M.A. (Clinical Psychology) / This study was undertaken in an attempt to validate the hypothesis that anxious subjects who ingested diazepam (Valium) and were subjected to a helplessness inducing situation,would become more depressed and more hopeless than people who were subjected to the same situation and obtained anxiety relief by means of a response-contingent behaviour - a muscle relaxation exercise. Twenty-nine male and female students were selected from the undergraduate and post-graduate student population at the Rand Afrikaans University on the basis of scores on the IPAT Anxiety Scale and the Beck Depression Inventory. The subjects were randomly assigned to one of the three experimental groups and the one control group and were subjected to the helplessness inducing situation. A wide spectrum of measures were performed and the results subjected to analyses of variance. The results indicated support for the hypothesis that people who received response contingent anxiety relief became less depressed than people who obtained non-response-contingent anxiety relief. No support was found for the hopelessness construct. The lack of results of this were discussed in terms of the effectiveness of the measuring instruments and that hopelessness and helplessness might be different concepts.

The identification of drug treatments that are useful in diverse therapeutic settings is a significant driving force in biomedical research [Macarron et al., 2011], [Poureetezadi et al., 2014], [Lamb, 2007]. Typical means for measuring the efficacy of a drug for a given clinical application include protein-protein interactions, cell death, mitochondrial respiration and cell growth as well as broader measurements of absorption, distribution, metabolism, excretion and toxicity (ADMET), specifically related the the drug or drugs being tested [Szakcs et al., 2008]. A wide array of methods are routinely employed to perform these screens, from ligand binding assays [Wagner et al., 2016] to high-throughput proteomics [Verheul, 2014]. One method that is currently underutilized in small-molecule drug screens and drug discovery is high-throughput transcriptome sequencing, such as RNA-Seq. Although RNA-Seq is routinely used to profile patterns of genetic changes following perturbations such as drug treatment [Young et al., 2014], it has not, to my knowledge, yet been used as the primary readout of a drug screen.

General Abstract There has been a steady increase in the use of medicinal plants in the last two decades in both developed and developing countries for prevention, management and treatment of diseases. This increase has been due to reasons such as ease of access, better cultural acceptability and compatibility, cost effectiveness and also the bid to “go natural”. Unfortunately, the notion that herbal medicines are relatively safe because they are natural has led to serious and potentially fatal consequences in phytotherapy. The lack of rigorous research to prove the effectiveness and safety of many medicinal plants is of great concern to the health care system. This thesis therefore addresses not just the efficacy, but also the safety of the extracts of the berry of Solanum aculeastrum - a medicinal plant used, among other things, for the treatment of breast cancer in the Eastern Cape Province of South Africa. Particular attention was paid to the possible effect of different processing methods of the berry extracts on inflammation, cytotoxicity, and toxicity. In studying the comparative effects of various processing methods, four different preparations of the extracts were investigated. These include fresh, dried, boiled fresh, and boiled dried berries. While the effect of processing on the anti-inflammatory properties of the extracts was not dose dependent, the percentage reduction in inflammation was highly significant and more prominent in both concentrations of the boiled fresh berries than the reference drug, indomethacin. Furthermore, the four extracts varied in their ability to act either centrally or peripherally in their effect on pain. Assessment of the analgesic response using the formalin test showed that, at both concentrations tested, none of the extracts inhibited the first phase of the formalin test. Furthermore, it was observed that boiling had differing results on the activity of the iii fresh and dried extracts. While boiling of the dried berries reduced pain in the rats, the opposite trend was observed with the boiled fresh berries. Results of the influence of processing of the berries on cytotoxicity indicated that the extracts are potent inhibitors of human breast, cervical and colonic carcinoma cells and the non-cancerous cells (both the actively dividing and confluent Chang liver cells). Although, in terms of relative potency, the fresh berries appeared to be the most active of the extracts, processing of the berries caused an increase in apoptotic cells and a subsequent decrease in the necrotic cells. The effect of processing on the safety of the berry of S. aculeastrum on the rats fed for 28 days was also investigated. The various doses (1, 10 and 25 mg/kg body weight) of all the four extracts did not alter the activity and the weight of the animals throughout the period of treatment. A reduction in organ to body weight ratio of the heart, kidney, liver and spleen was observed in all the extracts. Regarding the haematological parameters, different patterns of effect were observed between the extracts and within the treated doses. The observed alterations in the biochemical parameters by the various extract of Solanum aculeastrum berries at all the doses may have consequential effects on the normal functioning of these organs. In conclusion, this study has shown that there is some justification for the traditional use of the berries of Solanum aculeastrum in the treatment of inflammation related ailments and cancer. However, the medicinal use of the plant also poses considerable health risks. Investigation conducted into the plant’s safety revealed that the berry extracts were nephrotoxic, hepatotoxic, haematotoxic and at higher doses, fatal. Another concern with regard to the plant’s safety is the non-selectivity of its extracts in the inhibition of carcinoma, actively dividing and un-dividing cells. Assessment of the effect of the processing on the berry’s efficacy and safety as herbal iv remedy produced mixed results. On the one hand, processing seemed to improve the extract’s anti-inflammatory and analgesic activity, while reducing its cytotoxic potential. On the other hand, a reduction in the toxicity was observed on the processed extracts compared to the fresh ones. This may be an indication that processing has an overall beneficial effect on the medicinal properties of the plant and should thus be considered as a method of making the berries of Solanum aculeastrum safer for use as a herbal remedy.

