Background: To throw light on the under-researched association between socioeconomic position (SEP) and health in Cuba, this study examined SEP gradients in health and their underlying mechanisms among urban Cuban adults aged 18-65. Methods: By applying linear regressions to data from the 2010 National Survey on Risk Factors and Chronic Diseases, the analysis explored the SEP-health gradient along three SEP dimensions-education, occupation, and skin colour-using ten health measures: Self-reported health (SRH), general and abdominal obesity, hypertension, high glucose, high cholesterol, high triglycerides, low high-density lipoprotein cholesterol, metabolic syndrome, and cumulative risk factors. Regressions also included behaviours and health-related risk perceptions (tobacco and alcohol consumption, diet, physical activity, and risk-related behaviours). It thus investigated the SEP-health gradient and its underlying mechanisms via both behaviours and health-related risk perceptions. Results: Once controlling for gender, age, marital status, region and provincial dummies, the analysis detected educational gradients in SRH (estimated coefficient [95% CI]: Middle-level education = 3.535 [1.329, 5.741], p < 0.01; high-level education = 5.249 [3.050, 7.448], p < 0.01) that are partially explainable by both health-affecting behaviours (tobacco and alcohol consumption, diet, physical and sedentary activity) and risk perceptions. Using objective measures of health, however, it found no SEP-health gradients other than hypertension among people identified as having Black skin color (adjusted for demographic variables, 0.060 [0.018, 0.101], p < 0.01) and high cholesterol among those identified as having Mulatto or Mestizo skin color (adjusted for demographic variables,-0.066 [-0.098,-0.033], p < 0.01). Conclusions: In terms of objective health measures, the study provides minimal evidence for an SEP-health gradient in Cuba, results primarily attributable to the country's universal healthcare system-which offers full coverage and access and affordable medications- A nd its highly developed education system.

No description available.

Previous studies showed that memantine inhibits tau hyperphosphorylation in vitro. In this study, phosphorylated tau (P-tau) and total tau (T-tau) were measured before and after 6 month treatment with memantine in 12 subjects ranging from normal cognition with subjective memory complaints, through mild cognitive impairment to mild Alzheimer's disease. Thirteen non-treated individuals served as controls. Treatment was associated with a reduction of P-tau in subjects with normal cognition. No treatment effects were seen among impaired individuals, suggesting that longer treatment time may be necessary to achieve biomarker effect in this group.

Introduction: Gestational diabetes mellitus (GDM) is a significant public health concern, due to its association with short- and long-term complications in both mothers and offspring. DNA methylation and single nucleotide polymorphisms (SNPs) offer potential to serve as molecular biomarkers, which may lead to improved detection of GDM with positive effects on health outcomes. Aim: The aim of this study was to investigate whether DNA methylation and SNPs are associated with GDM and may offer potential as molecular biomarkers for GDM in South Africa (SA). Methods: This study followed a two-pronged approach. Firstly, literature searches were conducted to collate and synthesise all published articles reporting on the prevalence of GDM in SA, the screening and diagnostic strategies used, and the current status of DNA methylation and SNPs as biomarkers for GDM. Secondly, we conducted experiments to investigate global (n=201), genome-wide (n=24) and gene-specific DNA methylation (n=286) of the adiponectin gene (ADIPOQ) in whole blood of women with and without GDM, using an Enzyme-Linked Immunosorbent Assay, a methylationEPIC BeadChip Array and pyrosequencing, respectively. In addition, genotype and allele frequencies of ADIPOQ rs266729 and rs17300539, and methylenetetrahydrofolate reductase (MTHFR) rs1801133 were determined, using quantitative real-time PCR (n=449) and DNA sequencing for validation. Results: The literature search showed that the prevalence of GDM in SA has increased over the years. Furthermore, it showed that the lack of uniformity in screening and diagnosis between and within countries hamper the accurate detection of GDM. Lastly, the literature search identified several studies that support the use of DNA methylation and SNPs as potential biomarkers for GDM. Experimentally, we showed no differences in global DNA methylation between GDM and non-GDM groups. Interestingly, global DNA methylation levels were 18% (p=0.012) higher in obese compared to non-obese pregnant women. Genome-wide methylation analysis identified 1046 differentially methylated CpG sites (associated with 939 genes) (Cut-off threshold: M>0.06 and p<0.01). Among the top five CpG sites identified, one CpG mapped to the calmodulin-binding transcription activator 1 (CAMTA1) gene, which has been shown to regulate insulin production and secretion. Two CpG sites (-3410: p=0.048 and -3400: p=0.004) in the ADIPOQ promoter were hypomethylated during GDM in HIV negative, but not in HIV positive women. Lastly, no association between the ADIPOQ and MTHFR polymorphisms and GDM was observed in our population. Conclusion: To our knowledge, this is the first study to investigate the association between DNA methylation or ADIPOQ (rs266729 and rs17300539) and MTHFR (rs1801133) polymorphisms and GDM in SA. Findings suggest that gene-specific, but not global methylation nor SNPs rs266729, rs17300539 and rs1801133, may offer potential as molecular biomarkers of GDM in this population. Future longitudinal studies in larger samples that include both HIV negative and positive pregnant women are warranted to explore the candidacy of DNA methylation as molecular biomarkers for GDM. / Thesis (PhD)--University of Pretoria, 2019. / National Research Foundation (NRF) of South Africa, Thuthuka Grant (unique grant no. 99391). / South African Medical Research Council (SAMRC) / Obstetrics and Gynaecology / PhD / Unrestricted

