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An investigation into dysfunctional feed-forward inhibition within the cortico-thalamocortical network on absence seizure generation using DREADD technology
Full text linkChildhood absence epilepsy (CAE) is one of the most prevalent paediatric epilepsies, accounting for between 10-17% of all diagnosed cases of epilepsies seen in school-aged children. Absence seizures are characterized by behavioural arrest/loss of awareness and electrographic signature of spike-wave discharges (SWDs) measuring 2.5-4 Hz on an electroencephalogram (EEG). These brief episodes of impaired consciousness can occur hundreds of times a day and might increase the chance of physical injury when undertaking activities like swimming and cycling. Current treatment options are not sufficient and up to 30% of patients are pharmaco-resistant. ~60% of children with CAE have severe neuropsychiatric comorbid conditions including attention deficits, mood disorders, impairments in memory and cognition. Ethosuximide (ETX), an anti-absence epileptic drug which was first introduced almost six decades ago remains the first choice for initial monotherapy for the treatment of CAE. Large-scale clinical trials suggested that efficacy of ethosuximide is considerably lower than previous findings. Thus, safe, effective and patient specific treatment approach is imperative. For this, it is crucial first to understand the precise cellular and molecular mechanisms of absence seizures which may enable the development of novel therapeutic targets and discovery of new anti-epileptic drugs (AEDs).
EEG and functional imaging evidence suggest that absence seizures are likely due to aberrant activity within the cortico-thalamocortical (CTC) network. Studies involving the genetic rodent models have shown that the cortex is the driving source for the origin of SWDs but is not capable of maintaining discharges on its own, nor is the thalamus. General consensus is that, within the CTC network, a cortical focus initiates rhythmic epileptic discharges, however, once the rhythmic oscillations are established, both the cortex and thalamus form an integrated network. Rhythmic absence-SWDs are sustained via the cortex and thalamus driving each other. Within the CTC network, feed-forward inhibition (FFI) is essential to prevent runaway excitation. FFI is mediated by fast spiking parvalbumin expressing (PV+) inhibitory interneurons in the somatosensory cortex (SScortex) and the reticular thalamic nucleus (RTN). Studies conducted in well-established stargazer mouse model of absence epilepsy with a genetic deficit in stargazin i.e. TARP [a transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein] have shown reduced expression of GluA4-AMPARs at excitatory synapses in feed-forward inhibitory (PV+) interneurons in the SScortex and RTN thalamus of the CTC network. However, the extent of this deficit in AMPARs expression impacting FFI and possibly contributing towards generation of absence-SWDs is not established via functional studies.
Hence, this thesis was aimed at investigating the impact of dysfunctional feed-forward inhibitory PV+ interneurons within CTC network on absence seizure generation and behaviour. For this purpose, inhibitory and excitatory Designer Receptors Exclusively Activated by Designer Drug (DREADD) approach was utilized to silence/excite feed-forward inhibitory PV+ interneurons within the CTC network. DREADD mediated regional silencing of PV+ interneurons within the CTC network generated ETX-sensitive absence-like SWDs. Activating PV+ interneurons either prevented or suppressed pentylenetetrazole (PTZ)-induced absence-SWDs. Finally, impact of impaired FFI in γ-aminobutyric acid (GABA) levels by affecting its synthesizing enzymes (GADs) and transporter proteins (GATs) in stargazer animal model of absence epilepsy and CNO treated inhibitory Gi-DREADD animals was determined. Results indicate that upregulation of GAD65 in the SScortex of epileptic stargazers may be a consequence of absence seizures or this may have contribution in absence seizure generation.
