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.

Myosin subfragment-2 (S2) is an intrinsically unstable coiled coil. This dissertation tests if the mechanical stability of myosin S2 would influence the availability of myosin S1 heads to actin thin filaments. The elevated instability in myosin S2 coiled coil could be one of the causes for hypercontractility in Familial Hypertrophic Cardiomyopathy (FHC). As hypothesized FHC mutations, namely E924K and E930del, in myosin S2 displayed an unstable myosin S2 coiled coil compared to wild type as measured by Fluorescence Resonant Energy Transfer (FRET) and gravitational force spectroscopy (GFS). To remedy this, anti-S2 peptides; the stabilizer and the destabilizer peptides by namesake were designed in our lab to increase and decrease the stability of myosin S2 coiled coil to influence the actomyosin interaction. Firstly, the effectiveness of anti-S2 peptides were tested on muscle myosin S2 peptides across MYH11 (smooth), MYH7 (cardiac), and MYH2 (skeletal) with GFS and FRET. The results demonstrated that the mechanical stability was increased by the stabilizer and decreased by the destabilizer across the cardiac and skeletal myosin S2 isoform but not for the smooth muscle isoform. The destabilizer peptide had dissociation binding constants of 9.97 × 10-1 μM to MYH7 isoform, 1.00 μM to MYH2 isoform, and no impact on MYH11, and the stabilizer peptide had dissociation binding constants of 2.12 × 10-2 μM to MYH7 isoform, 3.41 × 10-1 μM to MYH2 isoform, and no impact on MYH11 revealed by FRET. In presence of the stabilizer, FRET assay, affinity of the E930del and E924K increased by 10.23 and 0.60 fold respectively. The force required to uncoil muscle myosin S2 peptides in the presence of the stabilizer peptide was more than in its absence in muscle myosin S2 isoforms of MYH7 (1.80 fold higher), MYH2 (1.40 fold higher), and E930del (2.60 fold higher) and no change for MYH11 compared to control. The force required to uncoil muscle myosin S2 in presence of the destabilizer was less than in its absence in both MYH7 (2.00 fold lower) and MYH2 (2.5 fold lower) but the same for MYH11 compared to their controls. Both FRET and GFS assays demonstrated that both anti-S2 peptides do not have any impact on smooth muscle myosin S2 isoform. In FRET assay, there was no significant difference in the lifetime value in the presence or absence of anti-S2 peptides in smooth muscle myosin S2. In GFS assay, there was no significant difference in the force required to uncoil the dimer in presence or absence of the anti-S2 peptides smooth muscle myosin S2. Effectively, the stabilizer peptide improved the stability of FHC mutant (E924K and E930del) myosin S2 peptide. FHC mutations showed high lifetime value in FRET assay and low force to uncoil coiled coil myosin S2 in GFS assay. In the presence of the stabilizer, lifetime value decreased in FRET assay and more force was required to uncoil myosin S2 coiled coil in GFS assay. This study demonstrated that structure of muscle myosin S2 can be altered by small peptides. The stabilizer peptide enhanced dimer formation in wild type and mutant cardiac, and skeletal myosin S2 peptides, and destabilizer increased flexibility of cardiac and skeletal myosin S2 wild type peptide. Neither anti-S2 peptides had impacts on smooth muscle myosin S2 isoform. The study thus effectively demonstrates the mechanical stability of myosin S2 coiled coil in striated muscle system could be modified using the specific anti-S2 peptides. Stabilizer of the anti-S2 peptide was effective to remedy the dampened stability of FHC myosin S2 coiled coil thus providing a new dimension of treating cardiovascular and skeletal muscle disorders by targeting the structural property of muscle proteins.

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.