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Classical Hodgkin's lymphoma (cHL), although originating from B-cells, is characterized by the virtual lack of gene products whose expression constitutes the B-cell phenotype. Epigenetic repression of B-cell-specific genes via promoter hypermethylation and histone deacetylation as well as compromised expression of B-cell-committed transcription factors were previously reported to contribute to the lost B-cell phenotype in cHL. Restoring the B-cell phenotype may not only correct a central malignant property, but render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling. We conducted now a high-throughput pharmacological screening based on more than 28,000 compounds in cHL cell lines carrying a CD19 reporter to identify drugs that promote re-expression of the B-cell phenotype. Three chemicals were retrieved that robustly enhanced CD19 transcription. Subsequent chromatin immunoprecipitation-based analyses indicated that action of two of these compounds was associated with lowered levels of the transcriptionally repressive lysine 9-trimethylated histone H3 mark at the CD19 promoter. Moreover, the anti-leukemia agents all-trans retinoic acid and arsenic trioxide (ATO) were found to reconstitute the silenced B-cell transcriptional program and reduce viability of cHL cell lines. When applied in combination with a screening-identified chemical, ATO evoked re-expression of the CD20 antigen, which could be further therapeutically exploited by enabling CD20 antibody-mediated apoptosis of cHL cells. Furthermore, restoration of the B-cell phenotype also rendered cHL cells susceptible to the B-cell Non-Hodgkin's lymphoma-tailored small compound inhibitors Ibrutinib and Idelalisib. In essence, we report here a conceptually novel, re-differentiation-based treatment strategy for cHL.

The emergence of multidrug-resistant tuberculosis (MDR-TB; defined as resistance to at least rifampicin and isoniazid) represents a growing threat to public health and economic growth. Never before in the history of mankind have more patients been affected by MDR-TB than is the case today. The World Health Organization reports that MDR-TB outcomes are poor despite staggeringly high management costs. Moreover, treatment is prolonged, adverse events are common, and the majority of affected patients do not receive adequate treatment. As MDR-TB strains are often resistant to one or more second-line anti-TB drugs, in-depth genotypic and phenotypic drug susceptibility testing is needed to construct personalised treatment regimens to improve treatment outcomes. For the first time in decades, the availability of novel drugs such as bedaquiline allow us to design potent and well-tolerated personalised MDR-TB treatment regimens based solely on oral drugs. In this article, we present management guidance to optimise the diagnosis, algorithm-based treatment, drug dosing and therapeutic drug monitoring, and the management of adverse events and comorbidities, associated with MDR-TB. We also discuss the role of surgery, physiotherapy, rehabilitation, palliative care and smoking cessation in patients with MDR-TB. We hope that incorporating these recommendations into patient care will be helpful in optimising treatment outcomes, and lead to more MDR-TB patients achieving a relapse-free cure.

