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Coming dissertations at MedFak

  • Therapy-resistant enuresis : In search of new therapies and prognostic markers Author: Elisabet Lundmark Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-389838 Publication date: 2019-09-12 10:48

    A large minority of children with enuresis do not respond to treatment with either desmopressin or the enuresis alarm. Anticholinergics have not proven as successful as expected. The fourth evidence-based treatment of enuresis, the tricyclic antidepressant imipramine, is cardiotoxic when overdosed, which has led to diminished use. Since the long-term consequences of enuresis are potentially grave it is important that effective treatments of therapy-resistant enuresis are found.

    When investigating the enuretic child a full voiding-chart - in addition to the case history - is the method of choice. However, there is no robust evidence that daytime voiding chart data actually do predict nocturnal detrusor function.

    The aim of this thesis was to determine whether there is a role for the noradrenergic antidepressant reboxetine in the treatment of therapy-resistant enuresis, and whether anamnestic data and the voiding chart provides prognostic information regarding response to treatment with anticholinergics and antidepressants respectively in therapy-resistant patients.

    In a retrospective evaluation of 61 children who for humanitarian purposes had been treated with reboxetine 32(52%) responded to this treatment, 21 of them after desmopressin had been added. We then proceeded with a randomized placebo-controlled study with 18 patients, in which the reduction of wet nights was much better with either reboxetine in monotherapy or in combination with desmopressin than during the placebo period (p=0.002). However, no patient achieved complete dryness. No prognostic markers for therapy-response were found in either of these studies.

    In the randomized study we also sought to investigate whether reboxetine had any statistically significant effect on voiding-chart data. No such effect was found, but in respect to this secondary aim the sample size was too small. Nonetheless , this led to the speculation whether reboxetine exerts its antienuretic effect via modulation of arousal mechanisms.

    Prognostic markers were sought in a retrospective evaluation of 154 patients treated with anticholinergics or antidepressants, but few and inconsistent differences were found between the groups responding or not responding to the various treatment regimens, and this was true both for anamnestic and voiding chart data.

    In conclusion reboxetine seems to be an alternative in the treatment of enuretic children who have not responded to standard treatment, but further trials with higher doses and larger study populations are needed. The internationally recommended assessment of children with therapy-resistant enuresis does not seem to give the prognostic information intended.

  • Challenges of transnational parenthood : Exploring different perspectives of surrogacy in Sweden and India Author: Anna Arvidsson Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-385699 Publication date: 2019-09-06 13:16

    Transnational surrogacy challenges traditional norms of parenthood, especially motherhood; additionally, it is viewed as the exploitation of poor women. The overall aim of this thesis was to shed light on the consequences of an unregulated situation on surrogacy in the Swedish and Indian contexts, and to give different perspectives on surrogacy and the surrogate. The experiences of using transnational surrogacy and the consequences of using this reproductive method in a context of a largely unregulated situation had rarely been explored at the start of the study. Between 2012 and 2015, qualitative interviews were conducted with commissioning parents in Sweden who used transnational surrogacy mainly in India, as well as with social workers in Sweden, who have handled cases regarding the legal recognition of parenthood. To capture a non-western perspective on surrogacy, the views of women and men in different social strata in Assam, India were explored through individual interviews and focus group discussions. At the start of the project, India was the most common country to turn to for surrogacy. The results reveal that both commissioning parents and social workers needed to navigate inadequate parental legislation, with the result that commissioning parents felt questioned as parents. Social workers tried to balance the protection of the surrogate’s rights with the child’s best interest. The ethical aspects made the users of surrogacy ambivalent, and, for social workers, it resulted in further reluctance to handle legal parenthood cases. However, from an Assamese point of view, no ethical considerations were expressed; instead, the surrogate would either be stigmatized for her act and seen as though she was “selling her child,” or seen as a woman doing a noble act, helping a childless couple. All the informants demonstrated a pragmatic view of legal parenthood, but the current legal situation in Sweden limits the scope to act as parents in relation to society, because of the length of time it takes to be recognized as legal parents. This comes with a risk for children. From the perspective of reproductive justice, a clearer regulation on surrogacy, and kinship rules that are more adjusted to the current family practice, are needed. Additionally, to limit the risks for all parties involved in the surrogacy process, a more transparent surrogacy process is needed.

  • Multi-Resistance Plasmids : Fitness Costs, Dynamics and Evolution Author: Fredrika Rajer Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-389855 Publication date: 2019-09-05 10:10

    Antibiotic resistance is an escalating problem, not only due to less desirable treatment options and outcome, but also due to the economic burden to health care caused by resistant pathogens. Since the process of developing new antibiotics is slow, we need to carefully consider the usage of the antibiotics still available. Therefore it is of importance to minimize the development and spread of resistant pathogens. To do so, we need a better understanding of the mechanisms and dynamics underlying the evolution of highly resistant bacteria.

    In this thesis I have investigated one of the major drivers of resistance gene dissemination in Gram-negative bacteria, namely multi-resistance plasmids. We show that multi-resistance plasmids display a dynamic behavior in vivo, where genes can be readily acquired and lost again. Additionally, plasmids can be shared amongst different bacteria, especially in environments such as the human gut. Interestingly, some resistance plasmids confer a fitness disadvantage to their host displayed by decreased growth rate in absence of antibiotics. We could elucidate that two resistance genes of the multi-resistance plasmid pUUH239.2 were the cause of the lowered growth rate, namely blaCTX-M-15 and tetR/A. In contrast, other resistance genes on the plasmid were cost-free even when overexpressed and likely enable persistence in the bacterial population even under non-selective conditions. Lastly, we studied how the presence of several β-lactamase genes on a plasmid affects treatment with different combinations of β-lactam/β-lactamase inhibitors. We found that an efficient mechanism for bacteria to overcome high levels of antibiotics was by amplification of plasmid-borne resistance genes. This mechanism works as a stepping-stone for additional mutations giving rise to high-level resistance.

    With this work we provide insight into the mechanisms underlying resistance evolution and dissemination due to multi-resistance plasmids. Plasmids enable fast dissemination of multiple resistance genes and therefore simultaneously disable multiple treatment options. Examining the effects of resistance genes and antibiotics on strains carrying multi-resistance plasmids will enable us to understand what factors assist or inhibit plasmid spread. Hopefully, this will aid us in treatment design to prevent resistance development to effective antibiotics and have implications for resistance surveillance as well as prediction.

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