The work presented in this thesis provide an electrophysiological insight into the possible mechanism underlying the absence seizure generation. This work provides convincing evidence that dysfunctional feed-forward inhibitory PV+ interneurons within the CTC network is likely to be involved in altered excitation/inhibition balance resulting SWDs as activating these interneurons dramatically protected animals from PTZ induced absence seizures. The clinical relevance of this study is that it potentially uncovers the possibility of focally targeting PV+ interneurons within the CTC network to control absence seizures in human patients
Monitoring surveying students’ environmental attitudes as they experience higher education in New Zealand
Full text linkWe investigate the environmental attitudes (EA) of New Zealand’s land surveying students and how they change during a four-year programme. We implemented a multi-cohort survey and developed a longitudinal statistical model of change. Findings suggest that although the EA scores of groups of students vary at different times within and between cohorts, there are no significant general trends when genders are combined. But females tend to start their studies with higher mean EA scores than males and this difference declines overtime. This occurs consistently across the four cohorts studied. This is discussed in relation to women’s role within the profession
Consumers’ Behaviors and Attitudes toward Doggy Bags: Identifying Barriers and Benefits to Promoting Behavior Change
Full text linkThis study identifies barriers and benefits of consumers’ current doggy bag behaviors and provides the information required to run an effective community-based social marketing campaign encouraging consumers to take their uneaten restaurant and café food home. This is done by applying a two-stage methodology, including quantitatively analyzing existing survey data and qualitatively investigating focus group discussion. Multiple barriers to widespread doggy bag participation were common and varied for different individuals and included both convenience and social stigma-related factors. The rational appeal of “saving money” was found to be the most effective motivator for encouraging doggy bag usage, especially for women, young people, students/unemployed, and low-income earners. Social marketing strategies and behavior change tools can be developed to remove the barriers and enhance the benefits of using doggy bags, such as developing positive social norms around using doggy bags and highlighting the financial incentive of using them. This research contributes to a limited but growing literature on out-of-home food waste and provides practicable insights for both public policy and for the food service sector for future initiatives aiming to reduce food waste
Parental attitudes toward weaning practices and weaning foods for health in Malaysia
Full text linkThe purpose of this paper is to gain insight on parental attitudes towards weaning practices and weaning foods for health in Malaysia using Q-methodology. The study population was parents that had a child aged three years or less. A total of 47 parents were recruited to partake in a one-on-one activity which involved sorting 69 statements about weaning practices and weaning food products into a grid that was normally distributed ranging from “strongly disagree” to “strongly agree”. Sorting was immediately followed by a short interview to understand the reasons behind the placement of particular statements. Data analysis identified three statistically distinct participant attitudes towards weaning practices and foods for health that were then interpreted using the rich qualitative data from the post-sort interviews. The attitudes identified were “All Homemade and Natural”, “Commercial Convenience and Trust” and “Balance and Variety”. This study identified the dominant sets of attitudes held by Malaysian parents towards weaning practices and weaning foods for health using Q-methodology. To authors’ knowledge, this is the first paper focusing on weaning foods for health, specifically on functional weaning food. This new understanding of shared attitudes will allow product developers, marketers and health communicators to more effectively design their products and their marketing mix to ensure that these messages resonate well with the target audience who want to provide the best weaning foods possible for their children
Gauging attitudes and behaviours: Meat consumption and potential reduction
Full text linkThe present study focused on adding to the understanding of meat consumption and potential drivers for its reduction in New Zealand. Using the Theory of Planned Behaviour (TPB) and the recently developed Meat-Attachment Questionnaire (MAQ), this study investigated New Zealand consumers' attitudes, motivations and behaviours in regards to meat consumption. Results derive from a questionnaire sent across New Zealand in March 2017, in which 841 responses were obtained from representative consumer panels. Consumer awareness of the severity of meat's environmental impacts was found to be quite low in comparison to other sustainable food behaviours. Motivations for reduction seem to shift across consumer groups, with different considerations rising and falling in importance depending on current meat consumption habits. Among the TPB components, only attitudes were found to accurately and consistently predict willingness and intentions to reduce personal meat intake, while both attitudes and subjective norms predicted agreement with proposed structural measures that would promote meat reduction and/or plant-based food consumption. In addition, the MAQ was found to provide explanatory power above and beyond that of the TPB components alone and this research supports its use as a tool to further understand meat consumption and potential motivations for reduction. The authors believe these results could be useful for governments or organizations wishing to implement meat reduction strategies, as well as providing a stepping stone for further research inquiry into motivations behind meat consumption and its potential reduction
