Artemisinin-induced parasite dormancy : a plausible mechanism for treatment failure

Background Artemisinin-combination therapy is a highly effective treatment for uncomplicated falciparum malaria but parasite recrudescence has been commonly reported following artemisinin (ART) monotherapy. The dormancy recovery hypothesis has been proposed to explain this phenomenon, which is different from the slower parasite clearance times reported as the first evidence of the development of ART resistance. Methods In this study, an existing P. falciparum infection model is modified to incorporate the hypothesis of dormancy. Published in vitro data describing the characteristics of dormant parasites is used to explore whether dormancy alone could be responsible for the high recrudescence rates observed in field studies using monotherapy. Several treatment regimens and dormancy rates were simulated to investigate the rate of clinical and parasitological failure following treatment. Results The model output indicates that following a single treatment with ART parasitological and clinical failures occur in up to 77% and 67% of simulations, respectively. These rates rapidly decline with repeated treatment and are sensitive to the assumed dormancy rate. The simulated parasitological and clinical treatment failure rates after 3 and 7 days of treatment are comparable to those reported from several field trials. Conclusions Although further studies are required to confirm dormancy in vivo, this theoretical study adds support for the hypothesis, highlighting the potential role of this parasite sub-population in treatment failure following monotherapy and reinforcing the importance of using ART in combination with other anti-malarials.

Simultaneous localization and planning on multiple map hypotheses

This paper presents a novel method to rank map hypotheses by the quality of localization they afford. The highest ranked hypothesis at any moment becomes the active representation that is used to guide the robot to its goal location. A single static representation is insufficient for navigation in dynamic environments where paths can be blocked periodically, a common scenario which poses significant challenges for typical planners. In our approach we simultaneously rank multiple map hypotheses by the influence that localization in each of them has on locally accurate odometry. This is done online for the current locally accurate window by formulating a factor graph of odometry relaxed by localization constraints. Comparison of the resulting perturbed odometry of each hypothesis with the original odometry yields a score that can be used to rank map hypotheses by their utility. We deploy the proposed approach on a real robot navigating a structurally noisy office environment. The configuration of the environment is physically altered outside the robots sensory horizon during navigation tasks to demonstrate the proposed approach of hypothesis selection.

Which industry is greener? An empirical study of nine industries in OECD countries

This study analyzed the relationship between the CO2 emissions of different industries and economic growth in OECD countries from 1970 to 2005. We tested an environmental Kuznets curve (EKC) hypothesis and found that total CO2 emissions from nine industries show an N-shaped trend instead of an inverted U or monotonic increasing trend with increasing income. The EKC hypothesis for sector-level CO2 emissions was supported in the (1) paper, pulp, and printing industry; (2) wood and wood products industry; and (3) construction industry. We also found that emissions from coal and oil increase with economic growth in the steel and construction industries. In addition, the non-metallic minerals, machinery, and transport equipment industries tend to have increased emissions from oil and electricity with economic growth. Finally, the EKC turning point and the relationship between GDP per capita and sectoral CO2 emissions differ among industries according to the fuel type used. Therefore, environmental policies for CO2 reduction must consider these differences in industrial characteristics. © 2013 Elsevier Ltd.

Unpacking the role of mindfulness on conscientiousness and spirituality

The present study examined relationships between conscientiousness and intrinsic spirituality, with the proposed trait ‘mindfulness’ as mediator. The results from 161 functioning adults within an Australian context revealed that mindfulness was significantly predicted by conscientiousness. This study examined the relationship among conscientiousness, trait mindfulness and intrinsic spirituality. It was hypothesised that trait mindfulness would mediate the relationship between conscientiousness and spirituality. We found this hypothesis partially supported. Practically, these results suggest that conscientious individuals do significantly connect with mindfulness, and it was only the more mindful of conscientious individuals that also displayed high levels of intrinsic spirituality. Additional analyses also suggest that conscientious individuals connect with mindfulness through attending to current actions or regulating impulses (act aware) and have an accepting attitude towards thoughts and feelings (non-judge). Possible explanations and implications of these results are discussed in relation to theory, practice and delivery mechanisms of mindfulness.

