L'hypertension artérielle pulmonaire (HTAP) est une maladie qui est caractérisée par l'augmentation progressive des résistances vasculaires pulmonaires causant une insuffisance cardiaque droite et ultimement le décès prématuré des patients. Malgré des traitements spécifiques, les patients souffrant d'HTAP demeurent dyspnéiques et intolérants à l'effort. L'atteinte vasculaire pulmonaire présentement irréversible dans cette maladie est la source de plusieurs anomalies au niveau des systèmes cardiovasculaires, ventilatoires et musculaires constituant les principaux déterminants physiologiques de la capacité à l'exercice. Cette thèse a voulu investiguer les trois différentes facettes de la tolérance à l'effort en HTAP : les causes, les méthodes d'évaluation ainsi que les moyens visant son amélioration. Nous avons premièrement documenté l'existence d'une étroite relation entre le niveau d'activité physique quotidien et la tolérance à l'effort dans cette maladie. Également, ce projet a permis de démontrer pour la première fois que le test de marche de six minutes (TM6) était objectivement représentatif des activités de la vie quotidienne des patients. Nous avons ensuite évalué la demande physiologique que représentaient cinq différents tests d'effort, dont deux épreuves à charge constante n'ayant jamais été formellement évaluée en HTAP. Ces résultats ont permis de mettre en lumière que chacun d'entre eux induisait une demande physiologique maximale semblable, mais que leur progression était différente. De plus, les paramètres physiologiques étaient légèrement plus élevés suite à un test de nature imposée par rapport à un test autogéré. Par la suite, nous avons vérifié l'effet de l'ajout du citrate de sildénafil à la médication de base de patients sur leur tolérance à l'effort. Premièrement l'efficacité clinique de ce type de thérapie, aussi appelée traitement de combinaison, a été objectivée par une amélioration significative de la distance marchée au TM6. Nous avons finalement testé la répétabilité et la sensibilité de trois différents tests d'effort en HTAP. Cette étude a démontré que le TM6 était le test à l'effort le plus sensible à détecter un changement clinique significatif suite à l'ajout du citrate de sildénafil à la médication de base des patients en HTAP. Ceci s'expliquait entre autre par la meilleure répétabilité de ce test comparativement à deux autres tests à charge constante. Malgré que les paramètres physiologiques n'aient été que modestement modulés, l'amélioration de la durée/distance des tests était représentative de la perception subjective des patients. Les résultats obtenus au cours de ce doctorat supportent donc l'utilisation du TM6 comme outil essentiel dans l'évaluation de la tolérance à l'effort des patients HTAP.