PURPOSE: Ischemic retinopathies such as diabetic retinopathy (DR), retinal vein occlusions (RVO), and age-related macular degeneration (AMD) are ocular diseases caused by abnormal changes in the microvasculature that results in ischemia. This is often followed by a secondary phase characterized by pathological neovascularization and leakage of fluid, which contributes to a loss of visual acuity in affected patients. Anti-VEGF therapy, the current standard of treatment for ischemic retinopathies, is invasive, costly, and lacks a known treatment period. Supplemental oxygen provides the therapeutic potential of not only oxygenating hypoxic retinal cells, but also reducing the neovascularization and edema associated with many ischemic retinopathies through the downregulation of proangiogenic and pro-inflammatory cytokines.The objective of this study is to understand the biochemical underpinnings of treating ischemic retinopathies with hyperoxia. The elucidation of the effect hyperoxia on the molecular level may help guide the development of future studies regarding this novel treatment. METHODS: 68 undiluted vitreous samples were obtained during pars plana vitrectomy (PPV) and the concentration analysis of 34 proteins was analyzed using the Bio-Plex Pro Human Cancer Biomarker Assay. Vitreous samples were divided into three groups: (1) eyes of patients who underwent PPV for epiretinal membrane peeling (ERMP) and/or macular hole (MH) with no history of diabetes mellitus (non-DM group); (2) eyes of patients who underwent PPV for ERMP and/or MH with a history of diabetes or nonproliferative diabetic retinopathy (DM group); (3) eyes of patients who underwent PPV for proliferative diabetic retinopathy (PDR group). Mann-Whitney U tests were performed to compare the biomarker concentrations between the three groups. RESULTS: Numerous growth factors and inflammatory cytokines were significantly upregulated between the non-DM and PDR groups - Angiopoietin-2, EGF, Endoglin, G-CSF, HB-EGF, HGF, PDGF, PIGF, sHER2/neu, TIE-2, VEGF-A, VEGF-D, IL-18, IL-6, IL-8, PECAM-1, sCD40L, SCF, sFASL, sIL-6Ra, TNF-⍺, Leptin, PAI-1, and uPA. A literature search of these proteins revealed many to be directly activated by HIF-1 transcription factor, which is the "master switch" for genes transcribed during a hypoxic event. CONCLUSION: The abundance of proangiogenic and pro-inflammatory factors in PDR that are also upregulated by HIF-1 demonstrate the potential for using hypoxia to treat PDR (and other ischemic retinopathies) through the reduction of HIF-1. This study also shows the wide variability in the expression levels of these proteins which helps provide a better understanding of their degree of involvement in the pathogenesis of ischemic retinopathies. / 2021-06-14T00:00:00Z

