Includes bibliographical references. Electronic publication; Full text available in PDF format; abstract in HTML format. Investigates the regulation of the expression of CYP27B1, CYP24 and vitamin D receptor (VDR) mRNA, both in the bone and in the kidney, with the aim to determine whether the regulation of the vitamin D metabolism in the bone is independent from that in the kidney. The effects of age, dietary calcium and vitamin D status on the expression of these genes in both the kidney and the bone, as well as on a number of biochemical factors known to regulate the renal metabolism of 1,25D, such as PTH, calcium and 1,25D itself, were examined. CYP27B1 mRNA expression was also studied in histological sections of rat femoral bone. Electronic reproduction.[Australia] :Australian Digital Theses Program,2001.

Bibliography: leaves [280]-301

Coccolithophores are unicellular microscopic algae (Haptophyta) surrounded by calcium carbonate plates that are produced during their life cycle. These species, whose contemporary contributor is Emiliania huxleyi, are mainly found in the sub-polar and temperate oceans, where they produce huge blooms visible from space. Coccolithophores are sensitive to ocean acidification that results from the ongoing accumulation of anthropogenic carbon dioxide (CO2) in the atmosphere. The response of these organisms to global change appears to be related to the reduction of their ability to produce calcium carbonate at the cellular level. At the community levels, one anticipates changes in the carbon fluxes associated to their blooms as calcification is reduced. However, the consequences of such environmental changes on this species are speculative and require improvements in the description of the mechanisms controlling the organic and inorganic carbon production and export. The first aspect of this work was to study the response of these organisms to artificially modified CO2 concentrations representative of the conditions occurring in the past (glacial) and those expected by the end of the century (2100). Two different levels were examined: the continuous monospecific cultures (chemostats) allowed us to work at the cellular level while the mesocosms gave light to the mechanisms taking place in an isolated fraction of the natural community. The second aspect of this work consisted of field studies carried out during four cruises (2002, 2003, 2004 and 2006) in the northern Bay of Biscay, where the occurrence of E. huxleyi blooms were observed in late spring and early summer. We describe the vertical profiles of biogeochemical variables (nutrients, chlorophyll-a, dissolved inorganic chemistry, particulate carbon, transparent exopolymer particles (TEP)) and study processes such as primary production, calcification and bacterial production. The properties of these blooms are compared with those reported in the literature and enriched with original measurements such as the abundance and concentration of TEP that could play an important role in carbon export to the deep ocean, modifying the properties of the settling ballasted aggregates.

La zone côtière représente seulement une petite partie de la surface océanique, mais elle joue un rôle important dans le cycle du carbone. Pour contribuer à préciser ce rôle, l'objectif de cette thèse était d'étudier les flux de carbone, en immersion et en émersion, des communautés benthiques intertidales vivant sur les estrans rocheux. La respiration et la calcification des principales espèces macrozoobenthiques ont été mesurées en laboratoire pour d'estimer les différentes adaptations métaboliques liées à une vie en milieu intertidal. En complément, les flux globaux de carbone des communautés ont été quantifiés aux interfaces air-sédiment et eau-sédiment grâce à des mesures in situ. D'une manière générale, la respiration de la communauté prévaut sur la production primaire, en conséquence les estrans rocheux semi-battus peuvent être considérés comme hétérotrophes. Grâce aux mesures de respiration en laboratoire et aux comptages d'espèces effectués sur les côtes rocheuses bretonnes, nous avons pu estimer la contribution du macrozoobenthos aux flux de carbone à une échelle régionale. La comparaison entre les résultats in situ et les études en laboratoire à permis de valider nos méthodes.

