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Research has reported that increased levels of plasma TC are directly related, while low levels of plasma HDL-C are inversely related, to coronary heart disease. Regular physical exercise has been suggested as a method for reducing plasma TC and increasing plasma HDL-C. Thirty-one healthy, sedentary women (ages 18-30) were studied to determine the effects of a jogging, weight training, or a combined jogging and weight training program on plasma total cholesterol, high-density lipoproteins, body composition. Experimental subjects were randomly assigned to the treatment conditions. The subjects trained three days a week for nine weeks. The R group ran for 30 minutes a session at 75% predicted maximum HR. The W group trained with weights utilizing exercises to strengthen all major muscle groups for one hour at 60% one repetition maximum the first 3 weeks and 75% one repetition maximum weeks 4 - 9. The RW group ran for 25 minutes a session at 75% predicted maximum HR, then lifted weights using the leg-strengthening exercises for 30 minutes, similar to the W group. Preceding and following the treatment period, plasma TC, HDL-C, body weight, and percent body fat was assessed for all four groups. Plasma TC was not significantly altered, although a downward trend was observed for all three treatment groups. Plasma HDL-C did not change over the treatment period for any group. The plasma TC/HDL-C ratio changed significantly among groups over the treatment period, with the R group decreasing their ratio from 3.5 to 2.9 (p < .05). No changes were noted In percent body fat, fat-free mass, or body weight for any of the groups. The Pearson product-moment correlations performed between the changes in blood lipids and the changes in body composition found no significant relationships. The results of this study indicate that an exercise program consisting of endurance training for 30 minutes, 3 times per week, or weight training for one hour, 3 times per week, or a combination aerobic/weight training program 3 times per week is not adequate to significantly improve plasma TC or HDL-C in young females over a nine week period. However, significant improvements may be made in the plasma TC/HDL-C ratio which may decrease the risk for CHD. / Master of Science

Twenty-eight endurance trained male volunteers, 18-41 years or age, were studied to determine whether the heart rate-oxygen consumption relationships observed during Bruce protocol stress tests were similar to those observed during steady-state exercise. In addition, maximal oxygen consumption and maximal heart rate values obtained during the stress tests were compared to predicted values. The heart rate-oxygen consumption relationship observed during the stress tests was dissimilar from the relationship observed during the steady-state exercise tests. Heart rate was round to be significantly higher during the stress tests. No significant difference was round in predicted maximal oxygen consumption and maximal heart rate and actual values obtained during the stress tests. / M.S.

The American College of Sports Medicine has published formulae that are widely used to predict functional aerobic capacity for any treadmill speed and grade combination. However, it has been demonstrated that these formulae overpredict oxygen consumption (V̇O₂) for patients with coronary artery disease as well as for apparently healthy individuals. To study this, we measured V̇O₂, ventilation (V̇_E), and respiratory exchange ratio (R) responses in 21 apparently healthy subjects (AH) and 16 coronary artery diseased subjects (CAD) during a modified Balke protocol. Modification of the protocol consisted of extending the stage time from two minutes to three minutes at the higher intensities to allow a greater time for a physiological steady-state to occur. The attainment of a steady-state may lead to the reduction of or the elimination of prediction errors. No differences were observed between two and three minute VO₂ responses at maximal and submaximal exercise for either group. At peak exercise, the AH group was significantly (P≤.05) different from the CAD group when compared for heart rate (164±2.6 vs 140±4.8 bts•min⁻¹ ), V̇O₂ (33.3±1.1 vs 26.7±2.3 ml•kg⁻¹•min⁻¹), and total treadmill time (9.9±.33 vs 8.1±.54 min). At submaximal exercise, V̇O₂ responses were also significantly (p≤.05) greater for the AH group when compared to the CAD group (26.6±.95 vs 21.9±1.8 ml•kg⁻¹•min⁻¹). No significant differences were observed for RPE and blood lactate at peak exercise and V̇_E and R responses at submaximal or peak exercise between the two groups. Predicted values for peak V̇O₂ were significantly (p≤.05) higher than measured values (33.3±1.1 vs 38.8±1.1 ml•kg⁻¹•min⁻¹) and (26.7±2.3 vs 34.1±1.7 ml•kg⁻¹•min⁻¹) for the AH and CAD groups, respectively. However, no significant differences were noted between predicted and measured V̇O₂ responses at submaximal exercise for either group. Individuals classified as Type A were not significantly different from classified Type B individuals when compared for the cardio-respiratory variables measured. These data demonstrate that the ACSM prediction formulae significantly overpredict V̇O₂ for both AH and CAD subjects at maximal treadmill intensities. However, at submaximal intensities, these prediction formulae are acceptable for both groups of subjects. Furthermore, these data suggest that two minutes per stage allows sufficient time for physiological steady-state to occur at clearly submaximal intensities. Although at the higher intensities, extending the stage time beyond two minutes may be indicated. / M.S.

