Magister Scientiae (Medical Bioscience) - MSc(MBS) / Nanotechnology is a rapidly expanding field with a multitude of practical uses namely textiles, cosmetics, agriculture, and health sciences. The focus, for the purposes of this thesis, will be on carbon dots. The small size and low surface-to-volume ratio result in different physico-chemical behaviour of these particles in comparison to its significantly larger bulk-produced counterparts.

Turmeric extract or active component curcumin may have anti-inflammatory effects in people with chronic inflammatory diseases. The effect of turmeric or curcumin on a wide range of inflammatory markers has not been evaluated in a systematic review. We performed a systematic review of randomized controlled trials (RCTs)evaluating the effects of oral turmeric or curcumin on inflammatory markers (CRP, hsCRP, IL-1, IL-6, TNF)in patients with a wide range of chronic inflammatory diseases. Pubmed, EMBASE, Scopus, the Web of Science, and the Cochrane library were evaluated until June 2018. Random effects meta-analyses with inverse variance methods and stratified by turmeric or curcumin were performed. Effects were expressed as mean differences (MD)and their 95% confidence intervals (CI). Risk of bias of RCTs was evaluated with the Cochrane tool. Nineteen RCTs were identified; included patients had rheumatic diseases, advanced chronic kidney disease with hemodialysis, metabolic syndrome, and cardiovascular diseases. Turmeric was the intervention in 5 RCTs (n = 356)and curcumin/curcuminoids in 14 RCTs (n = 988). Follow up times ranged between 4 and 16 weeks. One RCT had high risk of bias. In comparison to controls, turmeric or curcumin did not significantly decrease levels of CRP (MD -2.71 mg/L, 95%CI -5.73 to 0.31, p = 0.08, 5 studies), hsCRP (MD -1.44 mg/L, 95%CI -2.94 to 0.06, p = 0.06, 6 studies), IL-1 beta (MD -4.25 pg/mL, 95%CI -13.32 to 4.82, p = 0.36, 2 studies), IL-6 (MD -0.71 pg/mL, 95%CI -1.68 to 0.25, p = 0.15), and TNF alpha (MD -1.23 pg/mL, 95%CI -3.01 to 0.55, p = 0.18, 7 studies). There were no differences between turmeric and curcumin interventions. High heterogeneity of effects was observed for all markers across studies, except hsCRP. Other inflammatory markers such as IL-1 alpha, TNF beta, IL-17, and IL-22 had scarce data. Turmeric or curcumin did not decrease several inflammatory markers in patients with chronic inflammatory diseases. / Revisión por pares

BACKGROUND: Early identification of pediatric patients with Inflammatory Bowel Disease (IBD), including ulcerative colitis and Crohn disease, is important to help clinicians design optimal treatment regimens. Existing endoscopic techniques are effective in identifying disease activity. However, these methods are invasive, expensive, and less amenable to serial measurement. Recent studies have identified potential serologic and fecal biomarkers that may have the potential to provide clinicians with a more objective evaluation of disease activity. In the case of ulcerative colitis (UC), in which disease is confined to the large intestine, the information provided by fecal biomarkers is likely to be more specific than that provided by serologic biomarkers. Fecal lactoferrin (FLA) is one such biomarker that has shown to be useful not only in identifying levels of colonic inflammation, but also for use as a predictor of disease relapse and treatment efficacy. Measurement of fecal lactoferrin, in conjunction with information provided by other diagnostic modalities could expedite patient assessment and treatment. Additionally, it has been suggested that fecal lactoferrin levels may also provide prognostic information about response to treatment and disease outcome in pediatric patients with UC. The goal of this study is to explore the relationship between changes in FLA levels and response to medical therapy in hospitalized pediatric patients with UC. METHODS: Serial stool samples were collected daily from 10 patients admitted for management of severe active UC. Of these 10 patients, 3 responded favorably to standard treatment with intravenous corticosteroid therapy and were discharged to complete a course of oral steroids. 7 were unresponsive to steroid therapy and went on to require rescue (more intensive) medical therapy. Changes in FLA were correlated with steroid response and medical disposition at the time of discharge. RESULTS: A t-test was performed to determine the significance of the differences in percent change in FLA levels between patients discharged on steroids and patients discharged on rescue therapy. Patients discharged on steroids demonstrated a net decrease in FLA levels over the course of the first three days of steroid treatment while patients ultimately requiring rescue medical therapy demonstrated a net increase in FLA levels (mean values = -64.4% and +203.8%, respectively). A difference was found between the averages; however, this value did not reach statistical significance when analyzed with a t-test (p = 0.18). CONCLUSIONS: This study suggests that quantitative FLA levels may prove useful in predicting clinical course and discharge outcome in pediatric patients with ulcerative colitis. Future research in this field should seek larger sample sizes, increased longitudinal sample collection, and the potential for a composite assessment that will yield additional objective measures of disease activity.