Does energy substitution affect carbon dioxide emissions : income relationship?

Considerable discussion has taken place during the last decade regarding the role of economic growth in determining environmental quality. Using data from 30 OECD countries for the period 1960-2003 and the nonparametric method of generalized additive models, which enables us to use flexible functional forms, this paper examines the environmental Kuznets curve hypothesis for carbon dioxide (CO2). We find that the reduction of coal share in energy use has a significant effect on CO2. Our results imply that economic growth is not sufficient to decrease CO2 emissions.

Adoption of accountable-eHealth systems by future healthcare professionals: An empirical research model based on the Australian context

This paper provides a first look at the acceptance of Accountable-eHealth systems, a new genre of eHealth systems, designed to manage information privacy concerns that hinder the proliferation of eHealth. The underlying concept of AeH systems is appropriate use of information through after-the-fact accountability for intentional misuse of information by healthcare professionals. An online questionnaire survey was utilised for data collection from three educational institutions in Queensland, Australia. A total of 23 hypothesis relating to 9 constructs were tested using a structural equation modelling technique. A total of 334 valid responses were received. The cohort consisted of medical, nursing and other health related students studying at various levels in both undergraduate and postgraduate courses. The hypothesis testing disproved 7 hypotheses. The empirical research model developed was capable of predicting 47.3% of healthcare professionals’ perceived intention to use AeH systems. A validation of the model with a wider survey cohort would be useful to confirm the current findings.

Effects of driver familiarity and prolonged or intermittent right-side failure on level crossing safety

This paper investigates the adverse effects of familiarity and human factors issues associated with the reliability of low-cost warning devices at level crossings. The driving simulator study featured a repetitive, low workload, monotonous driving task in which there were no failures of the level crossing (control) or prolonged or intermittent right-side failures (where the device reverts to a safe failure mode). The results of the experiment provided mixed support for the familiarity hypothesis. Four of the 23 participants collided with the train when it first appeared on trial 10 but safety margins increased from the first train to the next presentation of a train (trial 12). Contrary to expectations, the safety margins decreased with repeated right-side failure only for the intermittent condition. The limited head movement data showed that participants in the prolonged failure condition were more likely to turn their head to check for trains in the right-side failure trials than in earlier trials where there was no signal and no train. Few control participants turned their head to check for trains when no signal was presented. This research highlights the need to consider repetitive tasks and workload in experimental design and accident investigation at railway level crossings.

Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet

Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR βgeo/+ mice were generated from embryonic stem (ES) cells with a gene trap integration of a β-galactosidase-neomycin phosphotransferase (βgeo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GRβgeo/+ mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin- aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GRβgeo/+ mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GRβgeo/+ mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet.

Emotional climate and behavioral management during sleep time in early childhood education settings

The majority of children cease napping between 3 and 5 years of age yet, internationally, the allocation of a sleep time during the day for children of this age remains a practice in many early childhood education (ECE) settings. These dual circumstances present a disjuncture between children's sleep needs and center practices, that may cause conflict for staff, increase stress for children and escalate negative emotional climate in the room. Testing this hypothesis requires observation of both the emotional climate and behavioral management used in ECE rooms that extends into the sleep time. This study was the first to apply the Classroom Assessment and Scoring System (CLASS) Pre-K (Pianta, La Paro, & Hamre, 2008) to observe the emotional climate and behavioral management during sleep time. Pilot results indicated that the CLASS Pre-K functioned reliably to measure emotional climate and behavioral management in sleep time. However, new sleep-specific examples of the dimensions used were developed, to help orient fieldworkers to the CLASS Pre-K rating system in the sleep time context. The CLASS was then used to assess emotional climate and behavior management between the non-sleep and sleep time sessions, in 113 ECE rooms in Queensland, Australia. In these rooms 2.114 children were observed. Of these children, 71% did not sleep at any point during the allotted sleep times. There was a significant drop in emotional climate and behavioral management between the non-sleep and sleep-time sessions. Furthermore, the duration of mandated sleep time (a period of time where no activities are provided to non-sleeping children) accounted for significant independent variance in the observed emotional climate during sleep-time. The CLASS Pre-K presents a valuable tool to assess the emotional climate and behavior management during sleep-time and draws attention to the need for further studies of sleep time in ECE settings.

