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Heart catheterization in the investigation of congenital heart disease.Johnson, Arnold Livingstone. January 1947 (has links)
No description available.
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Mutation screening of candidate genes and the development of polymorphic markers residing on chromosome 19q13.3, the progressive familial heart block I gene search areaMakubalo, Zola 03 1900 (has links)
Thesis (MSc)--Stellenbosch University, 2000. / ENGLISH ABSTRACT: Progressive familial heart block type I (PFHBI) is a cardiac ventricular conduction disorder of
unknown cause associated with risk of sudden death, which has been described in several
South African families. Clinically, PFHBI is characterised by right bundle branch block on
ECG, which may progress to complete heart block, necessitating pacemaker implantation.
The disease shows an autosomal dominant pattern of inheritance with evidence of genetic
anticipation. Using genetic linkage analysis, the PFHBI-causative gene was mapped to a 10
eentimorgan (cM) gene-rich area of chromosome (C) 19q13.3, which has, subsequently, been
reduced to 7cM by fine mapping with polymorphic dinucleotide (CA)n short tandem repeat
(STR) markers. Several attractive candidate genes, including muscle glycogen synthase
(GSY 1) and histidine-rich calcium binding protein (HRC), lie within this region.
The aim of the present study was two-fold: 1) to identify and characterise tetranucleotide
(AAAT)n STRs within the PFHBI critical region that could be developed as polymorphic
markers for use in genetic fine mapping and 2) to screen selected regions of GSY 1and HRC,
positional candidate genes, for the presence ofPFHBI-causing mutation(s).
Cosmids harbouring CI9q13.3 insert DNA were screened for the presence of (AAAT)n STRs
by dot blot and Southern blot hybridisation using a radiolabelled (AAAT)lO oligonucleotide
probe. To characterise the harboured (AAAT)n STRs, the positively hybridising fragments
identified by Southern blot were sub-cloned, sequenced and primers designed from the unique
repeat-flanking sequences. These primers were used to genotype the (AAAT)n repeat locus to
assess its polymorphic nature in a panel of unrelated individuals. Alternatively, vectorette
PCR, a rapid method of identifying repeat sequences and obtaining the flanking sequences in
large inserts, was employed to develop polymorphic markers from the positively hybridising
clones. Selected exons of GSY1 and HRC were screened for the presence of potentially
disease-causing mutations by PCR-SSCP analysis and direct sequencing, respectively, in
PFHBI-affected and unaffected family members.
Of the available cosmid clones that gave strong signals on dot blot and Southern blot
hybridisation, three, 29395, 24493 and 20381, were located within the critical PFHBI area
and were used for marker development. An interrupted (AAAT)n repeat motif (n less than 5)
was identified in cosmid 29395, however, the repeat locus was not polymorphic in the tested
population. No (AAAT)n motif, single or repeated was observed in the partial sequence of the sub-cloned fragment of cosmid 24493. Using vectorette peR, no repeated (AAAT)n motif
was identified on sequencing the generated products in either cosmid 24493 or 2038l.
However, diffuse single AAAT motifs were detected in both cosmids. Exons 4, 5, 11, 12 and
16 of GSY 1, containing domains that are conserved across species, and the conserved eterminus-
encoding exons 2-6 of HRC were selected for screening for potential PFHBI-causing
mutation(s). However, no sequence variations were detected.
The interrupted (AAAT)n repeat identified in cosmid 29395 was not polymorphic, which
confirmed reports that complex repeats, especially those containing AAAT motifs of less than
6 repeats, are not polymorphic. One possible explanation for the absence of a repeated AAAT
motif in cosmids 24493 and 20381, which both gave positive hybridisation signals, is that the
low annealing temperature of the AfT -rich repeat-anchored primers used in vectorette peR
may have resulted in transient annealing to the diffuse single AAAT motifs detected on
sequencing. The screened regions of candidate genes GSYI and HRC were excluded from
carrying the disease-causing mutation(s).
