A conceptual model for the development of indicators for informal markets

Informal markets are recognised as presenting lucrative business opportunities for the private sector. However, informal markets function by a different set of rules when compared to the formal sector, and so require a different paradigm altogether. The approach proposed in this report sees the convergence of conventional micro economics with development economics and the theories of sustainable development.A community is used as the unit of analysis for the informal market. A model is proposed that uses the sustainable livelihoods framework to describe the various elements of the community as a system, and how these interact to produce desired outcomes. This study was designed from the perspective of measuring the informal market. Measurement allows quantification and qualification of the phenomenon of the informal market and allows for more effective decision making. The conceptual model was therefore developed to gain a theoretical understanding of the phenomenon to be measured. A systems perspective is taken to develop a high-level framework for indicator selection. This is considered to be the first, in a series of steps, towards developing indicators for the informal market, and even a single composite indicator for the informal market.A small sample of experts was interviewed to explore the informal economy from their own observation and experience. The insights shared in the interviews pointed to the applicability of the proposed model to informal markets, and demonstrated the complexity of these markets. A number of further research opportunities can be explored to further develop this concept.Dissertation (MBA)--University of Pretoria, 2010.Gordon Institute of Business Science (GIBS)unrestricte

The applicability of remote sensing methods for the detection of fires on coal discard dumps

Faculty of Engineering School of Civil and Enviromental Engineering 9506023j [email protected] report investigates the viability of satellite remote sensing in monitoring the rehabilitation of coal discard dumps. Four levels of thermal monitoring data were assessed in this project. These were: ground and below surface temperature probes; aerial thermal and atmospheric monitoring surveys; high altitude aircraft; and satellites. Remote sensing methods measure only variation of temperatures on the surface of the dump. Fires on discard dumps are sub-surface fires, and the depth and extent of the fire below the surface cannot be easily inferred. The resolution of satellite sensors is a limiting factor for detecting individual hotspots on dumps. Small mine dumps occupy just a few pixels and the position of fires cannot be accurately assessed. Although the larger dumps are discernable, the variation of temperatures across the dump cannot be easily determined. For the present, aircraft monitoring may be the most viable means of monitoring spontaneous combustion in coal discard dumps, until satellite resolutions improve further

Predicting tyrosinaemia: a mathematical model of 4-hydroxyphenylpyruvate dioxygenase inhibition by nitisinone in rats

Nitisinone or 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione, is a reversible inhibitor of 4- hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme important in tyrosine catabolism. Today, nitisinone is successfully used to treat Hereditary Tyrosinaemia type 1, although its original expected role was as a herbicide. In laboratory animals, treatment with nitisinone leads to the elevation of plasma tyrosine (tyrosinaemia). In rats and Beagle dogs, repeat low-dose exposure to nitisinone leads to corneal opacities whilst similar studies in the mouse and Rhesus monkey showed no comparable toxicities or other treatment related findings. The differences in toxicological sensitivities have been related to the upper limit of the concentration of tyrosine that accumulates in plasma, which is driven by the amount/activity of tyrosine aminotransferase. A physiologically based, pharmacodynamics ordinary differential equation model of HPPD inhibition to bolus exposure of nitisinone in vivo is presented. Going beyond traditional approaches, asymptotic analysis is used to separate the different timescales of events involved in HPPD inhibition and tyrosinaemia. This analysis elucidates, in terms of the model parameters, a critical inhibitor concentration (at which tyrosine concentration starts to rise) and highlights the contribution of in vitro measured parameters to events in an in vivo system. Furthermore, using parameter-fitting methods, a systematically derived reduced model is shown to fit well to rat data, making explicit how the parameters are informed by such data. This model in combination with in vitro descriptors has potential as a surrogate for animal experimentation to predict tyrosinaemia, and further development can extend its application to other related medical scenarios

Predicting tyrosinaemia: a mathematical model of 4-hydroxyphenylpyruvate dioxygenase inhibition by nitisinone in rats