Interactive content analysis : evaluating interactive variants of non-negative Matrix Factorisation and Latent Dirichlet Allocation as qualitative content analysis aids

This thesis addressed issues that have prevented qualitative researchers from using thematic discovery algorithms. The central hypothesis evaluated whether allowing qualitative researchers to interact with thematic discovery algorithms and incorporate domain knowledge improved their ability to address research questions and trust the derived themes. Non-negative Matrix Factorisation and Latent Dirichlet Allocation find latent themes within document collections but these algorithms are rarely used, because qualitative researchers do not trust and cannot interact with the themes that are automatically generated. The research determined the types of interactivity that qualitative researchers require and then evaluated interactive algorithms that matched these requirements. Theoretical contributions included the articulation of design guidelines for interactive thematic discovery algorithms, the development of an Evaluation Model and a Conceptual Framework for Interactive Content Analysis.

Stop-signal task difficulty and the right inferior frontal gyrus

The stop-signal paradigm is increasingly being used as a probe of response inhibition in basic and clinical neuroimaging research. The critical feature of this task is that a cued response is countermanded by a secondary ‘stop-signal’ stimulus offset from the first by a ‘stop-signal delay’. Here we explored the role of task difficulty in the stop-signal task with the hypothesis that what is critical for successful inhibition is the time available for stopping, that we define as the difference between stop-signal onset and the expected response time (approximated by reaction time from previous trial). We also used functional magnetic resonance imaging (fMRI) to examine how the time available for stopping affects activity in the putative right inferior frontal gyrus and presupplementary motor area (right IFG-preSMA) network that is known to support stopping. While undergoing fMRI scanning, participants performed a stop-signal variant where the time available for stopping was kept approximately constant across participants, which enabled us to compare how the time available for stopping affected stop-signal task difficulty both within and between subjects. Importantly, all behavioural and neuroimaging data were consistent with previous findings. We found that the time available for stopping distinguished successful from unsuccessful inhibition trials, was independent of stop-signal delay, and affected successful inhibition depending upon individual SSRT. We also found that right IFG and adjacent anterior insula were more strongly activated during more difficult stopping. These findings may have critical implications for stop-signal studies that compare different patient or other groups using fixed stop-signal delays.