PhD (Physiology), North-West University, Potchefstroom Campus MOTIVATION - Cardiovascular disease (CVD) prevalence is escalating and influences general health and well-being. Blacks were more at risk of developing CVD and coronary artery disease (CAD). In addition, silent myocardial ischemia (SMI), which underscores the ischemic burden of CAD and CVD, is an underestimated health risk and unravelling the presence of SMI and reduced perfusion to coronary circulation and the myocardium may therefore be important in Blacks from South Africa. This ethnic group is also more likely to be diagnosed with symptomatic occlusive vascular disease. The determination of the CVD risk factors, insulin resistance (IR) and elevated high-sensitivity cardiac Troponin T (hs-cTnT) for prediction of SMI events in separate ethnic groups, can underpin the prognostic relevance of SMI, and contribute to prognostic screening in healthcare practice. In addition, considering subclinical atherosclerosis and conduction disturbances in relation to these risk markers, may further inform the medical community on the CAD and CVD burden in this cohort. AIMS - The main aim of this SABPA (Sympathetic activity and Ambulatory Blood Pressure) sub-study was to indicate the prevalence of SMI in an urban South African bi-ethnic sex cohort and its association with hs-cTnT. In addition, to predict the resulting compensatory hypertension, the effect of hs-cTnT was researched. Furthermore, assessing the risk markers IR and hs-cTnT to determine the possible emerging mechanism of SMI was also explored, since possible racial disparity may be evident. When taking conduction disturbances into account, the association between CVD risk markers hs-cTnT, and IR in relation to subclinical atherosclerosis improved our understanding of myocardial ischemia and CVD burden. METHODOLOGY - The SABPA is a target population study which encompassed 409 urban black and white South African teachers from the Dr Kenneth Kaunda Education district situated in the North West province, South Africa (13). The cohort ensured homogeneity with regards to socio-economic status and working environment, although diverse cultural backgrounds could not be accounted for. Eligible participants aged between 20 and 65 years partook in this study. The following individuals were excluded for the current sub-study: pregnant or lactating women, individuals who had donated blood or had vaccinations less than 3 months prior to the onset of data collection, dependance on or abuse of psychotropic substances and individuals with a history of any cardiac events or myocardial infarction (heart attack) (n=5). The final cohort used for this sub-study included 198 Blacks and 206 Whites (N=404). For Manuscript 2, clinically diagnosed individuals with diabetes (n=17) were excluded. Human immunodeficiency virus- (HIV) infected individuals (n=18) were excluded for Manuscript 3. Groups were stratified according to ethnicity and sex after interaction terms were fitted for CVD risk. Cardiometabolic variables included in this study were: body surface area (BSA), cholesterol, glycated haemoglobin A1C (HbA1C), glucose, homeostasis model of assessment (HOMA IR), high sensitivity C-reactive Protein (hs-CRP), plasma γ-glutamyl transferase (γ-GT), plasma cotinine levels, hs-cTnT and blood pressure (BP). Left carotid intima-media thickness (L-CIMT) of the far wall, left cross sectional wall-area (L-CSWA) and the lumen diameter of the left carotid indicated subclinical atherosclerosis. SMI was automatically detected by 24-hour (24-h) ambulatory electrocardiogram (ECG) measurement, where 1st degree atrioventricular-block (AV block) was determined with 6 cardiac cycles of 12-lead ECG. Means and proportion were calculated with student T-tests, analysis of covariance (ANCOVA) as well as Chi squares (X2). Multivariate linear regression analysis determined associations between major variables where receiver-operating characteristic (ROC) curves established cut-points for exacerbated CVD risk. RESULTS AND CONCLUSIONS: - The results and conclusions of the three manuscripts are as follows: 1.Troponin T release is associated with silent myocardial ischaemia in black men: theSABPA Study Significant differences were evident in hs-cTnT and its relation with SMI and hypertension in Blacks and Whites from this cohort. These findings indicate that hs-cTnT can possibly be a potential proficient marker of SMI and increases in compensatory systolic blood pressure (SBP). A lower hs-cTnT cut-point ≥ 4.2 pg/ml for 24-h systolic hypertension was predicted in Blacks compared to ≥ 5.6 pg/ml in Whites with a respective sensitivity/specificity of 64/68% and 61/71%. The SBP rises to alleviate myocardial ischemia in the Blacks and risk-factor clustering. The results also underscored the need for ethnic-specific reference values of hs-cTnT, which in turn should be interpreted in consideration of existing risk factors. In-depth assessment of hs-cTnT can thus be a useful improvement in risk prediction research. 