Modelling the dynamics of Plasmodium falciparum histidine-rich protein 2 in human malaria to better understand malaria rapid diagnostic test performance

BACKGROUND: Effective diagnosis of malaria is a major component of case management. Rapid diagnostic tests (RDTs) based on Plasmodium falciparumhistidine-rich protein 2 (PfHRP2) are popular for diagnosis of this most virulent malaria infection. However, concerns have been raised about the longevity of the PfHRP2 antigenaemia following curative treatment in endemic regions. METHODS: A model of PfHRP2 production and decay was developed to mimic the kinetics of PfHRP2 antigenaemia during infections. Data from two human infection studies was used to fit the model, and to investigate PfHRP2 kinetics. Four malaria RDTs were assessed in the laboratory to determine the minimum detectable concentration of PfHRP2. RESULTS: Fitting of the PfHRP2 dynamics model indicated that in malaria naive hosts, P. falciparum parasites of the 3D7 strain produce 1.4 x 10(-)(1)(3) g of PfHRP2 per parasite per replication cycle. The four RDTs had minimum detection thresholds between 6.9 and 27.8 ng/mL. Combining these detection thresholds with the kinetics of PfHRP2, it is predicted that as few as 8 parasites/muL may be required to maintain a positive RDT in a chronic infection. CONCLUSIONS: The results of the model indicate that good quality PfHRP2-based RDTs should be able to detect parasites on the first day of symptoms, and that the persistence of the antigen will cause the tests to remain positive for at least seven days after treatment. The duration of a positive test result following curative treatment is dependent on the duration and density of parasitaemia prior to treatment and the presence and affinity of anti-PfHRP2 antibodies.

Comparative analysis of the Metarhizium anisopliae secretome in response to exposure to the greyback cane grub and grub cuticles

Metarhizium anisopliae is a well-characterized biocontrol agent of a wide range of insects including cane grubs. In this study, a two-dimensional (2D) electrophoresis was used to display secreted proteins of M. anisopliae strain FI-1045 growing on the whole greyback cane grubs and their isolated cuticles. Hydrolytic enzymes secreted by M. anisopliae play a key role in insect cuticle-degradation and initiation of the infection process. We have identified all the 101 protein spots displayed by cross-species identification (CSI) from the fungal kingdom. Among the identified proteins were 64-kDa serine carboxypeptidase, 1,3 beta-exoglucanase, Dynamin GTPase, THZ kinase, calcineurin like phosphoesterase, and phosphatidylinositol kinase secreted by M. ansiopliae (FI-1045) in response to exposure to the greyback cane grubs and their isolated cuticles. These proteins have not been previously identified from the culture supernatant of M. anisopliae during infection. To our knowledge, this the first proteomic map established to study the extracellular proteins secreted by M. ansiopliae (FI-1045) during infection of greyback cane grubs and its cuticles.

Adaptations to a subterranean environment and longevity revealed by the analysis of mole rat genomes

Subterranean mammals spend their lives in dark, unventilated environments that are rich in carbon dioxide and ammonia and low in oxygen. Many of these animals are also long-lived and exhibit reduced aging-associated diseases, such as neurodegenerative disorders and cancer. We sequenced the genome of the Damaraland mole rat (DMR, Fukomys damarensis) and improved the genome assembly of the naked mole rat (NMR, Heterocephalus glaber). Comparative genome analyses, along with the transcriptomes of related subterranean rodents, revealed candidate molecular adaptations for subterranean life and longevity, including a divergent insulin peptide, expression of oxygen-carrying globins in the brain, prevention of high CO2-induced pain perception, and enhanced ammonia detoxification. Juxtaposition of the genomes of DMR and other more conventional animals with the genome of NMR revealed several truly exceptional NMR features: unusual thermogenesis, an aberrant melatonin system, pain insensitivity, and unique processing of 28S rRNA. Together, these genomes and transcriptomes extend our understanding of subterranean adaptations, stress resistance, and longevity.

Malaria rapid diagnostic test performance : results of WHO product testing of malaria RDTs : round 5 (2013)

WHO estimates that half the world’s population is at risk of malaria. In 2012, there were an estimated 207 million cases (with an uncertainty range of 135 million to 287 million) and an estimated 627 000 deaths (with an uncertainty range of 473 000 to 789 000). Approximately 90% of all malaria deaths occur in sub-Saharan Africa, and 77% occur in children under 5 years. Malaria remains endemic in 104 countries, and, while parasite-based diagnosis is increasing, most suspected cases of malaria are still not properly confirmed, resulting in over-use of antimalarial drugs and poor disease monitoring (1)...

