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.

No description available.

This thesis includes three studies examining the role of the type I (NPT1) and type II (NPT2) renal sodium (Na+)-phosphate (Pi) cotransporter genes in inherited hypophosphatemias. In the first study, the chromosomal locations of the NPT1 and NPT2 genes in human and rabbit are determined by physical mapping techniques. The NPT1 and NPT2 genes map respectively to human chromosomes 6p22 and 5q35 and to rabbit chromosomes 12p11 and 3p11. The localization of the two cotransporter genes to autosomes excludes them as candidate genes for X-linked hypophosphatemia. In addition, these assignments agree with the previously reported homology between rabbit chromosome 12 and human chromosome 6 and provide the basis for the establishment of a conserved syntenic group between rabbit chromosome 3 and human chromosome 5. / The goal of the second study was to clone, sequence and characterize the structure of the human NPT2 gene in order to design intronic primers to amplify NPT2 exons from patient DNA. Parallel experiments were performed on the mouse Npt2 gene, so that a vector could be designed to knockout the mouse Npt2 gene. In both species, the type II renal Na+-Pi cotransporter gene is approximately 16kb in length and is comprised of 13 exons and 12 introns. This work provides a basis for the study of the regulation of NPT2 transcription and facilitates the screening of DNA samples from patients with autosomally inherited disorders of renal Pi reabsorption for mutations in the NPT2 gene. / In the third study, polymorphic markers flanking the NPT1 and NPT2 genes were typed in members of a Bedouin kindred segregating the autosomal disorder Hereditary hypophosphatemic rickets with hypercaloiuria (HHRH). Genotype data were examined for excess homozygosity and allele sharing among affected pedigree members. Data did not reveal excess allele sharing on either chromosome 6 or 5, where the NPT1 and NPT2 genes are located, but suggested chromosome 3p as a site for further investigation. Identification of a HHRH locus is the first step toward identifying a gene involved in the pathophysiology of this disorder.

Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 3 uppsatser.

Class of 2017 Abstract / Objectives: To determine the cost-effectiveness of proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors with high-intensity statins compared to high-intensity statins alone for the treatment of heterozygous familial hypercholesterolemia (HeFH). Methods: A Markov model was built through TreeAge Pro to model two groups: patients taking PCSK9 inhibitors with high-intensity statins or high-intensity statins alone. For each group, there were five health states that patients could be in: well, unstable angina, myocardial infarction, ischemic stroke, or death. The data used in the model were extracted from published clinical trials evaluating PCSK9 inhibitors and statins. Results: For the primary analysis, the overall cost and effectiveness was $31,390.93 and 23.01 for the statin alone group and $362,798.50 and 24.32 for the PCSK9 with statin group, respectively. The incremental cost, incremental QALY, and incremental cost-effectiveness ratio (ICER) was $331,407.60, 1.31 QALYs, and $252,833.60/QALY, respectively. Conclusions: Since the calculated ICER was higher than the pre-established threshold of $150,000, the results from our primary analysis suggest that treatment of patients with HeFH with a PCSK9 inhibitor and a high-intensity statin is not cost effective, compared to treatment with a high-intensity statin alone. However, when certain parameters (cost of PSCK9 and mortality rate) were adjusted in the secondary analyses, these agents appear to be cost-effective.

No description available.

Diss. (sammanfattning) Umeå : Univ., 2007. / Härtill 5 uppsatser.

No description available.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

La prévalence du trouble oppositionnel avec provocation (TOP) chez les enfants est particulièrement élevée dans la population générale québécoise. Les conséquences liées à ce trouble sont lourdes et tendent à persister dans le temps. Puisque le TOP réside plus spécifiquement dans la relation problématique que l'enfant entretient avec ses figures d'autorité, porter attention aux variables du fonctionnement familial qui y sont associées est une avenue prometteuse pour identifier les cibles d’intervention à préconiser. L'objectif poursuivi dans ce mémoire est donc de déterminer les variables du fonctionnement familial les plus fortement associées à la présence d’un TOP chez les enfants et de vérifier l’effet modérateur du sexe. L'utilisation du modèle de fonctionnement familial de Pauzé et Petitpas (2013) a permis d'identifier les variables familiales les plus proximales à l'enfant et plus susceptibles d'avoir une influence sur son fonctionnement quotidien. L'échantillon est composé d'un groupe de 197 enfants (141 garçons et 56 filles) ayant un TOP comparé à un groupe témoin composé de 185 enfants (93 garçons et 92 filles) sans TOP, ni autres troubles de comportement. Au plan univarié, les résultats montrent que le fonctionnement familial global plus faible, la relation détériorée entre le parent et l'enfant, le faible engagement parental, le manque de supervision et la discipline inconstante sont significativement associés au groupe d'enfants présentant un TOP, en comparaison au groupe témoin. Au plan multivarié, les résultats montrent que la structure familiale (le fait de vivre dans une famille monoparentale ou recomposée) ainsi qu'une relation détériorée entre le parent et l'enfant ressortent comme étant les variables les plus fortement associées au TOP chez les enfants. La qualité de la relation parent-enfant serait d’ailleurs particulièrement importante pour les filles. Il y a donc tout lieu de travailler l'engagement parental, la supervision, la discipline et enfin, le fonctionnement familial global, mais la relation entre le parent et l'enfant demeure une cible d'intervention à prioriser.