Malignant tumors remain one of the leading causes of mortality with over 8.2 million deaths worldwide in 2012. Over the last two decades, high-throughput profiling of the human transcriptome has become an essential tool to investigate molecular processes involved in carcinogenesis. In this thesis I explore how gene expression profiling (GEP) can be used in multiple aspects of cancer research, including prevention, patient stratification and subtype discovery. The first part details how GEP could be used to supplement or even replace the current gold standard assay for testing the carcinogenic potential of chemicals. This toxicogenomic approach coupled with a Random Forest algorithm allowed me to build models capable of predicting carcinogenicity with an area under the curve of up to 86.8% and provided valuable insights into the underlying mechanisms that may contribute to cancer development. The second part describes how GEP could be used to stratify heterogeneous populations of lymphoma patients into therapeutically relevant disease sub-classes, with a particular focus on diffuse large B-cell lymphoma (DLBCL). Here, I successfully translated established biomarkers from the Affymetrix platform to the clinically relevant Nanostring nCounter© assay. This translation allowed us to profile custom sets of transcripts from formalin-fixed samples, transforming these biomarkers into clinically relevant diagnostic tools. Finally, I describe my effort to discover tumor samples dependent on altered metabolism driven by oxidative phosphorylation (OxPhos) across multiple tissue types. This work was motivated by previous studies that identified a therapeutically relevant OxPhos sub-type in DLBCL, and by the hypothesis that this stratification might be applicable to other solid tumor types. To that end, I carried out a transcriptomics-based pan-cancer analysis, derived a generalized PanOxPhos gene signature, and identified mTOR as a potential regulator in primary tumor samples. High throughput GEP coupled with statistical machine learning methods represent an important toolbox in modern cancer research. It provides a cost effective and promising new approach for predicting cancer risk associated to chemical exposure, it can reduce the cost of the ever increasing drug development process by identifying therapeutically actionable disease subtypes, and it can increase patients’ survival by matching them with the most effective drugs. / 2016-12-01T00:00:00Z

Ce travail de thèse est consacré à l'étude des bases neurobiologiques de la résilience et de la vulnérabilité dans des groupes d’adolescents et de jeunes adultes à risque d'addiction qui sont au cœur des campagnes de prévention des conduites addictives. Même si la recherche en addictologie a permis des avancées majeures dans la compréhension des bases cérébrales de l'addiction, très peu de recherches se sont portées sur ceux qui arrivent à arrêter ou à résister en dépit de la présence de facteurs de risque et de vulnérabilité. L'objectif était de rechercher des modifications de la structure cérébrale associées à l'interruption spontanée de la poly-consommation ainsi que des modifications anatomo-fonctionnelles associées à une histoire familiale d'alcoolodépendance. A l'aide de logiciels de traitement d'images acquises en imagerie par résonance magnétique (IRM) anatomique, de diffusion, et fonctionnelle sollicitant le circuit de la récompense, nous avons mis en évidence des variations anatomiques et fonctionnelles discrètes en particulier dans le gyrus cingulaire, région clé du cerveau qui relie les structures frontales et sous-corticales impliquées dans le circuit de la récompense. La découverte de facteurs cérébraux sous-jacents à l’expression de la résilience et de la vulnérabilité pourrait alimenter de nouveaux modèles de recherche et thérapeutiques ciblant la réhabilitation des fonctions cingulaires chez les individus à risque. / This thesis is devoted to the study of the neurobiological bases of resilience and vulnerability in groups of adolescents and young adults at risk of addiction who are at the heart of prevention campaigns of addictive behaviours. Although addiction research has led to major advances in the understanding of the bases of addiction, very little research has been conducted on those who are able to stop or resist despite the presence of risk and vulnerability factors. The main objective was to investigate changes in brain structure associated with spontaneous recovery from multiple-substance use as well as structural and functional changes associated with a family history of alcohol-dependence. Magnetic resonance images (MRI) were acquired using sequences of anatomical, diffusion, and functional that solicits the reward system. We have demonstrated discreet anatomical and functional variations, particularly in the cingulate gyrus, a key brain region that connects the frontal and subcortical structures involved in the reward system. These advances regarding the neurobiological underpinnings of resilience and vulnerability could fuel new research and therapeutic models targeting the rehabilitation of cingulate functions in at-risk individuals.

