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For thousands of years, Nature has been considered to be essential to human beings for the treatment of their diseases. Amphibians are an important component of the Animal Kingdom and have played a significant role in sourcing many active and some therapeutic compounds. The secretions of amphibians act as defensive substances spreading out over their skins to protect them from predator attack and infections by microorganisms. These skin secretions represent a spectacular library of bioactive molecules, including peptides. In recent years, many different kinds of antimicrobial and pharmacological peptides have been isolated from amphibian skin secretions and some of these are providing potential human therapeutic leads. In the course of this research, genomic and proteomic techniques have been used to investigate the bioactive peptides from the skin secretions of four species of frog: the Central American red-eyed leaf frog, Agalychnis callidryas; the Peruvian purple-sided leaf frog, Phyllomedusa baltea; the European edible frog, Pelophylax kl. esculentus; the Fujian large-headed frog, Limnonectes fujianensis. The peptides isolated in these studies could be divided into two antimicrobial peptide families (balteatide and QUB3276) and two pharmacological peptide families (the bombesin-related peptides and AcT-2). The latter peptide was found to have both antimicrobial and pharmacological functions. Synthetic replicates of each peptide were prepared and used in an extensive range of biological assays.These discoveries of novel peptides from amphibian skin secretions have enriched our knowledge of bioactive peptides from this source and may provide the basis for several drug development programmes.

Mycotoxins, heavy metals and pesticides are ubiquitous in the environment, contributing to multiple contamination of foodstuff. However, due to complications of determining their combined toxicity, legal limits of exposure are determined for single compounds, based on long standing toxicological techniques. Governmental regulatory bodies must begin to contemplate how to safeguard the population when such mixtures of contaminants are present in food. The aim of this thesis was to study the interactive and cytotoxic effects .of mixtures of chemical food contaminants when present at their corresponding regulatory limits, the capability of high content analysis (HCA)at determining these biological effects and to determine possible mechanistic approaches behind the adverse effects measured.

miRNAs have been shown to play a role in fundamental cellular processes. They are also involved in drug-resistance mechanisms, which hamper the treatment of many types of cancer, including haematological malignancies. This study sought to uncover mechanisms of miRNA-induced drug-resistance in two haematological malignancies: diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). To this end, profiling of DLBCL and MM-derived cell lines was carried out to identify miRNAs whose levels were altered relative to their respective controls. The expression levels of these miRNAs were then modulated in the cell lines to examine the effect upon cell survival. The miRNA profiling data of the DLBCL cell lines compared to their control “normal” B-cell lines, was then combined with the results of previously performed “translational profiling” in which levels of mRNA translation are compared. Translational profiling identified upregulation of certain DNA damage repair (including BRCA2) and anti-apoptotic (including Bcl-2) proteins in the DLBCL cell lines. Importantly, the miRNA profiling data identified downregulation of miR-34a and miR-146 in the DLBCL cell lines, which are reported to target Bcl-2 and BRCA2, respectively. In GCB-DLBCL patient samples low miR-34a expression correlated with poor prognosis. In MM, the miRNA profile of an acquired multidrug-resistant cell line (8226/R5) was compared with the profile of its parental sensitive cell line and the miR-200 family was identified as upregulated in the resistant line. Overexpression of miR-200b, miR-200c or miR-429 in the parental cell line increased resistance to the proteasome inhibitor bortezomib. The increased resistance was due to direct targeting of the pro-apoptotic protein, Noxa, by the miR-200bc/429 family. Acquired bortezomib-resistant cell lines, which were only resistant to proteasome inhibitors, were then generated. miR-200b was again upregulated in these new cell lines, suggesting that increased expression of the miR-200bc/429 family is a possible mechanism for acquired bortezomib-resistance in MM.

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No description available.

No description available.

No description available.

Diarrhoeal diseases remain a main cause of preventable death, particularly among children under five years of age in developing countries. In addition, many studies related to infant diarrhoea causation have demonstrated that the level of contamination is higher in weaning foods than in drinking water. Furthermore, many studies addressed food microbiological contamination and its role in diarrhoea causation. But few of them resulted in an intervention. Although the Hazard Analysis, Critical Control Point (HACCP) approach has been developed and widely applied to food promotion in industrialised countries, and adapted to small and/or less Developed Businesses, few studies have examined its relevance to domestic preparation of food. However, these latter predicted that the implementation of the approach could lead to an improvement of household bacteriological food safety, but none of them completed the approach to find out how effective it is. Therefore, this study aimed to take that work one step further, and carried out a small-scale intervention developed on the basis of the HACCP approach. This latter has been extended to health district level in order to find out its impact on microbial reduction in weaning food. Experiment: The HACCP approach has been applied step by step, to two selected weaning foods prepared by 15 volunteer mothers in peri urban Mali. After setting Critical Control Point (CCP), actions were taken to control, reduce or eliminate microbial growth at these points. 432 food samples were collected and analysed in local Laboratory for FC count to assess the effectiveness of the approach. Lessons learnt were translated into messages delivered in a pilot study. Pilot study: Sample of 60 volunteer mothers selected randomly was split into two groups of 30, the first undergoing messages directed to actions implementation, and the second standing as a control. Bacteriological samples were taken and analysed and physical parameters were measured,· as in the experiment, in 60 households before the intervention and data collected set as baseline. After three weeks training, alongside with observations, foods samples were taken in both intervention and control households for Fe count in local Laboratory. Flow diag~ams of foods, Moni and Fish Soup indicated that they were exposed to contamination at all steps of their preparation and handling. The hazard analysis confirmed FC contamtnation of all suspected steps except cooking. Four CCPs were identified for each food (cooking, reheating, child service with cooled food after cooking, and child service with cooled food after reheating). The experiment showed that traditional cooking was very effective in FC elimination; reheating was as effective as cooking when adopted, because no difference existed between two operations' temperatures (P<0.0001). Behavioural corrective actions were effective in controlling FC contamination at remaining CCPs (child service after cooking and child service after reheating). In conclusion, the HACCP experiment improved significantly the bacterial safety of the two type of weaning foods studied. Thus its behavioural corrective actions were translated into educational messages for the following phase aiming to confirm the effectiveness of the HACCP approach in improving foods safety at household level. The pilot study data showed the effectiveness of cooking in FC elimination at CCPs considered. A comparison of seasonal variation of FC contamination levels at CCPs showed that these levels were higher at Moni cooking CCP in December (cold season) (P<0.0004) and in August (rainy season) (P<0.0002), compared to June (dry season). They were also higher at Fish Soup storage CCP in December compared to August (P< 0.0098). There was significant difference in FC contamination levels between cooking and storage CCPs, the latter was higher than the former, for both Moni and Fish Soup (P< 0.0001). A comparison of FC contamination levels before and after intervention showed that the intervention was very effective in FC contamination reduction at the two remaining CCPs (service after cooking and service after reheating), (P<0.0001). Indeed, at the end of the intervention, contamination levels were less than 10FC/g in more than 83% of cooled food samples (prior to child service) after cooking and about 96% of cooled food samples (prior to child service) after reheating. An assessment of the intervention mothers' ability to perform actions three months later resulted in a better effect, 83 % to 100% of food samples' FC contam.ination levels met the standard. The present research findings showed that not only was the HACCP approach effective in improving home food safety but also, it was relevant for food hygiene and safety promotion in low income community. Two research questions were highlighted: firstly, could food safety improvement achieved through the HACCP approach result in diarrhoea morbidity and mortality reduction among young children? And secondly, is the approach scalable and cost effective?