L’hypertension artérielle pulmonaire (HTAP) est nouvellement caractérisée par une élévation de la pression artérielle pulmonaire moyenne au-dessus de 20mmHg, une pression capillaire pulmonaire inférieure à 15 mmHg et une résistance vasculaire pulmonaire supérieure ou égale à 3 unités Wood. Cette élévation de la pression et de la résistance vasculaire pulmonaire entraine une hypertrophie cardiaque droite et peut éventuellement mener à la mort prématurée des patients. L’augmentation de la résistance vasculaire est causée par une vasoconstriction et un remodelage important des artères pulmonaires distales, due en grande partie à une prolifération excessive et une résistance à l’apoptose des cellules musculaires lisses d’artères pulmonaires (PASMCs), mais également d’autres cellules constituant la paroi des artères pulmonaires distales telles que les cellules endothéliales et les fibroblastes. Malheureusement, les traitements actuellement disponibles sont limités et ne permettent pas une rémission complète de la maladie. Dans le cancer, le facteur de transcription FOXM1 est fréquemment surexprimé et a été décrit comme un régulateur important de plusieurs processus cellulaires tels que la prolifération, l’inflammation et la réparation des dommages à l’ADN, favorisant le développement et la progression tumorale. Considérant les similitudes entre les PASMCs HTAP et les cellules cancéreuses, nous avons posé l’hypothèse qu’une surexpression de FOXM1 favorise le phénotype des PASMCs HTAP et que son inhibition pourrait représenter une nouvelle cible thérapeutique potentielle. Lors de cette étude, nous avons démontré que FOXM1 est surexprimé dans les PASMCs isolées et dans les poumons de patients HTAP comparativement aux individus témoins, de même que dans différents modèles précliniques. Nous démontrons que la diminution de l’expression de miR-204 observée en HTAP est en partie responsable de la surexpression de FOXM1. L’inhibition moléculaire de FOXM1 par ARN interférant et son inhibition pharmacologique à l’aide de la thiostrepton diminue in vitro la prolifération cellulaire et la résistance à l’apoptose. In vivo, l’administration de la thiostrepton permet d’améliorer l’HTAP établie dans deux modèles. L’amélioration des données hémodynamiques est associée à une diminution du remodelage vasculaire. Nous avons montré que la réversion du phénotype HTAP des PASMCs est attribuable à la diminution de l’expression du facteur anti-apoptotique Survivin et de NBS1, membre du complexe MRN impliqué dans la reconnaissance des dommages à l’ADN, entrainant une diminution de l’activation de voie de réparation des dommages à l’ADN. Nous avons par la présente étude démontré pour une première fois l’implication de FOXM1 dans l’étiologie de l’HTAP et l’intérêt de cibler cette protéine dans le développement de futures thérapies. / Pulmonary arterial hypertension (PAH) is a progressive vascular disease newly characterizedby increased mean pulmonary artery pressure above 20 mmHg, capillary pressure under 15mmHg and vascular resistance above or equal to 3 Wood units. This increase in pressure leads to right heart hypertrophy, failure and, eventually, premature death. Increased vascular resistance is caused by vasoconstriction and remodeling of the distal pulmonary arteries, mainly due to excessive proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs), but also from other cells found in the vascular wall such as endothelial cells and fibroblasts. Despite recent advances made in understanding the cellular mechanisms involved in PAH etiology, available treatments remain limited and do not provide a complete cure. In cancer, transcription factor FOXM1 is frequently overexpressed and has been described as a master regulator of multiple cellular process such as proliferation, inflammation and DNA damage repair signaling, thus promoting tumor development and progression. Because of the similarities between PAH-PASMCs and cancer cells, we hypothesized that overexpression of FOXM1 promotes cell proliferation and resistance to apoptosis in PAH and that its inhibition could represent a new therapeutic target. In this study, we demonstrated that FOXM1 is overexpressed in isolated PASMCs and total lung from PAH patients compared to controls as well as in two preclinical animal models. Decreased expression of miR-204 in PAH-PASMCs accounts for FOXM1 overexpression. Molecular (siRNA) and pharmacological inhibition of FOXM1 using thiostrepton decrease cell proliferation and resistance to apoptosis. Daily administration of thiostrepton improves established PAH in two animal models. Improved hemodynamic data are associated with decreased vascular remodeling. We demonstrated that reversal of PAH phenotype is in part due to the downregulation of anti-apoptotic factor Survivin and NBS1, member of the MRN complex involved in DNA damage recognition, which impairs activation of DNA damage repair signaling. With this study, we demonstrated for the first time that FOXM1 is involved in PAH etiologyand the interest in targeting FOXM1 for the development of futures therapies.

Dissertation submitted in partial compliance with the requirements for the Master’s Degree in Technology: Homoeopathy, Durban University of Technology, 2011. / Hypertension is a serious problem in South Africa, affecting 18.8 percent of women (South African Demographic and Health Survey, 2003), prompting investigation into treatment. In total, approximately 6.1 million people suffer from Hypertension in South Africa. AIM The purpose of this double-blind study was to evaluate the efficacy of the Homoeopathicsimillimum and a Homoeopathic complex (Aurummetallicum6CH, Lachesismuta6CH, Natrummuriaticum6CH, and Veratrum album 6CH) in the treatment of Primary Hypertension in adult females. METHODOLOGY A minimum of 30 patients were recruited and were selected on the basis of specified inclusion and exclusion criteria, and randomly divided into two equal groups by the research supervisor, with the first group receiving the Homoeopathic simillimum andthe second group receiving the Homoeopathic complex.The initial consultation took place at the Durban University of Technology or at the Umlazi Medical Centre after obtaining informed consent from the patients (Appendix D).A detailed case history was taken, followed by a complete physical examination, including blood pressure readings and cardiovascular system examinations. Follow up consultations occurred weekly for a period of four weeks to record blood pressure readings, any changes in the general health and well being of the participants, in order to prescribe more medicines if needed. A mercury sphygmomanometer and a Littmann Classic 2 stethoscope were the tools of measurement and was used according to the method outlined by Bates (2007), which states that an accurate measurement of blood pressure is dependent on the appropriate cuff size of the sphygmomanometer and whether the type of gauge used needs to be calibrated or not. SPSS version 18 was used to analyse the data. A p value <0.05 was considered as statistically significant. Repeated measures ANOVA tests were done to compare the blood pressures over time between the treatment groups. Specific remedies used at each time point were described by treatment group. Potencies of the remedies were compared within each remedy between the treatment groups using Pearson’s chi square tests. RESULTS Within each of the two treatment groups there was a highly significant decrease in systolic blood pressure over time (p<0.001). This means that both treatments were effective at lowering systolic blood pressure. Within each of the two treatment groups there was a highly significant decrease in diastolic blood pressure over time (p=0.001 and p<0.001 respectively). This means that both treatments were effective at lowering diastolic blood pressure. Systolic and diastolic blood pressures at five time points were compared between the two treatment groups using repeated measures ANOVA. There was an overall significant change over time in both groups (p<0.001), but the change over time was not different according to treatment groups (p=0.355). The decrease in systolic blood pressure over time was nearly identical in the two groups as the profiles are almost parallel. Therefore in terms of systolic blood pressure there was no statistical evidence for one treatment being more beneficial than the other. There was an overall significant change over time in both groups (p<0.001) but the change over time was not different according to treatment groups (p=0.187). The decrease in diastolic blood pressure over time was almost the same rate in both groups as the profiles are almost parallel. Therefore in terms of diastolic blood pressure there was no statistical evidence for one treatment being more beneficial than the other. CONCLUSION The results of the study led to the conclusion that both the simillimum and complex treatments were effective at reducing blood pressure over time, but there was no evidence that one treatment was more beneficial than the other, since the rates of change over time in systolic and diastolic blood pressure were similar in both treatment groups.

