A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand in fulfilment of the requirements for the Degree of Master of Medicine in the branch of Internal Medicine / Untreated patients with heterozygous familial hypercholesterolaemia (hFH) are at increased risk for atherosclerosis. Surrogate markers to predict atheroma include the presence of endothelial dysfunction (ED) as well as increased levels of inflammatory markers / IT2018

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Child sexual abuse (CSA) has been shown to differ depending on the relationship between child complainant and defendant, yet no found studies have compared intra-familial and extra-familial CSA in Sweden. The present thesis aimed to study quantitative differences between alleged intra-familial and extra-familial cases of CSA. Cases from Swedish District Courts (n = 174) of sexual abuse against children up to 7 years old were analyzed. In line with previous research, several differences in characteristics between alleged intra- and extra-familial cases were found. A significant difference in juridical decision to convict or acquit was also shown, with more intra-familial cases resulting in acquittal and more extra-familial cases resulting in conviction. Extra-familial relationship was also a significant predictor to conviction. Future studies may want to further examine whether an explanation for the difference in juridical decision could be found in differences in evidence provided. / Fall rörande sexuella övergrepp på barn har visats vara olika beroende vilket förhållande det målsägande barnet och den anklagade har. Trots det har inga svenska studier hittats som jämför rättsfall som berör sexuella övergrepp på barn med avseende på skillnader mellan fall som skett inom och utom familjen. Syftet med denna examensuppsats var att undersöka kvantitativa skillnader mellan påstådda rättsfall av sexuella övergrepp som skett inom och utom familjen. Rättsfall som berörde sexuella övergrepp på barn upp till 7 år från svenska tingsrätter (n = 174) analyserades. I linje med tidigare forskning påvisades flertalet skillnader mellan fall som skett inom och utanför familjen. Det påvisades även en signifikant skillnad i domstolens beslut att fria eller fälla, med fler friade fall som skett inom familj och fler fällda fall där det påstådda brottet skett utanför familj. En utom-familjär relation mellan målsägande och anklagade var dessutom en signifikant prediktor för en fällande dom. Förslag på framtida forskning kan vara att vidare undersöka huruvida skillnaden i beslutet att fria eller fälla kan förklaras av skillnader i tillgången på bevis.

Texte remanié de: Thesis Ph. D.--University of Washington. / Bibliogr. p. 261-273.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

In this report, I study familial longitudinal count data with a Poisson regression model. The data is collected from individuals who are nested in families. I focus on two main issues to fit a model. The first one is the large number of excess zeros and the second one is multi-level random effects. My approach for solving these problems are to use either Zero Inflated Poisson (ZIP) or Negative Binomial (NB) models to control for the excess zeros which allow for estimation of another parameter for over dispersion while developing the model with individual and familial random effects. First, I use a Poisson regression model with only main effects. After that, I fit a ZIP model to control for the extra zeros. I provide information about general form of the exponential families and a discussion about the dispersion parameter. I also fit a Negative Binomial model instead of the ZIP model. I also build these models with only individual random effects and with both individual and familial random effects as well. I discuss the generalized estimating equation (GEE) approach to estimate the parameters of a generalized linear model with auto regressive correlation between outcomes. / text

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Mutations in the melanocortin 2 receptor (MC2R) and its accessory protein (MRAP), in the ACTH signalling pathway, and the antioxidant genes nicotinamide nucleotide transhydrogenase (NNT) and thioredoxin reductase 2 (TXNRD2) have been associated with familial glucocorticoid deficiency (FGD). Using a tandem affinity purification and mass spectrometry approach to identify interacting partners of MC2R and MRAP failed to identify putative candidate genes for further FGD cases. However in a male patient a homozygous mutation in another antioxidant gene, glutathione peroxidase 1 (GPX1), was identified. In vitro studies showed H295R cells with knockdown of GPX1 had 50% less basal GPX activity and were less viable than wild-type when exposed to oxidative stress. Adrenals from Gpx1-/- mice showed no gross morphological changes and corticosterone levels were not significantly different from their wild-type counterparts (in contrast to the Nnt mutants). Sequencing of >100 FGD patients did not reveal any other GPX1 mutations. This equivocal data lead to the hypothesis that there could be a second gene defect present in this proband contributing to his disease. Whole exome sequencing revealed a homozygous loss-of-function mutation in peroxiredoxin 3 PRDX3 (p.Q67X) in this patient, that was also present in his unaffected brother. In vitro studies revealed both single and double knockdown of the two genes in H295R cells reduced cell viability, but redox homeostasis and cortisol production were unaffected. GPXs and PRDXs work simultaneously to reduce H2O2, preventing cellular damage. My data suggest that loss of PRDX3 alone is insufficient to cause adrenal failure and further that mutation in GPX1, either alone or in combination with PRDX3 mutation, may tip the redox balance to cause FGD.

Myelodysplasia (MDS) is characterised by inefficient haematopoiesis with dysplastic features of blood and bone marrow, reduction of mature blood cells and continuous bone marrow failure (BMF). Acute myeloid leukaemia (AML) is characterised by the accumulation of immature myeloid blasts in the bone marrow. MDS and AML are mostly sporadic clonal disorders affecting older patients. Familial occurrence of MDS/AML is rare, and most of these cases occur in the setting of genetic syndromes. However, it has also been reported to be caused by germline heterozygous mutations in genes including RUNX1, CEBPA, TERC, TERT, GATA2, SRP72, and ANKRD26. Our group has collected 115 families that have two or more individuals with BMF with at least one of whom has MDS or AML. The aim of this project was to identify disease causing gene variants that can lead to familial MDS/AML. Identification of predisposing variants to familial MDS/AML is critical for effective management in these families. This will also provide new insights into the biology of MDS/AML in general. Herein, we have characterised a subset of families with MDS/AML as well as identified candidate disease genes using a range of genetic studies. Specifically, we have: i. Identified new genetic variants in some of the known disease genes such as RUNX1 and GATA2. ii. Our studies have substantiated the discovery of DDX41 as a disease gene as we have identified several families harbouring novel heterozygous loss of function (LoF) DDX41 variants. iii. Identified germline heterozygous LoF RTEL1 variants in a subset of families with myelodysplasia and liver disease. This defines a new disease group in this field, RTEL1 can now be added to the list of familial MDS/AML disease genes. iv. We have identified nine new candidate disease genes which are involved in RNA splicing, transcription factor, DNA modification, cell signalling and intracellular transport.