The availability of new sequence data generated by the Human Genome Project will influence
future strategies to identify the PFHBI gene. Electronic searches will allow identification of
STR sequences for development of polymorphic markers and gene annotation will allow
selection of new candidate genes for mutation screening. / AFRIKAANSE OPSOMMING:
Sien volteks vir opsomming
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Elucidating the Unknown Role of Cyclin Dependent Kinase 5 in Cardiac Pathophysiological ConditionsAina-Badejo, Danielle January 2021 (has links)
Until now, the role of cyclin dependent kinase 5 (CDK5) in cardiac pathophysiology has not been explored. While CDK5 has been well studied in the neuroscience/Alzheimer’s field as a cyclin-independent kinase, there is currently no investigation into the cardiac-specific role of CDK5. Recently, it was established that inhibition of CDK5 in stem cell derived cardiomyocytes from individuals with Timothy Syndrome (TS) rescued the delayed inactivation phenotype; TS is a fatal genetic long QT syndrome (LQTS) caused by delayed inactivation of the L-type voltage gated Ca2+channel CaV1.2. While it is evident that CDK5 plays an important role in regulating CaV1.2 function, its role in cardiac tissue remains to be elucidated.
To determine whether CDK5 is essential for cardiac function, two separate mouse models were established—a cardiac-deficient Cdk5 mouse model (Cdk5 flox x αMHC-MerCreMer+) and a Cdk5 activation mouse model via overexpression of Cdk5’s known activator, p35 (Cdk5r1/p35 OE x αMHC-MerCreMer+). Immediately after spatiotemporal induction of deficiency/activation of Cdk5 in adult mice, echocardiography, histology and proteomic analysis were performed to examine effects on cardiac structure and function. Analysis of cardiac function and morphology in Cdk5 deficient mice revealed severe systolic dysfunction and a dilated cardiomyopathy-like phenotype. These results were further validated by a pathway analysis of quantified global proteome changes. Conversely, mice with an activation of Cdk5 displayed only minor changes in cardiac function with a modest reduction in fractional shortening and ejection fraction. Notably, these mice did not have any significant changes in cardiac chamber morphology, nor any significant changes to their global proteome. Interestingly, however, phosphoproteomic analysis revealed over 3,000 differentially phosphorylated proteins.
Pathway and gene ontology analysis of proteome changes revealed significant hits related to cell adhesion. Evidence for the extensively studied role of CDK5 in the brain has demonstrated a critical role for CDK5 kinase activity in the regulation of cell adhesion. Alterations in cell adhesion are observed in a number of cardiac pathologies including heart failure and dilated cardiomyopathy; it is therefore plausible that CDK5 potentially regulates cardiac function via cell adhesion mechanisms. A comparison of the phospho-proteome acutely after Cdk5 depletion vs the phospho-proteome acutely after Cdk5 activation, allowed for the identification of a novel cardiac-specific Cdk5 substrate, beta taxilin (Txlnb). Validation of this potential phospho-substrate with an in situ proximity ligation assay demonstrated the co-localization of Cdk5-Txlnb in wildtype mouse cardiac tissue sections. When looking at co-localization in Cdk5 deficient tissue sections, no signals were observed.
Lastly, our lab obtained donor cardiac tissue samples from individuals who passed away due to either heart failure or non-cardiac causes (serving as control cardiac tissue). Analysis of cardiac tissue samples revealed a significant increase in both CDK5 and p35 expression in heart failure samples. Dysregulation of phosphorylation has been implicated in cardiac dysfunction, with known contribution to contractile failure and a number of cardiac pathologies including cardiomyopathies. These findings further support a role for CDK5 in cardiac function.
In conclusion, it appears that CDK5 is imperative for the maintenance of healthy cardiac function. Cardiac-specific homozygous and heterozygous Cdk5 deficiency revealed severe systolic dysfunction along with a dilated cardiomyopathy-like phenotype. While the effects of Cdk5 activation in the heart need to be further investigated, initial findings report significant downstream effects on the phosphorylation of a number of proteins, including Txlnb. Moreover, Txlnb was identified as a potential novel cardiac-specific substrate of Cdk5.
The importance of identifying a role for CDK5 in the heart extends beyond this study. CDK inhibitors have been at the forefront of drug development for cancer therapeutics and immunotherapy. While modulation of CDK5 activity may be beneficial in one physiological system, it may prove deleterious in another. It is therefore imperative that the full range of molecular and physiological roles of each CDK be fully elucidated prior to therapeutic application. Furthermore, outcomes from this study have the potential to be translational for drug discovery and the development of new therapeutic avenues for heart disease.