2.Silent ischemia, insulin resistance and cardiovascular risk in a bi-ethnic sex cohort:the SABPA study Insulin resistance (IR) as determined by elevated homeostasis model of assessment (HOMA IR) levels, was positively related to longer SMI events over 24 hours in White sex groups. Furthermore, White men also showed significant relations between IR and more frequent SMI events. Our findings suggested that IR increases are related to metabolic susceptibility leading to the development of SMI in the Whites but not necessarily in the Blacks. However, the Black men presented positive associations between hs-cTnT and more frequent and longer SMI events. Findings in Blacks implied a cardiovascular susceptibility to develop ischemic heart disease and underscoring ethnic-related mechanism which could diagnose emergent SMI. 3.Troponin T release is associated with subclinical atherosclerosis in Blacks with firstdegree AV-block: the SABPA study In Blacks presenting 1st degree AV-block, elevations in hs-cTnT were positively associated with subclinical atherosclerosis. Similar associations were not evident in Whites. First (1st) degree AV-block in Blacks reflected increases in hs-cTnT and enhanced susceptibility for a compensatory high blood pressure system resulted in carotid hypertrophic remodelling. Thus, by identifying conduction disturbances and perfusion deficits in early screening programs a contribution can be made to CVD prevention programs. GENERAL CONCLUSION - In Blacks from this cohort, a higher cardiometabolic susceptibility to develop CVD was revealed. This was accentuated with lower hs-cTnT cut-points to predict compensatory SBP hypertension. In addition, when considering electricical conduction disturbances, the use of hs-cTnT cut-points may contribute to the preventive cardiology. In Whites, IR underscored the development of ischemic heart disease more so than hs-cTnT, and can be translated to heath care practice. The adverse CVD risk in a South African Black cohort is concerning and the contribution of risk factors due to urbanization (poor nutrition, lower activity levels, obesity, alcohol abuse and smoking) further exacerbated a CVD burden. Doctoral

Differential diagnosis of parkinsonian syndromes is a major challenge in movement disorders. Dysautonomia is a common feature but may vary in clinical severity and onset. The study attempted to find a pattern of autonomic abnormalities discriminative for patients with different parkinsonian syndromes. The cross-sectional study included 38 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 26 patients with idiopathic Parkinson's disease (IPD) and 27 age-matched healthy controls. Autonomic symptoms were evaluated by a standardized questionnaire. The performance of patients and controls was compared on five autonomic function tests: deep breathing, Valsalva manoeuvre, tilt-table testing, sympathetic skin response, pupillography, and 24-h ambulatory blood pressure monitoring (ABPM). Disease severity was significantly lower in IPD than PSP and MSA. Except for pupillography, none of the laboratory autonomic tests distinguished one patient group from the other alone or in combination. The same was observed on the questionnaire. Receiver operating characteristic curve revealed discriminating performance of pupil diameter in darkness and nocturnal blood pressure change. The composite score of urogenital and vasomotor domains significantly distinguished MSA from IPD patients but not from PSP. Our study supports the observation that even mild IPD is frequently indistinguishable from more severe MSA and PSP. Thus, clinical combination of motor and non-motor symptoms does not exclusively point at MSA. Pupillography, ABPM and the questionnaire may assist in delineating the three syndromes when applied in combination.

Thesis (PhD (Physiology))--North-West University, Potchefstroom Campus, 2013. Motivation - Hypertension is a pertinent health problem for urban black African men (hereafter referred to as African). Sympathetic hyperactivity and a dominant α-adrenergic response pattern have both been implicated as contributing factors to their poor cardiovascular health. In addition to the deleterious effect of neurogenic hypertension on target organs, sympathetic hyperactivity may promote the accelerated progression of left ventricular hypertrophy and structural vascular disease. Aim - The overarching aim of this study is to scrutinize autonomic control of the cardiovascular system in a cohort of urban African and Caucasian men during a mental challenge. Associations were investigated between potential sympatho-vagal imbalance, blood pressure and target organ damage markers to determine cardiovascular risk in ethnic male groups. Methodology - The SABPA (Sympathetic activity and Ambulatory Blood Pressure in Africans) study involved the participation of 200 male teachers (99 African and 101 Caucasian) in the Kenneth Kaunda Education District of the North-West Province, South Africa. Of the participant group, HIV-infected (13 African) and clinically confirmed diabetics (1 