Diseases of the aorta rank as the 20th leading cause of mortality in the US, contributing to 10,000 deaths annually. Thoracic aortic aneurysms are typically asymptomatic, often undetected until life-threatening aortic dissection or rupture occurs. Familial cases constitute one in five instances of thoracic aortic aneurysm and dissection (TAAD), with genetic causes being heterogeneous and known risk genes explaining only a small fraction of cases. We hypothesized that additional TAAD risk genes remain undiscovered. This thesis aims to investigate the genetic etiology of TAAD using genetic and genomic approaches. Our methodological approach included: 1) exome sequencing of DNA from TAAD patients with subsequent genomic analysis, integrating clinical data, and 2) single-cell RNA sequencing (scRNA-seq) of the developing (embryonic) mouse aorta. We sequenced 1650 DNA samples from 1429 TAAD patients and, after quality control, analyzed genomic data from 1278 unrelated TAAD patients of European ancestry. For controls, we used 145,103 unrelated individuals of European ancestry from the UK BioBank. We conducted a per-gene and per-domain burden analysis using a binomial test. To improve the power of detection of novel risk genes, we integrated case-control association of rare damaging variants with cell-type specific gene expression data from scRNA-seq of the ascending and descending aorta of 17 mouse embryos (harvested at the E15 stage) with the hypothesis that true risk genes are highly expressed early in development. Our analysis of known TAAD risk genes identified 52 pathogenic or likely pathogenic variants, explaining 4.1% of TAAD cases, and 75 variants of uncertain significance (5.9%). Next, two potential novel candidate genes emerged from the unbiased case-control analysis, which utilized AlphaFold domain-based annotation of protein structure: β-propeller domain of VPS8 (p = 8.8 × 10-9) and UTP11 (p = 3.9 × 10-8). scRNA-seq of the developing mouse aorta revealed significant cell-type-specific expression differences between the ascending and descending aorta, identifying five subtypes of vascular smooth muscle cells in the ascending aorta and four in the descending aorta. Differentially expressed genes between major aortic cell types were also identified. Both, VPS8 and UTP11 were found to expressed in all three major aortic cell types – vascular smooth muscle cells, fibroblasts, and endothelial cells. In conclusion, our case-control association analysis identified two promising candidate risk genes for TAAD (VPS8 and UTP11), warranting further investigation and confirmation in additional cohorts of patients with aortopathy.

The purpose of this study was to describe the prevalence of increasing coronary heart diseases (CHD) among the Indian population in Chatsworth, Kwa Zulu-Natal. A quantitative, descriptive survey was conducted using non-probability purposive sampling. Respondents were sampled from four medical wards at the RK Khan Hospital. The results of this study indicate that the Indian population is at risk for the development of CHD. Although the increasing rate could not be attributed to a single risk factor, 72% of the respondents had a familial history of CHD and 52% had both parents at risk of CHD. Implementation of the primary prevention programmes recommended by the American Heart Association might reduce the prevalence among the Indian population. / Health Studies / M.A. (Health Studies)

The purpose of this study was to describe the prevalence of increasing coronary heart diseases (CHD) among the Indian population in Chatsworth, Kwa Zulu-Natal. A quantitative, descriptive survey was conducted using non-probability purposive sampling. Respondents were sampled from four medical wards at the RK Khan Hospital. The results of this study indicate that the Indian population is at risk for the development of CHD. Although the increasing rate could not be attributed to a single risk factor, 72% of the respondents had a familial history of CHD and 52% had both parents at risk of CHD. Implementation of the primary prevention programmes recommended by the American Heart Association might reduce the prevalence among the Indian population. / Health Studies / M.A. (Health Studies)