This is a pre-copyedited, author-produced version of an article accepted for publication in Mathematical Medicine and Biology following peer review. The version of record WARD, J. ... et al., 2016. Predicting tyrosinaemia: a mathematical model of 4-hydroxyphenylpyruvate dioxygenase inhibition by nitisinone in rats. Mathematical Medicine and Biology, dqw006. is available online at: http://dx.doi.org/10.1093/imammb/dqw006Nitisinone or 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione, is a reversible inhibitor of 4- hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme important in tyrosine catabolism. Today, nitisinone is successfully used to treat Hereditary Tyrosinaemia type 1, although its original expected role was as a herbicide. In laboratory animals, treatment with nitisinone leads to the elevation of plasma tyrosine (tyrosinaemia). In rats and Beagle dogs, repeat low-dose exposure to nitisinone leads to corneal opacities whilst similar studies in the mouse and Rhesus monkey showed no comparable toxicities or other treatment related findings. The differences in toxicological sensitivities have been related to the upper limit of the concentration of tyrosine that accumulates in plasma, which is driven by the amount/activity of tyrosine aminotransferase. A physiologically based, pharmacodynamics ordinary differential equation model of HPPD inhibition to bolus exposure of nitisinone in vivo is presented. Going beyond traditional approaches, asymptotic analysis is used to separate the different timescales of events involved in HPPD inhibition and tyrosinaemia. This analysis elucidates, in terms of the model parameters, a critical inhibitor concentration (at which tyrosine concentration starts to rise) and highlights the contribution of in vitro measured parameters to events in an in vivo system. Furthermore, using parameter-fitting methods, a systematically derived reduced model is shown to fit well to rat data, making explicit how the parameters are informed by such data. This model in combination with in vitro descriptors has potential as a surrogate for animal experimentation to predict tyrosinaemia, and further development can extend its application to other related medical scenarios

Characterisation of a functional rat hepatocyte spheroid model.

Many in vitro liver cell models, such as 2D systems, that are used to assess the hepatotoxic potential of xenobiotics suffer major limitations arising from a lack of preservation of physiological phenotype and metabolic competence. To circumvent some of these limitations there has been increased focus on producing more representative 3D models. Here we have used a novel approach to construct a size-controllable 3D hepatic spheroid model using freshly isolated primary rat hepatocytes (PRH) utilising the liquid-overlay technique whereby PRH spontaneously self-assemble in to 3D microtissues. This system produces viable spheroids with a compact in vivo-like structure for up to 21 days with sustained albumin production for the duration of the culture period. F-actin was seen throughout the spheroid body and P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) transporters had polarised expression on the canalicular membrane of hepatocytes within the spheroids upon formation (day 3). The MRP2 transporter was able to functionally transport 5 μM 5-chloromethylfluorescein diacetate (CMFDA) substrates into these canalicular structures. These PRH spheroids display in vivo characteristics including direct cell-cell contacts, cellular polarisation, 3D cellular morphology, and formation of functional secondary structures throughout the spheroid. Such a well-characterised system could be readily exploited for pre-clinical and non-clinical repeat-dose investigations and could make a significant contribution to replace, reduce and refine the use of animals for applied research

Impact of cell types and culture methods on the functionality of in vitro liver systems - A review of cell systems for hepatotoxicity assessment.

Xenobiotic safety assessment is an area that impacts a multitude of different industry sectors such as medicinal drugs, agrochemicals, industrial chemicals, cosmetics and environmental contaminants. As such there are a number of well-developed in vitro, in vivo and in silico approaches to evaluate their properties and potential impact on the environment and to humans. Additionally, there is the continual investment in multidisciplinary scientists to explore non-animal surrogate technologies to predict specific toxicological outcomes and to improve our understanding of the biological processes regarding the toxic potential of xenobiotics. Here we provide a concise, critical evaluation of a number of in vitro systems utilised to assess the hepatotoxic potential of xenobiotics

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

An investigation of genotoxicity and antioxidant treatment of DNA repair in human cells

