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Coming dissertations at MedFak

  • Craniofacial malformations and psychiatric disorders from a neurodevelopmental perspective Author: Karin K. Tillman Link: Publication date: 2020-11-12 09:09

    Orofacial clefts (OFC) and craniosynostosis (CS) are the two most common craniofacial malformations. Of note, craniofacial abnormalities share some overlapping risk factors with psychiatric disorders. Thus, this thesis aimed to study psychiatric and educational outcomes in this group.

    In study I and III we examined psychiatric outcomes among children with nonsyndromic OFC stratified on cleft lip (CL), cleft lip and palate (CLP), cleft palate only (CPO), unilateral and bilateral CL and CLP. In study II we studied associations between nonsyndromic CS (NSCS) and psychiatric disorders. Study IV assessed national standardised tests in Swedish and mathematics, school grades and university degrees in children with CL, CLP and CPO. Children with craniofacial malformations were identified through the Swedish National Patient Register and compared to a cohort from the general population that was matched for month and year of birth, sex and county of birth. In addition, children with craniofacial malformations were compared to their unaffected siblings.

    Individuals with OFC presented risk increases for intellectual disability, language disorders, psychosis, autism spectrum disorder, attention-deficit/hyperactivity disorder and behavioural disorders in childhood. CPO showed the most robust associations, followed in descending order by CLP and CL. Nonaffected siblings had a lower risk of psychiatric disorders. Females generally had higher risks for psychiatric comorbidity (Study I).

    Children with bilateral clefts had higher risk increases for psychiatric disorders compared to children with unilateral clefts. We also found that females with bilateral CLP showed higher risks for intellectual disability and neurodevelopmental disorders compared to males with bilateral CLP (Study III).

    Risk increases for any psychiatric disorder including intellectual disability, language disorders, other neurodevelopmental disorders and other psychiatric disorders, were seen in individuals with NSCS. In the crude analyses full siblings with NSCS, as compared to nonaffected siblings, were more likely to be diagnosed with any psychiatric disorder, intellectual disability, language disorders and other neurodevelopmental disorders. The higher risk for any psychiatric disorder and intellectual disability remained after adjusting for confounders. Females displayed borderline higher risk increases than males (Study II).

    Finally, children with OFC had lower school performance almost throughout the educational years, especially in mathematics. Lower academic achievement was most evident in children with OFC without a concurrent psychiatric disorder. In the ninth school year and upper secondary school female academic outcomes were more negatively affected than male academic outcomes (Study IV).

    In summary, craniofacial malformations were associated with increased risks for multiple psychiatric disorders and lower academic achievement.

  • Efficient GPU-based Image Registration : for Detailed Large-Scale Whole-body Analysis Author: Simon Ekström Link: Publication date: 2020-11-06 12:21

    Imaging has become an important aspect of medicine, enabling visualization of internals in a non-invasive manner. The rapid advancement and adoption of imaging techniques have led to a demand for tools able to take advantage of the information that is produced. Medical image analysis aims to extract relevant information from acquired images to aid diagnostics in healthcare and increase the understanding within medical research. The main subject of this thesis, image registration, is a widely used tool in image analysis that can be employed to find a spatial transformation aligning a set of images. One application, that is described in detail in this thesis, is the use of image registration for large-scale analysis of whole-body images through the utilization of the correspondences defined by the resulting transformations. To produce detailed results, the correspondences, i.e. transformations, need to be of high resolution and the quality of the result has a direct impact on the quality of the analysis. Also, this type of application aims to analyze large cohorts and the value of a registration method is not only weighted by its ability to produce an accurate result but also by its efficiency. This thesis presents two contributions on the subject; a new method for efficient image registration with the ability to produce dense deformable transformations, and the application of the presented method in large-scale analysis of a whole-body dataset acquired using an integrated positron emission tomography (PET) and magnetic resonance imaging (MRI) system. In this thesis, it is shown that efficient and detailed image registration can be performed by employing graph cuts and a heuristic where the optimization is performed on subregions of the image. The performance can be improved further by the efficient utilization of a graphics processing unit (GPU). It is also shown that the method can be employed to produce a model on health based on a PET-MRI dataset which can be utilized to automatically detect pathology in the imaging.

  • Influence of Islet-derived Factors in Islet Microcirculation and Endocrine Function Author: Carl Johan Drott Link: Publication date: 2020-11-06 08:34

    Diabetes mellitus is a disorder with complex pathology and is frequently associated with vascular complications. In the islet micro milieu locally generated factors may affect both the physiology and the morphology of the tissue. This thesis examines the impact of four different islet-derived factors; thrombospondin-1 (TSP-1), ghrelin, Cocaine and amphetamine regulated transcript (CART) and irisin, and how they influence the endocrine pancreas.

    TSP-1 is an angiogenesis inhibitor. Islets from TSP-1 deficient mice were hypervascular, but with normal endocrine mass. Beta-cell dysfunction was present in islets of TSP-1 deficient mice, both in vivo and in vitro. When trying to reconstitute TSP-1 in islets of TSP-1 deficient animals through a transplantation model, adult islets failed to recover, showing the importance of TSP-1 for glucose stimulated insulin secretion and thereby glucose homeostasis.

    Ghrelin inhibited glucose stimulated insulin secretion and decreased the islet blood flow, while the ghrelin receptor antagonist GHRP-6 in fasted, but not fed, rats increased the islet blood flow fourfold and improved the peak insulin response to glucose. The ghrelin receptor GHS-R1α was identified in the alpha cells and the islet arterioles.

    CART selectively reduced the islet blood flow in the pancreas, and this effect was unaltered by simultaneous administration of an endothelin-A receptor antagonist. CART administration did not affect insulin release, neither in insulin release from isolated islets or in an intravenous glucose tolerance test. 

    Irisin was confirmed located within the pancreatic islets predominately in the alpha-cells. Irisin reduced islet and white adipose tissue blood flow. Irisin was secreted as a response to increased glucose concentrations in vivo.  Irisin had no direct effect on insulin secretion.

    In conclusion, all factors investigated proved to have roles locally in the endocrine pancreas. TSP-1 deficiency caused vascular morphological alterations, and chronic β-cell dysfunction. Ghrelin, CART and irisin all decreased islet blood flow. Ghrelin acted directly through its receptor GHS-R1α in islet arterioles, thereby restricting the insulin response to hyperglycemia, whereas for CART and irisin the specific mechanism continues to be unknown, without identification of a receptor. In order to reach full physiological understanding, the receptors for CART and irisin need to be identified. All four islet-derived factors hold potential for the treatment of type 2 diabetes.