Clarifying the waters: A critical analysis of turbidity and its role in environmental monitoring in New Zealand
Full text linkTurbidity is widely-used as a water quality indicator to infer the mass of suspended sediment (SS) transported through riverine systems, and is inexpensive, readily available, and can be easily deployed to record continuous measurements. However, using turbidity as a surrogate for SS concentration (SSC) is frequently confounded by the composition of riverine suspended material, and the particle size and shape of sediments. Presented as a series of research papers, this thesis provides a distinctly Southern Hemisphere perspective of sediment, organic matter, organic carbon, and turbidity across southern New Zealand, and offers a critical reflection on the role of turbidity in environment monitoring. The suspended material of southern New Zealand rivers under base flow was mostly comprised of inorganic suspended material, although the total composition also includes variable amounts of organic material (<10%, and up to 50 – 80%). The proportion of organic to inorganic particulate material in southern New Zealand is significant under certain land covers, and contributes a significant proportion of particulate organic carbon flux to the Southern Oceans (0.04 – 2.7 t km-1 a-1). In addition, different catchment morphologies and lithologies have a propensity to discharge different particle size distributions of inorganic sediment. These differences in particle sizes are most likely a function of underlying lithology from in channel attrition. This thesis has also identified that specific turbidity (turbidity normalised to mass concentration of particulates) is a potentially effective metric to indicate a ‘non-standard’ light attenuation response (that is, greater turbidity per mass of SS). Specific turbidity is shown through both in-field measurements and laboratory experiments to be affected by organic composition (particulate and dissolved) and the particle size distribution. Multiple regression analysis of catchment characteristics show that suspended particulate material composition and particle size are linked to discharge and flow behaviour, landcover, and lithology. The application of these findings is applied to monitoring SSC with turbidity across New Zealand by examining the specific turbidity for 77-monitoring stations. It is evident that organic composition and particle size have a notable effect on SS-turbidity ratings across New Zealand, which has limitations for the comparability, and relevance of SS data derived from turbidity when used as a regulatory tool. This thesis shows that although turbidity is pragmatic, its use in SS monitoring is problematic
Post-disaster housing recovery and community resilience: the case of the Canterbury earthquakes of 2010 and 2011
Full text linkBackground:
After a major natural disaster like the Canterbury earthquakes of 2010 and 2011, western democracies like New Zealand tend to enact top-down recovery statutes and regulations that are thought to enable a nimble response to national emergencies, save lives, and restore social order. But these statutory changes in governance not only determine the sustainability of the natural and built environments. They can also affect the wellbeing of those impacted, impairing their democratic ability to have a say and actively participate in the urban renewal processes taking place around them. What does this mean in terms of community action and resilience? This project is a case study of post-disaster housing recovery in Christchurch after the Canterbury earthquake of 2010 and 2011.
Aims:
In this qualitative study, I analysed the statutory framework governing the process of post-disaster housing recovery in Christchurch and its impact on local democracy. I also explored the role of communities and the third sector in housing and urban renewal. This aim was to contribute to the development of a critical theoretical understanding of community resilience as an inherently political concept. Community resilience is influenced by causal factors or generative mechanisms that impact upon the relations between people in a particular social context. I undertook this empirical study to develop a critical realist approach to understanding community resilience.
Methods:
I completed a narrative synthesis of textual data, derived from a thematic analysis of in-depth interviews with key informants, related policies, media, and fieldwork.
Results:
I found that a centralisation of government authority over housing recovery resulted in an erosion of democracy and representative government at a local level. This centralisation had a major impact on communities and their voice in the process of post-disaster housing recovery. Communities, however, never relented and worked tirelessly among themselves and with other social sectors to make a positive impact to post-disaster housing and urban recovery against difficult odds and stretched resources. This immense social capital and inspiring sense of community must be fostered and given the opportunity to democratically participate in the development of recovery policy as a key element of community resilience
Spatial and temporal genetic structuring in yellow-eyed penguins
Full text linkImproving our understanding of the forces driving population decline and the processes that affect the dynamics of threatened populations is central to the success of conservation management. The application of genetic tools,
including our ability to examine ancient DNA, has now revolutionised our ability to investigate these processes. The recent human settlement of the Pacific, particularly in New Zealand, provides a unique, accessible system for
revealing anthropogenic impacts on native biota. In this thesis I use genetic analyses from modern, historic and subfossil DNA to investigate temporal and spatial genetic structuring of the endangered yellow-eyed penguin
(Megadyptes antipodes), and use these analyses to answer questions related to the conservation of this species.
