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Coming dissertations at MedFak

  • Proteomic, metabolomic, and microbiome studies of blood pressure Author: Yi-Ting Lin Link: Publication date: 2021-04-16 14:25

    Hypertension is a major risk factor for cardiovascular disease and premature death with a substantial global economic burden. To prevent and treat hypertension, it is crucial to improve our understanding of the pathophysiological mechanisms. Hypertension is a multifactorial condition influenced both by genetic and environmental factors. Detailed measurement of the molecular composition in plasma (“omics”) and the gut microbiota can enable novel biological understanding. The overall aim of this thesis was to investigate the associations of proteins, metabolites, and gut microbiome composition with blood pressure and blood pressure changes over time.

    Study I investigated the associations of 79 proteins with 5-year blood pressure progression using a proximity extension assay. Only renin was significantly associated with blood pressure stage progression in discovery cohort. In the replication cohort, the association was attenuated and not statistically significant. However, in all three cohorts combined, higher baseline renin was associated with higher blood pressure at follow-up.

    Study II investigated the longitudinal associations of 220 metabolites with 5-year blood pressure progression using gas chromatography mass spectrometry and liquid chromatography-tandem mass spectrometry. Levels of ceramide (d18:1,C24:0), triacylglycerol (C16:0,C16:1), total glycerolipids, and oleic acid (C18:cis[9]1) were positively associated, and cholesterylester C16:0 was negatively associated, with diastolic blood pressure change in the discovery cohort. Of the five top findings in the discovery cohort, two had related metabolites with a similar chemical structure that were also associated with diastolic blood pressure change over time in an independent cohort (the glycerolipids diacylglycerol (36:2) and monoacyl-glycerol (18:0)).

    Study III investigated the prevalence, variability, and reproducibility of blood pressure phenotypes based on office and 24-hour ambulatory measurements in SCAPIS (Swedish CArdioPulmonary BioImage Study), a large community-based cohort. The total sample size was 5881 participants (3026 women), with a mean office blood pressure of 125/77 mmHg and mean 24-hour ambulatory blood pressures of 124/76 mmHg. Approximately one-third of the participants had evidence of white-coat hypertension, similar to the proportion that had evidence of masked hypertension.

    Study IV investigated the associations between gut microbiota species and 24-hour ambulatory blood pressure in the SCAPIS study. We found robust evidence of a positive association of Dorea longicatena, and a negative association of Alistipes sp. 6CPBBH3, with the 24-h mean systolic blood pressure and diastolic blood pressure.

    This thesis demonstrated the utility of high-throughput omics technologies to identify proteins, metabolites and gut microbiota species associated with blood pressure phenotypes, and highlights the large problem of uncontrolled hypertension.

  • Exposure to Bisphenol A (BPA) and Metabolic Disruption Author: Linda Dunder Link: Publication date: 2021-04-16 13:28

    Metbolic disorders such as obesity, type 2 diabetes, liver lipid disorders and metabolic syndrome are increasing rapidly and have largely been attributed to genetic background and changes in diet, exercise and aging. However, there is now considerable evidence showing that other environmental factors, including environmental chemicals, may contribute to the rapid increase in the incidence of these metabolic diseases. Of particular growing concern is low-dose developmental exposure to endocrine disrupting chemicals (EDCs). The developing period is an extremely sensitive window of exposure to environmental stressors, including EDCs, and early life exposure has been linked to metabolic disorders later in life. Consistent with hormones, EDCs can act at very low serum concentrations and even small changes in the endocrine system may lead to extensive effects. 

    The overall aim of this thesis has been to investigate potential metabolic disruption following exposure to Bisphenol A (BPA), which is a known EDC. The experimental animal study demonstrated that male and female rat offspring generally exhibited differential susceptibility to developmental exposure to BPA (0.5 µg/kg BW/day or 50 µg/kg BW/day). The main results showed that the lowest dose of BPA induced increased plasma triglyceride levels and increased adipocyte cell density in inguinal white adipose tissue in female offspring. Further, this low dose increased fatty acid indices and altered the fatty acid composition in male offspring and enhanced insulin secretion in pancreatic islets from male and female offspring and dams. Contrastingly, the higher BPA-dose decreased insulin secretion in pancreatic islets from male and female offspring and dams. The increased fatty acid indices, and the altered fatty acid composition together with enhanced insulin secretion may be early risk factors for insulin resistance. Furthermore, depending on the tissue, dose and sex, BPA altered the expression of genes involved in lipid and adipocyte homeostasis.

    The epidemiological study with a meta-analysis of data from the National Health and Nutrition Survey (NHANES) did not disclose any associations between urinary BPA and dyslipidemia. However, considering the cross-sectional nature of the present study, this should rather be investigated in carefully designed prospective cohort studies with repeated BPA measurements. Nonetheless, we hope that this paper can encourage researchers to evaluate NHANES data using meta-analyses instead of pooling of data.

    This thesis concludes that exposure to BPA, which is a known EDC, most likely is a contributor, along with genetic, social and behavioral factors, to the development of metabolic disorders. 

  • Short- and long-term consequences of sport-related concussion Author: Fredrik Vedung Link: Publication date: 2021-04-16 10:06

    Concussions are common in contact sports. Symptoms such as confusion and/or loss of consciousness following an impact to the head indicate that a sport-related concussion (SRC) has occurred. The symptoms normally resolve within 10-14 days following an SRC in adults although at least 10 % of athletes suffer from prolonged symptoms. Repeated SRCs have been linked to increased incidence of neurodegenerative disorders including tau aggregation, attributed to axonal injury and neuroinflammation. This thesis investigates the epidemiology and management of SRC in Swedish elite soccer, and pathophysiologic aspects of concussed athletes.

    In questionnaire-based studies, paper I (retrospective) and II (prospective), >1000 Swedish elite soccer players were evaluated. One third of players continued to play at time of SRC, in opposition to current guidelines. In addition, the concussion incidence (ca 1.19 /1000 game hours) was similar in males and females. However, females had a higher symptoms load at baseline, at time of SRC, and had a longer duration of symptoms than male players. In Papers III and IV, pathophysiological aspects were evaluated in young athletes with ≥ 3 previous SRCs, diagnosed with post-concussion syndrome, and moderate to severe traumatic brain injury (TBI) patients ≥6 month post-injury. We used 3T PET/MR in addition to blood and cerebrospinal fluid biomarkers, and cognitive evaluation. MR imaging (arterial spin labelling; ASL) was used to estimate cerebral blood flow (CBF) in Paper III. Here, increased TBI severity was associated with decreased total grey matter CBF, and female athletes had globally decreased CBF. In Paper IV, tau aggregations were investigated by the PET tracer THK5317, and microglial neuroinflammation by the PK11195 tracer. SRC athletes had increased tau in the corpus callosum, and increased neuroinflammation medially in the medial temporal lobes. In TBI patients, tau was increased in thalami, temporal white matter and midbrain, with widespread neuroinflammation in white matter tracts. The alterations of CBF, and increased tau and neuroinflammation, in persistently symptomatic SRC athletes may contribute to the pathophysiology of SRC and the risk of long-term consequences. However, to determine whether these changes are persistent, exacerbate with time or may resolve spontaneously longitudinal studies are required.