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Coming dissertations at MedFak

  • A stargazer's guide to neurodegeneration : Astrocytes' role in the propagation of pathological proteins Author: Tobias Mothes Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-523852 Publication date: 2024-03-21 09:55

    Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by brain accumulation of pathogenic protein aggregates. In the AD brain, amyloid-β (Aβ) and tau form plaques respective tangles, while in the PD brain α-synuclein (α-syn) form Lewy bodies and Lewy neurites. In addition, deposits of Aβ, tau and α-syn are frequently present in glial cells, including astrocytes. Historically, the focus was on neuronal dysfunction, leaving the involvement of glia largely understudied. The overall aim of this thesis was to investigate the role of glial cells in the disease progression, primarily focusing on astrocytes and the role they play in tau pathology.

    Paper I focuses on the crosstalk between astrocytes and microglia in respects to degradation of α-syn and Aβ fibrils. Our results show that mono-cultured microglia are more effective than astrocytes at degrading exogenously added fibrils. However, when cultured together, microglia and astrocytes work synergistically, leading to an overall increase in the degradation.

    In Paper II, we show that astrocytic tau inclusions are not benign, but in fact act as a reservoir for seeding competent tau species. The astrocytes engulf and process, but fail to fully degrade internalized material. Instead, seeding competent pathogenic tau spreads to nearby cells via secretion and tunneling nanotube mediated transfer. Furthermore, we show that tau and debris burdened astrocytes negatively affected the health of nearby neurons.

    In Paper III, we investigated the cellular effects following astrocytic engulfment of human brain-derived tau. Our results show that astrocytes internalize and accumulate both AD and control tau fibrils. However, fibrils from AD brains were more neurotoxic and induced a stronger immune response in astrocytes, compared to fibrils derived from control brains.

    In Paper IV, we studied the effects of APOE-genotype on astrocytic processing of tau by comparing astrocytes homozygous for APOEε2 and APOEε4. Our results showed that APOE2/2 astrocytes contained more and larger tau aggregates. Moreover, APOE 2/2 astrocytes excreted higher levels of pro-inflammatory cytokines, including IL-8, CCL2 and CXCL10 compared to APOE 4/4 astrocytes.

    Paper V aimed to establish a cortical organoid model for studies of AD and PD. Exposure to α-syn especially led to internalisation by the organoid cells and active spreading throughout the tissue.

    Our results demonstrate that astrocytes work closely with microglia to degrade internalised material. Furthermore, astrocytes actively contribute to neurodegeneration and disease propagation by affecting the health of neurons and by spreading seeding competent tau species.

  • Chronic obstructive pulmonary disease: exacerbations and mortality : Prognostic value of biomarkers and comorbidities Author: Jens Ellingsen Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-523303 Publication date: 2024-03-21 08:24

    Background: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. COPD is associated with systemic inflammation, and comorbidities are common. A characteristic feature is acute exacerbations (AECOPDs), i.e., episodes of worsening symptoms. AECOPDs are associated with increased mortality.

    Aim: To find prognostic risk factors for COPD mortality and AECOPDs, focusing on comorbidities and inflammatory biomarkers.

    Methods: In Paper I, associations between comorbidities, pharmacological treatment, and mortality were analysed in a real-world cohort of almost 18,000 primary care COPD patients. Data from medical records and national registers were analysed in Cox proportional hazards regressions.

    Papers II–IV were based on the Tools Identifying Exacerbations (TIE) cohort study of 572 COPD patients recruited from primary and secondary care in three Swedish regions. Participants were invited to three yearly visits, including phlebotomy, spirometry, and health questionnaires.

    In Paper II, the ability of blood neutrophil-to-lymphocyte ratio (NLR) and eosinophils (B-Eos) to predict AECOPDs was analysed with mixed-effects logistic regressions.

    In Paper III, the ability of C-reactive protein (CRP), fibrinogen, blood leukocytes (B-Leu), and four blood cell indices to predict AECOPDs was analysed with ordinal logistic regressions.

    In Paper IV, an algorithm for clinical phenotyping previously developed to predict mortality was studied. The algorithm’s ability to predict AECOPDs and mortality was analysed with Cox proportional hazards regressions; additionally, the identified phenotypes were analysed concerning differences in blood-based inflammatory biomarkers.

    Results: Several comorbidities, including heart diseases, were associated with increased mortality risk. Some pharmacological treatments were associated with increased or decreased mortality risk (Paper I). NLR, B-Eos, CRP, fibrinogen, and B-Leu (Papers II–III) predicted AECOPDs after adjustment for confounders, whereas other blood cell indices were of limited value (Paper III). The clinical phenotyping algorithm predicted AECOPDs and mortality, and the phenotypes had different patterns of inflammatory biomarkers (Paper IV).

    Conclusions: Comorbidities, particularly heart diseases, are substantial risk factors for mortality in COPD and should be an integral part of management of COPD patients. NLR, B-Eos, CRP, fibrinogen, and B-Leu are independent predictors of AECOPDs and should be further investigated as parts of, e.g., risk prediction tools. A previously developed algorithm for clinical phenotyping predicts mortality and AECOPDs.

  • Trauma Care - Implementation, Evaluation and Validation Author: Lina Holmberg Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-521759 Publication date: 2024-03-20 10:21

    Trauma is a major cause of death and morbidity in all ages, which makes continuous improvement of trauma care a high priority. During the last decades, Sweden’s trauma system has evolved with initiation of a national trauma registry (SweTrau) in 2011 and the Swedish National Trauma Triage criteria (SNTTC) in 2017. However, the Swedish trauma panorama has evolved as well, something this thesis aimed to explore, alongside with evaluating the safety and accuracy of the SNTTC and performing the first validation of SweTrau. Paper I is a prospective stepped-wedge cohort study, showing unchanged 30-day mortality, over- and undertriage after the implementation of the SNTTC, as well as a reduction of the lowest level of trauma call by almost 50%, proving that the SNTTC are safe to use. In Paper II, a retrospective multicentre cohort study, the SNTTC are further investigated, displaying a sensitivity of almost 85% while also assessing specificity, positive predictive value (PPV) and positive likelihood ratio (LR+). With no additional enhancing criteria found, the SNTTC are concluded to efficiently identify severely injured patients. Paper III reports the first validation of SweTrau; an on-site re-registration compared with the original registration in SweTrau. It demonstrates that the data in SweTrau is reliable, with high accuracy (85.8%), correctness (89.7%), data completeness (88.5%) and correlation (87.5%), while being comparable to international trauma registries using the Utstein template of trauma. Case completeness and timeliness are identified as areas of improvement. In Paper IV, nine-year trauma trends in two major trauma centres are analysed in a retrospective cohort study. A sharp reduction in intensive care unit admissions is seen, as well as a worrying increase in penetrating trauma (>50%) and mortality for patients with a low injury severity score (1.3%-2.7%, p=0.005), all of which require further investigation. In conclusion; this thesis has confirmed that the SNTTC are safe and efficient, as well as pin-pointed important trauma areas to focus on in the future. Finally, it has established the validity of the data in SweTrau - a major source of Swedish trauma research.   

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