Liu, Qilin. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 97-110). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts also in Chinese; appendixes includes Chinese.

Wan Wing Kuen. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 114-128). / Abstracts in English and Chinese. / Thesis Abstract --- p.i / Dedication --- p.iii / Acknowledgements --- p.iv / List of Figures --- p.xii / List of Tables --- p.xiv / Abbreviations --- p.xv / Chapter CHAPTER 1: --- INTRODUCTION --- p.1 / Chapter 1.1 --- Research Initiative and Significance --- p.1 / Chapter 1.2 --- Cardiomyocyte and Terminal differentiation --- p.4 / Chapter 1.3 --- Hypertension and Myocardial Hypertrophy --- p.7 / Chapter 1.3.1 --- Hypertension --- p.7 / Chapter 1.3.2 --- Myocardial Hypertrophy --- p.8 / Chapter 1.4 --- Experimental Animal Models --- p.13 / Chapter 1.4.1 --- Spontaneously Hypertensive Rats --- p.15 / Chapter 1.4.2 --- Wistar-Kyoto Rats --- p.16 / Chapter 1.5 --- Combination of Suppression Subtractive Hybridization and cDNA Microarray Analysis --- p.17 / Chapter 1.5.1 --- Suppression Subtractive Hybridization --- p.17 / Chapter 1.5.2 --- cDNA Microarray A nalysis --- p.21 / Chapter 1.5.3 --- Combination of SSH and cDNA microarray --- p.24 / Chapter CHAPTER 2: --- MATERIALS AND METHODS --- p.25 / Chapter 2.1 --- Experimental Animal Models --- p.25 / Chapter 2.2 --- RNA Isolation from Rat Ventricle --- p.26 / Chapter 2.2.1 --- Total RNA Isolation --- p.26 / Chapter 2.2.2 --- Deoxyribonuclease I Digestion --- p.27 / Chapter 2.3 --- Suppression Subtractive Hybridization --- p.29 / Chapter 2.3.1 --- First-Strand cDNA Synthesis --- p.29 / Chapter 2.3.2 --- Second-Strand cDNA Synthesis --- p.30 / Chapter 2.3.3 --- Column Chromatography --- p.31 / Chapter 2.3.4 --- Rsa I Endonuclease Digestion --- p.32 / Chapter 2.3.5 --- Adaptor Ligation --- p.33 / Chapter 2.3.6 --- Ligation Efficiency Analysis --- p.34 / Chapter 2.3.7 --- First Hybridization --- p.35 / Chapter 2.3.8 --- Second Hybridization --- p.36 / Chapter 2.3.9 --- Primary PCR Amplification --- p.36 / Chapter 2.3.10 --- Secondary PCR Amplification --- p.38 / Chapter 2.3.11 --- Subtraction Efficiency Analysis --- p.38 / Chapter 2.4 --- Construction of Subtracted cDNA Libraries --- p.40 / Chapter 2.5 --- cDNA Microarray Analysis --- p.42 / Chapter 2.5.1 --- PCR amplification of Subtracted Clones --- p.42 / Chapter 2.5.2 --- Purification of PCR Products of Subtracted Clones --- p.42 / Chapter 2 5.3 --- Rearrangement of Subtracted Clones into cDNA Microarray Format --- p.43 / Chapter 2.5.4 --- cDNA Microarray Fabrication --- p.43 / Chapter 2.5.5 --- Probe Preparation --- p.44 / Chapter 2.5.6 --- cDNA Microarray Hybridization --- p.46 / Chapter 2.5.7 --- Scanning cDNA Microarray Image and Data Analysis --- p.46 / Chapter 2.6 --- Sequencing of Differentially Expressed Genes --- p.48 / Chapter 2.6.1 --- Dye-terminator Cycle Sequencing --- p.48 / Chapter 2.6.2 --- Post-reaction Cleanup --- p.49 / Chapter 2.6.3 --- Signal Detection and Data Collection --- p.49 / Chapter 2.6.4 --- Sequencing Analysis --- p.50 / Chapter 2.7 --- Reverse Transcription Polymerase Chain Reaction --- p.51 / Chapter 2.8 --- Northern Blot Analysis --- p.54 / Chapter 2.8.1 --- RNA Transfer --- p.54 / Chapter 2.8.2 --- Probe Labeling --- p.55 / Chapter 2.8.3 --- Hybridization --- p.55 / Chapter 2.8.4 --- Chemiluminescent Detection --- p.56 / Chapter CHAPTER 3: --- RESULTS --- p.58 / Chapter 3.1 --- Suppression Subtractive Hybridization --- p.58 / Chapter 3.1.1 --- The Optimal Cycle for SMART cDNA Synthesis --- p.58 / Chapter 3.1.2 --- Adaptor