How Does the VSG Coat of Bloodstream Form African Trypanosomes Interact with External Proteins?

Variations on the statement "the variant surface glycoprotein (VSG) coat that covers the external face of the mammalian bloodstream form of Trypanosoma brucei acts a physical barrier" appear regularly in research articles and reviews. The concept of the impenetrable VSG coat is an attractive one, as it provides a clear model for understanding how a trypanosome population persists; each successive VSG protects the plasma membrane and is immunologically distinct from previous VSGs. What is the evidence that the VSG coat is an impenetrable barrier, and how do antibodies and other extracellular proteins interact with it? In this review, the nature of the extracellular surface of the bloodstream form trypanosome is described, and past experiments that investigated binding of antibodies and lectins to trypanosomes are analysed using knowledge of VSG sequence and structure that was unavailable when the experiments were performed. Epitopes for some VSG monoclonal antibodies are mapped as far as possible from previous experimental data, onto models of VSG structures. The binding of lectins to some, but not to other, VSGs is revisited with more recent knowledge of the location and nature of N-linked oligosaccharides. The conclusions are: (i) Much of the variation observed in earlier experiments can be explained by the identity of the individual VSGs. (ii) Much of an individual VSG is accessible to antibodies, and the barrier that prevents access to the cell surface is probably at the base of the VSG N-terminal domain, approximately 5 nm from the plasma membrane. This second conclusion highlights a gap in our understanding of how the VSG coat works, as several plasma membrane proteins with large extracellular domains are very unlikely to be hidden from host antibodies by VSG.The authors’ lab is funded by the Wellcome Trust (093008/Z10/Z) and the Medical Research Council (MR/L008246/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It was first available from PLOS via http://dx.doi.org/10.1371/journal.ppat.100525

New discoveries in the transmission biology of sleeping sickness parasites: applying the basics

The sleeping sickness parasite, Trypanosoma brucei, must differentiate in response to the changing environments that it encounters during its complex life cycle. One developmental form, the bloodstream stumpy stage, plays an important role in infection dynamics and transmission of the parasite. Recent advances have shed light on the molecular mechanisms by which these stumpy forms differentiate as they are transmitted from the mammalian host to the insect vector of sleeping sickness, tsetse flies. These molecular advances now provide improved experimental tools for the study of stumpy formation and function within the mammalian bloodstream. They also offer new routes to therapy via high-throughput screens for agents that accelerate parasite development. Here, we shall discuss the recent advances that have been made and the prospects for future research now available

Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a prior history – an open-label randomised trial (the EPPI trial): study protocol

BACKGROUND: Preeclampsia and intrauterine fetal growth restriction (IUGR) are two of the most common causes of maternal and perinatal morbidity and mortality. Current methods of predicting those at most risk of these conditions remain relatively poor, and in clinical practice past obstetric history remains the most commonly used tool. Aspirin and, in women at risk of preeclampsia only, calcium have been demonstrated to have a modest effect on risk reduction. Several observational studies and randomised trials suggest that low molecular weight heparin (LMWH) therapy may confer some benefit. METHODS/DESIGN: This is a multicentre open label randomised controlled trial to determine the effect of the LMWH, enoxaparin, on the prevention of recurrence of preeclampsia and/or IUGR in women at high risk due to their past obstetric history in addition to standard high risk care for all participants. Inclusion criteria: A singleton pregnancy >6(+0) and <16(+0) weeks gestation with most recent prior pregnancy with duration >12 weeks having; (1) preeclampsia delivered <36(+0) weeks, (2) Small for gestational age (SGA) infant <10(th) customised birthweight centile delivered <36(+0) weeks or, (3) SGA infant ≤3(rd) customised birthweight centile delivered at any gestation. Randomisation is stratified for maternal thrombophilia status and women are randomly assigned to ‘standard high risk care’ or ‘standard high risk care’ plus enoxaparin 40 mg from recruitment until 36(+0) weeks or delivery, whichever occurs sooner. Standard high risk care includes the use of aspirin 100 mg daily and calcium 1000–1500 mg daily (unless only had previous SGA with no preeclampsia). The primary outcome is preeclampsia and/or SGA <5(th) customised birthweight centile. Analysis will be by intention to treat. DISCUSSION: The EPPI trial has more focussed and clinically relevant inclusion criteria than other randomised trials with a more restricted composite primary outcome. The inclusion of standard use of aspirin (and calcium) for all participants will help to ensure that any differences observed in outcome are likely to be related to enoxaparin use. These data will make a significant contribution to future meta-analyses and systematic reviews on the use of LMWH for the prevention of placental mediated conditions. TRIAL REGISTRATION: ACTRN12609000699268 Australian New Zealand Clinical Trials Registry. Date registered 13/Aug/2009 (prospective registration)

Use of medication for cardiovascular disease during pregnancy

One-third of women with heart disease use medication for the treatment of cardiovascular disease (CVD) during pregnancy. Increased plasma volume, renal clearance, and liver enzyme activity in pregnant women change the pharmacokinetics of these drugs, often resulting in the need for an increased dose. Fetal well-being is a major concern among pregnant women. Fortunately, many drugs used to treat CVD can be used safely during pregnancy, with the exception of high-dose warfarin in the first trimester, angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, amiodarone, and spironolactone. A timely and thorough discussion between the cardiologist and the pregnant patient about the potential benefits and adverse effects of medication for CVD is important. Noncompliance with necessary treatment for cardiovascular disorders endangers not only the mother, but also the fetus. This Review is an overview of the pharmacokinetic changes in medications for CVD during pregnancy and the safety of these drugs for the fetus. The implications for maternal treatment are discussed. The Review also includes a short section on the cardiovascular effects of medication used for obstetric indications