Assessment of the effects of maternal exposure to heatwave on birth outcomes in Brisbane, Australia

Even though heatwave events have become more frequent and intense in most regions around the world, little is known about the impact of heatwave on birth outcomes. This thesis uses a population-based study design to investigate the relationship between maternal heatwave exposure and adverse birth outcomes in Brisbane, Australia. This study found that heatwave exposure at any stage of pregnancy can be harmful to fetal growth, and further increase the risk of adverse birth outcomes. Both short- and long-term effects of heatwave on adverse birth outcomes were found. The findings in this thesis may have significant public health implications.

Modelling attitudes to climate change : an order effect and a test between alternatives

Quantum-like models can be fruitfully used to model attitude change in a social context. Next steps require data, and higher dimensional models. Here, we discuss an exploratory study that demonstrates an order effect when three question sets about Climate Beliefs, Political Affiliation and Attitudes Towards Science are presented in different orders within a larger study of n=533 subjects. A quantum-like model seems possible, and we propose a new experiment which could be used to test between three possible models for this scenario.

Construction of volcanic records from marine sediment cores : a review and case study (Montserrat, West Indies)

Detailed knowledge of the past history of an active volcano is crucial for the prediction of the timing, frequency and style of future eruptions, and for the identification of potentially at-risk areas. Subaerial volcanic stratigraphies are often incomplete, due to a lack of exposure, or burial and erosion from subsequent eruptions. However, many volcanic eruptions produce widely-dispersed explosive products that are frequently deposited as tephra layers in the sea. Cores of marine sediment therefore have the potential to provide more complete volcanic stratigraphies, at least for explosive eruptions. Nevertheless, problems such as bioturbation and dispersal by currents affect the preservation and subsequent detection of marine tephra deposits. Consequently, cryptotephras, in which tephra grains are not sufficiently concentrated to form layers that are visible to the naked eye, may be the only record of many explosive eruptions. Additionally, thin, reworked deposits of volcanic clasts transported by floods and landslides, or during pyroclastic density currents may be incorrectly interpreted as tephra fallout layers, leading to the construction of inaccurate records of volcanism. This work uses samples from the volcanic island of Montserrat as a case study to test different techniques for generating volcanic eruption records from marine sediment cores, with a particular relevance to cores sampled in relatively proximal settings (i.e. tens of kilometres from the volcanic source) where volcaniclastic material may form a pervasive component of the sedimentary sequence. Visible volcaniclastic deposits identified by sedimentological logging were used to test the effectiveness of potential alternative volcaniclastic-deposit detection techniques, including point counting of grain types (component analysis), glass or mineral chemistry, colour spectrophotometry, grain size measurements, XRF core scanning, magnetic susceptibility and X-radiography. This study demonstrates that a set of time-efficient, non-destructive and high-spatial-resolution analyses (e.g. XRF core-scanning and magnetic susceptibility) can be used effectively to detect potential cryptotephra horizons in marine sediment cores. Once these horizons have been sampled, microscope image analysis of volcaniclastic grains can be used successfully to discriminate between tephra fallout deposits and other volcaniclastic deposits, by using specific criteria related to clast morphology and sorting. Standard practice should be employed when analysing marine sediment cores to accurately identify both visible tephra and cryptotephra deposits, and to distinguish fallout deposits from other volcaniclastic deposits.

Estrogen deficiency-associated bone loss in the maxilla: A methodology to quantify the changes in the maxillary intra-radicular alveolar bone in an ovariectomized rat osteoporosis model

The effects of estrogen deficiency on bone characteristics are site-dependent, with the most commonly studied sites being appendicular long bones (proximal femur and tibia) and axial bones (vertebra). The effect on the maxillary and mandibular bones is still inconsistent and requires further investigation. This study was designed to evaluate bone quality in the posterior maxilla of ovariectomized rats in order to validate this site as an appropriate model to study the effect of osteoporotic changes. Methods: Forty-eight 3-month-old female Sprague-Dawley rats were randomly divided into two groups: an ovariectomized group (OVX, n=24) and Sham-operated group (SHAM, n=24). Six rats were randomly sacrificed from both groups at time points 8, 12, 16 and 20 weeks. The samples from tibia and maxilla were collected for Micro CT and histological analysis. For the maxilla, the volume of interest (VOI) area focused on the furcation areas of the first and second molar. Trabecular bone volume fraction (BV/TV, %), trabecular thickness (Tb.Th.), trabecular number (Tb.N.), trabecular separation (Tb.Sp.), and connectivity density (Conn.Dens) were analysed after Micro CT scanning. Results: At 8 weeks the indices BV/TV, Tb.Sp, Tb.N and Conn.Dens showed significant differences (P<0.05) between the OVX and SHAM groups in the tibia. Compared with the tibia, the maxilla developed osteoporosis at a later stage, with significant changes in maxillary bone density only occurring after 12 weeks. Compared with the SHAM group, both the first and second molars of the OVX group showed significantly decreased BV/TV values from 12 weeks, and these changes were sustained through 16 and 20 weeks. For Tb.Sp, there were significant increases in bone values for the OVX group compared with the SHAM group at 12, 16 and 20 weeks. Histological changes were highly consistent with Micro CT results. Conclusion: This study established a method to quantify the changes of intra-radicular alveolar bone in the posterior maxilla in an accepted rat osteoporosis model. The degree of the osteoporotic changes to trabecular bone architecture is site-dependent and at least 3 months are required for the osteoporotic effects to be apparent in the posterior maxilla following rat OVX.