Detection of coronary calcification from computed tomography scans is a noninvasive examination and has great potential for heart disease diagnosis. This study proposes new features to characterize calcium lesions. Different from the traditional calcium score features, these features are generated from the texture, shape, and gray level statistics of the calcium lesions. We study the correlation between these features and acute myocardial infarction and then compare the results with traditional calcium score features. According to the location of the lesions, patients are first divided into two groups. In one group, the myocardial infarction is located in segment of culprit lesion. For the second group, myocardial infarction is located in segment of non-culprit lesion. In comparing their means, the corresponding p-value of gray level statistics feature ¡§histogram relative smoothness¡¨ could reach 4.47E-07, which has fairly high significance. Furthermore, in studying the differences among patients, experiment on Hypercholesterolemia provide a good result. By comparing the means of patients which are classified into Hypercholesterolemia and non-Hypercholesterolemia groups, the corresponding p-value of texture feature ¡§inverse difference moment¡¨ could reach 3.74E-04. Initially, acute myocardial infarction do not have statistically significant result However, after adding the location weighting factor for the lesions, the corresponding p-value of texture feature ¡§average of information measures of correlation¡¨ could be reduced to 8.8921E-03, and p-value of gray level statistics feature ¡§Histogram relative Smoothness¡¨ could be improved to 2.4019E-02.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 180-209).

Background: Atherosclerosis is an important cause of stroke. Ultrasound offers the convenience of real-time and detailed assessment of carotid plaque features as well as arterial wall thickening and composition. Evaluation of these features is important for determining patients’ risk of suffering vascular events and also contributes to selecting the best treatment strategy. Methods: Using ultrasound data analysis we have determined plaque features in the bifurcation and internal carotid artery (ICA), including: surface plaque irregularities, calcification, echogenicity (grey scale median-GSM) and other textural plaque features (Juxtaluminal black area, entropy, coarseness). In addition, intima media thickens (IMT) and its grey scale median (IM-GSM) was measured in common carotid artery (CCA). Using Cone Beam CT (CBCT) we have quantified calcification volume of the carotid plaques extracted after carotid endarterectomy procedure. For the meta-analysis we have used comprehensive meta-analysis software version 3. Study I: We have included 39 patients and we compared carotid plaque features of the contralateral arteries with those located ipsilateral to symptomatic side and arteries of asymptomatic patients. Study II: The accuracy of US to detect atherosclerosis calcification was assessed against CBCT in 88 patients. Study III: Based on the previous vascular events in coronary, carotid and lower extremity arterial system, 87 patients were divided into three groups: asymptomatic, symptoms in one vascular system and symptoms in more that one vascular system. IMT, IM-GSM and plaque features were compared between groups. Study IV: We have meta-analyzed ten cohort prospective studies evaluating carotid plaque echogenicity for cerebrovascular symptoms prediction. Results: Study I. Plaques of the contralateral to symptomatic arteries had similar features to those in symptomatic and more vulnerable than asymptomatic arteries. Study II. Carotid ultrasound was accurate in detecting calcification volumes of ≥8mm3 with very high sensitivity but it was less accurate in detecting lower calcification volumes (<8mm3). Carotid calcification was not different between symptomatic and asymptomatic patients. Study III. Echogenicity of the intima-media complex (IM-GSM), but not its thickness (IMT), was significantly decreased with increasing number of arterial systems affected by atherosclerosis. IM-GSM was lower in patients with prior myocardial infarction and stroke. Study IV. Carotid plaque echogenicity evaluated by US could predict future cerebrovascular events in patients with asymptomatic, relative risk RR 2.72 (95% CI, 1.86 to 3.96), and recurrent symptoms in symptomatic patients, RR 2.97 (95% CI, 1.85-4.78). Conclusion: Plaques located in the contralateral to symptomatic arteries have similar features as symptomatic side and more vulnerable than asymptomatic arteries. Carotid ultrasound could accurately detect larger but not smaller carotid plaque calcification volumes (<8 mm3). Low IM- GSM could identify patients with multi-system atherosclerosis disease, suggesting a better marker for determining systemic atherosclerosis disease burden compared to conventional IMT. Finally, carotid plaque echogenicity predicts future cerebrovascular events in patients with symptomatic and asymptomatic carotid stenosis.