The yellow-eyed penguin is endemic to the New Zealand region and currently breeds on the subantarctic Auckland and Campbell Islands and the southeast coast of the South Island. The current total population size is estimated
around 6000-7000 individuals, of which more than 60% inhabit the subantarctic. Despite intensive conservation measures by governmental and local community agencies, population sizes have remained highly unstable
with strong fluctuations in numbers on the South Island. The species was believed to be more widespread and abundant before human colonisation of New Zealand, thus current management assumed the mainland population to be a declining remnant of a larger prehistoric population.
Genetic and morphological analyses of subfossil, historic and modern penguin samples revealed an unexpected pattern of penguin extinction and expansion. Only in the last few hundred years did M. antipodes expand its
range from the subantarctic to the New Zealand mainland. This range expansion was apparently facilitated by the extinction of M. antipodes' previously unrecognised sister species, M. waitaha, following Polynesian settlement in New Zealand. The demise of M. waitaha is the only known human-mediated extinction of a penguin species.
Despite M. antipodes' recent range expansion, genetic analyses of microsatellite markers reveal two genetically and geographically distinct assemblages: South Island versus subantarctic populations. We detected only two first generation migrants that had dispersed from the subantarctic to the South Island, suggesting a migration rate of less than 2%. Moreover, the South Island population has low genetic variability compared to the subantarctic population. Temporal genetic analyses of historic and modern penguin specimens further revealed that the harmonic mean effective population size of the M. antipodes South Island population is low ( <200). These findings suggest that the South Island population was founded by only a small number of individuals, and that subsequent levels of gene flow have remained low.
Finally, we present a novel approach to detect errors in historic museum specimen data in cases where a priori suspicion is absent. Museum specimens provide an invaluable resource for biological research, but the scientific value of specimens is compromised by the presence of errors in collection data. Using individual-based genetic analysis of contemporary and historic microsatellite data we detected eight yellow-eyed penguin specimens
with what appear to be fraudulently labelled collection locations. This finding suggests errors in locality data may be more common than previously suspected, and serves as a warning to all who use archive specimens to invest time in the verification of specimen data.
Overall, yellow-eyed penguins have a remarkable dynamic history of recent expansion, which has resulted in two demographically independent populations. These results reveal that anthropogenic impacts may be far more complex than previously appreciated
The social value of rescuing food, nourishing communities
Full text linkThe purpose of this paper is to explore the social value food rescue enterprises can create for both their stakeholders and the wider community “in the meantime” whilst longer term solutions to the problems of insecurity and waste are sought. FoodShare, a New Zealand urban-based social enterprise specialising in food redistribution, served as a case study for this research. Semi-structured interviews (n ¼ 13) were conducted with FoodShare staff and key stakeholder groups (food donors, financial donors, recipient agencies and volunteers). In addition, an anonymous online survey (n ¼ 40) was completed by the wider organisational volunteer network. The interview guides were structured around a new social value evaluation tool, Social Return on Investment, which is increasingly used to demonstrate the impact of such programmes. Deductive methods were used to code the resulting transcripts to identify key outcomes experienced by FoodShare’s stakeholders. The outcomes of FoodShare’s work differed for the various stakeholders. For food donors, outcomes included “more involved relationships with community”, and “improved perceptions of corporate social responsibility”. Identified key outcomes for the financial donors included “key promotional opportunity” and “do something good”. For recipient agencies, important outcomes were “greater volume of food” and “increased reach”. Volunteers reported “meeting new people”, “a sense of accomplishment in helping others” and “learning new skills”. There were also a number of nutritional and environmental outcomes for the wider community. Given the dearth of evidence on the societal value that is created in redistributing unsold food to people in need, this novel perspective makes a significant contribution to the literature in this area
Formulation and evaluation of a stable penethamate hydriodide intramuscular injection for treatment of bovine mastitis
Full text linkPurpose: The aim of this thesis was to investigate the stability of penethamate (PNT), an ester prodrug of benzylpenicillin (BP), used intramuscularly (i.m.) in the treatment of bovine mastitis. The specific objectives were to understand the chemical stability of PNT in aqueous and oily vehicles; to develop some understanding of the effect of absorption rate from the i.m. site on milk levels of BP; to formulate a stable ready-to-use (RTU) product and to test this product in a pilot study in the target species (cow).