A national satellite-based land-use regression model for air pollution exposure assessment in Australia

Land-use regression (LUR) is a technique that can improve the accuracy of air pollution exposure assessment in epidemiological studies. Most LUR models are developed for single cities, which places limitations on their applicability to other locations. We sought to develop a model to predict nitrogen dioxide (NO2) concentrations with national coverage of Australia by using satellite observations of tropospheric NO2 columns combined with other predictor variables. We used a generalised estimating equation (GEE) model to predict annual and monthly average ambient NO2 concentrations measured by a national monitoring network from 2006 through 2011. The best annual model explained 81% of spatial variation in NO2 (absolute RMS error=1.4 ppb), while the best monthly model explained 76% (absolute RMS error=1.9 ppb). We applied our models to predict NO2 concentrations at the ~350,000 census mesh blocks across the country (a mesh block is the smallest spatial unit in the Australian census). National population-weighted average concentrations ranged from 7.3 ppb (2006) to 6.3 ppb (2011). We found that a simple approach using tropospheric NO2 column data yielded models with slightly better predictive ability than those produced using a more involved approach that required simulation of surface-to-column ratios. The models were capable of capturing within-urban variability in NO2, and offer the ability to estimate ambient NO2 concentrations at monthly and annual time scales across Australia from 2006–2011. We are making our model predictions freely available for research.

The relationship between ambient ultraviolet radiation (UVR) and objectively measured personal UVR exposure dose is modified by season and latitude

Despite the widespread use of ambient ultraviolet radiation (UVR) as a proxy measure of personal exposure to UVR, the relationship between the two is not well-defined. This paper examines the effects of season and latitude on the relationship between ambient UVR and personal UVR exposure. We used data from the AusD Study, a multi-centre cross-sectional study among Australian adults (18-75 years), where personal UVR exposure was objectively measured using polysulphone dosimeters. Data were analysed for 991 participants from 4 Australian cities of different latitude: Townsville (19.3 °S), Brisbane (27.5 °S), Canberra (35.3 °S) and Hobart (42.8 °S). Daily personal UVR exposure varied from 0.01 to 21 Standard Erythemal Doses (median=1.1, IQR: 0.5–2.1), on average accounting for 5% of the total available ambient dose. There was an overall positive correlation between ambient UVR and personal UVR exposure (r=0.23, p<0.001). However, the correlations varied according to season and study location: from strong correlations in winter (r=0.50) and at high latitudes (Hobart, r=0.50; Canberra, r=0.39), to null or even slightly negative correlations, in summer (r=0.01) and at low latitudes (Townsville, r=-0.06; Brisbane, r=-0.16). Multiple regression models showed significant effect modification by season and location. Personal exposure fraction of total available ambient dose was highest in winter (7%) and amongst Hobart participants (7%) and lowest in summer (1%) and in Townsville (4%). These results suggest season and latitude modify the relationship between ambient UVR and personal UVR exposure. Ambient UVR may not be a good indicator for personal exposure dose under some circumstances.

Influence of polymorphisms of GSTM1 and GSTT1 for risk of renal cell cancer in workers with long-term high occupational exposure to trichloroethene

Suspected nephrocarcinogenic effects of trichloroethene (TRI) in humans are attributed to metabolites derived from the glutathione transferase (GST) pathway. The influence of polymorphisms of GSTM1 and GSTT1 isoenzymes on the risk of renal cell cancer in subjects having been exposed to high levels of TRI over many years was investigated. GSTM1 and GSTT1 genotypes were determined by internal standard controlled polymerase chain reaction. Fourty-five cases with histologically verified renal cell cancer and a history of long-term occupational exposure to high concentrations of TRI were studied. A reference group consisted of 48 workers from the same geographical region with similar histories of occupational exposures to TRI but not suffering from any cancer. Among the 45 renal cell cancer patients, 27 carried at least one functional GSTM1 (GSTM1 +) and 18 at least one functional GSTT1 (GSTT1 +). Among the 48 reference workers, 17 were GSTM1 + and 31 were GSTT1 +. Odds ratios for renal cell cancer were 2.7 for GSTM1 + individuals (95% CI, 1.18-6.33; P < 0.02) and 4.2 for GSTT1 + individuals (95% CI, 1.16-14.91; P < 0.05), respectively. The data support the present concept of the nephrocarcinogenicity of TRI.