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Cardiomyopathy at the Intersection of Stem Cells and Tissue EngineeringWang, Bryan Zicheng January 2022 (has links)
Advances in genome editing, human induced pluripotent stem cells (iPSC), and cardiac tissue engineering have significantly improved the ability of in vitro models to model cardiac disease. The objective of this dissertation is to leverage cardiac tissue engineering to generate meaningful biological insights into human genetic cardiomyopathies. First, we studied a novel, de novo mutation in the filamin C (FLNC) gene which causes restrictive cardiomyopathy in a young patient. Using engineered cardiac tissues, we showed that this mutation causes a restrictive phenotype marked by increased passive tension and slowed contraction velocities.
Complementing our engineered tissues, we used high-throughput calcium imaging to identify compounds which improved myocardial relaxation in mutant cardiomyocytes. These compounds improved function of mutant cardiac tissues, suggesting a potentially targetable pathway in the patient’s mutation. In another study, engineered cardiac tissues and stem cells were used to study BAG3, a dilated cardiomyopathy- related gene, in cardiac fibroblasts. BAG3-/- and wild-type iPSCs were differentiated to cardiac fibroblasts and cardiomyocytes. By generating fully isogenic cardiac tissues and altering cellular genotypes, we determined that the loss of BAG3 in cardiac fibroblasts was deleterious to cardiac tissue function despite genetically normal cardiomyocytes. Further work studying cardiac fibroblasts revealed a mechanistic function of BAG3 in regulating cardiac fibroblast extracellular matrix synthesis. Together, this work highlights the ability of cardiac tissues and stem cells to unravel the complexities of genetic heart disease.
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Molecular Genetic Analysis of CRELD1 in Patients with Heterotaxy DisorderZhian, Samaneh 01 January 2011 (has links)
Heterotaxy refers to the abnormal arrangement of internal organs in relation to each other. Model organism studies have shown that functions of more than eighty genes are required for normal asymmetric left-right organ development. CRELD1 has been shown to be necessary for proper heart development and mutations in CRELD1 are known to increase risk of cardiac atrioventricular septal defects (AVSD). AVSD is the most common form of heart defect associated with heterotaxy, and we have previously shown that some individuals with heterotaxy-related AVSD have mutations in CRELD1. Therefore, we propose to examine the CRELD1 gene in a large sample of patients with heterotaxy syndrome. Our goal was to determine if mutations in CRELD1 are associated with other manifestations of heterotaxy or if they only coincide with AVSD. To achieve this aim, a sample size of 126 patients with heterotaxy collected by Dr. Belmont, Baylor college of Medicine, Texas, with approximately 66% of the heterotaxy population with different types of heart defects, were used for this study. Ten exons, promoter regions, and regulatory elements in the introns of CRELD1 gene were sequenced and analyzed. In this study three different heterozygous missense mutations in CRELD1 were identified in three unrelated individuals. These three individuals were diagnosed with different forms of heart defects in addition to AVSD. All three mutations were identified in highly conserved regions of CRELD1 possibly altering the CRELD1 properties. This demonstrates that mutations in CRELD1 may increase the susceptibility of AVSD in heterotaxy population. This information can help us to find factors effecting disease susceptibility in heterotaxy patients since the heart defects are a complex trait with incomplete penetrance.
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Bioinformatics-based strategies to identify PFHBII-causing and HCM main locus and/or HCM modifying mutationsYako, Yandiswa 12 1900 (has links)
Thesis (MSc)--University of Stellenbosch, 2004. / ENGLISH ABSTRACT: Progressive familial heart block type II (PFHBII) is an inherited cardiac conduction disorder of
unknown aetiology, which has been described in a South African family. The disorder was
mapped to a 2.9 centimorgan (cM) locus on chromosome 1q32.2-32.3. Clinically, PFHBII
manifests cardiac conduction aberrations, that progress to a disease of the heart muscle, dilated
cardiomyopathy (DCM). DCM is also reported as an end phase in hypertrophic cardiomyopathy
(HCM), another heart muscle disorder. These cardiomyopathies are genetically heterogeneous
with some of the genes reported as causes of both disorders. Therefore, genes identified as causes
of HCM and DCM were considered plausible candidates for PFHBII mutation analysis.
Additionally, this study provided an opportunity to assess potential modifiers of HCM. HCM
exhibits marked phenotypic variability, observed within and between families harbouring the
same causative mutation.