Methods: A reversed phase HPLC assay was developed to study the degradation kinetics of PNT in aqueous vehicles. Several formulation approaches such as cosolvents, cyclodextrins, common ion and oily vehicles to enhance the
chemical stability of PNT were assessed. A simulation model was constructed for the prediction of absorption rate from i.m. injection site and concentration of BP, the hydrolytic product of PNT, in milk. A pilot animal study in cows was conducted to compare milk levels of BP after i.m. injection of a stable oily formulation of PNT with a marketed aqueous reconstituted suspension formulation.
Results: A reversed phase HPLC assay for simultaneous determination of PNT and its hydrolytic product BP using an isocratic system with photo diode array detection was developed and validated. The assay was linear over the concentration range 1-100 μg ml-1 for both analytes (r > 0.99) with satisfactory inter-day and intraday
precision (RSD ≤ l %) and accuracy (98-99%) for PNT.
The degradation of PNT in aqueous solutions followed pseudo-first-order kinetics over the pH range 2 - 9.3 with a V- shaped pH-rate profile with a sigmoid portion in the pH range 7.5 - 9.3 corresponding to the pKa (8.4) of PNT. The
minimum degradation rate of PNT was at pH 4.5 (half-life (t1/2) = 44 h at 30 °C). The impact of buffer concentration and ionic strength on PNT stability was small but at pH 6 the type of buffer salt had some influence with solutions in acetate being about twice as stable as those in phosphate. The Arrhenius activation energies determined at pH 3.01, 6.01 and 8.04 were 62.1, 74.1 and 98.8 kJ mol-1 respectively.
In aqueous solutions, propylene glycol (PG) increased the t1/2 of PNT from 1.8 days to 4.3 days at 30 °C, whereas hydroxypropyl- ß-cyclodextrin (HP-ß-CD) and ß-CD did not influence the t1/2 and iodide (I-) resulted in a decrease in t½ from 1.8 days to 1.1 days. The estimated shelf-life (t90) of PNT in solution of about 0.3 days (5% PG) and 0.7 days (60% PG) increased to 15 days (5% PG) and 11 days (60% PG) in a 50% PNT suspension. With increasing concentration of HP-ß-CD, the solubility of PNT increased linearly and resulted in a decrease in the estimated t90 of aqueous suspensions. The decrease in solubility of PNT due to the common ion effect resulted in an increase in the t90 (26 days) in aqueous suspension.
PNT stability (% drug remaining) in oily suspensions after 105 days was in the order LP (light liquid paraffin) (96.2%) > MIG (miglyol 812) (95.4%) > EO (ethyl oleate) (94.1%) > SO (sunflower oil) (86.4%). PNT degradation was rapid in oily solutions of LP, MIG, EO and SO and less than 10 % remained after 7-15 days.
The simulation model provided insights into the absorption rate of PNT from the i.m. injection site. Sensitivity analysis suggested that absorption rate constants (ka), clearance from plasma to milk (PA) and volume of distribution (Vd) are critical parameters for predicting concentrations of BP in milk. The developed oily suspension formulation of PNT in EO with 0.15 % Polysorbate 80 showed good physical and chemical stability. A pilot animal study in cow suggested that the oily formulation achieves concentrations of BP in milk similar to those obtained from a marketed aqueous suspension formulation of PNT. The AUC0-48 and t1/2el of BP in milk after i.m. administration of the marketed aqueous suspension formulation of PNT were 3.56 ± 0.17 mg.h L-1 and 4.9 ± 0.3 h respectively, while the corresponding data for Formulation B were 4.9 ± 1.4 mg.h L-1 and 4.6 ± 1.2 h respectively.
Conclusion: The chemical stability of PNT was greatly enhanced in oily suspensions with around 95% PNT remaining for over 3 months under intermediate storage conditions (30 °C). PNT can be formulated as a physically and chemically stable ready-to-use suspension. This suspension probably gives milk levels of BP comparable with the existing marketed aqueous suspension formulation and a larger animal study is warranted to test this