Coming dissertations at MedFak
-
Role of Fatty Acid Composition in Non-Alcoholic Fatty Liver Disease: a Dietary Perspective : Results from Interventional and Observational Studies
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-524500
The overall aim of this doctoral thesis was to investigate the role of circulating, liver and dietary fatty acids in non-alcoholic fatty liver disease (NAFLD). For circulating and liver fatty acids, special emphasis was given to fatty acids reflecting diet.
In paper I, circulating cholesteryl ester (CE) linoleic acid (18:2n-6), which is considered a good biomarker of dietary intake of 18:2n-6, was cross-sectionally inversely associated with liver fat in n=308 50-year old men and women. Several fatty acids reflecting both exogenous intake and endogenous metabolism were associated with liver fat, basal fat oxidation and resting energy expenditure (REE). No association between fatty acids and liver fat, except for docosahexaenoic acid (22:6n-3) and liver fat, were attenuated after adjusting for REE.
In paper II, phospholipid (PL) 22:6n-3 in liver tissue, a potential biomarker of dietary intake of 22:6n-3, was cross-sectionally inversely associated with liver fibrosis in n=60 men and women with biopsy-verified NAFLD. This finding was not replicated in plasma. Several other fatty acids reflecting both exogenous intake and endogenous metabolism were associated with fibrosis. Pooled saturated fatty acids (SFA) were generally positively associated whereas monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA) were inversely associated with fibrosis.
In paper III, no clear (i.e. imprecise) associations were observed for any of the nutrient or food substitutions with incidence NAFLD cirrhosis or hepatocellular carcinoma (HCC), over a median follow-up of 24 years in n>77 000 middle-aged to elderly men and women.
In paper IV, a 12-month randomized controlled trial (RCT) was conducted to investigate the effects of a low-carbohydrate high PUFA (LCPUFA) diet and a healthy Nordic diet (HND) on liver fat in men and women with type 2 diabetes (T2D) or prediabetes. The comparator diet (usual care (UC)) aligned with the Nordic Nutrition Recommendations. Liver fat decreased more in the LCPUFA diet and the HND versus UC. No difference in liver fat was observed between LCPUFA and HND. The LCPUFA diet and the HND improved several other cardiometabolic markers compared to UC, with more favorable improvements in the HND group.
In conclusion, findings from this thesis suggest that higher intakes of dietary unsaturated fatty acids (in particular PUFA) and lower intakes of SFA may be of importance for the prevention and treatment of NAFLD (at least for liver fat and fibrosis). Findings from this thesis also suggest that fatty acids reflecting both diet and endogenous metabolism may play a role in NAFLD.
-
Molecular mechanism of plasmid copy number control in Yersinia
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-523712
The ability of pathogenic bacteria to cause disease depends on various virulence mechanisms. The three pathogenic species of Yersinia use a type III secretion system (T3SS) to translocate effector proteins into host cells and disrupt the immune system. This T3SS is encoded on a 70kb, low-copy, virulence plasmid. A novel mechanism of virulence was identified in Y. pseudotuberculosis, where the plasmid copy number (PCN) increases during infection. The PCN needs to be tightly regulated, as it encodes important, but costly, virulence genes. This thesis expends our understanding of PCN regulation and its importance in Yersinia virulence.
In Paper I, we demonstrate that PCN regulation as a virulence mechanism is a dynamic system capable of adapting to different host environments. We found that an increased PCN is important at the onset of infection, particularly during the colonization phase. In later stages, within different organs, the PCN decreases, suggesting a reduced need for the T3SS once the infection is established. This insight was enabled by the development of a novel method based on droplet digital PCR, allowing accurate PCN detection in sample with very little target DNA.
In Paper II, we studied the PCN regulation by YopD. We showed that YopD represses PCN through the regulation of copA transcription. This YopD-dependant PCN control is released when YopD is secreted outside the bacteria upon contact with the host cell. YopD is a multifunctional protein. It possesses different domains crucial for its different functions. We found that the domains important for T3SS regulation are also required for PCN regulation.
In Paper III, we used phenotypical approaches together with Nuclear Magnetic Resonance (NMR) method to study YmoA, a protein regulating gene expression in Yersinia in response to environmental stresses. YmoA’s ability to control gene expression requires its interaction with H-NS, a global DNA regulator. YmoA up-regulates a great number of genes, the T3SS and its effectors protein for instance. We observed that it also down-regulates many others, such as flagellar assembly genes. Our findings reveal that YmoA regulates PCN and senses temperature and osmotic stress resulting in a change of its conformation, which affects its ability to form a complex with H-NS.
In summary, the studies presented in this thesis show that PCN is a highly dynamic, tightly regulated mechanism, important for Yersinia pathogenesis.
-
Surviving Birth and Thriving : Identifying infants at risk of death and disability in low- and middle-income countries
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-523713
Background: Ending preventable newborn deaths is an unfinished global health agenda. Infants surviving birth have a right to thrive and to reach their full developmental potential. The aim of this thesis was to evaluate methods for identification of infants in need of neonatal resuscitation and at risk of disability in low- and middle-income countries.
Paper I was an observational study conducted in Pokhara, Nepal, comparing the heart rate in the first 3 minutes in infants who were quietly breathing (n=54) versus crying (n=1155) immediately after birth. The median heart rate did not differ between the two groups, but both bradycardia and tachycardia were more common among non-crying but breathing newborns.
Paper II was a systematic review and meta-analysis of studies examining the incidence and outcomes of intrapartum-related neonatal encephalopathy in low- and middle-income countries. Altogether 53 articles were identified. The incidence ranged from 1.5 to 20.3 per 1000 live births (5 studies), the mean neonatal mortality was 19.3 % (45 studies, 3307 infants), and the incidence of combined outcome of death or moderate to severe disability at follow-up was 44.6 % (19 studies, 1595 children).
Paper III evaluated the feasibility of smartphone-aided remote General Movements Assessment for identification of children at risk of cerebral palsy in Kathmandu, Nepal. Children surviving birth asphyxia or neonatal seizures were filmed by parents using the NeuroMotion smartphone application at home at 3 months’ age. Altogether 31 children were enrolled, and 16 parents returned at least one video of approved technical quality. Usability of the app was good based on parental survey.
In Paper IV, individual (n=4) and group interviews (n=2) were conducted with ten mothers participating in the smartphone aided follow-up of their infants. The data were analysed using deductive qualitative content analysis. The remote follow-up was acceptable with support from the research assistants. Some participants would have preferred a face-to-face evaluation.
Conclusion: Not crying at birth is a potential indicator for need of neonatal resuscitation. Infants who survive resuscitation are at risk of intrapartum-related neonatal encephalopathy, which has persistently high burden particularly in low-income countries. All survivors of encephalopathy need follow-up and smartphone-aided remote General Movements Assessment could complement the assessments in settings similar to Kathmandu.