A postmarketing surveillance survey of sumatriptan use comprised 32 questions including patient demographics, headache history, and sumatriptan experience. One hundred and forty-one questionnaires were sent out, and 109 patients responded; a total of 108 patients were included in the data analysis. When compared with the national migraine population, on a percentage basis, significantly more African-Americans, females, young patients (less 45 years of age), and patients with higher mean incomes (>$45,000) were found in the present study of those taking sumatriptan (p Males (N=8) and females (N=55) had a significantly different percentage of relief from the second dose of 94.7%±7.1 and 83.5%±24.4, respectively (p=0.01). An average percent of pain relief from the first dose in those weighing less or greater than 144 pounds was 76.5%±28.3 and 86.9%±16.4, respectively (p=0.023). The incidence of the adverse effects reported in this study was significantly greater than those reported in the literature (p<0.005).

Thesis (MMed) -- Stellenbosch University, 2010. / Bibliography / Objective: The objective of this retrospective cohort study is to assess whether demographic and anthropometric parameters, laboratory tests, co-morbidity, co-infection, treatment regimen, IRIS and adherence to treatment predict the expected response to HAART and differences if any, in the pattern of response as measured by CD4 count, weight gain and haemoglobin levels in two cohorts of patients in Roma, The Kingdom of Lesotho. Method: Data were collected randomly from a computerised database of the Antiretroviral Centre of the hospital and two cohorts of 151 subjects in each of the two arms of the study were identified from hospital records from January 2008. Each of these subjects was followed up over a period of 12 months with data obtained for at least 2 visits within the 12 month span. Data were obtained at baseline, 3 months and also at 6 and 12 months marks. Data on characteristics were compared between the two arms. Variables that may be potential confounders were identified and univariate and multivariate logistic regression analyses were carried out to establish differences independent of confounding factors for the combined endpoints as well as for each endpoint separately. Results: In all 302 patients had their records analysed and comparison of clinical and immunological response patterns in patients taking AZT and TDF-containing ART regimens and the possible prediction of which the regimen would be better and within which population. Despite the perceived mismatch between two NRTIs it can be concluded from the results of this study that, overall, the inclusion of AZT in treatment regimen showed a modest protective effect over the TDF counterpart as measured by the endpoints of the discriminative powers of the Receiver Operating Curves of the explanatory variables being 66% , 77% and 66% for CD4, Haemoglobin and Weight respectively, and 63%, 70% and 65% for the same variables in the AZT and TDF arms of the study respectively. Conclusion: In a population of HIV patients on treatment in resource-limited settings AZT-containing regimens appear to show a slight improvement over the TDF-containing ones.

Indiana University-Purdue University Indianapolis (IUPUI) / Carboxylesterases (CES) are enzymes that metabolize a wide variety of compounds including esters, thioesters, carbamates, and amides. In humans there are three known carboxylesterase genes CES1, CES2, and CES3. Irinotecan (CPT-11) and capecitabine are important chemotherapeutic prodrugs that are used for the treatment of colorectal cancer. Of the three CES isoenzymes, CES2 has the highest catalytic efficiency for irinotecan activation. There is large inter-individual variation in response to treatment with irinotecan. Life-threatening late-onset diarrhea has been reported in approximately 13% of patients receiving irinotecan. Several studies have reported single nucleotide polymorphisms (SNPs) for the CES2 gene. However, there has been no consensus on the effect of different CES2 SNPs and their relationship to CES2 RNA expression or irinotecan hydrolase activity. Three CES2 mRNA transcripts of approximately 2kb,3kb, and 4kb have been identified by multi-tissue northern analysis. The expressed sequence tag (EST) database indicates that CES2 undergoes several splicing events that could generate up to six potential proteins. Four of the proteins CES2, CES2458-473, CES2+64, CES21-93 were studied to characterize their expression and activity. Multi-tissue northern analysis revealed that CES2+64 corresponds to the 4kb and 3kb transcripts while CES21-93 is located only in the 4 kb transcript. CES2458-473 is an inactive splice variant that accounts for approximately 6% of the CES2 transcripts in normal and tumor colon tissue. There is large inter-individual variation in CES2 expression in both tumor and normal colon samples. Characterization of CES2+64 identified the protein as normal CES2 indicating that the signal peptide is recognized in spite of the additional 64 amino acids at the N-terminus. Sub-cellular localization studies revealed that CES2 and CES2+64 localize to the ER, and CES21-93 localizes to the cytoplasm. To date CES2 SNP data has not provided any explanation for the high inter-individual variability in response to irinotecan treatment. Multi-tissue northern blots indicate that CES2 is expressed in a tissue specific manner. We have identified the CES2 variants which correspond to each mRNA transcript. This information will be critical to defining the role of CES2 variants in the different tissues.

Herbal formulations claimed to cure several medical conditions including skin eruptions, chest pains, wounds, gout, menstrual pains, stress, nervous disorders, microbial and viral infections as well as stomach ailments have recently appeared as part of South African traditional medicine. The formulations consist of mixtures of extracts of different plant parts from several different plant species packaged in labelled bottles or boxes. The mixtures are available for sale in herbal shops and public places. While there has been widespread use of these herbal mixtures, there has been no scientific evidence to support their use. This project was aimed at documenting, validating claimed efficacy and testing the safety of fourteen unregistered commercial herbal preparations commonly sold in Pietermaritzburg. A detailed investigation of the pharmacological effects and safety of the plant components of one of the mixtures, Imbiza ephuzwato was also carried out. / Thesis (Ph.D.) - University of KwaZulu-Natal, Pietermaritzburg, 2009.