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Coming dissertations at MedFak

  • Hormonal contraception, mood and sexual function Author: Cecilia Lundin Link: Publication date: 2020-10-30 09:06

    Hormonal contraceptives (HCs) are used by millions of women worldwide. Apart from their contraceptive effect, they also offer additional health benefits such as decreased menstrual bleedings and amelioration of menstrual-related pain. 

    Adverse mood and sexual side-effects during HC-use are commonly reported, and women who discontinue treatment with HCs often claim these side effects as reason for cessation.

    Although several studies have investigated associations of HCs and adverse mood and sexual side-effects, little is known about causally drug-related outcomes. Few randomised controlled trials (RCTs) have been conducted, and observational studies in the field are subject to several methodological caveats which limit what conclusions that can be drawn from them.

    The overall aim of this thesis was to investigate the effect of HCs on various aspects of mood and sexual function.

    Study one was a randomised controlled trial where participant women received a combined oral contraceptive (COC) or placebo. Mood and sexual function were assessesed through daily ratings and questionnaires and measured at baseline and after three months treatment. 

    Study two was a cross-sectional study that assessed which demographic, reproductive, and psychiatric factors are associated with self-reported HC-induced adverse mood symptoms.

    Study three was a register-based cohort study including all Nordic-born women aged 15-24 residing in Sweden between 2010 and 2017. Risk of depression – captured as redeemed prescription of antidepressant treatment or a depression diagnosis – among HC-users compared to non-users were estimated. 

    Women who were randomised to a COC reported increased anxiety, mood swings and irritability compared to women randomised to placebo. In contrast, women who received a COC improved in depressive symptoms (paper I). 

    Compared to women randomised to placebo, women who received a COC deteriorated regarding sexual interest and vaginal lubrication. Only deterioration in sexual interest remained after adjustments for depressive symptoms (paper II). 

    Compared to women with no self-reported HC-induced adverse mood symptoms, women with such experience more often suffered from an ongoing minor depressive disorder, had more often experienced any previous mental health problem, and had more often undergone induced abortion (paper III). 

    No uniform associations between use of HCs and subsequent risk of depression were found. In general, oral contraceptives conferred lower or no risk, while non-oral contraceptives were associated with small increased risks. Higher risks were found among HC-users aged 15-19 years compared to older HC-users (paper IV).

  • Studies of the Pancreas: Implications for Type 1 Diabetes Aetiology Author: Peter Seiron Link: Publication date: 2020-10-30 08:08

    Type 1 diabetes (T1D) is a disease of severe insulin deficiency through loss of β cells in the endocrine pancreas. The T1D dogma maintains that a precipitating event unleashes autoimmunity in at-risk individuals, often measured through autoantibodies against β cell antigens. This is followed by the death of β cells at the hands of autoreactive cytotoxic T cells. However, several findings have not found their place within this dogma; first, the immune cell infiltrate in islets is usually located outside the islets, and second, there is a pronounced impact on the exocrine pancreas with lower pancreatic weight and fibrosis surrounding the ducts. In this thesis, pancreata from human subjects without diabetes (ND) as well as with T1D or type 2 diabetes (T2D) have been examined in an attempt to clarify the aetiology of T1D.

    The consensus definition of insulitis (≥15 CD45+ cells per islet in ≥3 islets) was validated against ND pancreata. In paper I we show that this definition cannot sufficiently discriminate between the findings in T1D and T2D pancreata, due to an increase in exocrine infiltration in T2D, predominantly made up by macrophages. As exocrine infiltration is also a common finding in T1D, we propose a new definition. In paper II we found tissue resident memory T (TRM) cells in association to islets in both ND and T1D pancreata, and they made up a significant proportion of the insulitic lesion in T1D. Islets contain on average 60% β cells. In paper III we found that despite the seeming loss of this predominant cell type in the T1D islets, islet size remained the same. Instead, islet density was markedly reduced. The islets contained mainly α cells, some of which expressed PDX1, a transcription factor marker of β cells. In paper IV we examined pancreata from ND organ donors aged 1-81 years. For the first time, the islet transcriptome was analysed without prior enzymatic digestion of the tissue. We corroborate earlier findings of reduced cell cycle activity and increased senescence with increasing age, as well as present a hypothesis of how islet age might affect T1D.

    The findings in this thesis sprout an alternative hypothesis that disturbed establishment of β cells in early life, due to lower islet density and lower pancreatic weight, would lead to β cell stress as insulin demand increases with physical growth. However, as islets do not decrease in size, we suggest that the disappearance of β cells could be explained by transdifferentiation into glucagon-producing cells.

  • Clinical and experimental studies on the diaphragm during physiological and pathophysio-logical conditions Author: Antonella Lo Mauro Link: Publication date: 2020-10-29 14:22

    The diaphragm is the most important respiratory muscle. It separates the thorax from the abdomen and it is innervated by phrenic nerve. The action of the diaphragm strongly depends on the combination of: the conductivity of the phrenic nerve; b) the developed force (pressure); c) the length at which it contracts; d) the velocity of short- ening and e) the level of activation.

    The general aim of this doctoral thesis is to study the diaphragm in different conditions in which different mechanical loads and/or different agents modified one or more of these factors in order to understand how the diaphragm copes with anesthesia, phrenic nerve injury, severe lung diseases and increasing abdominal load.

    In Study I, the movement induced by the diaphragm on tumor marker surrogate, being a source of noise while planning target volume during stereotactic body radiation ther- apy was quantified. High Frequency Jet Ventilation at a frequency of 200 min-1 seemed to be the best compromise between immobilization and gas exchange.

    In Study II, the role of the diaphragm during the emergence from anesthesia (namely, propofol) was investigated, finding no contribution because of active contraction of the expiratory muscles in this phase, presumably triggered by the resistance in the tracheal tube.

    In Study III, an animal model (porcine) of phrenic nerve damage was created and the compensatory mechanisms of non-diaphragmatic respiratory muscles studied. A 12- fold augmentation of the drive to ribcage muscles occurred during inspiration, while it almost doubled for abdominal muscles during expiration. Increasing level of pres- sure support ventilation masked these respiratory muscles strategy.

    Study IV described, within an integrated multidisciplinary longitudinal study, differ- ent functional aspects (geometry, weakness, force, mobility, contractility, electrical activity and kinematics) of the diaphragm before and after lung transplantation. A subclinical diaphragmatic dysfunction occurs after surgery, despite appropriate clini- cal course and respiratory outcome, induced by phrenic nerve neurapraxia secondary to surgical procedure.

    Study V was a non-invasive and longitudinal study of the progressive changes of the diaphragm during healthy pregnancy. During pregnancy, the diaphragm is condi- tioned to optimize its active role provided during parturition, as its co-contraction with abdominal muscles plays a fundamental role in the phase of baby expulsion.