Investigating the chemical space and metabolic bioactivation of natural products and cross-reactivity of chemical inhibitors in CYP450 phenotyping

Includes bibliographical references.Natural products have been exploited by humans as the most consistently reliable source of medicines for hundreds of years. Owing to the great diversity in chemical scaffolds they encompass, these compounds provide an almost limitless starting point for the discovery and development of novel semi-synthetic or wholly synthetic drugs. In Africa, and many other parts of the world, natural products in the form of herbal remedies are still used as primary therapeutic interventions by populations far removed from conventional healthcare facilities. However, unlike conventional drugs that typically undergo extensive safety studies during development, traditional remedies are often not subjected to similar evaluation and could therefore harbour unforeseen risks alongside their established efficacy. A comparison of the ‘drug-like properties’ of 335 natural products from medicinal plants reported in the African Herbal Pharmacopoeia with those of 608 compounds from the British Pharmacopoeia 2009 was performed using in silico tools. The data obtained showed that the natural products differed significantly from conventional drugs with regard to molecular weight, rotatable bonds and H-bond donor distributions but not with regard to lipophilicity (cLogP) and H-bond acceptor distributions. In general, the natural products were found to exhibit a higher degree of deviation from Lipinski’s ‘Rule-of-Five’. Additionally, these compounds possessed a slightly greater number of structural alerts per molecule compared to conventional drugs, suggesting a higher likelihood of undergoing metabolic bioactivation

A Lipopolysaccharide (LPS) inhalation model to characterise divergent innate cellular responses and presence of alveolar leak, early in the course of acute lung inflammation

M. D. Thesis.Acute respiratory distress syndrome (ARDS) is a common condition presenting to the intensive care unit (ICU) and is associated with high morbidity and mortality. Experimental models in humans using bacterial lipopolysaccharide (LPS, delivered by nebulised inhalation or bronchial instillation) create reproducible acute lung inflammation and can be used to model early stages of the pathological process leading to ARDS. A significant body of evidence already exists from animal and human studies suggesting LPS inhalation results in rapid release of pro-inflammatory cytokines and movement of innate immune cells (neutrophils and monocytes) into the alveolar space. The functional status of neutrophils in response to this stimulus is largely unknown, based on circumstantial evidence provided by predominant cytokines, chemokines and cell surface protein expression. Most studies rely on invasive assessment of the alveolar space using bronchoalveolar lavage (BAL), and imaging modalities have been poorly explored in LPS respiratory models. This thesis aimed to test the hypothesis that, following inhalation of LPS, neutrophils circulating within peripheral blood increase their capacity for phagocytosis and generation of reactive oxygen species (ROS), and that dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) detects early increases in pulmonary vascular permeability. Forty-nine healthy human volunteers were recruited to an LPS inhalation study. Volunteers underwent inhalation of 60μg of LPS or Saline via a nebuliser dosimeter, with peripheral blood sampling. A subset underwent DCE MRI scans and bronchoscopy with BAL. Functional assays of phagocytosis and respiratory burst activity were performed on isolated neutrophils from blood. Neutrophils demonstrated a trend towards increased phagocytosis following LPS inhalation (change from baseline of 3.6% versus 1.2% in control subjects, p=0.058). This was not supported by any change in respiratory burst activity or flow cytometry assessment of cell surface protein expression. Analysis of DCE MRI of the lungs proved difficult and was complicated by significant artefact from surrounding structures and respiratory motion. In conclusion, LPS inhalation did not significantly affect phagocytosis or respiratory burst activity of neutrophils in the systemic circulation. DCE MRI was unable to detect changes in vascular permeability following LPS inhalation above the background noise

An inclusive approach towards designing medical devices for use in the home environment

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.An emerging trend of the healthcare industry is the huge increase in the number of medical devices being used by lay people at home. Home use medical devices range from simple inhalers to very complicated devices such as defibrillators. This research aimed to assist designers in developing home use medical devices by providing information and suggestions regarding lay users and how to address their needs and expectations. For this purpose a qualitative and inductive approach was adopted and several studies were carried out, including: (1) a comprehensive literature review to understand the background of the phenomena; (2) observational studies with 40 lay users (i.e. 10 younger lay users, 10 older lay users, 10 users with mobility and sensory disabilities, and 10 users with cognitive disabilities) in order to identify their characteristics when interacting with products; (3) an online questionnaire survey with 53 designers to understand designers‟ requirements when designing home use medical devices, as well as their expectations for a proposed design support tool; (4) the development of the design support tool; and (5) an evaluation study with 12 professional designers in order to assess the effectiveness of the tool (in a format of a design guidance). This research adopted an inclusive approach which investigated both lay users‟ characteristics and designers‟ perspectives. It has, for the first time, outlined lay user characteristics based on empirical studies with different groups of people. It is also one of few studies focussing on designing home use medical devices; the requirements of professional designers have provided an in-depth insight into the challenges of designing medical devices for use in the home environment. The design guidance, as commended by the designers in the evaluation, was the first comprehensive information source in the UK for the emerging home use medical device field where little support is currently available.This work is funded by the Council of Higher Education (Turkey)

in vitro Characterisation of the Complement Cascade for Predicting Patient Outcome Post-operatively