Thesis (MSc)--University of Stellenbosch, 2007. / ENGLISH ABSTRACT: Introduction Cardiovascular disease is one of the leading causes of death in the world. Formation of harmful reactive oxygen species (ROS) is associated with several pathological conditions, and contributes to ischaemia/reperfusion injury. Antioxidants can be added to the diet in an attempt to decrease the prevalence of cardiovascular disease by decreasing the harmful effects of ischaemia/reperfusion injury. Red Palm Oil (RPO) consists of saturated, monounsaturated and polyunsaturated fatty acids and is rich in antioxidants such as -carotene, tocopherols and tocotrienols. It has previously been shown that RPO-supplementation improved reperfusion mechanical function. In these studies it was found that RPO might exert its beneficial effects during reperfusion through increased PKB/Akt pathway activity, which may lead to inhibition of apoptosis and improved mechanical function. Aims The aims of this study were: 1) to determine whether RPO-supplementation protected against ischaemia/reperfusion injury in the isolated perfused rat heart, 2) to confirm RPO-supplementation’s effect on the PKB/Akt pathway activity and, 3) to elucidate the regulators in the PKB/Akt pathway that RPOsupplementation influenced. Methods Male Wistar rats were divided into 4 groups, 2 control groups and 2 experimental groups. The 2 control groups were fed a standard rat chow (SRC) for 4 weeks. The two experimental groups received SRC and RPOsupplementation for 4 weeks. Hearts were excised and transferred to a Langendorff perfusion apparatus and perfused with Krebs-Henseleit buffer. Mechanical functional recovery was measured after 25 min of total global noflow ischaemia. The following parameters were also measured during various time points in the protocol: left ventricular develop pressure, heart rate, coronary flow, rate pressure product. Hearts were also freeze-clamped for biochemical analysis at 10 min during reperfusion. The biochemical analysis was aimed at determining PKB/Akt involvement. In a second protocol, hearts were subjected to the same perfusion protocol, but wortmannin was also added to the perfusion fluid, in order to inhibit PI3- kinase. Results Hearts from the RPO-supplemented rats showed an improved RPP recovery (92.26 ± 5.89 % vs 63.86 ± 7.74 %) after 10 min of reperfusion. This finding corroborated the findings of previous studies. Hearts of the RPOsupplemented rats perfused with wortmannin, showed increased RPP recoveries at several time points. Biochemical results showed that wortmannin did indeed inhibit PI3-K phosphorylation in the RPO-supplemented group, as was expected. The RPO-supplemented group that was perfused with wortmannin had an increased PKB/Akt (Ser473) phosphoyrylation, when compared to the wortmannin control group. It was also found that the combination of RPO and wortmannin had prosurvival effects. Discussion This study showed that RPO-supplementation offered protection against ischaemia/reperfusion injury in the Langendorff-perfusion apparatus at 10 min into reperfusion. Thereafter the significance of the protection was lost. This protection has been confirmed in several previous studies and several mechanisms have been proposed for this protection. Since no conclusive evidence exists on the precise mechanism of protection, our investigation focused on the regulators of the pro-survival PKB/Akt pathway. An improved functional recovery was also seen in the RPO-supplemented group that was perfused with wortmannin. This was an unexpected finding, because Wortmannin is a known PI3-kinase inhibitor (as was confirmed by our biochemical data). PI3-kinase phosphorylation leads to PKB/Akt phosphorylation and therefore, activation of a pro-survival pathway. It would be expected that wortmannin would inhibit PKB/Akt and thus decrease the survival of the cells. The RPO-supplementation thus reversed wortmannin’s detrimental effect to such an extent that the functional recovery was far better than RPO-supplementation alone. In the RPO + wortmannin group, PKB/Akt (Ser473) phosphorylation was increased, contrary to previous findings. This is an indication that RPO may have the ability to override wortmannin’s inhibitory effect on PI3-kinase, or that