A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfilment of the requirements for the degree of Doctor of Philosophy Johannesburg, 2017. / Background: In spite of the contributions of cardiovascular disease (CVD) to morbidity and mortality in chronic kidney disease (CKD) worldwide, there are no studies that have looked at cardiovascular risk factors (CVRFs) and their association with cardiovascular changes in African children with CKD. Several CVRFs have been implicated in the initiation and progression of cardiovascular changes in children with CKD, and these changes have been reported even in early CKD. This study investigated CVRFs and their association with cardiovascular changes in South African children with CKD. Method: This comparative cross sectional study recruited children (5-18 years) with CKD being followed up at the Division of Paediatric Nephrology of the Charlotte Maxeke Johannesburg Hospital and the Chris Hani Baragwanath Academic Hospital. One hundred and six children with a spectrum of CKD including those on chronic dialysis (34 CKD I, 36 CKD II-IV and 36 CKD V-dialysis) were enrolled over a 12 month study period. All patients had a short history taken along with a physical examination. Blood samples for serum creatinine, urea, albumin, calcium, phosphorus, parathyroid hormone (PTH), alkaline phosphatase, total cholesterol, haemoglobin and C-reactive protein, Vitamin D, Fibroblast growth factor-23 (FGF-23), Fetuin-A and genomic DNA studies were taken. Where feasible, transthoracic echocardiography and high resolution ultrasonography of the common carotid artery was performed. Results: The overall median age of the patients was 11 years (8-14 years), with a male female ratio of 2.1:1. Several CVRFs detected include hypertension, proteinuria, anaemia, hypercholesterolaemia and dysregulated mineral bone metabolism. The most common CVRF detected was anaemia (39.6%) and its prevalence was highest in the dialysis group when compared with the other CKD groups. The overall median (range) cIMT was 0.505mm (0.380-0.675), and was highest in patients with dialysis dependant CKD (p=0.003). The distribution of left atrial diameter (LAD) and left ventricular mass (LVM) differed significantly (p<0.05) across the different CKD groups. Abnormal LAD was seen in 10% of patients; left ventricular hypertrophy (LVH) in 27%; left ventricular systolic dysfunction in 6% and diastolic dysfunction in one patient. Mean arterial pressure and haemoglobin levels were independently associated with cIMT; hypertension was independently associated with concentric LVH; and age and hypoalbuminaemia were independently associated with eccentric LVH. Overall, the dialysis group had the highest prevalence of vascular changes, cardiac changes and associated risk factors. A skewed pattern of Fetuin-A and FGF-23 levels with medians (range) of 57.7 (0.9-225.2) mg/dL and 28.9 (0-3893.0) pg/ml respectively, were observed. The levels of these two biomarkers varied significantly between the different CKD groups (p<0.05). Fetuin-A was independently associated with abnormal LAD but no similar relationship with other cardiovascular changes and plasma levels of Fetuin-A and FGF-23 was found. Plasma FGF-23 levels correlated better with markers of bone mineralization than Fetuin-A. Eight Fetuin-A SNPs were analysed; rs2248690, rs6787344, rs4831, rs4917, rs4918, rs2070633, rs2070634 and rs2070635. We found an association between log-transformed Fetuin-A levels and the SNP rs4918 G-allele compared to the rs4918 C-allele (p=0.046) and the rs2070633 T-allele when compared to the rs2070633 C-allele (p=0.015). Markers of MBD such as phosphate and PTH levels were associated with Fetuin-A SNPs. The rs6787344 G-allele was significantly associated with phosphate levels (0.042), and the rs4918 G-allele with PTH (p=0.044). Seven deaths were recorded in the dialysis group during the study period and severe hypertension and intracranial bleed were the most common causes of death. Modifiable risk factors such as increased total cholesterol (TC) and decreased albumin levels were more commonly seen among the deceased dialysis patients. Conclusion: A high prevalence of CVRFs and cardiovascular changes were observed in the study groups, even in those with mild to moderate disease. Information obtained from the study highlights the need to address modifiable CVRFs such as hypertension, anaemia and hypoalbuminaemia in children with CKD and also the need to determine new, population specific, paediatric reference values for cIMT in healthy African children. Finally, the study was able to demonstrate differences in the relationship between Fetuin A SNPs and Fetuin-A levels and cardiovascular changes in our study population when compared with previously published data. We postulate that these differences may be due to genetic differences between our population and other population groups previously studied. / LG2018

