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Coming dissertations at MedFak

  • The psycho-metabolic consequences of sleep loss in people Author: Lieve T. van Egmond Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-489681 Publication date: 2023-01-13 10:52

    Night work is vital for maintaining our 24/7 society; however, in the long run, it may have adverse health consequences like obesity and Alzheimer’s disease. By performing one of the most extensive experimental in-laboratory studies to date, I sought to investigate how sleep deprivation impacts important features like how a person responds to others and how well a person can sustain attention and wakefulness during simulated night work. To this end, in Paper I, I used eye tracking to show that young adults were less visually attentive to faces after sleep deprivation, irrespective of the displayed emotion. Additionally, participants rated faces as less trustworthy and attractive after the nocturnal vigil. In conclusion, the observed effects suggest that night work may impact emotional regulation. Whether the change in face processing increases the odds of negative affect and social withdrawal remains unclear.

    Using the same cohort in Paper II, I found that women and people with obesity struggled more with overnight wakefulness (measured by questionnaires, vigilance, and electroencephalography) than men and people with normal weight, respectively. Strikingly, these groups also exhibited increased blood levels of brain health biomarkers following total sleep loss. These results indicate that a person’s biological sex and weight status may moderate to which extent night work adversely affects brain health and occupational performance.

    Sleep deprivation drives the development of obesity. However, whether similar mechanisms accounting for this weight-promoting effect of sleep loss apply to people who already have obesity is not well researched. Additionally, most experimental studies focused on the effects of acute sleep loss on the energy balance in men. With these gaps in mind, using the above-described cohort, Paper III focused on three prominent endocrine regulators of energy balance, namely leptin, known to promote satiety, and the hunger-promoting hormones ghrelin and adiponectin. Overall, I observed that lower blood leptin concentrations followed one night of total sleep deprivation while those of ghrelin and adiponectin increased. In addition, post-hoc analyses suggested some sex- and weight-specific differences in the hormonal response to sleep loss. For example, leptin dropped to a greater extent in women. These sex- and weight-specific differences must be replicated in larger studies.

    While acute sleep loss may predispose humans to gain weight, what we eat can influence our sleep. At age 70, 970 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) filled out a seven-day food diary and questionnaires surveying for possible sleep problems. Thus, in Paper IV, I investigated whether healthy dietary habits were associated with lower odds of suffering from subjective sleep disturbances. Contrary to my hypothesis, neither the Mediterranean diet nor the Healthy Diet Indicator (based on WHO recommendations) was associated with sleep outcomes. Thus, more controlled interventional studies are needed to systematically evaluate how dietary habits may influence sleep in older men.

  • Periprosthetic Joint Infection : – prevention, diagnosis, and treatment Author: Hannah K. Eriksson Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-489931 Publication date: 2023-01-11 12:36

    Prosthetic joint infection (PJI) is a serious complication that may occur after total joint arthroplasty (TJA). In addition, PJI has a devastating impact on the patient's quality of life. Therefore, it is imperative to increase our knowledge of PJI prevention, diagnosis, and treatment.

    Prevention of PJI through effective strategies must be taken to avoid this catastrophic complication. Diagnosing PJI is a major challenge, with no gold standard diagnostic criteria. Although there are several diagnostic algorithms available, these are not sufficiently accurate and require continuous evaluation and improvement. Treating PJI is complex and includes a combination of surgical intervention and long-term antibiotic treatment. In this thesis we investigated whether various preventive, diagnostic, and treatment methods could improve the outcome after PJI.

    We found that patients suffering from superficial surgical site infection (SSSI) after primary hip or knee arthroplasty had a high risk of progression to PJI. Patient-related factors such as age, high American Society of Anesthesiologists (ASA) classification, and obesity were associated with a high prevalence of SSSI. High ASA classification seems to be a crucial factor in progressing from SSSI to PJI.