PKB/Akt (Ser473) may be phosphorylated independently of PI3-kinase. / AFRIKAANSE OPSOMMING: Inleiding Kardiovaskulêre siektes is een van die hoof oorsake van sterftes in die wêreld. Die vorming van skadelike reaktiewe suurstof spesies word geassosieer met verskeie patologiese kondisies en dra ook by tot isgemie/reperfusie skade. ‘n Moontlike manier om die voorkoms van isgemie/herperfusie skade asook kardiovaskulêre siektes te voorkom, is om antioksidante by die dieet te voeg. Rooi Palm Olie (RPO) bevat versadigde, mono-onversadigde en polionversadigde vetsure. RPO bevat ook ‘n oorvloed van antioksidante soos β- karoteen en tokoferole en tokotriënole. Dit is bewys in vorige studies dat RPO-aanvulling verbeter funksionele herstel. Hierdie voordelige effekte mag dalk wees agv verhoogde PKB/Akt pad aktiwiteit. Die PKB/Akt pad word geassosieer met die inhibisie van apoptose en verhoogde meganiese funksie. Doelwitte Die doelwitte van hierdie studie was om te bepaal of 1) RPO-aanvulling beskermende effekte teen isgemie/herperfusie skade in die geisoleerde rotharte het, 2) Bevestig of RPO-aanvulling wel die PKB/Akt pad beïnvloed 3). om die effekte wat RPO-aanvulling het op die reguleerders van die PKB/Akt pad te onthul. Metodes Manlike Wistar rotte is in 4 groepe verdeel. 2 Groepe kontrole rotte is ‘n standaard rotkosmengsel gevoer vir 4 weke. Die 2 eksperimentele groepe het ook ‘n standaard rotkosmengsel gekry plus ‘n RPO-aanvulling vir 4 weke. Harte is uitgesny en op ‘n Langendorff perfusie sisteem gemonteer en met Krebs-Henseleit buffer geperfuseer. Meganiese funksie herstel is gemeet na 25 min totale globale geen-vloei isgemie. Linker ventrikulêre ontwikkelde druk, harttempo, koronêre vloei en tempo druk produk is gemeet by verskillende tydpunte. Sommige harte is na 10 min herperfusie vir biochemiese analiese gevriesklamp. Die biochemiese analisiese was beoog om die PKB/Akt pad betrokkenheid te bepaal. ‘n Tweede stel harte is aan dieselfde perfusie protokol blootgestel, maar wortmannin (PI3-kinase inhibitor) is ook bygevoeg by die perfusie vloeistof. Resultate Die groep wat met RPO aangevul is, het na 10 min herperfusie, ‘n verbeterde tempo druk produk herstel getoon (92.26 ± 5.89 % vs 63.86 ± 7.74. Hierdie bevinding is ook met ander studies bevestig. ‘n Interessante bevinding was dat die groep wat met RPO aangevul is en met wortmannin geperfuseer is, ‘n verbeterde meganiese funksionele herstel getoon het. Biochemiese resultate het getoon dat wortmannin wel PI3-K fosforilering geinhibeer het. Die harte van die rotte in die groep wat aangevul is met RPO en daarna met wortmannin geperfuseer is, het ‘n toename in PKB/Akt (Ser473) fosforilering getoon, relatief tot die wortmannin geperfuseerde harte van die rotte in die kontrole groep. Hierdie groep (RPO-aanvulling en wortmannin perfusie) het beskermende effekte getoon. Bespreking Hierdie studie het getoon dat RPO-aanvulling beskerming gebied het teen isgemie/herperfusie skade in die Langendorff geperfuseerde rothart na 10 min herperfusie. Daarna is die beduidenheid van die beskerming verloor. Hierdie bevindings ondersteun die resultate van vorige studies. Verskeie moontlike meganismes is voorgestel vir die beskerming, maar die presiese meganisme is nog nie duidelik nie. In hierdie studie is daar gekyk na die reguleerders van die PKB/Akt pad. Geen vorige studies het al gefokus op RPO-aanvulling en sy effek op die reguleerders van die PKB/Akt pad nie. ‘n Onverwagte bevinding is dat harte van die rotte in die RPO + wortmannin groep ‘n verbeterde funksionele herstel getoon het. Wortmannin is ‘n PI3- kinase inhibitor. PI3-K fosforilering lei tot PKB/Akt fosforilering, wat tot sel beskerming lei. Dus, aangesien wortmannin PI3-K inhibeer, sou dit verwag word dat wortmannin sel beskerming sal verminder. Die RPO het egter die wortmannin se nadelige effekte tot so ‘n mate oorskrei dat die funksionele herstel baie beter was as die RPO-aanvulling alleen. Die verhoogde PKB/Akt (Ser473) fosforilering, wat gesien is in die RPO + wortmannin groep kan toegeskryf word aan RPO se vermoë om wortmannin se nadelige effekte te oorskrei. ‘n Moontlike verduideliking vir hierdie bevinding mag wees dat rooi palm olie PKB/Akt (Ser473) op ‘n PI3-K onafhanklike manier fosforileer.