Arsenic is a toxic metalloid that continues to contaminate the water and food sources of millions of people globally. Among the numerous health effects of arsenic exposure are urothelial toxicity and cancer. In recent years, small extracellular vesicles (SEVs) have been shown to be vital in intracellular communication and have been used in clinical studies as biomarkers of disease. The overall goal of this thesis is to understand the mechanisms of cell communication during arsenic exposure and to develop minimally invasive biomarkers for the toxic responses. The specific objectives are to: a) determine if SEVs released from arsenic exposed urothelial cells are responsible for mediating urothelial toxicity; and b) assess the application of urinary SEVs as novel biomarkers of arsenic exposure in an exposed population. The hypothesis leading this research is that the biology and protein packaging profile of urothelial SEVs are altered following arsenic exposure because of the induction of cell stress signaling pathways. I also hypothesize that urinary SEV proteins can be used as biomarkers of arsenic exposure because they are positively correlated with urinary arsenic concentrations in an exposed population. SVHUC1 human urothelial cells were dosed with sodium meta arsenite (1, 2, and 5 uM) for 48 hours. T24 urothelial carcinoma cells were also grown in parallel to compare for carcinogenicity. A label-free quantitative proteomics approach was used to assess the differentially expressed proteins in the cell lysate and the SEVs extracted from the culture media to determine the mechanistic pathways involved and how well the protein profiles in SEVs correlate with those in the cell lysate. SEVs were isolated from the archived urine samples of participants (n=36) enrolled in the Yellow Knife Health Effects Monitoring Program (YKHEMP) and two potential biomarkers, transforming growth factor beta receptor 1 (TGFBR1) and ribonuclease inhibitor 1 (RNH1), were measured by an enzyme linked immunosorbent assay (ELISA). SEVs in all samples were successfully characterized based on their size (50-200 nm) and positive antibody array for eight protein markers indicating their endosomal biogenesis. The total number of SEVs was not shown to increase following arsenic exposure in the in vitro study. However, the cancerous T24 cells had nearly four times higher numbers of SEVS compared to the non-cancerous SVHUC1 cells. The changes in the protein profiles in SEVs released following arsenic dosage indicated activation of pathways important for cell survival, viability, and migration and inactivation of pathways related to cell death and necrosis which were also observed in the paired cell lysate samples. Comparison between paired SEV and cell lysate samples, however, indicated selective SEV packaging of proteins which may be for the purpose of intracellular communication. Comparative assessment of SEVs from T24 and arsenic exposed SVHUC1 cells showed similar activation of cancer related pathways including those responsible for malignant tumors and increased proliferation rates. From the in vitro study results, we identified 8 potential SEV biomarkers. Of which, TGFBR1 showed the most promising association, having been positively associated with both inorganic arsenic and cadmium concentrations in urine samples. This thesis showed that SEVs are important mediators of arsenic exposure in urothelial cells and highlighted the comparability of SEV and cell lysate analysis. Furthermore, TGFBR1 was identified as a promising biomarker of arsenic exposure for its positive association with increased arsenic both in vitro and in human biomonitoring analysis.

No description available.