Genes within the PFHBII locus were selected for PCR-SSCP analysis based on homology to
genes previously reported as causing conduction system disorders associated with arrhythmias,
DCM and/or HCM. Results were confirmed by direct sequencing and association between the
detected variants and HCM parameters was assessed using a quantitative transmission
disequilibrium test (QTDT).
Eleven plausible candidate genes were selected within the PFHBII locus and two of the genes,
PFKFB2 and ATF3, that encode for 6-phosphofructo-2,6-bisphosphatase (PFK-2/FBPase-2) and
activating transcription factor 3 (ATF3), respectively, were analysed for PFHBII-causing and
HCM main locus and/or HCM modifying mutations. Mutation analysis of PFKFB2 and ATF3 in
the PFHBII family revealed no PFHBII causal mutation. PFKFB2 and ATF3 were later localised outside the PFHBII locus, and, therefore, were excluded as PFHBII plausible candidates. Further
analysis of the two genes for HCM main locus and/or HCM modifying mutations in the HCM
panel identified several sequence variants. QTDT analysis of these variants showed no significant
association.
Completion of the Human Genome Project (HGP) and annotation of new genes within the
PFHBII locus allowed the identification of more PFHBII plausible candidate genes. Identification
of causal mutations in plausible PFHBII candidate genes will allow molecular diagnosis of
PFHBII pathophysiology. Furthermore, identification of both HCM-modifying and HCM-causing
genes will give insight into the phenotypic variability noted among South African HCM-affected
individuals and into the molecular cause of the disease among individuals with HCM-like clinical
features. / AFRIKAANSE OPSOMMING: Progressiewe familiële hartblok tipe II (PFHBII) is ʼn oorgeërfde hart geleidingsiekte van
onbekende etiologie wat in ʼn Suid-Afrikaanse familie beskryf is. Die siekte is ʼn 2.9 sentimorgan
(cM) lokus op chromosoom 1q32.2-32.3 gekarteer. Klinies presenteer PFHBII met
geleidingsfwykings wat uitloop op gedilateerde kardiomiopatie (DCM). DCM word ook
gerapporteer as ʼn endfase in hipertrofiese kardiomiopatie (HCM), ʼn ander hartspiersiekte. Die
kardiomiopatieë is geneties heterogeen, met ʼn aantal gene wat as oorsaak van altwee
siektetoestande gerapporteer word. Daarom is alle gene wat geïdentifiseer is as oorsake van DCM
en HCM, as moontlike kandidaatgene vir PFHBII mutasieanaliese beskou. Bykomend het hierdie
studie die geleentheid gebied om potensiële modifiseerders van HCM te assesseer. HCM toon
beduidende fenotipiese variasie binne en tussen families wat dieselfde siekteveroorsakende
mutasie het.
Gene binne die PFHBII-lokus is geselekteer vir PCR-SSCP-analiese gebaseer op homologie met
gene wat voorheen gerapporteer is om betrokke te wees by geleidingsiesisteemsiektes,
geassosieerde arritmieë, DCM en/of HCM. Resultate is bevestig deur volgordebepaling.
Assosiasie tusssen ontdekte variante en die siekteparameter is bepaal met ʼn kwantitatiewe
transmissie disekwilibrium toets (QTDT).
Elf moontlike kandidaatgene in die PFHBII-lokus is geselekteer en twee van die gene, PFKFB2
en ATF3, wat kodeer vir 6-fosfofrukto-2,6-bifosfatase (PFK-2/FBPase-2) en
aktiveringstranskripsiefaktor 3 (ATF3) respektiewelik, is vir PFHBII-oorsakende en HCMhooflokus
en/of HCM-modifiseerende mutasies ondersoek. Mutasie-analiese van PFKFB2 en
ATF3 in die PFHBII-familie het nie ʼn siekteveroorsakende mutasie onthul/uitgelig nie. PFKFB2 en ATF3 is later buite die PFHBII-lokus geplaas en dus ook as moontlike PFHBII-kandidate
uitgesluit. Verdere ondersoek van díe twee gene vir HCM-hooflokus en/of HCM-modifiserende
mutasies in die HCM-paneel het ʼn aantal volgorde variante geïdentifiseer. QTDT-analiese van
die variante het geen beduidende assosiasies aangetoon nie.