Orofacial clefts (OFCs) are among the most common congenital birth defects and are characterized by incomplete development of the lip or the palate or both. The lip and palate develop separately at different times during the first trimester of pregnancy. The etiology of OFCs is multifactorial and includes a combination of genetic and environmental factors. This project aims to examine role of maternal diabetes mellitus in orofacial clefts through studies of medical histories, biomarkers, and genes. In a study of Utah birth certificates, mothers with pre-existing diabetes and gestational diabetes mellitus (GDM) had an increased risk of OFCs, and obese mothers also had an increased risk. Mothers of children with OFCs were more likely than mothers of unaffected children to develop obesity, metabolic syndrome and gestational diabetes mellitus later in life. These result were more strongly related to cleft palate than cleft lip. Many genes related to GDM were associated with OFCs through genetic effects alone and gene-environment interaction effects with periconceptional maternal multivitamin use, maternal smoking, and environmental tobacco smoke. These results support the hypothesis that GDM may be causally related to OFCs via multiple GDM susceptibility genes and interactions with environmental factors. Individuals with OFCs face both physical and mental health problem, which require multi-specialty team care. OFC prevention and prediction are important to public health. This dissertation reported that maternal diabetes mellitus, maternal pre-pregnancy weight and genes related to GDM had an association with the risk of OFCs. Mothers having an OFC child had an increased risk of developing metabolic abnormalities later in life. Potential risk factors were reported in this dissertation that may be useful for OFC prevention. This dissertation also reported potential biomarkers for predicting OFCs. Moreover, mothers having an OFC child may require regular monitoring of metabolic abnormalities later in life.

