Synthesising 30 Years of Mathematical Modelling of Echinococcus Transmission

Background

Echinococcosis is a complex zoonosis that has domestic and sylvatic lifecycles, and a range of different intermediate and definitive host species. The complexities of its transmission and the sparse evidence on the effectiveness of control strategies in diverse settings provide significant challenges for the design of effective public health policy against this disease. Mathematical modelling is a useful tool for simulating control packages under locally specific transmission conditions to inform optimal timing and frequency of phased interventions for cost-effective control of echinococcosis. The aims of this review of 30 years of Echinococcus modelling were to discern the epidemiological mechanisms underpinning models of Echinococcus granulosus and E. multilocularis transmission and to establish the need to include a human transmission component in such models.

Methodology/Principal Findings

A search was conducted of all relevant articles published up until July 2012, identified from the PubMED, Web of Knowledge and Medline databases and review of bibliographies of selected papers. Papers eligible for inclusion were those describing the design of a new model, or modification of an existing mathematical model of E. granulosus or E. multilocularis transmission. A total of 13 eligible papers were identified, five of which described mathematical models of E. granulosus and eight that described E. multilocularis transmission. These models varied primarily on the basis of six key mechanisms that all have the capacity to modulate model dynamics, qualitatively affecting projections. These are: 1) the inclusion of a ‘latent’ class and/or time delay from host exposure to infectiousness; 2) an age structure for animal hosts; 3) the presence of density-dependent constraints; 4) accounting for seasonality; 5) stochastic parameters; and 6) inclusion of spatial and risk structures.

Conclusions/Significance

This review discusses the conditions under which these mechanisms may be important for inclusion in models of Echinococcus transmission and proposes recommendations for the design of dynamic human models of transmission. Accounting for the dynamic behaviour of the Echinococcus parasites in humans will be key to predicting changes in the disease burden over time and to simulate control strategies that optimise public health impact.     

Role of cytokines and testosterone in regulating lean body mass and resting energy expenditure in HIV-infected men

Although catastrophic weight loss is no longer common in HIV-infected men, we hypothesized that a more gradual process of cachexia [loss of lean body mass (LBM) without severe weight loss, often accompanied by elevated resting energy expenditure (REE)] is still common and is driven by excessive production of the catabolic cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta). We performed a longitudinal analysis of an ongoing cohort study of nutritional status in 172 men with HIV infection. LBM loss of >1 kg occurred in 35% of the cohort, and LBM loss of >5% occurred in 12.2% over 8 mo of observation, but classical wasting (loss of approximately 10% of weight) was rare (2%). Both TNF-alpha (-150 g LBM. ng(-1) x ml(-1), P < 0.02) and IL-1 beta production (-130 g LBM x ng(-1) x ml(-1), P < 0.01) by peripheral blood mononuclear cells predicted loss of LBM. A rise in REE of >200 kcal/day was found in 17.7% of the subjects regardless of weight change. IL-1 beta (+9 kcal/day per ng/ml, P < 0.002) and TNF-alpha (+10 kcal/day per ng/ml, P < 0.02) production predicted Delta REE. Serum free testosterone was inversely associated with TNF-alpha production and was not an independent predictor of either Delta LBM or Delta REE after adjustment for cytokine production. Even though weight loss was rare in this cohort of patients treated with highly active antiretroviral therapy, loss of LBM was common and was driven by catabolic cytokines and not by inadequate dietary intake or hypogonadism.     

Collagen turnover in the adult femoral mid-shaft: modeled from anthropogenic radiocarbon tracer measurements

We have measured the (14)C content of human femoral mid-shaft collagen to determine the dynamics of adult collagen turnover, using the sudden doubling and subsequent slow relaxation of global atmospheric (14)C content due to nuclear bomb testing in the 1960s and 1970s as a tracer. (14)C measurements were made on bone collagen from 67 individuals of both sexes who died in Australia in 1990-1993, spanning a range of ages at death from 40 to 97, and these measurements were compared with values predicted by an age-dependent turnover model. We found that the dataset could constrain models of collagen turnover, with the following outcomes: 1) Collagen turnover rate of females decreases, on average, from 4%/yr to 3%/yr from 20 to 80 years. Male collagen turnover rates average 1.5-3%/yr over the same period. 2) For both sexes the collagen turnover rate during adolescent growth is much higher (5-15%/yr at age 10-15 years), with males having a significantly higher turnover rate than have females, by up to a factor of 2. 3) Much of the variation in residual bomb (14)C in a person's bone can be attributed to individual variation in turnover rate, but of no more than about 30% of the average values for adults. 4) Human femoral bone collagen isotopically reflects an individual's diet over a much longer period of time than 10 years, including a substantial portion of collagen synthesised during adolescence.     