Phytoplankton dynamics and chemical characteristics of the euphotic zone were measured from 1998-2000 (an El Niño/La Niña cycle) at the 5 major stations along Line P. Near-shelf and offshore stations exhibited low seasonality in chlorophyll and moderate seasonality in particulate organic carbon (POC) production. During the 1998 El Niño, June was characterized by low chlorophyll and POC productivity due to nitrate depletion. In contrast, during the 1999 La Niña, and in 2000, higher POC productivity and nitrate occurred in June. During 1999, chlorophyll and POC productivity were similar to 1998 in late summer. Near-shelf biomass was highest in June and lowest in Feb. for the near-shelf stations. High nitrate, low chlorophyll (HNLC) stations had the highest chlorophyll in Feb. followed by June. The coccolithophore assemblage was usually numerically dominated by Emiliania huxleyi, particularly in June. Along the transect, coccolithophore abundance was much higher in June during the 1998 El Niño than in the 1999 La Niña, with Aug./Sept. abundance of both years being very low. Higher abundances were measured along the transect in June and the late summer of 2000 with sporadic ‘blooms’ of >1000 cells ml⁻¹ at some stations. Particulate inorganic carbon (PIC) production was high along the transect during June 1998, and low during both winters, June 1999 and during late summers of 1998 and 1999. There was an increase in diatom biomass and >20 µm POC production during the 1998 El Niño, specifically in the farthest offshore HNLC stations, yet diatoms were rarely found to dominate total phytoplankton biomass or production. However, there were some sporadic examples of anomalously high diatom biomass (carbon and abundance) as well as >20 µm POC production, specifically at P12 in Aug./Sept 2000. The same major diatom species were found throughout Line P (near-shelf, P16, and HNLC). Integrated silica production measured by ³²Si ranged from 0.2 to 4.7 mmol Si m⁻² d⁻¹ between 1999-2000. Silicic acid and nitrate were never limiting at all stations in Feb. and generally increased in concentration along Line P during all seasons.

