microvascular capacity. LSCI and LDF have different strengths and drawbacks, with LSCI having the advantage of having a large spatial resolution that allows for measurements of control areas in the same field of view as the provoked areas. LDF in combination with DRS enabled us to further assess perfusion and oxygenation simultaneously which could be an advantage in fibrotic skin where skin perfusion and oxygen saturation may not correlate with each other. Although the study groups differed between the study examining the early effects of PMRT with the late effects of PMRT, we have been able to non-invasively visualize changes in microcirculation in relation to the acute and chronic phase after PMRT. Future studies are needed to investigate the value of pre-operative measurements with MN provocation for predicting surgical outcome.
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Asthma epidemiology : prognosis of asthma with onset in childhood and in adulthood
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-223661
Aim: to update the knowledge on the epidemiology of asthma with onset in childhood and adulthood as well as examine the importance of risk factors in early childhood and clinical characteristics on the incidence and prognosis of asthma.
Methods: The thesis is based on the epidemiological research program Obstructive Lung Disease in Northern Sweden (OLIN) studies. Pediatric cohort: recruited in 1996 (age 8y, n=3430, 97% of invited) and followed annually by questionnaire about asthma, allergy and risk factors until 19y and a postal questionnaire at 28y. Clinical examinations included skin prick tests (SPT at 8, 12 and 19y) and spirometry (19y). Adult cohort: 309 adults (age 20–60y) with asthma onset in the last 12 months were recruited 1995-99 and re-examined in 2012-14 (n=205). Structured interviews, spirometry and SPT were performed at recruitment and follow-up and bronchial hyperreactivity (BHR) at recruitment.
Results: The asthma incidence rate was 10-13/1000/year in childhood and adolescence and 6/1000/year in young adulthood. Several risk factors in early life were associated with asthma onset in childhood, adolescence and young adulthood, e.g. family history of asthma, <3 months breastfeeding, rhinoconjunctivitis and positive SPT at 8y, while low birthweight, maternal smoking during pregnancy, severe respiratory infections and eczema were associated with onset in childhood and adolescence. Among those with asthma at 8y, 62% still had asthma at 28y and this was associated with positive SPT, rhinoconjunctivitis, severe respiratory infection in childhood, and bronchial hyperreactivity (BHR) in adolescence. Coexistence of asthma, rhinitis and eczema increased by age, especially among those with a positive SPT. However, having all three conditions was uncommon. In the 15y follow-up adult onset asthma, 89% had persistent asthma. Better lung function at recruitment and less severe BHR was associated with remission. Remission rate of adult onset asthma was <1% per year.
Conclusion: The incidence of asthma was high during childhood and adolescence and then decreased in young adulthood. Factors in early life that were associated with incident asthma during childhood were still associated with the incidence in adult age. Among those with asthma onset by 8 years, 62%, still had asthma as young adults. The coexistence of asthma, rhinitis and eczema varied from 8 to 28y without following a specific pattern, only a small proportion reported having all three conditions. Remission of adult onset asthma was rare.
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Astrocytes in Alzheimer’s disease : Exploring the impact of amyloid-β pathology on neurotoxicity, metabolism and inflammation.
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-525110
Astrocytes play a central role in brain homeostasis, but are also tightly connected to the pathogenesis of Alzheimer’s disease (AD). Yet, their exact role in amyloid-beta (Aβ) pathology and chronic neuroinflammation is unclear. The aim of this thesis was to elucidate the impact of astrocytes in AD progression. For this purpose, astrocytes in different culture set-ups were exposed to soluble Aβ aggregates. The astrocytes engulf and process, but fail to fully degrade the Aβ aggregates, which are instead stored as large intracellular deposits. In Paper I, we show that extracellular vesicles (EVs), secreted from the Aβ-containing cells induce synaptic loss, axonal swelling and vacuolization of primary neurons, which consequently leads to apoptosis.
Astrocytes play a central role in the brain’s energy metabolism and we were therefore interested in how Aβ pathology affects their metabolism. In Paper II, we report that Aβ accumulation in astrocytes disrupts mitochondrial fission/fusion homeostasis, resulting in decreased mitochondrial respiration and altered glycolysis. Interestingly, the astrocytes switch to fatty acid β oxidation with the aid of peroxisomes to maintain stable energy production.
Another important task is to understand how astrocytes modify the ingested Aβ. In Paper III, we characterized the astrocytic Aβ inclusions by isolating them with magnetic beads. Our analysis showed that the astrocytes truncate and pack together the Aβ aggregates. Moreover, we found that astrocytes release specifically truncated forms of Aβ via different routes.
Astrocytes’ involvement in lipid metabolism and inflammation has recently gained much interest, but many questions remain about the connection between these processes. In Paper IV, we show that Aβ pathology causes lipid droplet (LD) accumulation in astrocytes. Moreover, we could show that astrocytes frequently transfer LDs to neighboring cells, both through direct cell-to-cell contacts and via secretion. Astrocytes have previously been reported to express major histocompatibility complex II (MHCII) and have the capacity to perform as professional antigen presenting cells. Interestingly, our results demonstrate that LDs contain MHCII, identifying a link between LDs and inflammation in astrocytes.
Taken together, this thesis contributes with important knowledge of the role of astrocytes in AD pathology.