Caucasian and 6 African men) were excluded from further analyses. Stratification was based on ethnicity and further as indicated through statistical interaction effects. Cardiovascular and autonomic responses were assessed during rest and on stressor exposure (cold pressor test and Stroop colour-word conflict test). Autonomic measures included baroreceptor sensitivity (BRS), 3-methoxy-4-hydroxy-phenylglycol (MHPG) and nitric oxide metabolite (NOx) levels. Cardiovascular variables consisted of blood pressure, cardiac output, stroke volume, total peripheral resistance, heart rate, arterial compliance and ST-segment from the 12-lead electrocardiogram. Markers of target organ damage included the Cornell product (indication of left ventricular hypertrophy) and carotid intima-media thickness as indication of structural vascular disease. Means and proportions were compared by means of standard t-test and Chi-square test, respectively. Significant differences of mean cardiovascular and autonomic measures between ethnic male groups were also determined through analysis of covariance. Uni- and multivariate regression analyses were employed to demonstrate associations between target organ damage, cardiovascular and autonomic markers. Results and conclusion of each manuscript To assess autonomic nervous system and cardiovascular function as well as target organ damage, we clearly focussed on responses where our participants were challenged. Markers of autonomic responses assessed were baroreceptor sensitivity, 3-methoxy-4-hydroxyphenylglycol and nitric oxide metabolites. *The first manuscript (Chapter 2) focused on left ventricular hypertrophy as marker of target organ damage, blood pressure and baroreceptor sensitivity as marker of autonomic function. The objective was to determine whether BRS was significantly lower in African men than in the Caucasian men. Furthermore, the possible association between attenuation of BRS and increased levels of ambulatory blood pressure as well as left ventricular hypertrophy was investigated in these population groups. Results revealed that the African men had significantly lower BRS stress responses. This attenuated BRS profile was coupled with dominant α-adrenergic response patterns, which was associated with an elevation of ambulatory blood pressure. BRS attenuation (rest and stress response) was not associated with left ventricular hypertrophy. It was concluded that lower BRS, especially during stress, may pose a significant health threat for urban African men regarding the development or promotion of α-adrenergic-driven hypertension and higher cardiovascular disease risk. *The aim of the second sub-study (Chapter 3) was to investigate possible associations between structural vascular disease (carotid intima-media thickness as marker), autonomic function (MHPG as marker) and nocturnal blood pressure in the African and Caucasian men. Results showed a higher prevalence of nocturnal hypertension in the African men, with night-time blood pressure significantly higher compared to the Caucasian men. In the African and Caucasian men, carotid intima-media thickness was linearly predicted by nocturnal systolic and diastolic blood pressure respectively. In conclusion, no associations were demonstrated between MHPG and carotid intimamedia thickness or between MHPG and nocturnal blood pressure. Elevated nocturnal blood pressure evidently seems to promote structural vascular disease in this cohort of urban African and Caucasian men. *The aim of the third manuscript presented in Chapter 4, was to investigate bioavailability of NO during mental challenge (autonomic function marker) and the possible association with structural vascular disease (carotid intima-media thickness as marker). In the African men, an attenuated NOx response was demonstrated to the Stroop colour-word conflict test. After stratification into high and low NOx response groups, in the African men with a low NOx response enhanced α-adrenergic with significant ST-segment depression responses was demonstrated indicating reduced myocardial oxygen supply during mental stressor exposure. Only in the African men, a ST-segment depression was significantly associated with structural vascular disease. It was concluded that the African men demonstrated a vulnerable cardiovascular profile. In this cohort of African men, the significant association between structural vascular disease and myocardial ischemia may particularly indicate a possible higher risk for future cardiovascular events. General conclusion Through the assessment of autonomic and cardiovascular responses a possible higher cardiovascular risk was demonstrated in the African men. In this cohort sympathetic hyperactivity was evident, coupled with dominant vascular response patterns and reduced myocardial oxygen supply during mental stress exposure. Based on these findings, this population group’s risk for accelerated target organ damage, as well as for future cardiovascular events, appear significantly higher than those of the Caucasian male cohort. Doctoral