Voltooiing van die Menslike Genoom Projek (HGP) en annotasie van nuwe gene in die PFHBIIlokus
het tot die identifikasie van verdere moontlike PFHBII-kandidaatgene gelei. Identifikase
van siekte-veroorsaakende mutasies in die moontlike PFHBII-kandidaatgene sal die molekulêre
diagnose van PFHBII toelaat en insig in die patofisiologie van die siekte gee. Verder,
identifikasie van beide HCM-veroorsakende of HCM-modifiserende gene kan insig gee in die
fenotipiese varieerbaarheid wat onder Suid-Afrikaanse HCM-geaffekteerde individue
waargeneem word en ook in die molekulêre oorsake van die siekte in individue met HCMsoortige
kliniese kenmerke.
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Multiple-imputation approaches to haplotypic analysis of population-based data with applications to cardiovascular diseaseMcCaskie, Pamela Ann January 2008 (has links)
[Truncated abstract] This thesis investigates novel methods for the genetic association analysis of haplotype data in samples of unrelated individuals, and applies these methods to the analysis of coronary heart disease and related phenotypes. Determining the inheritance pattern of genetic variants in studies of unrelated individuals can be problematic because family members of the studied individuals are often not available. For the analysis of individual genetic loci, no problem arises because the unit of interest is the observed genotype. When the unit of interest is the linear combination of alleles along one chromosome, inherited together in a haplotype, it is not always possible to determine with certainty the inheritance pattern, and therefore statistical methods to infer these patterns must be adopted. Due to genotypic heterozygosity, mutliple possible haplotype configurations can often resolve an individual's genotype measures at multiple loci. When haplotypes are not known, but are inferred statistically, an element of uncertainty is thus inherent which, if not dealt with appropriately, can result in unreliable estimates of effect sizes in an association setting. The core aim of the research described in this thesis was to develop and implement a general method for haplotype-based association analysis using multiple imputation to appropriately deal with uncertainty haplotype assignment. Regression-based approaches to association analysis provide flexible methods to investigate the influence of a covariate on a response variable, adjusting for the effects of other variables including interaction terms. ... These methods are then applied to models accommodating binary, quantitative, longitudinal and survival data. The performance of the multiple imputation method implemented was assessed using simulated data under a range of haplotypic effect sizes and genetic inheritance patterns. The multiple imputation approach performed better, on average, than ignoring haplotypic uncertainty, and provided estimates that in most cases were similar to those observed when haplotypes were known. The haplotype association methods developed in this thesis were used to investigate the genetic epidemiology of cardiovascular disease, utilising data for the cholesteryl ester transfer protein gene (CETP), the hepatic lipase (LIPC) gene and the 15- lipoxygenase (ALOX15) gene on a total of 6,487 individuals from three Western Australian studies. Results of these analyses suggested single nucleotide polymorphisms (SNPs) and haplotypes in the CETP gene were associated with increased plasma high-density lipoprotein cholesterol (HDL-C). SNPs in the LIPC gene were also associated with increased HDL-C and haplotypes in the ALOX15 gene were associated with risk of carotid plaque among individuals with premature CHD. The research presented in this thesis is both novel and important as it provides methods for the analysis of haplotypic associations with a range of response types, while incorporating information about haplotype uncertainty inherent in populationbased studies. These methods are shown to perform well for a range of simulated and real data situations, and have been written into a statistical analysis package that has been freely released to the research community.