Understanding the mechanisms defying endogenous and exogenous processes that threaten DNA integrity remains critical to the elucidation of cancer, disease processes and ageing. The research presented in this thesis examines the formation and the removal of two distinctly different DNA lesions in human cell culture systems. Significant differences in the formation of cyclobutane pyrimidine dimers following monochromatic ultraviolet irradiations at 305nm and 315nm in cultured keratinocytes and DNA were demonstrated immunochemically, offering a non-invasive model to gauge wavelength-specific damage and their potencies. The formation of the oxidative lesion, 7, 8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodG), was also demonstrated immunochemically and by HPLC with electrochemical detection. In addition the measurement of intracellular reactive oxygen species generation was monitored by a fluorimetric assay. All three approaches clearly illustrated that sub-lethal doses of hydrogen peroxide caused a dose-dependent increase in the genotoxic potential in cultured human cells. Further to the confirmation of this prooxidant condition, the generation of a potentially antioxidant environment was achieved through the uptake and/or regeneration of ascorbic acid, confirmed by capillary electrophoresis measurements of intracellular extracts. The modulation of two base excision repair enzymes, human 8-oxoguanine glycosylase (hOGG1) and human apurinic/apyrimidinic endonuclease (hAPE), important in the removal of 8-oxodG, was investigated in response to prooxidant and antioxidant treatments. No significant change in mRNA and protein expression of hOGG1 and hAPE was observed under either experimental condition. In conclusion however, there may be modulation of these repair enzymes at the post-translational level possibly in response to the changes in cellular redox status and the formation of 8-oxodG. Therefore measuring repair activities alongside genotoxicity may provide useful indications of perturbations that can lead to potential mutational events and cellular dysfunction. Appreciating the interplay of multiple DNA repair pathways presents an interesting challenge for future studies

p38 Mitogen-Activated Protein Kinase Mediates Cell Death and p21-Activated Kinase Mediates Cell Survival during Chemotherapeutic Drug-induced Mitotic Arrest

Activation of the mitotic checkpoint by chemotherapeutic drugs such as taxol causes mammalian cells to arrest in mitosis and then undergo apoptosis. However, the biochemical basis of chemotherapeutic drug-induced cell death is unclear. Herein, we provide new evidence that both cell survival and cell death-signaling pathways are concomitantly activated during mitotic arrest by microtubule-interfering drugs. Treatment of HeLa cells with chemotherapeutic drugs activated both p38 mitogen-activated protein kinase (MAPK) and p21-activated kinase (PAK). p38 MAPK was necessary for chemotherapeutic drug-induced cell death because the p38 MAPK inhibitors SB203580 or SB202190 suppressed cell death. Dominant-active MKK6, a direct activator of p38 MAPK, also induced cell death by stimulating translocation of Bax from the cytosol to the mitochondria in a p38 MAPK-dependent manner. Dominant active PAK suppressed this MKK6-induced cell death. PAK seems to mediate cell survival by phosphorylating Bad, and inhibition of PAK in mitotically arrested cells reduced Bad phosphorylation and increased apoptosis. Our results suggest that therapeutic strategies that suppress PAK-mediated survival signals may improve the efficacy of current cancer chemotherapies by enhancing p38 MAPK-mediated cell death

Integrated metabolic models for xenobiotic induced mitochondrial toxicity in skeletal muscle.

There is a need for robust in vitro models to sensitively capture skeletal muscle adverse toxicities early in the research and development of novel xenobiotics. To this end, an in vitro rat skeletal muscle model (L6) was used to study the translation of transcriptomics data generated from an in vivo rat model. Novel sulfonyl isoxazoline herbicides were associated with skeletal muscle toxicity in an in vivo rat model. Gene expression pathway analysis on skeletal muscle tissues taken from in vivo repeat dose studies identified enriched pathways associated with mitochondrial dysfunction, oxidative stress, energy metabolism, protein regulation and cell cycle. Mitochondrial dysfunction and oxidative stress were further explored using in vitro L6 metabolic models. These models demonstrated that the sulfonyl isoxazoline compounds induced mitochondrial dysfunction, mitochondrial superoxide production and apoptosis. These in vitro findings accurately concurred with the in vivo transcriptomics data, thereby confirming the ability of the L6 skeletal muscle models to identify relevant in vivo mechanisms of xenobiotic-induced toxicity. Moreover, these results highlight the sensitivity of the L6 galactose media model to study mitochondrial perturbation associated with skeletal muscle toxicity; this model may be utilised to rank the potency of novel xenobiotics upon further validation