Genotoxicity of inorganic mercury salts based on disturbed microtubule function

This study investigated the hypothesis that the chromosomal genotoxicity of inorganic mercury results from interaction(s) with cytoskeletal proteins. Effects of Hg2+ salts on functional activities of tubulin and kinesin were investigated by determining tubulin assembly and kinesin-driven motility in cell-free systems. Hg2+ inhibits microtubule assembly at concentrations above 1 μM, and inhibition is complete at about 10 μM. In this range, the tubulin assembly is fully (up to 6 μM) or partially (∼6-10 μM) reversible. The inhibition of tubulin assembly by mercury is independent of the anion, chloride or nitrate. The no-observed-effect- concentration for inhibition of microtubule assembly in vitro was 1 μM Hg2+, the IC50 5.8 μM. Mercury(II) salts at the IC 50 concentrations partly inhibiting tubulin assembly did not cause the formation of aberrant microtubule structures. Effects of mercury salts on the functionality of the microtubule motility apparatus were studied with the motor protein kinesin. By using a "gliding assay" mimicking intracellular movement and transport processes in vitro, HgCl2 affected the gliding velocity of paclitaxel-stabilised microtubules in a clear dose-dependent manner. An apparent effect is detected at a concentration of 0.1 μM and a complete inhibition is reached at 1 μM. Cytotoxicity of mercury chloride was studied in V79 cells using neutral red uptake, showing an influence above 17 μM HgCl2. Between 15 and 20 μM HgCl2 there was a steep increase in cell toxicity. Both mercury chloride and mercury nitrate induced micronuclei concentration-dependently, starting at concentrations above 0.01 μM. CREST analyses on micronuclei formation in V79 cells demonstrated both clastogenic (CREST-negative) and aneugenic effects of Hg2+, with some preponderance of aneugenicity. A morphological effect of high Hg2+ concentrations (100 μM HgCl2) on the microtubule cytoskeleton was verified in V79 cells by immuno-fluorescence staining. The overall data are consistent with the concept that the chromosomal genotoxicity could be due to interaction of Hg2+ with the motor protein kinesin mediating cellular transport processes. Interactions of Hg 2+ with the tubulin shown by in vitro investigations could also partly influence intracellular microtubule functions leading, together with the effects on the kinesin, to an impaired chromosome distribution as shown by the micronucleus test.

Melatonin synthesis : a possible indicator of intolerance to shiftwork

Hypothesis Melatonin synthesis, which is directly controlled by the central circadian pacemaker indicates the circadian phase better than rectal temperature. Methods: Thirty four men (16-32 years, 7 morning, 13 neither, 14 evening types) performed a constant routine (24-26-hr bedrest, < 30 lux, 18-20°C, hourly isocaloric diet). Salivary melatonin level was determined hourly and rectal temperature was continuously recorded. Results: The nadir of rectal temperature occurred 1.5 hr (P = 0.017), the onset of melatonin synthesis 3 hr earlier (P < 0.0001) in morning than in evening types. Morningness was not related to the quantitative but significantly to the temporal parameters, closer to those of melatonin than of rectal temperature. Conclusions: The melatonin onset is a more reliable indicator of the diurnal type than the nadir of rectal temperature. As morningness has been associated with intolerance to shiftwork, melatonin profiling provides a suitable basis for the establishment of directed preventive measures.

Interaction of metal salts with cytoskeletal motor protein systems

Interactions of chemicals with the microtubular network of cells may lead to genotoxicity. Micronuclei (MN) might be caused by interaction of metals with tubulin and/or kinesin. The genotoxic effects of inorganic lead and mercury salts were studied using the MN assay and the CREST analysis in V79 Chinese hamster fibroblasts. Effects on the functional activity of motor protein systems were examined by measurement of tubulin assembly and kinesin-driven motility. Lead and mercury salts induced MN dose-dependently. The no-effect-concentration for MN induction was 1.1 μM PbCl2, 0.05 μM Pb(OAc)2 and 0.01 μM HgCl2. The in vitro results obtained for PbCl2 correspond to reported MN induction in workers occupationally exposed to lead, starting at 1.2 μM Hg(II) (Vaglenov et al., 2001, Environ. Health Perspect. 109, 295-298). The CREST Analysis indicate aneugenic effects of Pb(II) and aneugenic and additionally clastogenic effects of Hg(II). Lead (chloride, acetate, and nitrate) and mercury (chloride and nitrate) interfered dose-dependently with tubulin assembly in vitro. The no-effect-concentration for lead salts in this assay was 10 μM. Inhibition of tubulin assembly by mercury started at 2 μM. The gliding velocity of microtubules along immobilised kinesin molecules was affected by 25 μM Pb(NO3)2 and 0.1 μM HgCl2 in a dose-dependent manner. Our data support the hypothesis that lead and mercury genotoxicity may result, at least in part, via disturbance of chromosome segregation via interaction with cytoskeletal proteins.