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Etude des manifestations cardiovasculaires chez les patients présentant un syndrome de Noonan porteurs de mutation au sein du gène PTPN11: rôles des gènes de la voie de signalisation des MAP kinases pour les syndromes apparentésSznajer, Yves 31 August 2009 (has links)
Les patients décrits initialement par J. Noonan se ressemblent et ont une cardiopathie congénitale :soit une sténose valvulaire pulmonaire (SVP), soit une persistance du canal artériel. Avant la découverte du premier gène responsable de ce qui est devenu le syndrome de Noonan, cinq études de cohortes décrivant ces patients ont répertorié la prévalence de SVP mais le spectre des cardiopathies semble large, n’a pas été décrit de manière exhautive et aucune hypothèse n’est émise ou ne fait de lien entre ces différentes manifestations cardiaques et une compréhension intégrée du développement embryonnaire. Le gène PTPN11 est le premier gène identifié chez 40% de ces patients. Une corrélation existe entre la présence d’une mutation et la survenue de SVP de même qu’entre l’absence de mutation et la présence d’une cardiomyopathie hypertrophique. Six études de cohortes ont repris la description des mutations identifiées au sein du gène PTPN11 et les phénotypes associés, mais les cardiopathies n’ont pas été systématiquement ou spécifiquement analysées (tant au sein des groupes de patients porteurs de mutation que de ceux sans mutation). Le syndrome LEOPARD est allélique du syndrome de Noonan depuis que des mutations spécifiques au sein des exons 7,12 et 13 du gène PTPN11 ont été identifiées chez 95% des patients. <p><p>Afin d’appréhender les implications possibles du gène PTPN11 dans la survenue des cardiopathies chez les patients porteurs de ces deux syndromes, nous avons conduit une étude chez 272 patients au syndrome de Noonan et une étude chez 19 patients porteurs du syndrome LEOPARD. Parmi la cohorte de patients atteints du syndrome de Noonan, 104 ont été diagnostiqués porteurs d’une mutation du gène (38%). Une prévalence de survenue de cardiopathies affectant les structures droites du cœur se dégage chez les patients identifiés porteurs d’une mutation avec une différence significative pour la SVP, une tendance est relevée pour le canal atrio-ventriculaire et la communication inter-auriculaire de type Ostium Secundum. L’absence de mutation est corrélée avec la survenue de cardiomyopathie hypertrophique et de cardiopathies du cœur gauche. Parmi les patients atteints du syndrome LEOPARD, il n’existe pas de différence statistiquement significative pour les patients porteurs d’une mutation ou non et/ou pour une cardiopathie particulière. <p><p>Toutes les mutations identifiées du gène PTPN11 sont des mutations ‘faux-sens’. Ce gène appartient à la famille des gènes codant pour une protéine tyrosyl phosphatase, SHP-2, ne possédant pas de récepteur trans-membranaire. Cette phosphatase est impliquée dans la voie de signalisation cellulaire des MAP (‘Mitogen-activated protein’) kinases dont l’expression est ubiquitaire et inclut le coeur. Depuis nos travaux, le concept de syndrome « neuro-cardio-facio-cutané » est établi puisque, à ce jour, 9 gènes (SOS1, RAF1, BRAF, KRAS, NRAS, HRAS, NF1, SPRED1 et SHOC2), tous impliqués dans la voie de signalisation RAS (voie des MAP kinases) sont identifiés. Un spectre phénotypique existe avec des signes communs mais aussi distinctifs chez les patients présentant le syndrome de Noonan, le syndrome LEOPARD, le syndrome de Costello, le syndrome Cardio-Facio-Cutané (CFC), le syndrome « Noonan-NF1 », le syndrome de Legius et le syndrome « Noonan/Multiple Giant Cell Lesion ». Nous rapportons enfin l’observation d’une patiente atteinte du syndrome CFC et porteuse d’une mutation (p.R257Q) au sein du gène BRAF ayant développé une cardiomyopathie hypertrophique. <p><p>Ces travaux de cohortes de patients au phénotype du syndrome de Noonan, du syndrome LEOPARD et cette dernière description d’une patiente au syndrome CFC ont permis de participer à la découverte de l’implication d’une voie de signalisation cellulaire dont l’origine génétique est maintenant démontrée. Les résultats de nos travaux réalisés depuis 2002 auront permis, avec les équipes travaillant sur le même sujet, d’orienter les investigations et les nouveaux projets de recherche qui étudient spécifiquement le rôle du gène PTPN11 dans l’embryologie du cœur. Les études des orthologues (zebrafish, murin et Drosophila) porteurs à l’état hétérozygote d’une mutation du gène PTPN11 permettent d’intégrer les anomalies phénotypiques et cardiaques observées. Ces études permettent de postuler les effets cellulaires produits par les mutations chez les patients atteints du syndrome de Noonan et chez les patients atteints du syndrome LEOPARD engendrant in vitro une activation de la phosphatase (effet « gain de fonction ») pour les premiers ou une réduction de l’activité phosphatase (« dominant négatif ») mais engendrant un effet gain de fonction in vivo. Nous discutons les connaissances acquises, les compréhensions obtenues et intégrées et traçons enfin les perspectives offertes par ces travaux.<p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished
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