Thesis (PhD)--Stellenbosch University, 2004. / ENGLISH ABSTRACT: Progressive familial heart block I (PFHBI) is an inherited autosomal dominant cardiac conduction disorder which segregates in a large South African (SA) pedigree, two smaller SA families and a Lebanese family. It specifically affects conduction in the ventricles and is of unknown cause. Clinically, PFHBI is detected on electrocardiogram (ECG) by evidence of bundle-branch disease, i.e., as right bundle branch block, left anterior or posterior hemiblock, or complete heart block with broad QRS complexes. The PFHBI-causative gene was mapped to a lOcM region on chromosome 19ql3.3 using linkage analysis, and the locus was subsequently reduced to 7cM by genetic fine mapping. The present study involved a multi-strategy approach to search for the PFHBI gene. The objectives were the further reduction of the PFHBI locus by genetic fine mapping using published and novel markers, searching for short gene transcripts from publicly available databases and the generation of an integrated map of the locus to which genes were mapped. Prioritised genes were screened for PFHBI-causing mutations and, in addition, the PFHBI locus was searched for the presence of a G protein-encoding gene (PI 15- RhoGEF), a connexin (Cx) gene and any genes containing a CTG repeat expansion motif, since these genes are plausible PFHBI candidate genes. Genotyping and fine genetic mapping using known and novel polymorphic dinucleotide (CA)n and novel tetranucleotide (A3G)n repeat markers across the PFHBI locus were performed. Publicly available databases, such as LLNL (Livermore, USA), and GENEMAP (NCBI) were searched for ESTs which, in turn, were extended using clustering programmes, such as UNIGENE (NCBI) and STACK (SANBI), and the resulting consensus sequences were subsequently BLAST-searched against the protein databases. Using the available data, an integrated physical and genetic map of the PFHBI locus was generated and, as the HGP progressed, a number of novel genes were placed thereon. Subsequently, genes were prioritised on the basis of position, function and expression profile. Genetic fine mapping reduced the PFHBI locus from 7cM to 4cM. The EST approach yielded 38 ESTs, of which 24 ESTs matched proteins, such as activating transcription factor 5 (ATF5), actin-binding protein (KPTN) and zinc finger protein 473 (ZFP473) (May 2003). All the map data generated experimentally and computationally were placed on the PFHBI map. The PI 15-RhoGEF was excluded as a PFHBI candidate gene and although homologous sequences to connexin 37 (Cx37) was located on both chromosome 19 radiation hybrid clones (RHG12 and ORIM-7), it was not identified on the DNA clones spanning the PFHBI locus. No evidence of an expansion of a CTG repeat motif sequence in PFHBI-affected individuals was found. Five highly prioritised candidate genes, namely, 5CZ2-associated X protein (BAX), potassium voltage-gated channel Shaker-related subfamily member 7 (KCNA7’), potassium inwardly-rectifying channel, subfamily J, member 14 (KIR2.4), lin-7 homolog B {LIN-7B) and glycogen synthase 1 (GSYI) were selected for mutation screening. No disease associated mutations were identified in the exonic and flanking intronic regions of these genes. In summary, this study reduced the PFHBI locus substantially and generated a detailed map of the region. A number of attractive candidate genes were excluded from causing PFHBI; however, several plausible candidate genes are still present at this gene-rich locus and remain to be screened. Identifying the PFHBI-causative gene and associated mutation will provide a platform for further studies to understand the pathophysiology, not only of PFHBI, but also of other more commonly occurring conduction disturbances. / AFRIKAANSE OPSOMMING: Progressiewe familiele hartblok I (PFHBI) is ‘n autosomaal dominant oorerflike kardiale geleidingstoomis wat in ‘n groot Suid-Afrikaanse (SA) familie, twee kleiner SA families en ‘n Lebanese familie segregeer. Dit affekteer hoofsaaklik die geleiding in die ventrikels en die oorsaak daarvan is onbekend. Klinies word PFHBI op elektrokardiogram (EKG) geidentifiseer as a bondeltak-siekte, naamlik, as regter bondeltakblok, linker anterior of posterior hemiblok, of volledige hartblok met wye QRS komplekse. Die PFHBI-veroorsakende geen is voorheen deur koppelingsanalise tot ‘n lOcM gebied op chromosoom 19ql3.3 gekarteer, en daaropvolgens is die lokus verklein tot 7cM deur genetiese fyn kartering. Die huidige studie behels ‘n veelvuldige-strategie benadering in die soektog na die PFHBI geen. Die doel van die studie was die verdere verkleining van die PFHBI lokus deur gebruik te maak van beide gepubliseerde en nuwe genetiese merkers, die identifisering van kort geentranskripte (ESTs) uit publieke databanke en die generasie van ‘n geintegreerde kaart van die lokus. Geprioritiseerde gene is geanaliseer vir die PFHBI-veroorsakende mutasie en, daarby, is die PFHBI lokus deursoek vir die teenwoordigheid van ‘n G proteien-enkodeeringsgeen (PIJ5-RhoGEF), ‘n konneksien (Kx) geen en enige gene wat ‘n uitgebreide CTG-herhalingsmotief bevat, aangesien hierdie gene as sterk PFHBI kandidaatgene geag is. Genotipering en fynkartering deur die gebruik van bekende asook nuwe polimorfiese dinukleotied- [(CA)n] en nuwe tertranukleotied- [(A3G)n] herhalingsmerkers wat die PFHBI lokus oorbrug, is uitgevoer. Publieke databanke, soos LLNL (Livermore, USA), en GENEMAP (NCBI) is ondersoek vir ESTs wat vervolgens verleng is deur gebruik te maak van groeperende programme soos UNIGENE (NCBI) en STACK (SANBI) en die gevolglike konsensus volgordes is daama met behulp van BLAST geanaliseer teen die protei'endatabanke. Die bekomde data is vervolgens gebruik om ‘n geintegreerde fisiese en genetiese kaart van die PFHBI lokus te produseer en, soos die mens genoomprojek gevorder het, is nuwe gene daarop geplaas. Daarna is gene geprioritiseer vir mutasie analise gebaseer op posisie, funksie en uitdrukkingsprofiele. Genetiese fynkartering het die PFHBI lokus van 7cM tot 4cM verklein. Die EST benadering het 38 ESTs gei'dentifiseer, waarvan 24 ESTs proteien gelyke gehad het, bv aktiverende transkripsie faktor 5 (ATF5), aktien-verbindingsprotei'en (KPTN) en sink-vingerproteien 473 (ZFP473) (Mei 2003). A1 die karterings data wat eksperimenteel en rekenaar-gewys gegenereer is, is op die PFHBI kaart geposisioneer. Die P115-RhoGEF is uitgeskakel as ‘n PFHBI kandidaatgeen en alhoewel ’n volgorde met homologie aan konneksien37 (Kx37) gevind is op albei chromosoom 19 radiasiehibried klone (RGH12 and ORIM-7), is dit nie gei'dentifiseer in die DNS klone wat die PFHBI lokus oorbrug nie. Geen bewyse van uitbreiding van CTG herhalingsmotiewe is gevind in PFHBIaangetasde persone nie. Vyf hoogs-geprioritiseerde kandidaat gene, naamlik, BCL2-geassosieerde X proteien (BAX), kalium spanningsbeheerde kanaal, subfamilie J, lid 14 (KIR2.4), lin-7 homoloog B (LIN-7b) en glikogeen sintase 1 (GYS1), is geselekteer vir mutasie-analise. Geen siekteveroorsakende mutasie is egter gei'dentifiseer in die eksoniese of die naasliggende introniese gebiede van hierdie gene nie. Ter opsomming, hierdie studie het die PFHBI lokus verklein en het ‘n omvattende kaart van die gebied gegenereer. Verskillende kandidaat gene is uitgesluit as die oorsaak van PFHBI, alhoewel daar nog heelwat goeie kandidaat gene in hierdie geen-ryke lokus is wat geanaliseer behoort te word. Die identifiseering van die PFHBI-veroorsakende mutasie sal ‘n platform bied vir verdere studies om die patofisiologie van nie alleen PFHBI nie, maar ook meer algemene geleidingstoomisse, te verstaan.

published_or_final_version / Medicine / Master / Doctor of Medicine