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Valvular heart disease : novel epidemiological and imaging studiesd'Arcy, Joanna Louise January 2016 (has links)
Since living conditions have improved and antibiotics have entered routine use, valvular heart disease (VHD) in the developed world is mostly degenerative in origin, rather than rheumatic. Our population is increasing with age, and therefore the burden of VHD is likely to increase. Despite this, the epidemiology & prognostication in VHD remain poorly understood. A better understanding of the prevalence of VHD in our population, and improved methods of predicting outcomes, are essential if we are to be better equipped to meet the challenges of this new “epidemic”. This thesis aims to improve our knowledge of the prevalence of VHD in the elderly, and the potential benefits of cardiac magnetic resonance (CMR) assessment of patients with clinically significant mitral regurgitation. The prevalence of undiagnosed valvular heart disease in those aged 65 and over is examined in Chapters 2 and 3. Chapter 2 outlines a population-based screening study for VHD in primary care in Oxfordshire, which the author played a central role in establishing. The results show that VHD is extremely common in this cohort, and is strongly associated with increasing age. In chapter 4, the level of anxiety provoked by screening for VHD is looked at; this demonstrates that only a small number of patients have significant anxiety levels, but it is more likely in those with a new diagnosis of VHD, and in women. From Chapter 5 onwards, the thesis focuses on the use of CMR in patients with significant mitral regurgitation (MR). In Chapter 5, the clinical value of quantitative assessment of MR using CMR is examined, showing that it was able to predict progression to symptoms or surgery in these patients. In conclusion, this thesis offers insights into the prevalence of VHD in the elderly population, and looks at the anxiety associated with looking for VHD in this group. The potential clinical benefits of CMR in patients with MR are examined, and quantification of MR with this modality would appear to be of prognostic utility.
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Oligonucléotides comme modulateurs de l'expression génique / Oligonucleotides as gene expression modulatorsRouleau, Samuel January 2017 (has links)
L’ARN est sans aucun doute la molécule biologique la plus versatile qui soit. Tout comme l’ADN, il peut contenir et transmettre de l’information génétique. Tout comme les protéines, il peut accomplir une multitude de fonctions biologiques. De plus, son rôle le plus connu demeure celui d’intermédiaire entre l’ADN et les protéines. L’ARN est donc au cœur d’un bon nombre de processus biologiques. Ceci lui confère un immense potentiel thérapeutique qui jusqu’à présent demeure largement inexploité. Pour accomplir ses fonctions, l’ARN doit adopter une structure tridimensionnelle précise qui est dépendante à la fois de sa séquence et de son environnement. Ainsi, en modifiant la structure d’un ARN, il est possible d’en moduler sa fonction. C’est l’objectif global des travaux présentés dans cette thèse. Pour y parvenir, de courts oligonucléotides antisens (OA) ont été utilisés. Cette stratégie revêt plusieurs avantages. Comme les OA s’apparient à leur cible en formant des paires de bases Watson-Crick, ils offrent une grande spécificité et leur design est facile. De plus, en se fiant aux données structurales et aux logiciels de prédictions de structures des ARN, on peut aisément identifier les régions à cibler avec les OA. Enfin, cette technique est versatile puisqu’on peut cibler différents motifs d’ARN. La première cible a été le ribozyme du virus de l’hépatite D. Cet ARN, qui catalyse une réaction d’auto-coupure, a été modifié afin que son activité devienne dépendante à la liaison d’OA. Plusieurs modules ont ainsi été créés et combinés afin d’obtenir des ribozymes qui répondaient à la présence d’un ou plusieurs OA. En insérant ces interrupteurs moléculaires dans les régions non traduites d’un ARNm, nous avons ainsi modulé l’expression de ce gène avec les OA. Cet outil a des applications intéressantes pour la régulation de gènes en biologie synthétique. Un autre motif ciblé a été le G-quadruplex (G4). Cette structure non canonique exerce de nombreuses fonctions biologiques et représente donc une cible thérapeutique intéressante. Lorsque présent dans la région 5’ non traduite d’un ARNm, le G4 mène généralement à une diminution de la traduction. En utilisant des OA qui empêchent la formation du G4, nous avons été en mesure d’augmenter la traduction du gène ciblé. De plus, il a été possible de développer des OA qui favorisent la formation d’un G4 dans le but de diminuer l’expression de la cible. Finalement, dans le dernier chapitre de cette thèse, il est démontré que les G4 présents dans les microARN primaires influencent leur maturation en microARN matures. Des OA ciblant ces G4 ont été utilisés afin de favoriser la maturation de microARN suppresseurs de tumeurs, ce qui présente un potentiel thérapeutique intéressant. En bref, les travaux présentés dans cette thèse démontrent clairement que les OA sont un outil de choix pour cibler et modifier la structure de motifs d’ARN spécifiques. / Abstract : RNA is a versatile biological molecule. Like DNA, it can contain and transmit genetic