    On PJI diagnostics, our studies revealed that the measurement of alpha-defensin levels in synovial fluid play a role in the diagnostic algorithm of PJI. The diagnostic accuracy of the alpha-defensin lateral flow test is inferior to the immunoassay test. However, the rapid availability of the lateral flow test result gives this method a place in ruling in a suspected PJI intraoperatively. In preoperative diagnostics identifying causative bacteria is essential in planning the optimal treatment regime. 

    We found that debridement antibiotics and implant retention, as the surgical choice in patients suffering from early PJI caused by Staphylococci, has a higher rate of failure if the causative Staphylococci is resistant to rifampicin. Oral antibiotic alternatives to intravenously administered antibiotics are highly valued for lowering the risks of intravenous administration and reducing longer hospital stays. Our results provide evidence that linezolid is a useful alternative with manageable and reversible adverse events (AEs) in patients with PJI caused by coagulase-negative staphylococci.

    In conclusion, arthroplasty surgery can provide a pain-free life for many patients if complications such as PJI can be avoided. This thesis argues that the best treatment outcome after arthroplasty surgery involves optimising the patient, applying accurate PJI diagnostic tools with no or low risk for the patient, and having available treatment options that closely follow established guidelines. 

  • Mechanisms of modulation of PDGFRβ signaling Author: Niki Sarri Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-489074 Publication date: 2023-01-10 09:36

    Platelet-derived growth factors (PDGF) constitute a family of five functional dimers that bind to two structurally related tyrosine kinase receptors i.e. PDGF receptor α and β (PDGFRα and PDGFRβ, respectively), controlling cell growth, proliferation, and migration in cells of mesenchymal origin. However, the aberrant activation of PDGF-induced intracellular signalling pathways is a frequent event in cancer. Therefore, the aim of this thesis has been to discover novel molecular mechanisms of modulation of PDGFRβ signalling. 

    Since mitogen-activated protein (MAP) kinases are activated in PDGF signalling and their spatiotemporal activity is defined by a balance in phosphorylation and dephosphorylation events, in paper I we focused on dual-specificity MAPK phosphatases (MPKs or DUSPs).  We found MKP2/DUSP4 to be induced in response to PDGF-BB stimulation. We then demonstrated that the expression of MKP2/DUSP4 was dependent on ERK1/2 activation and on the STAT3/p53 signalling.  

    Endocytosis of RTKs is another mechanism that serves for signal attenuation and termination and this process can be regulated by ubiquitination or deubiquitination of cell-surface receptors. In paper II, we have identified that ubiquitin specific proteases USP4 and USP17 act as deubiquitinases (DUBs) for PDGFRβ. Both deubiquitinases impacted the timing of PDGFRβ trafficking and prolonged STAT3 activation. Consequently, high transcriptional activity of STAT3 led to the increased expression of STAT3-inducible genes c-MYC, CSF1, JUNB and CDKN1A. USP4 deletion attenuated cell proliferation in response to PDGF-BB stimulation. 

    The family of Cbl E3 ligases is essential for ubiquitination of PDGFRβ upon ligand stimulation, followed by the receptor internalization from the cell surface and downregulation of signalling. In paper III, we have identified a new E3 ligase, i.e. tripartite motif-containing protein TRIM21, that deubiquitinates PDGFRβ and regulates its basal levels and its availability on the cell surface in a PDGF-BB independent manner. 

    In paper IV, we described a regulatory role of the endoribonuclease Ras GTPase-activating protein-binding protein 1 (G3BP1) in PDGF signalling. G3BP1 was identified as a PDGFRβ interacting protein which also interacts with BAF155, a core component of SWI/SNF chromatin remodelling complex. G3BP1 depletion upregulated c-FOS, c-MYC and c-JUN mRNA and negatively affected STAT3 and ERK1/2 mRNA and protein levels, stalling cell proliferation. 

    Collectively, we present new mechanisms that regulate PDGF signalling by controlling either PDGFRβ protein levels, availability on the cell surface, subcellular trafficking or activation of downstream signalling affecting regulation of cell proliferation.

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