BackgroundScabies is a parasitic skin infestation caused by the burrowing mite Sarcoptes scabiei. It is common worldwide and spreads rapidly under crowded conditions, such as those found in socially disadvantaged communities of Indigenous populations and in developing countries. Pruritic scabies lesions facilitate opportunistic bacterial infections, particularly Group A streptococci. Streptococcal infections cause significant sequelae and the increased community streptococcal burden has led to extreme levels of acute rheumatic fever and rheumatic heart disease in Australia's Indigenous communities. In addition, emerging resistance to currently available therapeutics emphasizes the need to identify potential targets for novel chemotherapeutic and/or immunological intervention. Scabies research has been severely limited by the availability of parasites, and scabies remains a truly neglected infectious disease. We report development of a tractable model for scabies in the pig, Sus domestica.Methodology/Principal FindingsOver five years and involving ten independent cohorts, we have developed a protocol for continuous passage of Sarcoptes scabiei var. suis. To increase intensity and duration of infestation without generating animal welfare issues we have optimised an immunosuppression regimen utilising daily oral treatment with 0.2mg/kg dexamethasone. Only mild, controlled side effects are observed, and mange infection can be maintained indefinitely providing large mite numbers (>6000 mites/g skin) for molecular-based research on scabies. In pilot experiments we explore whether any adaptation of the mite population is reflected in genetic changes. Phylogenetic analysis was performed comparing sets of genetic data obtained from pig mites collected from naturally infected pigs with data from pig mites collected from the most recent cohort.Conclusions/SignificanceA reliable pig/scabies animal model will facilitate in vivo studies on host immune responses to scabies including the relations to the associated bacterial pathogenesis and more detailed studies of molecular evolution and host adaption. It is a most needed tool for the further investigation of this important and widespread parasitic disease.

T acrolimus, a potent immunosuppressive agent, has emerged as a valuable therapeutic alternative to cyclosporine after adult liver transplantation. 1 Similar to cyclosporine, tacrolimus has a narrow therapeutic window. 2 Continuous adequate immunosuppression is imperative for maintenance of the graft, whereas overimmunosuppression can lead to serious toxicities, infections, and increased risk for lymphoproliferative disease. It is not possible to give a standard dosing regimen to all adults and achieve concentrations within this narrow therapeutic range. Tacrolimus shows considerable interindividual and intraindividual variability in its pharmacokinetics, with poor correlation between drug dosage and blood concentrations. 2 These factors make defining an optimal dosing schedule for this agent difficult. 3 A number of studies have evaluated the pharmacokinetic properties of tacrolimus. 2 Oral bioavailability of this agent is generally low (ϳ25%), but can vary from 4% to 93%. Tacrolimus binds extensively to erythrocytes and, in plasma, to ␣1-acid glycoprotein and albumin. It is extensively metabolized by the cytochrome P-450 system and subject to P-glycoprotein countertransport. 4 Greater than 95% of tacrolimus is eliminated by the biliary route; renal excretion of the parent drug accounts for less than 1% of total body clearance.To date, the majority of pharmacokinetic studies in adult liver transplant recipients have used a classic approach to data generation. [5][6][7][8][9][10][11][12] Kinetic information has been obtained through multiple blood sampling in small relatively homogenous patient groups during a single dosing interval or during a short time span in the immediate posttransplantation period. Different factors that may alter drug pharmacokinetics have not been investigated simultaneously. Such studies provide little information on interindividual and intraindividual pharmacokinetic variability. Furthermore, kinetic information has been based on immunoassay analysis of tacrolimus blood samples. Such assays are not specific for the parent drug, with reports of significant and variable cross-reactivity of assay antibody with some tacrolimus metabolites. 3 Such assay techniques as liquid chromatography-tandem mass spectrometry

In order to eliminate potential selection bias, more RCTs need to be conducted in this area so that effectiveness, as well as efficacy, can be ascertained. The interlock programme appears to be effective while the device is installed in the vehicle of the offender. Studies need to address ways of improving recidivism rates in the long term, as the major challenges are participation rates, compliance and durability.

Despite the methodological limitations and the variability in degree of signal to noise effect, the consistency of reported reductions in speed and crash outcomes across all studies show that speed cameras are a worthwhile intervention for reducing the number of road traffic injuries and deaths. However, whilst the the evidence base clearly demonstrates a positive direction in the effect, an overall magnitude of this effect is currently not deducible due to heterogeneity and lack of methodological rigour. More studies of a scientifically rigorous and homogenous nature are necessary, to provide the answer to the magnitude of effect.

Scabies is a parasitic infestation of the skin by the mite Sarcoptes scabiei that causes significant morbidity worldwide, in particular within socially disadvantaged populations. In order to identify mechanisms that enable the scabies mite to evade human immune defenses, we have studied molecules associated with proteolytic systems in the mite, including two novel scabies mite serine protease inhibitors (SMSs) of the serpin superfamily. Immunohistochemical studies revealed that within mite-infected human skin SMSB4 (54 kDa) and SMSB3 (47 kDa) were both localized in the mite gut and feces. Recombinant purified SMSB3 and SMSB4 did not inhibit mite serine and cysteine proteases, but did inhibit mammalian serine proteases, such as chymotrypsin, albeit inefficiently. Detailed functional analysis revealed that both serpins interfered with all three pathways of the human complement system at different stages of their activation. SMSB4 inhibited mostly the initial and progressing steps of the cascades, while SMSB3 showed the strongest effects at the C9 level in the terminal pathway. Additive effects of both serpins were shown at the C9 level in the lectin pathway. Both SMSs were able to interfere with complement factors without protease function. A range of binding assays showed direct binding between SMSB4 and seven complement proteins (C1, properdin, MBL, C4, C3, C6 and C8), while significant binding of SMSB3 occurred exclusively to complement factors without protease function (C4, C3, C8). Direct binding was observed between SMSB4 and the complement proteases C1s and C1r. However no complex formation was observed between either mite serpin and the complement serine proteases C1r, C1s, MASP-1, MASP-2 and MASP-3. No catalytic inhibition by either serpin was observed for any of these enzymes. In summary, the SMSs were acting at several levels mediating overall inhibition of the complement system and thus we propose that they may protect scabies mites from complement-mediated gut damage.

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Pharmacokinetic information obtained in this study may assist physicians in making individualized dosage decisions in regard to tacrolimus in pediatric liver transplant recipients. Children who received a whole child's liver appeared to retain "pediatric" clearance, whereas those who received a cut-down adult liver had "adult" clearances (on average 7-fold less).

In this study, we conduct an in-depth analysis of annexin proteins from a diverse range of invertebrate taxa, including the major groups that contain the parasites and vector organisms that are harmful to humans and domestic animals. Using structure-based amino acid sequence alignments and phylogenetic analyses, we present a classification for this protein group and assign names to sequences with ambiguous annotations in public databases. Our analyses reveal six distinct annexin clades, and the mapping of genes encoding annexins to the genome of the human blood fluke Schistosoma mansoni supports the hypothesis of gene duplication as a major evolutionary event in annexin genesis. This study illuminates annexin diversity from a novel perspective using contemporary phylogenetic hypotheses of eukaryote evolution, and will aid the consolidation of annexin protein identities in public databases and provide a foundation for future functional analysis and characterisation of these proteins in parasites of socioeconomic importance.