Rat epidermal keratinocytes as an organotypic model for examining the role of Cx43 and Cx26 in skin differentiation

In order to characterize connexin expression and regulation in the epidermis, we have characterized a rat epidermal keratinocyte (REK) cell line that is phenotypically similar to basal keratinocytes in that they have the ability to differentiate into organotypic epidermis consisting of a basal cell layer, 2-3 suprabasal cell layers, and a cornified layer. RT-PCR revealed that REK cells express mRNA for Cx26, Cx31, Cx31.1, Cx37, and Cx43, which mimics the reported connexin profile for rat tissue. In addition, we report the expression of Cx30, Cx30.3, Cx40, and Cx45 in rat keratinocytes, highlighting the complexity of the connexin complement in rat epidermis. Furthermore, 3-dimensional analysis of organotypic skin revealed that Cx26 and Cx43 are exquisitely regulated during the differentiation process. The life-cycle of these connexins including their expression, transport, assembly into gap junctions, internalization, and degradation are elegantly depicted in organotypic epidermis as keratinocytes proceed from differentiation to programmed cell death.     

Chiral analysis of methadone and its major metabolites (EDDP and EMDP) by liquid chromatography-mass spectrometry

Racemic methadone (MET) is administered to heroin users undergoing methadone maintenance therapy (MMT) in Australia. The enantiomers of methadone possess different pharmacological effects, and the enantioselective metabolism of methadone to its two major metabolites, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP) has been demonstrated. Therefore, a stereoselective method capable of quantifying methadone, EDDP and EMDP in biological samples could be of benefit in the monitoring of MMT patients. In particular, the analysis of hair samples would provide a means by which long-term monitoring of MMT patients could be achieved. To date, no HPLC method has been published for the simultaneous separation of the six enantiomers. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the chiral analysis of methadone, EDDP and EMDP was developed using an alpha-glycoprotein (AGP) stationary phase. The method development involved the utilisation of factorial analysis experimental designs and the application of artificial neural networks (ANNs) to model the chromatographic response surfaces. The optimal conditions were determined to be 20mM acetic acid: isopropanol (93:7, pH 7.4), with a flow rate of 0.9mL/min. The method was validated and subsequently applied to the analysis of 20 hair samples collected from MMT patients.     

A virgin flight across the Tasman Sea? Satellite tracking of post-fledging movement in the Australasian Gannet Morus serrator

New technologies enable tracking of the route, duration, and destination of previously unassessed long-distance movements. Fledgling Australasian Gannets Morus serrator from breeding populations in New Zealand had been reported to fly across the Tasman Sea to Australia, with this historic knowledge derived from the recovery of banded carcasses and from observations of initial flight direction. We deployed Argos satellite devices on ten M. serrator fledglings at Cape Kidnappers Gannetry, North Island, New Zealand, across 2 years. Birds that were tracked leaving the colony initially appeared to have landed on the sea. A male bird and two female birds were tracked moving along the east coast to the south tip of New Zealand. The two females then crossed the Tasman Sea to eastern Australian coastal waters in 4 and 5 days, respectively. We suggest that, contrary to historic reports, the route via Stewart Island constitutes a realized migration path for fledglings from Cape Kidnappers, which might minimize the distance traveled across the open sea to southeastern Australia or Tasmania. Our results further imply that initial direction of flight needs not be indicative of the subsequent migration route taken by M. serrator. This highlights the importance of direct tracking technology for adequate assessment of dispersal and migration in seabirds and other highly mobile species.     

Local traditions of bower decoration by spotted bowerbirds in a single population

Recent work has shown that elaborate secondary sexual traits and the corresponding preferences for them may be transmitted culturally rather than by genetic inheritance. Evidence for such cultural transmission commonly invokes spatial patterns of local similarity, with neighbouring individuals or populations appearing similar to each other. Alternative explanations for local similarity include ecological similarity of neighbouring environments and confounding genetic effects caused by aggregations of kin. We found that bowers built by male spotted bowerbirds, Chlamydera maculata, within a single population showed fine-scale similarities between neighbours in the decorations displayed on them. Such similarities did not covary with local decoration availability, local display environment or kinship and could not be explained by stealing behaviour by neighbours. Instead, we suggest that these similarities are products of local tradition, either culturally transmitted by neighbouring males who regularly inspect neighbours' bowers, or as localized responses to variable individual female preferences.