Ligation Efficiency --- p.60 / Chapter 3.1.3 --- Primary and Secondary PCR Amplification of Subtracted cDNA --- p.63 / Chapter 3.1.4 --- Subtraction Efficiency --- p.66 / Chapter 3.2 --- Subtracted cDNA Libraries --- p.68 / Chapter 3.3 --- cDNA Microarray Analysis --- p.69 / Chapter 3.3.1 --- Isolation and Amplification of Subtracted cDNA Clones --- p.69 / Chapter 3.3.2 --- Microarray Scanning and A nalysis --- p.69 / Chapter 3.4 --- Sequencing Results of Subtracted cDNA Clones --- p.81 / Chapter 3.5 --- Reverse Transcription Polymerase Chain Reaction --- p.87 / Chapter 3.6 --- Northern Blot Hybridization --- p.90 / Chapter CHAPTER 4: --- DISCUSSION --- p.93 / Chapter 4.1 --- Subtraction Quality --- p.93 / Chapter 4.2 --- Differential Screening by cDNA Microarray --- p.95 / Chapter 4.2.1 --- Elimination of False Subtracted Clones --- p.95 / Chapter 4.2.2 --- Limitations of cDNA Microarray --- p.96 / Chapter 4.3 --- Differentially Expressed Genes in Hypertensive Heart --- p.98 / Chapter 4.3.1 --- Candidate Genes Showing Up-regulation --- p.99 / Chapter 4.3.1.1 --- Voltage-dependent Anion Channel 1 --- p.99 / Chapter 4.3.1.2 --- Protein Tyrosine Phosphatase 4a 1 --- p.101 / Chapter 4.3.1.3 --- Choline Transporter-like Protein 1 Splice Variant a --- p.102 / Chapter 4.3.2 --- Candidate Genes Showing Down-regulation --- p.103 / Chapter 4.3.2.1 --- Ryanodine Receptor 2 --- p.103 / Chapter 4.3.2.2 --- Guanine Nucleotide-binding Protein β1 Subunit --- p.104 / Chapter 4.3.2.3 --- Solute Carrier Family 3 Member 1 --- p.105 / Chapter 4.4 --- The Pros and Cons of Using Ventricular Tissue but not Cardiomyocytes --- p.107 / Chapter 4.5 --- Future Prospect --- p.109 / Chapter 4.5.1 --- Expression Profiling of Candidate Genes at Different Stages --- p.109 / Chapter 4.5.2 --- In vitro Studies of Candidate Genes --- p.110 / Chapter 4.5.2.1 --- Over-expression of up-regulated genes in Normal Cardiac Cells --- p.110 / Chapter 4.5.2.2 --- Suppression of down-regulated genes in Normal Cardiac Cells --- p.111 / Chapter 4.5.3 --- In vivo Studies of Up-regulated Genes --- p.111 / Chapter 4.5.4 --- Confirmation of Other Potential Candidate Genes --- p.112 / Chapter 4.6 --- Conclusion --- p.113 / REFERENCES --- p.114

Bibliography: leaves 67-75

Reproduction de : Thèse d' exercice : Médecine spécialisée : Nancy 1 : 2002. / Thèse : 2002NAN11144. Titre provenant de l'écran-titre.

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

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Previous studies have showed an association between emotional distress and decreased physical functioning in patients with pulmonary hypertension (PH); however, none controlled for demographic and disease characteristics. This study investigates the independent association of depressive symptoms with physical functioning after controlling for both demographic and disease characteristics. Fifty-two patients, mean age 61 (SD = 14) years, undergoing cardiac catheterization, completed self-report questionnaires of depressive symptoms and physical functioning. Results showed that depressive symptoms (beta = -.28, p &lt; .05) accounted for a statistically significant 8% of incremental variance in physical functioning over and above the variance explained by demographic and disease characteristics. The direction of effects cannot be determined because of the cross-sectional design. As such, the association of depressive symptoms with physical functioning in PH patients indicates the need for longitudinal research regarding the possible effect of depression on disease outcomes in this population.