information. Like proteins, it can accomplish multiple biological functions. Also, its most
known role remains that of intermediary between DNA and proteins. RNA is thus a key
player in many biological processes. This gives it an immense therapeutic potential which
remains largely untapped. To fulfill its functions, RNA must adopt a precise threedimensional
structure that is dependent on both its sequence and its environment. Thus, by
modifying the structure of an RNA, it is possible to modulate its function. This is the
overall objective of the work presented in this thesis. To achieve this, small antisense
oligonucleotides (ASO) have been used. This strategy has several advantages. As ASO
bind their target with Watson-Crick base pairs, they offer great specificity and their design
is easy. Moreover, reliance on structural data and RNA structure prediction softwares
makes it easy to identify the regions to be targeted with ASO. Finally, this technique is
versatile since it is possible to target different RNA motifs. The first target was the HDV
self-cleaving motif. This RNA, which catalyzes a self-cleaving reaction, has been modified
so that its activity became dependent on the binding of ASO. Several modules were thus
created and combined in order to obtain ribozymes which responded to the presence of one
or more ASO. By inserting these molecular switches into an mRNA’s UTR, the expression
of this gene was modulated with the ASO. This has interesting applications for the
regulation of genes in synthetic biology. Another target motif was the G-quadruplex (G4).
This non-canonical structure exerts many biological functions and therefore represents an
interesting therapeutic target. When present in the mRNA’s 5’UTR, G4 generally lead to a
decrease in translation. Using ASO that prevent G4 formation, we were able to increase the
translation of the target gene. In addition, it has been possible to develop ASO which
promote the formation of a G4 in order to decrease the expression of the target. Finally, in
the last chapter of this thesis, it is demonstrated that the G4 present in the primary
microRNAs influence their maturation in mature microRNAs. ASO targeting these G4
have been used in order to promote the maturation of tumor suppressor microRNAs, which
has an interesting therapeutic potential. The work presented in this thesis clearly
demonstrates that ASO are ideal for targeting and altering the structure of specific RNA
motifs.
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Plausible Functional Diagnostics by Rational Echocardiography in the Assessment of Valvular Heart Disease: Role of Quantitative Echocardiography in the Assessment of Mitral RegurgitationHagendorff, Andreas, Stöbe, Stephan 08 June 2023 (has links)
The echocardiographic assessment of valvular heart diseases is the basic analysis
of valvular defects next to clinical investigation and stethoscopy. Severity of mitral
regurgitation (MR) is usually estimated by an integrated approach using semi quantitative
parameters and is still one of the biggest challenges of echocardiography. Quantitative
echocardiographic analysis of MR severity often fails to describe comprehensible
hemodynamic conditions. However, comprehensive echocardiography based on
standardized image acquisition and proper image quality is required to properly assess
hemodynamic parameter comparable to cardiac magnetic resonance tomography. This
review focuses on the uncertainty of MR severity assessed by echocardiography in
recent trials of interventional MR treatment. In addition, the necessity to provide plausible
echocardiographic data for individual decision making is highlighted. In conclusion,
plausible functional diagnostics by rational echocardiography is a prerequisite in patients
with valvular heart diseases.
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Napojení nového nádraží v Brně na systém veřejné dopravy / Public transport connection of the new Brno Railway stationBartoň, Daniel January 2018 (has links)
The diploma thesis deals with the issue of the availability of the new Main Railway Station in Brno, its transfer to other location, modernization or reconstruction and its connection to the public transport system. It focuses in particular on the public transport in Brno affected by the transfer of the railway station and on regional passenger railway transport in the vicinity of Brno. It describes, evaluates and assesses various variants of the transfer of the new railway station in terms of time savings for passengers traveling through the Main Railway Station and their source or destination of travel is in Brno or in the vicinity of Brno. The most suitable appears variant B - the transfer of the station under Petrov.
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