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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, 2016 / Background: Despite preventive guidelines, iatrogenic contrast-induced nephropathy (CIN) ranks third as a cause of hospital acquired acute kidney injury (AKI), and impacts significantly on morbidity and mortality and is associated with high hospital costs. In Sub-Saharan Africa, the rates and risk factors for CIN remain unexplored. Despite the positive association of genetic polymorphisms in the TNFα and IL10 genes with CIN in Asian populations, the CIN genetic susceptibility in other races is unknown. Serum creatinine is a sub-optimal biomarker for the early diagnosis of CIN resulting in delayed interventions. This study investigated rates, risk factors and outcomes of CIN, the influence of genetic susceptibility to CIN in the black population and lastly, the accuracy of novel biomarkers in the early diagnosis of CIN and prognosticating patient outcomes. Methods: This was a prospective case-controlled study conducted at Charlotte Maxeke Johannesburg Academic Hospital, in South Africa from January 1, 2014 to December 30, 2015.Hospitalized patients undergoing enhanced computed tomography and angiography were consecutively recruited to the study and followed up for development of CIN. CIN was defined as an increase in serum creatinine >25% or an absolute increase of >44 μmol/l from baseline at 48-72 hours after exposure to contrast media. In the second part of the study, a nested case-controlled cohort that included 30 CIN patients and 60 controls (those undergoing contrast administrations and not meeting CIN criteria) were ethnically matched for gender, and age in a case: control ratio of 1:2 at all-time intervals. Sera for neutrophil gelatinaseassociated lipocalin-2 (NGAL), cystatin C, beta-2 microglobulin (β2M), interleukin 18 (IL18), IL10, and tumor necrosis factor alpha (TNFα) were collected at four time points: baseline (pre-contrast), 24 hours, 48 hours and ≥5-7 days after contrast administration and their concentrations were determined using luminex assays and an enzyme linked immunosorbent assay for β2M as per manufacturer’s instructions. The areas under receiver operating characteristic curves (AUROC) were generated to determine accuracy of novel biomarkers to diagnose CIN and CIN mortality. Genomic DNA was extracted from peripheral blood samples of 208 black South Africans using the Maxwell DNA purification kit (Promega AS1010, USA) and their genotypes for - 308(rs1800629) and -857(rs1799724) in the TNFα gene and -592(rs1800872), - 819(rs1800871), -1082 (rs1800896) and +1582(rs1554286) in the IL10 gene were determined by restriction fragment length polymorphism (RFLP). Results: We recruited 371 hospitalized patients (mean age 49.3±15.9); the rates of CIN were4.6% and 16.4% respectively, using an absolute or relative increase in serum creatinine from baseline. Anaemia was an independent predictor for the development of CIN (RR 1.71, 95% 1.01-2.87; p=0.04). The median serum albumin was 34 g/l (IQR: 29-39.5) vs. 38 g/l (IQR: 31-42), p=0.01 in the CIN and control groups respectively.Mortality was significantly increased in the CIN group (22.4% vs. 6.8%; p<0.001), and CIN together with anaemia predicted mortality with a 2-fold (p=0.01) and a 3-fold (RR p=0.003) riskrespectively. The median cystatin C at 24 hours (p<0.001) and β2M(at all-time points)levels were significantly higher in the CIN group compared to controls. The median cystatin C at 24 hours and β2Mlevels at 48 hours were 856.59 ng/ml (IQR 620.75-1002.96) vs. 617.42 ng/ml (IQR 533.11-805.20); p<0.001 and 5.3 μg/ml (IQR 3.8-6.9) vs. 3.3 μg/ml (IQR 2.7-4.5); p<0.001 with AUROCs of 0.75 and 0.78 respectively for early CIN discrimination.Pre-contrast IL18 (p <0.001), β2M (p=0.04) and TNFα (p<0.001) levels were significantly higher in the nonsurviving group and their AUROC were 0.83, 0.82 and 0.94 for CIN+ mortality. Baseline NGAL was a better marker for excluding patients at higher risk of developing CIN with negative predictive and positive predictive values of 0.81 and 0.50 respectively. The frequency of TNFα -308 AA genotype was significantly increased in the CIN group compared to controls (13.3% vs.1.82%, p=0.016) and the presence of the TNFα-308 AA (high producer) vs. GA genotypes was associated with a 9-fold CIN risk (9.24, 95% CI, 1.88-45, p=0.006). The IL10-1082 AA-allele (low producer) was significantly higher in the non-surviving CIN+ patients compared to controls (p=0.01). Conclusions:CIN occurred at a relatively high rate in our study and predicted poorer clinical outcomes. The presence of CIN and anaemia positively predicted mortality. Caution should be exercised in patients with anaemia and hypoalbuminaemia undergoing contrast studies. Serumcystatin C was the best novel biomarker for the early diagnosis of CIN and while baseline NGAL is superior as a biomarker for excluding patients at higher risk for CIN. IL18, β2M and TNFα are the best novel biomarkers for predicting the prognosis of patients with CIN. Increased frequency of the TNFα-308 AA genotype is a predisposing factor for CIN development. The low producer IL10-1082 AA genotype decreases survival in patient with CIN. / MT2017

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As science and medicine advance, it becomes ever more important to be able to control and analyze smaller and smaller bioparticles all the way down to single molecules. In this dissertation several studies aimed at improving our ability to manipulate and monitor single biomolecules will be discussed. First, we will discuss a study on developing a way to map dielectrophoresis with nanoscale resolution using a novel atomic force microscopy technique. Dielectrophoresis can be applied on nanoparticles through micron-scale electrodes to separate and control said particles. Therefore, this new method of mapping this force will greatly improve our ability to manipulate single biomolecules through dielectrophoresis. The next two studies discussed will be aimed at using carbon nanotube nanocircuits to monitor single protein kinetics in real time. Drug development and delivery methods rely on the precise understanding of protein interactions, thus creating the need for information on single protein dynamics that our techniques provides. The proteins studied in these sections are MMP1 and HDAC8, both of which are known targets of anti-cancer drugs. Finally, we developed a new strategy for diagnosing pancreatic cancer. Our strategy involves using graphene nanotransistors to detect exosomes released from the pancreatic tumor. The ability to reliably diagnose pancreatic cancer before it reaches metastasis would greatly improve the life expectancy of patients who develop this condition. We were able to test our technique on samples from a number of patients and were successfully able to distinguish patients with pancreatic cancer from noncancerous patients.