The identification of surgical patients at higher risk of infection enables targeted allocation of critical care resources to improve patient mortality. The Complement cascade of the innate immune system is known to increase risk of infection if compromised and can be tested in vitro as a potential method for stratification of high-risk patients. Existing assays of Complement function are laboratory bound and require trained personnel to operate and interpret. This thesis describes the development of novel immunoassays for C3, C5a, TCC and TNFα, based on a multiplex biosensor platform with a duty cycle of 0.05) from the serum data of 22 volunteers. The model and cohort data provide an initial estimate of effect size for future clinical studies investigating the ability of these Complement activation phenotypes to identify high-risk surgical patients or identify the onset of infection

Data-driven methods for analyzing ballistocardiograms in longitudinal cardiovascular monitoring

Cardiovascular disease (CVD) is the leading cause of death in the US; about 48% of American adults have one or more types of CVD. The importance of continuous monitoring of the older population, for early detection of changes in health conditions, has been shown in the literature, as the key to a successful clinical intervention. We have been investigating environmentally-embedded in-home networks of non-invasive sensing modalities. This dissertation concentrates on the signal processing techniques required for the robust extraction of morphological features from the ballistocardiographs (BCG), and machine learning approaches to utilize these features in non-invasive monitoring of cardiovascular conditions. At first, enhancements in the time domain detection of the cardiac cycle are addressed due to its importance in the estimation of heart rate variability (HRV) and sleep stages. The proposed enhancements in the energy-based algorithm for BCG beat detection have shown at least 50% improvement in the root mean square error (RMSE) of the beat to beat heart rate estimations compared to the reference estimations from the electrocardiogram (ECG) R to R intervals. These results are still subject to some errors, primarily due to the contamination of noise and motion artifacts caused by floor vibration, unconstrained subject movements, or even the respiratory activities. Aging, diseases, breathing, and sleep disorders can also affect the quality of estimation as they slightly modify the morphology of the BCG waveform.Includes bibliographical reference

An exploratory study of developmental confabulation in children.

Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder estimated to affect approximately 5 percent of the population, although prevalence studies can vary between 3 to 12 percent of the paediatric population. There is a significant literature reporting that ADHD has significant implications for children, their families, and health and education systems. Difficulties with challenging behaviour, learning, academic achievement and psychosocial functioning are commonly reported in children who have a diagnosis of ADHD and stimulant medication is the routinely recommended treatment. However, despite the documented behavioural and learning difficulties reported in this population, there has been little attempt to examine these children from a neuropsychological perspective in which detailed objective cognitive assessments are performed and with confounding variables controlled for by assessing children from similar social backgrounds, with comparable levels of intellectual functioning, comparable ages and gender, but without ADHD diagnoses. Such a perspective would significantly inform our understanding of the underlying cognitive attention deficits associated with children who have ADHD and provide a means of reliably measuring the effectiveness of stimulant medication. This assignment describes ADHD in terms of the criteria and process by which the diagnosis is made. The behavioural and educational challenges that children with ADHD commonly present to educational and health professionals are discussed. Psychological models of cognitive attention are outlined in order to consider specific attention deficits that might underlie the behavioural and attentional problems shown in children who have a diagnosis of ADHD. Neuropsychological methods of assessing cognitive attention are illustrated with particular reference to the Test of Everyday Attention for Children (TEA-Ch - Manly et al., 2001) and the application of such measures with this group of children are discussed. The use of stimulant medication for the treatment of ADHD is discussed in terms of its effectiveness in the management of behavioural difficulties. A controlled trial is described to evaluate the effectiveness of stimulant medication on cognitive attention in which 15 children with a diagnosis of ADHD performed a neuropsychological assessment before and after they were administered stimulant medication. To control for possible confounding variables, 16 children without diagnoses of ADHD were matched on age, gender, social background and intellectual functioning and were administered the neuropsychological assessments at similar time points to the ADHD group to control for possible practice effects of same day testing. This investigation reports significant improvement in many aspects of cognitive attention for children with ADHD compared to controls when stimulant medication was administered. The implications for diagnosis, management and educational support of children who may have ADHD are discussed, particularly in terms of the possible role for educational psychologists when working with this significant percentage of the paediatric population