Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available, rapidly killing all asexual stages of Plasmodium falciparum. Artemisinins are sesquiterpene lactones widely used to treat multidrug-resistant malaria, a disease that annually claims 1 million lives. Despite extensive clinical and laboratory experience their molecular target is not yet identified. Activated artemisinins form adducts with a variety of biological macromolecules, including haem, translationally controlled tumour protein (TCTP) and other higher-molecular-weight proteins. Here we show that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor). As predicted, thapsigargin also antagonizes the parasiticidal activity of artemisinin. Desoxyartemisinin lacks an endoperoxide bridge and is ineffective both as an inhibitor of PfATP6 and as an antimalarial. Chelation of iron by desferrioxamine abrogates the antiparasitic activity of artemisinins and correspondingly attenuates inhibition of PfATP6. Imaging of parasites with BODIPY-thapsigargin labels the cytosolic compartment and is competed by artemisinin. Fluorescent artemisinin labels parasites similarly and irreversibly in an Fe2+-dependent manner. These data provide compelling evidence that artemisinins act by inhibiting PfATP6 outside the food vacuole after activation by iron.

] free (3.2-320 M) than are an avian SERCA1 pump or rabbit SERCA 1a (maximal activity < 10 M). The activity of PfATP4 is resistant to inhibition by ouabain (200 M) or thapsigargin (0.8 M) but is inhibited by vanadate (1 mM) or cyclopiazonic acid (1 M). We used a quantitative polymerase chain reaction to assay expression of mRNA encoding PfATP4 relative to that for ␤-tubulin in synchronized asexual stages and found variable expression throughout the life cycle with a maximal 5-fold increase in meronts compared with ring stages. This analysis suggests that PfATP4 defines a novel subclass of Ca 2؉ -ATPases unique to apicomplexan organisms and therefore offers potential as a drug target.

Aims: To determine the prevalence of coeliac disease in a group of patients in the community who have been shown in the laboratory to have iron and/or folate deficiency. To assess the cost efficiency of this laboratory based case finding strategy. Methods: The study was undertaken in a large general hospital in the UK serving a population of 300 000. Three hundred and thirty three eligible patients with iron and/or folate deficiency were identified and contacted over an 18 month period. Case finding was by testing for coeliac disease using serological methods and subsequent histological confirmation. Results: Of the 333 eligible and contactable patients with iron and/or folate deficiency, 258 (77%) consented to coeliac disease antibody testing. Twenty eight patients (10.9%) were positive for coeliac disease antibodies. Of these, 24 patients proceeded to endoscopy and biopsy, resulting in 12 cases of histologically confirmed coeliac disease (4.7% (95% confidence interval, 2.1% to 6.8%) of patients tested for coeliac disease antibodies). Conclusions: This laboratory based methodology detected a considerable number of new coeliac disease cases in the community. Many of these patients did not present with clinical findings suggestive of malabsorption and might not otherwise have been diagnosed. Laboratory based methodologies should be considered in conjunction with other strategies for the early identification and treatment of coeliac disease.