L’hypercholestérolémie familiale (FH) est un désordre lipidique associé aux maladies cardiovasculaires les plus fréquentes. La FH est causée par des mutations dans les gènes LDLR, APOB et PCSK9. Toutefois, chez 20% des patients souffrant de FH, aucune mutation dans ces gènes n'a été détectée et ceci suggère que d’autres gènes seraient à l’origine de la FH. Actuellement, le seul traitement de la FH est une thérapie aux statines. En général les statines sont bien tolérées, cependant, une monothérapie ne permet pas d’atteindre des niveaux thérapeutiques acceptables et dans bien des cas, une thérapie combinée devient nécessaire. De plus, l’intolérance aux statines est présente dans environ 12% des patients. Dans les trois dernières décennies, la survie des patients avec la FH a augmentée de façon notoire mais on observe aussi l’apparition d’une calcification vasculaire sévère chez certains d’entre eux. Il est donc primordial de développer des nouvelles approches thérapeutiques afin de prévenir ces complications tardives. Dans cette thèse doctorat, nous présentons l’étude d’une famille avec un phénotype de FH sévère non causé par des mutations dans les gènes LDLR, APOB et PCSK9. Par des études biochimiques et par séquençage d’ADN utilisant les technologies de nouvelle génération (NextGenSeq), nous avons découvert une mutation dans le gène de l’APOE (Leu167del). Ceci nous permet de proposer le gène codant pour l’APOE comme le 4e locus responsable de la FH (FH4). Par la suite, nous avons effectué deux études de cohortes chez les patients atteints de FH. Premièrement, dans l’étude JUPITER, nous avons démontré que la rosuvastatin augmente les niveaux sanguins de la protéine PCSK9 et ceci limiterait l’efficacité du traitement aux statines. Nous avons aussi étudié l’influence du mutant naturel R46L (perte de fonction de la PCSK9) dans la réponse aux statines. Deuxièmement, nous avons examiné les effets de la perte de fonction de la PCSK9 sur le profil cardiométabolique au sein d’une population pédiatrique. Nous avons déterminé que le génotype de l’APOE est déterminant dans ce profil cardiométabolique. Enfin, nous avons étudié la calcification vasculaire chez les patients atteints de FH. Cette calcification vasculaire progresse de façon indépendante des niveaux de cholestérol sérique et n’est pas associée aux anomalies de l’homéostasie du calcium. En utilisant des modèles murins, nous avons démontré que les souris Ldlr-/- et Tg(Pcsk9) développent des calcifications vasculaires semblables à celles observées chez l’homme. De plus, nous avons confirmé l’implication de la voie de signalisation LRP5/Wnt dans la pathophysiologie de la calcification artérielle. Avec une étude interventionnelle, nous avons trouvé que l’inhibition de l’interleukine 1β (IL-1β) diminue fortement l’apparition de calcifications vasculaire dans notre modèle murin. En conclusion, nos études ont permis l’identification d’un nouveau gène impliqué dans la FH, ont démontré aussi que les statines augmentent les niveaux sériques de PCSK9 et que la perte de fonction de la PCSK9 altère le profil cardiométabolique. Enfin, nous avons établi que la calcification vasculaire représente une complication tardive chez les patients atteints de FH et que, dans notre modèle murin, la calcification vasculaire peut être retardée par l’inhibition d’IL-1β. Ces découvertes peuvent avoir d’importantes répercussions cliniques chez l’humain. / Familial Hypercholesterolemia (FH) is the most common lipoprotein disorder associated with premature cardiovascular disease. Mutations in the LDLR, APOB and PCSK9 genes cause the FH phenotype, but in 20% of FH patients, no mutations in these genes are identified, suggesting that mutations in other genes cause FH. Treatment with statins has been the cornerstone of therapy. While statins are generally well tolerated, statin intolerance is found in approximately 12% of patients. Furthermore, statin use may not allow reaching LDL-C goals and combination therapy is often required. Nevertheless, survival of FH patients over the past 3 decades has improved significantly. As FH patients live longer, severe vascular calcifications have been described as a late complication in these patients. Given the increased survival rate and late complications, novel approaches and therapies are needed. In the present thesis we examined a kindred with a severe FH phenotype, where sequencing of candidate genes failed to identify a causal mutation. Through biochemical analysis and next-generation exome sequencing we report a mutation (Leu167del) within the APOE gene that identifies the 4th locus causing FH (FH4). Next, we performed two cohort-based studies. Firstly, in the JUPITER trial we report that 20mg rosuvastatin treatment increases PCSK9 levels by 30%, thereby possibly limiting the efficacy of statin therapy. Then we show the effect of a loss-of-function (LOF) mutation of PCSK9, p.R46L, on the response to rosuvastatin. Secondly, we report that two PCSK9 gene variants, p.R46L and insLEU, were more frequent in French Canadian individuals. We also report that the APOE genotype determine the metabolic risk profile in these mutations. Finally, we studied vascular calcifications in FH individuals. These calcifications appear to progress independently of cholesterol levels and are not associated with disturbances in calcium homeostasis. Using mouse models, we show that Ldlr-/- and Tg(Pcsk9) mice develop aortic calcifications similar to that observed in humans. Furthermore, the involvement of the LRP5/Wnt pathway in the pathogenesis of calcification is illustrated. In a proof-of-concept experiment, inhibiting the upstream pro-inflammatory cytokine IL-1β attenuates calcification in mice. In conclusion, we have contributed to the identification of a novel locus responsible for FH, reported the increase in PCSK9 levels with a statins treatment and the associated altered cardiometabolic profile in PCSK9 LOF. Finally, we demonstrated that vascular calcifications represent a severe complication of FH that can be prevented by inhibiting IL-1β in a mouse model. The latter novel approach may have an important translational application in human.

An uncommon case with semi-spheric perivesical calcification after pelvic radiotherapy is reported and the possible pathogenesis of this phenomenon is discussed. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.