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Coming dissertations at MedFak

  • Regulation of docking and priming in pancreatic α- and β-cells Author: Muhmmad Omar-Hmeadi Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-388354 Publication date: 2019-08-20 13:34

    The secretion of islet hormones from endocrine cells of the pancreas plays vital roles in maintaining glucose homeostasis. Dysfunction of these cells leads to diabetes, a devastating metabolic disorder affecting millions worldwide, but underlying mechanisms remain poorly understood. In hyperglycemic conditions, β-cells secrete insulin, whereas α-cells secrete an increased amount of glucagon in hypoglycemic conditions. Both insulin and glucagon are stored in secretory granules preceding their release by regulated exocytosis. This process involves several steps, including tethering, docking, priming, and finally, a fusion of the granules with the plasma membrane. Soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) proteins and phosphoinositides (PIs) drive pancreatic hormone exocytosis and secretion, which follows a biphasic time course. Biphasic secretion is thought to reflect the vastly different release probabilities of individual granules, but direct evidence for this is still lacking.  Therefore, this thesis investigates exocytosis in the two main pancreatic cell types with a particular focus on preceding steps docking and priming, to identify rate-limiting steps in health and type-2 diabetes (T2D). Our data indicated that granule docking is critical for sustained secretion in α- and β-cells. Glucagon granule exocytosis had a U-shaped sensitivity to glucose in both healthy and T2D α-cells. However, T2D α-cells exhibited a marginal decrease in exocytosis, as well as docking, and they were markedly insensitive to somatostatin and insulin. T2D β-cells reduced exocytosis dramatically, and docking was compromised and no longer responsive to glucose, which correlated with reduced insulin secretion and elevated donor HbA1c. These results were further strengthened by the finding that expression of a group of genes that are involved explicitly in granule docking was reduced (by RNAseq of islets from over 200 human donors), and overexpression of the corresponding proteins increased granule docking in human β-cells.

    We further aimed to study the basis for the recruitment of these proteins to the docking site. Here we tested the hypothesis that highly charged lipids mainly PIs act as a hotspot to interact with SNARE proteins that initiate docking. We showed the homogenous distribution of all PIs markers in the plasma membrane, with no PIs microdomains at the exocytotic site during granule docking. However, rapid and local PI(4,5)P2 signaling at fusion sites was crucial for stabilizing fusion pore by binding to proteins related to the release site. These results suggested a role of PI(4,5)P2 in priming and fusion regulation rather than docking. Overall, this work gives new insights into the mechanisms underlying pancreatic hormone secretion in both healthy and diabetic conditions.

  • A cross-service approach to identify mental health problems in 3–5-year-old children using the Strengths and Difficulties Questionnaire Author: Elisabet Fält Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-384328 Publication date: 2019-08-16 14:59

    The Child Healthcare Services (CHS) in Sweden offer regular health check-ups and reach almost all 0–5-year-old children. Although one of the objectives of the CHS is to detect mental health problems, evidence-based methods are not used for this purpose at the Child Health Clinics (CHCs). Therefore, an evidence-based instrument to assess children’s emotional and behavioural problems through parent and teacher reports, the Strengths and Difficulties Questionnaire (SDQ), was introduced, as part of the Children and Parents in Focus trial, run between 2013 and 2017 in Uppsala, Sweden. The overall aim of this thesis was to evaluate the introduction of the procedure, including the facilitation strategies provided to support implementation, and to provide inter-rater correlations and norms for the SDQ in this population.

    Data were collected through individual interviews with nurses, parents and preschool teachers; group interviews with nurses; and a survey performed at the end of the trial to evaluate nurses’ experiences of the SDQ-procedure and the implementation process. In addition, delivery, response rate and population coverage of the questionnaires were calculated. Quantitative data were analysed using descriptive statistics, Pearson correlations and Intraclass Correlation Coefficients (ICC), and qualitative data using Grounded Theory and content analysis.

    Results showed that nurses found it useful for their assessment to have access to preschool teachers’ SDQ-ratings. Parents were also positive to the procedure but had concerns regarding confidentiality of the responses. Preschool teachers were least positive, fearing labelling of children and negative parental reactions. Significant, albeit poor, agreement (ICC) was found between parent and teacher ratings and good agreement between parents’ ratings. Teachers were found to report lower levels of problems compared to parents. Cut-off values differed for age and were somewhat higher for boys (lower for prosocial), suggesting that boys display more behaviour problems. Nurses perceived facilitation strategies used by the research team useful to support implementation and delivered the procedure, essentially, as intended. However, response rate remained lower than expected, around 50%.

    The findings suggest that implementing the SDQ to aid CHC-nurses’ assessment of 3-5-year-olds’ mental health is feasible, but requires further effort in regular services to reach all children.

  • Nocturnal enuresis and rapid maxillary expansion : – long-term effect, prognostic variables, respiration during sleep and quality of life Author: Ingrid Jönson Ring Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-383405 Publication date: 2019-08-16 10:44

    Background:The orthodontic technique rapid maxillary expansion (RME) has been reported to have a potentially curative effect on nocturnal enuresis (NE). The mechanism behind this is unknown but could possibly be due to placebo and/or effects on respiration during sleep. 

    Aim: This thesis aims to approach an answer to the following questions, with a randomized, placebo-controlled method: 1) Does rapid maxillary expansion have a curative effect on therapy-resistant NE? 2) Is the potential curative effect due to respiratory events that can be measured during sleep? 3) Do enuretic children have an impaired quality of life (QoL)?  

    Subjects & Methods: In study I we evaluated the QoL in enuretic children while assessing the test re-test reliability of a Swedish version of an established QoL questionnaire. Study II and IV assess respiration during sleep in children with NE; in study II comparisons are made with healthy control children and in study IV we evaluate the respiratory effects of RME. Study III is a randomized placebo-controlled study investigating whether RME is a useful therapy for NE and if the treatment effect is due to placebo.

    Results: Study I:The Swedish version of the questionnaire proved to be a reliable tool (Chronbach’s alpha 0.87) with excellent test-retest stability (ICC = 0.762). Enuresis affects the children’s QoL and interactions with peers.

    Study II:The hypopnea index (HI) and the oxygen desaturation index were both significantly higher in the enuretic children compared to the healthy controls, (p=0.04 and p=0.05) but all values fell within the normal range.

    Study III:RME resulted in a significant reduction in wet nights i.e. the mean number of wet nights out of 14 was 11.4 before and 9.2 after RME. (p=0.003) This was not observed in the placebo group (p=0.40).

    Study IV:There was a significant reduction of sleep efficiency during RME. (p=0.001) The mean HI was also affected. (p=0.005)

    Conclusions:

    Children with nocturnal enuresis have an impaired self-esteem and their quality of life is affected in their relationship with friends.

    There were no major differences in respiration during sleep between enuretic children and controls.

    Rapid maxillary expansion reduces the number of wet nights in children with enuresis, but the effect is of limited clinical value.

    The antienuretic effect does not seem to be due to a placebo effect of the appliance.

    The majority of the children in our study sample did not have sleep disordered breathing as a co-morbidity to their nocturnal enuresis. 

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